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VISION THE PAN-AMERICAN JOURNAL OF OPHTHALMOLOGY ISSN 2219-4665 December 2013, Vol. 12(4)

Editorial Dantas PEC

Message from the President Mayorga Arganaz EP and Palis G

Latin American Consensus on Age-related Macular Degeneration Rodriguez FJ et al

Laser In Situ Keratomileusis Retreatment with Wavefront-Optimized Technique after Primary Wavefront-Guided LASIK: Proof of Concept Mohamed EM et al

Modificaciones de la curvatura posterior de la córnea después de LASEK miópico. Ortega Diaz L et al

Encouraging Result of Voriconazole Treatment for Cladosporium Corneal Keratitis Marcomini LAG et al

Síndrome de isquemia ocular: un caso dramático Garcia-Fernandez M et al

Intravitreal Dexamethasone implant migration to the anterior chamber in an aphakic child de Juan-Marcos L et al

Letter from the Chairman of the Board of Directors De La Peña W

Announcements Circle of Vision

Proud to be PAN-AMERICAN

Preserva la visión alcanzando las menores presiones-objetivo en más pacientes Investigadores de diversos estudios, (AGIS, Shirakashi, Shields) han comprobado que alcanzar y mantener la PIO entre 14 y 15 mmHg reduce la progresión de pérdida del campo visual1,2,3. Lumigan® alcanza la PIO-objetivo de 14/15 mmHg en un mayor número de pacientes: ®

vs. timolol 4

vs.

dorzolamida/ timolol 5

vs. latanoprost 6

Porcentaje de Pacientes que alcanzaron la PIO-Objetivo ≤14

21%

17%

19%

Porcentaje de Pacientes que alcanzaron la PIO-Objetivo ≤15

31%

16%

24%

29%

14%

Lumigan ® (bimatoprost) Forma farmacéutica y pr esentación. Composición. Cada ml contiene: 0,3 mg de bimatoprost. Vehículo: cloreto de sódio, fosfato de sódio presentación. esentación.Frascos cuenta-gotas conteniendo 5 ml de solución oftalmológica estéril de bimatoprost a 0,03%. USO ADULTO.Composición. hepta-hidratado, ácido cítrico mono-hidratado, ácido clorídrico y/o hidróxido de sódio, cloruro de benzalconio y agua purificada qsp. Indicaciones. LUMIGAN® (bimatoprost) es indicado para la reducción de la presión intra-ocular elevada en pacientes con glaucona o hipertensión ecauciones y Adver tencias. Advertencias. Fueron relatados aumento gradual del crescimiento Contraindicaciones. LUMIGAN ® (bimatoprost) está contraindicado en pacientes con hipersensibilidad al bimatoprost o cualquier otro componente de la fórmula del producto. Pr Precauciones Advertencias. ocular.Contraindicaciones. de las pestañas en el largo y espesura, y oscurecimiento de las pestañas (en 22% de los pacientes después 3 meses, y 36% después 6 meses de tratamiento), y, oscurecimiento de los párpados (en 1 a <3% de los pacientes después 3 meses y 3 a 10% de los pacientes después 6 meses de tratamiento). También fue relatado oscurecimiento del íris en 0,2% de los pacientes tratados durante 3 meses y en 1,1% de los pacientes tratados durante 6 meses. Algunas de esas alteraciones pueden ser permanentes. Pacientes que deben recibir el tratamiento ecauciones LUMIGAN® (bimatoprost) no fue estudiado en pacientes con insuficiencia renal o hepática y por lo tanto debe ser utilizado con cautela en tales pacientes.Las lentes de contacto deben Precauciones de apenas uno de los ojos, deben ser informados a respecto de esas reacciones. Pr ser retiradas antes de la instilación de LUMIGAN® (bimatoprost) y pueden ser recolocadas 15 minutos después. Los pacientes deben ser advertidos de que el producto contiene cloruro de benzalconio, que es absorvido por las lentes hidrofílicas.Si más que un medicamento de uso tópico ocular estuviera siendo utilizado, se debe respetar un intervalo de por lo menos 5 minutos entre las aplicaciones.No está previsto que LUMIGAN® (bimatoprost) presente influencia sobre la capacidad del paciente conducir vehículos u operar máquinas, sin embargo, así como para cualquier colírio, puede ocurrir visión borrosa transitoria después de la instilación; en estos casos el paciente debe aguardar que la visión se normalice antes de conducir u operar máquinas. Interacciones medicamentosas. medicamentosas.Considerando que las concentraciones circulantes sistemicas de bimatoprost son extremadamente bajas después múltiplas instilaciones oculares (menos de 0,2 ng/ml), y, que hay varias vías encimáticas envueltas en la biotransformación de bimatoprost, no son previstas interacciones medicamentosas en humanos. eacciones adversas. LUMIGAN® (bimatoprost) es bien tolerado, pudiendo causar eventos adversos oculares leves a moderados y no graves.Eventos adversos ocurriendo en 10-40% de los pacientes que recibieron doses únicas diarias, durante No son conocidas incompatibilidades. RReacciones 3 meses, en orden decreciente de incidencia fueron: hiperenia conjuntival, crecimento de las pestañas y prurito ocular.Eventos adversos ocurriendo en aproximadamente 3 a < 10% de los pacientes, en orden decreciente de incidencia, incluyeron: sequedad ocular, ardor ocular, sensación de cuerpo estraño en el ojo, dolor ocular y distúrbios de la visión.Eventos adversos ocurriendo en 1 a <3% de los pacientes fueron: cefalea, eritema de los párpados, pigmentación de la piel periocular, irritación ocular, secreción ocular, astenopia, conjuntivitis alérgica, lagrimeo, y fotofobia.En menos de 1% de los pacientes fueron relatadas: inflamación intra-ocular, mencionada como iritis y pigmentación del íris, ceratitis puntiforme superficial, alteración de las pruebas de función hepática e infecciones (principalmente resfriados e infecciones de las vías respiratorias).Con tratamientos de 6 meses de duración fueron observados, además de los eventos adversos relatados más arriba, en aproximadamente 1 a <3% de los pacientes, edema conjuntival, blefaritis y astenia. En tratamientos de asociación con betabloqueador, durante 6 meses, además de los eventos de más arriba, fueron observados en aproximadamente 1 a <3% de los pacientes, erosión de la córnea, y empeoramiento de la acuidad visual. En menos de 1% de los pacientes, blefarospasmo, depresión, retracción de los párpados, Posología y Administración. hemorragia retiniana y vértigo.La frecuencia y gravedad de los eventos adversos fueron relacionados a la dosis, y, en general, ocurrieron cuando la dosis recomendada no fue seguida.Posología Administración.Aplicar una gota en el ojo afectado, una vez al día, a la noche. La dosis no debe exceder a una dosis única diaria, pues fue demostrado que la administración más frecuente puede disminuir el efecto hipotensor sobre la hipertensión ocular.LUMIGAN® (bimatoprost) puede ser administrado concomitantemente con otros productos oftálmicos tópicos para reducir la hipertensión intra-ocular, respetándose el intervalo de por lo menos 5 minutos entre la administración de los medicamentos. VENTA BAJO PRESCRIPCIÓN MÉDICA.“ESTE PRODUCTO ES UM MEDICAMENTO NUEVO AUNQUE LAS INVESTIGACIONES HAYAN INDICADO EFICACIA Y SEGURIDAD, CUANDO CORRECTAMENTE INDICADO, PUEDEN SURGIR REACCIONES ADVERSAS NO PREVISTAS, AÚN NO DESCRIPTAS O CONOCIDAS, EN CASO DE SOSPECHA DE REACCIÓN ADVERSA, EL MÉDICO RESPONSABLE DEBE SER NOTIFICADO. 1. The AGIS Investigators: The Advanced Glaucoma Intervetion Study - The Relationship Between Control of Intraocular Pressure and Visual Field Deterioration. Am. J. Ophthalmol, 130 (4): 429-40, 2000. 2. Shirakashi, M. et al: Intraocular Pressure-Dependent Progression of Visual Field Loss in Advanced Primary Open-Angle Glaucoma: A 15-Year Follow-Up. Ophthalmologica, 207: 1-5, 1993. 3. Mao, LK; Stewart, WC; Shields, MB: Correlation Between Intraocular Pressure Control and Progressive Glaucomatous Damage in Primary Open-Angle Glaucoma. Am. J. Ophthalmol, 111: 51-55, 1991. 4. Higginbotham, EJ et al. One-Year Comparison of Bimatoprost with Timolol in Patients with Glaucoma or Ocular Hypertension. Presented at American Academy Ophthalmology, Nov 11-14, 2001. 5. Gandolfi, S et al. Three-Month Comparison of Bimatoprost and Latanoprost in Patients with Glaucoma and Ocular Hypertension. Adv. Ther, 18 (3): 110-121, 2001. 6. Coleman, AL et al: A 3-Month Comparison of Bimatoprost with Timolol/Dorzolamide in Patients with Glaucoma or Ocular Hypertension. Presented at American Acedemy of Ophthalmol, New Orleans, La, 2001.

Mejor comodidad posológica: 1 vez al día. No requiere refrigeración. Presentación conteniendo 3 ml.

December 2013, Vol. 12(4) Indexed Editor-in-Chief: Paulo Elias C. Dantas, MD Prof. of Ophthalmology Department of Ophthalmology Santa Casa of São Paulo, Brazil Vision Pan-America is also listed at the collection of the National Library of Medicine Catalog under the serial #101553235

Membership, Associations and Editorial Guidelines

Aims and scope: Vision Pan-America (printed version ISSN 2219-4665, electronic version ISSN 2219-4673), the official publication of the Pan-American Association of Ophthalmology, is a quarterly fully peer reviewed scientific publication that publishes original research in Ophthalmology, including review articles on ophthalmic diseases and surgical techniques, clinical scientific studies, basic investigation, case reports, brief communications and letters to the editor in four languages: Spanish, English, Portuguese and French. In addition, the journal publishes critical reviews of new texts in ophthalmology deemed to be of importance to the Pan-American practitioner.

Section Editor, Cataracts: Nestor Gullo, MD (La Plata, Argentina) Section Editor, Cornea and External Disease: Allan R. Slomovic, MD (Ontario, Canada)

Section Editor, Prevention of Blindness: Fernando R. Barría von Bischhoffshausen, MD (Concepción, Chile)

Section Editor, Oncology: Rubens N. Belfort, MD (São Paulo, Brazil)

Section Editor, Refractive Surgery: Luis Izquierdo Jr, MD (Lima, Peru) Section Editor, Retina and Vitreous: Mauricio Maia, MD (São Paulo, Brazil) Section Editor, Statistics and Epidemiology: Niro Kasahara, MD (São Paulo, Brazil) Section Editor, Uveitis and Immunology: Lourdes Arellanes-García, MD (Mexico City, Mexico)

Editorial Advisory Board

Editorial Review Board

Denise de Freitas, MD (São Paulo, Brazil)

Alejandro Lichtinger, MD (Toronto, Ontario, Canada)

Maria Audina Berrocal, MD (Miami, FL, USA)

Eduardo Alfonso, MD (Miami, FL, USA)

Ashley Behrens, MD (Riyadh, Saudi Arabia)

Daniel Weil, MD (Buenos Aires, Argentina)

Eduardo Arenas, MD (Bogotá, Colombia)

Ana Luisa Höﬂing-Lima (São Paulo, Brazil)

Marian Macsai, MD (Chicago, IL, USA)

J. Fernando Arévalo, MD (Riyadh, Saudi Arabia)

Bruno Fontes, MD (Rio de Janeiro, Brazil)

Marie Eve Legare, MD (Quebec City, Canada)

Alfredo Sadun, MD (Los Angeles, CA, USA)

Carol L. Karp, MD (Miami, FL, USA)

Natalio Izquierdo, MD (San Juan, Puerto Rico)

Enrique Graue-Hernández, MD (Mexico City, Mexico)

Peter Quiros, MD (Los Angeles, CA, USA)

Eugenio Maul de La Puente (Santiago, Chile)

Renato Ambrósio Jr. (Rio de Janeiro, Brazil)

3TouchMedia strategy

marketing

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Ivan Schwab, MD (Sacramento, CA, USA) Ofﬁce Staff Managing Editor Teresa Bradshaw (Arlington, TX, USA)

Production Editor Terri Grassi (Arlington, TX, USA)

Production Editor Mapy Padilla (Lima, Peru)

• Abbott Medical Optics Inc.

• Bausch+Lomb Inc.

• Rayner Intraocular Lenses Ltd.

• Alcon Inc.

• Johnson & Johnson Vision Care Latin America

• Merck & Co Inc.

PAOF INDUSTRY SPONSORS

• Allergan Inc.

3TouchMedia strategy

CREATIVE LATIN MEDIA, LLC. 2901 Clint Moore PMB. 117 Boca Raton FL. 33496 USA Tel: (561) 443 7192 Fax: (561) 443 7196 Atención al cliente: E-mail: suscripciones@clatinmedia.com

Section Editor, Neurophthalmology: Karl Golnik, MD (Cincinnati, OH, USA)

Section Editor, Ophthalmic Section Editor, Eye Banking: Luciene Barbosa de Sousa, MD Plastics and Orbital Diseases: Chun Cheng Lin Yang, MD (São Paulo, Brazil) MSc (San José, Costa Rica) Section Editor, Genetics: Eduardo José Gil Duarte Silva, Section Editor, Pathology: MD (Figueira da Foz, Portugal) J. Oscar Croxatto, MD (Buenos Aires, Argentina) Section Editor, Glaucoma: Section Editor, Pediatric James C. Tsai, MD (New Ophthalmology and Strabismus: Haven, CT, USA) Maria Estela Arroyo Yllanes, MD (México City, México)

Pan-American Association of Ophthalmology

Pan-American Association of Ophthalmology (PAAO) Pan-American Ophthalmological Foundation (PAOF) 1301 S Bowen Road #450, Arlington TX 76013 USA Tel: (817) 275-7553 • Fax: (817) 275-3961 Email: info@paao.org • www.paao.org

Administrative Editorial Council: Ana Luisa Hoﬂing-Lima,MD (PAAO President.), Mark Mannis, MD (PAAO Imediate Past-President, Sacramento, CA, USA.) and William De La Peña, MD (PAOF Chairman, Montebello, CA, USA)

Section Editor

@paao_vision

Associate Editor-in-Chief: Lihteh Wu, MD (San José, Costa Rica)

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Producida / Editada / Diseñada / Distribuida por: 3 Touch Media S.A.S.

Printed in Printer Colombiana S.A. – Colombia PAN-AMERICA

PAAO EXECUTIVE COMMITTEE 2013-2015 President Ana Luisa Höﬂing Lima, MD President Elect duardo C. Al onso, MD Past President Mark J. Mannis, MD

PAOF BOARD

Secretary, nglish Language Region James C. sai, MD MBA

Secretary, Spanish Language Region Lihteh u, MD

Associate Secretary, nglish Language Region Carol L. arp, MD

Associate Secretary, Spanish Language Region Jorge . Valde , MD MA

Vice President Jos Antonio Roca, MD

Secretary, Portuguese Language Region Paulo . C. Dantas, MD

Executive Vice President J. ernando Ar alo, MD ACS

Associate Secretary, Portuguese Language Region Maur cio Maia, MD

Chairman o the Board illiam De La Pe a, MD Past Chair Mr. elson Mar ues Vice Chair Mark J. Mannis, MD

ecuti e Director eresa J. Bradsha

Secretary- reasurer Liana Ventura, MD ecuti e Director eresa J. Bradsha

PAAO BOARD OF DIRECTORS 2013-2015 AR I A Carlos Ignacio eolite MD1 nri ue S. Malbr n Sr. MD2 rnesto errer Abad MD , usta o ederico Bodino MD1 Ja ier ernando Casiraghi MD1 Joa u n Al redo Ba alluy, MD1 Juan Oscar Cro atto, MD4 Pablo Luis Daponte MD1

DOMI ICA R P BLIC Del na Orti , MD4 Jaime A. e uerra, MD , Juan rancisco Batlle Pichardo, MD1 C ADOR Luis Sarra in Moreira, MD Mario P lit Macias, MD1 Robin Alberto R os Arreaga, MD1 L SALVADOR mmanuel Jes s Sal ador Mena M nde , MD ,

BOLIVIA Carlos alter Ar abe A., MD , usta o Aguirre r ui u, MD1 BRA IL Andr Correa de Oli eira Romano, MD1 Bruno Machado ontes, MD PhD1 duardo B chele Rodrigues MD1 Jos Al aro P. omes, MD4 Luciene Barbosa De Sousa, MD , Marcus Vinicius Abbud Sa ady, MD1 Milton Rui Al es, MD , Rubens Bel ort Jr., MD PhD2 Sergio elberg, MD1 Vin cius Coral hanem, MD1 CA ADA Allan R. Slomo ic MA MD RCS(C Paul . Ra use, MD PhD RCS(C ,

COLOMBIA Al aro Rodr gue on le , MD2 Angela Mar a ern nde Delgado, MD , Angela Mar a uti rre Mar n, MD1 Carlos Alberto Restrepo Pelae , MD , Hugo Hern n Ocampo Dom ngue , MD Jos Ramiro Prada Reyes MD1 Pedro I an a arro aran o MD1 Roberto Ba uero H., MD1 COS A RICA Claudio Orlich Dundor , MD Joa u n Mart ne Arguedas, MD1 eodoro ans MD1 C BA Armando Capote Cabrera, MD Beatri . Rodr gue Rodr gue , MD1 Ibrain Piloto D a , MD1

SPAI Jos A. Crist bal Bescos MD1 Luis ern nde Vega, MD Miguel A. ato me de Lia o MD PhD1

