Glaucoma in the New Millennium [1 ed.] 9789062997909, 9789062991938

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From pertinent discussions on the current literature to provocative round-table and controversial clinical presentations, the participants discuss clinically worthwhile topics in the various fields. The attendees were treated to creative thinking from speakers, who were especially chosen for their lively approach to science and teaching. The contributors to this Glaucoma meeting provided chapters on the wide range of issues that confront not only the general ophthalmologist, but the glaucoma specialist as well.

Glaucoma in the New Millenium edited by Jonathan D. Nussdorf

For the past fifty years, the New Orleans Academy of Ophthalmology has maintained a strong tradition of providing ophthalmologists with a valuable venue for learning by way of exceptional mentors and innovative leaders. Their symposia have always been a combination of relevant clinical thought, based on superior knowledge, and current research.

New Orleans Academy of Ophthalmology

GLAUCOMA IN THE NEW MILLENNIUM edited by Jonathan D. Nussdorf

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GLAUCOMA IN THE NEW MILLENNIUM

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GLAUCOMA IN THE NEW MILLENNIUM edited by Jonathan D. Nussdorf

Copyright © 2003. Kugler Publications. All rights reserved.

Proceedings of the 50th Annual Symposium on Glaucoma, New Orleans, LA, USA, April 6-8, 2001, organized by the New Orleans Academy of Ophthalmology

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ISBN 90 6299 193 9

Distributors: For the U.S.A. and Canada: Pathway Book Service 4 White Brook Road Gilsum, NH 03448 Telefax (603) 357 2073 For all other countries: Kugler Publications P.O. Box 97747 2509 GC The Hague, The Netherlands Telefax (+31.70) 3300254

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© Copyright 2003 Kugler Publications All rights reserved. No part of this book may be translated or reproduced in any form by print, Glaucoma in the photoprint, New Millennium, Kugler Publications, 2003. means ProQuest Ebook Central, microfilm, or any other without prior written permission of the publisher.

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Table of contents

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Table of contents

Preface Editor Contributors

vii viii ix Defining Glaucoma

An approach to glaucoma pathogenesis H.A. Quigley How do we kill the idea of low-tension glaucoma? H.A. Quigley How much glaucoma damage is pressure-dependent? P. Palmberg Ocular blood flow and glaucoma G.A. Cioffi Microvascular changes of the human anterior optic nerve in glaucoma G.A. Cioffi and D.-Y. Zhao Neuroprotection and glaucoma. How do I tell if a drug is neuroprotective? G.A. Cioffi

3 13 21 29 37 43

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The Angle The true nature of angle-closure glaucoma H.A. Quigley Gonioscopy in the laser age P. Palmberg Round table: How I make the decision to do a peripheral iridotomy: my laser, lens and settings (P. Palmberg, presiding) Round table: How I make the decision to do ALT: my laser, lens and settings (C.F. Burgoyne, presiding)

51 65 77 89

The Optic Nerve Head Evaluation of optic disc and nerve fiber layer in glaucoma. Clinical techniques J. Caprioli Round table: How I follow the optic nerve head and nerve fiber layer: my step by step approach (C.F. Burgoyne, presiding) Workshop: Imaging the optic nerve head and nerve fiber layer in glaucoma (J. Caprioli and H. Quigley)

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107 115 129

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Table of contents

Round table: My most confusing optic nerve head (J. Nussdorf, presiding)

133

Psychophysics Update on psychophysical tests for glaucoma J. Caprioli The variability of perimetry. Reassessing an important clinical tool E.J. Higginbotham, N. Ellish and R. Kalsi Round table: Visual field (E.J. Higginbotham, presiding) Update on perimetry. New developments C.A. Johnson Questions directed to Chris Johnson in his absence

151 165 183 185 207

Treatment Issues, Problems & Repairs

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Using combination drugs in glaucoma management E.J. Higginbotham The use of topical anesthesia for a combined cataract and glaucoma procedure A.S. Crandall Update on antimetabolic use A.S. Crandall Plumbing pearls. An effective method for reversing hypotony maculopathy and how to save failing filtering blebs at the slit lamp P. Palmberg Round table: My procedure and antimetabolite dose of choice for a primary trabeculectomy (A. Etienne, presiding) Round table: Refractive surgery: thin corneas, inaccurate intraocular pressures, and the myopic disc at risk (D.A. Long, presiding)

213 223 235 237 243 257

Duke-Elder lectures Lecture 1: Maintenance and pathophysiology of intraocular pressure Lecture 2: Natural history of simple open-angle glaucoma Lecture 3: Natural history of congestive narrow-angle glaucoma

271 279 288

Appendix 1 Glaucoma Symposiums of the New Orleans Academy of Ophthalmology

297

Appendix 2 Sponsors

300

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Preface

vii

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Preface The 50th annual symposium of the New Orleans Academy of Ophthalmology was held from April 6th – 8th, 2001. This was the Academy’s ninth meeting devoted to glaucoma and consisted of formal lectures, round table discussions, and workshop presentations. The New Orleans Academy of Ophthalmology maintains a strong tradition of providing the ophthalmologist with a venue for learning from exceptional mentors and innovative leaders. Inspection of the list of Academy meetings pertaining to glaucoma will highlight the fact that we have been privileged to have outstanding contributors and notable repeat performers (Appendix 1). The first symposium of this Academy was held in 1952 and, with its focus on glaucoma, the contributors were Sir Stewart Duke-Elder, Paul A. Chandler, MD, and Peter C. Kronfeld, MD. The first three lectures from that 1952 meeting were presented by Sir Stewart Duke-Elder and are published for the first time, from a copy of the original transcript, in this collection of papers. I think you will find his discussion of ‘simple’ and ‘congestive’ glaucoma enlightening and instructive. The Program Committee chairpersons, Claude F. Burgoyne, MD and Katherine Loftfield, MD, were instrumental in putting together a strong assembly of contributors and a well-balanced meeting. Special acknowledgment for their hard work in organizing this symposium goes to committee members Rameish Ayyala, MD, Annemarie Etienne, MD, Kenneth Haik, MD, Jill B. Koury, MD, and Daniel A. Long, MD, and to executive secretaries, Emily Busby and Amber Howell. For his dedicated and thoughtful leadership, much appreciation is given to the president of the New Orleans Academy of Ophthalmology, 2000-2002, George S. Ellis, Jr, MD, and to the board of directors. The Academy acknowledges its sponsors for providing unrestricted financial support, which helped to defer the expense of this medical education meeting and subsequent publication. Special thanks go to Peter Bakker at Kugler Publications for his guidance and wisdom, as well as his unending support for the task of publishing this glaucoma specialty symposium. The contributors to this symposium on glaucoma are outstanding. They provided chapters covering a wide range of issues that confront the general ophthalmologist, as well as the glaucoma specialist. Due to an unfortunate circumstance, Chris A. Johnson, PhD, was unable to attend the meeting; however, he was gracious enough to provide his written contribution, which is included in this compilation of papers. You will find that the lectures, round table discussions, and workshop sessions are filled with pearls of wisdom that will help guide you toward a modern, common sense approach in addressing the special needs of your glaucoma patients. Jonathan D. Nussdorf, MD Ochsner Clinic Foundation New Orleans, Louisiana, USA

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Contributors

ix

Contributors

JOSEPH CAPRIOLI, MD Professor of Ophthalmology Chief, Glaucoma Division Jules Stein Eye Institute Los Angeles, California

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GEORGE CIOFFI, MD Director, Glaucoma Service Director, Discoveries in Sight Portland, Oregon

ALAN S. CRANDALL, MD Professor of Ophthalmology and Vice Chair of Clinical Services Director of Glaucoma and Cataract John A. Moran Eye Center Salt Lake City, Utah

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Contributors

EVE J. HIGGINBOTHAM, MD Professor and Chair Department of Ophthalmology University of Maryland School of Medicine Baltimore, Maryland

CHRIS A. JOHNSON, PhD Director of Diagnostic Research and Senior Scientist Oregon Lions Anderson-Chenoweth-Ross Discoveries in Sight/Devers Eye Institute Portland, Oregon

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PAUL PALMBERG, MD, PhD Professor of Ophthalmology Bascom Palmer Eye Institute University of Miami School of Medicine Miami, Florida

HARRY A. QUIGLEY, MD Director, Glaucoma Service and Director DANA Center for Preventive Ophthalmology Edward Maumenee Professor of Ophthalmology Wilmer Eye Institute Baltimore, Maryland

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An approach to glaucoma pathogenesis

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Defining Glaucoma

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H.A. Quigley

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An approach to glaucoma pathogenesis

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An approach to glaucoma pathogenesis Harry A. Quigley Glaucoma Service and Dana Center for Preventive Ophthalmology, Wilmer Ophthalmological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Introduction

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Most of those interested in the pathogenesis of glaucoma have abandoned simplistic scenarios in which glaucoma is either ‘mechanical’ or ‘vascular’, though anachronistic thinking persists. Like all diseases, glaucoma results from many factors, and we must take new approaches to cause and effect that will improve investigations into its treatment. Glaucoma is a heterogeneous disorder characterized by progressive loss of mid-peripheral visual function, associated with excavation of the optic disc. From angle closure to exfoliation, from senile sclerotic to traumatic, there are many entry points to this definition. Yet, for 70 million or so persons with glaucoma worldwide, there are enough common factors in optic nerve damage that their pathogenesis can be discussed together. Glaucoma primarily causes the death of retinal ganglion cells (RGC), though additional loss of their synaptic partners in the brain also occurs. In normal eyes without glaucoma, RGC die with age, at about 2500 RGC per year to the age of 50 years, accelerating to 7500/year thereafter.1 RGC death in glaucoma exceeds the average loss due to aging, and only when loss exceeds 30% of the cells in any one area does functional loss become measurable by present visual field tests.2 A modest proportion of all those with open-angle glaucoma (OAG) becomes legally blind during their lifetime, i.e., less than 10%. But, the disease is so prevalent that the absolute number of sufferers who are blind causes it to be ranked as the second most frequent blinding condition worldwide.1 The linear causation pathway Previous conceptualizations of glaucoma pathogenesis were both simple and linear. One cause of glaucoma was championed (e.g., mechanical compression of nerve fibers or insufficiency of RGC vascular nutrition) and vigorous arguments were constructed to make the ‘other’ concept impossible. Even when more than Address for correspondence: Harry A. Quigley, MD, Wilmer 120, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287, USA. e-mail: [email protected] Glaucoma in the New Millennium, pp. 3–12 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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one possible cause was considered as an option, it was proposed that one cause always preceded the other. For example, a simple, linear formulation might propose that the intraocular pressure (IOP) compresses nerve head capillaries, causing a failure of nutritional blood flow, followed by RGC death. Recent research into RGC death in glaucoma has added many potential contributors to any simple formula.3 To redesign our concepts of glaucoma pathogenesis, let us expand the set of possible events leading to RGC death. This is merely an initial illustration, not a proposal of known sequence, though I believe that the stages are plausible. In Table 1, I list 15 events leading to RGC death. The location of each event is indicated, and steps are grouped into Initiator, Promotor, or Secondary. Initiators occur early, before actual alterations in RGC themselves (this is sometimes called ‘upstream’). Promotor steps act later, within RGC (‘downstream’), and Secondary steps occur after initial RGC death, and result from it. For each step, I have presented one potential risk factor (each event could have many). A risk factor is a condition that would make this event more likely to occur. For instance, risk factors can be features of the person, of ocular cells and their extracellular matrix, of RGC geography, of the individual’s genetic endowment, or his response to altered conditions. A detailed linear exposition allows us to dissect more carefully how and where certain risk factors might participate in the process. For example, mitochondria could be important either in the axon or at the cell body. While it could be important to know how to inhibit the caspase enzymes that carry out apoptotic cell death, these are far downstream and the process may have gone beyond therapy

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Table 1. Linear conceptualization of steps in RGC death in glaucoma Steps to RGC death

