PAAO V.11-4 Diciembre 2012

Proud to be PAN-AMERICAN

VISIONTHE PAN-AMERICAN JOURNAL OF OPHTHALMOLOGYISSN 2219-4665Diciembre 2012, Vol. 11(4)

Dantntas PECA PRETTY RICH YEAR… AND MORE TO COME!

Mannis MMJMESSAGE FROM THE PRESIDENT

Medina CA et al

NOVEL CONCEPTS IN THE IMMUNOLOGY AND TREATMENT OF VASCULARIZED HIGH-RISK CORNEAL ALLOTRANSPLANTS

Alvarez ER and Sotero JG

MORFOMETRÍA CORNEAL IN VIVO VERSUS MAGNITUD DE LA AMETROPÍA EN PACIENTES OPERADOS CON LÁSER DE EXCÍMEROS POR LA TÉCNICA LASIK

Maldonado-Bas A et al

NON PENETRATING DEEP SCLERECTOMY AND TRABECULECTOMY FOR GLAUCOMA

Mannis TE et al

RECURRENT INVASIVE SQUAMOUS CARCINOMA OF THE OCULAR SURFACE REQUIRING PENETRATING THERAPEUTIC SCLERO-KERATOPLASTY

Vélez M et alCORNEAL HYMENOPTERA STINGS: A NEW THERAPEUTIC APPROACH.

Ho ST and Valenzuela AA

A PERSISTENT CASE OF PERIOCULAR CYSTIC SQUAMOUS CELL CARCINOMA

Izquierdo NJADVOCACY: LEADERS NEED TO BECOME PUBLIC SPEAKERS

Marques NRAPAOF NEWS

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 VisualField 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 Bimatoprostand 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 ofOphthalmol, New Orleans, La, 2001.

Preserva la visión alcanzando las menorespresiones-objetivo en más pacientes

Mejor comodidad posológica:

1 vez al día.

No requiere refrigeración.

Presentación conteniendo 3 ml.

LLLLLumiganumiganumiganumiganumigan® ® ® ® ® (bimatoprost) Forma farmacéutica y prForma farmacéutica y prForma farmacéutica y prForma farmacéutica y prForma farmacéutica y presentación.esentación.esentación.esentación.esentación.Frascos cuenta-gotas conteniendo 5 ml de solución oftalmológica estéril de bimatoprost a 0,03%. USO ADULTO.Composición. Composición. Composición. Composición. Composición. Cada ml contiene: 0,3 mg de bimatoprost. Vehículo: cloreto de sódio, fosfato de sódiohepta-hidratado, ácido cítrico mono-hidratado, ácido clorídrico y/o hidróxido de sódio, cloruro de benzalconio y agua purificada qsp. Indicaciones.Indicaciones.Indicaciones.Indicaciones.Indicaciones. LUMIGAN®®®®® (bimatoprost) es indicado para la reducción de la presión intra-ocular elevada en pacientes con glaucona o hipertensiónocular.Contraindicaciones.Contraindicaciones.Contraindicaciones.Contraindicaciones.Contraindicaciones. LUMIGAN®®®®® (bimatoprost) está contraindicado en pacientes con hipersensibilidad al bimatoprost o cualquier otro componente de la fórmula del producto. Pr Pr Pr Pr Precauciones y Adverecauciones y Adverecauciones y Adverecauciones y Adverecauciones y Advertencias.tencias.tencias.tencias.tencias. Advertencias. Fueron relatados aumento gradual del crescimientode 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 después6 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 tratamientode apenas uno de los ojos, deben ser informados a respecto de esas reacciones. PrPrPrPrPrecaucionesecaucionesecaucionesecaucionesecauciones 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 debenser 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 medicamentode 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.Interacciones medicamentosas.Interacciones medicamentosas.Interacciones medicamentosas.Interacciones medicamentosas.Considerando que las concentracionescirculantes 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.No son conocidas incompatibilidades. R R R R Reacciones adversas.eacciones adversas.eacciones adversas.eacciones adversas.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, durante3 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 infeccionesde 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,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 y Administración.Posología y Administración.Posología y Administración.Posología y Administración.Posología y 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 oftálmicostópicos 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 HAYANINDICADO 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.

vs. timolol 4 vs. latanoprost6

Porcentaje de Pacientes quealcanzaron la PIO-Objetivo ≤≤≤≤≤14 21% 9% 17% 2% 19% 9%

Porcentaje de Pacientes quealcanzaron la PIO-Objetivo ≤≤≤≤≤15 31% 16% 24% 9% 29% 14%

dorzolamida/ timolol 5vs.

®®®

Lumigan® alcanza la PIO-objetivo de 14/15 mmHg en un mayor númerode pacientes:

Investigadores de diversos estudios, (AGIS, Shirakashi, Shields)han comprobado que alcanzar y mantener la PIO entre 14 y 15 mmHgreduce la progresión de pérdida del campo visual1,2,3.

PAN-AMERICA

Diciembre 2012, Vol. 11(4)

Aims and scope:

Vision Pan-America (printed version ISSN 2219-4665, electronic version ISSN 2219-4673), the offi cial publication of the Pan-American Association of Ophthalmology, is a quarterly fully peer reviewed scientifi c publication that publishes original research in Ophthalmology, including review articles on ophthalmic diseases and surgical techniques, clinical scientifi c 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.

Prepress Creative Latin Media. Printed in Printer Colombiana – Colombia

Section Editor, Cataracts: Nestor Gullo, MD (La Plata, Argentina)

Section Editor, Cornea and External Disease: Allan R. Slomovic, MD (Ontario, Canada)

Section Editor, Eye Banking: Luciene Barbosa de Sousa, MD (São Paulo, Brazil)

Section Editor, Genetics: Eduardo José Gil Duarte Silva, MD (Figueira da Foz, Portugal)

Section Editor, Glaucoma: James C. Tsai, MD (New Haven, CT, USA)

Section Editor, Neurophthal-mology: Karl Golnik, MD (Cincinnati, OH, USA)

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

Section Editor, Ophthalmic Plastics and Orbital Diseases: Chun Cheng Lin Yang, MD MSc (San José, Costa Rica)

Section Editor, Pathology: J. Oscar Croxatto, MD (Buenos Aires, Argentina)

Section Editor, Pediatric Ophthalmology and Strabismus: Maria Estela Arroyo Yllanes, MD (México City, México)

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

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)

Section Editor

PAOF INDUSTRY SPONSORS

• Abbott Medical Optics Inc.

• Alcon Inc.

• Allergan Inc.

• Bausch & Lomb Inc.

• Carl Zeiss Meditec Inc.

• Johnson & Johnson Vision Care Latin America

• Merck & Co Inc.

Director of Printed Matters CLM: Eliana Barbosa

Graphic Design CLM: Juan David Medina / Catalina Lozano O.

Databases and Distribution CLM: Ximena Ortega Bernal

[email protected]

Copyediting: Piedad Camacho and Vanessa Carmona

Prepress: Alejandro Bernal

Production Staff

Managing Editor: Teresa Bradshaw (Arlington, TX, USA)

Production Editor: Terri Grassi(Arlington, TX, USA)

Mapy Padilla(Lima, Peru)

Offi ce Staff

Alejandro Lichtinger, MD (Toronto, Ontario, Canada)

Ashley Behrens, MD (Riyadh, Saudi Arabia)

Ana Luisa Höfl ing-Lima (São Paulo, Brazil)

Bruno Fontes, MD (Rio de Janeiro, Brazil)

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

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

Eugenio Maul de La Puente (Santiago, Chile)

Ivan Schwab, MD (Sacramento, CA, USA)

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

Daniel Weil, MD (Buenos Aires, Argentina)

Marian Macsai, MD (Chicago, IL, USA)

Marie Eve Legare, MD (Quebec City, Canada)

Natalio Izquierdo, MD (San Juan, Puerto Rico)

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

Renato Ambrósio Jr. (Rio de Janeiro, Brazil)

Editorial Review Board

Denise de Freitas, MD (São Paulo, Brazil)

Eduardo Alfonso, MD (Miami, FL, USA)

Eduardo Arenas, MD (Bogotá, Colombia)

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

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

Editorial Advisory Board

Administrative Editorial Council:Mark Mannis, MD (PAAO Presi-dent, Sacramento, CA, USA.), and Nelson Marques, MBA (PAOF Chairman, São Paulo, Brazil)

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

Editor-in-Chief:Paulo Elias C. Dantas, MDProf. of OphthalmologyDepartment of OphthalmologySanta Casa of São Paulo, Brazil

Membership, Associations and Editorial Guidelines

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Pan-American Association of Ophthalmology

1 Delegate2 PAAO Past President3 President, Affi liated National Society4 President, Affi liated Subspecialty Society

PAAO EXECUTIVE COMMITTEE 2011-2013

PresidentMark J. Mannis, MD

President ElectAna Luisa Höfl ing-Lima, MD

Past PresidentCristián Luco, MD

Vice PresidentPeter A. Quiros, MD

Executive Vice PresidentJ. Fernando Arévalo, MD FACS

Secretary, English Language RegionJames C. Tsai, MD MBA

Associate Secretary, English Language RegionCarol L. Karp, MD

Secretary, Portuguese Lan-guage RegionPaulo E.C. Dantas, MD

Associate Secretary, Portu-guese Language RegionMauricio Maia, MD

Secretary, Spanish Lan-guage RegionLihteh Wu, MD

Associate Secretary, Spanish Language RegionJorge E. Valdez Garcí a, MD MA

Executive DirectorTeresa Bradshaw

Chairman of the BoardMr. Nelson Marques

Past ChairRubens Belfort Jr, MD PhD

Vice ChairWilliam C. de La Peña, MD

Secretary TreasurerJ. Fernando Arevalo, MD

Executive DirectorTeresa Bradshaw

PAOF BOARD

ARGENTINAEnrique S. Malbrán, Sr., MD1

Ernesto Ferrer Abad, MD1,3

Gustavo Federico Bodino, MD1

J. Ignacio Manzitti, MD1

Joaquin Alfredo Bafalluy, MD1

Juan Oscar Croxatto, MD4

Lidia López, MD4

María Celeste Mansilla, MD1

Nestor Gullo, Jr., MD4

Roberto N. Ebner, MD1

S. Fabián Lerner, MD4

BOLIVIAJosé Luis Sebastián Salas, MD3

José Vladimir Justiniano Talavera, MD1

Vania Licett García Aliaga, MD1

BRAZILBruno Machado Fontes, MD1

Eduardo Büchele Rodrigues, MD1

José Alvaro P. Gomes, MD4

Liana Maria V. de O. Ventura, MD PhD1

Luciene Barbosa de Sousa, MD4

Luciene Chaves Fernandes, MD4

Marco Antonio Rey de Faria, MD1,3

Maria Cristina Nishiwaki-Dantas, MD1

Mário Junqueira Nóbrega, MD1

Nilo Holzchuh, MD1

Paulo Augusto de Arruda Mello, MD PhD1

Rubens Belfort, Jr., MD PhD2

CANADAAllan R. Slomovic, MA MD FRCS(C)1

Paul E. Rafuse, MD PhD FACS1,3

CHILECristián Luco, MD2

Fernando Barría von Bischhoffshausen, MD1,4

Francisco José Conte Silva, MD1

Gonzalo Matus, MD1

Javier Lagos Rodríguez, MD1

Juan Verdaguer Taradella, MD2

Pedro Bravo C., MD1,4

COLOMBIAAlvaro Rodríguez González, MD2

Angela María Fernández Delgado, MD1,4

Angela María Gutiérrez Marín, MD1

Carlos Alberto Restrepo Pelaez, MD1

H. Fernando Gómez Goyeneche, MD1,3

Pedro Ivan Navarro Naranjo, MD1

COSTA RICAJavier A. Montero Alpizar, MD1

Joaquín Martínez Arguedas, MD3

Lihteh Wu, MD4

Teo Evans, MD1

CUBACaridad Chiang Rodríguez, MD1

Carlos Alberto Perea Ruiz, MD1

Marcelino Rio Torres, MD3

Reinaldo Ríos Caso, MD1

DOMINICAN REPUBLICJoaquin Lora Hernández, MD1

Miguel Angel López Pimentel, MD1

Miriam Cortina, MD3

ECUADORGregorio Gabela, MD1,4

Patricio Flor Arteaga, MD1

Ximena Velasteguí Camorali, MD3

EL SALVADORCarlos Eduardo Alas Gudiel, MD1

Jaime Ricardo Avila Guerra, MD3

Rodrigo Antonio Quesada Larez, MD1

GUATEMALAPaulina Castejón, MD1

Rudy Oliver Gutiérrez Díaz, MD1,3

HAITIFrantz Large, MD3

HONDURASDoris Alvarado de Jaúregui, MD1,3

Sergio Rolando Zúñiga Castillo, MD1

MEXICOCecilio Francisco Velasco Barona, MD4

Enrique L. Graue Wiechers, MD2

Humberto Ruiz Orozco, MD1,3

José Luis Tovilla Canales, MD4

Lourdes Arellanes, MD4

María Estela Arroyo Yllanes, MD4

Raul Macedo Cué, MD1

NICARAGUASylvia Bravo Mendiola, MD1,3

PANAMABenjamín F. Boyd, MD2

Félix Emilio Ruiz Díaz, MD1,3

Miguel Fco. Wong Tang, MD1

PARAGUAYCirila Espinola de Ruiz Díaz, MD1,3

Miriam R. Cano, MD1

PERUDino Fernando Natteri Marmol, MD1

Francisco Contreras Campos, MD2

Juan Carlos Corbera Gonzalo, MD1

Juan Fernando Mendiola Solari, MD1

Miguel Guzmán Ahumada, MD3

Rocío Ardito Vega, MD1

PORTUGALEduardo José Gil Duarte Silva, MD PhD1

Maria Manuela Pires Carmona, MD1,3

PUERTO RICOIan Piovanetti Pérez, MD1,3

María Hortencia Berrocal, MD1

SPAINCarlos Cortés Valdés, MD1

Luis Fernández Vega Sanz, MD3

Miguel A. Zato Gómez de Liaño, MD PhD1

URUGUAYAlicia Martínez de Pacheco, MD1

María del Rosario Varallo, MD1

Miguel Zylberglajt Cordones, MD1,3

USAAlice R. McPherson, MD2

Andrew G. Lee, MD1

Anthony C. Arnold, MD1

Arun D. Singh, MD4

Bradley Dean Fouraker, MD1

Bradley R. Straatsma, MD JD2

Carl D. Regillo, MD1

Charles M. Zacks, MD1

David K. Coats, MD1

Eduardo C. Alfonso, MD1

George A. Williams, MD1

J. Bronwyn Bateman, MD2

James P. McCulley, MD1

John A. Irvine, MD1

Nelson R. Sabates, MD1

Paul R. Lichter, MD2

Richard K. Parrish, II, MD1

Richard L. Abbott, MD2

Robert B. Bhisitkul, MD PhD1

Robert C. Drews, MD2

Robert Ritch, MD1

Ruth D. Williams, MD3

Stephanie Jones Marioneaux, MD1

Stuart R. Seiff, MD1

VENEZUELAClaudia Luz Pabón Bejarano, MD1

Luis Felipe Rivero Caret, MD1

María Angélica Cortez Bernal, MD1

Morayma Coromoto Acevedo Sorondo, MD3

Oscar Vicente Beaujón Balbi, MD1

WEST INDIESDonovan Calder, BSc MBBS FRCS3

Terrence Allan, BSc MBBS FRCS1

PAAO BOARD OF DIRECTORS 2011-2013

PAN-AMERICA 99PAN-AMERICA

EDITORIAL

2012 has passed, the Mayan and Aztec prophecies failed, and we are still here as humanity. Let’s celebrate!

In my first year in the position of Editor-in-Chief of VPA, I have a lot of reasons to celebrate and congratulate my fellow Pan-Americans.

After an exceptional work done by the Brazilian designer Felipe Ferrari Marques from Agenzia Comunicação, Vision Pan-America assumed its new visual identity and became Vision Pan-America, The Pan-American Journal of Ophthalmology. More than just signaling a design change, the new visual identity led to the inclusion of extremely important bibliometric elements, preparing our scientific journal to deal with contemporary indexing database requirements.

Thanks to a great team effort by our Editorial Board, this year we published four beautiful issues with reviews on contemporary subjects, compelling original articles and intriguing case reports on various subjects, sent from scientists from all over the Americas, proving our vocation of being the harbinger of the Pan-American science. We kept an average of 33 days to fully review a submitted paper and 77 days to publish it. We have a record of 82% of papers approved after peer review and 18% of declination, similar to iconic and well-established ophthalmology journals.

Special pages such as Message of the President and PAAO Advocacy were fundamental in offering to our members an overview on highly pertinent issues related

Paulo E.C. Dantas, M.D.Editor-in-Chief Vision Pan-America, The Pan-American Journal of [email protected]@me.com

to our profession and became the necessary bridge to communicate with our members and readers.

With the new submission management software at http://journals.sfu.ca/paao, the editorial process, from submission to publication, was made easier and accessible to all Pan-Americans. Besides the printed journal, VPA is published online and can be accessed and read on any personal computer, laptop, iPad and mobiles such as iPhone.

In 2013, we hope to celebrate more achievements such as indexation on relevant databases, more pages, more scientific articles, bringing to you an even more complete and fundamental learning and scientific tool.

Happy, healthy and fruitful 2013 to everyone!

A pretty rich year… and more to come!

EditorialPaulo E.C. Dantas, MD Editor-in-Chief

Unbelievable!

100 PAN-AMERICA

Vis. Pan-Am. 2012;11(4):100

Message from the PresidentDr. Mark MannisPresidente, Asociación Panamericana de OftalmologíaPresident, Pan-American Association of Ophthalmology

Leadership and Investment

It is a wonderful and exciting time to be an ophthalmologist. I have pondered this more often recently as I watch my youngest child begin her training as an ophthalmology resident this year. I am excited for her and for all beginning residents who are starting their careers in an era in which there is an explosion of knowledge, increasing access to information through technology, advances in therapy that give hope for cures to diseases previously thought untreatable, and technical surgical achievements that are revolutionizing vision care.