HAI I rant Large, MD

SA Alice R. McPherson, MD2 Arun D. Singh, MD4 Bradley R. Straatsma MD JD2 Cynthia Ann Brad ord MD1 Daniel J. Briceland MD1 J. Bron yn Bateman, MD2 regory Skuta, MD Lynn D. Anderson, PhD4 Lynn . ordon MD PhD1 Mark J. Mannis, MD2 Mildred M. . Oli ier MD1 Paul R. Lichter MD2 Paul Sternberg MD Peter A. uiros MD1 R.V. Paul Chan, MD1 Richard L. Abbott MD2 Robert C. Dre s MD2 Robert einreb, MD4 Victor L. P re , MD1 lia Correa, MD PhD1

ICARA A Marcelo igueroa Bra o, MD

PA AMA Ben am n . Boyd MD2 li milio Rui D a , MD Samuel Boyd Le is MD1

R A Alicia Mart ne de Pacheco, MD1 Andrea ern nde L pe MD1 Mart n S nche , MD

M ICO Arturo Ramire -Miranda, MD1 Cecilio rancisco Velasco Barona, MD4 Da id Lo ano Rechy MD1 nri ue L. raue iechers, MD2 duardo Ch e Mondrag n, MD4 li il Carrasco MD1 Jos Luis o illa Canales MD1 Lourdes Arellanes arc a, MD , Raul Macedo Cu MD1 ito Ram re Lu uin, MD

CHIL Ale andro V ue de art o , MD4 Cristi n Luco, MD2 ernando R. Barr a on B., MD4 on alo Vargas D a , MD1 Juan Verdaguer aradella, MD2 Rodigo Vidal Sobar o, MD1 Ver nica A car ., MD Ver nica ern nde Salgado, MD4

P R O RICO H ctor Villarrubia, MD Mar a Berrocal, MD ,

A MALA Byron Polanco, MD4 Cristi n Rolando Ace edo Campos, MD1 Paulina Caste n, MD ,

HO D RAS duardo Jos lores Sauceda MD1 r in Ochoa, MD ,

POR AL duardo Jos il Duarte Sil a MD PhD1 Paulo . de Ancede Aires S orres, MD PhD

PARA A Pablo Rub n Cibils arr s, MD1 alter imcke Holst, MD , P R Dino ernando atteri Marmol, MD1 rancisco Contreras Campos MD2 Jos Antonio Roca ern nde , MD Juan Carlos Corbera on alo, MD1 Juan ernando Mendiola Solari, MD1 Miguel u m n Ahumada, MD1 Roc o Ardito Vega MD1

V LA Claudia Lu Pab n Be arano, MD1 ernando L. Colombo Rengel, MD4 Jos Luis Rinc n Rosales, MD1 Mar a Ang lica Corte Bernal, MD1 Morayma Ace edo Sorondo, MD Oscar Vicente Beau n Balbi, MD1 S I DI S Li ette Mo att, MB BS MMedSci , Son a . Johnston BSc MB BS RCS1

Delegate PAAO Past President President, A liated ational Society 4 President, A liated Subspecialty Society

EDITORIAL

Editorial Paulo E.C. Dantas, MD Editor-in-Chief

How happy could we be? As a proud father, I celebrate each and every accomplishment of my daughters Claudia and Carolina. From the simplest, like taking a driver’s license, to more complex one, such as passing the admission exam for the university. The same happens with Vision Pan-America, which has incorporated many bibliometric features since we embraced the challenge of honoring and replacing one of the brightest mind in the world of ophthalmology, Dr. Mark J. Mannis, adding value, getting importance and respect, hence increasing exposure of its content to the international scientific community.

Thanks also to the VPA office (Teresa, Terri and Mapy), to Colombia’s office (Eliana and Creative Latin crew) and to the Editorial Board, that has been extremely responsive to journals duties and activities. A great journal begins with a great team and I am completely sure that we have one of the most accredited group of scientists and doctors in the universe of ophthalmological science. Looking forward for 2014! Happy Hollidays!

Recently, we were honored with the inclusion in four international indexing agencies: Directory of Open Access Journals (DOAJ® www.doaj.org), Directory Indexing of International Research Journals (Cite Factor® www.citefactor.org), Index CopernicusTM (www.indexcopernicus.com) and EBSCO Research DatabaseTM (www.ebscohost.com). Additionally, we were included in the popular database Google Scholar® (www.scholar.google.com), increasing exponentially the international visibility of all articles published in VPA. It is important to emphasize that indexing is retroactive, meaning that all articles published since 2002 were automatically indexed. Should we be proud or not? I must acknowledge and thank the support given by PAAO and PAOF Board for making all these achievements possible, supporting our ideas and sharing the same excitement for making VPA the main source of ophthalmologic science to the PanAmerican community.

Paulo E.C. Dantas, M.D. Editor-in-Chief Vision Pan-America, The Pan-American Journal of Ophthalmology pauloecdantas@uol.com.br pauloecdantas@me.com

PAN-AMERICA

Vis. Pan-Am. 2013;12(4):100

Message from the President The Webinar Network: a Teaching Model for Latin America.

Authors: Eduardo P. Mayorga Argañaraz1,2,3, Ana Gabriela Palis1,2,3 International Council of Ophthalmology, Pan-American Association of Ophthalmology, 3 Hospital Italiano de Buenos Aires, Argentina

Continuing medical education of ophthalmologists is a fundamental requirement for quality eye care in the populations they serve. Latin America faces several challenges for continuing education of ophthalmologists. With a total area of 8 million square miles and varied economies, geographical, time and economic difficulties to access courses and congresses contribute to make continuing education a difficult and expensive process for ophthalmologists. While Spanish and Portuguese are the prevailing languages in the region, there is a scarcity of educational resources in these languages as compared to those in English, making self-education even more difficult to those not proficient in English as a second language. Evidence suggests that e-learning is as effective as traditional face-to-face1,2 training. E-learning online activities can be asynchronous (learners and teachers are not online at the same time - e.g. online courses) or synchronous. As compared with asynchronous activities, giving presentations through synchronous webinars (a contraction of web-based seminars) offer the advantage of lower costs and less time needed for content preparation. Webinars also promote a social environment: a greater feeling of human presence and less isolation, as students and teachers are able to interact. Several studies have suggested the benefits of e-learning. In one of the most extensive and thorough published reviews, carried out by the United States Department of Education in 2009 and reviewed in 20101, a critical analysis of 176 studies comparing online or mixed (blended) learning with inperson education showed that online students had a slightly better performance than those who studied the same material through 100

PAN-AMERICA

traditional in-person or exclusive online education. When used in their pure forms, online learning seemed to be as effective as traditional in-person education. According to the authors, the effect was greater when online education had been collaborative or directed by a tutor than when students worked independently. In a systematic review evaluating the effect of Internet-based education for health sciences, Cook et al2 conclude that Internet-based education is as effective as education by traditional methods. An additional advantage that was not assessed in these studies is the opportunity of remote education that e-learning offers. This is particularly key in professions requiring a continuous update of knowledge (such as the health sciences), but where traditional education methods may result expensive, impractical and difficult to access for professionals living in remote areas. Even for those living in big cities, attending to congresses and lectures implies that they leave their practices and losing profit to get education. Synchronous e-learning interventions, such as teleconferences, webinars and chats, allow for a format almost similar to traditional education: teachers present lively while students listen, take notes, ask questions, etc. People do not need to be at the same physical space, with the resulting benefit in practicality and less costs of classroom, accommodation, traveling, meals. The only physical requirement is a computer (or mobile phone) with an updated operating system, high-speed Internet connection, and software for transmission of the lecture. The Pan-American Association of Ophthalmology (PAAO) has established as its mission: “to prevent blindness through lifelong education and cultural exchange among ophthalmologists in the Western hemisphere”3. Under the presidencies of Drs. Mark Mannis and Ana Luisa HöflingLima, the PAAO is working, jointly with the International Council of Ophthalmology, on developing the Webinars Network Project http://ophthalmologywebinars.blogspot.com. ar/?ref=paao-ico. The goal of the Webinar Network is to facilitate and make continuing medical education for ophthalmologists in Latin America more efficient, as well as to increase the scientific, educational and cultural exchange among teachers and students in the Americas. The project plans to: 1) establish a network of academic programs that share training activities for residents and ophthalmologists, 2) create a clearing house of synchronous learning activities in Spanish, Portuguese, and English, 3) help content experts meet the quality guidelines of medical education accreditation

organizations, 4) assist academic programs with the logistics to develop webinars, and 5) help academic programs develop abilities to create effective, significant and interesting online teaching interventions. As a part of this project, the PAAO started organizing monthly conferences by top subject matter experts. The presentations alternate short segments of lecturing with questions to the audience and immediate feedback. There is also time allotted for questions and comments at the end, a valued moment of dialogue for attendants and lecturers. Consideration of adult learning principles (relevance, interactivity, immediate feedback, appropriately defined objectives) and an adequate use of images, videos and text in the presentations are key factors that have proven to improve learning from lectures and conferences. Lectures are recorded and uploaded to the Internet for those unable to attend or willing to review the conference. http://www.campuspaao.org/ While there are no data about the exact number of ophthalmologists in Latin America, it is estimated that today there is an average of 51 ophthalmologists per million population4. This would imply about 29 thousand ophthalmologists serving a population of 570 million people. We expect the benefit of being able to attend these conferences from the comfort of their own home, without traveling or accommodation expenses, and no lost income, will be attractive for ophthalmologists in the region, in particular those who live in more isolated places or with lower resources for continuing education. Language, time, and cost barriers could be overcome to enhance ophthalmic education of residents and ophthalmologists in the region.

REFERENCES: 1. U.S. Department of Education, Office of Planning, Evaluation, and Policy Development. Evaluation of Evidence-Based Practices in Online Learning: A Meta-Analysis and Review of Online Learning Studies, Washington, D.C., 2010. 2. Cook DA, Levinson AJ, Garside S, Dupras DM, Erwin PJ, Montori VM. Internet-Based Learning in the Health Professions. A Metaanalysis. JAMA 2008;300(10):1181-96. 3. www.paao.org 4. Resnikoff S, Felch W, Gauthier TM, Spivey B. The number of ophthalmologists in practice and training worldwide: a growing gap despite more tan 200,000 practitioners. Br J Ophthalmol 2012;96(6):783-7

Rodriguez FJ et al. Latin American Consensus on AMD.

Latin American Consensus on Age-Related Macular Degeneration Francisco J Rodríguez MD1, Lihteh Wu MD2, Arturo Alezzandrini MD3, J Fernando Arevalo MD4, Joaquín Bafalluy MD5, Maria Hortensia Berrocal MD6, Cristian Carpentier MD7, Eduardo Cunha de Souza MD8, Michel Farah MD9, Jans Fromow Guerra MD10, Gregorio Gabela MD11, Federico Graue Wiechers MD12, Ricardo Infante de Germán Ribón MD13, Mauricio Maia MD14, Fernando Marcondes Penha MD15, Virgilio Morales Canton MD16, Hugo Ocampo MD17, Hugo Quiroz-Mercado MD18, Jose Antonio Roca Fernandez MD19, Juan Gonzalo Sánchez MD20, Patricio G. Schlottmann MD21, Martín A Serrano MD22, Walter Takahashi MD23 Affiliations: 1Fundación Oftalmológica Nacional, Bogota, Colombia, 2Instituto de Cirugia Ocular, San José, Costa Rica 3 Oftalmos, Buenos Aires, Argentina, 4Wilmer Eye Institute at Johns Hopkins University, Baltimore, MA, USA, 5 Universidad Nacional de Rosario, Rosario, Argentina, 6Centro Oftalmológico Berrocal y Asociados, Santurce, Puerto Rico, 7Fundación Oftalmológica Los Andes, Santiago, Chile, 8Universidad de São Paulo (FMUSP), Sao Paulo, Brazil, 9 Universidade Federal de São Paulo, Sao Paulo, Brazil, 10Colegio Nacional de Investigación en Ciencias Visuales MéxicoARVO, Mexico City, Mexico, 11Hospital Metropolitano, Quito, Ecuador, 12Instituto de Oftalmología Conde de Valenciana, Mexico City, Mexico, 13Fundación Oftalmológica Nacional, Bogota, Colombia, 14Instituto Brasileiro de Luta contra a Cegueira, São Paolo, Brazil, 15Escola Paulista de Medicine, Universidade Federal de São Paulo, São Paulo, Brazil, 16 Asociación para Evitar la Ceguera en México I.A.P, Mexico City, Mexico, 17Clínica de Oftalmología de Cali, S.A., Cali, Colombia, 18Médico Consultante del Servicio de Retina, APEC, Mexico City, Mexico and Denver Health Medical Center, CO, USA, 19Universidad Peruana Cayetano Heredia, Lima, Peru, 20Instituto Nacional de Investigación en OftalmologíaINIO, Medellin, Colombia, 21Organización Médica de Investigación, Buenos Aires, Argentina, 22Clínica Oftalmológica Centro Caracas, Caracas, Venezuela, 23Serviço de Retina e Vítreo, Departamento de Oftalmologia, Universidade de São Paulo, São Paulo, Brazil.

Abstract

Age-related macular degeneration (AMD) is a chronic disease affecting the retina and is the most common cause of blindness in the ageing population in the developed world. Correct and timely diagnosis and classification allows physicians to estimate which patients are at high risk of progressing to more advanced stages of the disease In February 2012, 23 Latin American experts met in Cartagena, Colombia, to develop a Consensus on AMD. This paper summarizes the main points of the discussions including definitions, diagnosis, antiangiogenic treatments, and hopes for the future. Dry AMD remains untreatable but results from promising Phase II trials are awaited eagerly. Antiangiogenics, such as the licensed vascular endothelial growth factor (VEGF) inhibitors, aflibercept and ranibizumab, have revolutionized the treatment of wet AMD in recent years. These drugs work by inhibiting the choroidal neovascularization that causes the rapid vision loss in wet AMD. Another antiangiogenic, bevacizumab, is also commonly used off-label, but is not approved currently for intraocular use. However, barriers to treatment compliance, due to the frequency of monthly injections,

Corresponding author: Dr Francisco J Rodríguez, Universidad del Rosario, Bogota, Colombia Tel: +57 1 345 1754; Fax: +57 1 348 7330 ; E-mail: fjrodriguez@fon.org.co Funding: Development of this manuscript was supported by an educational grant from Bayer HealthCare Pharmaceuticals, with editorial support provided by Edelman and Flow Healthcare Consultancy. Proprietary/financial interest: The following authors have relevant financial information to disclose: Dr Rodríguez: Advisory Boards - Bayer, Novartis; Speakers’ Bureaus - Allergan, Bayer, and Novartis; Travel Grants - Alcon, Bayer. Dr Bafalluy: Advisory Boards - Bayer, Novartis; Travel Grants - Bayer, Novartis. Dr Farah: Speakers’ Bureaus - Bayer, Novartis; Travel Grants: Bayer, Novartis. Dr Fromow Guerra: Consultant - Novartis, Bayer; Travel Grants - Novartis, Bayer. Dr Marcondes Penha: Consultant - Bayer, Zeiss; Speakers’ Bureaus - Bayer, Zeiss; Travel Grants: Bayer, Zeiss, Novartis. Dr Morales: Speakers’ Bureaus - Sanofi, Oraya; Travel Grants - Bayer, Oraya, Sanofi. Dr Ocampo: Speakers’ Bureaus - Bayer, Novartis; Travel Grants - Novartis, Bayer, Allergan. Dr Roca: Travel Grants - Novartis, Bayer, Sophia. Dr Sánchez: Speakers’ Bureaus Bayer, Novartis, Allergan; Travel Grants: Novartis, Bayer, Allergan, Alcon. Dr Schlottman: Consultant – Bayer, Novartis; Speakers’ Bureaus: Bayer, Novartis; Travel Grants: Bayer, Novartis. Dr Serrano: Travel Grant: Bayer. Dr Takahashi: Consultant: Bayer, Novartis; Travel Grants: Bayer, Novartis. Date of submission: 10/06/2013 Date of approval: 07/08/2013

can also affect the efficacy of these antiangiogenic therapies. Aflibercept has a longer duration of action compared with other treatments and thereby offers reduced injection frequency. By relieving patients of the need for monthly visits, it can help reduce the growing burden of AMD patients on healthcare resources.

Introduction

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population of the developed world and is a chronic condition affecting the macula, resulting in reduction or loss of central vision. AMD is usually classified as early, intermediate, and advanced. There are two main types of advanced AMD – dry and wet – with the most common AMD pathology being the dry form (where degenerative changes in the retinal pigment epithelial cells [RPE] are seen), and which comprises 80% of all AMD cases. However, there is no effective treatment available currently for dry AMD. Wet AMD –the growth of abnormal new blood vessels under the retina – accounts for only 10% of all AMD cases, but 90% of blindness from this condition.1 Several therapies are available for wet AMD, but only antiangiogenic treatments and sometimes phototherapy can help prevent further vascularization. PAN-AMERICA 101

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In the United States, AMD is estimated to affect approximately 1.75 million people.2 Less is known on the prevalence in Latin America due to the limited number of epidemiology studies; however, one Colombian study by Rodríguez et al. reported an overall prevalence of 4.86% in a cohort of 535 volunteers.3 In Cartagena, Colombia, in February 2012, 23 international experts from Colombia, Costa Rica, Brazil, Argentina, Mexico, Chile, Peru, Venezuela and Ecuador met to develop a Latin American consensus on AMD. These experts are also members of the Pan-American Retina and Vitreous Society, and most are members of PACORES (Pan-American Collaborative Retina Study Group), a Latin American group of eye specialists dedicated to the investigation of the most relevant diseases of the retina, vitreous, and macula. The Latin American AMD Consensus group discussed the most relevant aspects of AMD and the full report is available at http://www.sprv.org/paginas/archforo/ LATAM%20CONSENSUS_LAST_SPA.pdf. This paper represents a summary of this report and focuses on definitions, diagnosis, antiangiogenic treatments, and hopes for the future. Thanks to the advent of antiangiogenic therapy for wet AMD, a revolution in treatments has been achieved. However, challenges and controversy exist regarding subsequent clinical results and the regulatory barriers still do exist, which need to be addressed.