Risk factor

Anterior eye or outside eye 1 Myocilin mutation, chromosome 1q 2 Increased aqueous outflow resistance 3 IOP rise due to imbalanced inflow/outflow Optic nerve head 4 Compression of lamina cribrosa sheet 5 Lamina capillary lumen narrowed 6 Poor nutritional blood flow to axons 7 Fall in local axon energy stores 8 Disassembly of axon tubule proteins 9 Alteration of axonal transport 10 Retrograde neurotrophic signals slow RGC body in retina 11 Mitochondrial membrane potential falls 12 Change in intracellular calcium level 13 Activation of caspase enzymes 14 Activation of DNAse enzymes 15 Completion of apoptotic cell death Retina or optic nerve head 16 Environment altered neighboring RGC 17 Rise in extracellular glutamate level 18 NMDA receptor stimulation 19 Neighbor RGC initiates step 9 or 11

Initiator steps (1-5) Marital choice Trabecular matrix composition Autoregulation of aqueous formation Thinner sheet in lower nerve head Elastin/collagen composition Promotor steps (6-15) Local autoregulation processes Axon mitochondrial number Motor protein composition Transport movement rate Trophic receptor resistance Mito membrane channel states Responsiveness of high calcium Resting level of precursor enzyme Activation efficiency of enzymes Lack of inhibiting factors Secondary steps (16-19) Activation of microglia Poor glutamate transporters Low receptor channel blockers Proximity to toxic events

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by that point. Even with our present rudimentary knowledge, events in the process are much more complex than shown, and many more variables and risk factors could be involved from initial steps to the final ones. No wonder all patients with an IOP averaging 24 mmHg do not suffer visual field loss at the same rate. The specification of events and risk factors in the pathological process provides clues to potential therapeutic interventions. For example, if an altered mitochondrial membrane potential contributes to apoptotic death, treatments could be devised and tested to block this event. Weakness of elastin or its connection to the extracellular matrix represent another possible avenue for treatment. It has become common to speak of ‘neuroprotection’ therapy for glaucoma, or of protecting RGC by a method other than lowering IOP. But, which events are those that are interrupted in neuroprotection? Might it interrupt an Initiator event (e.g., improving nerve head blood flow)? Could it involve intervention in a Promotor, perhaps one of those within the RGC body during the induction of apoptosis? Or, does it refer to prevention of the Secondary degeneration among innocently bystanding RGC that were not primarily injured? One disadvantage of a series of linear pathogenic events is that there are surely inter-individual variations in how the process proceeds. Some events may never happen in some glaucoma eyes. Many eyes are susceptible to glaucoma at normal IOP, so they could suffer lamina collapse (event 4) or poor blood flow in the nerve head (event 6) without the preceding events ever occurring. Furthermore, some eyes might scramble the order. It has been suggested that the death of some RGC might make the nerve head more sensitive to further injury than it was before damage. Hence, the person with poor blood flow who suffered non-glaucoma RGC loss might make glaucoma damage more likely. This puts poor autoregulation of blood flow at multiple sites along the path.

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Multivariate approaches Therefore, the linear stepwise analysis must be generalized to allow for variations in sequence, multiple effects of some events, and interactive behaviors that are non-linear. How can we understand this without hopeless complexity? The wellknown biostatistical approach called multivariate analysis is a model solution dealing with many effects all at once. An equation is constructed with a dependent variable on the left side (here it is RGC death), and on the right side of the equation are a series of variables, each of which may be related to RGC death. Risk factors are independent variables in the equation for this analysis. Spaeth was probably one of the first to use multivariate analysis for assessment of glaucoma risk factors,4 and it has been applied many other times to the clinical issues of glaucoma outcome.5 Since we are considering glaucoma pathogenesis, the dependent variable in our first formulation is RGC death, not its clinical recognition in disc analysis or field testing. If we were to use functional impairment as the analytic outcome, risk factors would include things like how reliable the subject is at field testing and confounding factors like cataract. That is a different model for a different essay. Variables (risk factors) can be associated with RGC death in a variety of ways and can express themselves in different forms. For a multivariate model, we can treat risk factors in mathematical analogies. IOP is a familiar risk factor that we

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could place in the equation in several formats, depending upon which manifestation of IOP we wish to assess. These could be the mean IOP over time, the range of diurnal fluctuation, or the amount that the optic disc surface bows back or subsides when IOP increases or decreases. These three formats could be described as the following manifestations of IOP: static (mean), dynamic (diurnal), and interactive (effect on another risk factor, here, the nerve head tissues). We may not know at present which manifestation of IOP is most important, but, in a model, we can put them all into the formula and assess their effects together or separately. For each format, the state of the variable could be protective or detrimental to glaucoma outcome. Some variables might always be one or the other, but others could be both. For example, IOP lowering is beneficial for field outcome to a point, but hypotony maculopathy acts in the opposite direction. Interaction of one variable with another could involve the variable as the active partner (causing the change in another variable, good or bad), or the passive partner (receiving an effect for better or for worse) (Table 2). Table 2 shows properties of the risk factor IOP, including its static and dynamic components. The way in which these elements would be incorporated into a mathematical model of glaucoma pathogenesis is indicated by the symbols in the last line Some variables are inherently static, since they are fixed for that person: ethnicity and chromosomal gender are examples. Others provide a measure of the state of the individual, but are dynamic, e.g., age. While these are fixed for the individual at a point in time, they can be interactive with other variables. For example, young persons with systemic high blood pressure are less likely to have OAG, while persons over the age of 65 years with hypertension are more likely than average to have it.6 We could describe this as a dynamic interaction of age with hypertension relative to glaucoma; or, older age may be a surrogate for the duration of hypertension. In a model, we can deal with both simultaneously and not have to decide that one is important and not the other. Ethnicity and gender may be variables that express the effects of groups of genes that are more common in certain races. As we determine what those genes are, the variables will be more appropriately specified (the myocilin gene may be approaching this status). Alternatively, race and gender may be important because they indicate differential environmental effects for persons of particular groups Table 2. Mathematical description of risk factor: IOP Type of effect

Feature

Protect/enhance (sign)

Strength

Static Dynamic Interactive acting

mean diurnal fluctuation

higher = worse (+) greater = worse (+)

a b

decrease perfusion stretch connect tissue therapy lowers

worse worse better

c d e

receiving

Model mathematical translation: aSiop + b(Siop)2 static dynamic

+cSiop(Sbf) interaction blood flow

(+) (+) (-) + dSiop(Sct) interaction connect tissue

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- eSiop(S ther) interaction with therapy

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An approach to glaucoma pathogenesis

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that make glaucoma more likely to be present or to progress. Persons of one ethnicity can have lower socioeconomic status, higher access to care, negative cultural attitudes toward glaucoma screening, or personal behaviors that make disease less likely. For some individuals or glaucoma subtypes, one variable may dominate the process, while in other groups that variable may be subsidiary or even irrelevant. The strength of association is a way to describe the importance of a variable, since it is unlikely to be all or none. The strength can be measured empirically using criteria such as: 1. How strong is the variable’s association quantitatively? For example, a 25% lowering of IOP leads to a 40% decrease in field progression rate. 2. How consistent is the association? For example, a weak lamina cribrosa might initiate damage even at normal IOP, but in traumatic secondary glaucoma, IOP is high enough that the normal lamina structure is overpowered. 3. Is there a doseBresponse relationship? For example, the higher the IOP, the greater the chance of field loss. 4. How plausible is it that the variable is associated? For example, sunspot activity may be associated with angle-closure glaucoma, but the plausibility of a direct connection is weak. 5. Is there experimental proof that altering the variable affects the disease? For example, does a controlled clinical trial show that calcium channel blockers slow field loss. We can put the strength of a variable into the model by assigning it a mathematical coefficient, even making one for its static state, and one for the dynamic or interactive state, when present. It will be helpful to consider how this could be done. Consider a scatter plot of points, each defined by the values of two variables (x,y) or (IOP, RGC death). If these points all fell on one straight, perfect line, it would cross the y axis at an intercept and would have a slope. This is expressed as y = a0 + a1x, where a0 is the intercept and a1 the slope. But, real data are scattered around any perfect line. Simple linear regression analysis (the method of least squares) estimates the best fitting, straight line that would connect all the points. The slope indicated by the regression line is the coefficient that describes the form of the relationship between the dependent variable (y, RGC death) and an independent variable (x, say blood flow). If large changes in blood flow (x) cause very little increase in RGC death (y), then the slope is flat B and we describe the risk factor as weak in its association with the outcome. If the points are widely scattered, linear regression will generate a ‘best fitting’ line B but the measure called r2 judges how much of the variation in y is explained by x. If r2 is large (close to 1), then x explains a lot of the variation in y B the association is strong. Lower values of r2 indicate very little relationship between the two. So, the slope shows how much change in x there is for a change in y. The r2 shows how much confidence we have that the slope (steep or flat) represents a strong association. We could have a high r2 and a flat slope B a result showing conclusively no effect of x on y, or a steep slope and low r2 B a possible big effect of x on y, but no real confidence that the available data show a strong relationship. The best fitting line can be exponential or a power function instead of linear. But, what if we wish to evaluate the relationship between RGC death (dependent variable, y) and many risk factors simultaneously (independent variables, x1, x2, x3, etc.)? This is what multivariate analyses do B the effects of more than one

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independent variable are evaluated simultaneously. Just as linear regression assigns a slope and r2, in multivariate analysis, each variable is assigned its own coefficient and a judgment of the strength of association is made. In some multivariate methods, this is done by calculation of an odds ratio and its 95% confidence limit B the odds being the likelihood of a strong association between each dependent variable and the outcome, given the adjusting effect of data from the other variables in the equation. The point is to describe the general approach as potentially valuable for our thinking about glaucoma pathogenesis. Frequency

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While a variable may be highly associated with disease when it is present, if it is rare, its importance is minimal for most individuals. A mutation in the myocilin gene may be associated with a ten times greater chance of developing glaucoma. In multivariate analysis, this would lead to a high odds ratio, pointing to a strong association. But, what if the frequency of such mutations is low among all glaucoma patients? Consider the little town of Cornville with 1000 older adults, where 1% have glySTOP, the most frequent myocilin gene defect associated with glaucoma. Ten persons would have the mutation (1% times 1000). The prevalence of glaucoma is 2% among adults, so out of 990 persons without the mutation, there are 20 glaucoma cases, while the ten myocilin mutation carriers exhibit two cases (ten times the general prevalence of 2% = 20% of ten persons = 2). Hence, the attributable proportion related to myocilin mutation in this example is two of 22 total cases, or 9%. In one study, the proportion of those with OAG who had some myocilin mutation was about 3%. This allows speculation that a person with a mutation in this gene is actually three times more likely to have glaucoma (an odds ratio of three, not ten as in my example). Myocilin mutations might substantially increase glaucoma prevalence if many persons had them, but their effect is proportional to frequency. Thus, we should consider both the strength and frequency of a variable’s contribution. These two can be dissected if we perform the multivariate analysis with the data stratified into those who do and do not exhibit a trait, while including other important variables in both data sets. Variables might be factors associated with the initial onset of disease, others might influence its natural (untreated) rate of progression, and yet others could affect the response to therapeutic interventions in ways that influence ultimate visual impairment. This may mean that models would be needed for incidence, progression, and therapeutic response. Summary of multivariate approaches In summary, to place a variable (risk factor) in a model of disease, we must know its characteristics. Does it have only static features, or dynamic ones as well? Does it potentially interact with other variables, and in that interaction is it the acting or the receiving partner? Is it a variable that is beneficial in preventing the disease, or detrimental? How strong is the association of the variable with the disease? Is the variable frequently found in the population, or is it rare? Is the variable one that influences disease onset, disease progression, response to therapy, or more than one of these?