At the same time, ophthalmology in the Americas is besieged on all sides—by governmental agencies that devalue our training and work and by other para-medical professions who, without medical degrees, strive to assume leadership in medical as well as surgical vision care. For this reason, quality leadership in Pan-American ophthalmology is more crucial than ever before. The PAAO is dedicated to ensuring that education in ophthalmology throughout the Americas is at the highest level, and to this end, we are cultivating leaders who will carry us through the coming century.

New leadership in the Pan-American is crucial to our profession in the 21st century. Leadership can take the form of organizing courses and regional meetings, representing ophthalmology before governments and

regulating agencies, or simply active participation in one of the committees of the PAAO.

Although there is not a widespread culture of philanthropy in Latin America, leadership can also be expressed by providing financial support to the PAAO through the Pan-American Foundation. Donated funds enable us to go forward with new programs for our membership—programs that raise the level of ophthalmic care throughout the Americas. I would like to thank all those true leaders who have given so generously to the Pan-American Foundation to support the work of the PAAO and especially those who have become members of the Circle of Vision through their generosity. This generosity is a true investment in the future of Pan-American ophthalmology that will yield significant benefits. We hope that all Pan-American leaders will invest in the organization by contributing to its programming and by supporting it financially.

We have a bright and wonderful ophthalmic future in the Americas, but we must make it happen.

Mark MannisPresidentPan-American Association of Ophthalmology


Medina CA et al. Novel Concepts in High Risk Corneal Allotransplants

Corresponding Author:

Victor L. Perez, MD Bascom Palmer Eye Institute, 1638 Nw. 10th Avenue Mc Knight Building 60Miami, Fl. 33136 USA.Tel: 305 326 6302

ABSTRACT

Corneal allotransplantation has been the principal surgical treatment for vision loss caused by diseases of the cornea that result in scarring and opacification. Most authors define a “high-risk” cornea as that of a previously failed corneal graft or a cornea with vascularization in at least 2 quadrants. These high-risk corneal transplants have rejection rates approaching 70%, even with maximal local and systemic immune suppression. The management of high risk corneal transplants, which until recently was a slowly evolving field in ophthalmology, remains a highly controversial yet important topic. Management of these high-risk transplants has developed rapidly in the past 10 years. In this review, some of the challenges and controversies associated with high-risk corneal allotransplantation therapy will be discussed.

INTRODUCTION

Corneal allotransplantation has been the principal surgical treatment for vision loss caused by diseases of the cornea that result in scarring and opacification.1 Penetrating keratoplasty is the oldest and most common form of human solid tissue transplantation. The success of penetrating keratoplasty is high, with 5 year survival rates as high as 90%.2 This is in part due to the fact that the cornea has long been recognized as “immune privileged”. Regularly these “normal risk” corneal transplants, where the donor cornea is grafted into an avascular, non-inflamed non-sensitized eye, need only local immunosuppression with medications such as topical corticosteroids. Although dosing is easy and systemic side effects are low, long-term use of corticosteroids carries multiple risks in the eye such as infection, poor wound healing, glaucoma and cataracts. On the other hand, “high-risk” corneal transplant

Novel concepts in the immunology andtreatment of vascularized high-risk corneal allotransplants

Carlos A. Medina MD1, Sander R Dubovy MD2,3, Eduardo Alfonso MD4, Payman Haft MD4, Victor L. Perez MD4,5*

1. University of Pittsburgh Medical Center-Department of Ophthalmology, University of Pittsburgh, Pittsburgh PA. USA2. Bascom Palmer Eye Institute - Department of Ocular Pathology – University of Miami, Miami Fl. USA 3. Florida Lions Eye Bank, Miami Fl. USA4. Bascom Palmer Eye Institute - Cornea Department – University of Miami Miami Fl. USA5. Bascom Palmer Eye Institute Ocular Immunology and Transplantation Laboratory – University of Miami

Acknowledgment: Guillermo Amescua MD, Bascom Palmer Eye InstituteFunding Provided By: K08 EY014912-05 (VLP), R01 EY018624-01 (VLP), P30 EY014801, Research to Prevent Blind-ness, The University of Miami and the Florida Lions Eye Bank.

Date of submission: 12/08/2012 / Date of approval: 19/10/2012

prognosis is poor. These high-risk corneal grafts have rejection rates approaching 70% even with maximal local and systemic immune suppression. Strikingly, these rejection rates are even higher than those seen with living donor kidney transplantation, where five year survival rates are above 80%.3,4 The management of high-risk corneal transplants, which until recently was a slowly evolving field in ophthalmology, remains a highly controversial yet important topic.

BACKGROUND

Although not universally accepted, most authors define a “high-risk” cornea as that of corneas that have previously rejected a graft or a cornea with vascularization in at least 2 quadrants.5 Recent studies from multiple laboratories6-11 have shown that corneal neovascularization disrupts the immune privilege, otherwise enjoyed by naïve corneas. This “immune privilege,” first observed in the late 1800s by van Dooremaal and later extensively studied by Streilein is now known as anterior chamber associated immune deviation (ACAID).12,13 ACAID involves the eye, spleen, thymus and sympathetic nervous system.14 Multiple factors compose ACAID. One of these, transforming growth factor beta (TGF-Beta), is essential in the induction of ACAID.15 Antigen presenting cells exposed to TGF-B produce increased levels of IL-10, decreased levels of IL-12 and downregulate CD 40 co-stimulatory molecules. Regulatory T cells (CD4+ CD25+) have been shown to inhibit target cells by making direct contact.13,16-19 ACAID’s immunomodulatory role is essential for the maintenance of a clear cornea. It prevents excessive inflammation, scarring and, thus preserves corneal clarity. This occurs in the presence of foreign antigen from infection, or in transplantation, yet it permits a degree of immunologic protection against infection. The disruption of ACAID and its resultant neovascularization produces a host-mounted immune

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response more similar to that of vascularized solid tissue transplants than to naïve avascular corneas.7 In these high-risk corneas, rejection rate and tempo are directly proportional to the amount of vascularization in the recipient bed.20-22 In vascularized grafts, the recruitment of allospecific T cells by chemokines is seen very early. These allospecific T cells have been shown to promote destruction of endostatin-producing cells, resulting in increased corneal neovascularization, massive infiltration of effector T cells and graft rejection.23

Several factors have been known to confer a high-risk status to a corneal transplant. These include the proliferation of blood vessels and lymphatic channels, especially in the corneal deep stroma, increased MHC II expression, maturation of dendritic cells, chemokine production, and interruption of the blood-ocular barrier.17 It is well established that the risk of rejection is increased in regrafts. This is especially true when two or more grafts have been previously rejected.24 Although still controversial, it has been postulated that the increase in rejection rate is due to the neovascularization related to the rejection process of the previous cornea and not to allosensitization.25 Other host factors associated with a greater risk of rejection are uveitis, herpes simplex keratitis, atopic dermatitis and eczema. Active inflammation and/or infection during surgery greatly increase the probability of graft failure due to rejection. Other high-risk associations have been reported and include vitreous adhesions, multi-surgical approach, young recipient age, larger graft size, and eccentric grafts.24,26

Glaucoma is an important risk factor for graft failure but not graft rejection.27-29

The rejection of high-risk vascularized corneal allografts is an immunological process mediated principally by allospecific T cells.30-35 The use of immunosuppressive agents in high-risk corneal transplantation is associated with a high rate of systemic complications. A better understanding of how allospecific T cells mediate high-risk corneal allograft rejection may lead to the development of new and safer forms of anti-rejection therapy. Several laboratories, including ours, are dedicated to the understanding of high-risk corneal transplant kinetics. We have previously shown that high-risk vascularized corneal allografts behave like vascularized solid organ transplants.7 In these transplants, the production of early inflammatory signals is extremely important in regulating the subsequent production of T-cell chemo-attractants responsible for T-cell recruitment, and the increased rejection rate observed in high-risk vascularized corneal allografts. The modulation of these cytokines by upregulation, downregulation, blockade or mimicry may play a role in the treatment and prevention of rejection.

DETECTION OF ALLOGRAFT REJECTION

Early detection of graft rejection is essential. Regular frequent follow-ups as well as patient compliance are of paramount importance. Patient symptoms, including red eye tearing, photophobia, hyperemia and loss of vision are strongly associated with graft rejection.36 Therefore, patients should be instructed to advise the physician of any acute changes. Although further studies need to be performed in humans, we have shown in mice that corneal thickness measurements using spectral domain OCT as early as postoperative day 15 are a good predictor for graft outcome.37,38 The quantification of corneal edema, combined with early detection of endothelial loss and assessment clinical acute changes of signs and symptoms can lead to early detection and prompt treatment of graft rejection.

Epithelial rejection is the earliest form of rejection to be seen. An epithelial rejection line (deposits of lymphocytes) usually stains with fluorescein or Rose Bengal.39 Kaye’s dots (epithelial infiltrates) appear at the suture lines. Epithelial rejection is followed by endothelial rejection, which is the most common form of graft rejection. Fine keratic precipitates or a Khodadoust line of precipitates may be seen.40-42 The rejection episode is irreversible once endothelial decompensation is established, thus immediate treatment is warranted.41

MEDICAL MANAGEMENT

Since it is easier to prevent rejection than to stop rejection once it has started, prophylaxis is essential in the management of high-risk patients. Prophylaxis should be individualized according to the risk of rejection, and perhaps the primary cause of insult (Stevens-Johnson, caustic burn, failed graft, infection, etc). This is followed by topical steroids (1% prednisolone acetate) four times a day for the first 4 months and then slowly tapered off during a period of 2 more months. In the case of moderate to high-risk patients, a longer and more intense corticosteroid regimen is needed. Clinical practice varies widely. This is probably due to the fact that there is a scant amount of evidence-based clinical observations. We usually give 1% prednisolone acetate drops every 2 hours with a corticosteroid ointment at night. The dose is slowly tapered off over a period of 6 months and a low potency steroid is continued indefinitely. Based on evidence showing early inflammatory responses, we give patients with high-risk corneal grafts a one gram dose of methylprednisolone (Solu-medrol®, Pfizer) at the time of surgery and oral prednisone at 1mg/kg/day, with quick tapering over a month. In cases where adjunctive therapy is needed, either because of steroid side effects or ineffective treatment, topical cyclosporine A (0.5-2.0%) is added as our first line of adjunctive treatment.


Medina CA et al. Novel Concepts in High Risk Corneal Allotransplants

Cyclosporine A is a powerful immunomodulator that inhibits the proliferation of activated and cytotoxic T-lymphocytes and spares the T-suppressor cell populations that have been shown to prevent rejection of high-risk corneal allografts.42 Several authors have found systemic immunosuppression with cyclosporine A partially helpful. This practice has become less widely accepted in the last few years due to the high rate of side-effects.43-45 On the other hand, topical cyclosporine A has a more significant effect than systemic cyclosporine, with fewer side effects. Tacrolimus and Mycophenolate Mofetil have also been found to be helpful.46-50 (Figure 1A and B) Once rejection is detected, aggressive treatment is warranted. The mainstay of treatment is still topical corticosteroids. Several treatment options proposed in the literature have been summarized below. (Table 1)

FUTURE

Our knowledge of the immunology of corneal rejection has grown several folds in the last few decades. We are just beginning to understand the complex kinetics of cytokine production at the site

Table 1: Treatment proposed in the literature

Treatment Route Mode of Action Dose

Corticosteroids Topical Phospholipase A2 inhibitor Preoperatively four times a day for one week. Postoperatively hourly for 3 days, every 2 hours for 15 days, four times a day for 2 months, twice a day for 3 months, once a day for 4 months.

Corticosteroids Intrastromal Phospholipase A2 inhibitor At the time of diagnosis of acute rejection. 10ul of betamethasone injected intrastromally with a 30-gauge tuberculin syringe.61

Corticosteroids Oral Phospholipase A2 inhibitor, reduce the number of circulating T cells.

Combined with topical corticosteroids, it should be given at a dose of 60-80mg./day. Doses may be higher for cases of acute rejection. It should be tapered off slowly.

Corticosteroids IV. Phospholipase A2 inhibitor, reduce the number of circulating T cells.

Pulsed IV methylprednisolone treatment should be combined with topical corticosteroids and given at a dose of 500mg in 150 ml. The benefi cial effect of a second pulse is doubtful.

Azathioprine Oral Cytotoxic agent that inhibits cell replication. Given in conjunction with topical corticosteroids at a dose of 1-2mg/kg/day.62

Cyclosporin A Topical Powerful immunosuppressant that acts at the early stages of antigenic sensitization.

Reduces IL-2 production.

Combined with artifi cial tears or oil in a 0.5-2% solution. Given 5 times per day in conjunction with a topical corticosteroid. Monitoring of liver and renal function is required.63,64

Cyclosporin A Oral, IV. Powerful immunosuppressant that acts at the early stages of antigenic sensitization.

Reduces IL-2 production.

Recommended dosage is 15 mg/kg/day for 2 days followed by 7.5 mg/kg/day for two days. A maintenance dose should be adjusted to accomplish blood levels of 100-200ug for 1-6 months.

Monitoring of liver and renal function is required.44,65

FK-506 (Tacrolimus) Topical Similar to Cyclosporin A, acts by binding FK binding protein (an immunophyllin). 10-100

times more potent than Cyclosporin A.

0.03%, twice daily, tapered to the lowest possible therapeutic dose.66

FK-506 (Tacrolimus) Oral Similar to Cyclosporin A, acts by binding FK binding protein (an immunophyllin). 10-100

times more potent than Cyclosporin A.

In addition to topical steroids, 2-12 mg daily (0.125 mg/kg/day) by mouth for at least one year. Trough levels from 1-12 ng/ml (we prefer 5-7ng/ml).46,47

Rapamycin Oral Binds to FB binding protein therefore inhibiting immunophilimactivity.Interferes with

IL-2 induced signals.

In addition to topical and/or systemic steroids, Blood trough level 4-10 ng/ml for 6 months. Thereafter it should be tapered over 2 weeks.48

of transplantation; this will enhance the possibility of creating localized immunosuppression favorable to the graft with little or no systemic side effects. Promising immunomodulating drugs that may help suppress T-effector or activate T-regulatory cells are currently being studied.51 Our growing knowledge in the function of regulatory T-cells and their interaction with corneal allotransplantation is also opening a new field of research for the treatment of rejection.52,53 Currently, most of our treatments are administered topically to the corneal epithelium. This requires multiple applications and patient compliance. Gene therapy could enable us to treat a specific molecular mechanism of disease in a single dose.54 This could decrease reliance on patient compliance and side effects, which should enhance treatment outcomes. The cornea is an excellent site for gene therapy. Its anatomy, immune privilege, (ACAID) and accessibility make it an optimal target tissue.55 On the other hand, the prevention of a vascularization, or its regression, has been a big field of research.8 Recent publications have shown that by blocking vascular endothelial growth factor (VEGF), postoperative hemangiogenesis and lymphangiogenesis may be

Figure 1A) Right eye of a 30 year old patient who suffered from an alkali burn. The patient underwent an autologous conjunctival stem cell autograft followed by corneal transplantation 6 months after his autograft. He was initially treated with oral Tacrolimus and topical prednisone which where completely tapered after 8 months and transitioned to topical Tacrolimus twice a day. (Courtesy of Dr. Guillermo Amescua - Bascom Palmer Eye Institute)

B) 100 x hematoxylin and eosin stain of a high risk corneal button. (*) Bowman’s layer is absent and has been replaced by superfi cial stromal scarring. (Arrows) Areas of neovascularization are present through the corneal stroma. (Triangle) Chronic infl ammation composed mostly of lymphocytes and plasma cells is present in the corneal stroma. The endothelium is attenuated.

Figure 1 A

Figure 1 B

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11. Dana, M.R. and J.W. Streilein, Loss and restoration of immune privilege in eyes with corneal neovas-cularization. Invest Ophthalmol Vis Sci 1996 37(12):2485-94.

12. Niederkorn, J., J.W. Streilein, and J.A. Shadduck, Deviant immune re-sponses to allogeneic tumors injected intracamerally and subcutaneously in mice. Invest Ophthalmol Vis Sci 1981 20(3):355-63.

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15. Creyghton, W.M., H.J. Volker-Dieben, and M.J. Jager, Transforming growth factor beta2 levels in aqueous humor during corneal transplantation and cataract surgery. Ocul Immunol Infl amm 1995 3(1):29-36.

16. Streilein, J.W., Tissue barriers, im-munosuppressive microenvironments, and privileged sites: the eye’s point of view. Reg Immunol 1993 5(5):253-68.

17. Chong, E.M. and M.R. Dana, Graft failure IV. Immunologic mechanisms of corneal transplant rejection. Int Ophthalmol 2007.

18. Williams, K.A. and D.J. Coster, The immunobiology of corneal transplantation. Transplantation 2007 84(7):806-13.

19. Niederkorn, J.Y., The induction of anterior chamber-associated immune deviation. Chem Immunol Allergy 2007 92:27-35.

20. Alldredge, O.C. and J.H. Krach-mer, Clinical types of corneal trans-plant rejection. Their manifestations, frequency, preoperative correlates, and treatment. Arch Ophthalmol 1981 99(4):599-604.

21. Arentsen, J.J., Corneal transplant allograft reaction: possible predispos-ing factors. Trans Am Ophthalmol Soc 1983 81:361-402.

22. Khodadoust, A.A. and A.M. Sil-verstein, Transplantation and rejection of individual cell layers of the cornea. Invest Ophthalmol 1969 8(2):180-95.

23. Tan, Y., et al., Immunological disruption of antiangiogenic signals by recruited allospecifi c T cells leads to corneal allograft rejection. J Immunol 2012 188(12):5962-9.