Definitions

Dry AMD is caused by degenerative changes in the RPE, which is clinically recognized by macular pigmentation, changes and deposition of drusen (small yellow or white accumulations of extracellular material), patchy areas of atrophy, and geographic atrophy (GA).4 The latter has been implicated in 20% of legal blindness cases in the USA.5 The progression of dry AMD is gradual and, by itself, rarely causes severe visual loss or blindness.6 Wet AMD, also known as neovascular or exudative AMD, is caused by the development of abnormal, new blood vessels beneath and within the retina (choroidal neovascularization), which bleed or leak blood constituents, resulting in retinal scarring. The progression of wet AMD is usually more rapid than dry.1

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AMD is classified according to a scale of severity.7 Early AMD is characterized by any or all of the following: multiple small drusen, a few medium-sized drusen, or RPE abnormalities. Intermediate AMD is characterized by extensive medium-sized drusen and ≥1 drusen, or non-foveal GA. Advanced AMD is defined as GA involving the fovea or neovascular AMD.7

Diagnosis

The early and intermediate stages of AMD are usually asymptomatic. Typical symptoms of late stage AMD include vision loss, vision blurring, metamorphosis, and scotoma; atypical symptoms include change of color perception, dissymmetry, light sensitivity, and sense of darkness. A scoring system for AMD is used to characterize the disease stage, estimate the patient’s risk of progressing to more advanced disease, and choose the most appropriate treatment. In this way, asymptomatic patients can be identified who may otherwise go on to develop advanced disease without frequent monitoring. The Age-Related Eye Disease Study (AREDS) Research Group has developed a severity score for AMD using highly complex stereoscopic photography – measuring drusen and pigmentary changes.8 The AREDS score has four classifications: • AREDS 1 – no disease: no macular changes or few drusen <63 microns • AREDS 2 – early stage: intermediate drusen between 63–124 microns or pigmentary changes • AREDS 3 – intermediate: abundant, intermediate drusen, ≥1 large drusen >125 microns or non-foveal GA • AREDS 4 – advanced: ≥1 GA with fovea center compromise, choroidal neovascularization, serous detachment, RPE hemorrhage, or disc form scar AREDS has also developed a simplified severity score for AMD, taking into account drusen size, depigmentation, and degree of GA7 – both the left and the right eye are assigned a risk factor for the presence of ≥1 large drusen and pigment changes. By summing the risk factors across both eyes, a five-step scale (0 to 4) provides an approximate 5-year risk for developing AMD. Optical coherence tomography (OCT)

Rodriguez FJ et al. Latin American Consensus on AMD.

Right Eye

Left Eye

Large Drusen Pigment Changes Large Drusen Pigment Changes

Large Drusen and pigment Changes

No=0 Yes=1 No=0 Yes=1 No=0 Yes=1 No=0 Yes=1

1 1 1 1

Patient Severity Score=4 Risk Factors

Risk of age-related macular degeneration progression in at least one eye (with both). Estimated Probability %

Risk factor estimation table.

80 70 60 50 40 30 20 10 0

Score=0 Score=1 Score=2 Score=3 Score=4

43% 27% 9% 3%

Years

Figures reproduced with permission from the Latin American Consensus on AgeRelated Macular Degeneration (http://www.sprv.org/paginas/archforo/LATAM%20 CONSENSUS_LAST_SPA.pdf) is a non-invasive technique that takes highresolution images of the retina using light interferometry, and allows easy diagnosis of retinal and subretinal conditions such as AMD.9 Current management of exudative AMD requires the use of anti-VEGF drugs, and OCT is advised before starting the treatment. In fact, most treatment programs are based on OCT findings to decide whether or not to continue with anti-VEGF drugs. Diagnosis of non-responder AMD patients is based on the absence of change or increase of subretinal or intraretinal fluid after a loading dose of antiVEGF drug compared with the baseline OCT and/or vision loss greater than 15 letters.

Antiangiogenic treatments

Current treatment for wet AMD is focused on blocking ocular vascular endothelial growth factor (VEGF) in the eye using monoclonal antibodies or fragments, and fusion proteins.10 Two VEGF-inhibiting drugs are approved11: ranibizumab (Lucentis®, Genentech/Novartis; FDA approved in 200612), and aflibercept (Eylea®, Regeneron/Bayer, FDA approved in 201113). An alternative drug, bevacizumab (Avastin®, Genentech/Roche), has been used off-label since 2005,10 but it has not formally been approved for intraocular use.

Ranibizumab

Ranibizumab is the Fab fragment of a recombinant, humanized murine monoclonal antibody, which was developed specifically for intraocular use. It binds all forms of VEGF-A,14 inhibiting angiogenesis and reducing vascular permeability.15

The FDA approval was supported by data from two pivotal level 1 studies: ANCHOR16 (anti-VEGF antibody for the treatment of predominantly classic choroidal neovascularization in AMD) and MARINA12 (Minimally Classic/Occult Trial of the AntiVEGF antibody Ranibizumab in the treatment of neovascular AMD). • In the ANCHOR study, patients with classic membranes were randomized to receive either 24 monthly injections of ranibizumab (0.5 mg) or photodynamic therapy (PDT).16 After 24 months, 90– 96% of patients in the ranibizumab group lost <15 letters in vision compared with 64–66% receiving PDT; 34–41% of the rani i uma group gained ≥1 letters compared with 6% receiving PDT.16 • In the MARINA study, patients with minimally classic and occult membranes were randomized to receive 24 monthly injections of ranibizumab (0.5 mg or 0.3 mg) or placebo.12 In the eyes treated with ranibizumab, 90–95% lost <15 letters compared with 53–64% receiving placebo; 25–34% of the ranibizumab group gained ≥1 letters compared with 4–5% receiving placebo.12 The frequency of intraocular injections has generated a number of issues including patient compliance, cost, and logistic feasibility. Since the completion of ANCHOR and MARINA, a number of new studies have examined alternative injection frequencies – including PIER, SAILOR, EXCITE, SUSTAIN, and PrONTO.

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•

n the ER stud level 1 , patients were treated with a monthl in ection for months and then one in ection ever months thereafter. After 4 months, the improvement in vision gained in the first months was lost, showing the importance of maintaining the in ection schedule.1 Efforts to e tend the dosing intervals forfeited previous enefits in clinical outcome. he E E stud level 1 was similar to the ER stud ut used monthl in ections of rani i uma . mg as the control group. After 1 months, the gain in vision was higher in the monthl group . mg compared with the month group . mg and . mg .1 he SA R stud level 1 applied three loading doses of rani i uma followed monthl in ections . – . mg according to visual acuit and optical coherence tomograph . isual acuit improved after the loading dose, ut then decreased, showing superior results than the ER stud , ut not superior to AR A or A R.11 he S S A stud level 1 applied three loading doses of rani i uma . mg followed in ections according to visual acuit and . After 1 months, most of the visual acuit gained during the loading phase was maintained until the end of the stud .1 , he r stud level applied three loading doses of rani i uma . mg followed a monthl control in ection according to visual acuit and . After 4 months, patients gained 11.1 letters over the levels of aseline visual acuit . 1

Aflibercept

Afli ercept, also nown as EG rap-E e, is a chimeric protein formed the fusion of EG -1 and - receptor domains and the c segment of a human gG, resulting in a higher EG - inding affinit than either rani i uma or evaci uma . t was designed specificall to loc all mem ers of the EG famil , including isoforms of EG -A and - , and lacental Growth actor lG . he DA approved afli ercept in ovem er 11 for treating neovascular A D, and this was ased primaril on the results of two identical pivotal multicenter – aimed at studies – E 1 and E defining the non-inferiorit of afli ercept compared with rani i uma .1 104

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•

E 1 included 1, 1 patients from the SA and anada – E comprised 1, 4 patients from Europe, Asia– acific and atin America Argentina, ra il, olom ia and e ico . atients with neovascular mem ranes of all t pes were randomi ed to one of four treatment arms: afli ercept . mg ever 4 wee s, afli ercept mg ever 4 wee s, afli ercept mg ever wee s after three loading doses , or rani i uma . mg ever 4 wee s.1 After wee s, all patients receiving afli ercept showed etter results in visual acuit than those receiving rani i uma the percentage of patients that lost 1 letters , showing no statistical inferiorit . Afli ercept mg ever wee s was e uivalent to rani i uma . mg ever 4 wee s, with a similar safet profile. • nterestingl , there was no difference in the clinical efficac of afli ercept etween treatments ever 4 or wee s, and it was well tolerated oth locall and s stemicall . ts longer duration of action ma allow ph sicians to administer fewer in ections, at the same time relieving patients of the need for monthl visits, there helping to reduce the growing urden of A D patients on healthcare resources.

Bevacizumab

evaci uma is a humani ed monoclonal anti od human, murine that inhi its all forms of EG -A 4 – received DA approval in 4 for the treatment of metastatic choroidal cancer. S stemic evaci uma has een applied in ophthalmolog with a mg g dose successfull demonstrating a reduction in the neovascular mem rane and in the thic ness, and an improvement in visual acuit . ntravenous evaci uma has never een widel adopted despite the fact that intravitreal application uses times less of the drug, is therefore more economic, and has a etter safet profile due to the reduced s stemic dose. n , Rosenfeld et al. first descri ed the treatment of A D using intravitreal evaci uma 1. mg .1 Since then, several small retrospective efficac and safet studies have een pu lished and evaci uma is now in widespread off-la el use. A retrospective stud of intravitreal evaci uma in ection in human e es

Rodriguez FJ et al. Latin American Consensus on AMD.

evaluating two doses of bevacizumab (1.25 mg and 2.5 mg) by the PACORES group did not detect any differences between the two groups.28 Bevacizumab appears to be well tolerated by most patients. A retrospective study of 4,303 injections in 1,319 eyes only reported a 1.5% incidence of systemic AEs (elevated blood pressure and other cardiovascular events). The rate of ocular complications was low: endophthalmitis (0.16%), uveitis (0.09%), and retinal detachment (0.02%).29 Despite the fact that the safety and efficacy of bevacizumab had not been reported in randomized, multicenter studies prior to the Comparison of AMD Treatments Trials (CATT) study,21 its use became widespread due to its low cost. In fact, 2-year results from CATT also showed that ranibizumab and bevacizumab had less gain on visual acuity, whether instituted at enrollment or after 1 year of monthly treatment, and that there appeared to be a persistence of higher rates of serious adverse events with bevacizumab, although this interpretation is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF.30 A systemic review recently evaluated whether off-label bevacizumab is as well tolerated as licensed ranibizumab, and whether it can be justifiably offered to patients as a treatment for AMD. Evidence from head-to-head trials has raised concerns about an increased risk of ocular and multiple systemic AEs with bevacizumab. Therefore, clinicians and patients should continue to carefully weigh up the benefits when choosing the best treatment.31

Conclusion and hopes for the future

AMD is a chronic disease and it is vital for patients that important developments for its treatment are on the horizon. We have learned and developed our treatment of wet AMD with ranibizumab and off-label bevacizumab. It is also encouraging to see the emergence of other antiangiogenics such as the VEGF Trap-Eye (aflibercept for intraocular injection), which differs from the two above in that it has a longer-lasting effect. External or intravitreous administered radiotherapy will also most likely play an important role, either in a combined form with antiangiogenics or as monotherapy in some cases of AMD.

REFERENCIAS 1 Chen Y, Han F. Profile of ranibizumab: efficacy and safety for the treatment of wet age-related macular degeneration. Ther Clin Risk Manag 2012;8:343-51 2 Seddon JM, Chen CA. The epidemiology of age-related macular degeneration. Int Ophthalmol Clin 2004;44:17-39 3 Rodríguez FJ, Posso H, Abdala C et al. Prevalencia y factores de riesgo en degeneración macular relacionada con la edad en Colombia. Revista SCO 2009;42:117-27 4 Age-related macular degeneration. Guidelines for management. Royal College of Ophthalmologists. http://www.rcophth.ac.uk/docs/publications/AMD_GUIDELINES_FINAL_VERSION_ Feb_09.pdf. Accessed 8 September 2012 5 Mata NL, Vogel R. Pharmacologic treatment of atrophic age-related macular degeneration. Curr Opin Ophthalmol 2010;21:190-6 6 Gehrs KM, Anderson DH, Johnson LV, Hageman GS. Age-related macular degeneration--emerging pathogenetic and therapeutic concepts. Ann Med 2006;38:450-71 7 Ferris FL, Davis MD, Clemons TE et al. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol 2005;123:1570-4 8 Davis MD, Gangnon RE, Lee LY et al. The Age-Related Eye Disease Study severity scale for agerelated macular degeneration: AREDS Report No. 17. Arch Ophthalmol 2005;123:1484-98 9 Zweifel SA, Engelbert M, Laud K et al. Outer retinal tubulation: a novel optical coherence tomography finding. Arch Ophthalmol 2009;127:1596-602 10 Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36:331-5 11 Mitchell P, Korobelnik JF, Lanzetta P et al. Ranibizumab (Lucentis) in neovascular age-related macular degeneration: evidence from clinical trials. Br J Ophthalmol 2010;94:2-13 12 Rosenfeld PJ, Brown DM, Heier JS et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-31 13 Benz MS, Nguyen QD, Chu K. Interim reults of the Phase II, randomized, controlled dose-and inteval-ranging study of repeated intravitreal VEGF trap administration in patients with neovascular age-related macular degeneration (AMD). Invest Ophthalmol Vis Sci 2007;48:E-Abstract 4549 14 Mordenti J, Cuthbertson RA, Ferrara N et al. Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration. Toxicol Pathol 1999;27:536-44 15 Gaudreault J, Fei D, Rusit J et al. Preclinical pharmacokinetics of Ranibizumab (rhuFabV2) after a single intravitreal administration. Invest Ophthalmol Vis Sci 2005;46:726-33 16 Brown DM, Kaiser PK, Michels M et al. Ranibizumab versus verteporfin for neovascular agerelated macular degeneration. N Engl J Med 2006;355:1432-44 17 Regillo CD, Brown DM, Abraham P et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol 2008;145:239-48 18 Bolz M, Schmidt-Erfurth U. Ranibizumab EXCITE study: Exploring the value of optical coherence tomography for the management of ranibizumab therapy in age-related macular degeneration. 8th EURETINA Congress. Vienna, Austria. 19 Meyer CH, Eter N, Holz FG, Fulano FM. Ranibizumab in patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration. Interim results from the SUSTAIN trial. Invest Ophthalmol Vis Sci 2008;49:E-abstract 273 20 Lalwani GA, Rosenfeld PJ, Fung AE et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 2009;148:43-58 e1 21 Martin DF, Maguire MG, Ying GS et al. Ranibizumab and bevacizumab for neovascular agerelated macular degeneration. N Engl J Med 2011;364:1897-908 22 Holash J, Davis S, Papadopoulos N et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 2002;99:11393-8 23 Heier JS, Brown DM, Chong V et al. Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration. Ophthalmology 2012;119:2537-48 24 Han DP. Intravitreal human immune globulin in a rabbit model of Staphylococcus aureus toxin-mediated endophthalmitis: a potential adjunct in the treatment of endophthalmitis. Trans Am Ophthalmol Soc 2004;102:305-20 25 National Cancer Institute. FDA Approval for Bevacizumab. 08/05/2009. http://www.cancer. gov/cancertopics/druginfo/fda-bevacizumab. Accessed September 8, 2012 26 Michels S, Rosenfeld PJ, Puliafito CA et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study. Ophthalmology 2005;112:1035-47 27 Penha FM, Rosenfeld PJ. Management of neovascular AMD. In: Age-related macular degeneration diagnosis and treatment. London: Springer. 2011:78-98 28 Wu L, Arevalo JF, Berrocal MH et al. Comparison of two doses of intravitreal bevacizumab as primary treatment for macular edema secondary to branch retinal vein occlusions: results of the Pan American Collaborative Retina Study Group at 24 months. Retina 2009;29:1396-403 29 Wu L, Martinez-Castellanos MA, Quiroz-Mercado H et al. Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol 2008;246:81-7 30 Martin DF, Maguire MG, Fine SL et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration. Two-year results. Ophthalmology 2012;119:1388-98 31 Schmucker C, Ehlken C, Agostini HT et al. A safety review and meta-analyses of bevacizumab and ranibizumab: Off-label versus gold standard. PLoS One 2012;7:e42701

El texto en español estará disponible online en la version electronica en http://journal.sfu.ca/paao

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Laser In Situ Keratomileusis Retreatment with Wavefront-Optimized Technique after Primary Wavefront-Guided LASIK: Proof of Concept Engy M. Mohamed1,2, MD, Juan C. Arciniega1, MD, James P. McCulley1, MD; FRCOphth (UK), R. Wayne Bowman1, MD. 1Department of Ophthalmology, University of Texas Southwestern Medical Center, TX, USA 2 Department of Ophthalmology, University of Sohag, Sohag, Egypt Funding: Supported in part by Research to Prevent Blindness Inc. New York, NY; and the National Institutes of Health grants EY12430, EY016664 and P30 Core Grant. Proprietary/financial interest: The author(s) report no financial or other conflict of interest relevant to the subject of this article.