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Practical implications of multivariate analysis Does all this mathematical talk have any practical value? There have been a number of past uses of multivariate modeling in glaucoma, e.g., trying to predict variables that are important in determining which suspects will develop glaucoma.5 The entry of data from a particular group of persons will produce an evaluation of risk factors relevant to that population, but not necessarily generalizable to other groups. For instance, in past textbooks, diabetes mellitus was listed as a risk factor for OAG, but recent population-based studies found no association between diabetes and glaucoma in black persons,7 although the relationship is probably present, but weak, in white persons. A further consideration derives from the fact that glaucoma develops late in life. If we are attempting to associate a risk factor that is present at the age of 30 years (say, pigment dispersion syndrome) with glaucoma, we have to recognize that glaucoma may not have developed yet. The subjects would have to be followed for 30-40 years in order to associate the pigment abnormality with the incidence of glaucoma. A similar anomaly presents itself when trying to determine if persons with OAG are more likely to have a blood relative with glaucoma.8 The association differs for parents, siblings, and children. An 85-year-old proband would have long-dead parents, whose eye care and status would be problematic. Siblings and children of this person would have the chance of being old enough to develop glaucoma. Substitute a 40-year-old subject, and her parents would be old enough to have developed glaucoma and may be alive and diagnosed in a way that would be documentable. But, siblings and children of this person would have a low chance of having glaucoma now, even if they were going to develop it later. When OAG subjects are divided (stratified) into those who already know that they have the disease and those who have just found out, those already aware of their diagnosis are more likely to report a positive family history than the newly diagnosed. This probably results from their being told to have family members examined. The risk can only be more accurately assessed by examining all living family members.9 Mathematical models of glaucoma pathogenesis would have inherent limitations. By entering a variable into the model, we can value its contribution, but cannot ascribe either the truly causal nature of its association, or the positional order of its action. And, where interactive terms are introduced, the specific contribution of a variable becomes even more abstruse. While some event orders are obvious (e.g., death of RGC cannot be the start of the process, cause must precede effect), we will probably never understand how all the pieces fit together. Furthermore, individual human heterogeneity requires consideration. In one person, eight factors may be needed to lead to glaucoma damage, while in another, only four will produce the injury B and they may be different variables in these two patients. Necessary and sufficient components What causes influenza? While we could answer quickly “the influenza virus”, sufficient virus must be inoculated into the respiratory tract to proliferate, and the immune system must be ineffective in preventing it. In a brilliant analysis of what constitutes a cause of disease, the epidemiologist Rothman distinguished component causes from sufficient cause.10 In persons who develop influenza, he labels virus

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and an immune system failure as component causes, which in a simple formulation would together make up a sufficient cause. Note that if a person is run down by a truck five minutes after exposure to the virus, there will not be sufficient induction time to allow the final component cause to lead to the effect. In fact, the induction time is different for each component cause, long for those acting early (upstream) and zero for the final component cause in a set of sufficient cause. The induction time for the myocilin gene mutations associated with glaucoma appears to be more than 20 years. Why does glaucoma not develop earlier? Possibly, other component causes must follow the genetic defect in time, ultimately reaching sufficient cause. There will surely be more than one sufficient cause, made up of component causes that are either shared or unique to that sufficient cause set. Each sufficient cause consists of a minimally sufficient set of components (none is extraneous). Note how this approach deals with the weakness of the linear model in Table 2, which assumes that all persons go through the same set of steps in the same order. The diagrams in Figure 1 show sufficient causes, each made up of four component causes. Disease would only happen in each of the three conditions if all its components were present. Consider what would be true if glaucoma were caused by these three sufficient cause sets (each case of glaucoma was a result of one set, and all glaucoma cases were caused by one of the three sets). Component cause A might be defective autoregulation of the optic nerve head blood flow. What proportion of all cases are caused by A? All of them, since, in this hypothetical example, A is a component cause in all sufficient cause examples. That makes A into a necessary cause. On the other hand, if D stands for IOP, then it would play a role in glaucoma caused by the first two sets, but not the third one, and it would be a component in some cases, but not a necessary cause for any case of glaucoma.

Fig. 1. The component risk factors (causes) that make up a theoretical sufficient cause set for glaucoma in three different types of patients are given in the three schematic circles. In each case, there are four component causes for each patient, although only one is present in all three scenarios (making it a necessary cause).

Above we discussed the frequency of a risk factor (here a component cause) and its effect on our view of its participation in the disease. Consider that component cause E is weak elastin in the optic nerve head lamina and that components A, B, C, and D are relatively common in the population, but E is rare (say Ehlers-Danlos syndrome). Its sufficient cause would also be rare. But, if we compare the risk of glaucoma among those with E to those without E, the relative risk is much higher. However, components A and B would have smaller differences in risk among those with and without the traits. Thus, E(lastin) may be a biological cause of glaucoma, but its frequency in a population, and the prevalence of other compo-

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nent and sufficient causes, will affect its apparent strength of association (as shown above for myocilin).

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Ascertainment bias Prevalence of a component must be evaluated in the context of who we wish to evaluate with a disease. Those who voluntarily come to a doctor’s office are not representative of the overall population with respect to many glaucoma-related issues. They are more likely to have an affected family member, and more often have higher IOP, diabetes, and myopia. If we wish to know the strength of association for component causes of glaucoma among those who can afford health care and have the motivation to come to the office, then it is fine to analyze a case series from available charts. This should be considered only a first, exploratory step, if we ideally wish to know the nature of glaucoma in all persons. An example is the interesting observation by Airaksinen and Tuulonen that those with glaucoma at lower IOP have larger disc diameters than those with higher IOP glaucoma. I suspected (as did these authors) that their finding might have been influenced by ascertainment bias. In this case, the bias would arise because eyes with larger disc diameter would have larger physiological cup/disc ratios, and would be more likely to be referred to an ophthalmologist B regardless of their IOP. Those with higher IOP would be referred anyway, independent of cup/disc ratio, thereby producing more persons with larger disc diameter among those who actually turn out to have glaucoma among the lower IOP group. To unmask this bias, we evaluated the disc diameter of those with OAG in the Baltimore Survey compared to their IOP. In fact, there is a modest tendency for a population-based group of glaucoma subjects to have larger disc diameter than those who do not have glaucoma.11 This confirms the logical idea that a larger disc would resist physical deformation less well than a small disc. But, the discs of those with lower IOP were not larger than higher IOP persons among those with glaucoma, suggesting that the clinic-based data were subject to the ascertainment bias effect. The populationbased Blue Mountains Eye Study in Australia found the same association as the Baltimore study, but the association was made stronger and more generalizable. Population-based studies are frequently held up as the ultimate standard to debunk findings derived from other settings. This should be examined critically and not taken to the extreme. While we should examine persons randomly selected from the overall population of interest in order to know best what causes a disease in that group, population-based studies suffer from weaknesses of their own. One frequent problem in population studies for glaucoma is the low prevalence of the disease, which leads to a small number of actual cases for study. In the original Baltimore Survey, the optic disc was available to be examined in about 100 black and 40 white persons with defined OAG. Clinic-based studies from large centers can evaluate hundreds of cases. Data unselected with respect to a population are useful, but larger samples give greater confidence that, if a difference is present, it will be detected.

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Conclusions Glaucoma pathogenesis should not be viewed simplistically and ‘one cause theories’ belong in the 20th century. The analogy of multivariate regression provides a way of thinking about the many factors that interact and play a role in pathogenesis, as well as an actual analytic approach to data derived from laboratory or clinical studies. We should not be surprised if some persons apparently have the same disease clinically, but different sufficient cause. Component causes have several possible features (static, dynamic, interactive), and occur in a variety of sequences. The relative frequency of a component cause, its induction period, and how we ascertain its presence, will affect the apparent strength of its association with glaucoma. Pathogenic research requires epidemiological studies to test for likely associations and their frequency and strength. The role of laboratory investigations is to use model systems that change one variable, and that can measure the effect of so doing. Clinical trials in humans allow us to test for the therapeutic benefit of altering a risk factor in order to improve the relevant outcome for our patients, the preservation of their quality of life. References

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1. Quigley HA: The number of persons with glaucoma worldwide. Br J Ophthalmol 80:389393, 1996 2. Baumrind-Kerrigan LA, Quigley HA, Pease ME, Kerrigan DF, Mitchell RS: The number of ganglion cells in glaucoma eyes compared to threshold visual field tests in the same persons. Invest Ophthalmol Vis Sci 41:741-748, 2000 3. Schumer RA, Podos SM: The nerve of glaucoma! Arch Ophthalmol 112:37-44, 1994 4. Spaeth GL: Visual loss in a glaucoma clinic. I. Sociological considerations. Invest Ophthalmol 9:73-82, 1970 5. Kass MA, Hart WM, Gordon M, Miller JP: Risk factors favoring the development of glaucomatous visual field loss in ocular hypertension. Surv Ophthalmol 25:155-162, 1980 6. Tielsch JM, Katz J, Sommer A, Quigley HA, Javitt JC: Hypertension, perfusion pressure and primary open-angle glaucoma: a population-based assessment. Arch Ophthalmol 113:216221, 1995 7. Leske MC, Connell AM, Wu SY, Hyman LG, Schachat AP: Risk factors for open-angle glaucoma: the Barbados Eye Study. Arch Ophthalmol 113:918-924, 1995 8. Tielsch JM, Katz J, Sommer A, Quigley HA, Javitt J: Family history and risk of primary open angle glaucoma: the Baltimore Eye Survey. Arch Ophthalmol 112:69-73, 1994 9. Wolfs RC, Klaver CC, Ramrattan RS, Van Duijn CM, Hofman A, De Jong PT: Genetic risk of primary open-angle glaucoma: population-based familial aggregation study. Arch Ophthalmol 116:1640-1645, 1998 10. Rothman KJ: Modern Epidemiology. Boston/Toronto: Little, Brown & Co 1986 11. Quigley HA, Varma R, Tielsch JM, Katz J, Sommer A, Gilbert DL: The relationship between optic disc area and open-angle glaucoma: the Baltimore Eye Survey. J Glaucoma 8:347-352, 1999

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How do we kill the idea of low-tension glaucoma? Harry A. Quigley Glaucoma Service and Dana Center for Preventive Ophthalmology, Wilmer Ophthalmological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA Half the glaucoma in the USA is undiagnosed. Half the glaucoma patients have an IOP of less than 21. Undiagnosed glaucoma patients have lower IOP.

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The tyranny of technology How did we get into this mess? At the start of the 20th century, the only persons who were called glaucoma patients had what we now call symptomatic angleclosure glaucoma. Using rudimentary tonometers, poor ophthalmoscopy, and no field tests, doctors recognized those who presented to them as ‘glaucoma’ when they had pain, blurred vision, red eyes, and very high intraocular pressure (IOP). However, in an amazingly prescient paper in 1930, Bengt Rosengren documented the depth of the anterior chamber in glaucoma, showing that subjects with the more common form, glaucoma irritativum (angle closure), had shallow chambers, but that those with ‘glaucoma simplex’ had normal chamber depths.1 He may have been one of the few who recognized that there were two major forms of glaucoma, differing in this measurement as well as in clinical picture. Barkan subsequently used the gonioscope to differentiate angle-closure from open-angle glaucoma. And so, a pattern began in which the latest technology separated diseases from each other. Some technological advances (such as gonioscopy) were real advances. But, as Rosengren wrote so wisely: “It must be borne in mind that (differentiation among glaucoma cases is) related to the system of classification employed. ...the boundaries between different forms of glaucoma are by no means clearly defined.” By trying to set boundaries that were too clear, based on IOP, we later fell into a trap. We have to sympathize with ophthalmologists in the early 20th century. It was logical to conclude that an IOP that felt hard to the fingers could blind someone. However, subjects with ‘glaucoma simplex’, who had no symptoms, and by the tonometry of the day often seemed not to have ‘high’ IOP, were a puzzle. Even the sharpest clinicians thought that open-angle glaucoma did not happen very Address for correspondence: Harry A. Quigley, MD, Wilmer 122, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287, USA. e-mail: [email protected] Glaucoma in the New Millennium, pp. 13–19 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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often. Curran is given appropriate credit for the concept that pupil block is important in angle closure. Yet, he denied the existence of open-angle glaucoma: “These classes of cases (open-angle glaucoma),... notwithstanding any prevailing opinion to the contrary, I have found to be very few.”2 (p 135). Why was he so sure? I suspect that open-angle glaucoma patients did not present themselves to him with symptoms and when they did, he failed to recognize it as having a relationship with angle-closure, the prevailing concept of glaucoma. But, that would not happen to us in modern times, or would it? By 1948, the Schiøtz tonometer’s new calibration made ophthalmologists think that they had another new solution. Any eye with an IOP of 28-30 mmHg by the tonometry of the day was considered abnormal enough to treat. The findings at the optic disc were recognized as important in glaucoma, but there were few who used the rudimentary visual field measuring approaches (such as those of Bjerrum and Traquair). Even into the 1960s, it took a pretty high IOP to be classified as glaucoma. Despite the gonioscopic separation of open-angle and angle-closure glaucomas, the association of this disorder with a high IOP replaced the association with pain, blurred vision, and shallow chambers. Then, Sloan, Aulhorn, and Goldmann began doing visual fields in a careful way. They found people with visual field defects who looked just like ‘real’ glaucoma at high IOP, but they had normal IOP. Even their optic discs were similar to glaucoma. IOP was ‘normal’ because by then Leydecker, Armaly, and Graham and Hollows had delineated the values present in population-based samples (in Germany, Iowa, and Wales). In European-derived persons, the IOP had a mean around 15 mmHg, and only 2.5% of the population exceeded 21 mmHg by applanation tonometry. Abnormal began to be defined by the upper limits of ‘normality’, and the tyranny of 21 was born. Trouble in paradise

