Paao September 2013 Vol. 12 No.3

VISION THE PAN-AMERICAN JOURNAL OF OPHTHALMOLOGY ISSN 2219-4665 September 2013, Vol. 12(3)

Editorial Dantas PEC

Message from the President Hofling-Lima AL

Bayesian methods and decision making in glaucoma Kasahara N

Optical coherence tomography findings in macular hole complicating exudative age-related macular degeneration treated with ranibizumab Dolz-Marco R et al

Tratamiento combinado de hemorragias subretinianas con activador del plasminógeno tisuar recombinante (rtPA), gas y Ranibizumab intravítreos.

Garcia-Fernández M et al

Implantation of an implantable collamer lens and iris cerclage for the treatment of Urrets-Zavalia syndrome Dias-Santos A et al

Ranibizumab for choroidal neovascularization following atrophic involution of adult-onset foveomacular vitelliform dystrophy.

Martinez-Castillo S et al

Atypical crystalline keratopathy by Candida parapsilosis.

Martinez-Chico R et al

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

Announcements Proud to be PAN-AMERICAN

4 :

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September 2013, Vol. 12(3) Indexed in Editor-in-Chief: Paulo Elias C. Dantas, MD Prof. of Ophthalmology Department of Ophthalmology Santa Casa of São Paulo, Brazil Membership, Associations and Editorial Guidelines

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

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

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

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

Editorial Review Board

Denise de Freitas, MD (São Paulo, Brazil)

Alejandro Lichtinger, MD (Toronto, Ontario, Canada)

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

Eduardo Alfonso, MD (Miami, FL, USA)

Ashley Behrens, MD (Riyadh, Saudi Arabia)

Daniel Weil, MD (Buenos Aires, Argentina)

Eduardo Arenas, MD (Bogotá, Colombia)

Ana Luisa Höfling-Lima (São Paulo, Brazil)

Marian Macsai, MD (Chicago, IL, USA)

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

Bruno Fontes, MD (Rio de Janeiro, Brazil)

Marie Eve Legare, MD (Quebec City, Canada)

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

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

Natalio Izquierdo, MD (San Juan, Puerto Rico)

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

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

Eugenio Maul de La Puente (Santiago, Chile)

Renato Ambrósio Jr. (Rio de Janeiro, Brazil)

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

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

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

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

PAOF BOARD

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

Secretary, Spanish Language Region Lihteh u, MD

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

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

Vice President Jos Antonio Roca, MD

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

Executive Vice President J. ernando Ar alo, MD ACS

Associate Secretary, Portuguese Language Region Maur cio Maia, MD

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

ecuti e Director eresa J. Bradsha

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

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

DOMI ICA R P BLIC Del na Orti , MD4 Jaime A. e uerra, MD , Juan rancisco Batlle Pichardo, MD1

L SALVADOR mmanuel Jes s Sal ador Mena M nde , MD , A MALA Byron Polanco, MD4 Cristi n Rolando Ace edo Campos, MD1 Paulina Caste n, MD ,

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

HAI I rant Large, MD

CHIL Ale andro V ue de art o , MD4 Cristi n Luco, MD2 ernando R. Barr a on Bischho shausen, MD4 Juan Verdaguer aradella, MD2 Miguel Srur, MD4 Ver nica A car ., MD Ver nica ern nde Salgado, MD4 COLOMBIA Al aro Rodr gue on le , MD2 Angela Mar a ern nde Delgado, MD , Angela Mar a uti rre Mar n, MD1 Carlos Alberto Restrepo Pelae , MD , Hugo Hern n Ocampo Dom ngue , MD Jos Ramiro Prada Reyes MD1 Pedro I an a arro aran o MD1 Roberto Ba uero H., MD1 ,

C BA Armando Capote Cabrera, MD Beatri . Rodr gue Rodr gue , MD1 Ibrain Piloto D a , MD1

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

V LA Claudia Lu Pab n Be arano, MD1 ernando L. Colombo Rengel, MD4 Jos Luis Rinc n Rosales, MD1 Mar a Ang lica Corte Bernal, MD1 Morayma Ace edo Sorondo, MD Oscar Vicente Beau n Balbi, MD1

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PA AMA Ben am n . Boyd MD2 li milio Rui D a , MD Samuel Boyd Le is MD1 PARA A Pablo Rub n Cibils arr s, MD1 alter imcke Holst, MD ,

S I DI S Li ette Mo att, MB BS MMedSci , Son a . Johnston BSc MB BS RCS1

P R Dino ernando atteri Marmol, MD1 rancisco Contreras Campos MD2 Jos Antonio Roca ern nde , MD Juan Carlos Corbera on alo, MD1 Juan ernando Mendiola Solari, MD1 Miguel u m n Ahumada, MD1 Roc o Ardito Vega MD1 POR AL duardo Jos il Duarte Sil a MD PhD1 Paulo . de Ancede Aires S orres, MD PhD

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

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

1

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

C ADOR Luis Sarra n Moreira, MD Mario P lit Macias, MD1 Robin Alberto R os Arreaga, MD1

BOLIVIA Carlos alter Ar abe A., MD , usta o Aguirre r ui u, MD1

COS A RICA Joa u n Mart ne Arguedas, MD eodoro ans MD1

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

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

1

2

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EDITORIAL

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

VPA gets first international database indexation: Why celebrate?

Among the many challenges that a scientific journal editor faces during his term, indexing the journal in scientific databases is one of the hardest.

The international databases are very selective and demand many important editorial features so the journal can comply with the international scientific editorial standards. After making all the adaptations asked, the journal goes through an observational period that could take a year or two; just after that, a selected committee evaluates the journal and emits a verdict that could be favorable or not. When not, this committee will send suggestions to the editor and sets a new observation/evaluation period that could take two or more years.

That’s why we have to celebrate our recently announced indexation in the Directory of Open Access Journal (DOAJ) www.doaj.org, one of the most prestigious databases in the world.

This certainly will increase visibility to all material published in VPA, promoting their increased usage and scientific impact.

Benefits of being indexed in DOAJ includes: • Journals with the content in PDF format will be included in long term preservation projects.

• Statistics show more than 10 millions successful requests a month for DOAJ site from all over the world.

• Once the article is available in DOAJ, it becomes automatically harvestable.

Once indexed in the DOAJ database, our journal was immediately included in the Directory Indexing of International Research Journals and to CiteFactor® http://citefactor.com increasing international visibility.

This is the first step to be seen, searched and cited by other international authors, increasing our visibility and chances of being indexed in other important databases.

Congratulations to all members of the Editorial Board, reviewers, authors and especially to our readers.

Let’s celebrate (and work harder)!

PS: Another useful tool was added to our cover page, the QR (Quick Response) Code, a matrix barcode (or two-dimensional code), readable by QR scanners, mobile phones with a camera, and smartphones that leads to our web page instantly. Try it!

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

• Many web crawlers are fetching the content of DOAJ to be a part of their search engines.

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Vis. Pan-Am. 2013;12(3):68

Message from the President Ana Luisa Hofling-Lima President of the Pan- American Association of Ophthalmology 2013-2015

Getting Started To start a presidency after the fantastic meeting that was organized in Rio de Janeiro by the Brazilian Council of Ophthalmology (CBO) and the Pan-American Association of Ophthalmology (PAAO) is a special pleasure. A team of friends and great people were involved in the success of the event. There were years of hard work from everyone, and we have heard a lot of good comments about the program and the event itself.

Mark Mannis, who was the president of PAAO for the last two years, taught us how to manage the macro and micro events and its associated challenges. I hope to carry out my term with the same feeling that Mark has as he wrote “I leave the office with some degree of sadness because it has been very exhilarating and wonderful to lead this organization.”

We have today a mature Pan-American Association and Foundation. Working closely with Bill De La Peña, who is now chairing the Foundation, will also be a good learning experience for the whole group. The Pan-American Association is the primary effort with the Foundation as a supporting agency.

With an active Executive Committee and Board of Directors who provide the main forum for discussions, decisions and coordination. We plan to organize an Executive Committee and Board of Directors Meeting at every American Academy of Ophthalmology and Pan-American Congresses. Additionally we plan to have Executive Committee meetings at some of the Regional Courses.

The national ophthalmological societies of the 26 partner countries were invited for the first time to be together in Rio for a full day in a meeting called “Summit of Americas.” The presidents were given an opportunity to present their ophthalmic practice situations and also to discuss solutions for common problems. After this excellent experience, we are looking forward to organizing future meetings with our partner societies.

The Pan-American has many committees. The Specific chairs have their goals and welldefined 68

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objectives, so they can move ahead, bringing to PAAO a diversity of educational policies and programs.

The 18 affiliated subspecialty societies of the Pan-American are active and also related to several National Subspecialty Societies, making an important communication bridge between specialists. This interaction makes it easier to prepare the scientific programs for all events.

Our Pan-American Regional Courses are also improving and growing. In 2014, we will meet in Uruguay and Panama in addition to our meetings at the ARVO and American Academy of Ophthalmology meetings in Chicago.

Vision Pan-America, The Pan-American Journal, has the first international indexation in the DOAJ (Directory of Open Access Journal). As a result of that we are also indexed in the Directory Indexing of International Research Journals, which gives us more international exposure and allows our journal to be included in the Academic Scientific Journals - CiteFactor®. This new door will certainly increase our visibility, and the space of the journal will be filled by better quality publications.

The improvement of the network among individual ophthalmologists, National Societies and Subspecialty Societies is our main goal. We aim to provide better ophthalmic education throughout the Americas. Our team is ready to take on new challenges.

Having the support of Mark Mannis as past president and Eduardo Alfonso as our future president, I am sure we will be able to do an outstanding job, I am sure It is a major undertaking for the whole team, but one that will be hugely rewarding.

Ana Luisa Hofling-Lima President of the Pan- American Association of Ophthalmology 2013-2015

Kasahara N. Bayesian methods and decision making in glaucoma

Bayesian methods and decision making in glaucoma Niro Kasahara, MD

Correspondence address:

Glaucoma Service and Ophthalmic Epidemiology & Statistics Service, Department of Ophthalmology, Santa Casa de Sao Paulo School of Medical Sciences, Irmandade da Santa Casa de Misericordia de Sao Paulo, Sao Paulo, Brazil.

Niro Kasahara, MD Rua Sao Mauro, 292 Sao Paulo – SP – 02526-050 Brazil Fone: (5511) 4195-3406 Email: nirokasahara@ig.com.br

Funding: None Financial/propretary disclosure: None

Abstract

This article reviews the Bayesian statistical approach to diagnostic test analysis and application in the management of glaucoma patients. The central idea of the Bayesian method is the use of study data to update the state of knowledge about a quantity of interest.

In diagnostic test analysis, the Bayesian approach explicitly elicits a clear interpretation of chances of a particular eye disease given a positive test result. The Bayesian method also provides a reasonable rationale for deciding whether to perform a laser iridotomy in a patient with occludable angles. We present several literature examples of Bayesian methods in practice, especially as it relates to glaucoma evaluation and progression.

Introduction

Bayes’ theorem is a procedure for revising and updating the probability of some event in the light of new evidence.1 It originated in an essay presented to the Royal Society of London for Improving Natural Knowledge by Reverend Thomas Bayes and published post mortem by his peer Richard Price in 1763.2 The Bayesian method is an approach to inference based on Bayes’s theorem, in which prior knowledge in the form of a specified probability distribution for the unknown parameters (prior distribution) is updated in the light of observed data to give a revised probability distribution for the parameters (posterior distribution). This form of inference differs from the classical form of frequentist inference in several respects, particularly in the use of a prior probability distribution for the parameters. The prior distribution represents the investigators’ knowledge before collecting data.3 The method can relate the chance that

Date of submission: 04/06/2013 Date of approval: 27/08/2013

an event A happened given the indicator X, or mathematically, P(A | X), as well as P(X | A), the chance the indicator X happened given that event A occurred.