ABSTRACT

Corresponding Author: James P. McCulley, MD Department of Ophthalmology, University of Texas Southwestern Medical Center at Dallas 5323 Harry Hines Blvd., Dallas, TX 75390-9057. Telephone: 214-648-2020; Fax: 214-648-9061 Email: james.mcculley@utsouthwestern.edu Date of submission: 29/09/2013 Date of approval: 04/11/2013

Purpose: To assess the visual outcome and refractive error following wavefront (WF)optimized laser in situ keratomileusis (LASIK) retreatment after previous WF-guided LASIK in myopic patients. Methods: A retrospective analysis of 19 eyes (14 patients) following WF-optimized LASIK retreatment after previous WF-guided LASIK that did not give desired refractive results was conducted. The primary LASIK procedures were performed using the Visx CustomVue™ laser with WF-guided technology. All of the subsequent retreatment LASIK procedures were performed with the Wavelight Allegretto™ Eye-Q 400 excimer laser using WF-optimized. Ophthalmic evaluations including uncorrected visual acuity (UCVA), best spectacle corrected visual acuity (BSCVA), and manifest refraction spherical equivalent (MRSE) were performed at baseline and postoperatively at 1, 3, 6 months. Results: UCVA and BSCVA improved following retreatment from 0.27±0.18 and 0.0±0.05 to 0.01±0.05 and -0.03±0.05 respectively at 6 months (p<0.001 and p=0.38). The MRSE decreased from -0.5 D pre-retreatment to -0.2 D at 6 months postretreatment. The pre-retreatment total HOA was 0.48±0.21 (0.24 to 1.01µm) and did not show correlation with the visual outcomes postoperatively. No intra-operative or postoperative complications occurred. Conclusions: The results of this small case series with patients presenting low degrees of residual ametropia indicate that

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WF-optimized LASIK retreatment could be considered as an option after primary WFguided LASIK. Retreatment with WF-optimized LASIK is safe and the results are predictable. Key Words: Laser in situ keratomileusis (LASIK); retreatment; residual refractive error; wavefront-optimized; wavefront-guided.

INTRODUCTION

Conventional excimer corneal ablation profiles proved to be effective and well tolerated over the years.1 However, conventional treatments had a tendency to alter the average prolate corneal shape towards a more oblate profile and induce spherical aberrations.2 This change in the corneal asphericity would affect the quality of vision; mainly night vision symptoms and contrast sensitivity testing.3-5 New strategies were employed to advance laser profiles. Wavefront (WF)-guided ablation uses technology to plan ablation patterns based on higher and lower order aberration profiles unique to the eye being treated.6 WF-optimized laser profiles aim to preserve the eye’s preexisting optical aberrations, which take some eye variables into account, but use pre-programmed ablation profiles based on population analysis.6 Laser in situ keratomileusis (LASIK) procedures have been widely reported to be safe and predictable.7-11 However, 6.35% to 17.5% of these eyes require additional surgical interventions to achieve adequate visual outcomes.12 Overcorrection rarely occurs after LASIK procedures for myopia and

Mohamed EM et al. LASIK and wavefront-optimized treatment.

myopic astigmatism using current excimer laser algorithms.13 However, under-correction or regression of originally acceptable correction occurs in some eyes.14-16 The causes of under-correction and regression are not completely elucidated. Some possible contributory factors include corneal epithelial hyperplasia, the molecular memory of corneal stromal collagen, stromal remodeling and intraocular pressure.17,18 To date, there are few papers evaluating the results of LASIK retreatments after WFguided LASIK treatments.18-20 The authors of this study have already evaluated the use of WF-guided LASIK retreatments, which proved to be effective.21 To the best of our knowledge the use of WF-optimized technology for LASIK retreatments with primary WF-guided LASIK for correction of myopia have not been described. The purpose of this retrospective analysis was to evaluate the visual outcome, and safety of WF-optimized LASIK retreatments after prior WF-guided LASIK in myopic patients (as all our primary LASIK patients underwent WF-guided LASIK).

METHODS Retrospective analyses of 19 eyes of 14 patients whom underwent WF-optimized LASIK following prior WF-guided LASIK procedures were enrolled in this study. All of the primary LASIK procedures were performed with the VisX CustomVue™ laser platform during the interval from August 2005 to April 2010. In all cases, the retreatment was achieved with the Wavelight Allegretto™ Eye-Q 400 excimer laser platform. All LASIK procedures were performed at the University of Texas Southwestern Medical Center at Dallas in accordance with Declaration of Helsinki. The retrospective analyses were conducted after the study was approved by the Institutional Review Board. The study group consisted of 14 patients (19 eyes). The mean age of the study group was 53 (37-70) year old. The inclusion criteria for the study group were: 1) previous LASIK surgery with residual myopia, hyperopia or mixed astigmatism; 2) stable refractive error for at least 3 months prior to retreatment; 3) predictable postretreatment residual stromal bed of 250 mm or more; 4) no contact lens wear for at least

two weeks prior to the baseline evaluation pre-retreatment; 5) WF-optimized procedure was used for the retreatment if WF-guided refraction and manifest were inconsistent or it was a hyperopic retreatment. The main cause for inconsistency was astigmatism axis and amount. Refractions using WFguided lower orders were assessed, however, if optimal visual acuity was not achieved, WF-optimized retreatment using manifest refraction was performed. The exclusion criteria were: 1) prior retreatment procedure(s); 2) corneal ectasia or keratoconus; 3) decentration of the pupil; 4) prior keratoplasty or intraocular surgery. The original flaps were created by one of two techniques: in 14 eyes the flaps were cut with the Femtosecond laser (IntraLase™, Abbott Laboratories, Abbott Park, IL, USA); and, in five eyes flaps were cut with the Hansatome™ microkeratome (Bausch+Lomb, Rochester, NY, USA). All retreatments were done by re-lifting the original flap. Patient who had photorefractive keratectomy (PRK) was excluded from the study. The optical zone used was 6.5mm with total ablation zone 9 mm. The mean pre-retreatment corneal thickness was 502 µm (410 to 590 µm). Complete ophthalmologic examinations were performed on all subjects prior to retreatment including manifest and cycloplegic refractions, UCVA and BSCVA, elevation computerized video keratography, slit lamp biomicroscopy, pneumotonometry, corneal pachymetry, and indirect ophthalmoscopy. Pre-operative data required for the retreatment were collected using the Pentacam® (Oculus Inc., Lynnwood, WA, USA) and WaveLight® Allegro Analyzer (Alcon Inc., Hünenberg, Switzerland). The ophthalmologic examinations were repeated at 1, 3, and 6 months post-retreatments. Preretreatment total root mean square (RMS) from third to sixth order- Zernike polynomials was calculated. Post-retreatment RMS was not determined. The original LASIK procedures were performed by two ophthalmic surgeons (W.B. or J.M.). They utilized the same protocol and technique. Following proparacaine topical anesthesia and cleansing with povidone iodine, the cornea was marked with an eccentric 3 mm optical zone marker with methylene blue to facilitate the repositioning of the flap. Then,

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Table 1. Pre-operative, pre-retreatment and post-retreatment values of refractive error Pre-operative

Pre-retreatment

PRM 1

PRM 3

PRM 6

Spherea

-5.0±2

-1.0±1.2

-0.2±0.4

-0.1±0.2

-0.3±0.2

Range

-9 to -1.5

-3 to 1

-1.25 to 0.5

-0.75 to 0.25

-0.5 to 0

Astigmatisma

0.6±0.4

1.0±0.5

0.08±0.2

0.12±0.2

Range

0 to 1.75

0 to 2

0 to 0.75

PRM= post-retreatment month. aUnits = diopter. aValues expressed as mean ± standard deviation.

the flap was lifted by dissection with a Sinskey hook, lifted and retracted with a forceps. This created a sharp delineation along the epithelial edge. Ablation was performed and the flap was repositioned to ensure that no epithelium was introduced in the interface. Post-retreatment the eye was treated with a topical antibiotic and corticosteroid four times a day for one week. The antibiotic was discontinued and the corticosteroid was tapered and stopped a onemonth post-retreatment. Statistical analyses were performed to compare various parameters prior to and 1, 3, and 6 months post-retreatment. A p value of . was considered statisticall significant. The Snellen visual acuity results were converted to logarithms of the minimum angles of resolution (LogMAR) and then statistically analyzed.

RESULTS

Figure 1. Change in manifest refraction spherical equivalent (MRSE) over time. (PRM = post-retreatment month).

Figure 2. Distribution of best spectacle corrected visual acuity (BSCVA) at 6 months after wavefront-optimized LASIK.

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The refractive error data comparing original pre-operative, pre-retreatment, and the three post-retreatment evaluations are summarized in Table 1. The mean sphere before the primary LASIK procedures was .1 D - to -1. D and the mean c linder was . .4 D to 1. D . rior to the retreatment LASIK, the mean sphere was -1. 1. D - . to 1. D and the mean c linder was 1. . D to . D . At 6-months post-retreatment the mean sphere was - . . D - . to D p-value . and the mean c linder was .1 . D to . D p-value . . he RSE efore the initial AS procedure was -4. D - . to -1. D and at -months post-retreatment was - . . D - .4 to D p-value . . At -month post-retreatment all e es were within . D of emmetropia (Figure 1). The visual acuity results are tabulated in a le . The mean UCVA LogMAR improved from a pre-retreatment value of . .1 to a post-retreatment value of . 1 . at the -month visit p . 1 . he S A was . . and reached - . . at the -month post-retreatment visit p . . o patient lost one or more lines of vision and gained one line of vision igure . A comparison etween pre-retreatment S A and post-retreatment UCVA at the 6-month visit demonstrates that all patients achieved or etter A following retreatment (Figure 3). There were no complications associated with the retreatment procedure

Mohamed EM et al. LASIK and wavefront-optimized treatment.

PRM 1

PRM 3

PRM 6

UCVA

0.27±0.18

0.03±0.09

-0.01±0.05

BSCVA

0.0±0.05

-0.02±0.04

-0.01±0.04

-0.03±0.05

MRSEa

-0.5±1.2

-0.12±0.3

-0.1±0.2

-0.2±0.2

PRM= post-retreatment months; UCVA= uncorrected visual acuity; BSCVA=best spectacle corrected visual acuity, MRSE= manifest refraction spherical equivalent; UCVA & BSCVA = logMAR scale. aUnits = diopter.

89. 4%

100

100%100%

84. 1% 80 60 40 20

10. 5%

5. 2%

20/ 15

20/ 20 V isual acuity

20/ 25

Pre- RT x . B SCV A Post- RT x . U CV A at 6 months

Figure 3. Pre-retreatment best spectacle corrected visual acuity (BSCVA) versus post-retreatment uncorrected visual acuity (UCVA) at 6 months.

1. 0 0. 8 0. 6 0. 4 0. 2 0. 0

tal To

de r Se co nd co ar ma y 6 th or de r A s Sec tig on ma da tis ry m

5 th or

de r Sp he ric al

4 th or

- 0. 2 de r

In our retrospective analysis, WFoptimized LASIK was evaluated in cases of retreatment for under or overcorrection. The results demonstrate that within the parameters of this pre-retreatment group, WF-optimized LASIK was highly efficacious and safe. WF-optimized LASIK profile is a population–based aspheric correction of myopia and myopic astigmatism, as well as hyperopia and mixed astigmatism, which preserves the natural aspheric shape of the cornea and neutralizes the laser-induced aberration that typically accompanies conventional laser vision correction. Multiple studies have compared WFguided with WF-optimized platforms for primary LASIK surgery.13,22-27 Moshirfar et al28 and Awwad et al29 compared outcomes of WFguided LASIK with the Custom-Cornea platform (Alcon) and the WF-guided platform Visx S4 Star (Abbott Medical Optics); Moshirfar et al. reported a slight advantage for the Visx S4 WF-guided platform and Awwad et al. for the other platform. Padmanabhan et al24 compared WF-guided and WF-optimized treatments and found no statistically significant differences in visual acuity or refractive outcomes; however, they did find a statistically significant difference in the induction of HOAs, with WF-guided technology outperforming WFoptimized technology. Stonecipher and Kezarian30 found similar equivalent acuity and refractive outcomes between WF-guided and WF-optimized treatments and found that only small subpopulations of eyes with high preoperative aberrations benefited from WF-guided treatments. Brint22 found that WF-guided technology induced fewer HOAs, especially coma, than WF-optimized treatments. In contrast, Tran and Shah26 found no significant differences between the 2 platforms. Several studies approached the use of WF-guided LASIK retreatment but to the best of our knowledge we are the first to

Pre-retreatment

3 rd or

DISCUSSION

Table 2. Values of UCVA, BSCVA and MRSE over follow-up time

Eyes ( %)

or over the 6-month span following the procedure. Specifically, no flap complications including interface scarring, epithelial ingrowth or haze were observed. Figure 4 shows the pre-retreatment HOA. The preretreatment total HOA was 0.48±0.21 (0.24 to 1.01µm) and did not show correlation with the visual outcomes postoperatively.

H igh order aberrations

Figure 4. Pre-retreatment total high order aberrations (HOA).

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report the use of WF-optimized LASIK in cases of retreatment. Brahma et al12 used WF-guided LASIK retreatment, which yielded less predictability than our WF-optimized technique at 6 months. A higher percentage of eyes receiving WF-optimized were within ±0.50 D (100% in our study compared to 58%). Montague and Manche31 conducted a study on WF-guided LASIK retreatment (Visx S4) on 120 eyes. Their study reported 83% of eyes with SE within ±0.5D at a 3 months follow-up, compared with 100% of eyes with WF-optimized LASIK at 3 months in our study. Mohamed et al21 investigated retreatment on 77 eyes and reported that WF-guided LASIK retreatment using the Visx S4 with iris registration yielded stable and predictable results in eyes requiring one retreatment session with less predictability. Alió et al32 compared WF-guided LASIK with standard LASIK in cases of residual refractive errors in 20 eyes in each group and found that WF-guided LASIK seems to be better than standard LASIK for retreatments with no increase in high order aberrations in the WFguided group. Our experience with WF-optimized LASIK for retreatments documents that this procedure achieves emmetropia in all patients. The results appear stable in terms of refractive error, BSCVA and UCVA. In our study a slight residual myopia was targeted based on the mean age of our group (53 years old), which is ideal considering their presbyopic state. The safety of the procedure and the lack of postretreatment complications further validate the use of WF-optimized LASIK for this purpose. We understand that our study has limitations, such as a small sample size and lack of post-retreatment HOA given that it was a retrospective study. However, our data demonstrates that WF-optimized LASIK seems to be a safe and predictable option to perform retreatments to achieve better visual results. Further studies are needed to compare standard LASIK retreatments to WF-optimized and WF-guided LASIK retreatments. Although the LASIK platforms and paradigms continue to improve and the proportion of patients needing retreatments decrease, it is unlikely that the need for retreatments will ever be eliminated. Thus, it is vital that methodologies for successful retreatments be determined.

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REFERENCES 1 Farah, SG, Azar DT, Gurdal C, Wong J. Laser in situ keratomileusis: literature review of a developing technique. J Cataract Refract Surg 1998;24:989-1006. 2 Munnerlyn CR, Koons SJ, Marshall J. Photorefractive keratectomy: a technique for laser refractive surgery. J Cataract Refract Surg 1988;14:46-52. 3 Oshika T, Klyce SD, Applegate RA, Howland HC, El Danasoury MA. Comparison of corneal wavefront aberrations after photorefractive keratectomy and laser in situ keratomileusis. Am J Ophthalmol 1999;127:1-7. 4 Mutyala S, McDonald MB, Scheinblum KA, Ostrick MD, Brint SF, Thompson H. Contrast sensitivity evaluation after laser in situ keratomileusis. Ophthalmol 2000;107:1864-7. 5 Nakamura K, Bissen-Miyajima H, Toda I, Hori Y, Tsubota K. Effect of laser in situ keratomileusis correction on contrast visual acuity. J Cataract Refract Surg 2001;27:357-61. 6 Kohnen T. Classification of excimer laser profiles. J Cataract Refract Surg 2006;32:543-4. 7 Kashani S, Rajan M, Gartry D. Wavefront-guided retreatment after primary wavefront-guided laser in situ keratomileusis in myopes and hyperopes: long-term follow-up. Am J Ophthalmol 2009;147:417-23. 8 Perez-Santonja JJ, Ayala MJ, Sakla, HF, Ruiz-Moreno JM, Alio JL. Retreatment after laser in situ keratomileusis. Ophthalmol 1999;106:21-8. 9 Lyle WA, Jin GJ. Retreatment after initial laser in situ keratomileusis. J Cataract Refract Surg 2000;26:650-59. 10 Rojas MC, Haw WW, Manche EE. Laser in situ keratomileusis enhancement for consecutive hyperopia after myopic overcorrection. J Cataract Refract Surg 2002;28:37-43. 11 Zadok D, Maskaleris G, Garcia V, Shah S, Montes M, Chayet A. Outcomes of retreatment after laser in situ keratomileusis. Ophthalmol 1999;106:2391-4. 12 Brahma A, McGhee CN, Craig JP, Brown AD, Weed KH, McGhee J, Brown R. Safety and predictability of laser in situ keratomileusis enhancement by flap reelevation in high myopia. J Cataract Refract Surg 2001;27:593-603. 13 Perez-Straziota CE, Randleman JB, Stulting RD. Visual acuity and higherorder aberrations with wavefront-guided and wavefront-optimized laser in situ keratomileusis. J Cataract Refract Surg 2010;36:437-41. 14 Bragheeth MA, Fares U, Dua HS. Retreatment after laser in situ keratomileusis for correction of myopia and myopic astigmatism. Br J Ophthalmol 2008;92: 1506-10. 15 O’Doherty M, O’Keeffe M, Kelleher C. Five year follow up of laser in situ keratomileusis for all levels of myopia. Br J Ophthalmol 2006;90:20-3. 16 Perez-Santonja JJ, Bellot J, Claramonte P, Ismail M M, Alio JL. Laser in situ keratomileusis to correct high myopia. J Cataract Refract Surg 1997;23:372-85. 17 Lohmann CP, Guell JL. Regression after LASIK for the treatment of myopia: the role of the corneal epithelium. Semin