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But, quite soon contradictions began to pile up. Firstly, a large number of subjects who had ‘abnormal’ IOP and were followed without therapy in the Collaborative Glaucoma Study, showed no visual field abnormalities year after year.3 Only about 1% per year of those followed up developed some detectable defect. Paradox #1: how can you be abnormal (with regard to IOP) without developing a disease? In fact, we now know that the majority of those with IOP above the normal number will never develop a disease. Secondly, Drance wrote eloquently about persons with typical open-angle glaucoma damage to the optic nerve and visual field who had levels of IOP that were considered normal by population standards.4 Paradox #2: if glaucoma is a disease of high IOP, how can it happen at normal IOP? There were many who had explanations for this. First of all, there were those who thought that if you just measure the IOP enough times, you will ‘catch’ those with glaucoma at normal IOP ‘spiking’ to an abnormal number. Doing tonometry at home,5 or around the clock, or in various body positions have each enjoyed popularity as explanations for how the IOP can seem normal at the 10 a.m. office visit, but ‘really’ be high enough to explain the glaucoma damage. Then, some said that these eyes did not have glaucoma at all, but had some neurological disorder masquerading as glaucoma. Prior to MRI scanning, this

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approach led to truly medieval torture, including arteriography, pneumoencephalography, and plunging the victim’s hands into freezing water. Even now, the most frequent unnecessary diagnostic testing in ophthalmology is neurological evaluation of glaucoma patients with normal IOP. The vast majority of those with glaucoma at normal IOP have field defects that do not respect the vertical midline, and their discs are excavated, not pale. They simply do not look sufficiently ‘neurological’ to merit this testing. Thirdly, some viewed the glaucoma patient at normal IOP as having glaucoma, but stated that it had nothing to do with the IOP. In fact, some suggested that IOP really had no causative role in any person with glaucoma, and that the IOP increased because of glaucoma damage, instead of the other way around.6 This led to investigations of blood pressure, sedimentation rate, migraine, and other risk factors. Detailed comparisons were made of eyes with glaucoma at lower and higher IOP, to try to find the difference. Since these risk factors are important in glaucoma, this research contributed significantly to the field. Indeed, some modest differences were thought to be characteristic of lower IOP glaucoma eyes, such as larger diameter discs, disc hemorrhages, focal disc damage, and deep, central field defects. But, data from population-based glaucoma surveys for glaucoma brought light to the end of this tunnel (vision).

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The population perspective In Sweden, Wales, and Baltimore,7-9 surveys were conducted on how many had glaucoma in the general population, not just those who presented to an eye doctor’s office. These studies sought to discover who had glaucoma (diagnosed or not), and what it looked like. In order to define glaucoma, we have to decide whether to include IOP in the definition. Each prevalence survey found that subjects with the defined visual field defects, and whose optic discs met glaucoma criteria, were seen to have eyes with IOP higher and lower than the magic number 21 mmHg. This forced a decision: whether to include them all as glaucoma and eliminate IOP from the definition of open-angle glaucoma; or to report, separately, the detection of persons with high-pressure glaucoma and those with low-pressure glaucoma. While some studies split and others lumped, the similarity of the glaucoma eyes above and below the divide was increasingly apparent. In 1985, I was involved with the Baltimore Eye Survey, separating those who had glaucoma and those who did not during a definitive examination. We found that half those with disc and field defects typical for glaucoma had normal IOP. We brought a number of them back for examination on additional days, and about 25% never had an abnormal IOP. This led us and others to begin to define glaucoma without an IOP criterion. So what? What have we learned about glaucoma in the last ten years, and what are the practical consequences of that knowledge? Firstly, the relationship between IOP and glaucoma has been found to be real. In study after study, IOP level is the risk factor as closely linked to glaucoma as age.10 If IOP is high enough, it will damage any eye. Elevated IOP damages an animal optic nerve indistinguishably from

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human glaucoma.11 In fact, increasing the IOP is the only experimental model approach that has ever simulated glaucoma. In every population study, the higher the IOP the more likely the person is to have glaucoma.12 Not only is IOP associated with the presence of glaucoma, but also the higher it is, the more severe the glaucoma is likely to be, even in the normal pressure range.13 Past and recent studies show that the level of IOP during the follow-up of glaucoma is highly correlated with outcome – the lower the IOP, the slower the damage.14 In addition, in a recent clinical trial, therapy that lowered IOP improved the outcome compared to no treatment, even in those whose IOP was on average below 21 at baseline.15 In rats, as in humans, while higher IOP will damage the optic nerve, lowering it is protective.16 So, it has been established that the level of IOP is an important determining factor in who gets glaucoma and how fast it progresses. But, notice that it is the level of IOP, not high IOP, not elevated IOP, and not some particular level of IOP. In fact, if we estimate the risk of developing initial glaucoma damage as a function of IOP,17 the risk increases exponentially from low to high, without any particular break point. In many of our heads, we have conceptualized glaucoma as a disease in which there is no substantial chance of its happening until the IOP is over (the magic) 21. Then, we are energized to wake up, do a field, photograph/image the disc, and start eyedrops. But, in fact, the true situation is a continuous (exponential) increase in risk related to IOP that is never really zero. There is no place to hide, and glaucoma can occur at an IOP of 11. The chance someone will have glaucoma at an IOP of 30 is much higher than the chance at 15 – but, there are so many more people with an IOP of 15 that the absolute number of those with glaucoma at this IOP is really rather large. If this is true, then why do we not see them? Why did Curran think that openangle glaucoma was rare? First of all, they do not present to our offices as often as those with higher IOP. Those with higher IOP get screened into our examination rooms from air puff machines and army discharge physicals. Secondly, they are in our offices and we do not recognize them. Population-based surveys show that those with undiagnosed glaucoma (50% of the US total) are more likely to have lower IOP. Whatever type of eye care professional you are, there are persons with glaucoma, more often with normal IOP, not being identified.18 A recently recognized anomaly related to this issue is the reportedly higher rate of ‘normal-tension glaucoma’ among Asians. Shiose probably first recognized that Japanese persons have lower measured IOP than Europeans.19 But, in reporting the prevalence of open-angle glaucoma, he used the European normal IOP distribution to compare his patients, leading to the amazing conclusion that 80% of open-angle glaucoma in Japanese persons is ‘normal tension’. IOP was indeed lower than 21, the cutoff for European-derived persons, but the 97.5th percentile for Japanese is 18 mmHg. If we wish to make the same mistake in Asians that we have in European/Americans, we should define normal-tension glaucoma in Asia by an IOP of less than 18. It is possible that applanation tonometry underestimates the true pressure in the eyes of Asians, making this an artifact.20 In either case, the absolute level of IOP is irrelevant in a person with glaucoma damage. It does not matter if they have a thick cornea that reads artificially high or a post-LASIK cornea that reads artificially low. The take-home-message of epidemiology is that the actual level of IOP in a newly diagnosed glaucoma patient is irrelevant, except as a baseline for determining the treatment target. The frequency of glaucoma in

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Asians is related to their (measured) IOP distribution in nearly an identical fashion to the same relationship in Europeans; just shifted down 2 mmHg. If this is a tonometric artifact, then we are all susceptible to glaucoma damage at the same hydrostatic forces. If Asians really have lower absolute IOP, they develop openangle glaucoma at the same rate that Europeans do, but at lower IOP. This would mean that their IOP susceptibility is higher, or that other risk factors supplement the risk related to IOP. Clearly, many factors other than IOP are important in causing glaucoma (see Pathogenesis paper in this symposium).

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Baseline-target If you cannot trust 21 mmHg, what can you trust? Jampel wrote a summary of the new approach to glaucoma therapy, the use of baseline and target IOP.21 In past research, the measure of success was often the frequency with which the IOP was reduced to less than 21. If the risk of disease and the risk of progression is a continuous function of IOP with no break point, then this is an erroneous choice for success. For the glaucoma patient who suffers damage at IOP = 19, lowering the IOP to 19 is not success. Rather, we must define the treatment target using IOP that prevails at the time we recognize the glaucoma damage. This may not really be the IOP that caused the damage – that could have been different in the past (higher or lower). But, pragmatically, we can only measure it now, so that is what must be done, and it must be done more than once in order to get a decent estimate. In a given patient, baseline can be anywhere, and it may be different for the two eyes of one person. But, how much below the baseline should we set the target? This concept is new enough that there is insufficient evidence to decide. The practical range is between 20 and 50% lower. Jampel set out a large number of variables for consideration, but there are really only two in most cases – what percentage to lower it from baseline, and should we take the amount of existing field loss into account. As we get the results of more and more clinical trials over the next five years, we will have better data to judge the efficacy of target goals. The Normal Tension Glaucoma Study goal of 30% lowering slowed the progression of glaucoma to half the untreated rate. What is clear is that no longer can we equate good therapy with ‘normalizing the pressure’. Normal IOP is meaningless in setting a target. We must get used to writing down a target (or at least a target range) and assessing therapy by this standard. While we should not be slaves to each decimal point of IOP near the target, neither can we set a target and then ignore it. Congress may do this with budget guidelines, but their deficits do not blind people. We should take the level of injury into account when setting the target, making it lower when there is more field loss. This is logical and is supported by the anecdotal experience of experts like Morton Grant.22 Who cares what the IOP is? Does it ever really matter to know the absolute IOP? It does for the person with no optic nerve damage of the disc or field and who has an abnormal IOP for his/ her ethnicity. In some persons, this may be an artifact of tonometry and routine

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ocular follow-up will show no disease in the long term. Recent efforts have evaluated corneal thickness as an explanation for some of these eyes. But, if the IOP is to be credited as above normal, the ocular hypertensive is at greater risk for lifetime damage, and the person merits more detailed examination than others in the population. The degree to which IOP-lowering therapy is beneficial to this group is the subject of the Ocular Hypertension Treatment Study. I would go so far as to say that there is no such disorder as low-tension or normal-tension glaucoma. Since there is no meaningful dividing line among glaucoma patients by their IOP level, these definitions are patently arbitrary. Schulzer et al. found that glaucoma subjects can be divided into two groups by their clinical features, but that IOP level was not one of the distinguishing features.23 What harm does it do to keep using the term low-tension glaucoma? It is a legitimate research technique arbitrarily to separate glaucoma subjects into stratified groups by IOP level, though IOP data on subjects can be more effectively used as a continuous variable. But, for many ophthalmologists and the patients who listen to them, this ‘diagnosis’ is interpreted to mean that IOP-lowering therapy will be useless or less effective. I encounter many patients who have been told that those with glaucoma at lower IOP will go blind more often. This is simply not supported by any evidence. Secondly, the continued use of the low-tension concept probably perpetuates the mindset that we do not have to look for glaucoma until the IOP is over 21. The undiagnosed 50% will continue to be overpopulated by those with glaucoma at lower IOP. Thirdly, the use of this pseudo-diagnosis is a cause of expensive and terror-provoking neurological evaluations. Patients never get over the fear that a brain tumor may be lurking up there that was somehow missed by the first two imaging studies. Fourthly, arbitrary separation of glaucoma patients into IOP dichotomies frustrates the use of baseline and target pressure approaches. The ultimate irony of dividing glaucoma into two groups by IOP level is that those who study non-IOP-related risk factors in glaucoma decrease their ability to do so by using the low-tension glaucoma concept. Many studies of ocular blood flow in glaucoma patients only look at those with ‘low tension’. As a result, the study fails to evaluate half or more of those with glaucoma. Is it not possible that poor blood flow autoregulation is a contributor in those with higher IOP? I would even argue that this is more likely. By not studying those with IOP over 21, the power of a study to find risk factors is decreased. Some reports do include the higher IOP cases, dividing glaucoma into two groups. Since IOP is a continuous variable, the power to determine whether a risk factor other than IOP is important will be enhanced if IOP is treated continuously or in stratified groups of 5-mm increments. What does it take to change popular beliefs in medicine? How much more data do we need to see that the normal-tension concept is as Neanderthal as ‘glaucoma simplex’ was in the 1930s? There is a lot more to learn about glaucoma, but we should use what we know, now. References 1. Rosengren B: Reprinted from the original 1930 German version as: Studies in depth of the anterior chamber of the eye in primary glaucoma. Arch Ophthalmol 44:523-538, 1950