Bayesian inference has found application in a range of fields including computer science (anti-spam email filtering, artificial intelligence and expert systems), engineering, philosophy, marketing (pricing decision, promotional campaign, logistic of distribution), medicine and law (to coherently accumulate the evidence for and against a defendant). In brief, this article will discuss the clinical application of the Bayesian method in diagnostic testing for eye disease and focus on its use in glaucoma research and patient management.

Clinical example: anatomy of a test*

Consider a hypothetic eye condition with 1% prevalence in the population. The diagnostic test can detect up to 80% of cases (real positive) and miss up to 20% (undetected disease). Conversely, the same diagnostic test gives 10% false positive results (so, 90% correctly return a negative result). Plotting these data on Table 1, one can easily notice that if the patient has the disease (first column) there is 80% chance he will test positive and 20% chance he will test negative. Healthy subjects are in the second column. They have 10% chance of being tested positive, and 90% chance of being tested negative.

Consider a patient with a positive test result. What are the real chances that he has the eye disease? If he was tested positive, he can either be a true positive or a false positive (first row of Table 1). At this point, it is wise

*Adapted from Kalid Azad. An Intuitive (and Short) Explanation of Bayes’ Theorem. Available at: http://betterexplained.com/articles/ an-intuitive-and-short-explanation-of-bayes-theorem/

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not make any assumption. The chance of a true positive is given by the product of the chance he has the eye disease times the chance test detected it (1% x 80% = 0.008). The chance of a false positive is calculated multiplying the chance he does not have the eye disease by the chance the test detected it anyway (99% x 10% = 0.099). Placing those figures on Table 2 facilitates the understanding.

The chances that a patient with positive test result definitively has the disease can be estimated by simple probability formulae.

The chance of an event is the number of ways it could happen given all possible outcomes (probability = desired event ÷ all outcomes). In the example, the chance of getting a real, positive result is 0.008. The chance of getting all positive result is the chance of a true positive plus the chance of a false positive (0.008 + 0.099 = 0.107).

Hence, the chance of eye disease is 7.4% (0.008 ÷ 0.107 = 0.074).

Unexpectedly, the real chance that a patient with positive test result has the disease is very low (7.4% chance of disease, rather than the supposed accuracy of the test of 80%). However, when we analyze this figure on population grounds it seems more logical. The test gives a false positive 10% of the time, so that in a given population there will be a large number of false positives, to such an extent that most of the positive test results will be incorrect.

introduced by false positives getting the real chance of having the event. It imparts the actual probability of an event given the measured test probabilities. Assuming one knows the real probabilities and the chances of false positive and false negative, adequate correction for measurement errors can be made. The equation is: P(A | X)= P(X | A). P(A) / P(X | A). P(A) + P(X | ~A). P(~A) Where: P(A | X) is the chance of having eye disease (A) given a positive test (X). This is the answer to the question; P(X | A) is the chance of a positive test (X) given that the patient has the disease (A) or the chance of a true positive (80%); P(A) is the chance of having the disease (1%); P(X | ~A) is the chance of a positive test (X) given that the patient does not have the disease (~A) or the chance of a false positive (10%); and P(~A) is the chance of not having the disease (99%).

The equation can be further simplified when one realizes that it amounts to the chance of a true positive result divided by the chance of any positive result.

P(A | X) = P(X | A) · P(A) / P(X) In the algorithm, Pr(X) is a normalizing constant and it helps to scale the equation.

This factor corrects the false belief that a positive test result gives an 80% chance of having the eye disease. Besides, Pr(X) conveys the chance of getting any positive result, both true positive and false positive, serving as a weighted average. In the example, Pr(X) is very large because of the potential for false positives.

Ideally, if a diagnostic test were completely accurate, the test probabilities and real probabilities corresponded to each other. In clinical practice, however, diagnostic tests do give false positive results in healthy subjects and fail to detect disease in affected patients.

Bayes’ theorem allows one to look at the skewed test results and correct for errors, recreating the original population and finding the real chance of a true positive result.

Clinical example: Bayes’ theorem

Clinical applications in glaucoma

Table 1. Frequency of test results for eye disease.

Disease (1%)

No disease (99%)

Positive test

80%

10%

Negative test

20%

90%

Table 2. Probability of test results for eye disease.

Disease (1%)

No disease (99%)

Positive test

True positive (0.008)

False positive (0.099)

Negative test

False negative (0.992)

True negative (0.901)

What are the real chances that a patient with a positive test result has the eye disease?

One can answer the question using the Bayes’ theorem. The theorem allows one to take the test results and correct for the “skew”

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Bayesian statistics have been extensively used in glaucoma research with especial interest in disease diagnosis and progression analysis.

In order to determine whether an unsupervised machine learning classifier

Kasahara N. Bayesian methods and decision making in glaucoma

can identify patterns of visual field loss in standard visual fields consistent with typical patterns learned by decades of human experience, Sample et al evaluated standard perimetry thresholds plus age from patients with glaucoma and healthy subjects clustered with an unsupervised machine classifier, variational Bayesian mixture of factor analysis (vbMFA). Without training-based diagnosis (unsupervised learning), the vbMFA identified four important patterns of field loss in eyes with glaucomatous optic neuropathy in a manner consistent with years of clinical experience.4 Jansonius estimated the specificity of a clinical evaluation of a series of visual fields and calculated the positive predictive value of progression using Bayes’s theorem. The author concluded that the realistic series of visual fields that were apparently progressive had a positive predictive value of typically 0.5, i.e., half of them were stable. In the case of a high prior probability (uncontrolled glaucoma or long interval between successive fields), four fields may suffice to diagnose progression, whereas at least six fields were required if the prior probability was low.5 Progressive loss of the field of vision is characteristic of a number of eye diseases such as glaucoma. Recently, there has been an explosion in the amount of data being stored on patients who suffer from visual deterioration including field test data, retinal image data and patient demographic data. However, there has been relatively little work in modeling the spatial and temporal relationships common to such data. Tucker et al introduced a novel method for classifying visual field data that explicitly models these spatial and temporal relationships. The authors used a spatiotemporal Bayesian classifier and compared it to a number of classifiers from the machine learning and statistical communities. The authors concluded that the results outlined in the study paved the way for a substantial program of study involving many other spatial and temporal datasets, including retinal image and clinical data.6 Intraocular pressure (IOP) fluctuation over 24 hours is an independent risk factor for glaucoma progression, however, nighttime lOP measurement is not routine practice.

Using a Bayesian network (BN), Nordmann and Berdeaux assessed the likelihood of a nighttime IOP peak >18 mm Hg based on daytime measurements. The authors concluded that daytime IOP measurements

were highly intercorrelated. According to this BN, IOP at 12:00 and 20:00 hours were more strongly associated with the nighttime IOP peak than other IOP measurements. BN can estimate the risk of a nighttime IOP peak >18 mm Hg. Daytime IOP control was important for nighttime IOP control.7 Zhu et al developed a method of predicting visual function from retinal nerve fiber layer (RNFL) structure in glaucoma.

RNFL thickness measurements from scanning laser polarimetry (SLP) and visual field (VF) sensitivity from standard automated perimetry were made available for 535 eyes. In a training dataset, structure-function relationships were characterized by using linear regression and a type of neural network: radial basis function customized under a Bayesian framework (BRBF). These two models were used in a test dataset to predict sensitivity at individual VF locations from RNFL thickness measurements and predict the spatial relationship between VF locations and positions at a peripapillary RNFL thickness measurement annulus.

Predicted spatial relationships were compared with a published anatomic structure–function map. The BRBF generated clinically useful relationships that related topographical maps of RNFL measurement to VF locations and allowed the VF sensitivity to be predicted from structural measurements.8 In a observational cohort study, Medeiros et al presented and evaluated a Bayesian hierarchical model to integrate information from the longitudinal measures and classify individual eyes as progressing or not. Estimates of sensitivity and specificity of the Bayesian method were compared with those obtained by the conventional approach of ordinary least squares (OLS) regression. The Bayesian hierarchical modeling approach for combining functional and structural tests performed significantly better than the OLS method for detection of glaucoma progression.9 In an observational cohort study with 357 glaucoma patients, Medeiros et al created a hierarchical Bayesian model to incorporate results from the Guided Progression Analysis in the prior distribution for the visual field index slopes, allowing the event-based method to influence the inferences made for the trend-based assessment and compared with the conventional ordinary least squares (OLS) regression method of trend-based assessment. The Bayesian hierarchical modeling approach for integrating eventPAN-AMERICA

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and trend-based assessments of visual field progression performed better than either method used alone. Estimates of rates of change obtained from the Bayesian model had increased precision and may be superior to the conventional OLS method for providing information on the risk of development of functional impairment in the disease.10 Russell et al assessed whether neuroretinal rim area (RA) measurements of the optic disc could be used to improve the estimate of the rate of change in visual field (VF) mean sensitivity in patients with ocular hypertension (OHT) using a Bayesian linear regression (BLR), compared to a standard ordinary least squares linear regression (OLSLR) of mean sensitivity (MS) measurements alone.

The authors concluded that BLR provided a significantly more accurate estimate of the rate of change in MS than the standard OLSLR approach, especially in short time series, suggesting that structural measurements could be used successfully in statistical models to assist clinicians monitoring VF progression in patients with OHT.11 Goldbaum et al evaluated the ability of Progression of Patterns (POP) to identify progression of glaucomatous visual field (VF) defects. POP, which uses variational Bayesian independent component mixture model (VIM), a machine learning classifier, added to the information available to the clinician for detecting VF progression.12

Bayesian’s inference to decide on laser iridotomy

In a comprehensive review on the subject, Thomas et al exemplified the use of Bayesian inference to decide whether to perform a laser iridotomy in a primary angle closure suspect (PACS).13 The incidence of acute primary angle closure (APAC) in the general population is available, but the information needed is APAC in a PACS. This probability can be calculated using Bayes’ theorem. The APAC usually occurs in PACS or primary angle closure (PAC). In time, some normal subjects can become PACS, so one can make an initial assumption that P (PACS | APAC) is 0.95 (95%). The probability of APAC is 0.00012 per year and the estimate probability of PACS is 0.08 (8%).

P(APAC | PACS) = P(PACS | APAC) · P(APAC) / P(PACS) = 0.95 x 0.00012 / 0.08 = 0.00142 or 14 per 10,000 PACS per year.

Assuming that P (PACS | APAC) is 99%, this calculation becomes 0.00014 or 14 per 72

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100 000 PACS per year. Using the reported rate of APAC in those over 60 years of age, the rate of APAC in PACS over 60 years of age can be calculated as 1%. Clearly if we perform iridotomies for all PACS a great number of patients will have unnecessary procedures.

The use of Bayes’ theorem allows practitioners to make reasonable clinical decisions.13

Conclusion

In summary, the Bayesian’s method is the use of study data to update the state of knowledge about a quantity of interest.

In diagnostic test analysis, the Bayesian approach explicitly elicits a clear interpretation of chances of a particular eye disease given a positive test result. The Bayesian method also provides a reasonable rationale for deciding whether to perform a laser iridotomy in a patient with occludable angles. The clinical utility of Bayes’ theorem is dependent on a knowledge of and access to relevant valid literature. It imparts the actual probability of an event given the measured test probabilities and increases the chances of certainty.

REFERENCES 1. Everitt B. Medical Statistics from A to Z. 2nd edition. Cambridge: Cambridge University Press;2006. p.22.

2. Bayes T, Price R. An Essay towards solving a Problem in the Doctrine of Chance. Philosophical Transactions of the Royal Society of London 1763;53:370-418.

3. Etzioni RD, Kadane JB. Bayesian Statistical Methods in Public Health and Medicine. Annual Review of Public Health 1995;16:23-41.

4. Sample PA, Chan K, Boden C, et al. Using Unsupervised Learning with Variational Bayesian Mixture of Factor Analysis to Identify Patterns of Glaucomatous Visual Field Defects. Invest Ophthalmol Vis Sci 2004;45:2596-605.

5. Jansonius NM. Bayes’ theorem applied to perimetric progression detection in glaucoma: from specificity to positive predictive value. Graefes Arch Clin Exp Ophthalmol 2005;243:433-7.