Ophthalmol 1998;13:79-82. 18 Bas AM, Onnis R. Excimer laser in situ keratomileusis for myopia. J Refract Surg 1995;11:S229-33. 19 Jin GJ, Merkley KH. Retreatment after wavefront-guided and standard myopic LASIK. Ophthalmol 2006;113:1623-8. 20 Jin GJ, Merkley KH. Conventional and wavefront-guided myopic LASIK retreatment. Am J Ophthalmol 2006;141:6608. 21 Mohamed EM, Muftuoglu O, Bowman W, Cavanagh HD, Mootha VV, Radwan GA, McCulley JP. Wavefront-guided ablation retreatment using Iris registration. Eye Contact Lens 2010;36:54-9. 22 Brint SF. Higher order aberrations after LASIK for myopia with alcon and wavelight lasers: a prospective randomized trial. J Refract Surg 2005;21:S799-803. 23 Miraftab M, Seyedian MA, Hashemi H. Wavefront-guided vs wavefront-optimized LASIK: a randomized clinical trial comparing contralateral eyes. J Refract Surg 2011;27:245-50. 24 Padmanabhan P, Mrochen M, Basuthkar S, Viswanathan D, Joseph R. Wavefront-guided versus wavefrontoptimized laser in situ keratomileusis: contralateral comparative study. J Cataract Refract Surg 2008:34:389-97. 25 Stonecipher KG, Kezirian GM. Wavefront-optimized versus wavefrontguided LASIK for myopic astigmatism with the ALLEGRETTO WAVE: three-month results of a prospective FDA trial. J Refract Surg 2008;24:S424-30. 26 Tran DB, Shah V. Higher order aberrations comparison in fellow eyes following intraLase LASIK with wavelight allegretto and customcornea LADArvision4000 systems. J Refract Surg 2006;22:S961-4. 27 Moshirfar M, Churgin DS, Betts BS, Hsu M, Sikder S, Neuffer M, Church D, Mifflin MD. Prospective, randomized, fellow eye comparison of WaveLight Allegretto Wave Eye-Q versus VISX CustomVueTM STAR S4 IRTM in photorefractive keratectomy: analysis of visual outcomes and higher-order aberrations. Clin Ophthalmol 2011;5:1185-93. 28 Moshirfar M, Espandar L, Meyer JJ, Tanner JR, Holz HA. Prospective randomized trial of wavefront-guided laser in situ keratomileusis with the CustomCornea and CustomVue laser systems. J Cataract Refract Surg 2007;33: 1727-33. 29 Awwad ST, Bowman RW, Cavanagh HD, McCulley JP. Wavefront-guided LASIK for myopia using the LADAR CustomCornea and the VISX CustomVue. J Refract Surg 2007;23:26-38. 30 Kezirian GM, Moore CR, Stonecipher KG, SurgiVision Consultants Inc WaveLight Investigator Group. Four-year postoperative results of the US ALLEGRETTO WAVE clinical trial for the treatment of hyperopia. J Refract Surg 2008;24:S431-8. 31 Montague AA, Manche EE. CustomVue laser in situ keratomileusis treatment after previous keratorefractive surgery. J Cataract Refract Surg 2006;32:795-798. 32 Alio JL, Montes-Mico R. Wavefrontguided versus standard LASIK enhancement for residual refractive errors. Ophthalmol 2006;113:191-7.

Ortega Díaz L et al. Modificaciones de la curva posterior de la córnea.

Modificaciones de la curvatura posterior de la córnea después de LASEK miópico.

Changes in the posterior corneal curvature after myopic LASEK Lorelei Ortega Díaz, MD1, Eglys Blanco Mesa, MD2, Juan Raúl Hernández Silva, MD, PhD3, Marcelino Rio Torres, MD, PhD4, Meisy Ramos López, MD, PhD3, Yanaisa Riverón Ruiz, MD2. 1. Especialista de 2do grado en Oftalmología y MGI. Profesor Instructor. 2. Especialista de 1er grado en Oftalmología y MGI. 3. Dr. en Ciencias Médicas. Especialista en 2do. grado en Oftalmología. Profesor Titular. Investigador Auxiliar. 4. Dr. en Ciencias Médicas. Especialista en 2do. grado en Oftalmología. Profesor Titular. Investigador Titular.

Autor correspondiente: Dra. Lorelei Ortega Díaz Instituto Cubano de Oftalmología “Ramón Pando Ferrer”, Centro de Post Grado Ave. 31 y 76. Marianao. CP: 10400. La Habana. Cuba E-mail: loreleiod@infomed.sld.cu Fecha de submission: 21/09/2012 Fecha de aprobación: 22/10/2013

Funding: None Proprietary/financial interest: None

RESUMEN

Objetivo: Determinar las modificaciones de la curvatura posterior de la córnea en pacientes a los que se realizó queratomileusis subepitelial asistida por laser miópico en el período de abril a noviembre 2011. Método: Fueron estudiados 15 pacientes (29 ojos), a los que se realizó queratomileusis subepitelial asistida por laser miópico. Se analizaron variables como edad, sexo, equivalente esférico, paquimetría preoperatoria, cantidad de ablación, estroma residual y diferencia de elevación posterior corneal, esta última obtenida del mapa de diferencia del tomógrafo Pentacam HR con medición preoperatoria, al mes y tres meses de la cirugía. Se realizó análisis de regresión múltiple. Resultados: El equivalente esférico, la paquimetría, cantidad de ablación y el estroma residual se encontraron dentro de los parámetros de seguridad establecidos. La diferencia promedio de la elevación posterior corneal fue de 3,3 µm al mes, disminuyendo a 2,4 µm a los tres meses. Se observó relación con la cantidad de ablación y el estroma residual. Conclusiones: La queratomileusis subepitelial asistida por laser determinó modificaciones en la superficie corneal posterior, las cuales fueron más evidentes en el primer mes del posoperatorio. El estroma residual fue el factor más relacionado con estas modificaciones. Palabras clave: LASEK, elevación corneal posterior, paquimetría, estroma residual, total de ablación.

ABSTRACT

Purpose: To determine the posterior corneal surface forward shift in myopic patients after laser-assisted subepithelial keratectomy from April to November 2011. Material and methods: Fifteen patients (29 eyes) were submitted to laserassisted subepithelial keratectomy surgery. Age, sex, spherical equivalent, preoperative corneal thickness, total ablation, residual bed thickness and variations in the posterior corneal surface elevation were evaluated. Posterior corneal surface elevation maps were assessed by Pentacam HR tomography and compared with the data of maps obtained prior to the surgery, one and 3 months after the procedure. Results: The spherical equivalent, pachymetry, microns of ablation and residual bed thickness were within the established parameters. The posterior corneal surface displayed a forward shift of 3,3 µm after a month and 2,4 µm three months later. A relation was found between total ablation, and residual bed thickness. Stepwise lineal multiple regression was used. Conclusions: The use of the laserassisted subepithelial keratectomy determined a forward shift of the posterior corneal surface in the early postoperative that gradually decreased. Residual bed thickness was a relevant factor associated to this change. Key words: LASEK, posterior corneal surface, pachymetry, residual bed thickness, total ablation. PAN-AMERICA 111

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INTRODUCCIÓN

La córnea aporta 43,0 dioptrías (D) del poder refractivo ocular. Sobre ella se aplican diversas técnicas quirúrgicas asistidas por excimer laser como la queratomileusis con laser in situ (LASIK), queratomileusis subepitelial asistida por laser (LASEK), la queratectomía fotorrefractiva (PRK) y la epipolis queratomileusis in situ asistida por laser (EpiLASIK). Todas técnicas contemporáneas, en las que a través del uso de un haz de luz ultravioleta, es posible tallar y cambiar su curvatura, consiguiendo el enfoque correcto de las imágenes y finalmente lograr corregir la miopía, hipermetropía y/o astigmatismo con un porcentaje de éxito alto.1, 2 Cada vez es mayor el número de pacientes que optan por esta modalidad quirúrgica, la cual no está exenta de complicaciones, por lo que se debe hacer una correcta evaluación y selección preoperatoria. Los mencionados procedimientos refractivos asistidos por excimer laser tienen como fin modificar las propiedades refractivas del ojo induciendo modificaciones en la cara anterior de la córnea. Aunque este concepto sigue siendo válido, el reconocimiento de que algunas alteraciones corneales como el queratocono y las ectasias posquirúrgicas pueden tener sus primeras manifestaciones en la cara posterior de la cornea, ha despertado el interés en el estudio de ésta y de su comportamiento tras la cirugía. Entre las complicaciones más temidas se encuentra la ectasia posquirúrgica. Varios factores han sido reportados como predisponentes, dentro de ellos se mencionan los cambios en la curvatura corneal posterior.3,4 Se conoce que la elevación posterior corneal es un signo temprano de queratocono, razón por lo que es necesario evaluarla en todos los pacientes candidatos a cirugía refractiva corneal asistida por excimer laser con el objetivo de detectarla precozmente e impedir así, que se exacerbe la queratectasia.5 En la actualidad para la evaluación pre y posoperatoria existen herramientas muy valiosas, tal es el caso de la tomografía corneal que aporta imágenes tridimensionales, que les permiten a los cirujanos examinar el grosor de la córnea junto con la superficie anterior y posterior de ésta.6 Los mapas de elevación permiten evaluar la curvatura corneal posterior posibilitando la

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detección precoz de formas subclínicas de queratocono, así como cambios ectásicos secundarios a cirugía refractiva laser; sin embargo, aún no están suficientemente bien definidos los parámetros de riesgo que permitan predecir estas alteraciones, lo que sería importante para su prevención.6 Por esto se decidió la realización de esta investigación con el propósito de determinar las modificaciones de la curvatura posterior de la córnea en pacientes a los que se les realizó LASEK miópico.

MÉTODOS

Se realizó un estudio descriptivo, observacional, longitudinal y prospectivo, en el Servicio de Cirugía Implanto Refractiva del Instituto Cubano de Oftalmología “Ramón Pando Ferrer”, en el período comprendido de abril a noviembre del 2011. Fueron incluidos en el estudio 15 pacientes (29 ojos) los cuales reunían los criterios para la realización de LASEK y que estuvieron de acuerdo en participar en la investigación. Fueron excluidos pacientes que no asistieron a alguna de las consultas programadas en el estudio, pacientes con inmunosupresión, epilepsia, enfermedades del colágeno y otras condiciones oftalmológicas como ojo único, enfermedades corneales inflamatorias, infecciosas y degenerativas, glaucoma, uveítis, cirugías corneales anteriores múltiples, estrabismo y ambliopía. En el preoperatorio, se realizaron los siguientes estudios: medición de la mejor agudeza visual sin corrección (MAVSC) y mejor corregida (MAVC), queratometría, biometría, paquimetría, exploración del segmento anterior mediante biomicroscopía en lámpara de hendidura, oftalmoscopía indirecta y tomografía corneal con Pentacam HR. Se realizaron consultas en el posoperatorio inmediato y fueron repetidos los estudios antes citados, al mes y a los tres meses posteriores a la cirugía. Se estudiaron las siguientes variables: edad, sexo, equivalente esférico, paquimetría preoperatoria, cantidad de ablación, estroma residual y la diferencia de la elevación corneal posterior; esta última se obtuvo del mapa de diferencia presente en el tomógrafo Pentacam HR, generado desde el mapa de elevación preoperatorio y los subsecuentes posoperatorios. El procedimiento LASEK se realizó

Ortega Díaz L et al. Modificaciones de la curva posterior de la córnea.

Tabla 1: Distribución de pacientes intervenidos por queratomileusis epitelial asistida por laser (LASEK) miópico, según datos demográficos y quirúrgicos. Datos demográficos y quirúrgicos

Media

Desviación típica.

Mínimo

Máximo

Relación Hombre/Mujer

6/9

Edad (años)

32,3

8,87

Equivalente Esférico (D)

-4,0

1,67

-7,88

-1

Paquimetría pre (µm)

546,2

26,25

493

584

Total de ablación (µm)

55,3

21,1

104

Estroma residual (µm)

486,42

30,22

435,18

548,21

creando un colgajo epitelial removido con la aplicación previa de alcohol absoluto al 20% durante 20 segundos y se aplicó el laser [Excimer laser modelo ESIRIS (SCHWIND eye-tech-solutions GmbH & Co. KG, Kleinostheim, Alemania), con una longitud de onda de 193 nm, energía del pulso de 12 mj (Clase 4) y diámetro del spot de 0.8 mm]. Si la cantidad de ablación superaba las 60 micras, se utilizó Mitomicina C al 0,02 % (0,2 mg/ml) durante 15 a 20 segundos sobre el lecho estromal corneal con una esponja de merocel. Al concluir el procedimiento, se colocó durante siete días un lente de contacto terapéutico e indicamos colirios de antibiótico, antiinflamatorios esteroideos y lágrimas artificiales en una frecuencia de al menos cuatro veces al día, durante un mes. Se calcularon las medias y desviaciones estándar de las variables cuantitativas estudiadas. También se utilizó el modelo de regresión múltiple para estudiar la posible relación entre la diferencia en la elevación posterior a los tres meses y las siguientes variables: edad, cantidad de ablación, paquimetría y estroma residual. En todas las pruebas estadísticas se consideraron significativos los valores de p< 0,05. La investigación estuvo justificada desde el punto de vista ético pues en todos los casos se contó con el consentimiento de los pacientes, acorde a la Declaración de Helsinki.

µm, así como la cantidad de ablación media fue de 55,3 µm y el estroma residual medio de 486,42 µm. (Tabla 1) Otro aspecto evaluado fue el promedio de la diferencia de elevación de la superficie corneal posterior al mes cuyo valor fue de 3,3±2,34 µm y a los tres meses de 2,4±2 µm. La diferencia de elevación de la curvatura corneal posterior a los tres meses disminuyó, con respecto a la del mes del posoperatorio (p=0,049). (Figura 1) Con relación al análisis del modelo de regresión múltiple para determinar la relación entre la diferencia de elevación de la curvatura corneal posterior y las variables que se muestran, encontramos una asociación estadísticamente significativa con el total de ablación (p=0,027) y el estroma residual (p=0,041). No existió asociación con la edad (p=0,535) o la paquimetría (p=0,836) Figura 1: Pacientes intervenidos por queratomileusis subepitelial asistida por laser (LASEK) miópico, según diferencia de la elevación posterior central (EPC).

RESULTADOS

Se evaluó un total de 15 pacientes, donde más de la mitad fueron del sexo femenino. La edad promedio fue de 32,3± 8,8 años. La media del equivalente esférico preoperatorio fue de – 4,00 D, paquimetría media 546,2

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CLINICAL SCIENCES / Vis. Pan-Am. 2013;12(4):111-115 Tabla 2: Análisis de regresión lineal múltiple para determinar las variables relacionadas con la diferencia de la elevación posterior a los tres meses. R = 0.346, R² = 0.119, R² ajustada = 0.086. Variable

Beta

Edad (años)

0,145

0,630

0,535

Total ablación (µm)

-0,349

-1,270

0,027*

Estroma residual (µm)

-0,213

-0,838

0,041*

Paquimetría pre (µm)

-0,049

-0,209

0,836

*p≤0,05 estadísticamente significativas Tabla 3: Análisis de regresión lineal múltiple recalculado con las variables relacionadas notablemente con la diferencia de elevación posterior a los tres meses. Variable

Coeficiente

Correlación parcial

Total ablación (µm)

2,117

0,121

0,607

0,029

Estroma residual(µm)

2,008

0,008

0,042

0,046

Constante

226,319

*p≤0,05 estadísticamente significativas

preoperatoria y la diferencia de elevación de la superficie corneal posterior. (Tabla 2) En la Tabla 3 se observa un análisis recalculado, teniendo en consideración las variables que más influyeron en la diferencia de elevación de la superficie corneal posterior en este estudio: total de ablación y estroma residual. Encontrándose asociación significativa para ambas variables p=0,029 y p=0,046 respectivamente.

DISCUSIÓN

Existen evidencias que indican que los resultados refractivos y visuales con el LASEK son comparables con los obtenidos con LASIK y PRK.7 Las cirugías de superficie tienen la ventaja sobre el LASIK de conservar más tejido, pero en ambos casos se altera la membrana de Bowman y el tercio estromal anterior, relevantes en la estabilidad corneal.1,8 Miyata et al9 encontraron una edad media de 33,2±9,3 años, elemento que es vital en la estabilidad refractiva de los pacientes. Con un ligero predominio del sexo femenino, esta serie mostró un comportamiento similar a este estudio. Numerosos autores1,3,9-11 coinciden al referir que existe un incremento subclínico y precoz de la elevación corneal posterior luego de cirugía refractiva laser por técnica LASIK; sin embargo, no hay muchos que valoren estos cambios en el LASEK.