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2. Curran EJ: A new operation for glaucoma involving a new principle in the aetiology and treatment of chronic primary glaucoma. Arch Ophthalmol 49:131-155, 1920 3. Armaly MF, Krueger DE, Maunder L, Becker B, Hetherington J, Kolker AE, Levene RZ, Maumenee AE, Pollack IP, Shaffer RN: Biostatistical analysis of the collaborative glaucoma study. I. Summary report of the risk factors for glaucomatous visual field defects. Arch Ophthalmol 98:2163-2171, 1980 4. Drance SM: Some factors in the production of low tension glaucoma. Br J Ophthalmol 56:229242, 1972 5. Jensen AD, Maumenee AE: Home tonometry. Am J Ophthalmol 76:929-932, 1973 6. Krakau CE, Bengtsson B, Holmin C: The glaucoma theory updated. Acta Ophthalmol (Kbh) 61:737-741, 1983 7. Bengtsson B, Krakau CE: Automatic perimetry in a population survey. Acta Ophthalmol (Kbh) 57:929-937, 1979 8. Hollows FC, Graham PA: Intra-ocular pressure, glaucoma, and glaucoma suspects in a defined population. Br J Ophthalmol 50:570-586, 1966 9. Sommer A, Tielsch JM, Quigley HA, Gottsch JD, Javitt J, Singh K: Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans: the Baltimore Eye Survey. Arch Ophthalmol 109:1090-1095, 1991 10. Tielsch JM: The epidemiology and control of open angle glaucoma: a population-based perspective. Ann Rev Publ Hlth 17:121-136, 1996 11. Quigley HA, Addicks EM: Chronic experimental glaucoma in primates. II. Effect of extended intraocular pressure on optic nerve head and axonal transport. Invest Ophthalmol Vis Sci 19:137-152, 1980 12. Leske MC, Connell AM, Wu SY, Hyman LB, Schachat AP: Risk factors for open-angle glaucoma. The Barbados Eye Study. Arch Ophthalmol 113:918-924, 1995 13. Cartwright MJ, Anderson DR: Correlation of asymmetric damage with asymmetric intraocular pressure in normal-tension glaucoma (low-tension glaucoma). Arch Ophthalmol 106:898900, 1988 14. The AGIS Investigators: The advanced glaucoma intervention study (AGIS). 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol 130:429-440, 2000 15. Collaborative Normal-Tension Glaucoma Study Group: Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol 126:487-497, 1998 16. Morrison JC, Nylander KB, Lauer AK, Cepurna WO, Johnson E: Glaucoma drops control intraocular pressure and protect optic nerves in a rat model of glaucoma. Invest Ophthalmol Vis Sci 39:526-531, 1998 17. Sommer A: Intraocular pressure and glaucoma. Am J Ophthalmol 107:186-188, 1989 18. Wang F, Ford D, Tielsch JM, Quigley HA, Whelton PK: Undetected eye disease in a primary care clinic population. Arch Intern Med 154:1821-1828, 1994 19. Shiose Y, Kitazawa Y, Tsukahara S, Akamatsu T, Mizokami K, Futa R, Katsushima H, Kosaki H: Epidemiology of glaucoma in Japan: a nationwide glaucoma survey. Jpn J Ophthalmol 35:133-155, 1991 20. Foster PJ, Wong JS, Wong E, Chen FG, Machin D, Chew PT: Accuracy of clinical estimates of intraocular pressure in Chinese eyes. Ophthalmology 107:1816-1821, 2000 21. Jampel HD: Target pressure in glaucoma therapy. J Glaucoma 6:133-138, 1997 22. Grant WM, Burke JF: Why do some people go blind from glaucoma. Ophthalmology 89:991998, 1982 23. Schulzer M, Drance SM, Carter CJ, Brooks DE, Douglas GR, Lau W: Biostatistical evidence for two distinct chronic open angle glaucoma populations. Br J Ophthalmol 74:196-200, 1990

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How much of glaucoma damage is pressure-dependent?

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How much glaucoma damage is pressure-dependent? Paul Palmberg Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, USA

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The dose-response relationship of intraocular pressure and visual field progression How effective is pressure lowering in preventing further visual field loss in openangle glaucoma? How low does the pressure have to be to achieve the maximum benefit? Finally, definitive data have arrived and the answers to these questions will have a major impact on our theoretical understanding of the disease and treatment decisions. The investigators in the Advanced Glaucoma Intervention Study (AGIS) have reported what they found in analyzing the relationship between intraocular pressure (IOP) and visual field loss in 789 eyes followed for six to 11 years.1 The patients in that National Eye Institute (NEI) sponsored clinical trial had, on average, moderate visual field loss, and had failed medical therapy. They were randomized to either initial argon laser trabeculoplasty or initial trabeculectomy without an antimetabolite. Subsequent management was dictated by a detailed protocol. The initial IOP averaged 25 mmHg, and was reduced at one year to about 16 in the surgery group and 17 in the laser group. At seven years’ follow-up, the investigators reported that, in white patients, 34% treated initially with laser had suffered field progression versus 20% treated initially with surgery, while, in black patients, 25% of laser and 24% of surgery patients progressed.2 But those results did not tell the whole story. Now the investigators have provided an additional analysis to delve into the dose-response relationship between IOP and visual field progression in the total group of patients. Of several complex analyses presented in the paper, one is fundamental. In it, the patients were divided, for analysis purposes, into four groups, based upon the percentage of time they achieved an IOP < 18 mmHg. The four groups achieved the goal in either 100%, 75-99%, 50-74%, or less than 50% of visits, respectively. The corresponding mean IOP values of the groups were 12.3, 14.7, 16.9 and 20.2 mmHg, respectively. As can be seen in Figure 1, the lowest pressure group had a flat curve throughout follow-up, meaning that, on average, glaucoma damage was halted. Each sucAddress for correspondence: Paul Palmberg, MD, PhD, Bascom Palmer Eye Institute, University of Miami School of Medicine, P.O. Box 016880, Miami, FL 33101, USA Glaucoma in the New Millennium, pp. 21–27 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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Fig. 1. The relationship between IOP and visual field loss in the Advanced Glaucoma Intervention Study.

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cessively higher pressure group had a correspondingly greater mean progression of field loss. The visual field defect scores were measured in a scoring system particular to the study, AGIS units.3 The mean baseline field defect was 8.4 AGIS units, which corresponded to a mean deviation of -10.5 dB in the more generally understood Humphrey visual field scoring. The comparison of mean change in visual field defect scores for groups of patients in this analysis is far more powerful statistically than would be a comparison of the percentage of patients found to progress by any specific criteria. Any ‘noise’ (variability not due to true progression or true improvement) is cancelled. The AGIS investigators reported that, in the lowest pressure group, 15% of patients would have met their formal criterion for progression, but also, 15% would have moved in the direction of improvement by the same degree. How much was due to noise and how much to a true getting worse or getting better at these pressures? Perhaps a trend analysis, such as that with the Progressor Program developed at Moorfields Eye Hospital, would identify progression in individual cases more reliably, or a random walk through the data in the low pressure group could estimate inherent noise in the testing procedure. The data are currently undergoing further analysis in order to clarify the signal/noise components. What are the implications and limitations of these data? Firstly, they are specific for patients with primary open-angle glaucoma with moderate damage, and do not apply to persons with ocular hypertension only, or to persons with normaltension glaucoma (NTG).

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Fig. 2. The relationship between IOP and the risk of progressive visual field loss at five years.

Patients with ocular hypertension clearly have less sensitivity to IOP, and their dose-response relationship between IOP and risk of visual field loss must be shifted far to the right. We should learn about that relationship when the results of the Ocular Hypertension Treatment Trial are eventually reported. On the other hand, persons with NTG have a greater sensitivity to IOP than is seen in the AGIS data. In the Collaborative Normal Tension Glaucoma Trial, patients with documented field progression or with split fixation were randomized to observation or to treatment aimed to reduce the IOP by 30%. In those in whom a 30% IOP reduction was actually achieved, and after correcting for the effects of surgically induced cataracts upon the fields, the investigators reported that only 20% of treated patients suffered field progression at five years, at an average IOP of 11 mmHg, while 60% of controls had progressed at five years, at an average IOP of 16 mmHg.4 Those results correspond to a shift to the left from the AGIS data. The AGIS data correspond well with the dose-response relationship between IOP and risk of visual field loss in our meta-analysis of other surgery outcome studies. That analysis was first distributed at an American Academy of Ophthalmology regional update meeting in 1988,5 and was then included in the first Preferred Practice Pattern for Primary Open-Angle Glaucoma issued by the American Academy of Ophthalmology in 1989.6 In that guide, I introduced the term ‘target pressure’7 as a way of thinking about glaucoma management in the light of our emerging understanding of the dose-response relationship between IOP and risk of further field loss. The meta-analysis was updated this year8 (Fig. 2) to include our studies of patients undergoing primary filtering surgery with either 5-FU (Table 1) or mitomycin C (Table 2), the NTG study, and earlier results of the AGIS study. In our primary 5-FU and MMC filtering procedure study, we took a group quite similar to the AGIS patients (failure of medical therapy, mean IOP 26 mmHg, baseline Humphrey MD of –14 dB) and reduced the IOP throughout the followup to 10-11 mmHg, with resultant flat curves of both the mean of the mean deviation and the mean of the pattern standard deviation over time, in agreement with the result for the best-controlled IOP group in AGIS. In our data, 17% of patients ‘improved’ and 15% ‘worsened’ from a regrettably single baseline field by 3 dB

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Table 1. IOP and visual field results in our study of primary filtering surgery with 5-FU

Preoperatively One year Two years Three years Four years Five years Six years Seven years

IOP

MD

CPSD

n

26.9 10.7 11.2 10.5 9.3 9.5 9.8 9.4

-13.8 -13.0 -11.2 -12.8 -11.0 -10.1

7.1 6.5 6.0 8.0 5.8 6.0

57 44 37 27 24 30 15 15

IOP: mean intraocular pressure; MD: mean of the Humphrey visual field mean deviation; CPSD: corrected pattern standard deviation; n: sample size Table 2. IOP and visual field results of our study of primary filtering surgery with mitomycin C

Preoperatively One year Two years Three years Four years Five years Six years

IOP

MD

CPSD

n

26.6 11.1 10.2 11.5 11.0 11.3 9.9

-14.6 -13.3 -12.8 -12.9 -13.6 -12.6 -12.9

7.5 7.7 8.0 7.0 6.2 7.5 8.5

117 73 56 60 37 29 15

IOP: mean intraocular pressure; MD: mean of the Humphrey visual field mean deviation; CPSD: corrected pattern standard deviation; n: sample size

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in mean deviation and/or pattern standard deviation, a result seen at one year of follow-up and which remained unchanged for six years. But inspection of sequential fields indicated that only about 5% had an improvement or worsening that exceeded variability. Thus, we conclude that 95% of glaucoma progression in primary open-angle glaucoma is pressure-dependent and avoidable. The one caveat is that, in both AGIS and in our study, only patients who could be followed with Humphrey fields were included, thereby omitting patients with very advanced visual field damage. Patients with milder glaucoma damage, as might be seen at diagnosis, may not be as sensitive to pressure as either the AGIS patients or ours. Such patients were randomized in the Comparison of Initial Glaucoma Treatments Study (CIGTS, NEI) to initial medical treatment or initial surgery, and are currently being studied.9 We should await the results of that study before abandoning the usual practice of trying medical therapy and/or laser trabeculoplasty before using surgery, as the dose-response curve may be shifted to the right for such patients in comparison to the AGIS cohort.