6. Tucker A, Vinciotti V, Liu X, Garway-Heath D. A spatiotemporal Bayesian network classifier for understanding visual field deterioration. Artif Intell Med 2005;34:163-77.

7. Nordmann JP, Berdeaux G. Use of a Bayesian network to predict the nighttime intraocular pressure peak from daytime measurements. Clin Ther 2007;29:1751-60.

8. Zhu H, Crabb DP, Schlottmann PG, et al. Predicting Visual Function from the Measurements of Retinal Nerve Fiber Layer Structure. Invest Ophthalmol Vis Sci 2010;51:5657-66.

9. Medeiros FA, Leite MT, Zangwill LM, Weinreb RN. Combining Structural and Functional Measurements to Improve Detection of Glaucoma Progression using Bayesian Hierarchical Models. Invest Ophthalmol Vis Sci 2011;52:5794-803.

10. Medeiros FA, Wienreb RN, Moore G, et al. Integrating eventand trend-based analyses to improve detection of glaucomatous visual field progression. Ophthalmol 2012;119:458-67.

11. Russell RA, Malik R, Chauhan BC, et al. Improved Estimates of Visual Field Progression Using Bayesian Linear Regression to Integrate Structural Information in Patients with Ocular Hypertension. Invest Ophthalmol Vis Sci 2012;53:2760–9.

12. Goldbaum MH, Lee I, Jang G, et al. Progression of Patterns (POP): A Machine Classifier Algorithm to Identify Glaucoma Progression in Visual Fields. Invest Ophthalmol Vis Sci 2012;53:6557-67.

13. Thomas R. Mengersen K, Parikh RS, et al. Enter the reverend: introduction to and application of Bayes’ theorem in clinical ophthalmology. Clin Exp Ophthalmol 2011;39:865-70.

Dolz-Marco R et al. OCT and macular hole in ARMD.

Optical coherence tomography findings in macular hole complicating exudative age-related macular degeneration treated with ranibizumab Rosa Dolz-Marco1, Roberto Gallego-Pinazo1, J Fernando Arévalo2,3, Lihteh Wu4, M Dolores Pinazo-Durán5, Manuel Díaz-Llopis1,6 1. Department of Ophthalmology. University and Polytechnic Hospital La Fe, Valencia, Spain 2. Retina Division. Wilmer Eye Institute. Johns Hopkins University School of Medicine. Baltimore, MD, USA. 3. King Khaled Eye Specialist Hospital. Riyadh, Kingdom of Saudi Arabia.

4. Instituto de Cirugia Ocular, San José, Costa Rica.

5. Ophthalmology Research Unit “Santiago Grisolía”. University Hospital Doctor Peset. Valencia (Spain).

6. Faculty of Medicine. University of Valencia, Valencia, Spain.

Corresponding author: Rosa Dolz Marco Bulevar Sur s/n 46026, Valencia, Spain Phone Number: +34 650314806 E-mail address: rosadolzmarco@gmail.com Date of submisson: 18/01/2013 Date of approval: 27/08/2013

Funding: None Financial/propretary disclosure: None

Abstract

Purpose: To analyze the prevalence and morphometric characteristics of macular hole development in patients with neovascular age-related macular degeneration treated with ranibizumab.

Methods: Patients diagnosed of neovascular age-related macular degeneration from January 2009 to December 2010 have been analyzed.

Measurement of visual acuity and optical coherence tomography were scheduled.

Results: Two hundred and thirteen eyes (patients) with exudative age-related macular degeneration were analyzed. Development of macular hole was evidenced in 4 eyes (1,9%)

Discussion: Macular hole formation is a severe complication in patients with choroidal neovascularization treated with ranibizumab, frequently undervalued, which interferes with final outcome.

Keywords: Macular hole, choroidal neovascularization, age-related macular degeneration, Optical Coherence Tomography, Ranibizumab.

INTRODUCTION

Age-related macular degeneration (ARMD) is a leading cause of visual impairment in the elderly, especially the neovascular form of the disease. The development of macular hole (MH) as a spontaneous complication of choroidal neovascularisation (CNV) due to ARMD has been described.1 Other publications report MH formation after intravitreal injection of ranibizumab2 and photodynamic therapy3 for the treatment of exudative ARMD. Optical coherence tomography (OCT) imaging has made possible

Figure 1: An 83 year-old woman was diagnosed of occult choroidal neovascularisation (CNV) in her left eye. In OCT cross sectional images we observed CNV type 2 with intraretinal cysts in the overlaying retina. Posterior hyaloid was detached with the presence of an operculum over the fovea. After 11 month follow-up and 6 intravitreal injections OCT image demonstrated foveal lamellar MH with persistence of the operculum over the fovea.

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REFERENCES 1. Emerson GG, Ghazi NG. Spontaneous rip of the retinal pigment epithelium with a macular hole in neovascular age-related macular degeneration.

Am J Ophthalmol.

2005;140: 316-318.

Figure 2: Cross sectional OCT image of a 57 year-old woman showed a large area of CNV type 2 with multiple intraretinal cysts in her left eye. Posterior hyaloid was not visible. After 5 intravitreal injections and 7 month follow-up OCT demonstrated progressive retinal thinning and full thickness MH formation.

to analyze the anatomical evolution of CNV in ARMD4 and MH.5-6 The aim of the present study was to analyze the prevalence and OCT characteristics of MH in patients diagnosed of CNV secondary to ARMD treated with ranibizumab.

MATERIAL AND METHODS

OCT images from patients diagnosed with exudative ARMD and treated with 0.5 mg/0.05 mL of intravitreal ranibizumab (Lucentis, Genentech Inc., San Francisco, CA) in the Macula Unit of the University and Polytechnic Hospital La Fe (Valencia, Spain) from January 2009 to December 2010 were analyzed.

A qualitative analysis was performed with special attention to: type of MH (full-thickness or lamellar) and status of the posterior hyaloid (attached or detached).

RESULTS

Two-hundred and thirteen eyes (213 patients; 93 men and 120 women); mean age of 67.3 years [range 59-83] were included in the present study. After a mean follow up of 16 months (range: 10-18), we found 4 cases (1.9% of patients) of MH development (Figure 1). In two of four cases full-thickness MH was present (Figure 2), and two of four cases showed detachment of the posterior hyaloid.

DISCUSSION

Development of idiopathic MH is usually related to anterior-posterior traction from the vitreous on the fovea causing a retinal operculum when the posterior hyaloid detaches from the fovea.7 Another less frequent cause of MH is the formation of traumatic macular holes, whose pathogenesis is more uncertain; it may be the result of a break in

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the foveal inner retina and a cyst formation extending laterally to the outer retinal tissue.8 In the cases we report, the development of MH associated with CNV in patients with ARMD could be explained by several mechanisms.

One possibility is that intravitreal injection induced vitreous incarceration at the needle insertion site, causing increased vitreoretinal traction on the fovea leading to development of a macular hole; however, this may not explain the mechanism of MH formation in cases with detached posterior hyaloid. On the other hand, centrifugal stretching forces along the posterior surface of the neurosensory retina may play a role in the formation of MH.1 Another mechanism might be that ranibizumab by itself could induce contraction of the neovascular complex, thus leading to increase tangential traction on the overlying retina.2 Moreover, in patients with ARMD, the presence of CNV leads to the emergence of both intra and subretinal fluid, hemorrhage, progressive fibrosis and atrophy with loss of retinal tissue.

Limitations of our study include its retrospective nature and a relatively small sample size. The low prevalence of MH in patients with CNV secondary to ARMD was insufficient to determine the influence of these on the visual outcomes in these patients.

In conclusion, MH formation is a sightthreatening complication in patients with CNV treated with ranibizumab, which is commonly underestimated. Its multifactorial nature hinders the knowledge of the exact mechanism of its development. New studies with larger number of patients and longer follow-up are warranted to explain the pathogenesis of MH in patients with CNV secondary to ARMD and its influence on final visual prognosis.

2. Querques G, Souied EH, Soubrane G. Macular hole following intravitreal ranibizumab injection for choroidal neovascular membrane caused by age-related macular degeneration.

Acta Ophthalmol.

2009;87:235-7.

3. Rishi P, Kasinathan N, Sahu C. Foveal atrophy and macular hole formation following intravitreal ranibizumab with/ without photodynamic therapy for choroidal neovascularization secondary to age-related macular degeneration.

Clin Ophthalmol.

2011;5:167-70.

4. Freund KB, Zweifel SA, Engelbert M. Do we need a new classification for choroidal neovascularization in age-related macular degeneration? Retina 2010;30:1333-1349.

5. Altaweel M, Ip M. Macular hole: improved understanding of pathogenesis, staging, and management based on optical coherence tomography.

Semin Ophthalmol 2003;18:58-66.

6. Arevalo JF, Sanchez JG, Costa RA, Farah ME, Berrocal MH, Graue-Wiechers F, Lizana C, Robledo V, Lopera M. Optical coherence tomography characteristics of full-thickness traumatic macular holes. Eye 2008 22:1436-41.

7. Gaudric A, Haouchine B, Massin P, Paques M, Blain P & Erginay A. Macular hole formation: new data provided by optical coherence tomography. Arch Ophthalmol. 1999;117: 744–751.

8. Oehrens AM & Stalmans P. Optical coherence tomographic documentation of the formation of a traumatic macular hole.

Am J Ophthalmol.

2006;142: 866–869.

García-Fernández M et al. Tratamiento combinado de hemorragias subretitinanas.

Tratamiento combinado de hemorragias subretinianas con activador del plasminógeno tisular recombinante (rtPA), gas y Ranibizumab intravítreos Combined intravitreous therapy for subretinal hemorrhage with recombinant tissue plasminogen activator), gas and Ranibizumab Miriam García-Fernández, Ana García Alonso, Marta Fonollá Gil

Autor Correspondendiente:

Departamento de Oftalmología, Hospital Universitario Central de Asturias Oviedo, Asturias, España.

Miriam García-Fernández, MD. Departamento de Oftalmología, Hospital Universitario Central de Asturias.

C/Dionisio Ridruejo, nº5, 11ºD. CP: 33007 Oviedo, Asturias (España) Tel:+34-629-85-38-00 Email: migarci@hotmail.es

Funding: None Financial/proprietary interest: None

Date of submission: 24/06/2012 Date of approval: 04/11/2012

Abstract

Purpose: To present six cases of macular suberetinal hemorrhage who underwent intravitreal treatment with rtPA, ranibizumab and SF6.

Methods: Size and location of the hemorrhage and visual acuity were evaluated prior and after treatment.

Results: Mean pretreatment visual acuity was hand movements at one meter, and three months later, 0.18 (decimal notation) (p>0.05). A partial displacement of de suberetinal hemorrhage from the fovea was achieved in all patients.

Discussion: This triple procedure is an useful option for the treatment of suberetinal hemorrhage. However, the tissular damage associated to the subjacent disease in some cases does not allow significant functional improvement.

Key words: subretinal hemorrhage, rtPA, gas, ranibizumab, visual acuity.

Resumen

Objetivo: Presentar seis casos de hemorragia subretiniana macular que recibieron tratamiento intravítreo mediante rtPA, ranibizumab y SF6.

Métodos: El tamaño y localización de la hemorragia subretiniana y la agudeza visual fueron evaluados antes y después del tratamiento.

Resultados: La agudeza visual media pretratamiento fue movimiento de manos a un metro y a los tres meses, de 0.18 (notación decimal) (p>0.05). En todos se consiguió desplazamiento parcial de la hemorragia subretiniana fuera de la fóvea.

Discusión: Este triple procedimiento es una opción útil para el tratamiento de hemorragias subretinianas maculares. Sin embargo, en muchos casos el daño tisular asociado a la enfermedad subyacente impide mejorías funcionales significativas.

Palabras clave: hemorragia subretiniana, rtPA, gas, ranibizumab, agudeza visual.