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Lee et al12 obtuvieran una diferencia promedio de la elevación corneal posterior de 23,4+/-10,5 µm, 23,6+/-10,55 µm en el LASEK a los dos y cuatro meses respectivamente. Los resultados de Ciolino et al13 realizado en 18 ojos con la técnica PRK, una cantidad de ablación total de 53,2 µm y estroma residual de 464 µm, muestran una diferencia posoperatoria de la elevación corneal posterior de 0,88+/- 4,64 µm al mes, menor que en este trabajo. Miyata et al9 señalaron que la mayor elevación corneal posterior después de PRK se presentaba dentro de la primera semana de cirugía. La progresión era más pronunciada entre el primer y el sexto mes, pero con estabilidad hacia el sexto mes, también señalan que la elevación corneal posterior fue mayor en aquellos ojos con córneas residuales delgadas. Kim et al2, en un estudio comparativo entre LASEK y LASIK, demostraron cambios tempranos de la elevación corneal posterior tras LASEK, significativamente más duraderos que en los pacientes a los que se les realizó LASIK, parámetros que gradualmente se redujeron, pero no retornaron a cifras preoperatorias. Hernández-Quintela et al14 y Lee et al12 refieren que no se producen diferencias significativas en la elevación corneal posterior en el tiempo entre los procedimientos de superficie e intraestromales. Como se puede apreciar, los resultados son disímiles. Es difícil en las series publicadas encontrar un consenso en cuanto al momento y por que tiempo se produce el incremento de la superficie corneal posterior, así como su posterior disminución. Sin embargo, en este estudio los resultados evidencian la presencia de modificaciones en la cara posterior de la córnea, coincidiendo con lo encontrado en México1 y en Korea2, los cuales hallaron en su serie de caos un aumento en la elevación corneal posterior durante las primeras semanas después de la cirugía, con notable disminución hacia el tercer mes y menos pronunciada hacia el cuarto mes, con significación estadística de la tercera semana al cuarto mes. Estas diferencias en el comportamiento de la elevación corneal posterior con respecto al estudio realizado por Miyata et al9 pueden deberse a que el procedimiento se limitaba a pacientes con córneas más delgadas, dejando un estroma residual menor. Kim et al2 y Miyata et al9 coinciden respecto al período en que se presenta una mayor

Ortega Díaz L et al. Modificaciones de la curva posterior de la córnea.

elevación corneal posterior, pero difieren en cuanto a la progresión que presenta. Mientras unos señalan aumento progresivo hasta los seis meses posoperatorios con estancamiento posterior, otros refieren regresión de la elevación corneal posterior durante los dos primeros meses posoperatorios con estabilidad a los dos años de seguimiento. En este estudio resulta fácil percatarse de una reducción en los valores promedios de diferencia de elevación corneal posterior central entre el primer y tercer mes del posoperatorio, pero no fue posible definir un momento en la estabilidad de la superficie corneal posterior por el breve tiempo que abarcó, pues solo pudimos estudiar los pacientes hasta los tres meses después de la cirugía. Algunos autores consideran que con el tiempo existe una tendencia hacia la estabilidad, la cual puede ser explicada por la respuesta a la curación de las heridas.1,2,6,15 Después de la cirugía, los queratocitos adyacentes a la herida penetran por el estroma; al final de la primera semana, la fuerza tensil de la herida se incrementa por el depósito de colágeno, lo que continúa hacia el tercer y sexto mes; el tejido cicatrizal se vuelve más compacto; sin embargo, la organización de las fibras de colágeno nunca se restaura por completo, motivo por el que la superficie corneal posterior no puede volver a los niveles preoperatorios. Existen criterios diversos en relación con el momento en el cual la córnea posterior adquiere estabilidad. Ciolino y Belin13 en Estados Unidos plantean que a los 12 meses, mientras que Miyata et al9 y Zhang y Wang17 refieren que a los seis meses del procedimiento quirúrgico, sin diferencias significativas entre una u otra técnica. Similar a otros estudios1,12, el grosor corneal residual estuvo significativamente relacionado con la elevación de la superficie corneal posterior. Esto fue especialmente notable en los casos de miopía elevada, (que requieren una mayor ablación), en los cuales se consume un número importante de micras, son los que se encuentran más propensos a tener un estroma residual menor y, por tanto, los que tienen más posibilidades de presentar un aumento en la curvatura corneal posterior. Baek et al11 reportaran como factor más relevante la cantidad de ablación. Muchos estudios demostraron en sus investigaciones un mayor incremento en la curvatura corneal posterior en ojos con estroma residual delgado (correlación inversa), provocado quizás por afectación de

la estabilidad en la biomecánica corneal.1,9,10,14 Miyata et al9 añaden que, en caso de miopías elevadas que requiere ablacionar gran cantidad de micras, puede observarse una elevación mantenida no ectásica de la superficie corneal anterior y superficie corneal posterior. Como plantean Miyata et al9, el estroma residual es un factor crucial generalmente implicado en la etiología de la ectasia iatrogénica posterior a cirugía refractiva laser. En una córnea determinada existe un espesor mínimo que no puede resistir la deformación causada por la presión intraocular de ese ojo: este espesor mínimo variará dependiendo de la resistencia de las fibras de colágeno de cada córnea. Es por esto que se pueden encontrar córneas que desarrollen ectasias a pesar de ser respetadas las medidas de seguridad; lo contrario también puede ocurrir: ojos en los que se haya sobrepasado los límites de seguridad universalmente aceptados, pueden permanecer inalterados en su estructura corneal. Concluimos que el LASEK miópico determinó modificaciones en la superficie corneal posterior que se evidencian por un aumento en la elevación corneal posterior en las primeras semanas con disminución progresiva hacia el tercer mes. El factor que más se relacionó con estos cambios fue el estroma residual.

REFERENCIAS BIBLIOGRÁFICAS 1. Alvarado-Castillo B, Vázquez-Maya L. Cambios en la elevación posterior corneal en pacientes sometidos a LASEK. Rev Med Hosp Gen Mex. 2007; 70 (1). 2. Kim H, Kim HJ, Joo CK. Comparison of forward shift of posterior corneal surface after operation between LASIK and LASEK. Ophthalmologica. 2006;220(1):37-42. 3. Vicente D, Clinch TE, Kang PC. Changes in posterior corneal elevation after laser in situ keratomileusis enhancement. J Cataract Refract Surg. 2008;34(5):785-8. 4. Binder PS, Lindstrom RL, Stulting RD, Donnenfeld E, Wu H, McDonnell P, et al. Keratoconus and corneal ectasia after LASIK. J Cataract Refract Surg. 2005;31(11):2035-8. 5. Feinerman G, Peters NT, Nguyen K, Scott Sh. Siatema diagnóstico del Obrbscan IIz y análisis del frente de Onda. En: Agarwal S, Agarwal A, Agarwal A, editores. Paso a paso Topografía Corneal. 2da ed. New Delhi: Jaypee Brothers Medical Publishers; 2007. p.87-119.

10. Baek TM, Lee KH, Kagaya F, Tomidokoro A, Amano S, Oshika T. Factors affecting the forward shift of posterior corneal surface after Laser in Situ Keratomileusis. Ophthalmology. 2001;108(2):317-20. 11. Randleman JB, Woodward M, Lynn MJ, Stulting RD. Risk assessment for ectasia after corneal refractive surgery. Ophthalmology. 2008;115(1):37-50. 12. Lee M, Lee S, Lee H, Wee W, Lee J, Kim M. The changes of posterior corneal surface and high-order aberrations after refractive surgery in moderate myopia. Korean J Ophthalmol. 2007;21(3):131-6. 13. Ciolino JB, Belin MW. Changes in the posterior cornea after laser in situ keratomileusis and photorefractive keratectomy. J Cataract Refract Surg. 2006;32(9):1426-31. 14. Hernández-Quintela E, Samapunphong S, Khan BF, Gonzalez B, Lu PC. Posterior corneal surface changes after refractive surgery. Ophthalmology. 2001;108(8):1415-22.

6. Belin MW, Khachkian SS. Introducción y Visión General. En : Belin MW, Khachkian SS, Ambrosio R Jr. Tomografia corneal basada en la elevación. 2da ed. Panamá: Jaypee Brothers Medical Publishers; 2012. pp. 1-14.

15. Miyai T, Miyata K, Nejima R, Honbo M, Minami K, Amano S. Comparison of laser in situ keratomileusis and photorefractive kera tectomy results: Long-term follow-up. J Cataract Refract Surg. 2008;34(9):1527-31.

7. O’Brart D, Al-Attar M, Hussein B, Angunawela R, Marshall J. Laser subepithelial keratomileusis for the correction of high myopia with the Schwind ESIRIS Scanning Spot Laser. J Refract Surg. 2006;22(3):253-62.

16. Zhou H, Zhou X, Chu R, Dai J, Qu X. The effect of the flap thickness on forward shift of posterior corneal surface in excímer laser surgery correcting high myopia. Zhonghua Yan Ke Za Zhi. 2008;44(7):591-5.

8. Rumelt S, Cohen I, Skandarani P, Delarea Y, Ben Shaul Y, Rehany U. Ultrastructure of the lamellar corneal wound after laser in situ keratomileusis in human eye. J Cataract Refract Surg. 2001;27(8):1323-7.

17. Zhang L, Wang Y. The shape of posterior corneal surface in normal, post- LASIK and post-Epi-LASIK eyes. Invest Ophthalmol Vis Sci. 2010;51(7):3468-75.

9. Miyata K, Kamiya K, Takahashi T, Tanabe T, Tokunaga T, Amano S, et al. Time course of change in corneal forward shift after Excimer Laser Photorefractive Keratectomy. Arch Ophthalmol. 2002;120(7):896-900.

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CASE REPORT / Vis. Pan-Am. 2013;12(4):116-119

Encouraging Result of Voriconazole Treatment for Cladosporium Corneal Keratitis Luís Antonio Gorla Marcomini1, Gleilton Carlos Mendonça da Silva2, Sidney Júlio de Faria-e-Sousa2

Correspondence address:

1 Department of Medicine of the Center of Biologic Sciences and Health of the Federal University of São Carlos – UFSCar – São Carlos (SP) Brazil 2 Department of Ophthalmology of the Faculty of Medicine of Ribeirão Preto, University of São Paulo – USP – Ribeirão Preto (SP) – Brazil.

Luis Antonio Gorla Marcomini Department of Medicine – Federal University of São Carlos Rodovia Washington Luís - Km 235 - São Carlos (SP) Brazil - CEP 13565-905 Phone: (16) 3351-8340 E-mail: lamarcomini@gmail.com

Funding: None Financial/proprietary interest: None

Date of submission: 16/01/2013 Date of Acceptance: 05/02/2013

ABSTRACT

A 45-year-old man submitted to radial keratotomy 19 years ago acquired Cladosporium sp. infection in one of the incisions of the left eye. The infection was resistant to topical amphotericin B, topical natamycin and systemic fluconazole. The keratitis was cured with voriconazole 200 mg PO, BID for 10 days. Keywords: corneal infection, fungal keratitis, infectious keratitis, radial keratotomy, refractive surgery, voriconazole.

INTRODUCTION

Radial keratotomy (RK) is an obsolete form of surgical correction of myopia. The surgery consists in deep symmetric radial corneal incisions around a small central circular area that is left intact.1 Fyodorov was the first to present good results with this procedure in human eyes. His data were first published in English literature in 1979.2 In the late 80s, RK became popular around the world. Later, it was revealed that the radial incisions did not heal completely, generating two main complications: progressive hyperopia and propensity to corneal infection.3-5 Since the surgery was popular among young adults, ophthalmologists still need to be prepared to treat late complications of the procedure. The purpose of this paper is to report a case of very late onset infection in a RK incision caused by a recalcitrant fungus, quickly cured by oral voriconazole. Voriconazole is a synthetic derivative of fluconazole with an expanded activity. It has good penetration into the corneal stroma and reaches high concentrations in the vitreous and aqueous, even when administered orally.6

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CASE REPORT

A 45-year-old male, owner of a pet food shop, came to our corneal service complaining of foreign body sensation in the left eye that started six days before. In the first three days, he used a combination of 0.35% neomycin and 0.1% dexamethasone eye drops QID, showing no improvement of the symptoms. In this interval, he noticed a corneal white spot in the affected eye. He consulted an ophthalmologist, who diagnosed corneal ulcer and started treatment with 0.5% moxifloxacin (Vigamox®, Alcon, São Paulo, Brasil) hourly around the clock. About 48 hours later, he was referred to our service because his eye was not improving. Visual acuity was 0.7 in the right eye and light perception in the left eye. Slit lamp biomicroscopy of the right cornea showed eight regular scars of RK negative to fluorescein staining. The left cornea also showed eight RK scars. The ones of the upper quadrant were epithelialized. The incisions of the inferior quadrant were partially opened and stained with fluorescein. The most vertical incision of this quadrant presented a deep 3 millimeter-diameter paracentral grayish-white infiltrate (Figure 1A). The lesion stained with fluorescein. There was no visible anterior chamber reaction. In terms of antecedents, the patient referred that he had RK in both eyes 19 years ago and Diabetes mellitus type II diagnosed two years ago Due to the presence of onychomycosis on every fingernail of the patient’s hands and feet, we suspected fungal etiology. After scraping the lesion, we started with topical 0.25% amphotericin B and 5% natamycin hourly and 1% atropine eye drop BID. The result of

Marcomini LAG et al. Voriconazole for fungal keratitis.

Figure 1: Cladosporium keratitis. A. Initial lesion; B. Perforation treated with cyanoacrylate glue; C. Immediately after the glue fell off.

the culture came on the 5th day revealing Cladosporim sp. Oral Fluconazole 150 mg BID was started as an adjunctive therapy; topical medication was maintained. Two days later, the patient presented shallow chamber and an aqueous humor leakage through the ulcer bed and one of the adjacent RK incisions. Both perforations were treated with cyanoacrylate glue and soft contact lens (Figure 1B). The next day slit lamp examination revealed restoration of the anterior chamber and decreased redness of the eye. Twenty days later, the glue fell off, and the eye was much better (Figure 1C). One week later the condition worsened again. The ulcerated area became thinner and accompanied by a massive vascularization of the lower RK incisions and hypopyon (Figure 2A). A corneal transplantation at this time would have had a bad prognosis due to intense inflammatory reaction. Recurrence of the fungal infection on the graft was another important concern. As a last resort, to avoid surgery, all previous medications were stopped and a systemic treatment with oral voriconazole (VFEND, Pfizer) 200 mg BID was started. On the third day, one could see a marked reduction of the stromal infiltration and vascularization accompanied by total clearance of the hypopyon. On the tenth day, the ulcer was completely healed and oral voriconazole was interrupted. Due to the high inflammatory activity triggered by fungal infection, the patient developed nearly 360º posterior synechia, resulting in glaucoma of difficult control leading to trabeculectomy in the left eye. At

that time, we noticed that the patient was completely free from the onychomycosis. Nine months after the first examination, the best-corrected visual acuity was 0.7 in the right eye and 0.25 in the left eye. Slit lamp biomicroscopy showed no changes in the right eye. The left eye showed a central corneal scarring with fine vessels, anterior synechiae, partial cataract and a conspicuous trabeculectomy bleb on the superior limbus (Figure 2B). Intraocular pressure was 12 mm Hg in both eyes. The patient was using only artificial tears QID in both eyes. He was last seen on December 14, 2010 (3½ years later). Visual acuity with the best spectacle correction was 0.7 in the right eye and 0.4 in the left eye. Slit lamp biomicroscopy of the left eye showed the same changes of the last examination, but the scarring was less dense (Figure 3B).

DISCUSSION Cladosporium is a pigmented mold widely distributed in the air and rotten organic material and frequently isolated as a contaminant on foods. It commonly grows on insulation in AC systems, on bathroom ceilings when there isn’t enough ventilation, on walls in rooms where insulation is lacking, on foundation walls and on attic sheathing. Indoors species can cause respiratory infections, especially in people with existing respiratory problems such as asthma. Many of them also produce toxins which stimulate allergic responses. The prevalence of Cladosporium keratitis among the fungal corneal infections seems to be small. In our service, it is 2%; in northern India it is about 3% and in south India about 5%.7,8 Very limited PAN-AMERICA 117

CASE REPORT / Vis. Pan-Am. 2013;12(4):116-119

Figure 2: Cladosporium keratitis. A. Immediately after voriconazole treatment; B. Seven months later; C. 3Â˝ years later.

data are available on the susceptibility profiles of Cladosporium species.9-11 RK surgery, petfood-shop laboring and the use of antibioticsteroid eye drops probably were the main factors responsible for the fungal infection in the corneal incisions. The generalized onychomycosis raises the suspicion that the patient had already some sort of deficient immune response to fungal infection. Maybe Diabetes mellitus type II was playing a role in this scenario. No test was done to find out the etiology of onychomycosis. It is probable that its etiology was the same of the corneal infection since the nail colonization was eradicated only with the specific treatment that cured the cornea. Fungal treatment begun before the result of the culture tests due to the evident failure of the previous therapy. Amphotericin B was chosen owing to its action against yeasts and filamentous fungi.12 It acts by binding to ergosterol, a major component of the cytoplasmic membrane of fungi. However, it also binds to molecules of mammalian cells, such as cholesterol, which explains the toxicity of this drug to the human body when used systemically. Natamycin was also used because of its proved efficacy against filamentous fungus infections of the eye surface.13 We were not concerned with the poor penetration of these drugs in deep-seated corneal infections because the lesion was placed in the gap of an open incision. Since both drugs belonged to the same antifungal group, i.e., polyenes, we accepted the risk that if the etiological agent was resistant to one of them, it would be more prone to be resistant to the other. After the labâ€™s confirmation of fungus infection, we decided to continue with both amphotericin B and natamycin since very little 118

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data were available about the susceptibility profile of Cladosporium. Antifungigram was not available in our service at that time. The decision to include oral fluconazole in the therapy was based on favorable reports in literature regarding the use of this antifungal in the treatment of Cladosporium infections.9,10 Oral and IV fluconazole are very safe and penetrate very well into corneal tissue. It belongs to the first generation triazoles (fluconazole and itraconazole). The azoles act by inhibiting ergosterol synthesis by selective inhibition of an enzyme present in fungal cell: the 14-Îą-demethylase. These drugs do not interfere with the synthesis of components of mammal cells membranes, and for this reason are less toxic than the polyenes.14 The major limitation of fluconazole is its narrow spectrum of antifungal activity.15 Literature also presents a case of Cladosporium keratitis that was cured with oral itraconazole.9 Since this drug is commonly associated with gastrointestinal side-effects and has poor penetration into the cornea after systemic administration, we were not confident about using it.16 When the situation became critical, we started thinking about surgery. Theoretically, we were left with two options: covering the cornea with a conjunctival flap or performing a corneal transplantation. Conjunctival flap was the main treatment before the development of antifungal agents.17 The rationale for this procedure is that bringing vessels to the site of infection should facilitate the action of the blood over the infectious agents; bringing conjunctive tissue should improve its healing. The problem with this procedure is that we end up losing visual control over the evolution of the infection. If the treatment fails the trouble is even worse. We definitely are not

Marcomini LAG et al. Voriconazole for fungal keratitis.

enthusiasts of this kind of therapy particularly for fungi that can progress inside the cornea even after epithelialization.17 Corneal transplantation would be a reasonable solution to reestablish the tectum of the globe albeit not a good solution for vision in the long run. The chances of rejection were high due to the acute inflammation. Yet, acute inflammation should not to be the only factor to put the blame on. In our corneal service, corneas from healed fungal infections, without any visible vascularization that were submitted to transplantation six or more months later had a rate of rejection of 90% in five years. Would be this a particular finding of our service18 or an intrinsic consequence of a severe infection like a persistent dysfunction of the hemato-aqueous barrier? When no other option besides corneal transplantation was left, we decided as a last resort to use voriconazole that was hitting Brazilian market at the time. Voriconazole belongs to the second generation of triazoles. It is a synthetic derivative of fluconazole with an expanded activity.19 Being quite soluble, voriconazole has good penetration into the corneal stroma, and reaches high concentrations in the vitreous and aqueous even when administered orally.6 Voriconazole concentrations achieved in the cornea are sufficient to cover a wide spectrum of fungi agents.19 Elated with this result, we tried the same therapy in one patient with severe Fusarium corneal ulcer without vascularization, unresponsive to 5% natamycin eye drops and oral ketoconazole. The ulcer improved very slowly with voriconazole 200 mg, PO, BID for 20 days. The treatment was suspended before cure for economic reasons. Each 200 mg tablet costs about 300 U.S. $ in our country. Eventually the lesion healed, with the subsequent use of eye drops of amphotericin B 0,25% six times per day during another 20 days. We do not know if the latter eye drops had any effect at all. The point is: if the protracted course of this case cannot be explained by the lack of corneal vascularization since literature says the drug has enough penetration to reach high concentrations in the cornea,6,19 one has to suspect that voriconazole might have a modest effect on this type of fungus, which contradicts the expectation conveyed by the same literature that the drug is the one that has the best activity against Fusarium species.20,21 This raises a last question: at what extent should one trust data from the literature?