24. Maguire, M.G., et al., Risk factors for corneal graft failure and rejection in the collaborative corneal transplantation studies. Collaborative Corneal Transplantation Studies Research Group. Ophthalmology 1994 101(9):1536-47.

25. Boisjoly, H.M., et al., Effect of factors unrelated to tissue matching on corneal transplant endothelial rejection. Am J Ophthalmol 1989 107(6):647-54.

26. Dua, H.S. and A. Azuara-Blanco, Corneal allograft rejection: risk factors, diagnosis, prevention, and treatment. Indian J Ophthalmol 1999 47(1):3-9.

27. Khvatova, A.V. and A.V. Pleskova, [Experience in penetrating kerato-plasty in children: graft survival, functional results and risk factors].

Vestn Oftalmol 2003. 119(5):3-7.

28. Rumelt, S., et al., Preexisting and postoperative glaucoma in repeated corneal transplantation. Cornea 2002 21(8):759-65.

29. Thompson, R.W., Jr., et al., Long-term graft survival after penetrating keratoplasty. Ophthalmology 2003 110(7):1396-402.

30. Boisgerault, F., et al., Role of CD4+ and CD8+ T cells in al-lorecognition: lessons from corneal transplantation. J Immunol 2001 167(4):1891-9.

31. Niederkorn, J.Y., The immune privilege of corneal allografts. Trans-plantation 1999 67(12):1503-8.

32. Sano, Y., B.R. Ksander, and J.W. Streilein, Murine orthotopic corneal transplantation in high-risk eyes. Rejection is dictated primarily by weak rather than strong alloantigens. Invest Ophthalmol Vis Sci 1997 38(6):1130-8.

33. Sano, Y., B.R. Ksander, and J.W. Streilein, Analysis of primed donor-specifi c T cells in recipient mice bearing orthotopic corneal allografts. Transplantation 2000 70(9):1302-10.

34. Sonoda, Y., et al., Characterization of cell-mediated immune responses elicited by orthotopic corneal al-lografts in mice. Invest Ophthalmol Vis Sci 1995 36(2): 427-34.

35. Yamada, J., I. Kurimoto, and J.W. Streilein, Role of CD4+ T cells in immunobiology of orthotopic corneal transplants in mice. Invest Ophthal-mol Vis Sci 1999 40(11):2614-21.

36. Kamp, M.T., et al., Patient-report-ed symptoms associated with graft reactions in high-risk patients in the collaborative corneal transplantation studies. Collaborative Corneal Trans-plantation Studies Research Group. Cornea 1995 14(1):43-8.

37. B. J. Sinicrope, C.M., M. Ruggeri, S. Jiao, J. Wang, M. West, and V. L. Perez., Correlation of Murine Anterior Segment Spectral Domain Optical Coherence Tomography Analysis With Corneal Allograft Rejection. Invest. Ophthalmol. Vis. Sci 2008 49(E-Abstract 5754).

38. McDonnell, P.J., et al., Corneal thickness changes after high-risk penetrating keratoplasty. Collaborative Corneal Transplantation Study Group. Arch Ophthalmol 1993 111(10):1374-81.

39. Norn, M., Double vital staining of corneal epithelium after corneal transplantation with a rose bengal-fl uorescein mixture. Acta Ophthalmol (Copenh) 1988 66(6):699-704.

40. Haft P, K.G., Goldman DA, Corneal Transplant Rejection. Expert Reviews 2008 3(3):293-297.

41. Panda, A., et al., Corneal graft rejection. Surv Ophthalmol 2007 52(4):375-96.

42. Belin, M.W., et al., Topical cyclosporine in high-risk corneal transplants. Ophthalmology 1989 96(8):1144-50.

43. Algros, M.P., et al., Danger of systemic cyclosporine for corneal graft. Cornea 2002 21(6):613-4.

44. Poon, A.C., et al., Systemic cyclosporin A in high risk penetrating keratoplasties: a case-control study. Br J Ophthalmol 2001 85(12):1464-9.

45. Kaminska, A., et al., [Immunologi-cal aspects of corneal graft rejection and own experience in immunosup-pressive therapy in high risk patients]. Klin Oczna 2004 106(3 Suppl):485-8.

46. Sloper, C.M., R.J. Powell, and H.S. Dua, Tacrolimus (FK506) in the management of high-risk corneal and limbal grafts. Ophthalmology 2001 108(10):1838-44.

47. Joseph, A., et al., Tacrolimus immunosuppression in high-risk corneal grafts. Br J Ophthalmol 2007 91(1):51-5.

48. Birnbaum, F., et al., Immuno-suppression with cyclosporine A and mycophenolate mofetil after penetrating high-risk keratoplasty: a retrospective study. Transplantation 2005 79(8):964-8.

49. Reinhard, T., et al., [Mycophe-nolate mofetil after penetrating high risk keratoplasty. A pilot study]. Klin Monatsbl Augenheilkd 1999 215(3):201-2.

50. Randleman, J.B. and R.D. Stulting, Prevention and treatment of corneal graft rejection: current practice patterns (2004). Cornea 2006 25(3):286-90.

51. CA. Medina-Mendez, A.S., G. Amescua, V. L. Perez., Role of CXCL10/IP10 Production in High Risk Corneal Allograft Transplanta-tion. Invest. Ophthalmol. Vis Sci 2008 49( E-Abstract 3721).

52. Xi, J., et al., [CD4+CD25+ T cells involved in induction of rat corneal allograft immune tolerance]. Zhonghua Yan Ke Za Zhi 2007 43(12):1114-8.

53. Jie, Y., et al., Upregulation of CD4+ NKT cells is important for al-lograft survival in staphylococcal-en-terotoxin-B-treated rats after high-risk corneal transplantation. Ophthalmic Res 2007 39(3):130-8.

54. Williams, K.A., C.F. Jessup, and

D.J. Coster, Gene therapy approaches to prolonging corneal allograft survival. Expert Opin Biol Ther 2004 4(7):1059-71.

55. Joyce, N.C., Proliferative capacity of the corneal endothelium. Prog Retin Eye Res 2003 22(3):359-89.

56. Shi, W., et al., FK506 in a biodegradable glycolide-co-clatide-co-caprolactone polymer for prolongation of corneal allograft survival. Curr Eye Res 2005 30(11):969-76.

57. Shi, W., et al., Sustained intra-ocular rapamycin delivery effectively prevents high-risk corneal allograft rejection and neovascularization in rabbits. Invest Ophthalmol Vis Sci 2006 47(8):3339-44.

58. Wu, X.G., et al., The biological characteristics and pharmacody-namics of a mycophenolate mofetil nanosuspension ophthalmic delivery system in rabbits. J Pharm Sci 2010.

59. Kagaya, F., et al., Intraocular dexamethasone delivery system for corneal transplantation in an animal model. Cornea 2002 21(2):200-2.

60. de Rojas Silva, M.V., et al., Effi cacy of subconjunctival cyclosporin-containing microspheres on keratoplasty rejection in the rabbit. Graefes Arch Clin Exp Ophthalmol 1999 237(10):840-7.

61. Arenas, E., E. Navarro, and M.A. Mietha, Aplicacion de corticoester-oides intracorneanos de depositon en el tratamiento de rechazo de queratoplastia. Archivos de la Socie-dad Española de Oftalmologia 2004 79(2):75-79.

62. Nguyen, P., et al., Management of Corneal Graft Rejection - A Case Series Report and Review of the Literature. J Clin Exp Ophthalmol 2010 1(103).

63. Sinha, R., et al., Effi cacy of topical cyclosporine A 2% in prevention of graft rejection in high-risk kerato-plasty: a randomized controlled trial. Graefes Arch Clin Exp Ophthalmol 2010 248(8):1167-72.

64. Inoue, K., et al., Long-term effects of topical cyclosporine A treatment after penetrating keratoplasty. Jpn J Ophthalmol 2000 44(3):302-5.

65. Hill, J.C., Systemic cyclosporine in high-risk keratoplasty: long-term results. Eye (Lond) 1995 9 ( Pt 4):422-8.

66. Dhaliwal, J.S., B.F. Mason, and S.C. Kaufman, Long-term use of topi-cal tacrolimus (FK506) in high-risk penetrating keratoplasty. Cornea 2008 27(4):488-93.

inhibited. This in turns leads to a decrease in recruitment of antigen presenting cells and therefore an improvement in graft survival.6 Ultimately, antiangiogenesis in its self may prove inadequate in preventing rejection and combined antiangiogenesis and immune suppression will be more effective in maintaining corneal allograft survival.23

The future of high-risk corneal transplantation is promising. Utilizing animal models, promising treatments are currently being developed. Our knowledge of the pathophysiological mechanisms of corneal disease has greatly increased in the last several years. Few of the current treatments reflect our newly

acquired knowledge and are, therefore, non-specific for the actual mechanism of disease. The anterior segment is a perfect model for slow drug delivery systems that are currently being developed. These include sustained release polymers, nanoparticles and implants that can be placed both inside the eye or in the subconjuntival space.56-60 These novel delivery systems combined with recent advances in the field of angiogenesis (VEGF inhibitors), localized immunomodulation, gene therapy as well as better surgical techniques where lower antigen load is transplanted are making their way to the bedside.


Alvarez RE & Sotero JG. Morfometria corneal in vivo after LASIK.

Morfometría corneal in vivo versusmagnitud de la ametropía en pacientes operados con láser de excímeros por la técnica LASIK

ABSTRACT

Purpose: To establish the correlation between morphometric corneal changes and the magnitude of the ametropia treated by excimer laser (LASIK) until the year of the surgery.

Design: Observational, descriptive, longitudinal and prospective investigation

Method: The studied group was comprised of 78 patients (151 eyes) operated with LASIK with a pendular microkeratome at the Abel Santamaría Hospital of November from November 2010 to June of 2011. Confocal microscopy with ConfoScan 4 (NIDEK) was performed for obtaining and studying the live corneal tissue images. Automatic scans were programmed with central fixation, speed of acquisition of the image to 25 images per second, magnification of 500x, lateral resolution of 0.6 μm/pix, with 350 images for scan, and distances of work of 1,98 mm. Statistical analysis of the variables was done by descriptive statistic, Pearson’s correlation test and linear regression.

Results: After LASIK, a significant statistic correlation was found on the magnitude of the treated ametropia with the following variables: epithelial thickness, pachymetry, stromal residual bed and keratocyte density in the posterior flap or in the retroablation zone.

Conclusions: The higher the magnitude of the ametropia treated with LASIK, the greater the increase in the epithelial thickness in the first half of the postoperative period and, the lower the values of pachymetry, and residual stromal bed, keratocytes density on both sides of the lamellar flap, after one year of treatment.Key words: LASIK, Morfometría, cornea, microscopy confocal.

Key words: LASIK, morphometry, cornea, confocal microscopy.

Resumen

Objetivo: Establecer la correlación entre los cam-bios morfométricos corneales y la magnitud de la ame-tropía tratada hasta el año de cirugía corneal con láser de excímeros por la técnica LASIK.

Diseño: Investigación observacional, descriptiva, longitudinal y prospectiva.

Método: La muestra quedó constituida por 78 pa-cientes (151 ojos) operados con LASIK con microque-rátomo pendular en el Hospital Abel Santamaría Cua-drado en Pinar del Río de noviembre de 2010 a junio de 2011. Se utilizó el microscopio confocal ConfoScan 4 de NIDEK para la obtención y estudio de las imáge-nes in vivo del tejido corneal. Se programó en modo escaneo automático, con fijación central, velocidad de adquisición de la imagen a 25 imágenes por segundo, magnificación de 500x, resolución lateral de 0.6 μm/píxel, con 350 imágenes por escaneo, distancia de tra-bajo de 1,98 mm. Se utilizaron métodos de estadística descriptiva, correlación de Pearson y regresión lineal.

Resultados: Se obtuvo posterior a LASIK correla-ción estadísticamente significativa entre la magnitud de la ametropía tratada y las variables grosor epitelial, paquimetría, lecho estromal residual y densidad de queratocitos en subcapas flap posterior y retroabla-ción anterior.

Conclusiones: Mientras mayor es la magnitud de la ametropía tratada con LASIK, mayor es el aumento del grosor epitelial en el primer semestre de postope-ratorio y menores los valores de paquimetría, lecho es-tromal residual y densidad queratocitaria a ambos lados del corte lamelar, al año de tratamiento.

Palabras claves: LASIK, morfometría, córnea, mi-croscopía confocal.

Date of submission: 21/05/2012 Date of approval: 22/09/2012

Eduardo Rojas Alvarez1, Janet González Sotero1

Funding: NoneProprietary/fi nancial interest: None

1. Especialista I grado Oftalmología. Asistente. Investigador Agregado.Hospital Abel Santamaría. Pinar del Río, Cuba.

Autor correspondiente:

Eduardo Rojas AlvarezPolvorín 158 altos, entre Delicia e Isabel la Católica. Pinar del Río, CP 20 100.Correo: [email protected]

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Introducción

Los trastornos de la refracción (miopía, hipermetropía, astigma-tismo, presbicia) se encuentran entre las alteraciones que con mayor frecuencia constituyen motivo de consulta y tratamiento quirúrgico fre-cuentes en Oftalmología. Su prevalencia varía con la edad, el país, el grupo étnico, el nivel educativo y la ocupación.1-5

Producto al gran desarrollo científico-tecnológico de la Oftalmología y en especial de la cirugía refractiva, la existencia de nuevos equipos lá-ser de alto impacto visual en cuanto a resultados visuales en el mercado internacional conjuntamente con los adelantos en la microscopía óptica han posibilitado el redimensionamiento de los conceptos morfofisio-lógicos del tejido corneal y estudiar fenómenos que hasta hace pocos años eran desconocidos para la especialidad. El estudio microscópico de la córnea posterior a cirugía refractiva corneal con láser de excímeros se ha convertido en los últimos años en tema de investigación recurren-te a nivel internacional, en vistas a obtener resultados in vivo del tejido corneal y por tanto evaluar estas novedosas tecnologías, es por ello que el objetivo de la actual investigación es establecer la correlación entre la magnitud de la ametropía tratada y los cambios morfométricos corneales hasta el año de la cirugía.

Método

Se realizó una investigación observacional, descriptiva, longitudinal y prospectiva. El universo de estudio estuvo constituido por todos los pacientes (146) que fueron intervenidos con láser de excímeros para la corrección de ametropías por el autor con las técnicas quirúrgicas: LASIK con microquerátomo pendular y LASEK, en el Hospital Abel Santamaría Cuadrado en Pinar del Río, de noviembre de 2010 a junio de 2011. La muestra quedó constituida por 78 pacientes (151 ojos) operados con LASIK. Se aplicaron métodos de estadística descriptiva, correlación de Pearson y regresión lineal. Los pacientes otorgaron su consentimiento para la participación en el estudio.

Se estudiaron las siguientes variables: magnitud de la ametropía, densidad de queratocitos, densidad de células del epitelio apical, den-sidad de células del epitelio basal, densidad endotelial, pleomorfismo, polimegatismo, grosor epitelial, grosor del flap, lecho estromal resi-dual y paquimetría.

Criterios de selección.

Criterios de inclusión:

• Edad mayor de 20 años con estabilidad refractiva de 2 años.

• Defecto refractivo: miopía hasta 8 dioptrías, astigmatismo hasta 4 dioptrías, astigmatismo miópico compuesto con menos de 8 diop-trías (en suma algebraica de esfera y cilindro).

• Agudeza visual sin corrección de 0.5 ó menos.

• Agudeza visual con corrección en el ojo de menor visión superior a 0.3.

• Lecho corneal residual programado mayor de 300 micras.

• Queratometría media inicial y programada final entre 36 y 48 diop-trías.

• Paquimetría preoperatoria superior a 500 micras.

Criterios de exclusión:

Generales:

• Pacientes que no cooperaron en la realización de la microscopía confocal.

• Pacientes que no otorgaron su consentimiento para participar en el estudio.

• Enfermedades sistémicas como diabetes mellitus, epilepsia, enfermedades del colágeno, inmunode-primidos, trastornos psiquiátricos, Síndrome Mar-fán, Ehlers Danlos, Psoriasis, alergias.

• Infecciones sistémicas, embarazo y puerperio (has-ta 6 meses).

Oculares:

• Ojo único.

• Alteración de los anexos oculares y de la lágrima (infección, inflamación, ojo seco).

• Configuraciones orbitarias anormales (órbitas pe-queñas o profundas, hendidura palpebral pequeña, enoftalmos, arco superciliar prominente).

• Enfermedad corneal previa (queratitis por herpes simple, zóster, ectasia corneal confirmada o en sospecha, erosiones corneales recidivantes, leuco-mas, pannus, distrofias, degeneraciones).

• Estrabismo o cirugía previa del mismo, cirugía re-fractiva corneal anterior.

• Glaucoma o hipertensión ocular, esclerosis del cristalino o catarata.

• Uveítis, enfermedades de la retina (desgarros, his-toria de desprendimiento de retina, vitrectomía, de-generación macular, retinosis pigmentaria).

Técnica quirúrgica y seguimiento de los pacientes.