Introducción

Las hemorragias subretinianas (HSR) pueden ser secundarias a diversas enfermedades oculares, siendo la causa más frecuente la neovascularización coroidea (NVC). A su vez, la causa más frecuente de NVC es la degeneración macular asociada a la edad (DMAE).1 Estas hemorragias se asocian habitualmente a un pobre pronóstico visual debido a la escasa probabilidad de resolución espontánea, la toxicidad retiniana por la hemoglobina, y la barrera física que representa la sangre, impidiendo la difusión de nutrientes y metabolitos.2 No hay consenso en cuanto a su tratamiento.1-2 Se ha descrito la evacuación mediante vitrectomía, inyección intravítrea de activador tisular del plasminógeno (rtPA) PAN-AMERICA

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A

A

B

B

Figura 1. Mujer, 72 años, con antecedente de membrana neovascular subfoveal en su ojo izquierdo. A: funduscopia de ojo derecho antes del tratamiento, con agudeza visual (AV) de Movimiento de Manos a 1 metro. B: a los tres meses, AV: 0.5.

Figura 2. Mujer, 77 años, con estrías angiodes y NVC secundaria bilateral tratada previamente con antiangiogénicos. A: aspecto funduscópico de ojo derecho antes del triple procedimiento, AV de Movimiento de Manos. B: a los tres meses, AV: 0.1. NVC: neovascularización coroidea.

asociado a gas expansible, gas sin rtPA, entre otras.

Recientemente, la llegada de los anti-VEGF ha abierto nuevos horizontes, empleándose como terapia combinada la inyección intravítrea de rtPA, bevacizumab y hexafluoruro de azufre (SF6) con buenos resultados.2-3 Sin embargo, son muy escasos los casos descritos acerca de la triple terapia empleando ranibizumab.1,4

notación decimal, fueron evaluadas antes del tratamiento y a los tres meses.

Se analizaron 6 ojos de 6 pacientes (3 varones y 3 mujeres) con edad media de 81.33 (rango:71-92) años. El intervalo medio de tiempo entre el diagnóstico y el tratamiento fue de 5.66 (rango:1-9) días. La MAVC pretratamiento fue de movimiento de manos en todos los casos y a los tres meses, de 0.18 (rango:0.02-0.5) (p>0.05). Ningún paciente perdió líneas de agudeza visual.

En todos los casos se consiguió el desplazamiento parcial de la HSR fuera de la fóvea, así como una reducción del tamaño de la misma (Figuras 1,2 y 3).

Un paciente desarrolló un desprendimiento de retina (DR) a los cinco días de la inyección, que requirió tratamiento mediante retinopexia neumática y posterior cirugía vítreorretiniana debido a la recidiva del desprendimiento, lo que supone una tasa de desprendimiento de retina del 17%. No se apreciaron variaciones estadísticamente significativas de la presión intraocular (PIO) y ningún paciente requirió tratamiento hipotensor.

Tras el triple procedimiento todos recibieron retratamientos con inyecciones de antiangiogénicos (bevacizumab o ranibizumab) en monoterapia, con un rango entre dos y

Serie de Casos Clínicos

Presentamos seis casos clínicos en los que se realizó terapia combinada con rtPA, hexafluoruro de azufre (SF6) y ranibizumab intravítreos para tratamiento de HSR macular. La causa de la hemorragia fue NVC asociada a DMAE en cinco ojos y NVC secundaria a estrías angiodes en un ojo. El tamaño inicial de la hemorragia osciló entre 5 y 10 diámetros de disco.

Cada uno de los pacientes recibió un triple procedimiento usando 50 microgramos de rtPA (Actilysa®), 0.05 ml de ranibizumab (Lucentis®), y a las dos horas de la inyección, 0.3 cc de SF6, seguido de posicionamiento terapéutico adecuado y tratamiento tópico con tobramicina + dexametasona (Tobradex®) y ciprofloxacino (Oftacilox®) durante 6 días.

El tamaño y localización de la HSR y la mejor agudeza visual corregida (MAVC) en

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García-Fernández M et al. Tratamiento combinado de hemorragias subretitinanas.

seis inyecciones, bien por persistencia de hemorragia submacular o por presentar signos de neovascularización coroidea activa.

Discusión

No existe una pauta de tratamiento estandarizada para el manejo de las hemorragias submaculares, y el resultado final es difícil de evaluar, pues la agudeza visual depende de varios factores, entre ellos la patología macular de base (siendo la de peor pronóstico la DMAE), el tiempo de permanencia de la hemorragia y su extensión.2 Tanto el gas como el rtPA tienen un objetivo físico, desplazando la hemorragia del área macular, y por tanto, minimizando la formación de cicatriz, y por ende, la repercusión en la agudeza visual del paciente.

La aplicación asociada de antiangiogénicos consigue además tratar el componente vascular, que es la causa subyacente de la HSR.1 Algunos autores proponen la realización de vitrectomía con coaplicación subretiniana de rtPA y bevacizumab, seguido de intercambio fluído-gas, con buenos resultados.5 Sin embargo, existen alternativas menos agresivas. Carsten et al2 describen buenos resultados anatómicos y funcionales tras el tratamiento de estas hemorragias con rtPA, SF6 y bevacizumab, con mejoría significativa de la agudeza visual. Un mes tras la triple terapia, 25% de los pacientes tenían una AV que les permitía la lectura (igual o superior a 0.4), y a los 3 meses, esta cifra era del 35%.Tan solo uno de los pacientes no experimentó mejoría debido a la presencia de una DMAE muy avanzada con daño de los fotorreceptores.

Matt et al4 estudiaron retrospectivamente 10 ojos tras triple terapia con rtPA, SF6 y ranibizumab, obteniendo estabilización de la agudeza visual y mejora en los parámetros morfológicos.

Nosotros en nuestro trabajo apreciamos desplazamiento de la hemorragia y mejoría de la agudeza visual en todos los pacientes. Sin embargo, la patología coroidea de base no permitió mejoras funcionales significativas.

A modo de conclusión, destacar que la combinación de rtPA, gas y ranibizumab intravítreos es una opción útil para el tratamiento de HSR secundarias a NVC de distinta etiología.

A

BIBLIOGRAFÍA 1. Gros-Otero J, Benítez-Herreros J, BeckfordTorngren C, Cámara-González C, Castro-Rebollo M. Tratamiento de una hemorragia subretiniana con r-TPA, SF6, y ranibizumab. Arch Soc Esp Oftalmol.

2010; 85:114-7.

B

C

2. Meyer CH, Scholl HP, Eter N, Helb HM, Holz FG. Combined treatment of acute subretinal haemorrhages with intravitreal recombined tissue plasminogen activator, expansile gas and bevacizumab: a retrospective pilot study. Acta Ophthalmol. 2008; 86:490-4.

3. Guthoff R, Guthoff T, Meigen T, Goebel W. Intravitreous injection of bevacizumab, tissue plasminogen activator, and gas in the treatment of submacular hemorrhage in age-related macular degeneration.

Retina. 2011; 31:36-40.

4. Matt G, Sacu S, Stifter E, Prünte C, SchmidtErfurth U. Combination of Intravitreal rTPA, gas and ranibizumab for extensive subfoveal haemorrhages secondary to neovascular age-related macular degeneration. Klin Monbl Augenheilkd. 2010; 227:221-5.

Figura 3. Mujer, 92 años, con MNV fibrótica en su ojo derecho. A: aspecto funduscópico de ojo izquierdo antes de la triple terapia, AV: Movimiento de Manos. B: a los tres meses, AV:0.05. MNV: membrana neovascular.

5. Treumer F, Klatt C, Roider J, Hillenkamp J. Subretinal coapplication of recombinant tissue plasminogen activator and bevacizumab for neovascular age-related macular degeneration with submacular haemorrhage.

Br J Ophthalmol. 2010; 94:48-53.

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CASE REPORT / Vis. Pan-Am. 2013;12(3):78-80

Implantation of an implantable collamer lens and iris cerclage for the treatment of Urrets-Zavalia syndrome Arnaldo Dias-Santos, M.D., Joana Ferreira, M.D., Duarte Amado, M.D., João P. Cunha, M.D. From Centro Hospitalar de Lisboa Central Funding: None Financial/propretary disclosure: None This work was presented as a poster in the XXX Congress of the ESCRS in September 2012.

Corresponding author: Arnaldo Dias-Santos, M.D. Rua Luís de Camões, nº12, ex-lote 11, Quinta Nova de São Roque, 2670-513, Loures – Portugal.

E-mail: arnaldomiguelsantos@gmail.com Phone: 00351919273677 Date of submission: 16/01/2013 Date of Acceptance: 05/02/2013

Abstract

Figure 1

Figure 2

Figures 1 and 2: Fixed paralytic mydriasis with no light reaction.

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A 27-year-old woman with bilateral high myopia had anterior chamber iris-claw phakic intraocular lens implantation in her left eye under local anesthesia and with no intraoperative complications. The preoperative slit-lamp examination was normal, and she had no relevant past medical history. On the second postoperative day, patient developed fixed, dilated mydriasis, and one month later, an IOL subluxation was noted on examination.

She had no history of intraocular hypertension and no mydriatic drops were used. She was ultimately diagnosed with Urrets-Zavalia syndrome. We removed the IOL and observed the patient for six months after fitting her with a colored contact lens. During this period of time, she complained of glare and photophobia and developed contact lens intolerance. To bring more comfort to the patient, we implanted a posterior chamber Implantable Collamer Lens (ICL) and performed iris cerclage in the left eye with good aesthetic and refractive outcome. Posterior chamber ICL implantation with iris cerclage proved to be a simple and effective approach in the management of this situation.

Keywords: Implantable collamer lens; Iris cerclage; phakic intraocular lens; UrretsZavalia syndrome.

Introduction

Paralytic mydriasis and iris atrophy, first noticed following penetrating keratoplasty in eyes of patients with keratoconus, was named Urrets-Zavalia syndrome.1 Later reports have also indicated the presence of this syndrome following intracameral gas injection for treatment of acute corneal hydrops2, deep

Dias-Santos et al. Treatment of Urrets-Zavalia Syndrome.

Figure 3

Figure 4

Figures 3 and 4: Anterior segment photography after ICL implantation and iris cerclage.

lamellar keratoplasty3, argon laser peripheral iridoplasty for glaucoma4, trabeculectomy5 and implantation of phakic intraocular lenses (IOLs) for myopia.6,7 It is also frequently related to high postoperative intraocular pressure (IOP).1-3,7,8 Herein, we describe a case of Urrets-Zavalia syndrome after an uneventful implantation of an iris-claw phakic IOL and the postoperative follow-up.

Case report

A 27-year-old woman with bilateral high myopia had anterior chamber iris-claw phakic IOL implantation in her left eye (LE) with no intraoperative complications. She had no relevant past medical history. The preoperative slit-lamp examination was normal; in fact, both pupils were light-reactive, isochoric, and 5.75 mm in diameter under scotopic illumination.

Preoperative best- corrected visual acuity (BCVA) was 20/20 bilaterally with a refraction of -11.00 -1.25 x 105 in the right eye (RE) and -11.25 -1.50 x 150 in the left eye (LE). The IOP was 14 mmHg in the RE and 13 mmHg in the LE. The anterior chamber depth was 3.35 mm in the RE and 3.41 mm in the LE. The limbus-to-limbus measurements were 11.02 mm in the RE and 11.25 mm in the LE, and the preoperative corneal topographic findings as measured by the rotating Scheimpflug camera (Pentacam速, OCULUS Optikgerate GmbH, Wetzlar, Germany) were normal in both eyes.

Central endothelial cell count (CECC) was 2790 cells/mm2 in the RE and 2812 cells/ mm2 in the LE. The surgical procedure in the LE was performed under topical anesthesia with oxybuprocaine 0.4% and intracameral lidocaine 2%. After a clear corneal superior incision was made, an intracameral injection

of acetylcholine 1% was administered, and the IOL was implanted on the iris with the help of sodium hyaluronate 1% (Healon速). After a peripheral iridectomy was performed, the ophthalmic viscosurgical device was removed from the anterior chamber via irrigation and aspiration with a balanced salt solution. No mydriatic drugs were given before, during, or after surgery.