CONCLUSION

Voriconazole administered orally seems to be a good alternative for treatment of Cladosporium spp. corneal infection, particularly when the current clinical options of treatment have failed.

REFERENCES 1. Kiskis AA. Cherry PM: Effect of radial and circular keratotomy in rabbits. Can J Ophthalmol. 1982;17:161-4. 2. Fyodorov SN, Durnev VV. Operation of dosaged dissection of corneal circular ligament in cases of myopia of mild degree. Ann Ophthalmol. 1979;11:1185-90. 3. Deg JK, Zavala EY, Binder PS. Delayed corneal wound healing following radial keratotomy. Ophthalmology. 1985; 92(6):734-40. 4. Salz JJ. Multiple complications following radial keratotomy in elderly patients: a case report. Ophthalmic Surg. 1985;16:579-90. 5. Robin JB, Beatty RF, Dunn S et al: Mycobacterium chelonei keratitis after radial keratotomy. Am J Ophthalmol. 1986;102:72-9. 6. Hariprasad SM, Mieler WF, Holz ER et al. Determination of vitreous, aqueous, and plasma concentration of orally administered voriconazole in humans. Arch Ophthalmol. 2004;122(1):42–7. 7. Chander J, Sharma A. Prevalence of fungal corneal ulcers in Northern India. Infection. 1994;22(3):207-9. 8. Bharathi MJ, Ramakrishnan R, Vasu S, Meenakshi, Palaniappan R. Aetiological diagnosis of microbial keratitis in South India. A study of 1618 cases. Indian J of Medical Biology. 2002;20(1):19-24. 9. GenT, Yoshitugu I, Naouki M, Hitoshi W, Yoshikasu S, Junko S, Seishi A, Kosuke T. A case of keratomicosis caused by Cladosporium trichoides. Folia Ophthalmologica Japonica. 2002 53;4:294-98. 10. Türker A, Altinörs N, Aciduman A, Demiralp O, Uluoglu U. MRI findings and encouraging fluconazole treatment results of intracranial Cladosporium thricoides infection. Infection. 1995;23(1):60-70. 11. Martins EA, Guerrer LV, Cunha KC et al. Onychomycosis: clinical, epidemiological and mycological study in the municipality of São José do Rio Preto. Rev Soc Bras Med Tropical. 2007; 40(5):596-98. 12. Wood TO, Tuberville AW, Monnet R: Keratomicosis and amphotericin B. Trans Am Ophthalmol Soc. 1985;83:397409. 13. O’Day D, Head W, Robinson R, Clanton J. Corneal penetration of topical amphotericin B and natamycin. Curr Eye Res. 1986;5(11):877–82. 14. Thomas PA. Current perspectives on ophthalmic mycoses. Clin Microbiol Rev. 2003;16(4):730–97 15. Rao S, Madhavan H, Rao G, Padmanabhan P. Fluconazole infilamentous fungal keratitis. Cornea. 1997;16(6):700. 16. Rajasekaran J, Thomas P, Kalavathy C, Joseph P, Abraham D. Itraconazole therapy for fungal keratitis. Indian J Ophthalmol. 1987;35(5–6):157–60. 17. Grayson M. Infectious Keratitis: Fungal and Parasitic. In: Grayson´s Diseases of the Cornea. Arffa RC ed. 3rd ed. St Louis, Mosby - Year Book, Inc, 1991, p.199-221. 18. Vieira-Silva J, Faria e Sousa SJ, Ferrante A M. Corneal transplantation in developing country: problems associated with technology transfer from rich to poor societies. Acta Ophthalmol Scand. 2006;84(3):396-400. 19. Johnson L, Kauffman C. Voriconazole: A new triazole antifungal agent. Clin Infect Dis. 2003;36(5):630–37. 20. Morangon F, Miller D, Giaconi J, Alfonso E. In vivo investigation of voriconazole susceptibility for keratitis and endophthalmitis fungal patogens. Am J Ophthalmol. 2004;137(5):820-25. 21. Klont R, Eggink C, Rijs A, Wesseling P, Verweij P. Successful treatment of Fusarium keratitis with cornea transplantation and topical and systemic voriconazole. Clin Infect Dis. 2005;40(12):110-12.

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Síndrome de isquemia ocular: un caso dramático Ocular ischemia syndrome: a dramatic case Miriam García-Fernández1,Joaquín Castro Navarro2, Francisco Álvarez Marcos3

Autor correspondente:

1,2 Departamento de Oftalmología, Hospital Universitario Central de Asturias, Oviedo, Asturias, España. 3 Departamento de Cirugía Vascular, Hospital Universitario Central de Asturias,Oviedo, Asturias, España.

Miriam García-Fernández, MD. Departamento de Oftalmología, Hospital Universitario Central de Asturias C/Dionisio Ridruejo, nº5, 11ºD. CP: 33007 Oviedo, Asturias (Spain) Tel:+34-629-85-38-00 Email: migarci@hotmail.es

Fundung: None Finantial/proprietary interest: None

Date of submission: 21/04/2013 Date of approval: 29/07/2013

ABSTRACT

Figura 1. Aspecto fundoscópico del ojo derecho (OD) en la primera exploración. Llama la atención la interrupción del flujo sanguíneo en los vasos retinianos, así como la presencia de vasos hialinizados, área blanco-lechosa a nivel macular en relación con posible oclusión arterial, y la presencia de cicatriz disciforme. También se observan numerosos microaneurismas arteriales en el polo posterior.

El síndrome de isquemia ocular es una patología rara, secundaria a hipoperfusión debido a estenosis o oclusión de las arterias carótidas común o interna. Varón, de 78 años, que acudió por disminución de agudeza visual progresiva, de meses de evolución, en su ojo derecho (OD). La Mejor Agudeza Visual Corregida (MAVC) en su OD era de no percepción de luz. La exploración biomicroscópica del polo anterior en OD reveló la presencia de microhipema y neovascularización iridiana en los 360º. La presión intraocular era normal. Mediante la exploración funduscópica y la angiografía fluoresceínica, se confirmó la presencia de signos de isquemia retiniana y coroidea, todo ello compatible con un posible síndrome de isquemia ocular. Se realizó panretinofotocoagulación, y se solicitó Eco-Doppler de Troncos Supraaórticos y angio-TC que confirmaron la presencia de una obstrucción completa en la arteria carótida interna derecha, no susceptible de tratamiento quirúrgico. A los 7 meses, el paciente permanece estable clínicamente, desde el punto de vista ocular y sistémico. En estos casos, es de gran trascendencia la evaluación sistémica del paciente, incluyendo realización de Eco-Doppler de TSA o angio-TC, y el abordaje multidisciplinar, pues un adecuado y precoz diagnóstico puede condicionar no solo el pronóstico visual, infausto en nuestro caso, sino también la supervivencia del paciente. Palabras clave: obstrucción carotídea, isquemia ocular, glaucoma, neovascularización, agudeza visual.

ABSTRACT

Figura 2. Aspecto fundoscópico del ojo izquierdo (OI) que muestra la presencia de una cicatriz disciforme macular. 120

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Ocular ischemic syndrome is a rare condition, secondary to hypoperfusion due to stenosis or occlusion of the common or internal carotid artery. A 78 year-old male, who complained of progressive acuity visual loss, in his right eye (RE). His Best Corrected Visual Acuity (BCVA) in RE was No light perception. Biomicroscopic exploration of anterior segment revealed the presence of microhyphema and iris neovascularization in 360 degrees. Intraocular pressure was normal. Fundoscopy and fluorescein angiography confirmed the presence of retinal and choroidal ischemia, compatible with an ocular ischemic syndrome. Panretinophotocoagulation was performed, and EcoDoppler of supraaortic trunks (SAT) and angio-CT were requested,

García-Fernández M et al. Síndrome de isquemia ocular.

and they confirmed the presence of complete obstruction of right internal carotid artery, surgically untreatable. Seven months ago, the patient remains clinically stable, with no ocular nor systemic changes. In these cases, systemic evaluation of the patients, including performance of Eco-Doppler of SAT or angio-CT, and the multidisciplinary approach, is crucial, as a prompt and adequate diagnosis can influence visual prognosis, awful in our case, and patient survival. Key words: carotid obstruction, ocular ischemia, glaucoma, neovascularization, visual acuity.

Introducción

El síndrome de isquemia ocular es una patología rara, secundaria a hipoperfusión debido a estenosis o oclusión de las arterias carótidas común o interna.1,2 Afecta fundamentalmente a varones, a partir de la quinta década de la vida, y suele ocurrir de modo unilateral, aunque puede ser bilateral hasta en el 20% de los casos. Los síntomas oculares más frecuentes son: pérdida de agudeza visual y dolor ocular. Los signos oftalmológicos más habituales en la exploración biomicroscópica del segmento anterior son: neovascularización iridiana, atrofia de iris, iridociclitis y catarata. A nivel del segmento posterior, lo más característico es el estrechamiento arteriolar, aunque también es posible encontrar dilatación vascular, y la presencia de neovasos epipapilares y/o retinianos. La angiografía fluoresceínica suele mostrar signos de isquemia retiniana y coroidea. El glaucoma de tensión normal es una asociación común. Es imprescindible el diagnóstico diferencial con otras patologías como la retinopatía diabética y las oclusiones venosas retinianas.3

Caso clínico

Varón, de 78 años, que acudió por disminución de agudeza visual progresiva, de meses de evolución, en su ojo derecho (OD). Como antecedentes personales destacaban: hipertensión arterial (HTA), diabetes mellitus, dislipemia, un episodio de ictus cerebral 2 años antes, insuficiencia cardíaca e insuficiencia renal crónica. No presentaba antecedentes oftalmológicos de interés, salvo facoexéresis bilateral.

Figura 3. Angiografía fluoresceínica de ojo derecho (OD) en la que destaca la presencia de una severa isquemia macular y de la región retiniana superior, fundamentalmente.

En la primera exploración, la Mejor Agudeza Visual Corregida (MAVC) en su OD era de No percepción de luz y en su ojo izquierdo (OI) de 0.05. La exploración biomicroscópica del polo anterior en OD reveló la presencia de microhipema y neovascularización iridiana en los 360º, sin mostrar hallazgos patológicos en OI. La presión intraocular era de 14 mmHg en ambos ojos. Fundoscópicamente, en OD se apreciaba una palidez papilar moderada, con signos de isquemia a nivel del polo posterior, con obstrucción de arteria central de la retina, y estrechamiento arterial muy marcado, con interrupción y segmentación de la columna sanguínea, así como presencia de numerosos microaneurismas en polo posterior y media periferia (Figura 1). En OI, pudimos constatar la presencia de una cicatriz disciforme macular (Figura 2). La angiografía fluoresceínica en OD mostró los siguientes hallazgos: retraso importante del tránsito arterio-venoso, llenado coroideo retrasado y parcheado, irregular, revelando una importante hipoperfusión coroidea; además, se apreció una hiperfluorescencia tardía, tinción macular, en relación con una membrana neovascular cicatricial antigua. No apreciamos presencia de neovascularización epipapilar ni retiniana (Figura 3). En OI se confirmó la presencia de cicatriz disciforme, sin signos de actividad (Figura 4). Ante estos hallazgos, y dada la sospecha de síndrome de isquemia ocular, solicitamos interconsulta al servicio de Cirugía Vascular y solicitamos Eco-Doppler de Troncos Supraórticos (TSA), así como angio-TC de TSA y Cerebral. Asimismo, realizamos panretinofotocoagulación (en distintas sesiones) en OD, de cara a prevenir un incremento en el dolor ocular, causado por la elevación de la presión intraocular debido al glaucoma PAN-AMERICA 121

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Figura 4. Angiografía fluoresceínica de ojo izquierdo (OI) en la que se aprecia hiperfluorescencia por tinción de la cicatriz macular.

Figura 5. Angio-TAC: corte axial a nivel unos milímetros superior a la bifurcación de ambos ejes carotídeos. Se aprecia la permeabilidad de ambas carótidas (interna y externa) en el lado izquierdo y la trombosis completa de la carótida interna derecha (CID) desde el origen (flecha verde).

REFERENCIAS 1. Chen CS, Miller NR. Ocular ischemic syndrome: review of clinical presentations, etiology, investigation, and management. Compr Opthalmol Update 2007;8(1):17-28. 2. Mendrinos E, Machinis TG, Pournaras CJ. Ocular ischemic syndrome. Surv Ophthalmol 2010;55(1):2-34. 3. Terelak-Borys B, Skonieczna K, Grabska-Liberek I. Ocular ischemic syndrome - a systematic review. Med Sci Monit 2012;18(8):138-144. 4. Hazin R, Daoud YJ, Khan F. Ocular ischemic syndrome: recent trends in medical management. Curr Opin Ophthalmol 2009;20(6):430-3. 5. Luo RJ, Liu SR, Li XM, Zhuo YH, Tian Z. Fifty-eight cases of ocular ischemic diseases caused by carotid artery stenosis. Chin Med J (Engl) 2010;123(19): 2662-5. egna ade , ie ec a , iec i e ic , a n s i , a a a , Zubilewicz T. Ophthalmological complications associated with clinically significant carotid stenosis]. Klin Oczna 2012;114(1):57-62. 7. Kawaguchi S, Sakaki T, Iwahashi H, Fujimoto K, Iida J, Mishima H, Nishikawa N. Effect of carotid artery stenting on ocular circulation and chronic ocular ischemic syndrome. Cerebrovasc Dis 2006;22(5-6):402-8.

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Figura 6. Angio-TAC: reconstrucción multiplanar curva donde se ve visualiza la carótida común derecha, la externa (con la rama tiroidea superior, faciales, etc) y el origen trombosado de la carótida interna derecha (CID), con una placa cálcica importante en localización anteroexterna.

neovascular, que hiciera necesario la práctica de técnicas más agresivas, como la evisceración. El Eco-Doppler de TSA mostró la presencia de una trombosis completa de la arteria carótida interna (ACI) derecha. El angio-TC de TSA y Cerebral mostró los siguientes hallazgos: estenosis del 50% en el origen de la arteria vertebral izquierda, y obstrucción en el origen de la ACI derecha con recanalización en la porción supraclinoidea (Figuras 5 y 6). Ante esto, el servicio de Cirugía Vascular decidió realizar anticoagulación y control evolutivo del paciente, al no estar indicada la cirugía (endarterectomía carotídea) en este caso. A los siete meses de la primera visita, la MAVC en OD es de No percepción luminosa. Biomicroscópicamente, se observa persistencia de la rubeosis iridis, y funduscópicamente, no se aprecian cambios, salvo la presencia de una atrofia óptica completa.

Discusión

Entre los factores de riesgo asociados en estos casos de síndrome de isquemia ocular, nos encontramos, como se refleja bien en el caso anteriormente presentado, la hipertensión arterial, la diabetes mellitus, la cardiopatía isquémica y los accidentes cerebrovasculares previos.1,4,5 Es de gran trascendencia la evaluación sistémica del paciente mediante analítica completa, tensión arterial y eco-Doppler carotídea (combinada, si es posible, con angio-TC o angiorresonancia). De ahí, la importancia de la interrelación del oftalmólogo con otros servicios, como Cirugía Vascular, Cardiología o Neurología, con el fin de conseguir un abordaje multidisciplinar de estos pacientes.3,6 El tratamiento puede ser local (drogas hipotensoras tópicas si la presión intraocular está elevada, panretinofotocoagulación) o sistémica (tratamiento conservador mediante anticoagulación, o quirúrgico, mediante endarterectomía, de la obstrucción carotídea).4

Conclusión

Como conclusion, destacar que el establecimiento del diagnóstico en los casos de síndrome de isquemia ocular es fundamental, no solo para el pronóstico visual, sino también para la supervivencia del paciente. Los oftalmólogos tienen un papel esencial en el reconocimiento precoz de esta entidad y en la coordinación de la evaluación multidisciplinar de estos pacientes. En nuestro caso, el estado avanzado de la enfermedad, desde el punto de vista vascular y ocular, no permitió realizar medidas terapeúticas, sino solamente paliativas.

de Juan-Marcos L et al. Migration of intravitreal implant in an aphakic child.