Todos los casos fueron operados por el autor de la investigación. La planificación de la cirugía se realizó con el programa ORK-CAM para tratamientos asféricos. El LASIK con microquerátomo pendular (Schwind- Ale-mania), programación de grosor del flap de 160 μm y lecho estromal residual mayor de 300 μm. El trata-miento se realizó con el ESIRIS (Schwind- Alemania) y siguió el siguiente protocolo quirúrgico:

Durante el preoperatorio se realizaron medidas de higiene palpebral y uso de cloranfenicol (colirio of-tálmico) una gota cada cuatro horas, desde 24 horas antes de la cirugía. Durante el transoperatorio se instiló colirio anestésico (Quimefa, Cuba) una gota en el ojo a operar, se realizó aislamiento del área quirúrgica con paño hendido, colocación de blefarostato exponiendo el globo ocular, lavado con solución salina balanceada en fondos de saco conjuntivales, colocación de anillo de succión 9.0 mm en córneas con curvatura superior



o igual a 43.0 dioptrías y anillo de succión 10.0 mm en córneas inferiores a 43.0 dioptrías de curvatura. Se realizó la succión con valores entre 609 y 612 mmHg, corte del flap con microquerátomo pendular Carriazo, ubicación de la bisagra nasal, secado debajo y anterior a la bisagra, enfoque y aplicación del láser con protección de la bisagra, lavado con solución salina balanceada de la zona tratada y la cara estromal del flap, recolocación del mismo en su posición original, procediendo a la limpieza de partículas o residuos que puedan permanecer en el lecho. Secado de los márge-nes y comprobación de la adhesión del flap. Instilación de una gota de cloranfenicol, prednisolona y lágrimas artificiales (Quimefa, Cuba) en fondo de saco inferior. Se realizó biomicroscopía anterior en el quirófano con el objetivo de precisar adhesión y regularidad del colgajo así como la ausencia de cuerpos extraños en la interfase.

Se realizaron consultas a las 24 horas, siete días, al mes, tres, seis meses y al año poscirugía. Se realizaron los exámenes programados por consulta (agudeza visual sin corrección, topografía corneal, refracción dinámica). No existieron complicaciones postoperatorias hasta el año de la cirugía. La agudeza visual sin cristales fue la pro-gramada previamente y permaneció sin variaciones durante todo el año en todos los casos. Todos los pacientes cumplieron el seguimiento.

Técnica de microscopía confocal de la córnea.

Se utilizó el microscopio confocal ConfoScan 4 de NIDEK para la obtención y es-tudio de las imágenes in vivo del tejido corneal. Se acopló el anillo Z para la fijación del globo ocular con el lente 40x. Se programó en modo escaneo automático, con fijación central, velocidad de adquisición de la imagen a 25 imágenes por segundo, magnificación de 500x, resolución lateral de 0.6 μm/píxel, con 350 imágenes por escaneo, distancia de trabajo de 1,98 mm.

Se instiló lidocaína (colirio anestésico, Quimefa) y posteriormente Viscotears (ungüento oftálmico) como medio de acoplamiento entre la córnea y el anillo Z. Se avanzó el lente hasta hacer contactar el anillo con la sustancia de acoplamiento. El lente objetivo fue alineado con el centro de la córnea hasta observar las primeras imágenes de epitelio corneal. Las imágenes digitales obtenidas fueron capturadas en modo automático y grabadas en computadora Pentium 4 con ambiente Windows 2000 para su posterior análisis. Antes y después de cada examen se realizó la lim-pieza del lente objetivo con isopropyl alcohol. Cada imagen obtenida se encuentra separada de la imagen adyacente por 4 micras, una profundidad de campo de 25 μm, nivel de intensidad de 0 a 255, presión del anillo Z de 20 %. Todas las tomas pertene-cen a los 4 mm centrales de la córnea. (Anexo 1) Ninguno de los sujetos experimentó síntomas visuales o complicaciones corneales durante o posterior al examen.

Se realizó microscopía confocal de la córnea en el preoperatorio, a los siete días, un mes, tres, seis meses y al año de la cirugía. Se realizaron los exámenes necesarios en cada paciente hasta obtener, por microscopía confocal cuantitativa de enfoque completo (curva CMTF), escaneos e imágenes de máxima estabilidad en cuanto a presión aplicada por el anillo Z con variaciones inferiores al 10 %, representado por la curva amarilla. Las imágenes seleccionadas no fueron modificadas en brillo y con-traste, fueron codificadas para realizar el análisis sin conocer el momento postopera-torio, la magnitud de la ametropía tratada y la técnica quirúrgica utilizada.

Resultados

La Tabla 1 muestra la correlación entre la magnitud de la ametropía y la densidad de células del epitelio basal y apical en diferentes momentos postoperatorios de LASIK. Se mantienen valores bajos de correlación no significativos entre magnitud de la ametropía y densidad de células a estos niveles epiteliales.

La Tabla 2 muestra una correlación directa significativa entre magnitud de la ame-tropía y grosor epitelial en varios momentos del postoperatorio de LASIK: a los siete días, uno, tres y seis meses. Esta correlación fue mayor a los siete días de postope-ratorio con disminución paulatina hasta no existir correlación significativa al año de la

cirugía. El grosor del epitelio corneal es mayor cuanto mayor es la magnitud de la ametropía tratada, hasta los seis meses posteriores a LASIK.

La Tabla 2 muestra además la correlación inversa significativa entre magnitud de la ametropía y paqui-metría, con un aumento progresivo de esta correlación hasta el año de la cirugía. La paquimetría corneal es menor cuanto mayor es la magnitud de la ametropía tra-tada por LASIK. En el caso del grosor del flap se obtuvo una correlación directa significativa en todo momento del postoperatorio, mayor a los siete días posLASIK, es decir, el grosor del flap es mayor cuanto mayor es la magnitud de la ametropía tratada.

Variables Pearson p

Densidad células epitelio basal

preoperatorio7 días1 mes3 meses6 meses1 año

-0,0150,0420,0270,0490,057-0,028

0,8510,6090,7420,5520,4840,737

Densidad células epitelio apical


-0,0820,027-0,0210,0160,027-0,119

0,3180,7460,8010,8480,7450,147

Tabla 1: Correlación entre magnitud de la ametropía y densidad de células epiteliales en LASIK.

Variables Pearson p

Grosor epitelial


0,1330,774(*)0,768(*)0,750(*)0,574(*)

0,157

0,1030,0000,0000,0000,0000,054

Paquimetría


-0,070-0,601(*)-0,605(*)-0,608(*)-0,605(*)-0,626(*)

0,3910,0000,0000,0000,0000,000

Grosor del fl ap

7 días1 mes3 meses6 meses1 año

0,510(*)0,430(*)0,439(*)0,425(*)0,429(*)

0,0000,0000,0000,0000,000

Lecho estromal residual


-0,231(*)-0,234(*)-0,231(*)-0,218(*)-0,226(*)-0,232(*)

0,0040,0040,0040,0070,0050,004

Tabla 2: Correlación entre magnitud de la ametropía y grosores corneales en LASIK.

* La correlación es signifi cativa al nivel 0,01 (bilateral).

108 PAN-AMERICA


Se obtuvo además una correlación inversa entre la magnitud de la ametropía tratada y el lecho corneal re-sidual, existe un menor lecho corneal residual a mayor magnitud de la ametropía tratada en todo momento del postoperatorio de LASIK. Los valores de correlación ob-tenidos con el grosor del flap y lecho estromal residual, aunque significativos, no son tan elevados como los de paquimetría y grosor epitelial.

La Tabla 3 muestra la baja correlación no significa-tiva entre magnitud de la ametropía tratada con LASIK y variables endoteliales.

La Tabla 4 muestra la correlación inversa signifi-cativa entre magnitud de la ametropía y densidad de queratocitos en las subcapas flap posterior y zona de retroablación anterior durante el postoperatorio hasta el año de la cirugía. La densidad de queratocitos a ambos lados del corte lamelar es menor cuanto mayor es la magnitud de la ametropía tratada en pacientes opera-dos con LASIK. Esta correlación inversa es superior en el flap posterior y aumenta el nivel de correlación en ambos casos a medida que avanza el postoperatorio hasta alcanzar el mayor nivel de correlación al año de la cirugía. En el resto de las subcapas estromales se hubo correlaciones muy bajas no significativas.

El análisis de regresión lineal en las variables don-de existió correlación con la magnitud de la ametropía mostró las funciones que se muestran en la Tabla 5 en el momento más avanzado del postoperatorio. Se incluye en la función el valor preoperatorio de cada va-riable analizada y fue realizado el análisis estadístico de los residuos con buenos resultados.

Los valores de R2 fueron elevados en las funciones del lecho estromal residual, grosor epitelial y paquime-tría. El 98,7 % de las variaciones del lecho corneal al año de LASIK se deben al valor preoperatorio progra-mado de esta variable y a la magnitud de la ametropía tratada. El 86,3 % de las variaciones del grosor epitelial a los seis meses posLASIK se debe a la magnitud de la ametropía tratada y al grosor epitelial preoperatorio. El 81,5 % de las variaciones de la paquimetría al año de la cirugía se deben al valor paquimétrico preoperatorio y a la magnitud de la ametropía tratada con LASIK.

El análisis de regresión lineal de densidad de quera-tocitos a ambos lados del corte lamelar también alcanzó niveles adecuados de R2. El 68,9 % de las variaciones de la densidad de queratocitos en el flap posterior se deben al valor de esta variable antes de LASIK y a la magnitud de la ametropía tratada, el 46,9 % de las variaciones de la densidad de queratocitos en la zona de retroablación anterior se deben al valor de esta variable en el preopera-torio y a la magnitud de la ametropía tratada.

Las funciones obtenidas posibilitan la predicción de los cambios morfométricos de la córnea al año de LASIK desde el momento preoperatorio, basta con te-ner la magnitud de la ametropía a tratar y el valor de

Variables Pearson p

Densidad células endoteliales

preoperatorio7 díasun mes3 meses6 meses1 año

-0,154-0,0130,0460,0180,0150,035

0,0590,8790,5780,8290,8510,666

Pleomorfi smo


0,0560,142

-0,027-0,0900,141

-0,005

0,4970,0830,7410,2720,0840,956

Polimegatismo


0,159-0,0020,0150,1070,0820,036

0,0520,9760,8550,1900,3150,659

Tabla 3: Correlación entre magnitud de ametropía y características del endotelio corneal en LASIK.

Variables Pearson p

Densidad de queratocitos fl ap anterior


-0,042-0,098-0,084-0,190-0,066-0,052

0,6070,2300,3070,0190,4230,526

Densidad de queratocitos fl ap posterior


-0,042-0,580(*)-0,745(*)-0,806(*)-0,806(*)-0,826(*)

0,6070,0000,0000,0000,0000,000

Densidad de queratocitos retroablación anterior


-0,568(*)-0,582(*)-0,630(*)-0,611(*)-0,642(*)-0,645(*)

0,0000,0000,0000,0000,0000,000

Densidad de queratocitos retroablación posterior


0,0560,1250,0030,0420,0360,058

0,4920,1260,9750,6100,6610,476

Densidad de queratocitos estroma posterior


0,0700,191

-0,1780,099-0,062-0,121

0,3900,0190,0290,2260,4530,140

Tabla 4: Correlación entre magnitud de la ametropía y densidad de queratocitos por subcapas estromales en LASIK.

* La correlación es signifi cativa al nivel 0,01 (bilateral).



Variable dependiente Función R2

GE (6 meses)PAQ (1 año)LER. ( 1 año)

� (Q) FP ( 1 año)� (Q) RA (1año)

1,988+0,753xMA +0,985x GEp 54,199-10,965xMA+0,880x PAQp-0,318-0,058xMA +1,002x LERp

20,272 -1,177xMA+0,371x � (Q) FPp6,3 -0,854x MA+0,804x � (Q) RAp

0,8630,8150,9870,6890,469

Tabla 5: Funciones de regresión lineal en LASIK.

la variable a analizar antes de la cirugía, con mayor valor predictivo en el caso del lecho estromal residual, grosor epitelial y paquimetría.

Discusión

El estroma corneal es la subcapa donde más cambios se producen debido que recibe de forma directa la acción del láser de excímeros. Es precisamente en el mol-deamiento del estroma donde se logra la modificación de la curvatura corneal en vistas al resultado refractivo final del paciente. La disminución de la paquimetría en el postoperatorio obedece a la pérdida del tejido estromal central que se produce en vistas a lograr el efecto refractivo deseado.1-3 La correlación directa negativa con la magnitud de la ametropía corresponde con lo expresado por Munnerlyn en cuanto a profundidad de la ablación y su relación con esta variable.2, 4, 5

Los valores del lecho corneal residual son superiores a 300 μm en LASIK, valor protocolizado en Cuba en vistas a prevenir la seguridad del proceder y la ectasia corneal posterior a este tratamiento, una de las complicaciones más temidas de esta cirugía.6-9 No existen diferencias significativas entre el grosor del lecho programado y el obtenido al año. Considero que la microscopía confocal de la córnea permite la medición óptima de esta variable, con mayor exactitud que los métodos ultrasónicos, su seguimiento y comprobación de estabilidad en el tiempo. (Anexo 2)

Los valores obtenidos de grosor del flap son menores que los programados en el preoperatorio. El grosor del flap depende, fundamentalmente, de la velocidad de avance del microquerátomo, no depende de la magnitud del defecto refractivo. Considero que el conocimiento in vivo por microscopía confocal de los valores exactos de grosor del flap contribuyen de forma decisiva en los resultados del cirujano refractivo, flap dema-siado delgados o gruesos se relacionan con complicaciones transoperatorias y/o posto-peratorias del LASIK12, por lo que el estudio microscópico de su grosor aporta aspectos que pasan desapercibidos en biomicroscopía anterior del globo ocular, además cons-tituye una variable de seguridad ya que influye en el grosor del lecho corneal residual.

Las ecuaciones de regresión lineal que relacionan las variables histológicas con la magnitud de la ametropía tratada son de vital importancia. La predicción del valor de paquimetría real al año de cirugía refractiva corneal a partir de la magnitud de la ametropía tratada y de la paquimetría preoperatoria medida por microscopía posibilitan una selección óptima de los pacientes tributarios a esta cirugía, factor determinante en el éxito quirúrgico de estos procederes y en su seguridad a largo plazo. Además la obtención de este valor paquimétrico con un año de antelación asegura una paquimetría óptima futura posterior a tratamiento, incluso la posibilidad de un nuevo tratamiento refractivo de ser necesario. Por otra parte, el conocimiento de esta variable a partir de la paquimetría in vivo preoperatoria influye en la selección del tipo de tratamiento a utilizar13, donde la elección de tratamiento con láser de superficie pudiera garantizar mayor paquimetría predictiva al año.

El análisis de regresión lineal adquiere mayor valor clínico debido a que los valo-res paquimétricos obtenidos se realizan en el paciente con un mayor valor de exacti-tud que las técnicas utilizadas habitualmente de paquimetría ultrasónica, los valores obtenidos in vivo a través de la microscopía posibilitan una exactitud casi perfecta de los valores reales, se analiza a cada paciente de forma más exacta con elevada confiabilidad de predictibilidad de parámetros morfológicos esperados después del año de la cirugía.

MA: Magnitud de la ametropía. GE: Grosor epitelial GEp: Grosor epitelial preoperatorio.PAQ: Paquimetría. PAQp: Paquimetría preoperatorio.LER: Lecho estromal residual. LERp: Lecho estromal residual preoperatorio.� (Q) FP : Densidad de queratocitos fl ap posterior.� (Q) FPp: Densidad de queratocitos fl ap posterior preoperatorio.� (Q) RA : Densidad de queratocitos retroablación anterior.� (Q) RAp: Densidad de queratocitos retroablación anterior preoperatorio.

La correlación directa negativa entre la disminu-ción de la densidad queratocitaria y la mayor magni-tud de ametropía a tratar es evidente. Mientras mayor es la profundidad de la ablación, mayor es la cantidad de tejido estromal removido y el factor fotoablativo es superior en tiempo de acción sobre el estroma corneal, con sus consecuencias histológicas.14

El factor tiempo de acción fotoablativo se relaciona con la frecuencia de aplicación de los disparos, especí-ficamente con los cambios de hidratación del estroma corneal que ocurren con el tiempo.15-17 Los tratamientos más prolongados pueden afectar adversamente la hidra-tación tisular. El tiempo de acción fotoablativo es inver-samente proporcional al nivel de hidratación corneal, la córnea pierde hidratación a medida que avanza el tiem-po de aplicación del láser por lo que más tejido corneal es removido, aspecto que justifica un mayor efecto fo-toablativo sobre la población queratocitaria en mayores magnitudes de ametropías tratadas y por tanto influye la disminución de la densidad de esta línea celular.6, 18

La significación clínica de esta pérdida gradual de queratocitos es desconocida, como también lo es la den-sidad necesaria de estas células para mantener la transpa-rencia corneal.19,20 El número mínimo necesario de que-ratocitos para mantener la salud corneal es desconocido, particularmente en el estroma anterior donde la densidad es mayor. Conocer la densidad de queratocitos es impor-tante para entender cómo es el comportamiento de estas células productoras del colágeno y los proteoglicanos necesarios para mantener el tejido corneal, su deficiencia durante años pudiera afectar la transparencia y curvatura corneal, la importancia de su estudio antes y después de intervenciones quirúrgicas corneales es un elemento que adquiere cada vez mayor importancia.16,17,21

En pacientes cubanos donde hemos constatado la disminución de la densidad queratocitaria, es un elemento de seguridad de la técnica quirúrgica aplicada la no mo-dificación de esta variable en subcapas más profundas del estroma que garantizan el mantenimiento de la salud cor-neal a largo plazo. Considero que la drástica disminución de la población queratocitaria en otros estudios a niveles profundos del estroma se deben a la mayor magnitud de ametropías tratadas con el consiguiente aumento de la profundidad de la ablación.

Si bien no se han reportado cambios corneales y en la agudeza visual postoperatoria cuando existe disminución de la densidad queratocitaria, la menor afectación posible de la homeostasis estromal debe convertirse en premisa

110 PAN-AMERICA


esencial de todo cirujano de defectos refractivos en vistas a propiciar de por vida una óptima agudeza visual y función corneal, que depende entre otros factores, de la integridad estructural y funcional de la célula fundamental del estroma corneal: el queratocito. Por lo que en pacientes con magnitudes de ametropías cercanas a 8 dioptrías, independiente-mente del valor de paquimetría corneal inicial, es prudente seleccionar un tratamiento de superficie con menor repercusión histológica en subcapas inferiores del estroma corneal y donde hemos constatado que la disminución de queratocitos es menor.