On the second postoperative day, the patient developed fixed, dilated mydriasis in her LE. No reaction to light or 0.125% or 1% pilocarpine, and the IOP was 15 mm Hg in both the RE and the LE (Figures 1 and 2). One month later, she developed IOL subluxation in the LE. We removed the IOL and observed her for six months after fitting her with a colored contact lens. During this period, she developed contact lens intolerance, which led to symptoms such as incapacitating glare, photophobia, and decreased vision.

At this point, specular microscopy revealed a CECC of 2695 cells/mm2 in the LE. We decided to implant a posterior chamber Visian implantable collamer lens (ICL) (STAAR Surgical, Inc. Nidau, Switzerland) to correct the refractive error and to protect the lens, and simultaneously performed an iris cerclage.

The cerclage was performed using a curved needle and 10-0 Prolene sutures with a running suture technique (Figures 3 and 4).

After five weeks of follow-up, she no longer suffered from glare or photophobia, and the visual acuity in the LE on examination was 20/25; moreover, the IOP was 14 mm Hg in the LE, and the CECC was 2771 cells/ mm2 in the RE and 2480 cells/mm2 in the LE. Ultimately, we are planning to implant an ICL in the RE as well.

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Discussion

Urrets-Zavalia syndrome has been reported most frequently following penetrating keratoplasty for keratoconus. However, it can accompany virtually all anterior segment surgeries.1-6 For example, Yuzbasioglu et al reported one case of fixed paralytic mydriasis following anterior phakic angle-supported IOL implantation.7 In that case, the primary causative factor was probably iris ischemia secondary to IOP elevation up to 60 mmHg on the first postoperative day7. Later, Park et al. reported a case of Urrets-Zavalia syndrome following anterior segment iris-claw phakic IOL implantation without high IOP.6 The pathogenesis of this syndrome remains uncertain. To date, iris ischemia secondary to high IOP, low sclera rigidity, intrinsic iris abnormalities, and intraoperative damage of the iris vessels or parasympathetic nerves have been identified as the main risk factors.1-3,6 However, other unidentified mechanisms must justify the occurrence of this syndrome after successful surgery with no postoperative complications or intraocular hypertension.

Our patient did not experience pre or postoperative IOP elevation, and no mydriatic drugs were used on her before, during, or after surgery.

Adie’s tonic pupil and third nerve palsy associated mydriasis were excluded as potential diagnoses, because no response was observed to the 0.125% and 1% pilocarpine instillation, respectively. The iris-claw IOL subluxation was probably due to pronounced iris atrophy. Posterior chamber ICL implantation offered a good refractive solution, and the iris cerclage using a running suture technique resulted in a good aesthetic and functional result. This technique minimizes any stretching and distortion of the iris and creates a pupil that is precisely sized and rather round9. Additionally, the implantation of an ICL prevents any damage to the lens. Also, it is noteworthy that the patient’s CECC was at a sufficient level to withstand another intraocular surgery. The minimum recommended CECC for phakic IOL implantation is 2500 cells/mm2 in patients over 21 years of age.10 The results from various studies on ICLs reveal an initial loss of endothelial cells; i.e, probably related to the surgical procedure, followed by stabilization over time.11,12 A large clinical trial showed that the cumulative corneal endothelial cell loss was between 8.4% and 8.9% over the first 3 years and between 8.4% and 9.5% over the first 4 years depending on the method of calculation.13,14 In this particular case, the initial cell loss was predictably higher due to increased anterior chamber manipulation, but the long-term variation in the endothelial cell density of this patient tends to approximate that obtained in these clinical trials.

Given the patient’s intolerance to colored contact lenses and the poor results obtained in the first experiments with phakic iris implants15, the only alternative solution to manage the dysphotoptic complaints would be to perform a corneal tattoo.16 Good functional and cosmetic outcomes have been reported with keratopigmentation using new micronized mineral pigments.17 Alió et al. recently reported the successful management of a case of Urrets-Zavalia syndrome using a double intrastromal tunnel femtosecond-assisted keratopigmentation technique.18 In our opinion, posterior chamber ICL implantation with iris cerclage is another effective and safe approach to manage this syndrome, provided the patient has normal endothelial cell counts and morphology. Moreover, it enables the surgeon to manage the refractive error and the iris atrophy in the same procedure while sparing the healthy corneal tissue.

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REFERENCES 1. Urrets-Zavalia A. A fixed, dilated pupil iris atrophy and secondary glaucoma. A distinct clinical entity following penetrating keratoplasty in keratoconus. Am J Ophthalmol. 1963;56:257-265.

2. Aralikatti AK, Tomlins PJ, Shah S. Urrets-Zavalia syndrome following intracameral C3F8 injection for acute corneal hydrops. Clin Experiment Ophthalmol.

2008;36:198-199.

3. Minasian M, Ayliffe W. Fixed dilated pupil following deep lamellar keratoplasty (Urrets-Zavalia syndrome). Br J Ophthalmol. 2002;86:115-116.

4. Espana EM, Ioannidis A, Tello C, Liebmann JM, Foster P, Ritch R. Urrets-Zavalia syndrome as a complication of argon laser peripheral iridoplasty. Br J Ophthalmol. 2007;91:427-429.

5. Jain R, Assi A, Murdoch IE. Urrets-Zavalia syndrome following trabeculectomy. Br J Ophthalmol.

2000;84:338-339.

6. Park SH, Kim SY, Kim HI, Yang SW. Urrets-Zavalia syndrome following iris-claw phakic intraocular lens implantation. J Refract Surg. 2008;24(9):959-61.

7. Yuzbasioglu E, Hevacioglu F, Sencan S. Fixed, dilated pupil after phakic intraocular lens implantation.

J Cataract Refract Surg. 2006;32:174-176.

8. Tuft SJ, Buckley RJ. Iris ischaemia following penetrating keratoplasty for keratoconus (Urrets-Zavalia syndrome). Cornea. 1995;14:618-622.

9. Ogawa GS. The iris cerclage suture for permanent mydriasis: A running suture technique. Ophthalmic Surg Lasers. 1998;29(12):1001-9.

10. Güell JL, Morral M, Kook D, Kohnen T. Phakic intraocular lenses part 1: Historical overview, current models, selection criteria, and surgical techniques. J Cataract Refract Surg. 2010;36(11):1976-93.

11. Jiménez-Alfaro I, Benítez del Castillo JM, García-Feijoó J, Gilde Bernabé JG, Serrano de la Iglesia JM. Safety of posterior chamber phakic intraocular lenses for the correction of high myopia; anterior segment changes after posterior chamber phakic intraocular lens implantation. Ophthalmology.

2001;108(1):90-9.

12. Dejaco-Ruhswurm I, Scholz U, Pieh S, Hanselmayer G, Lackner B, Italon C, Ploner M, Skorpik C. Long-term endothelial changes in phakic eyes with posterior chamber intraocular lenses. J Cataract Refract Surg. 2002; 28(9):1589–1593.

13. Sanders DR, Doney K, Poco M. ICL in treatment of myopia study group. United States Food and Drug Administration clinical trial of the implantable collamer lens (ICL) for moderate to high myopia: Three-year follow-up. Ophthalmology.

2004;111(9):1683-92.

14. Edelhauser HF, Sanders DR, Azar R, Lamielle H. ICL in treatment of myopia study group. Corneal endothelial assessment after ICL implantation. J Cataract Refract Surg. 2004;30(3):576-83.

15. Garcia-Pous M, Udaondo P, Garcia-Delpech S, Salom D, Díaz-Llopis M. Acute endothelial failure after cosmetic iris implants (NewIris®). Clin Ophthalmol. 2011;5:721-3.

16. Hirsbein D, Gardea E, Brasseur G, Muraine M. Corneal tattooing for iris defects. J Fr Ophtalmol.

2008;31(2):155-64.

17. Alio JL, Rodriguez AE, Toffaha BT. Keratopigmentation (corneal tattooing) for the management of visual disabilities of the eye related to iris defects. Br J Ophthalmol. 2011;95(10):1397-401.

18. Alió JL, Rodriguez AE, Toffaha BT, El Aswad A. Femtosecond-assisted keratopigmentation double tunnel technique in the management of a case of Urrets-Zavalia syndrome. Cornea.

2012;31(9):1071-4.

Martinez-Castillo S et al. Ranibizumab and viteliform dystrophy.

Ranibizumab for choroidal neovascularization following atrophic involution of adult-onset foveomacular vitelliform dystrophy.

Sebastián Martínez-Castillo1, Rosa Dolz-Marco1, Enrique España-Gregori1, Roberto Gallego-Pinazo1, Lihteh Wu, MD2, J. Fernando Arévalo3,4, Manuel Díaz-Llopis1,5 1. University and Polytechnic Hospital La Fe. Valencia, Spain 2. Instituto de Cirugía Ocular, San José, Costa Rica 3. Department of Retina. Wilmer Eye Institute. Johns Hopkins University School of Medicine. Baltimore, MD, United States 4. King Khaled Eye Specialist Hospital. Riyhad, Saudi Arabia 5. Faculty of Medicine. University of Valencia. Valencia, Spain

Corresponding author: Sebastian Martinez-Castillo Department of Ophthalmology, University and Polytechnic Hospital La Fe Bulevar Sur s/n. 46026, Valencia (Spain) E-mail address: martinezcastillo.sebastian@gmail.com Date of submission: 04/02/2013 Date of approval: 10/06/2013

Funding: None Proprietary/financial disclosure: None

Abstract

We report a case of adult-onset foveomacular vitelliform dystrophy complicated with atrophic involution and subsequent choroidal neovascularization and treated with intravitreal ranibizumab.

A 71-year-old woman diagnosed with adult-onset foveomacular vitelliform dystrophy experienced a progression of the vitelliform lesion to the atrophic stage in her left eye immediately after cataract surgery.

Best-corrected visual acuity decreased from 0.5 to 0.16. Ten months later, the patient was referred with new worsening of her visual acuity (0.05) and metamorphopsia.

The spectral-domain optical coherence tomography confirmed the presence of type 2 choroidal neovascularization next to the atrophic area. The patient was treated with 2 monthly injections of ranibizumab.

Spectral-domain optical coherence tomography images improved significantly and her best-corrected visual acuity increased to 0.20 associated with subjective improvement of metamorphopsia.

Ranibizumab may be effective for choroidal neovascularization in patients with adult-onset foveomacular vitelliform dystrophy.

Key words: Adult-Onset Foveomacular

Vitelliform Dystrophy; Retinal Atrophy; Choroidal Neovascularisation; Ranibizumab

Resumen

Presentamos el caso de una paciente con distrofia foveomacular viteliforme del adulto que presentó una evolución atrófica complicada con neovascularización coroidea tratada con ranibizumab.

Mujer de 71 años diagnosticada de distrofia foveomacular viteliforme del adulto, que tras la cirugía de catarata en el ojo izquierdo, presentó una evolución atrófica en dicho ojo. Su mejor agudeza visual corregida disminuyó desde 0.5 a 0.16. Diez meses más tarde, la paciente viene referida de nuevo por empeoramiento de su visión, siendo 0.12, y metamorfopsia. La tomografía de coherencia óptica de dominio espectral confirmó la presencia de una neovascularización coroidea tipo 2 que se acompañaba de una leve exudación próxima a la zona de atrofia. La paciente fue tratada mediante 2 inyecciones mensuales de ranibizumab.

Las imágenes tomográficas mejoraron significativamente y su agudeza visual corregida mejoró hasta 0.2, así como una mejoría subjetiva de la metamorfopsia.

El tratamiento con ranibizumab de la

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A

B

neovascularizaci贸n coroidea en pacientes con distrofia foveomacular del adulto puede ser efectivo, requiriendo de controles peri贸dicos.

Palabras clave: Distrofia foveomacular viteliforme del adulto, atrofia, neovascularizaci贸n coroidea, ranibizumab

Introduction

Adult-onset foveomacular vitelliform dystrophy (AOFVD) is a rare macular disease that shares certain phenotypic features with the vitelliform stage of Best dystrophy.1 However, electrophysiological changes in AOFVD usually evidence normal or subnormal responses, whereas Arden index alteration is characteristic of Best dystrophy.