Intravitreal dexamethasone implant migration to the anterior chamber in an aphakic child Lourdes de Juan-Marcos. M.D. , Lucía Cabrillo-Estévez. M.D., Victoria Losada-Burgos. M.D., Emiliano Hernández-Galilea. M.D., PhD Department of Ophthalmology, Hospital Clínico Universitario, Salamanca, Spain Funding: None Financial and/or proprietary interest: None

Corresponding author: Lourdes de Juan Marcos, M.D. Department of Ophthalmology, Hospital Clínico Universitario, Paseo de San Vicente, 58-182, 37007. Salamanca, Spain. Phone: +34 923291427; Fax: +34 923291613 E-mail: mloujm@gmail.com Date of submission: 29/04/2013 Date of approval: 04/11/2013

Abstract

An 8-year-old girl, who underwent pars plana lensectomy and vitrectomy for non-infectious uveitis, was treated with a dexamethasone intravitreal implant (Ozurdex®, Allergan Inc., Irvine CA), because of the persistence of cystoid macular edema. The implant migrated into the anterior chamber; however, no cornea edema was detected and a complete resolution of macular edema was observed. Keywords: Aphakia; Cystoid macular edema; Intravitreal implant; Uveitis

Introduction

Cystoid macular edema (CME) is a common cause of vision loss complicating uveitis. Periocular and intravitreal corticosteroids have been used for treatment of noninfectious uveitis and uveitic macular edema, but the beneficial effects of a single injection are often temporary.1 Repeated injections have been associated with adverse events, such as cataract formation, increased intraocular pressure (IOP), and steroidinduced glaucoma. Ozurdex® implant (Allergan Inc., Irvine, California, USA) was approved by the Federal Drugs Administration (FDA) in the USA as a therapy for the treatment of macular edema following branch or central retinal vein occlusion.2 The use of this device has also been effective in the treatment of noninfectious uveitis, diabetic macular edema and pseudophakic macular edema.3,4 It utilizes a delivery system in which biodegradable material is combined with dexamethasone to form a small, rod-shaped implant. This material is injected into the vitreous cavity

using a specially designed injector and gradually delivers dexamethasone to the posterior chamber.

Case report

An 8-year-old girl presented to the emergency department having blurred vision in her right eye. The best-corrected visual acuity (BCVA) was 20/100 in the right eye and 20/20 in the left eye. Slit-lamp examination revealed chronic non-granulomatous anterior uveitis with extensive posterior synechiae and an incipient band keratopathy in the

Figure 1. Slit lamp photograph of anterior segment. Right eye shows band keratopathy, a pupillary membrane with rubeosis and a cataract

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Figure 2. Optical coherence tomography showing cystoid macular edema before Ozurdex® injection.

right eye. Her left eye presented an early band keratopathy and 2+ cells with trace flare in the anterior chamber. The IOP was 16mmHg in each eye. Dilated bilateral fundus examination was normal. The patient was treated with intensive topical corticosteroids and mydriatic. Her medical and ocular histories were unremarkable. She did not complain of any other symptoms. Patient was consulted with pediatricians and pediatric rheumatologists and a physical examination was performed. Laboratory evaluation consisted of a complete blood count with differential, biochemical analysis, urinalysis, and erythrocyte sedimentation rate. Antinuclear antibody, rheumatoid factor, C-reactive protein, human leukocyte antigen (HLA) typing, angiotensinconverting enzyme, pathergy test, skin tuberculin test, chest radiography, syphilis, HIV, toxoplasma, and herpes serology were performed. These tests did not reveal anomalies that could suggest any systemic disease. At 1 month of follow-up, the right eye had a persistent uveitis and the left eye showed the presence of posterior synechiae, snowballs

Figure 3. Slit lamp photograph of the right eye after pars plana lensectomy and vitrectomy showing migration of implant into the anterior chamber.

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in the inferior vitreous base and retinal vasculitis. Serological tests were performed for Borrelia, Rickettsia, Bartonella, Brucella and Coxiella. These tests were negative. Oral corticosteroids therapy was started. The left eye gradually improved, and cells in the anterior chamber and vitritis resolved. Despite continuous treatment with local and systemic corticosteroids, the right eye developed a pupillary membrane with rubeosis and significant cataract (Figure 1). The IOP was 25 mmHg. She underwent pars plana lensectomy and pars plana vitrectomy with vitreous biopsy in the right eye. No infections or systemic associated diseases were detected and the diagnosis of pars planitis was made. Control of inflammatory activity was maintained with oral corticosteroids and immunosuppressive therapy (azathioprine, 1.5 mg/kg/day). Three months after surgery, the BCVA was 20/200 in the right eye, the IOP was 14 mmHg and the posterior segment showed retinal vasculitis and a significant cystoid macular edema (CME), confirmed by optical coherence tomography. She was treated with periocular and intravitreal injection of steroids with complete resolution of edema and improved visual acuity. However, the treatment was temporarily effective and recurrence of edema was noted after one month (Figure 2). Informed consent was obtained from the child’s parents and she received an intravitreal injection of Ozurdex® as off-label treatment. Ten days after the injection, visual acuity of the right eye improved to 20/70. In addition, there was improvement of central macular thickness. At three weeks post-injection, the implant was found floating inferiorly in the anterior chamber (Figure 3). The IOP was 26 mmHg and was controlled with medical treatment. The device moved when patient changed posture. It was placed in the anterior chamber for 2 months, the eye was quiet, no corneal edema was observed and endothelial cell density examined by noncontact specular microscope was stable. The IOP was 16 mmHg with medical treatment and there was no CME (Figure 4). At 10 weeks postinjection, the implant was back in the vitreous cavity. At the last follow-up, 16 months after the initial presentation, the BCVA was 20/70 in the right eye and 20/20 in the left eye, and the CME has resolved in the treated eye.

de Juan-Marcos L et al. Migration of intravitreal implant in an aphakic child.

Discussion

Ozurdex® implant has a better safety profile that other intravitreal corticosteroids injection and its effects may be longer lasting.3 Several reports found that in patients with non-infectious intermediate or posterior uveitis, a single dose of the dexamethasone implant was well tolerated and produced significant improvements in intraocular inflammation and visual acuity that persisted for 6 months.3 However, the effect and safety of this drug in children remains to be established. Recent studies have evaluated the efficacy of Ozurdex® implant in vitrectomized eyes with macular edema and they have concluded that it is an effective treatment option in these patients.5 The results of its use in eyes with aphakia and eyes with an iris-claw lens have been previously reported in a few studies.6,7 The tendency of migration of the implant into the anterior chamber has been described in these eyes, and in many cases a deleterious effect on the cornea has been observed. Vela et al7 describe the dexamethasone implant reposition to the vitreous cavity when no corneal complications exist, in order to keep the efficacy of the implant in the eye. Nevertheless, this procedure may damage intraocular structures and the device may come back into the anterior chamber by patient posturing. In our patient, the dexamethasone implant was effective to control the ocular inflammation after its migration into the anterior chamber, it was well tolerated and no corneal edema was noted. However, when migration occurs, the patient is at risk for corneal edema and decompensation. Therefore, aphakic eyes should be examined closely and surgical removal of the implant from the anterior chamber must be performed when adverse effects are observed. To the best of our knowledge, this is the first description of intravitreal Ozurdex® injection in a girl. Our case report indicates that one single Ozurdex® injection induces morphologic and functional improvement in a child suffering from uveitic CME and this outcome continues during the 8-months-follow-up. No systemic side effects have been identified in our patient. Dexamethasone intravitreal implant may represent a successful off-label treatment in children, but further studies are needed to assess the safety and efficacy of this drug in this population. This report could be helpful for pediatric ophthalmologists in their management of similar challenging scenarios.

Figure 4. Optical coherence tomography showing resolution of macular edema 3 months after Ozurdex® injection.

REFERENCES 1. Sallam A, Comer RM, Chang JH, Grigg JR, Andrews R, McCluskey PJ, Lightman S. Short-term safety and efficacy of intravitreal triamcinolone acetonide for uveitic macular edema in children. Arch Ophthalmol 2008;126:200–5. 2. Haller JA, Bandello F, Belfort R Jr, Blumenkranz MS, Gillies M, Heier J, Loewenstein A, Yoon YH, Jacques ML, Jiao J, Li XY, Whitcup SM; OZURDEX GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010; 117:1134–46. 3. Lowder C, Belfort R Jr, Lightman S, Foster CS, Robinson MR, Schiffman RM, Li XY, Cui H, Whitcup SM; Ozurdex HURON Study Group. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol 2011;129: 545-53. 4. Haller JA, Kuppermann BD, Blumenkranz MS, Williams GA, Weinberg DV, Chou C, Whitcup SM; Dexamethasone DDS Phase II Study Group. Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Arch Ophthalmol 2010;128:289–96. 5. Reibaldi M, Russo A, Zagari M, Toro M, Grande De V, Cifalinò V, Rametta S, Faro S, Longo A. Resolution of Persistent Cystoid Macular Edema due to Central Retinal Vein Occlusion in a Vitrectomized Eye following Intravitreal Implant of Dexamethasone 0.7 mg. Case Report Ophthalmol 2012;3:30-4. 6. Bansal R, Bansal P, Kulkarni P, Gupta V, Sharma A, Gupta A. Wandering Ozurdex(®) implant. J Ophthalmic Inflamm Infect 2012;2:1-5 7. Vela JI, Crespí J, Andreu D. Repositioning of dexamethasone intravitreal implant (Ozurdex(®) migrated into the anterior chamber. Int Ophthalmol 2012; 32:583-4.

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Message from the Chairman

of the Board, PAOF William De La Peña, MD

Chair of the Board of Directors, Pan-American Ophthalmological Foundation

Dear Colleagues: As we come to a close for 2013, I would like to take this moment to share our exciting advances and to give thanks on behalf of the Pan-American Ophthalmological Foundation (PAOF). We would like to thank all those individual donors who sent in generous contributions via the PAAO’s Portal or as an add-on to their annual membership dues for the Pan-American Association of Ophthalmology (PAAO). These donations are vital to the maintenance of our existing educational programs. We received almost $10,000 from these individual donors. The participants in the Circle of Vision continued to grow this year. Not including our generous industry partners, we received over $65,000 in Circle of Vision membership donations. These donations will help us to expand our educational programs.

Our big fund raiser event this year was the Pan-American Carnival which took place during the 30th Pan-American Congress of Ophthalmology in Rio de Janeiro, Brazil. Its purpose was to raise funds to support the mission of the Pan-American to provide lifelong sight-saving ophthalmic knowledge and skills to thousands of ophthalmologists who are working daily to improve the quality of eye care and prevent blindness. Resulting in more than $20,000, the proceeds from this event will go to support our continuing education and prevention of blindness projects. We thank our industry partners and our family foundations who continue to be so generous and support our many programs with their restricted funding totaling over $200,000 this year: Abbott Medical Optics Inc., Alcon Laboratories Inc., Allergan International, Bausch+Lomb Inc., David

& Julianna Pyott Foundation, Lions Clubs Int’l Foundation, Rayner Intraocular Lenses Limited, the Allergan Foundation, the Retina Research Foundation, the Tim & Judith Sear Foundation and the Troutman-Véronneau Endowment Fund. We look forward to 2014 where we will continue working with our partners, big and small, to provide continuing education, cultural exchange and prevention of blindness programs to the Ophthalmologists of the Americas and in the world. Best regards,

William De La Peña, MD Chairman of the Board Pan-American Ophthalmological Foundation

Allergan organizational announcement from Douglas Ingram, President, Allergan Nelson Marques to retire February 28, 2014; Mauro Naddeo Promoted to Corporate Vice-President and President, Latin America effective January 1, 2014. After fifteen years of dedicated service to Allergan, and nearly 40 years of service to Latin America’s health and pharmaceutical sector, Nelson Marques will retire from Allergan on February 28, 2014. During Nelson’s four decades of service, he has served in a variety of regional and global commercial leadership roles, most importantly with Allergan as Corporate Vice-President and President of Latin America, and also as Corporate Vice-President, President and Chairman of Latin America, and as President of Alcon Laboratories from 1994– 1998. Allergan Latin America sales grew by more than 700% during Nelson’s tenure, and Nelson was instrumental in bringing BOTOX and our dermatology products to the region. During his career, Nelson has served as Chairman of the Board of the Pan-American Ophthalmological Foundation, a great honor 126

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for Allergan and for Nelson from 2009 – 2012, and served on their board since 1998. He has truly been a great leader for Allergan and Ophthalmology in Latin America. I am pleased to announce that I have promoted Mauro Naddeo, currently VicePresident of Global Strategic Marketing for Dermatology, Allergan Medical based in Irvine, to the role of Corporate Vice-President and President, Latin America, as well as membership on the Operating Committee effective January 1, 2014. Mauro joined Allergan in April 2000 as the leader of our Argentina Ophthalmology team. Since then he has also served as the Ophthalmology Sales and Marketing Director for Brazil; Business Head for Ophthalmology, Latin America; and Vice-President of Ophthalmology, Latin America and Managing Director of Mexico. In

2012 Mauro and his family relocated to Irvine where Mauro began his current role to expand his sphere of business knowledge, and gain valuable corporate and strategic experience. Mauro holds an Executive MBA (MEDEX) from the Instituto Panamericano de Alta Direccion de Empresas (IPADE) Business school (Mexico), and a Marketing Degree from UVM. I appreciate Nelson’s many contributions to Allergan and the Ophthalmology community, and I wish him great health and happiness as he enters this next phase. I am also excited to bring Mauro into this leadership role and very confident that he and his team will drive continued success in Latin America. Please join me in thanking and congratulating Nelson and Mauro on these important milestones.

Announcements

The Pan-American Association of Ophthalmology and the Pan-American Ophthalmological Foundation would like to thank the following members of the 2013-2014 Circle of Vision for their generosity and support of the organization and its mission. The Circle of Vision was established to acknowledge individual members, industry partners, and foundations who give an annual leadership gift of $1,000 or more to help expand the Pan-American’s education and prevention of blindness programs.

Founding Members ($25,000 + ) Alcon Laboratories Allergan Foundation Allergan International Dr. Robert C. Drews Dr. Alice R. McPherson / Retina Research Foundation David & Julianna Pyott Foundation Tim & Judith Sear Foundation Dr. Thomas & Michele Smith Dr. Richard Troutman Dr. Suzanne Véronneau-Troutman

Patron Members

Partner Members ($1,000 to 2,499)

($2,500 to 4,999)

Dr. Richard L. & Cecilia Abbott Dr. Eduardo Alfonso Dr. Eduardo Arenas Archila Dr. J. Bronwyn Bateman & Dr. Doug Hershey Dr. Rubens Belfort Jr. Dr. María H. Berrocal Ms. Teresa J. Bradshaw Dr. Michael W. & Helen Brennan Dr. António M. Barbante Casella Dr. Francisco Contreras Dr. Rafael T. Cortez Hernández Dr. Paulo E.C. Dantas Dr. Thomas & Leslie France Dr. Denise de Freitas Dr. Vinicius Coral Ghanem Dr. H. Fernando Gómez Goyeneche Dr. Enrique Graue Wiechers Dr. Miguel Guzmán Ahumada Herbert Family Foundation Dr. Jaime Jiménez-Agosto Dr. Carol L. Karp Dr. Deborah L. Klimek Dr. Paul R. & Carolyn Lichter Dr. Chun Cheng Lin Yang Lions Club International Foundation Dr. Waldo Loayza-Gamboa Dr. Cristián Luco

Dr. J. Fernando Arévalo Dr. Zelia Correa Dr. William C. De La Peña Dr. Ana Luisa Hofling & Dr. Michel Farah Dr. Luis Izquierdo Jr. Mr. J.C. Plotnicoff & Mrs. Laura Malkin-Stuart Dr. Mark J. & Judy Mannis Mr. Nelson R.A. Marques

If you would like to learn more about the Circle of Vision, please contact: Teresa J. Bradshaw PAAO/PAOF Executive Director Tel: 817-275-7553 teresa.bradshaw@paao.org

Ambassador Members ($10,000 to $24,999) Abbott Medical Optics Inc. Bausch + Lomb Johnson & Johnson Vision Care Latin America Rayner Intraocular Lenses Limited

Leader Members ($5,000 — $9,999) Anonymous Laboratorios Sophia

Dr. Elizabeth Maria Maia Dr. Maurício Maia Dr. Arturo R. Maldonado Bas Sr. Dr. J. Alberto Martínez-Marroquin Dr. Mário Junqueira Nóbrega Dr. Peter Quiros Dr. Marco A. Rio Olivares Dr. José Antonio Roca Dr. André Romano Dr. Elcio H. Sato Dr. Eduardo Silva Dr. Allan R. Slomovic Dr. Ronald E. Smith Dr. Bruce C. Spivey Dr. Paul Sternberg Jr. Dr. Bradley R. Straatsma Dr. James C. Tsai Dr. Jorge Valdez Dr. Liana Ventura Dr. Marcelo Ventura Dr. & Mrs. C.P. “Pat” Wilkinson Dr. Ruth Williams Dr. Agnes Wong Dr. Lihteh Wu Dr. Mercedes Zambrano Paco Dr. Andrea Araújo Zin PAN-AMERICA 127

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