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Implications of the data for our understanding of the mechanism of damage in primary open-angle glaucoma It is surprising that as much as 95% of glaucoma damage has turned out to be pressure-dependent. There was much evidence to indicate that, in glaucoma, IOP might only play a small role. In epidemiological investigations, such as the Baltimore Eye Survey,10 a receiver-operator curve using pressure alone to separate those in the population with glaucoma damage from those without, would indicate that only about 35% of glaucoma damage was due to pressure. Even worse, careful retrospective studies of patients undergoing medical therapy for glaucoma have often found virtually no correlation between IOP and the risk of visual field progression.11,12 How can we reconcile these disparate results? Firstly, we have to distinguish between that part of glaucoma damage which is due to elevated IOP (35%) and that part which is due to abnormal sensitivity to pressure, for which we can apparently compensate by achieving low-normal pressures. Further analysis of our patients operated upon with either 5-FU or mitomycin C indicates that there was no detectable dose-response relationship in the 5-11 mmHg range. Thus, getting down to about 10 mmHg gives the maximum benefit for primary open-angle glaucoma patients. We propose that this result is consistent with the hypothesis of Anderson13 that glaucoma damage is often due to faulty vascular autoregulation in the optic nerve head, occurring either chronically or episodically. Once the IOP is reduced to the level present in the ocular veins, about 10 mmHg, further lowering would not be expected to improve ocular perfusion. However, it would not have been possible to predict the degree to which IOP lowering could compensate for deficient autoregulation. The failure to show a strong correlation of IOP to visual field progression in retrospective studies of medical therapy has been disconcerting, and has led some to doubt that IOP control could play much of a role in slowing field loss in patients with IOPs in the normal range. Now that the AGIS results have shown a strong correlation of IOP to risk of field progression, we can wonder what was wrong with the retrospective study approach to the problem. A likely possibility is that the clinicians who were guiding the therapy of the patients in these studies were treating patients more aggressively who had had greater or more rapid damage in the past, resulting in a levelling of risk. That would be analogous to a handicap golf tournament, in which players are assigned an adjustment in their score based upon past performance, with the intent of equalizing the likelihood of anyone winning. If we were to look at the results of such handicap tournaments, we would conclude that neither the ability of the players, as reflected in the raw scores, nor the handicap assigned, would correlate with the adjusted scores. Similarly, in the retrospective studies, the mean IOP did not correlate with field progression. In addition, in the retrospective studies, patients with advanced damage and elevated pressures were operated upon, thus eliminating the top of a potential dose-response curve between IOP and risk of progression.

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Implications for practice

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In patients with at least moderate visual field loss, in whom medical therapy has failed, I believe a comparison of the AGIS results for surgery without antimetabolites to results for surgery with either 5-FU or MMC favors antimetabolite use. Low normal pressures can be achieved with the use of antimetabolites, and this is not likely to occur without them. The consequence is a marked reduction in the risk of visual field progression from 20% to 5%, and in blindness from 7% to 2%. However, precautions should be taken to reduce the potential complications of antimetabolite use.14 When treating patients medically, the AGIS results suggest that, in patients with moderate to severe glaucoma damage, we should strive to achieve pressures in the low-normal range. This is likely to require the use of multiple medications, and to bring the use of combination therapies into favor. The era in which it was reasonable to place a glaucoma patient with moderate glaucoma damage on a beta-blocker alone, and to observe the course at a pressure in the upper teens (just 25% lower than the initial pressure), should now be over. Except in emergencies, one medication should be added at a time, with one-eye trials being carried out to prove the effectiveness in pressure reduction, but medications should continue to be added until a low normal pressure has been achieved, if feasible, as well as at least a 3050% lowering of IOP. Supplemental laser trabeculoplasty will often be needed to achieve such results. These recommendations are based on results for groups of patients, since we cannot currently determine the true target pressure needed to prevent damage in a particular optic nerve. It would be highly desirable to have an ‘axon screamometer’ that could detect distress in an optic nerve, allowing us to titrate the pressure down just far enough, thus enabling us to maximize the risk/benefit of therapy. However, our enthusiasm for low normal target pressures should be balanced by knowledge of the dose-response curve relating IOP to risk of future damage, and especially by the past history of the patient at hand. The risk of progression in patients with primary open-angle glaucoma and at least moderate damage is about 5% at an IOP of 11 mmHg, 20% at 15 mmHg, 35% at 17 mmHg, and 50% at 20 mmHg. If the next step is surgery, which has risks of cataract progression and infection, the surgeon may reasonably choose to observe carefully at a pressure that is not optimal. If a patient’s visual fields have been stable for five or more years at the current level of IOP, there is even better reason to observe. Just as was shown in the Diabetes Control and Complications Trial for insulindependent diabetes,15 it appears that attempted ‘tight control’ is beneficial in glaucoma as well. However, we must always weigh the benefits and risks of medical and surgical therapy when choosing how to treat an individual patient. References 1. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS). 7: The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol 130:429-440, 2000 2. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS). 4: Comparison of treatment outcomes within race: seven year results. Ophthalmology 105:1046-1064, 1998

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3. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS). 2: Visual field test scoring and reliability. Ophthalmology 101:1445-1455, 1994 4. Collaborative Normal-Tension Glaucoma Study Group: Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol 126:487-497, 1998 5. Palmberg P: The rationale and effectiveness of glaucoma therapy. Distributed at the American Academy of Ophthalmology, Regional Update Meeting, Miami, FL, December 1998 6. Preferred Practice Pattern for Primary Open-Angle Glaucoma, 1989 Edn. San Francisco, CA: American Academy of Ophthalmology 1989 7. Palmberg P: Clinical controversies: target pressures—what are they? In: Leader BJ, Calkwood JC (eds) Peril to the Nerve: Glaucoma and Clinical Neuro-Ophthalmology, Proceedings of the New Orleans Academy of Ophthalmology 1996, Vol 45, pp 87-95. The Hague: Kugler Publ 1998 8. Palmberg P: Target pressure. In: Alm A (ed) The Gullstrand Foundation Meeting. April 1, 2001. CD-ROM. Uppsala: Uppsala University 2001 9. Sommer A, Teilsch JM, Katz J, Quigley HA, Gottsch JD, Javitt J, Singh K: Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans: the Baltimore Eye Survey. Arch Ophthalmol 109:1090-1095, 1991 10. Chauhan BC, Drance SM: The relationship between intraocular pressure and visual field progression in glaucoma. Graefe’s Arch Clin Exp Ophthalmol 230:521-526, 1992 11. Martinez-Bello CM, Chauhan BC, Nicolela MT, McCormick TA, LeBlanc RP: Intraocular pressure and progression of glaucomatous visual field loss. Am J Ophthalmol 129:302-308, 2000 12. Musch DC, Lichter PR, Guire KE, Standardi CL, the CIGTS Study Group: The comparison of initial glaucoma treatments study: study design, methods and baseline characteristics of enrolled patients. Ophthalmology 106:653-662, 1999 13. Anderson DA: Introductory comments on blood flow autoregulation in the optic nerve head and vascular risk factors in glaucoma. Surv Ophthalmol 43(Suppl 1):S5-9, 1999 14. Palmberg P: Surgery for complications of filtering surgery. In: Albert D (ed) Ophthalmic Surgery: Principles and Techniques, pp 476-478. Molde, MA: Blackwell Scientific 1999 15. The Diabetes Control and Complications Trial Research Group: Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Ophthalmology 102:647-661, 1995

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Ocular blood flow and glaucoma

29

Ocular blood flow and glaucoma George A. Cioffi Discoveries in Sight, Devers Eye Institute, Portland, OR, USA

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Introduction Despite extensive investigations into the relationship between the circulation of the eye and glaucoma, there remains substantial debate. The issue becomes more confused when the potential effects, either beneficial or detrimental, of medical therapy are included in the discussion. It is generally believed that circulatory abnormalities occur in greater frequency in individuals with glaucoma, and that vascular insufficiency leads to the development of glaucomatous optic neuropathy. Many studies are based on the premise that the vascular perfusion of the optic nerve or retina can be measured, and that ischemia within these tissues leads to retinal ganglion cell death. In fact, the relative benefit of various therapeutic agents is often evaluated by the perceived influence of the drug on the vascular status of the ocular tissues. When considering the potential effects of topical medications on the eye, there remains controversy regarding the ability of drugs to penetrate the eye and to reach the posterior segment in pharmacologically active levels. There are a myriad of important unanswered questions regarding research into the relationship between ocular blood flow and glaucoma. While investigating potential therapeutic agents that may enhance or diminish the circulatory status of the eye is important, we must remember that there are a series of sequential assumptions upon which all ‘glaucoma blood flow’ studies are based. Only by recognizing these assumptions and by realizing that they are hypotheses not fact, can we evaluate the relevance of the investigations.1 The three common assumptions are: 1. optic nerve ischemia directly causes or increases the susceptibility of the optic nerve to glaucomatous damage; 2. present knowledge of the optic nerve vascular anatomy and physiology allows investigators to identify the vascular beds of importance in this neuropathy; and 3. current measurement techniques provide the ability to monitor these vascular beds. The vascular hypothesis of glaucoma is based upon these three critically important, but unproven, assumptions.2 Experimental investigations examining each of these assumptions will allow a better understanding of the potential role of vascular abnormalities in the development of glaucomatous optic neuropathy. CareAddress for correspondence: G.A. Cioffi, MD, Devers Eye Institute, 1040 NW 22nd Avenue, N200, Portland, OR 97210, USA Glaucoma in the New Millennium, pp. 29–36 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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fully examining our current knowledge of each of these three assumptions will allow better interpretation of a plethora of publications describing vascular phenomena in glaucoma. The relationship between ischemia and glaucomatous optic neuropathy

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Abnormalities in the circulation of blood to the anterior optic nerve have been cited by many investigators as being potential causative factors in the development of glaucomatous optic neuropathy.2-5 There are many clinical reasons to believe that microvascular factors are important. Microvascular diseases, including systemic hypertension, peripheral vascular disease and possibly diabetes mellitus, are associated with glaucomatous optic neuropathy.2,6,7 Studies have shown a higher incidence of systemic vascular diseases, including systemic hypotension,4,8 nocturnal hypotension,9-11 and systemic hypertension,6,12 in glaucoma patients. Systemic hypertension, particularly in its late stages, has been epidemiologically related to glaucoma.13 Disorders associated with vasospasm, such as migraine headache or cold hands and feet, are more commonly seen in patients with glaucoma, both with and without elevated intraocular pressure.14-17 Studies of glaucoma patients have shown abnormalities in blood rheology,3,18-23 with increased blood viscosity and reduced erythrocyte deformability. Additional studies have suggested that the blood flow in the peripapillary region24-30 and the retrobulbar space31-39 is significantly reduced in eyes exhibiting glaucomatous optic nerve damage. In the optic nerve, evidence of decreased blood flow accompanied by visual field damage has been reported in glaucoma patients.40-47 Many of these studies remain controversial, as the validity of the various hemodynamic measurement techniques is still under investigation. The hypothesis that circulatory abnormalities are related to the development of glaucomatous optic neuropathy is well supported by these clinical associations. As reasonable as this hypothesis may be, ischemia has never actually been demonstrated to cause, or even contribute to, glaucomatous optic neuropathy. Direct evidence that ischemia is related to glaucoma, as a causative factor, is lacking. Vascular disease may be merely an associated finding. While the available clinical evidence supports the argument that circulatory anomalies are involved in the development of glaucomatous optic neuropathy, direct evidence that ischemia is related to glaucoma is considerably more suspect. The clinical arguments that vascular insufficiency has a role in the pathogenesis of glaucoma have been well rehearsed by myself and others. The belief that intraocular pressure alone does not account for the development of all glaucomatous optic neuropathy is now commonly accepted. The ischemic hypothesis states that ischemia of the ganglion cell, most likely in the anterior optic nerve, results in ganglion cell death, either directly or in conjunction with other factors. Each of the hypotheses relating ischemia and ganglion cell death provides a potential, yet unproven, mechanism by which apoptotic ganglion cell death may be initiated in glaucoma. We know that acute ischemic damage of the optic nerve (i.e., anterior ischemic optic neuropathy) has a very different clinical appearance from glaucomatous optic neuropathy. The effects of chronic optic nerve ischemia or prolonged blood flow insufficiency have not been documented. Direct evidence of a link between glaucoma and ocular ischemia may require a laboratory model or a more convincing clinical association. If ischemia is related to the development of glau-

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comatous optic neuropathy, certain observations should be possible. Every ‘blood flow’ study is based upon the fundamental assumption that optic nerve ischemia can, either directly or indirectly, cause glaucomatous optic neuropathy. However, the causal relationship between optic nerve ischemia and glaucomatous optic neuropathy remains an attractive, yet unproven, hypothesis.