Dilated fundus examination (DFE) typically shows a bilateral yellowish ovoid subretinal lesion, frequently larger than one papillary diameter, which usually results in slow progressive moderate vision loss. Further visual impairment may be severe when the lesion progresses to the atrophic stage or less frequently when the patient develops choroidal neovascularization (CNV).2 Herein we report a case of AOFVD with atrophic involution complicated with CNV and treated with intravitreal ranibizumab.

C

D

Case Report

E

Figure 1: A. Colour fundus photograph showed foveal atrophic changes with subretinal fibrosis within the temporal edge of the lesion and laminar haemorrhages. B. Fundus autofluorescence image highlighted the hypoautofluorescent atrophic area, surrounded by fibrous tissue. C. Fluorescein angiography revealed the presence of a predominantly classic choroidal neovascularization (CNV). D. Spectral-domain optical coherence tomography images showed type 2 CNV in close relationship to the temporal edge of the atrophic area. E. Following two intravitreal injections of ranibizumab, SD-OCT showed complete resolution of the intraretinal fluid.

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A 71-year-old woman clinically and electrophysiologically, electrooculogram (EOG) showed normal results (Arden index was 1.95), making the difference with the severe alteration of this electrophysiological test present in Best disease, diagnosed with AOFVD, experienced a progression of the vitelliform lesion to the atrophic stage in her left eye (OS) following immediately an uneventful cataract surgery. Best corrected visual acuity (BCVA) decreased from 0.5 preoperatively to 0.16 after surgery in her OS. DFE showed complete disappearance of the vitelliform lesion which was replaced by a geographic atrophy of the foveal retinal pigment epithelium Ten months later, the patient was referred to our department complaining of new worsening of her BCVA OS (0.05) associated with metamorphopsia. DFE revealed the presence of macular haemorrhages and

Martinez-Castillo S et al. Ranibizumab and viteliform dystrophy.

exudation due to the development of CNV next to the temporal margin of the atrophic area. Spectral-domain optical coherence tomography (SD-OCT) confirmed the presence of type 2 CNV. Treatment with 2 consecutive monthly intravitreal injections of ranibizumab was administered. SD-OCT images evidenced reduction of the retinal swelling, and BCVA improved to 0.20 with subjective improvement of metamorphopsia (Figure 1).

Discussion

The use of vascular endothelial growth factor (VEGF) inhibitors has been reported in cases of AOFVD with variable results.3-4 It has also been reported the treatment of CNV with ranibizumab in many other macular conditions associated with CNV such as high myopia5, angioid streaks6, pattern dystrophy7, retinal astrocytic hamartoma8,

choroidal hemangioma9, traumatic Bruch membrane rupture10, fundus flavimaculatus11, or Stargardt disease12. They all share the same tomographic appearance of type 2 neovascularization (growing above the RPE within the subretinal space). The use of ranibizumab for CNV related to AOFVD has previously been reported13,14 with positive outcomes, therefore offering a possible therapy for this condition.

In conclusion anti-VEGF drugs may be effective for CNV related to AOFVD albeit cases with severe disruption of the outer retinal layers or atrophic changes should have a limited visual improvement. Extended follow-up is warranted to asses possible recurrences and determine the need of retreatments in order to achieve the control of the CNV associated with AOFVD.

REFERENCES 1. Puche N, Querques G, Benhamou N, Tick S, Mimoun G, Martinelli D, Soubrane G, Souied EH. High-resolution spectral domain optical coherence tomography features in adult onset foveomacular vitelliform dystrophy. Br J Ophthalmol. 2010;94:1190-6.

2. Do P, Ferrucci S. Adult-onset foveomacular vitelliform dystrophy. Optometry.

2006;77:156-66.

3. Montero JA, Ruiz-Moreno JM, De La Vega C. Intravitreal bevacizumab for adult-onset vitelliform dystrophy: a case report. Eur J Ophthalmol.

2007;17:983-6.

4. Gallego-Pinazo R, Dolz-Marco R, PardoLópez D, Arevalo JF, Díaz-Llopis M. Primary intravitreal ranibizumab for adult-onset foveomacular vitelliform dystrophy. Graefes Arch Clin Exp Ophthalmol.

2011;249:455-8.

2010;20:789–91.

5. Lalloum F, Souied EH, Bastuji-Garin S, et al. Intravitreal ranibizumab for choroidal neovascularization complicating pathologic myopia. Retina 2010;30:399–406.

9. Querques G, Forte R, Querques L, Souied EH. Intravitreal ranibizumab for choroidal neovascularization associated with circumscribed choroidal hemangioma. Clin Experiment Ophthalmol 2011;39:916–8.

6. Mimoun G, Tilleul J, Leys A, et al. Intravitreal ranibizumab for choroidal neovascularization in angioid streaks.

Am J Ophthalmol 2010;150:692–700.

7. Parodi MB, Iacono P, Cascavilla M, et al.

Intravitreal bevacizumab for subfoveal choroidal neovascularization associated with pattern dystrophy. Invest Ophthalmol Vis Sci 2010;51:4358–61.

8. Querques G, Kerrate H, Leveziel N, et al.

Intravitreal ranibizumab for choroidal neovascularization associated with retinal astrocytic hamartoma.

Eur J Ophthalmol

10. Liang F, Puche N, Soubrane G, Souied EH. Intravitreal ranibizumab for choroidal neovascularization related to traumatic Bruch’s membrane rupture. Graefes Arch Clin Exp Ophthalmol 2009;247:1285–8.

11. Quijano C, Querques G, Massamba N, et al. Type 3 choroidal neovascularization associated with fundus flavimaculatus.Ophthalmic Res 2009;42:152–4.

12. Querques G, Bocco MC, Soubrane G, Souied EH. Intravitreal ranibizumab (Lucentis) for choroidal neovascularization associ-

ated with Stargardt’s disease. Graefes Arch Clin Exp Ophthalmol 2008;246:319–21.

13. Prieto-Calvo E, Torrón-Fernández Blanco C, Egea-Estopiñán C, Güerri-Monclús N, Ferrer-Novella E, RuizMoreno O, Pablo-Julvez LE. Intravitreal ranibizumab for choroidal neovascularisation associated with adult-onset vitelliform dystrophy.

Arch Soc Esp Oftalmol.

2012;87(5):149-52.

14. Mimoun G, Caillaux V, Querques G, Rothschild PR, Puche N, Souied EH. Ranibizumab for choroidal neovascularization associated with adult-onset foveomacular vitteliform dystrophy: One-Year Results. Retina.

2013;33(3):513-21.

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Queratopatia cristalina atípica por Candida parapsilosis.

Atypical crystalline keratopathy by Candida parapsilosis Raquel Martínez-Chico, MD1, José A. Gegúndez-Fernández, MD, PhD2, David Díaz-Valle, MD, PhD3, José M. Benítez-Del-Castillo Sánchez, MD, PhD4 1 Médico Interno Residente de Oftalmología de 4º año. Hospital Clínico San Carlos. Madrid. España.

2 Médico Adjunto. Unidad de Superficie e Inflamación Ocular. Servicio de Oftalmología. Hospital Clínico San Carlos. Jefe de Servicio de Oftalmología. Hospital Sanitas La Moraleja. Madrid. España.

3 Jefe de Sección. Unidad de Superficie e Inflamación Ocular. Servicio de Oftalmología. Hospital Clínico San Carlos. Madrid. España.

4 Catedrático de Oftalmología. Facultad de Medicina. Universidad Complutense de Madrid. Jefe de Sección.

Unidad de Superficie e Inflamación Ocular. Servicio de Oftalmología. Hospital Clínico San Carlos. Madrid. España

Autor correspondente: Dra. Raquel Martínez Chico Hospital Clínico San Carlos. Pabellón 8 C/ del Doctor Severo Ochoa s/n.

Ciudad Universitaria. Madrid 28040. España Email: raquelmchico@gmail.com Date of submission: 22/04/2013 Date of approval: 27/05/2013

Funding: None Financial/proprietary interest: None

Resumen

Figura 1. Queratoplastia tectónica y parche de membrana amniótica.

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La queratopatía cristalina es una infección corneal de evolución crónica en la que podemos encontrar un infiltrado estromal blanco arboriforme asociado a una mínima reacción inflamatoria. La mayoría de los casos ocurren en córneas transplantadas en tratamiento con corticoides tópicos.

Mujer de 91 años con antecedentes de perforación ocular tratada mediante queratoplastia penetrante excéntrica. Un año después presentó una agudeza visual de percepción de luz, gran reacción inflamatoria y un infiltrado corneal blanquecino de aspecto arboriforme. Se inició tratamiento con vancomicina intravenosa y vancomicina y amikacina intravítreas, tópicas e intracamerulares y se obtuvieron muestras de humor acuoso y del infiltrado corneal mediante arrastre con aguja de safil de 8/0 con resultado microbiológico positivo para Candida Parapsilosis. Se inició entonces tratamiento con voriconazol y trimetroprimsulfametoxazol tópicos con respuesta favorable.

En la queratopatía cristalina, la reacción inflamatoria inducida en el huésped suele ser leve debida, en parte, a la escasa replicación de los microorganismos implicados. El caso que presentamos es atípico puesto que encontramos una intensa reacción inflamatoria; sin embargo tanto el aspecto biomicroscópico de la córnea, como el

Martínez-Chico R et al. Atypical Crystalline keratopathy

resultado del análisis microbiológico y la respuesta positiva al tratamiento, apoyan el diagnóstico de queratopatía cristalina por Candida Parapsilosis.

Palabras clave: queratopatía, cristalina, infección, corneal,cándida

normales, sin ninguna patología1, lo habitual es encontrarlas en casos de queratoplastias penetrantes, de uso crónico de corticoides tópicos, subtenonianos o intravítreos, o abuso de anestésicos tópicos.6,9,10,11

Abstract

Mujer de 91 años con antecedentes de perforación ocular por úlcera corneal tratada mediante queratoplastia penetrante excéntrica y parche de membrana amniótica (Figura 1).

Durante el periodo postoperatorio evolucionó satisfactoriamente hasta que en una de las revisiones, un año después de la intervención quirúrgica, presentó una mejor agudeza visual corregida (MAVC) de percepción de luz, hiperemia conjuntival importante, gran reacción inflamatoria en cámara anterior sin hipopion, defecto epitelial corneal paracentral y un infiltrado corneal blanquecino de aspecto plumoso (Figuras 2 y 3). No era posible la visualización del fondo de ojo por la opacidad de medios pero mediante ecografía se observaron múltiples opacidades vítreas.

La paciente era alérgica a la penicilina, cefalosporinas, ampicilina y cloxaciclina, por lo que se inició tratamiento con vancomicina intravenosa (1 g/12h), intravítrea (1 mg/0,1 ml) y tópica (50 mg/ml), junto a amikacina intravítrea (400 µg/0,1 ml) y tópica (20 mg /ml). Los colirios reforzados fueron

Crystalline keratopathy is a corneal infection with chronic evolution in which we can find white branching aggregates in corneal stroma in absence of host inflammatory response. It most frequently occurs in corneal grafts with chronic topic corticosteroid treatment.

91-years-old woman with tectonic keratoplasty because of ocular perforation who presented one year later of surgery a best corrected visual acuity of light perception with intense inflammatory response and white branching aggregates in corneal stroma.

Treatment with intravenous vancomycin and topic, intravitreal and intracameral vancomycin and amikacin was started. Aqueous humor and corneal infiltrate samples were obtained. The second one was acquired by dragging using a safil 8/0 needle. Microbiological study showed an infection by candida parapsilosis, so treatment with topic voriconazol and trimethoprim sulfamethoxazole was started with good clinical evolution.

Crystalline keratopathy usually associates a small host inflammatory response, in part due to the poor replication of involved microorganisms. The case presented previously is an atypical one because of the intense inflammatory response, however, clinical appearance, microbiological results and treatment response are typical of crystalline keratopathy.