La densidad de células del epitelio apical, epitelio basal, endotelio corneal, así como los valores de pleomorfismo, polimegatismo, lecho estromal residual, grosor del flap y grosor epitelial no tuvieron variaciones morfométricas significativas con respecto a niveles preoperatorios.

En conclusiones se obtuvo posterior a LASIK corre-lación estadísticamente significativa entre la magnitud de la ametropía tratada y las variables: grosor epitelial, paquimetría, lecho estromal residual y densidad de queratocitos en subcapas flap posterior y retroablación anterior. Mientras mayor es la magnitud de la ametro-pía tratada con LASIK, mayor es el aumento del gro-sor epitelial en el primer semestre de postoperatorio y menores los valores de paquimetría, lecho estromal residual y densidad queratocitaria a ambos lados del corte lamelar, al año de tratamiento.

Anexos:

Anexo 1: Imágenes microscópicas in vivo a los tres meses de LASIK.

a- Epitelio corneal apical.b- Epitelio corneal basal.c- Estroma corneal.d- Interfase quirúrgica.e- Endotelio corneal.

Anexo 2: Medición de lecho estromal residual (tres meses posterior a LASIK). Por curva CMTF se selecciona la última imagen de interfase quirúrgica (imagen superior) y se lleva el cursor hasta la última imagen de endotelio corneal (imagen inferior). El grosor del lecho estromal re-sidual es el valor ilustrado como Distancia (μm)=439,0 en la parte superior izquierda de la imagen inferior. El ejemplo corresponde a tres meses posterior a LASIK.

Anexo 1

Anexo 2

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thelial cell density and central corneal thickness. Cornea 2011;30:754-59.

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6. Fares U, Al-Aqaba MA, Muneer A, Said DG, Dua HS. Effi cacy, predict-ability, and safety of wavefront-guided refractive laser treatment: Metaanalysis. J Cataract Refract Surg 2011;37:1465-75.

7. Li J WY. Characteristics of straylight in normal young myopic eyes and changes before and after LASIK. Invest Ophthalmol Vis Sci 2011;52:3069-73

8. Linke SJ, Mau-Thek E, Gisbert R, Katz T. Relationship between minimum corneal thickness and refractive state, keratometry, age, sex, and left or right

eye in refractive surgery candidates. J Cataract Refract Surg 2011;37:2175-80.

9. Chan C, Sutton G. External analysis of the randleman ectasia risk factor score system: a review of 36 cases of post LASIK ectasia. Clin Exp Ophthal-mol 2010;38.

10. Bansal AS, Randleman JB, Stulting RD. Infl uence of fl ap thickness on visual and refractive outcomes after laser in situ keratomileusis performed with a mechanical keratome. J Cataract Refract Surg 2010;36:810-13.

11. Ahn H, Kook CH, Heon G, Yul K, Kim E, Kim T. Comparison of laser in situ keratomileusis fl aps created by 3 femtosecond lasers and a microkeratome. J Cataract Refract Surg 2011;37:349-57.

12. Moshirfar M, Schliesser JA, Espan-dar L, Feiz V, Miffl in M et al. Laser in situ keratomileusis fl ap complications using mechanical microkeratome

versus femtosecond laser: Retrospective comparison. J Cataract Refract Surg 2010;36:1925-33.

13. Wallau AD. One-year outcomes of a bilateral randomised prospective clinical trial comparing PRK with mito-mycin C and LASIK. Br J Ophthalmol 2009;93:1634-38.

14. Khoramnia R, Wuellner C, Kobuch KA, Donitzky C, Winkler C. Effect of 3 excimer laser ablation frequencies (200 Hz, 500 Hz, 1000 Hz) on the cornea using a 1000 Hz scanning-spot excimer laser. J Cataract Refract Surg 2010;36:1385-91.

15. Weaving L, Storen R, Sosic D, Grigg JR, Patrick PL et al. Twist2: Role in cor-neal stromal keratocyte proliferation and corneal thickness. Invest Ophthalmol Vis Sci 2010;51:5561-70.

16. Sherwin T. Corneal epithe-lial homeostasis. Ophthalmology 2010;117:190-91.

17. Reynolds A, Naroo SA, Moore T, Shah S. Excimer laser surface abla-tion – a review. Clin Exp Ophthalmol 2010;38:168-82.

18. Alio J V, Piñero D. Laser-assisted in situ keratomileusis in high levels of myopia with the Amaris excimer laser using optimized aspherical profi les. Am J Ophthalmol 2011;152:954-63.

19. Benito-Llopis L, Drake P, Hernández JL, Teus MA. Keratocyte Density 3 Months, 15 Months, and 3 Years After Corneal Surface Ablation With Mitomycin C. Am J Ophthalmol 2012;153:17-23.

20. Sutton GL. Laser in situ keratomileusis in 2010 – a review. Clin Exp Ophthalmol 2010;38:192-210.

21. Nishida T. The cornea: stasis and dynamics. Nihon Ganka Gakkai Zasshi 2008;112 (3):179-212.y of Ophthalmology. Ophthalmology. 2011;118(5):986–1002.

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Maldonado-Bas A et al. Non penetrating deep sclerectomy and trabeculotomy for glaucoma.

INTRODUCTION

Trabeculectomy has been the gold standard for glaucoma surgery1. Recently, some surgeons are starting to replace it in the majority of the surgical cases by non-penetrating deep sclerectomy (NPDS)2-5, because of its fewer associated complications6-7. Nevertheless, NPDS seems to provide less IOP control over time. Intra-surgical absorbable devices8-9-10-11 or yag laser goniopuncture12 are now employed to maintain post-surgical filtration.

On the other hand, trabeculotomy13 has also been used to treat congenital glaucoma provoked by mesodermal remains in the angle14-15.

The purpose of this study is to evaluate the efficacy and safety of IOP control using a combined technique of NPDS with trabeculotomy16-17.

METHODS

All study participants signed an informed consent after full information of the procedure (for filtering surgery or for filtering surgery combined with cataract extraction and implant of intraocular lens, as indicated) prior to the surgery. This study was approved by the institutional review bureau and by the medical legal department.

In a prospective study, 61 eyes presenting open-angle glaucoma without intraocular pressure control with maximum medication were operated:

• 33 eyes underwent NPDS with trabeculotomy (Group I).

• 28 eyes underwent NPDS with trabeculotomy combined with phacoemulsification and intraocular lens implant (Group II).

Results obtained in the entire group of 61 eyes were analyzed.

The results obtained were compared between the two groups, by incorporating them in a database and analyzing them with the SPSS 16® statistics software (SPSS Inc®).

Descriptive statistics were determined for each variable by their measurement and distribution. Chi squared tests were performed to compare percentages, and Student’s t-tests to compare averages. The admitted significance level was alpha = 0.05.

Intraocular pressure equal to or less than 16 mmHg with or without medication was considered a success. Minimum follow-up period was 1 month for data analysis.

Data of the 61 eyes

Average age was 68 years (minimum=48; maximum=86). Sex distribution was 22 men and 39 women. Average pre-surgical intraocular pressure was 21.75±5.45 mmHg, ranging from 14 to 45 mmHg. Average follow-up was 22.55 months (mnimum=1; maximum=40 months). No antimetabolites, viscoelastics or devices were used to improve the results.

Data from Group I

Average age was 66 years (minimum= 46; maximum= 82). Sex distribution was 13 men and 20 women. Average pre-surgical intraocular pressure was 21.30 mmHg, ranging from 14 to 30 mmHg. Average follow-up was 22.08 months (minimum= 1 ; maximum= 40 months).

Data from Group II

Average age was 71 years (minimun= 57; maximum=82. Sex distribution was 9 men and 19 women. Average pre-surgical intraocular pressure was 22.29±6.95 mmHg, ranging from 14 to 45 mmHg. Average follow-up was 23.12 months (minimum= 1.8; maximum=38.73 months).

Surgical technique

1. Subtenonian anesthesia: Lidocaine at 2% without epinephrine.

2. Alvarado traction suture with 7-0 silk.

3. Fornix based conjunctival dissection.

4. A 4-3 mm scleral flap, 300 microns thick.

5. Paracenthesis with or without phacoemulsification, according to the case.

Arturo Maldonado-Bas, MD, PhD, Ana Maldonado-Junyent, MD, Arturo Maldonado-Junyent, MD, María Maldonado-Junyent, MD

Clínica de Ojos Maldonado Bas – Córdoba – Argentina.

Date of submission: 30/8/2012 Date of approval: 06/11/2012Funding: NoneProprietary/fi nancial disclosure: None

Corresponding author:

Arturo Maldonado Bas. Address: Achával Rodriguez 544. CP: 5000. Córdoba. Argentina.Phone/Fax: +543514686500E-mail: [email protected]

Non penetrating deep sclerectomy and trabeculotomy for glaucoma

112 PAN-AMERICA

CASE REPORT / Vis. Pan-Am. 2012;11(4):111-112

6. Deep scleral flap dissection, unroofing the Schlemm canal and exposing the Descemet membrane. Sclera must be dissected up to the deepest layers also to obtain uveal filtration (Figure 1).

7. Juxtacanalicular extraction by means of forceps (Figure 2).

8. Trabeculotomy to both sides with the Sourdille trabeculotome up to the scleral flap without invading the NPDS area (Figure 3).

9. Scleral suture with two to four 9-0 nylon sutures (may be removable).

10. 7 or 8-0 silk conjunctival flap suture.

RESULTS

Patients from general group (61 eyes) presented an average post-surgical IOP at 2 years follow-up was 12.25±1.06 mmHg, ranging from 14 to 10 mmHg. The average of the latest IOP of each patient was 12.79±4.31 mmHg, with a range between 9 and 40 mmHg. Average follow-up was 22.55 (minimum=1; maximum=40 months). Average surgical success was 88.52% (54 eyes). Intraocular pressure was controlled in 47 eyes (87.03%) without medication and in 7 eyes (12.96%) with medication. The failure rate was 11.47% (7 eyes). The difference between pre- and post-surgical measurements was 8.96 mmHg. Thirty-five (35) cases had hyphema one to twelve days after surgery, resolved without further consequences.

Analyzing separately the groups, we found in Group I an average post-surgical IOP at 2 years follow-up was 11.83±1.17 mmHg, ranging from 10 to 13 mmHg. The average of the latest IOP of each patient was 13±5.36 mmHg, ranging from 9 to 40 mmHg. Average follow-up was 22.08 months (minimum=1; maximum= 40 months). Average surgical success was 84.84% (28 eyes). Intraocular pressure was controlled in 23 eyes (82.14%) without medication and in 5 eyes (17.85%) with medication. The failure rate was 15.15% (5 eyes); in one of them, IOP was controlled for 18 months below 13 mmHg without medication until cataract surgery was performed with

phacoemulsification and intraocular lens implant, when the bleb stopped functioning and two trabeculectomies had to be performed in order to regulate the IOP once again. The difference between pre- and post-surgical measurements was 8.30 mmHg.

In Group II, the average postsurgical IOP at 2 years was 12.67±0.82 mmHg, ranging from 14 to 12 mmHg. The average latest IOP of each patient was 12.54±2.65 mmHg, ranging from 9 to 23 mmHg. Average follow-up was 23 months (minimum= 1.8; maximum=38.7 months). Average surgical success was 92.54% (26 eyes). Intraocular pressure was controlled in 24 eyes (92.30%) without medication and in 2 eyes (7.69%) with medication. The failure rate was 7.14% (2 eyes). The difference between pre- and post-surgical measurements was 9.75 mmHg.

Comparison of the results obtained between the two groups

Although a significantly higher mean IOP was found in group II at two years follow-up (T= 3.282; p=0.00173), the success surgical rates between the two groups were not statistically significant (ChiYates= 0.33048, p=0.5654).

Taking into account patients who needed postsurgical medication to regulate the IOP below 16 mmHg, no statistically significant differences were found between the two groups (ChiYates= 0.79598, p= 0.3723).

CONCLUSIONS

Combined procedure with non-penetrating deep sclerectomy with trabeculotomy showed better post-surgical results, than each separate procedure, resulting in a viable alternative procedure for surgical treatment of open-angle glaucoma.

According to the results of this study, it can be concluded that NPDS combined with trabeculotomy is a good surgical procedure to reduce IOP.

No statistically significant differences were found when the proposed technique was combined with phacoemulsification and intraocular lens implant.

Fig. 1: Deep Scleral fl ap.

Fig. 2: Yuxtacanalicular extraction

Fig. 3: Trabeculotomy

REFERENCES1. Sampaolesi, R. Glaucoma, Ed. Médica Panamericana, Buenos Aires 1991; 607-617.

2. Fyodorv SN et al: Deep sclerectomy: technique and mechanism of a new glaucomatous procedure. Glaucoma 1984;6: 281-283.

3. Zimmermann TJ, et al. Effectiveness of non penetrating trabeculectomy in aphakic patients with glaucoma. Ophthalmic Surg 1984;15:44-50.

4. Maldonado-Bas A, Maldonado-Junyent A: Filtering Glaucoma Surgery Using an Excimer Laser. J Cataract Refract Surg 2001;27:1403-08.

5. Maldonado-Bas A, Maldonado-Junyent A: Ultimas innovaciones en los

Glaucomas: Cirugía Filtrante con Laser Excimer. Highlights of Ophthalmology 2001;25:245-52.

6. Johnson DH & Johnson M: How does non-penetrating glaucoma surgery work? In Mermoud A and Shaarawy T (Eds) (2001): Non-penetrating glaucoma surgery. Martin Dunitz Ltd, United Kingdom. Chapter 4.

7. Sampaolesi JR, Sampaolesi R: Non-penetrating surgery for glaucoma. In World Clinics in Ophthalmology. Innovations in Primary Open Angle Glaucoma. Ed Jaypee- Highlights Medi-cal publishers, Inc 2012 Chapter 5

8. Demailly P, Jeanteur-Lunel MN, et al: Non-penetrating deep sclerectomy

associated with collagen device in primary open angle glaucoma: middle-term retrospective study. J Fr Ophtalmol 1996;19: 659-666.

9. Sourdille, P., Santiago, P., et al: Reticulated hyaluronic acid implant in non-perforating trabecular surgery. J Cataract Refract Surg 1999; 25:332-339.

10. Shaarawy T, Nguyen C, Schnyder C, Mermoud A. Comparative study between deep sclerectomy with and without collagen implant: long term follow up. Br J. Ophthalmol. 2004; 88; 95-98.

11. Kozlov VI, Kozlova TV: Non-penetrating deep sclerectomy with

collagen drainage implantation (ABSTRACT 9-02). 5th Congress and the Glaucoma Course of the European Glaucoma Society, June 1996, Paris. Abstract Book: 120.

12. Mermoud, A., et al: Yag gonio-puncture after deep sclerectomy with collagen implant. Ophthalmic Surg and Lasers 1999;30(2):120-125.

13. Sampaolesi R, Zarate J, Sampaolesi JR. The Glaucomas Volume I Pediatric glaucomas. Ed. Springer, Germany 2009;131-143.

14. Paufi que L et al. Technique et résultats de la trabeculotomie ab externo dans le traitement du glaucoma congénital. Bull et M de la Soc Franc

d´Ophtalmol. Masson et Cie Editeurs, París: 1970;54-65.

15. Harms H, Dannheim R: Epicritical consideration of 300 cases of trabecu-lotomy “ab externo”. Trans Ophtalmol Soc UK 1970;89:491-499.

16. Kotera, Y. Hayashi H et al: Short-term outcome of trabeculotomy by modifi ed deep sclerectomy. Japan J Clin Ophthalmol 2005; 59(9):1561-1565.

17. Lüke, C, Dietlein T et al: Phaco-trabeculotomy combined with deep scle-rectomy, a new technique in combined cataract and glaucoma surgery: compli-cation profi le. Acta Ophthalmologica Scandinavica 2007;85(2):143-148.


Mannis TE et al. Recurrent Invasive Squamous Carcinoma of the Ocular Surface.

ABSTRACT

Purpose: We review a case of invasive squamous cell carcinoma invading the cornea to discuss optimal management.

Methods: Observational case report with histopathologic analysis.

Results: Histopathology demonstrates corneal invasion by the tumor that appears to have been completely excised with a large therapeutic keratoplasty and adjuvant cryotherapy.

Conclusions: Successful management of ocular surface squamous neoplasia (OSSN) requires removal of identifiably abnormal tissue without disruption of normal protective architecture, careful histopathologic analysis, and the employment of adjuvant therapy at the time of or subsequent to surgical excision.

INTRODUCTION

Ocular surface squamous neoplasia (OSSN) is a relatively rare entity. However, in the elderly population, squamous lesions are the most common tumors of the ocular surface.1 Typically, OSSN presents as an exophytic, pearly grey lesion with increased surrounding vasculature, and its gross topography generally falls into one of three categories: leukoplakic, gelatinous, or papillaform.1 Invasive OSSN penetrates the epithelial basement membrane and spreads into the stromal tissue. Rarely, intraocular invasion can occur, and the lesion may spread into Schlemm’s canal, the trabecular meshwork, the anterior chamber, the iris, the ciliary body, and the choroid.2 Presumably due to the resistance of the Bowman’s layer, however, invasion by squamous cell carcinoma (SCC) occurs virtually exclusively in extra-corneal portions of the lesion3 barring any surgical interventions. We present

an unusual case of recurrent invasive squamous cell carcinoma that moved from the limbus to dissect the corneal stroma leaving the corneal epithelium intact.

CASE REPORT

A 58 year-old man was referred to the University of California Davis Eye Center with the history of a conjunctival tumor in the left eye that was first noted by the patient one year prior to initial presentation with steady growth. The tumor was excised at an outside facility in May 2010. At that time a sclerectomy was also performed but adjuvant cryotherapy was not used. The pathology report from that procedure demonstrated well-differentiated, squamous cell carcinoma with tumor present at the deep biopsy margins. The referring physician requested an evaluation to determine the next best steps in treating residual tumor.