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The ocular vascular anatomy and physiology related to glaucoma The second assumption may be more mundane, but is no less important. If we propose to monitor circulatory aberrations in the optic nerve that are associated with the development of glaucoma, our understanding of vascular anatomy and physiology must be sufficient to tell us where to look. The anterior optic nerve vasculature is a complex network of blood vessels with a dual arterial supply and a single vessel providing the bulk of venous outflow. The majority of the anterior optic nerve derives its blood from the posterior ciliary arteries, which unfortunately are less accessible to our investigative techniques than the retinal circulation. The complexity of the optic nerve vasculature, the peripapillary choroidal vasculature, and the retinal vasculature has perplexed scientists for more than a century. The possibility of interactions and collateralizations between these vascular beds remains controversial, and the physiological mechanisms that control the blood flow to the anterior optic nerve are still under investigation. At this time, it is unknown whether an increased blood flow volume in one vessel, such as the central retinal artery or ophthalmic artery, has any influence on the health of the optic nerve and the development of glaucomatous optic neuropathy. It is also unknown whether increased blood flow to one vascular bed positively or negatively affects blood flow to the other vascular beds. Continued investigations of ocular vascular physiology and anatomy in health and disease must underpin the interpretation of future ‘blood flow’ studies. The anterior optic nerve may be anatomically divided into four regions: the superficial nerve fiber layer, prelaminar region, laminar cribrosa, and retrolaminar region. Many laboratories have demonstrated that the optic nerve vascular supply varies, depending on the region.5,48-54 The superficial nerve fiber layer is principally supplied from the arterioles in the adjacent retina, which derive from the central retinal artery. The central retinal artery does not usually contribute to either the prelaminar or laminar region, although it may contribute occasional small branches within the retrolaminar optic nerve. The prelaminar, laminar, and retrolaminar regions are supplied by branches of the pial arteries and the short posterior ciliary arteries, both originating from the posterior ciliary arteries. The venous drainage of the anterior optic nerve is almost exclusively via the central retinal vein and its tributaries. Although the vascular anatomy of the anterior optic nerve is now well described in the normal primate (human and non-human) eye, the vascular anatomy in human and experimental glaucoma is not well understood. The capillary beds are anatomically confluent and form a continuous vascular network along the length of the anterior optic nerve. The blood flow within the capillaries of the more anterior regions (the superficial nerve fiber layer, prelaminar region, and laminar region) is normally higher than the blood flow within the posterior regions.55-57 The longitudinal anastomoses of capillaries throughout the

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anterior optic nerve might be viewed as a protective mechanism against regional ischemic insult. However, the blood supply from the posterior ciliary system cannot completely compensate for an experimental occlusion of the central retinal artery.57,58 Part of the reason for this may be the lack of large vessel collateral communication between the two vascular systems in the optic nerve. Moreover, flow resistance may be so high in these fine capillary networks that collateral flow is limited. To maintain adequate perfusion with changes in intraocular pressure, an autoregulatory mechanism is required. Local metabolic and myogenic autoregulation, integrated with the autonomic nervous system and circulating hormones, maintains the blood flow in the anterior optic nerve at a relatively constant level, over a wide range of changes in perfusion pressure. Perfusion pressure is determined by the blood pressure, intraocular pressure, and vascular resistance.5962 Since the density of capillaries within all the regions of the anterior optic nerve does not differ as significantly as the flow rates, it is thought that different regulatory mechanisms may exist in the various regions of the anterior optic nerve. The regulation of blood flow within these various regions and between the two arterial systems (central retinal artery and posterior ciliary arteries) remains poorly understood. The coexistence of glaucomatous optic nerve damage and any physiological abnormalities does not establish a causal relationship. We need to have a better understanding of the vascular anatomy of the anterior optic nerve in glaucoma (human and experimental). We also need to enhance our understanding of the complex regulatory system that governs optic nerve perfusion. Ocular hemodynamic measurement techniques

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The final assumption is that current investigative techniques provide reliable and accurate information about the circulatory status of the optic nerve. If we accept that ischemia is related to the development of glaucomatous optic neuropathy and we establish which vascular beds are important to the health of the optic nerve, do current measurement techniques provide the necessary tools for the assessment of these vascular beds? Non-invasive monitoring of ocular blood flow in humans is an example of technology in need of validation. Over the past two decades, many highly technical methods have been developed to examine in vivo ocular hemodynamics, but the validity of each of these methods has not been fully demonstrated, which has resulted in limited clinical and experimental utility of many of these devices.63,64 Failure to validate these technologies has led to a conceptual stagnation, as unsupportable conclusions have confused our understanding of the relationship between blood flow and glaucoma. These technologies include Doppler ultrasound, laser Doppler flowmetry, and scanning laser angiography. Color Doppler imaging and transcranial Doppler ultrasound are the two principal methods used to assess the retrobulbar hemodynamics. With these techniques, the retrobulbar vessels that contribute to the vascular supply of the anterior optic nerve (ophthalmic artery, central retinal artery, and posterior ciliary arteries) can be imaged. These Doppler techniques measure blood flow velocity within the imaged vessels. Fluorescein fundus angiography is a conventional method used to describe a two-dimensional vascular filling pattern of the retina, choroid, and anterior optic nerve. Fluorescein

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angiography of the optic nerve and peripapillary region has been widely used in the study of glaucoma.45,46 Vascular filling times, similar to blood flow velocity measurements, can also be derived from fluorescein angiography. However, relatively low resolution limits the usefulness of this method. Recently developed scanning laser ophthalmoscopy can be coupled with fluorescein angiography to enhance resolution.63 Laser Doppler flowmetry provides a measure of blood cell velocity in a volume of tissue, and estimates of volumetric blood flow can be derived.65 Laser Doppler flowmetry has also been combined with scanning laser ophthalmoscopy (Heidelberg Retinal Flowmeter) to provide two-dimensional blood flow perfusion maps.66 From these two techniques, volumes of clinical information about the blood flow within the retina and anterior optic nerve of the glaucomatous eye have been derived.29,30,40,41,55,67 However, the reproducibility and the depth of penetration of the these techniques have been points of controversy. Based on in vitro experiments, laser Doppler flowmetry has the potential to penetrate 1000 µm.68,69 Theoretically, scanning laser Doppler flowmetry can measure to a depth of approximately 300400 µm.30,66,70 It remains doubtful whether either of these techniques can penetrate in vivo beyond the superficial layers of the optic nerve.64,71 The importance of a limited depth of penetration is that the vasculature within the lamina cribrosa (potentially the primary site of altered perfusion in glaucoma) may be inaccessible. Only with validation of these machines will we better understand ocular hemodynamics in health and disease. Deciphering the myriad of numerical values produced by these instruments has become a daunting task. In a recent article, Hayreh examined the scope of these techniques, and elucidated questions of validity, reproducibility, variability, accuracy, confounding agents, and clinical pertinence which still exist.64 Does the high variability of measurement techniques limit their usefulness and contribute to the misinterpretation of their measurements? Do measurements reflect only changes in the circulation or do con-founders, such as intraocular pressure variations, alter the measurements? Is blood flow velocity directly, indirectly, or not related to volumetric blood flow in the vessel of interest? These questions are only a few of the current issues under investigation. Presently, there is no single method to assess the circulatory status of the human optic nerve, and familiarity with the technique in question is always necessary to be able to interpret the resulting data. Summary This manuscript is not intended to discourage investigation of the possibility that hemodynamic abnormalities are associated with glaucoma. In fact, I hope to stimulate more intense and rational ‘blood flow’ research. Investigators and observers must remember that the validity of each investigation is based upon acceptance of the assumptions listed above. In the future, each of these assumptions must be validated independently, if hemodynamic-modifying therapy is to be applied in the treatment of glaucoma. However, we must always be willing to accept the null hypothesis, that ischemia and glaucoma are not related.

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References

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1. Cioffi GA: Three common assumptions about ocular blood flow and glaucoma. Surv Ophthalmol 45(Suppl.): S325-331, 2001 2. Cioffi GA, Wang L: Optic nerve blood flow in glaucoma. Sem Ophthalmol 14(3):164-170, 1999 3. Van Buskirk EM, Cioffi GA: Glaucomatous optic neuropathy. Am J Ophthalmol 113:447452, 1992 4. Flammer J: The vascular concept of glaucoma. Surv Ophthalmol 38:S3-6, 1994 5. Hayreh SS: Progress in the understanding of the vascular etiology of glaucoma. Curr Opin Ophthalmol 5:26-35, 1994 6. McLeod SD, West SK, Quigley HA, Fozard JL: A longitudinal study of the relationship between intraocular and blood pressures. Invest Ophthalmol Vis Sci 31:2361-2366, 1990 7. Becker B: Diabetes mellitus and primary open-angle glaucoma. Am J Ophthalmol 71:1-16, 1971 8. Leighton DA, Phillips CI: Systemic blood pressure in open-angle glaucoma, low tension glaucoma, and the normal eye. Br J Ophthalmol 56:447-453, 1972 9. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WL: Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol 117:603-624, 1994 10. Graham SL, Drance SM, Wijsman K, Douglas GR, Mikelberg FS: Ambulatory blood pressure monitoring in glaucoma: the nocturnal dip. Ophthalmology 102:61-69, 1995 11. Meyer JH, Brandi-Dohrn J, Funk J: Twenty-four hour blood pressure monitoring in normal tension glaucoma. Br J Ophthalmol 80:864-867, 1996 12. Tielsch JM, Katz J, Sommer A, Quigley HA, Javitt JC: Hypertension, perfusion pressure, and primary open-angle glaucoma: a population-based assessment. Arch Ophthalmol 113:216221, 1995 13. Sommer A: Doyne Lecture. Glaucoma: facts and fancies. Eye 10(3):295-301, 1996 14. Phelps CD, Corbett JJ: Migraine and low-tension glaucoma. A case-control study. Invest Ophthalmol Vis Sci 26:1105-1108, 1985 15. Gasser P, Flammer J: Blood-cell velocity in the nailfold capillaries of patients with normal-tension and high-tension glaucoma. Am J Ophthalmol 111:585-588, 1991 16. Flammer J, Gasser P, Prünte C, Yao K: The probable involvement of factors other than intraocular pressure in the pathogenesis of glaucoma. In: Drance SM, Van Buskirk EM, Neufeld AH (eds) Pharmacology of Glaucoma, pp 273-283. Baltimore, MD: Williams & Wilkins 1992 17. Orgül S, Flammer J: Headache in normal-tension glaucoma patients. J Glaucoma 3:292-295, 1994 18. Klaver JH, Greve EL, Goslinga H, Geijssen HC, Heuvelmans JH: Blood and plasma viscosity measurements in patients with glaucoma. Br J Ophthalmol 69:765-770, 1985 19. Trope GE, Salinas RG, Glynn M: Blood viscosity in primary open-angle glaucoma. Can J Ophthalmol 22:202-204, 1987 20. Foulds WS: 50th Bowman lecture. ‘Blood is thicker than water’: some haemorheological aspects of ocular disease. Eye 1:343-363, 1987 21. Weinreb RN: Blood rheology and glaucoma. J Glaucoma 2:153-154, 1993 22. Hamard P, Hamard H, Dufaux J: Blood flow rate in the microvasculature of the optic nerve head in primary open angle glaucoma: a new approach. Surv Ophthalmol 38:S87-94, 1994 23. O’Brien C, Butt Z, Ludlam C, Detkova P: Activation of the coagulation cascade in untreated primary open-angle glaucoma. Ophthalmology 104:725-730, 1997 24. Park KH, Tomita G, Liou SY, Kitazawa Y: Correlation between peripapillary atrophy and optic nerve damage in normal-tension glaucoma. Ophthalmology 103:1899-1906, 1996 25. Tezel G, Kass MA, Kolker AE, Wax MB: Comparative optic disc analysis in normal pressure glaucoma, primary open-angle glaucoma, and ocular hypertension. Ophthalmology 103:2105-2013, 1996 26. Yin ZQ, Vaegan, Millar TJ, Beaumont P, Sarks S: Widespread choroidal insufficiency in primary open-angle glaucoma. J Glaucoma 6:23-32, 1997 27. Yamazaki S, Inoue Y, Yoshikawa K: Peripapillary fluorescein angiographic findings in pri-