Key words: keratopathy, crystalline, infaction, corneal, candida

Caso clínico

Introducción

La queratopatía cristalina es una infección corneal de curso subagudo o crónico caracterizada por la presencia de un infiltrado estromal arboriforme o en forma de helecho, asociado a una mínima reacción inflamatoria y a un epitelio supradyacente íntegro en la mayoría de los casos.1,2,3,4 Los microorganismos implicados son de baja virulencia, como Streptococcus viridans, Staphilococcus epidermidis, Haemophilus spp. o Candida spp.5,6,7,8 Aunque se han descrito infecciones de este tipo en córneas

Figura 2. Aparición de un infiltrado estromal de aspecto arboriforme.

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Figura 3. Detalle del infiltrado estromal de morfología arboriforme.

administrados a dosis de una gota cada hora con descanso nocturno de 5 horas. Además se pautó atropina 1% (1 gota/12h), suero autólogo 20% (1 gota/3h), lágrima artificial en unidosis (cada 2h) y medroxiprogesterona (1 gota/8h).

Dos días después, ante la falta de respuesta al tratamiento (Figura 4), se procedió a la toma de muestra de humor acuoso para estudio microbiológico y a una nueva inyección de vancomicina y amikacina intravítreas. Además se pautó imipenem intravenoso aunque fue necesaria su suspensión a las 48 horas debido a una elevación importante de los niveles de creatinina sérica. Un día después de la segunda dosis de antibióticos intravítreos comenzó a observarse ligera mejoría.

Tres semanas después del inicio del cuadro, la MAVC era de 0,16, persistía un tyndall 3+ en cámara anterior así como el infiltrado corneal de aspecto plumoso. El cultivo del humor acuoso extraído previamente fue negativo, por lo que se decidió proceder a la toma, para nuevo estudio microbiológico, de una muestra por arrastre de la zona del infiltrado mediante una sutura de safil 8/0, junto a la inyección intraestromal e intracamerular de vancomicina 1 mg/0,1ml y amikacina 400 µg/0,1ml .

El cultivo de la muestra tomada por arrastre fue positivo para candida parapsilosis por lo que se inició tratamiento con voriconazol tópico 1% (1 gota/2h) y trimetoprimsulfametoxazol (1 gota/8h), obteniéndose una respuesta favorable.

Actualmente, ocho meses después del inicio del cuadro, la MAVC es de 0,25 y se observa un leucoma en la región del infiltrado previo junto a neovascularización de la queratoplastia tectónica (Figura 5).

Discusión

Figura 4. Intensa reacción inflamatoria.

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El caso descrito presenta, biomicroscópicamente, un infiltrado típico de la queratopatía cristalina. Además nos encontramos ante una córnea con una queratoplastia tectónica en tratamiento crónico con corticoides tópicos, condiciones ambas relacionadas con la aparición de este tipo de infecciones. Aunque el microorganismo más frecuentemente implicado en esta patología es el Streptococcus viridans, también se han descrito casos originados por otros microorganismos tales como

Martínez-Chico R et al. Atypical Crystalline keratopathy

REFERENCIAS

Figura 5. Aspecto actual. Neovascularización del injerto y leucoma en la región de la queratopatía cristalina previa.

Staphilococcus epidermidis, Streptococcus pneumonae, Haemophillus aphrophilus, Peptostreptococcus, Pseudomona aeruginosa y, como en nuestro caso, Candida parapsilosis.12 Se cree que la solución de continuidad creada por la sutura permite el acceso de microorganismos hasta el estroma corneal, tejido inmunológicamente privilegiado puesto que carece de vasos sanguíneos y drenaje linfático.13 Los microorganismos implicados en esta patología son capaces de producir en determinadas circunstancias, como carencia de nutrientes o una temperatura ambiental determinada, un biofilm que los mantiene inmunológicamente aislados del huésped.1,14 La baja replicación de los microorganismos normalmente implicados, así como la pobre respuesta inmunológica ocasionada por el aislamiento inmunológico del biofilm y la deficiente inmunidad celular corneal, explican la escasa respuesta inflamatoria y el curso subagudo o crónico de esta patología.

Además, el crecimiento de las colonias en los espacios intralamelares del estroma corneal es el causante del aspecto biomicroscópico tan característico de esta infección.

Por todos estos condicionantes es muy poco común encontrar en este cuadro una respuesta inflamatoria tan acusada como la del caso que presentamos, con intensa reacción inflamatoria en cámara anterior e incluso en cavidad vítrea, como pudimos objetivar ecográficamente. Por el contrario, sí está descrito que manteniendo el tratamiento corticoideo tópico en ausencia de una cobertura antibiótica adecuada puede desencadenarse un rápido aumento de la inflamación.4 Aunque la antibioterapia inicial no fue la adecuada para el microorganismo que resultó ser el causante del cuadro, no se mantuvieron los corticoides tópicos y además se observó mejoría clínica antes de obtener los resultados del estudio microbiológico e iniciar el tratamiento tópico con voriconazol.

Por todos estos hechos nos resulta difícil explicar las causas de la intensa reacción inflamatoria originada en el presente caso.

1. Ormerod LD, Ruoff KL, Meisler DM, Wasson PJ, Kinter JC, Dunn SP, Lass JH, Van de Rijn I. Infectious crystallyne keratophaty.

Role of nutritionaly variant streptococci and other bacterial factors. Ophthalmology 1991; 98:15969.

2. Lubnieski AJ, Houchin KW, Holland EJ, Weeks DA, Wessels IF, McNeil JI, Cameron JD. Posterior infectious crystalline keratopathy with Staphylococcus epidermidis. Ophthalmology 1990; 97:1454-9.

3. Díaz- Valle D. Queratitis infecciosas. Revisiones prácticas en oftalmología. Badalona.

Euromedice Ediciones Médicas. Alcon.

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4. Jack J. Kansky.

Córnea. Oftalmología clínica.

Sexta edición. Elsevier. 2009; 277-8.

5. Khater TT, Jones DB, Wilhelmus KR. Infectious crystalline keratopathy caused by gram-negative bacteria. Am J Ophthalmol 1997; 124:19-23.

6. Kinter JC, Grossnisklaus HE, Lass JH, Jaconbs G. Infectious crystalline keratopathy with topical anesthetic abuse. Cornea 1990; 9:77-80.

7. Touzeau O, Bourcier T, Borderie VM, Laroche L. Recurrent infectious crystalline keratopathy caused by different organisms in two successive corneal graft in the same patient.

Br J Ophthalmol

2003;87:1053.

8. Myron Yanoff, Jay S. Duker. Bacterial keratitis. Ophthalmology. Second edition. 2003. Mosby.

466-8.

9. Hollander DA, Clay EL, Sidikaro Y. Infectious crystalline keratopathy associated with intravitreal and posterior subtenon triamcinolone acetonide injections.

Br J Ophthalmol 2006; 90:656.

10. Mc Ghee CN, Dean S, DanesMeyer H. Locally administered ocular corticosteroids: benefits and risks.

Drug Saf 2002; 25:33-55.

11. Huang AJW, Wichiesin P, Yang M. Bacterial Keratitis.

Krachmer JH, Mannis M, Holland EJ. Cornea second edition. Elsevier Mosby.

2005; 1005-33.

12. Rhem MN, Wilhelmus KR, Font RL. Infectious crystalline keratopathy caused by candida parapsilosis. Cornea 1996; 5:543-5.

13. Hazlett LD, Hendricks RL. Review for immune privilege in year 2010: immune privilege and infection. Ocul Immunol Inflamm 2010; 18:287-43.

14. Elder MJ, Stapleton F, Evans E, Dart JK. Biofilmrelated infections in ophthalmology. Eye 1995; 9:102-9

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PAAO / Vis. Pan-Am. 2013;12(3):88-89

Message from the Chairman

of the Board, PAOF William De La Peña, MD Chair of the Board of Directors, Pan-American Ophthalmological Foundation

Opening Ceremony: William De La Peña MD and Ana Luisa Hofling-Lima MD

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In keeping with the Pan-American’s mission of education, cultural exchange and prevention of blindness a Joint Congress took place August 7-10, 2013, with the 30th Pan American Congress of Ophthalmology and the 36th XXXVI Brazilian Congress of Ophthalmology in Rio de Janeiro, Brazil.

A new tradition at Pan-American Congresses was established this year: the “Summit of the Americas” meeting.

The Pan-American Ophthalmological Foundation (PAOF) supported this event which took place one day before the Joint Congress on August 6th and 21 of the 26 presidents and representatives from the PAAO affiliated national ophthalmological societies attended. Speakers were featured from all over the world and important medical and ophthalmology practice issues were discussed. The next Summit of the Americas meeting is planned to take place in conjunction with the 2015 Pan-American Congress in Bogotá, Colombia. We thank Alcon and Allergan, our industry partners, who supported this important, groundbreaking event.

Another PAOF tradition is to organize a ticketed charity event to support the educational programs of the Pan-American.

This year the Pan-American Carnival Dinner & Show was organized on August 8 at the Porcão Churrascaria. It was an outstanding

Message from the Chairman of the Board, PAOF

success. We are very pleased to inform you that it was sold-out with 325 people attending the show.

This fundraising event, organized every two years in conjunction with the Pan-American Congress, is an integral part of the fundraising strategy to support the PAAO educational programs for the ophthalmic community for visual rehabilitation and to confront preventable blindness in Latin America, North America, the Spain and Portugal.

We would like to thank everyone at the Joint Congress who made this meeting an unforgettable success. We thank our PanAmerican Members, our industry partners, the people who participated at the Pan-American Carnival Dinner & Show, and our members of the Circle of Vision. We look forward to organizing other events and we will keep you informed of our educational activities.

William De La Pe単a, MD Chairman of the Board Pan-American Ophthalmological Foundation

PAOF Carnival Dinner and Show: Mark J. Mannis MD (center), Ana Luisa Hofling-Lima MD (left) and Liana Ventura MD (right)

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PAAO / Vis. Pan-Am. 2013;12(3):90

Dr. Sebastião Cronemberger

and co-workers are the recipients of Vision Pan-America Editor’s Choice Award 2013

Dr. Sebastião Cronemberger and Paulo E.C Dantas

During the opening ceremony of the XXXVII Brazilian Congress of Ophthalmology/ XXX Pan-American Congress of Ophthalmology in Rio de Janeiro, Brazil, the Editor-in-Chief of Vision Pan-American, The PanAmerican Journal of Ophthalmology, Paulo E.C. Dantas, MD (right in the picture). presented the winner of the Editor’s Choice Award 2013.

Created originally to recognize the best original scientific paper published in our journal, this award was selected by a jury, constituted of the members of the Editorial Board, nominated by the Editor-inChief, Paulo E. C. Dantas, MD. » 1st place (US$1,000.00): Provocative tests, functional exams and daily curve of intraocular pressure in glaucoma suspects.

Authors: Sebastião Cronemberger (left in the picture), Nassim Calixto, Hélio de Maria Vieira Filho, Tiago Tomaz de Souza, Camila Araújo Souza and Roberto de Alencar Gomes.

From Glaucoma Service, Federal University of Minas Gerais, Brazil » 2nd place (Certificate of recognition): Topical Steroids in Bacterial Keratitis: A Retrospective Study.

Authors: Alejandro Lichtinger, Faik Orukov, Avi Solomon, Claudia Yahalom and Joseph Frucht-Pery.

From Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. » 3rd place (Certificate of recognition): Quality of life in keratoconus patients submitted to corneal collagen crosslinking.

Authors: Kelly Stefani Klein, Rita Caregnato, Eduardo Périco, Nelson Julio Balestro Junior.

From post-graduation program of Centro Universitário UNIVATES, Lageado, Rio Grande do Sul, Brazil Paulo E.C. Dantas Editor-in-Chief, Vision Pan-America, The Pan-American Journal of Ophthalmology

VPA Editor-in-Chief nominated as recipient of the

2013 AAO Life Long Achievement Award Paulo E.C. Dantas, MD, Editor-in-Chief of Vision Pan-America, The Pan-American Journal of Ophthalmology and PAAO Secretary for Portuguese Language, was nominated as recipient of the 2013 American Academy of Ophthalmology Life Long Achievement Award.