The patient was seen one month after his initial tumor excision. Visual acuity was 20/25 in the right eye and 20/60 in the left eye. Examination of the left eye revealed a 6.5mm (vertical) x 4.5mm (horizontal) area temporally that appeared to represent the location of excision. The area was not inflamed and was epithelialized except for a small area inferiorly. Hyperemic conjunctiva and conjunctival scarring surrounded the excision site. The intraocular pressure was 18 mm Hg in the left eye.

Given the history of positive margins, as seen in the original pathology report, the use of topical chemotherapy with Mitomycin C was recommended. The referring physician was encouraged to employ lubricating ointment to facilitate epithelial healing after which a two-week cycle of mitomycin would be undertaken. The patient returned to the care of the referring ophthalmologist.

In September 2010, four months after the patient’s original surgery, he returned for follow-up. The treating


Tova E. Mannis, MD1, Mark J. Mannis, MD, FACS1, George J. Harocopos, MD2, Bobeck S. Modjtahedi, MD1, Jennifer Li, MD1

1. Department of Ophthalmology & Visual Science, University of California, Davis Health System Eye Center.2. Department of Ophthalmology & Visual Sciences and Department of Pathology & Immunology, Washington University, St. Louis.

Funding: None Proprietary/fi nancial interest: None


Mark J. Mannis, MD, FACSProfessor and Chair, Department of Ophthalmology & Vision Science UC Davis Health System Eye Center, University of California, Davis4860 Y Street Suite 2400 Sacramento, CA 95817Phone 916-734-6957Fax 916-703-5076

Recurrent invasive squamous carcinomaof the ocular surface requiring penetrating therapeutic sclero-keratoplasty

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physician had noted an enlarging corneal opacity in the left eye and, due to concern for possible infectious keratitis, initiated antibiotic drops. He had not, however, employed topical chemotherapy as recommended. The patient was then referred back to UC Davis.

At this visit, visual acuity was 20/25 in the right eye and counting-fingers at 2 feet in the left eye. There was a temporal area of edematous and inflamed conjunctiva with dilated episcleral vessels and an area of leukoplakia adjacent to the temporal limbus. There was also a large, dense stromal opacity in the temporal cornea with evidence of corneal neovascularization and overlying microcystic epithelial changes. There was no epithelial defect. This corneal opacity extended into the visual axis. Intraocular pressure was 29 mm Hg in the left eye (Figure 1).

Ultrasound biomicroscopy revealed a large solid mass lesion (9.95mm x 8.23mm x 2.4mm) extending

into the cornea dissecting the corneal stroma. There was no clear evidence of invasion into the anterior chamber. We could not rule out possible ciliary body involvement. We elected to proceed with a large corneal-scleral graft with the application of cryotherapy. The patient was informed of the high-risk nature of this procedure including potential loss of the eye.

All abnormal-appearing conjunctiva was excised with 3 mm margins and submitted for pathology. In addition two specimens were submitted as “mapping” biopsies. Two rounds of overlapping cryotherapy application (freeze/thaw/freeze) were performed to encircle the entire area of the tumor in the cornea and sclera. The limbal portion of the lesion was excised in lamellar fashion, dissecting down to the base of invasion and excising the abnormal conjunctiva temporally. Since the lesion appeared to invade deeply into the stroma, the decision was made to perform penetrating sclero-keratoplasty in order to ensure complete removal of tumor while also maintaining globe integrity. Accordingly, a 10 mm full-thickness, eccentric trephination was performed to include the residual limbal/scleral bed temporally, extending to trabecular meshwork, as well as all abnormal cornea. The nasal portion of the cornea was left in place. A donor corneal-scleral graft was sutured into place using 9-0 nylon sutures. The conjunctival defect was then closed to cover bare sclera using Vicryl sutures.

Three weeks post-operatively, the patient’s vision in the left eye was counting-fingers at three feet. Examination revealed mild hyperemia, a clear corneal graft with sutures in place, a formed anterior chamber, and an intraocular pressure of 18. Two months post-operatively, the graft remained clear with well-controlled IOP. Visual acuity was counting fingers due to a cataract. There were no clinical signs of recurrence of the tumor (Figure 2). The graft remained clear at 18 months with no evidence of recurrence of tumor.

HISTOPATHOLOGIC FINDINGS

Sections of the limbal portion of the lesion from the patient’s left eye showed invasive squamous cell carcinoma extending to the base of the lamellar dissection (Figure 3). Surface keratinization correlated with the leukoplakia seen clinically. A chronic inflammatory response was present in the stroma. The temporal margin appeared free of neoplasia. The corneo-scleral button, encompassing all abnormal cornea along with the residual scleral bed beneath the aforementioned lamellar dissection, contained the remainder of the squamous carcinoma, emanating from the temporal area of invasion and dissecting along the mid- to deep corneal stroma, without involvement of the overlying corneal epithelium. The squamous

Figure 1: Pre-operative photograph demonstrating extension of the intracorneal mass into the central optical zone.

Figure 2: Post- operative appearance of the corneal-scleral graft.


Mannis TE et al. Recurrent Invasive Squamous Carcinoma of the Ocular Surface.

carcinoma did not extend to either the nasal edge of excised cornea or to the temporal edge of sclera, indicating a complete excision. The deep margin was clear, with no intraocular tumor extension. The conjunctival mapping biopsies were also negative for neoplasia. Accordingly, the lesion was staged as T3 as per the AJCC classification.4

DISCUSSION

Invasive OSSN often begins in the conjunctiva and extends across the limbus to involve the superficial adjacent cornea. Rarely does intraocular invasion occur, but to our knowledge, there are no other reports of corneal stromal extension of tumor without involvement of the corneal epithelium. Other reports document OSSN with extensive involvement of the corneal epithelium, but without corneal stromal invasion.5,6 Kafarnik and colleagues7 reported corneal stromal invasive squamous cell carcinoma in 10 horses, but in these cases there was no conjunctival or corneal epithelial involvement seen on histology. Similar cases in humans have not been identified in the literature. The authors do concede that there may have been an epithelial entrance to the stroma that was not included in the plane of the histologic sections.

One of the important factors that may prevent extension of neoplasm into the corneal stroma is

Figure 3: Histopathology of excised corneo-scleral button, hematoxylin and eosin stain. A. Limbal portion of lesion, lamellar dissection, showing invasive squamous carcinoma. Squamous neoplasia is seen arising from the limbal epithelium (arrow), with invasion into the stroma. The tongues of invasive squamous carcinoma are seen dissecting the stroma to the left of the arrow, i.e. nasally (asterisk), extending to the base and to the nasal edge of the lamellar dissection. The far temporal margin (beyond the right edge of the photograph) was negative for neoplasia (magnifi cation, x40). B. Higher magnifi cation (x200) of limbal portion of lesion, showing epithelial hyperplasia with cellular pleomorphism and surface keratinization (arrowhead) and invasion into the stroma, with keratin whorl (arrow). A chronic infl ammatory response is present in the stroma. C. Main portion of corneo-scleral button from penetrating sclero-keratoplasty. Lamellar excision shown in (A) fi ts into vacant area on the right side of this photograph (asterisk). Invasive squamous carcinoma is seen dissecting the mid- to deep corneal stroma nasally, without involvement of the overlying corneal epithelium. The far nasal edge of the button (left) is free of carcinoma. The residual scleral bed (right) beneath the previously shown lamellar dissection is also negative for carcinoma. The entire deep margin is negative for carcinoma, with no penetration of tumor into the anterior chamber. Normal trabecular meshwork is seen in the lower right corner (arrow) (magnifi cation, x20). D. Higher magnifi cation (x100) of corneal invasion shown in (C). Histologic features are similar to those shown in (B).

the protection afforded by the Bowman layer.3 It is extremely important, when possible, to maintain an intact Bowman’s layer during the surgical excision of a superficial OSSN. It is both possible and likely that the original surgeon crossed Bowman’s layer during the resection. If the tumor has already breached Bowman’s layer, demonstration of clean surgical margins is imperative. Since the initial pathology report indicated the presence of tumor at the surgical margin, it is probable that the surgeon had not removed all of the malignant invasive tissue. Conversely, if the tumor is superficial and exophytic, which is the usual case, deep keratectomy and/or sclerectomy may not be indicated and may both compromise the integrity of Bowman’s layer or provide access to the internal eye through the aqueous veins present under the limbus.

Recurrence rates for both pre-invasive and invasive OSSN following surgical excision range from 15% to 52%.1 Recurrence rates are significantly lower when surgical margins are demonstrated to be histologically negative. As a result, adjunctive therapy is often considered a way to limit tumor recurrence, since clinically the margin of the lesion may not be identifiable at surgery. Sudesh et al.8 demonstrated that recurrence rates were lowered significantly when cryotherapy was applied to the tumor margins following excision. They also emphasized that both primary and recurrent tumors generally involve the limbus and, therefore, adjunctive cryotherapy to this area may be

A

C

116 PAN-AMERICA


1. Basti, S. and Macsai M.S., Ocular surface squamous neoplasia: A review. Cornea 2003 22(7):687-704.

2. Pe’er, J., Ocular sur-face squamous neoplasia. . Ophthalmol Clin North Am 2005 18:1-13.

3. Warner, M.A. and Jakobiec F.A., Squa-mous neoplasms of the conjunctiva in Cornea, J. Krachmer, M. Mannis, and E. Holland, Editors. 2005, Elsevier Mosby. p. 557-567.

4. AJCC Cancer Staging Manual. 7th Ed. New York, NY, Springer 2010 Edge SB et al, Eds.).

5. Ramasubramanian, A., et al., Ocular surface squamous neoplasia after corneal graft. Am J Oph-thalmol 2010 149:62-65.

6. Papaioannou, I.T., et al., Corneal-conjunctival squamous cell carci-noma. Cornea 2008 27(8):957-958.

7. Kafarnik C., Rawl-ings M., and Dubielzig R.R., Corneal stromal invasive squamous cell carcinoma: a retrospec-tive morphological description in 10 horses. Vet Ophthalmol 2009 12(1):6-12.

8. Sudesh, S., et al., Surgical management of ocular surface squa-mous neoplasms. The experience from a cornea center. Cornea 2000 19(3):278-283.

9. Shields, C.L. and Shields J.A., Tumors of the conjunctiva and cornea. Surv Ophthalmol 2004 49(1):3-24.

10. Majmudar, P.A. and Epstein R.J., Anti-metabolites in ocular surface neoplasia. Curr Opin Ophthalmol 1998 9(4):35-39.

11. Sepulveda, R., et al., Topical chemotherapy for ocular surface squamous neoplasia: current status. Br J Ophthalmol 2009 94(5):532-535.

12. Chen, C., et al., Mito-mycin C as an adjunct in the treatment of localised ocular surface squamous neoplasia. Br J Ophthal-mol 2004 88:17-18.

13. Panda, A., et al., Effect of topical Mitomycin C on corneal endothelium. Am J Oph-thalmol 2008 145(4): 635-638.e2.

14. Hirst, LW., Random-ized control trial of topical mitomycin C for ocular surface squamous neoplasia: early resolu-tion. Ophthalmology 2007 114(5):976-982 Epub 2007, Jan.22. REFERENCES

1. Basti, S. and Macsai M.S., Ocular surface squamous neoplasia: A review. Cornea 2003 22(7):687-704.

2. Pe’er, J., Ocular sur-face squamous neoplasia. . Ophthalmol Clin North Am 2005 18:1-13.

3. Warner, M.A. and Jakobiec F.A., Squa-mous neoplasms of the conjunctiva in Cornea, J. Krachmer, M. Mannis, and E. Holland, Editors. 2005, Elsevier Mosby. p. 557-567.

4. AJCC Cancer Staging Manual. 7th Ed. New York, NY, Springer 2010 Edge SB et al, Eds.).

5. Ramasubramanian, A., et al., Ocular surface squamous neoplasia after corneal graft. Am J Oph-thalmol 2010 149:62-65.

6. Papaioannou, I.T., et al., Corneal-conjunctival squamous cell carci-noma. Cornea 2008 27(8):957-958.

7. Kafarnik C., Rawl-ings M., and Dubielzig R.R., Corneal stromal invasive squamous cell carcinoma: a retrospec-tive morphological description in 10 horses. Vet Ophthalmol 2009 12(1):6-12.

8. Sudesh, S., et al., Surgical management of ocular surface squa-mous neoplasms. The experience from a cornea center. Cornea 2000 19(3):278-283.

9. Shields, C.L. and Shields J.A., Tumors of the conjunctiva and cornea. Surv Ophthalmol 2004 49(1):3-24.

10. Majmudar, P.A. and Epstein R.J., Anti-metabolites in ocular surface neoplasia. Curr Opin Ophthalmol 1998 9(4):35-39.

11. Sepulveda, R., et al., Topical chemotherapy for ocular surface squamous neoplasia: current status. Br J Ophthalmol 2009 94(5):532-535.

12. Chen, C., et al., Mito-mycin C as an adjunct in the treatment of localised ocular surface squamous neoplasia. Br J Ophthal-mol 2004 88:17-18.

13. Panda, A., et al., Effect of topical Mitomycin C on corneal endothelium. Am J Oph-thalmol 2008 145(4): 635-638.e2.

14. Hirst, LW., Random-ized control trial of topical mitomycin C for ocular surface squamous neoplasia: early resolu-tion. Ophthalmology 2007 114(5):976-982 Epub 2007, Jan.22.

REFERENCESparticularly helpful in preventing recurrence. Typically, management of squamous cell carcinoma of the conjunctiva involves wide margin excision followed by freeze-thaw cryotherapy.9 Complications of cryotherapy include lack of selectivity between normal and abnormal tissues, iritis, corneal edema and scarring, peripheral retinal ablation, and changes in intraocular pressure.10

Similarly, topical chemotherapy with agents like mitomycin C, 5-fluorouracil, and alpha interferon-2B (alpha IFN-2B) have been effective in the treatment of recurrent and primary OSSN and may be particularly useful in the case of an excision with positive tumor margins.1 Sepulveda and colleagues11 found that all three agents were effective in the treatment of OSSN. They also identified the following relative indications for topical chemotherapy of non-invasive OSSN: greater than two quadrants of conjunctival involvement, greater than 180 degrees of limbal involvement, extension into the clear cornea, positive margins after excision, unsuitability of the patient for surgery. In a case series study, Chen et al.12 administered topical mitomycin C to 27 patients following OSSN excision and after a mean follow-up time of twenty-seven months, found no evidence of clinical recurrence in any of these cases. Ocular toxicity after administration of topical chemotherapeutic agents is generally limited to the duration of treatment, and in a small, prospective study Panda et al.13 demonstrated that treatment with mitomycin C had no significant effect on corneal endothelium. Nonetheless, adverse effects are more common when the these agents are applied to bare sclera with no overlying conjunctiva to provide blood flow.10 There are few randomized, prospective trials to determine the efficacy of adjuvant chemotherapy.14

The present case highlights the potential for corneal stromal dissection by SCC following deep, incomplete conjunctival tumor excision without adequate adjunctive cryotherapy or topical chemotherapy. In general deep sclerectomy is neither necessary nor desirable in most cases of OSSN, which is commonly exophytic, slow growing and non-invasive in the presence of normal anatomic barriers. Presumably in our case, there was already invasion of the stroma at the time of the original presentation based on the pathology report. This patient had a successful corneal-scleral graft following removal of residual tumor, but the procedure posed significant long-term risks. Successful management of OSSN requires removal of identifiably abnormal tissue without disruption of normal protective architecture, careful histopathologic analysis, and the employment of adjuvant therapy at the time of or subsequent to surgical excision.


Vélez M et al. Corneal hymenoptera stings

Abstract

Purpose: To describe five cases (four children) with ocular sequelae from honeybee or wasp sting injuries to the eye treated with anterior chamber irrigation to reduce venom concentration and subsequent complications.

Design: Interventional case series.

Methods: Patients with hymenoptera corneal sting injuries were treated in the operating room by performing an anterior chamber irrigation with balanced saline solution and triamcinolone in an effort to minimize the tissue damage induced by bee venom.

Results: Early clearing of inflammation and more rapid recovery of baseline acuity were associated with early surgical intervention. Late complications included corneal decompensation, iris heterochromia, paralytic mydriasis, glaucoma and cataract; these complications are irreversible and sight threatening.

Conclusion: Performing an early anterior chamber irrigation is a treatment option for this type of trauma, since it results in faster resolution and fewer late complications.

Key words: hymenoptera, cornea, bee, wasp, sting

Introduction

The most common treatment for hymenoptera corneal stings includes topical and systemic corticosteroids, topical antibiotics and cycloplegics. The prognosis for severe cases is poor and, in most of these eyes, the sting may lead to severe sight threatening complications.1 We often see patients, mostly children, with severe ocular hymenoptera stings and poor outcomes with traditional treatments. It is possible that a more aggressive treatment could lead

to better results. In our protocol, patients are submitted to surgery as soon as possible after the sting for an extensive irrigation of the anterior chamber, in an effort to remove all the venom and prevent further damage of intraocular structures.

We, hereby, present the report of corneal hymenoptera sting managed with the proposed technique.

Case Report 1

An 8-year-old boy from Chocó, western Colombia, was admitted with a wasp sting to his right cornea, that had occurred three days earlier. Visual acuity in the right eye (OD) was hand motion at 25 cm. In the left eye (OS) was 20/20. At the slit lamp, there was conjunctival hyperemia, a 70% epithelial defect, and diffuse corneal edema with bullae in the central and inferior cornea. Iris details could not be seen. The sting was partially removed at the time of the initial examination at the slit lamp, and topical treatment with ciprofloxacin and dexamethasone drops 4 times/day was started.

The patient returned five days later with intense pain and poor vision. There was severe corneal edema, ciliary congestion, intense flare, paralytic mydriasis and anterior subcapsular lens opacity. Intraocular pressure (IOP) was 38 mmHg, and, therefore, treatment with topical anti-glaucoma medication was initiated.

Two weeks later, the patient was submitted to surgery to perform irrigation of the anterior chamber and to extract the remaining foreign matter from the cornea. Subconjunctival steroid was administered at the end of the procedure.

The corneal opacity persisted, and IOP increased. A penetrating keratoplasty with cataract surgery and intraocular lens implantation was performed, in addition to two unsuccessful trabeculectomies and a


Mauricio Vélez Fernández1, Mark J. Mannis2, Juan Guillermo Ortega1, Camilo Andrés Tobón1

1.Professor of Ophthalmology, Universidad de Antioquia Cornea Service, Hospital Universitario San Vicente de Paúl Medellín, Colombia2. Professor and Chair, University of California, Davis Health System Eye Center, Sacramento, California USA

Funding/fi nancial suport: NoneProprietary interest: The authors have no fi nancial interest in any of the treatments mentioned.


Maurício Vélez F., M.D.Carrera 48 # 19 A 40, consultorio 1517, Torre Médica Ciudad del Río, Medellín, Colombia.Email: [email protected]

Corneal hymenoptera stingsA new therapeutic approach

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bleb revision. The patient was then scheduled for the implantation of a glaucoma drainage device.

CASE 2

A 4-year-old girl was admitted with anaphylactic shock that required intubation and mechanical ventilation for two weeks after experiencing a massive attack by Africanized bees. On examination, there were two stings in each cornea, severe corneal edema and infiltrates. The lens remained clear. It was not possible to assess visual acuity.

The patient was submitted to surgery twenty-four hours after admission. The sting fragments from the corneal stroma were removed, and an anterior chamber irrigation with a Simcoe cannula of both eyes was performed with 10 ml of balanced saline solution. Triamcinolone 0,2 ml (2 mg) was placed in the anterior chamber at the end of the procedure and subconjunctival corticosteroid was injected, additionally. Post-operatively, the treatment regimen included systemic methylprednisolone 60 mg/4 times a day for a total of twelve doses, topical moxifloxacin, prednisolone 1% every three hours, carboxymethylcellulose and therapeutic contact lenses.

One week later, the patient had pupillary paralysis on the right and a normally reactive left pupil. There was moderate right corneal edema with a sting fragment visible, and two infiltrates at the sites from which the stings had previously been removed. The left cornea was clear, with a normal anterior segment. The patient underwent surgery again for removal of the residual sting.

Case 3

A 7–year-old boy was admitted with a honeybee sting that had occurred the day before, and his mother had removed the sting from the cornea with her own hands. At the time of biomicroscopic examination, the patient had diffuse corneal edema, and an epithelial ulcer measuring 4.5 x 4.5 mm. Iris detail could not be seen. The IOP was normal. Treatment was begun with oral prednisolone 1mg/kg/day, topical prednisolone 1%, topical moxifloxacin, and cycloplegics.

The patient returned the next day with increased corneal edema and pain. He was submitted to surgery to perform an anterior chamber irrigation and steroid infusion similar to patients 2 and 3.

On the first postoperative, day the patient exhibited a decrease in corneal edema, no epithelial ulceration, and there was improved visualization through the cornea revealing an atrophic iris and a hypoactive pupil. Ten days after surgery, visual acuity was 20/25. Tonometry was normal and there was heterochromia iridis and a hypoactive pupil. (Figure 1).

Three months later, his condition is unchanged.

Figure 1: Heterochromia iridis and anisocoria 1 week post-treatment, case 3

Figure 2: Severe corneal edema with epithelial defect,case 4

Figure 3: Resolution of edema after treatment, case 4

Figure 4: Anterior subcapsular opacities, case 4


Vélez M et al. Corneal hymenoptera stings

Case 4

A 12-year-old boy was admitted with a corneal wasp sting to his right eye that had occurred 12 hours earlier. Visual acuity in his OD was 20/400, and in OS was 20/20. At the time of biomicroscopic examination, he had conjunctival hyperemia, a 90% corneal epithelial defect, corneal edema and opacification (Figure 2). There were small fragments of the sting in the anterior and mid-stroma with infiltrate around the fragments, Descemet folds, and anterior capsular lens opacity. The IOP was 14 mm Hg. Anterior chamber irrigation with 10 ml of balanced saline solution was performed 15 hours after, and triamcinolone 0,2 ml (2 mg) was placed in the anterior chamber at the end of the procedure.

Eleven days after surgery, visual acuity was 20/100. Cornea was clear, IOP was normal, and there was no cells or flare. Pupil was dilated and non-reactive, with no afferent pupillary defect. There was an anterior cortical cataract (Figures 3 and 4).

Results

Table 1 summarizes the cases, results and sequelae.2

Table 1: Visual results and sequelae of the case series.

Eye Patient No Age Sex Eye Insect Beginning VALogMAR

Time to surgery Final VALogMAR

Sequelae

1 1 8 M OD Wasp 2.4 17 days 2.4 Corneal opacity, glaucoma, cataract,

2 2 4 F OD Bee NA 1 day Fixes and follows Small peripheral leucoma

3 2 4 F OS Bee NA 1 day Fixes and follows None

4 3 7 M OD Bee 2.0 2 days 0.1 Iris Heterochromia, hypoactive pupil

5 4 12 M OD Wasp 1.7 15 hours 0.7 Cataract, esotropia

Discussion

In the large rural populations treated in our emergency department, insect stings to the eye is a common event. Although, insect sting in other areas of the body may be painful, more commonly this produces a relatively slight annoyance and only rarely anaphylaxis. On the other hand, direct ocular involvement is a serious injury that can lead to severe and permanent complications.3,4

The toxicity induced by the venom of the hymenoptera (bees, wasps and ants) is produced by non-enzymatic polypeptide toxins (mellitin, apamin, iminimine, mast-cell degranulating peptide) and enzymes (phospholipase A, phospholipase B, hyaluronidase, lipase, acid phosphatase, alkaline phosphatase, esterase, and phosphodiesterase).5,6

Mellitin causes iris heterochromia, induces serotonin and histamine liberation, as well as protein denaturation, that can lead to cataract and delayed zonulolysis favoring to lens subluxation.7 Apamin is a neurotoxin that can induce ophthalmoplegia and pupil paralysis. Furthermore, the high

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1. Gürlu VP, Erda M. Corneal Bee Sting–Induced Endothelial Changes. Cornea 2006;25:981–3.

2. Schulze-Bonsel K, Feltgen N, Burau H, Han-sen L, Bach M. Visual Acuities “Hand Motion” and “Counting Fingers” Can Be Quantifi ed with the Freiburg Visual Acuity Test. Invest Ophthal-mol Vis Sci 2006;47(3):1236-40.

3. Smith DG, Roberge RJ. Corneal bee sting with retained stinger. J Emerg Med 2001;20(2):125–8.

4. Wong BW, Lai JS, Law RW, Lam DS. In Vivo Confocal Microscopy of Corneal Insect. Cornea 2003; 22(1):56–8.

5. Yildirim N, Erol N, Basmak H. Bee sting of the cornea: a case report. Cornea 1998;17:333–4.

6. Schmidt JO, Blum MS, Overal WL. Com-parative enzymology of venoms from stinging Hymenoptera. Toxicon 1986;24:907–21.

7. King TP, Spangfort MD. Structure and biology of stinging. Int Arch Allergy Immunol 2000;123:99-106.

8. Maybodi M, Guler ML, Kaplan HJ: Immunol-ogy of uveitis. In Tasman W, Jaeger EA (eds): Duane’s Clinical Ophthalmology. Philadelphia: JB Lippincott, 2002

9. Chen CJ, Richardson CD. Bee sting-induced ocular changes. Ann Ophthalmol 1986;18:285– 6.

10. Hoffman DR, Shipman WH. Allergens in bee venom. I. Separation and identifi cation of the major allergens. J Allergy Clin Immunol. 1976;58(5):551-62.

11. Maltzman JS, Lee AG, Miller NR. Optic neuropathy occurring after bee and wasp sting. Ophthalmology 2000;107:193–5.

12. Al-Towerki AE. Corneal Honeybee Sting. Cornea 2003;22:672–4.

13. Jain V, Shome D, Natarajan S. Corneal Bee Sting Misdiagnosed as Viral Keratitis. Cornea 2007:26:1277–8.

14. Visscher PK, Vetter RS, Camazine S. Re-moving bee stings. Lancet 1996;348:301–2.

REFERENCESmolecular weight enzymes that enter the anterior chamber due to the sting are highly antigenic and responsible for the inflammation that results from enzymatic hydrolysis of structural phospholipids. They are also responsible for inducing vasodilation and dissemination of the other toxic components.8,9 This insult induces a reaction in the anterior chamber similar to a chemical burn.10

Some authors have described retrobulbar neuritis, papilledema, and optic atrophy in patients with stings in other areas of the body.11 The severity of the symptoms may differ depending on the type of insect and the amount of chemical agent that enters the anterior chamber.6

The described case series presents different outcomes, which, we believe, correlate with the celerity of the surgical intervention. The best results were achieved when we were able to remove the insect sting early, with a 90% improvement of the symptoms12 and resolution of the keratouveitis.13 However, attempts to remove the sting manually prior to ophthalmologic intervention, induced even greater inoculation of the venom due to the pressure exerted on the venom glands adherent to the sting.14

The poor outcome of the patient who underwent conventional treatment (Case 1), led us to consider a more aggressive approach on the other cases. This included an early irrigation of the anterior chamber with 10 ml of balanced saline solution, followed by intracameral application of triamcinolone (2 mg/0,2 ml) in order to decrease the inflammatory reaction as well as the amount of circulating toxins in the anterior chamber.

The excellent functional and visual outcomes in the patients with earlier and more aggressive treatment led us to suggest that the management of insect stings to the cornea should include early surgical intervention, in order to remove the stings and to perform an anterior chamber irrigation with balanced salt solution. Subsequent management includes topical corticosteroids and antibiotics. These patients require frequent and ongoing follow-up due to the risk of delayed complications including persistent endothelial loss, cataract, and glaucoma.1 Corneal transparency in the cases described in this report was achieved approximately 4 to 6 weeks after removing the sting and initiation of intensive anti-inflammatory treatment.1

Conclusion

Insect stings to the cornea are ophthalmic emergencies that can produce a severe toxic anterior segment syndrome. Early irrigation of the anterior chamber can result in faster resolution of the acute clinical picture and improvement in the long-term prognosis.


Ho and Valenzuela. Periocular Cystic Squamous Cell Carcinoma

Abstract

A 53-year-old man with a history of multiple cutaneous facial squamous cell carcinoma (SCC) presents with a progressively enlarging cystic mass of his right brow for two months associated with periocular pain and numbness along the right side of his scalp. In addition, several subcutaneous lesions were noticed along the nasolabial and nasojugal areas. All lesions were excised and confirmed to be SCC on pathology with perineural spread observed with the primary brow lesion. The presence of a cystic lesion and/or multiple subcutaneous lesions should prompt consideration of a metastatic presentation of SCC. Furthermore perineural invasion of SCC can be associated with sensory and/or motor deficits.

Key Words: squamous cell carcinoma, periocular, cyst, perineural invasion, subcutaneous metastasis.

Introduction

Squamous cell carcinoma (SCC) is the second most common eyelid malignancy in Caucasians and accounts for less than 5% of malignant eyelid neoplasms.1 SCC is a neurotrophic tumor and has the aggressive potential to become metastatic through perineural spread (PNS) often manifesting with facial dysesthesias and/or motor nerve palsies in the absence of visible masses or as subcutaneous metastasis appearing as satellite lesions.2-4 Although rare, there have been reports in the literature of PNS of SCC associated with a cystic lesion,3 however this case describes recurrence of SCC with a cystic component and associated PNS, as well as, the development of atypical lesions in the subcutaneous tissue likely representing metastatic spread and advanced disease.

Case Report

A 53-year-old man presents with complaints of pain and right-sided facial numbness along with a mass of

A Persistent Case of Periocular CysticSquamous Cell Carcinoma


Son T. Ho, M.D.1, Alejandra A. Valenzuela, M.D.1

1 Department of Ophthalmology, Tulane University School of Medicine, New Orleans, Louisiana, USA

Funding/fi nancial support: NoneProprietary interest:The authors have no proprietary interests in any of the products mentioned in this paper

his right upper eyelid. The mass had been present without symptoms for two months but recently became painful and swollen. The medical history was significant for excision of several squamous cell carcinomas of his face leaving a large surgical defect of the right maxillary sinus and his entire nose. On examination there was tender, cystic and mobile mass measured at 4.0 x 2.0 cm, located anterior to the superior orbital rim of the right eyebrow (Figure 1a). Several subcutaneous lesions were also noticed: two in the left nasolabial (3.5 x 3.0 cm and 2.5 x 2.0 cm), one on the right naslabial (4.3 x 3.0 cm), one in the left nasojugal (3.0 x 1.0 cm) and one eroding the medial orbital and anterior lacrimal crest, extending towards the brow (2.5 x 2.5 cm) (Figure 1b). A right lower lid cicatrical entropion was present


Son Ho, MD1430 Tulane Ave SL 69, New Orleans, LA 70112Email: [email protected]: 504-715-7135Fax: 504-988-2684

Figure 1: (a) Clinical photograph showing a large cystic SCC of the right brow and (b) multiple subcutaneous lesions along the nasolabial and nasojugal areas prominent on the left side of his face.

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along with paraesthesia along the V1 and V2 dermatome on the right. Best corrected visual was 20/25 OU with remainder of his ocular examination, including slit-lamp and dilated ophthalmoscopic examination was normal. A right medial orbital infiltration with opacities of the right ethmoidal sinuses was seen on CT.

The patient underwent a right brow tumor excision along with excision of the other facial subcutaneous lesions. Histopathologic examination was completed with Hematoxylin & Eosin and immunoperoxidase stains including both S100 protein for identifying nerves and MNF116 as a keratin marker (Figure 2a-2b). The brow lesion revealed poorly differentiated SCC with perineural invasion along the frontal nerve explaining the hypoesthesia. Examination of the subcutaneous lesions demonstrated malignant squamous epithelial tumor deposits and foci of necrotic SCC, as well as, scattered small nerve branches within the specimen, showing perineural and occasionally intraneural invasion.

Based on his previous history, metastatic SCC was the most likely the diagnosis. The surgical margins were positive with evidence of perineural spread in the primary brow lid lesion and metastatic disease was seen in the subcutaneous lesions. He has received maximal radiotherapy and has declined exenteration; unfortunately, our patient prognosis was poor. Management is now aimed at palliative care for pain and control of symptoms of this advancing disease.

Discussion

PNS associated with SCC of the head and neck may present in a variety of settings and cause significant morbidity and mortality. The confirmation of PNS despite suggestive signs and symptoms can prove difficult and it maybe until disease develops within the orbit, cavernous sinus and/or nerves/foramina that a diagnosis can be supported.5 PNS can present clinically in patients who complain of periocular pain, dysesthesias or paresthesia along the trigeminal dermatome and/or

ocular motility deficits.3,4 If a patient presents with pain and periocular and ocular neurological symptoms the diagnosis should be suggested even if the cutaneous lesion cannot be identified.

The pathophysiology of PNS associated with cystic SCC has not been well characterized. The presence of subcutaneous nodules along the pathway of the effected nerve has been noted and suggests that SCC penetrates beyond the nerve sheath.4-6 The microscopic appearances suggest that the tumor extends along the perineural space and penetrates through the epineurium to gain access to the orbital connective tissue. Initially the lesion appears maintains a solid structure, but with persistent growth there is progression to central necrosis and secondary cystic degeneration that leaves a thin rim of viable neoplastic epithelium lining the structure.3 The presentation of cystic SCC has been described on imaging (CT and MRI) and linked to PNS. The cases with radiographic evidence of PNS has been shown to be associated with a poorer prognosis (50% 5-year survival rate) than imaging- negative disease (86% 5-year survival rate).7

The occurrence of SCC in the secondary lesions excised likely demonstrated subcutaneous metastases. Clinical studies suggest that the cutaneous spread of SCC is caused by lymphatic dissemination and/or PNS and if distant possibly hematogenous spread.8 Metastases are often site-specific to areas of optimal cell proliferation and tend to be close to the primary tumor and areas of lymph node spread. This is slightly different in our case in that most of the subcutaneous lesions on presentation were located on the left side, whereas excisions of previous SCC were on the right side of the face. Studies have shown that subcutaneous spread of SCC in the head and neck have a poor prognosis.9

Treatment recommendations for PNS and/or dermal metastases of SCC vary and investigations determining the extent of disease will guide treatment. There is good evidence that combined modality treatment with surgery and adjuvant radiotherapy improves locoregional control

Figure 2: (a) Photomicrograph showing the histological appearance of SCC infi ltrating the dermis and epidermis (H&E 100x) and (b) perineural invasion.


Ho and Valenzuela. Periocular Cystic Squamous Cell Carcinoma

and survival in head and neck SCC. Surgery serves mainly for diagnostic purposes, as complete removal of an extensive lesion is unrealistic. It is likely in this case surgery can also be performed for palliative care as debulking the tumor can manage pain and minimize symptoms. In the setting of aggressive microscopic spread of disease, radiotherapy targeting the lesion and the possible areas of spread is the mainstay of treatment. Radiotherapy can be curative with early disease, but in advanced disease, the aim is growth restraint, reduction in local morbidity, and pain control.10 Despite extensive surgery and significant radiation therapy our patient underwent, the tumor continued to grow and invade the surrounding structures of his face. All treatment is now focused on palliative care.

In conclusion, the presence of a cystic lesion in a patient with a history of SCC of the face and ocular adnexa or sensory and/or motor deficits of the face in the periocular area is suggestive of PNS from a SCC. Further suspicion for metastatic disease should arise if small subcutaneous lesions arise by the primary site of malignancy. These characteristics highlight advance disease and should prompt for urgent biopsy and possible imaging studies to determine the extent of the disease and establish treatment.