The Achievement Award Program recognizes individuals who participate in Academy activities, including the scientific programs at the Annual Meeting and more than 25 other categories of contribution to the Academy.

The award will be presented at the 2013 AAO Annual Meeting in New Orleans in November.

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Events

XXXVII CONGRESO

BRASILEÑO DE OFTALMOLOGÍA Y

XXX CONGRESO PANAMERICANO DE OFTALMOLOGÍA,

TODO UN ÉXITO Río de Janeiro, Brasil, fue la sede del XXXVII Congreso Brasileño de Oftalmología y del XXX Congreso Panamericano de Oftalmología, que se llevó a cabo de manera conjunta, del 7 al 10 de agosto, en las instalaciones de Río Centro. Durante este evento, se realizaron un sinnúmero de actividades científicas, sociales y de la industria, en las que los oftalmólogos pudieron fomentar, actualizar e intercambiar información y, al mismo tiempo, obtener herramientas indispensables para su quehacer profesional.

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PAAO / Vis. Pan-Am. 2013;12(3):91-95

Apertura y homenaje 2013 La ceremonia de apertura tuvo lugar el 7 de agosto en el Auditorio de Río Centro.

El presidente de la sociedad Panamericana, el Dr. Mark Mannis, dio la bienvenida a los asistentes del congreso y a los invitados de honor- la Dra. Alice R. McPherson M.D. y David E.I. Pyott, CEO de Allergan y CBE; además, habló sobre las importantes aportaciones de la oftalmología latinoamericana al desarrollo de la oftalmología en general.

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Events

En esta ceremonia, la Dra. Ana Luisa Höfling Lima pasó a ocupar oficialmente el puesto de la presidencia de la sociedad Panamericana, y se anunció que el Dr. Eduardo Alfonso pasa a ser el presidente electo para el próximo congreso.

Por parte del Congreso Brasileño de Oftalmología, el Dr. Marco Antonio Rey de Faria también dio la bienvenida a los asistentes y habló, específicamente, sobre las problemáticas de la oftalmología en Brasil.

Homenajes

La Asociación Panamericana de Oftalmología (PAAO) hizo entrega oficial de nueve reconocimientos en el marco de la apertura del congreso.

Para la información completa de los premios siga el QR o ingrese a nuestro sitio web oftalmologoaldia.com

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PAAO / Vis. Pan-Am. 2013;12(3):91-95

Un congreso con

alta excelencia académica El XXXVII Congreso Brasileño de Oftalmología y el XXX Congreso Panamericano de Oftalmología presentó más de 500 horas de educación durante las cuales conferencistas brasileños e internacionales tuvieron la oportunidad de abordar el mismo tema desde diferentes realidades sociales, económicas, científicas y culturales.

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Events

Como comentó la Dra. Ana Luisa Höfling-Lima, una de las directoras del evento y nueva presidente de la Asociación Panamericana, “existen muy buenos congresos internacionales pero lo que caracterizó a este Congreso conjunto fue que desde su inicio se planificó con la intención de maximizar los intercambios y el debate sobre el conocimiento oftalmológico actual entre los mejores oftalmólogos brasileños y los mejores especialistas internacionales”. El tema oficial del congreso fue “Los Avances en Farmacología Ocular” y se plasmó en el libro del CBO, Farmacología y Terapéutica Ocular.

Destacamos algunas de las muchas y distinguidas conferencias que tuvieron lugar. La Pan-American Lecture que, en esta ocasión, fue dictada por el Dr. Cristian Luco que habló sobre el líder panamericano Moacyr Alvaro. La CBO Lecture presentada por el Dr. Paulo Augusto de Arruda Mello sobre los factores más allá de la presión intraocular que deben formar parte del criterio médico en la diagnosis del glaucoma. El Dr. Juan Batlle dictó el AJO Lecture sobre el estado actual de la catarata en Latinoamérica. El famoso cirujano Ivo Pitanguy habló sobre el proceso de envejecimiento y los ideales de belleza durante el simposio “Perlas de la Oculoplástica Estética”. Durante el primer día del congreso hubo muchos simposios sobre subespecialidades en las que colegas brasileños e internacionales pudieron cambiar impresiones.

PAN-AMERICA : 95

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

vs. timolol 4

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vs.

dorzolamida/ timolol 5

®

vs. latanoprost 6

Porcentaje de Pacientes que alcanzaron la PIO-Objetivo ≤14

21%

9%

17%

2%

19%

9%

Porcentaje de Pacientes que alcanzaron la PIO-Objetivo ≤15

31%

16%

24%

9%

29%

14%

Lumigan ® (bimatoprost) Forma farmacéutica y pr esentación.

Composición. Cada ml contiene: 0,3 mg de bimatoprost. Vehículo: cloreto de sódio, fosfato de sódio presentación. esentación.Frascos cuenta-gotas conteniendo 5 ml de solución oftalmológica estéril de bimatoprost a 0,03%. USO ADULTO.Composición. hepta-hidratado, ácido cítrico mono-hidratado, ácido clorídrico y/o hidróxido de sódio, cloruro de benzalconio y agua purificada qsp. Indicaciones. LUMIGAN® (bimatoprost) es indicado para la reducción de la presión intra-ocular elevada en pacientes con glaucona o hipertensión ecauciones y Adver tencias. Advertencias. Fueron relatados aumento gradual del crescimiento Contraindicaciones. LUMIGAN ® (bimatoprost) está contraindicado en pacientes con hipersensibilidad al bimatoprost o cualquier otro componente de la fórmula del producto. Pr Precauciones Advertencias. ocular.Contraindicaciones. de las pestañas en el largo y espesura, y oscurecimiento de las pestañas (en 22% de los pacientes después 3 meses, y 36% después 6 meses de tratamiento), y, oscurecimiento de los párpados (en 1 a <3% de los pacientes después 3 meses y 3 a 10% de los pacientes después 6 meses de tratamiento). También fue relatado oscurecimiento del íris en 0,2% de los pacientes tratados durante 3 meses y en 1,1% de los pacientes tratados durante 6 meses. Algunas de esas alteraciones pueden ser permanentes. Pacientes que deben recibir el tratamiento ecauciones LUMIGAN® (bimatoprost) no fue estudiado en pacientes con insuficiencia renal o hepática y por lo tanto debe ser utilizado con cautela en tales pacientes.Las lentes de contacto deben Precauciones de apenas uno de los ojos, deben ser informados a respecto de esas reacciones. Pr ser retiradas antes de la instilación de LUMIGAN® (bimatoprost) y pueden ser recolocadas 15 minutos después. Los pacientes deben ser advertidos de que el producto contiene cloruro de benzalconio, que es absorvido por las lentes hidrofílicas.Si más que un medicamento de uso tópico ocular estuviera siendo utilizado, se debe respetar un intervalo de por lo menos 5 minutos entre las aplicaciones.No está previsto que LUMIGAN® (bimatoprost) presente influencia sobre la capacidad del paciente conducir vehículos u operar máquinas, sin embargo, así como para cualquier colírio, puede ocurrir visión borrosa transitoria después de la instilación; en estos casos el paciente debe aguardar que la visión se normalice antes de conducir u operar máquinas. Interacciones medicamentosas. medicamentosas.Considerando que las concentraciones circulantes sistemicas de bimatoprost son extremadamente bajas después múltiplas instilaciones oculares (menos de 0,2 ng/ml), y, que hay varias vías encimáticas envueltas en la biotransformación de bimatoprost, no son previstas interacciones medicamentosas en humanos. eacciones adversas. LUMIGAN® (bimatoprost) es bien tolerado, pudiendo causar eventos adversos oculares leves a moderados y no graves.Eventos adversos ocurriendo en 10-40% de los pacientes que recibieron doses únicas diarias, durante No son conocidas incompatibilidades. RReacciones 3 meses, en orden decreciente de incidencia fueron: hiperenia conjuntival, crecimento de las pestañas y prurito ocular.Eventos adversos ocurriendo en aproximadamente 3 a < 10% de los pacientes, en orden decreciente de incidencia, incluyeron: sequedad ocular, ardor ocular, sensación de cuerpo estraño en el ojo, dolor ocular y distúrbios de la visión.Eventos adversos ocurriendo en 1 a <3% de los pacientes fueron: cefalea, eritema de los párpados, pigmentación de la piel periocular, irritación ocular, secreción ocular, astenopia, conjuntivitis alérgica, lagrimeo, y fotofobia.En menos de 1% de los pacientes fueron relatadas: inflamación intra-ocular, mencionada como iritis y pigmentación del íris, ceratitis puntiforme superficial, alteración de las pruebas de función hepática e infecciones (principalmente resfriados e infecciones de las vías respiratorias).Con tratamientos de 6 meses de duración fueron observados, además de los eventos adversos relatados más arriba, en aproximadamente 1 a <3% de los pacientes, edema conjuntival, blefaritis y astenia. En tratamientos de asociación con betabloqueador, durante 6 meses, además de los eventos de más arriba, fueron observados en aproximadamente 1 a <3% de los pacientes, erosión de la córnea, y empeoramiento de la acuidad visual. En menos de 1% de los pacientes, blefarospasmo, depresión, retracción de los párpados, Posología y Administración. hemorragia retiniana y vértigo.La frecuencia y gravedad de los eventos adversos fueron relacionados a la dosis, y, en general, ocurrieron cuando la dosis recomendada no fue seguida.Posología Administración.Aplicar una gota en el ojo afectado, una vez al día, a la noche.

La dosis no debe exceder a una dosis única diaria, pues fue demostrado que la administración más frecuente puede disminuir el efecto hipotensor sobre la hipertensión ocular.LUMIGAN® (bimatoprost) puede ser administrado concomitantemente con otros productos oftálmicos tópicos para reducir la hipertensión intra-ocular, respetándose el intervalo de por lo menos 5 minutos entre la administración de los medicamentos. VENTA BAJO PRESCRIPCIÓN MÉDICA.“ESTE PRODUCTO ES UM MEDICAMENTO NUEVO AUNQUE LAS INVESTIGACIONES HAYAN INDICADO EFICACIA Y SEGURIDAD, CUANDO CORRECTAMENTE INDICADO, PUEDEN SURGIR REACCIONES ADVERSAS NO PREVISTAS, AÚN NO DESCRIPTAS O CONOCIDAS, EN CASO DE SOSPECHA DE REACCIÓN ADVERSA, EL MÉDICO RESPONSABLE DEBE SER NOTIFICADO. 1. The AGIS Investigators: The Advanced Glaucoma Intervetion Study - The Relationship Between Control of Intraocular Pressure and Visual Field Deterioration. Am. J. Ophthalmol, 130 (4): 429-40, 2000. 2. Shirakashi, M. et al: Intraocular Pressure-Dependent Progression of Visual Field Loss in Advanced Primary Open-Angle Glaucoma: A 15-Year Follow-Up. Ophthalmologica, 207: 1-5, 1993. 3. Mao, LK; Stewart, WC; Shields, MB: Correlation Between Intraocular Pressure Control and Progressive Glaucomatous Damage in Primary Open-Angle Glaucoma. Am. J. Ophthalmol, 111: 51-55, 1991. 4. Higginbotham, EJ et al. One-Year Comparison of Bimatoprost with Timolol in Patients with Glaucoma or Ocular Hypertension. Presented at American Academy Ophthalmology, Nov 11-14, 2001. 5. Gandolfi, S et al. Three-Month Comparison of Bimatoprost and Latanoprost in Patients with Glaucoma and Ocular Hypertension. Adv. Ther, 18 (3): 110-121, 2001. 6. Coleman, AL et al: A 3-Month Comparison of Bimatoprost with Timolol/Dorzolamide in Patients with Glaucoma or Ocular Hypertension. Presented at American Acedemy of Ophthalmol, New Orleans, La, 2001.

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