REFERENCES

1. Donaldson MJ, Sul-livan TJ, Whitehead KJ, et al. Squamous cell carcinoma of the eyelids. Br J Ophthal-mol 2002;86:1161–5.

2. McNab AA, Francis IC, Benger R, Crompton JL. Perineural spread of cutaneous squamous cell carcinoma via the orbit. Clinical features and outcome in 21 cases. Ophthalmology. 1997;104(9):1457-62.

3. Valenzuela AA, Whitehead KJ, Sul-livan TJ. Ocular adnexal pseudo-cyst formation as a characteristic feature of perineural spread in squamous cell carcinoma. Ophthal Plast Reconstr Surg. 2006;22(3):201-5.

4. Bowyer JD, Sullivan TJ, Whitehead KJ,

Kelly LE, Allison RW. The management of perineural spread of squamous cell car-cinoma to the ocular adnexae. Ophthal Plast Reconstr Surg. 2003;19(4):275-81.

5. Hove MW, Glaser JS, Schatz NJ. Occult perineural tumor infi ltration of the trigeminal nerve: diag-nostic considerations. J Neuroophthalmol 1997;17:170–7.

6. Veness MJ, Biankin S. Perineural spread leading to orbital inva-sion from skin cancer. Australas Radiol 2000;44:296 –302.

7. Limawararut V, Hoyama E, Selva D, Davis G. Squa-mous cell carci-noma presenting as an orbital cyst with radiologic evidence of

perineural invasion. Eur J Ophthalmol. 2007;17(6):970-2.

8. Sesterhenn AM, Albers MB, Timmes-feld N, Werner JA, Wiegand S. Dermal metastases in squa-mous cell carcinomas of the head and neck. Head Neck. 2012, 14.

9. Kelder W, Ebrahimi A, Forest VI, Gao K, Murali R, Clark JR. Cutaneous head and neck squamous cell carcinoma with re-gional metastases: the prognostic importance of soft tissue metas-tases and extranodal spread. Ann Surg On-col. 2012;19(1):274-9.

10. Veness MJ, Mor-gan GJ, Palme CE, Gebski V. Surgery and adjuvant radiother-apy in patients with cutaneous head and

neck squamous cell carcinoma meta-static to lymph nodes: combined treatment should be consid-ered best practice. Laryngoscope. 2005; 115:870–875.

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PAAO / Vis. Pan-Am. 2012;11(4):124

My late grandfather gave a piece of advice to my father: to always be ready to give a speech in any professional meeting. Even if we are not asked to speak, we must be ready for it. When preparing for a public speech, I simply remember the VPA (as in Vision Pan-America) mnemonic.

Vision

The essence of a public speech remains in a private setting. At this point of the preparation phase, speakers use their imaginary vision. It takes a while to think about the subject of your talk, selecting and organizing ideas, and creating a presentation that may amplify or emphasize your message.

However, there is a real visual phase for every speech. Looking at the audience may be scary to some speakers. To avoid panic, direct your message to two or three people in the audience, one on each side of the room, so you may move your head freely, while looking at the other peoples hair (or bald heads). In this way, the audience believes you are comfortable. By the way, a bit of anxiety does not hurt anyone. I have heard some ophthalmologists use a Beta blocker eye drop before delivering a speech to prevent tachycardia.

On the other hand, may I say, it is a lot easier to look at a camera. While doing so, I never think of the thousands of viewers. Otherwise I may freeze. Further, cameramen have the tools to make you feel comfortable. They pamper you or give you constant positive feedback. Some may even remove lint from your shoulder during breaks.

Passion

A public speaker needs to convey his message with passion. His words need to transmit a contagious passion. That is why country leaders always have hymns to proclaim their victories: to unite people’s hearts in a song.

When arriving at the podium speakers may close their fist, to feel a testosterone rush. I suggest speakers take a deep breath, and put their shoulder-blades back. Lift the chin and visualize yourself as a gladiator. Leaders rule!

Your mystical imaginary armor is shining. You need to think you will convince them. Remember Julius Caesar phrase: “Vini. Vidi. Vinci.” A leader needs to walk into the podium as a conqueror.

Action

If the audience is small, an “Ipad” or even a paper may be used as visual aids to the speech. The presentation’s content may include detailed information (mostly text). In a small group the distance between speaker and the audience is reduced. The floor may be opened up for discussion, so the audience may participate actively, creating an informal atmosphere. The speaker may even choose to sit and become one of the members of the audience. In small groups, the speaker’s non-verbal communication should me moderate and facial gestures may emphasize his thoughts.

If the audience is large, a slide or power point projector works better. Text on the slides should be minimal, allowing images to predominate. The image should convey the message. Do not read the slides. Comment on the bullets you have as text. A person to person communication is limited in a large audience. However, some leaders greet imaginary friends at the audience, to make a preliminary contact. Questions coming from a large audience should be limited to the end of the speech. Speaker’s gestures should include arm movements, unless there is a camera focusing on the speaker’s facial gesticulations. If the speaker feels comfortable, he may move out of the podium, walk within the scenario and/or through the public.

While preparing a power point presentation the speaker needs to consider the time allocated for his talk. Good speakers make only one slide per minute. Repeat: one slide per minute. Latin languages tend to be grandiose, full of adverbs and adjectives. So being Latino, I need to remind myself to keep speeches short and to the point. Always leave some information to answer questions at the end.

Summary

In conclusion, a speaker needs to envision his talk. This is the longest process of a speech preparation: thoughts’ organization. A leaders’ passion must be contagious. In terms of action: be ready to give a speech anytime, anywhere, and adjust to the size of the audience. Convey an assertive attitude and smile. A leader is always in control.

Listen to a round of applause and Encore!

By Natalio J. Izquierdo, M.D.Chairman of the PAAO Professional Relations/Advocacy CommitteeEmail: [email protected]

Public SpeakersLeaders Need to Become

Salas C. Las once verdades de la comunicación, 2010, Editorial LID, Madrid

http://web.mit.edu/urop/resources/speaking.html

REFERENCES

PAN-AMERICA : 125PAN-AMERICA

Advocacy

My term as Chair of the Pan-American Ophthalmological Foundation ends now at the upcoming AAO. It feels like yesterday, when I was appointed to this prestigious position in San Francisco. Since the opening speech it was stated that our goal was to diversify sources for development and growth and to help to increase membership. I highlight the following topics as the most important of the past three years:

1. Strategic Plan 2010/2012 to set the priorities for the entire term. Done and due for review in 2013.

2. New branding for the PAAO and PAOF to make it more contemporary and active as visual identity

3. The New Portal is graphically ready, up and running, and we have just started to make use of our e-learning functionalities that over time will contribute to bring new members, will generate income through enrolment fees for specific courses, as well can be used for specific activities of our industry partners, if approved by the Education Committee. Live chats and mini sites are still to be completed next year.

4. The Circle of Vision, wonderful initiative created by Susan Jones and Teresa Bradshaw, has brought up once again the enthusiasm of traditional individual donors and new ones and has become an important source of funds for the PAAO. In 2011 we raised US$ 34,000, this year we expect to reach US$ 70,000 and next year or final and definitive goal of US$ 100,000. A warm thank you to all donors.

5. The hiring of a full time Resource Development Director gave us more agility in selling our products and bring contributions, not only from traditional industry partners but also bringing new companies, individuals and soon other Foundations to support the PAAO.

6. 6) The hiring of a true Executive Assistant, and the outsourcing of all non essential activities, increased the productivity of the Arlington office, instituted delegation, releasing a tremendous overload of work

from Teresa Bradshaw and Terri Grassi, who now can concentrate in more strategic issues.

7. The Congress in Argentina was financially very successful. Rio, next year, will probably be the biggest Pan-American Congress ever in the long history of PAAO. The Regional Course in Colombia generated good income to the PAAO.

8. The Endowment Fund is approaching his best historical mark gradually but safely. Special thanks to John Moffet.

9. E-vision and Vision Pan America growing in importance, redesigned, and attracting new advertisers.

But what I enjoyed most was the experience. I had the fortune of having two very special Presidents of the PAAO to partner up with the Foundation, Drs. Cristian Luco and Mark Mannis, now even better friends and counselors. The freedom and support they granted me was keen to hand over to my successor a healthier, more professional and proactive PAOF. It is traditional to thank Teresa and Terri for their superb commitment to both the Association and the Foundation. They did even better than in previous occasions this time. They embraced change and were extremely supportive and responsive to the ambitious goals. Susan Jones, keep up the good work. Sandra, welcome to the team. Thank you Mapy Padilla, for the heavy trip schedule all over Latin America and Caribbean promoting our products and services, collecting membership dues, recruiting new members and advertising our events. By now you, are the face of PAAO/F in the majority of National and Regional Courses and Congresses across the geographies we cover.

Finally a thank you to Drs Rubens Belfort, Cristián Luco, Richard Abbott and Mark Mannis, who gave me this extraordinary opportunity to serve the Pan-American community. I leave old friends, I made new ones and I can genuinely tell that more than ever I am “Proud to be Pan-American”. A big thank you to David Pyott, who created the environment in Allergan for me to be fully dedicated to the PAOF for most of the term.

We are a great organization and the Foundation has now all the tools and people to continue to grow steadily and consistently. I still will be around as Past Chair. The Pan-American is in my blood stream now. Wonderful opportunity, rewarding experience and the sense of mission accomplished. Thank you all for the support you have shown over the past three years.

By Nelson R. A. Marques.Chair, Pan-American Ophthalmological Foundation, 2009-2012

And 3 years have gone by...

126 PAN-AMERICA

PAAO / Vis. Pan-Am. 2012;11(4):126

A Associação Pan-Americana de Bancos de Olhos, APABO, realizou de 05 a 20 de julho de 2012, em São Paulo, o “X Curso Certificado de Treinamento Técnico e Científico em Banco de Olhos no Brasil”, capacitando profissionais de 22 cidades brasileiras. Durante duas semanas, representantes do Distrito Federal, Alagoas, Ceará, Espírito Santo, Goiás, Mato Grosso do Sul, Minas Gerais, Pará, Paraná, Pernambuco, Piauí, Rio de Janeiro, Rio Grande do Sul, Santa Catarina e São Paulo, receberam intenso treinamento para atuar nos Bancos de Olhos. Aspectos técnicos, científicos, administrativos, éticos e legais foram exaustivamente abordados, tanto na teoria quanto na prática.

Em sua décima edição, este modelo de curso já formou quase 500 profissionais no Brasil (médicos e técnicos), e foi o responsável pelas transformações no panorama das doações e dos transplantes de córnea no país. A profissionalização das atividades dos Bancos de Olhos levou o Brasil a saltar, entre 1991 e 2011, de 500 para 16.000 transplantes de córnea, anualmente.

Iniciadas em 1991, as atividades do escritório da APABO no Brasil são respeitadas em todo o mundo e,

CAPACITA NOVOS PROFISSIONAIS PARA OS BANCOS DE OLHOSX CURSO DA APABO NO BRASIL

em reconhecimento ao trabalho desenvolvido, a APABO será a anfitriã do “I Congresso Mundial de Bancos de Olhos” que acontecerá em agosto de 2013, durante o “XXXVII Congresso Pan-Americano de Oftalmologia”, no Rio de Janeiro (cidade sede da Associação no Brasil) e que reunirá as principais Associações e representantes de Bancos de Olhos de vários países.

Com o apoio da Associação Pan-Americana de Oftalmologia e da Fundação Pan-Americana de Oftalmologia, a APABO vem cumprindo com sucesso a missão de promover ações, em todo o continente americano, para a redução do número de deficientes visuais por problemas da córnea.

Associação Pan-Americana de Bancos de Olhos - APABOAna Maria Guimarães GarciaTelefone/Fax: 55 35 3421.2186 (português)Telefone/Fax: 55 35 3423.8661 (inglês e espanhol) Skype: apabobrasilE-mail: [email protected]

Benefi cios de ser miembro


Beneficios de ser miembroVISIONVISIONPAN-AMERICAPAN-AMERICA

Como miembro titular, tiene a su disposición los siguientes beneficios:

• Portal (sitio web) multilingüe, moderno y de van-guardia en educación oftalmológica a través de reuniones virtuales, blogs y representaciones en la web que estarán accesibles las 24 horas del día los siete días de la semana.

• Tarifas reducidas de inscripciones a los congresos y cursos regionales de la Panamericana.

* Abril 25-27, 2013 … 21° Curso Regional Paname-ricano en Santiago de Compostela, España

* Mayo 4, 2013 … Día Panamericano de la Investi-gación en Seattle, Washington

* Agosto 7-10, 2013 … 30° Congreso Panamerica-no de Oftalmología en Rio de Janeiro, Brasil

* Noviembre 20, 2013 … 27° Lo Mejor de la Acade-mia en Español en New Orleans, Louisiana

• Premios y reconocimientos

* Premio Global Paul Kayser/RRF que ofrece un pre-mio a destacados científicos en el área visual que estén a la vanguardia con innovaciones en ciencias clínicas y básica en oftalmología.

* Premio Humanitario Benjamín F. Boyd

* Premio Troutman-Véronneau

* Premio a la Prevención de Ceguera Leones/PAAO

• Becas, premios de viaje y oportunidades de entrena-miento de especialidad.

• El programa de profesores Visitantes ofrece a sus miembros la oportunidad de viajar a Con-gresos Nacionales.

• Becas para la reunión de ARVO para jóvenes y promi-sorios oftalmólogos.

La membresía en la Asociación Panamericana de Oftalmología le ofrece la oportunidad de lograr, a través de países y culturas, relaciones duraderas con colegas que están muy comprometidos en compartir nuevas formas de estandarizar y avanzar en el conocimiento oftalmológico y en las habilidades para mejorar la atención al paciente.

Para unirse o renovar su membre-sía, sírvase visitar www.paao.org

1301 S Bowen Road # 450

Arlington TX 76013 USA

Tel: 817.275.7553

Fax: 817.275.3961

Email: [email protected]

www.paao.org

“Un año de membresía gratis por ser residente”

• El curso de Liderazgo para futuros líderes de las socie-dades nacionales de oftalmología afiliadas a la PAAO.

• Esfuerzos de resguardo internacional a su favor.

• La oportunidad de publicar en la revista científica de la PAAO.

• Una suscripción anual a la revista científica multilin-güe Vision Pan-Americana.

• Recibir mensualmente el boletín electrónico Evision y actualizaciones trimestrales del presidente de la Junta Directiva.

• Certificado de Membresía y tarjeta anual de miembro al día de la Panamericana

• Invitación a los eventos culturales de la PAAO en donde se ofrece la oportunidad de reunirse informal-mente con sus colegas y familias.

CIRCLE OF VISION / Vis. Pan-Am. 2012;11(4):128

128 PAN-AMERICA

The Pan-American Association of Ophthalmology and the Pan-American Ophthalmological Foundation would like to thank the following members of the 2012 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.

Alcon Inc.

The Allergan Foundation

Allergan International

Dr. Robert C. Drews

Dr. Alice McPherson

/ Retina Research Foundation

David & Julianna Pyott Foundation

Tim & Judith Sear Foundation

Dr. Thomas & Mrs. Michele Smith III

Dr. Richard Troutman &

Dr. Suzanne Véronneau Troutman

Founder Members($25,000 + )

Abbott Medical Optics, Inc (AMO)

Bausch+Lomb

Johnson & Johnson Vision Care

Latin America

Merck & Co.

Rayner Intraocular Lenses Limited

Ambassador Members ($10,000 to $24,999)

Laboratorios Sophia

Leadership Members($5,000 - $9,999)

If you would like to learn more about the Circle of Vision, please contact:

Susan L. Jones, CFREDirector of DevelopmentTel: [email protected]

Dr. J. Fernando Arévalo

Dr. Carlos W. Arzabe

Anonymous

Dr. Zelia M. Correa

Lions Clubs International

Foundation (LCIF)

Dr. Mark J. Mannis

Mr. Nelson R.A. Marques

Dr. Eduardo Silva

Dr. Richard L. & Cecilia B. AbbottDr. Eduardo C. AlfonsoDr. Eduardo ArenasDr. Bronwyn Bateman & Dr. Doug HersheyDr. Maria H. BerrocalDr. Michael W. BrennanMs. Teresa J. BradshawDr. Antonio M.B. CasellaDr. Francisco ContrerasDr. Paulo E.C. DantasDr. William De La PeñaDr. Michel E. FarahDr. Thomas & Mrs. Leslie W. FranceDr. Denise de FreitasDr. Enrique L. Graue WiechersDr. Miguel Guzmán AhumadaHerbert Family FoundationDra. Ana Luisa Höfling-LimaDr. & Mrs. Dunbar HoskinsDr. Luis Izquierdo Jr.Ms. Susan L. JonesDr. Carol Karp & Dr. Jonathan CohenDr. Deborah L. Klimek

Patron Members

($2,500 to 4,999)

Partner Members

($1,000 to 2,499)Dr. Paul R. & Mrs. Carolyn LichterDr. Chun Cheng Lin YangDr. Cristián LucoDr. Maurício MaiaDr. Mário Junqueira NóbregaMr. Juan Carlos Plotnicoff & Mrs. Laura Malkin-StuartDr. Peter A. QuirosDr. Marco A. Rios OlivaresDr. José A. RocaDr. André RomanoDr. Stephen & Mrs. Anne RyanDr. Elcio H. SatoDr. Allan R. SlomovicDr. Ronald E. SmithDr. Bruce E. SpiveyDr. & Mrs. Bradley R. StraatsmaDr. James C. TsaiDr. Jorge E. Valdez GarcíaDr. & Mrs. C.P. WilkinsonDr. Ruth D. WilliamsDr. Agnes WongDr. Lihteh Wu

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PAAO V.11-4 Diciembre 2012