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mary open angle glaucoma. Br J Ophthalmol 80:812-817, 1996 28. Ulrich A, Ulrich C, Barth T, Ulrich WD: Detection of disturbed autoregulation of the peripapillary choroid in primary open angle glaucoma. Ophthalmic Surg Lasers 27:746-757, 1996 29. Michelson G, Groh MJ, Langhans M: Perfusion of the juxtapapillary retina and optic nerve head in acute ocular hypertension. German J Ophthalmol 5:315-321, 1996 30. Hollo G, Greve EL, Van den Berg TJ, Vargha P: Evaluation of the peripapillary circulation in healthy and glaucoma eyes with scanning laser Doppler flowmetry. Int Ophthalmol 20:7177, 1997 31. Yamazaki Y, Drance SM: The relationship between progression of visual field defects and retrobulbar circulation in patients with glaucoma. Am J Ophthalmol 124:287-295, 1997 32. Hesse RJ: The relationship between progression of visual field defects and retrobulbar circulation in patients with glaucoma. Am J Ophthalmol 125:566-567, 1998 33. Nicolela MT, Walman BE, Buckley AR, Drance SM: Ocular hypertension and primary openangle glaucoma: a comparative study of their retrobulbar blood flow velocity. J Glaucoma 5:308-310, 1996 34. Harris A, Spaeth GL, Sergott RC, Katz LJ, Cantor LB, Martin BJ: Retrobulbar arterial hemodynamic effects of betaxolol and timolol in normal-tension glaucoma. Am J Ophthalmol 120:168-175, 1995 35. Rankin SJ, Walman BE, Buckley AR, Drance SM: Color Doppler imaging and spectral analysis of the optic nerve vasculature in glaucoma. Am J Ophthalmol 119:685-693, 1995 36. Rojanapongpun P, Drance SM, Morrison BJ: Ophthalmic artery flow velocity in glaucomatous and normal subjects. Br J Ophthalmol 77:25-29, 1993 37. Butt Z, McKillop G, O’Brien C, Allan P, Aspinall P: Measurement of ocular blood flow velocity using colour Doppler imaging in low tension glaucoma. Eye 9:29-33, 1995 38. Kaiser HJ, Schoetzau A, Stumpfig D, Flammer J: Blood-flow velocities of the extraocular vessels in patients with high-tension and normal-tension primary open-angle glaucoma. Am J Ophthalmol 123:320-327, 1997 39. Cellini M, Possati GL, Profazio V, Sbrocca M, Caramazza N, Caramazza R: Color Doppler imaging and plasma levels of endothelin-1 in low-tension glaucoma. Acta Ophthalmol Scand Suppl: 11-13, 1997 40. Grunwald JE, Piltz J, Hariprasad SM, DuPont J: Optic nerve and choroidal circulation in glaucoma. Invest Ophthalmol Vis Sci 39:2329-2336, 1998 41. Nicolela MT, Hnik P, Drance SM: Scanning laser Doppler flowmeter study of retinal and optic disk blood flow in glaucomatous patients. Am J Ophthalmol 122:775-783, 1996 42. Michelson G, Langhans MJ, Harazny J, Dichtl A: Visual field defect and perfusion of the juxtapapillary retina and the neuroretinal rim area in primary open-angle glaucoma. Graefe’s Arch Clin Exp Ophthalmol 236:80-85, 1998 43. Schwartz B: Circulatory defects of the optic disk and retina in ocular hypertension and high pressure open-angle glaucoma. Surv Ophthalmol 38:S23-34, 1994 44. Adam G, Schwartz B: Increased fluorescein filling defects in the wall of the optic disc cup in glaucoma. Arch Ophthalmol 98:1590-1592, 1980 45. Schwartz B, Rieser JC, Fishbein SL: Fluorescein angiographic defects of the optic disc in glaucoma. Arch Ophthalmol 95:1961-1974, 1977 46. Hayreh SS, Walker WM: Fluorescent fundus photography in glaucoma. Am J Ophthalmol 63:982-989, 1967 47. Melamed S, Levkovitch-Verbin H: Laser scanning tomography and angiography of the optic nerve head for the diagnosis and follow-up of glaucoma. Curr Opin Ophthalmol 8:7-12, 1997 48. Lieberman MF, Maumenee AE, Green WR: Histologic studies of the vasculature of the anterior optic nerve. Am J Ophthalmol 82:405-423, 1976 49. Olver JM, Spalton DJ, McCartney AC: Microvascular study of the retrolaminar optic nerve in man: the possible significance in anterior ischaemic optic neuropathy. Eye 4(1):7-24, 1990 50. Olver JM, Spalton DJ, McCartney AC: Quantitative morphology of human retrolaminar optic nerve vasculature. Invest Ophthalmol Vis Sci 35:3858-3866, 1994 51. Hayreh SS: Vascular factors in the pathogenesis of glaucomatous optic neuropathy. In: Drance SM (ed) International Symposium on Glaucoma, Ocular Blood Flow, and Drug Treat-

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ment, pp 33-41. Baltimore, MD: William & Wilkins 1992 52. Hayreh SS: The 1994 Von Sallman Lecture. The optic nerve head circulation in health and disease. Exp Eye Res 61:259-272, 1995 53. Hayreh SS: Blood supply of the optic nerve head. Ophthalmologica 210:285-295, 1996 54. Onda E, Cioffi GA, Bacon DR, Van Buskirk EM: Microvasculature of the human optic nerve. Am J Ophthalmol 120:92-102, 1995 55. Geijer C, Bill A: Effects of raised intraocular pressure on retinal, prelaminar, laminar, and retrolaminar optic nerve blood flow in monkeys. Invest Ophthalmol Vis Sci 18:1030-1042, 1979 56. Weinstein JM, Duckrow RB, Beard D, Brennan RW: Regional optic nerve blood flow and its autoregulation. Invest Ophthalmol Vis Sci 24:1559-1565, 1983 57. Wang L, Cioffi GA, Van Buskirk EM, Zhao D-Y, Bacon DR: Comparison of optic nerve blood flow measured with laser Doppler flowmetry and microspheres. Invest Ophthalmol Vis Sci 40(4):1459, 1999 58. Hayreh SS, Weingeist TA: Experimental occlusion of the central artery of the retina. I. Ophthalmoscopic and fluorescein fundus angiographic studies. Br J Ophthalmol 64:896-912, 1980 59. Bill A: Blood circulation and fluid dynamics in the eye. Physiol Rev 55:383-417, 1975 60. Ernest JT: Autoregulation of optic-disk oxygen tension. Invest Ophthalmol 13:101-106, 1974 61. Sossi N, Anderson DR: Effect of elevated intraocular pressure on blood flow: occurrence in cat optic nerve head studied with iodoantipyrine I125. Arch Ophthalmol 101:98-101, 1983 62. Riva CE, Hero M, Titze P, Petrig B: Autoregulation of human optic nerve head blood flow in response to acute changes in ocular perfusion pressure. Graefe’s Arch Clin Exp Ophthalmol 235:618-626, 1997 63. Harris A, Kagemann L, Cioffi GA: Assessment of human ocular hemodynamics. Surv Ophthalmol 42:509-533, 1998 64. Hayreh SS: Evaluation of optic nerve head circulation: review of the methods used. J Glaucoma 6:319-330, 1997 65. Riva CE, Harino S, Petrig BL, Shonat RD: Laser Doppler flowmetry in the optic nerve. Exp Eye Res 55:499-506, 1992 66. Michelson G, Schmauss B, Langhans MJ, Harazny J, Groh MJ: Principle, validity, and reliability of scanning laser Doppler flowmetry. J Glaucoma 5:99-105, 1996 67. Hollo G, Van den Berg TJ, Greve EL: Scanning laser Doppler flowmetry in glaucoma. Int Ophthalmol 20:63-70, 1996 68. Koelle JS, Riva CE, Petrig BL, Canstoun SD: Depth of tissue sampling in the optic nerve head using laser Doppler flowmetry. Lasers Med Sci 8:49-54, 1993 69. Petrig BL, Riva CE, Hayreh SS: Optic nerve blood flow in the rhesus monkey measured by laser Doppler flowmetry: noninvasive assessment of the visual system. Technical Digest Series, Vol 1. Washington, DC: Optical Society of America 1992 70. Harris A, Cantor L, Kagemann L: Imaging of blood flow in glaucoma. In: Schuman JS (ed) Imaging in Glaucoma. Thorofare, NJ: Slack Inc 1997 71. Petrig BL, Riva CE, Hayreh SS: Laser Doppler flowmetry and optic nerve head blood flow. Am J Ophthalmol 127:413-425, 1999

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Microvascular changes of the human anterior optic nerve in glaucoma George A. Cioffi and Da-You Zhao Devers Eye Institute, Portland, OR, USA

Introduction It is hypothesized that anomalies of the optic nerve circulation are involved in the development of glaucomatous optic neuropathy. Circulatory alterations could result from changes in either the vascular anatomy or physiology, or both. The hemodynamic status of the human optic nerve in glaucomatous eyes has been the subject of histological, clinical, and experimental studies. Many investigations have shown potential vascular contributions to the glaucomatous optic neuropathy.1-6 Moreover, the anatomy of the anterior optic nerve vasculature has been investigated using a variety of different techniques.2-11 Selective microvascular corrosion casting techniques have been established as a method for studying the three-dimensional vascular patterns of the anterior optic nerve. This technique has been used to study the microvasculature of the human anterior optic nerve in normal and glaucomatous eyes, using modified methyl methacrylate media to permanently cast the vasculature.2,7 This allows detailed examination of the microvasculature using scanning electron microscopy. Using these techniques, comparisons can be made between the anterior optic nerve in glaucomatous and normal eyes of humans. In addition, the relationship between the microvasculature of the anterior optic nerve and the pre-mortem visual function can be described.

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Techniques Human eye-bank eyes with long retrobulbar optic nerve remnants (approximately 10 mm), allowing identification of the central retinal artery (CRA) and the posterior ciliary arteries (PCAs), are used in selective microvascular corrosion casting experiments. In the present investigation, 11 normal eyes were obtained from six Caucasian donors, ranging in age at the time of death from 63-83 years. Nine glaucomatous eyes were obtained from five patients, 70-88 years of age at the time

Address for correspondence: George A. Cioffi, MD, Devers Eye Institute, 1040 NW 22nd Avenue, Suite 200, Portland, OR 97210, USA Glaucoma in the New Millennium, pp. 37–41 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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of death. The clinical data from the donors was obtained following appropriate informed consent, and all procedures followed the tenets of the Declaration of Helsinki. None of the donors had a history of known systemic vascular diseases, including diabetes mellitus. Previously described techniques were used to selectively cannulate the posterior ciliary arteries and/or central retinal arteries.2,7 Following multiple flushing with tissue plasminogen activator (Activase, Genetech, Inc., South San Francisco, CA), the optic nerve vasculature was filled with modified Batson’s No. 17 methyl methacrylate media12 (Polysciences, Inc., Warrington, PA), which has a viscosity of approximately 11 cPs. After complete polymerization, the tissues surrounding the vascular casts were corroded in 6-M potassium hydroxide. Under a binocular dissecting microscope, the castings were microdissected, mounted, and coated with gold-palladium for examination using electron microscopy. Normal microvasculature of the anterior optic nerve The anterior optic nerve can be divided into four anatomical regions: the superficial nerve fiber layer, prelaminar region, lamina cribrosa, and retrolaminar region. In the prelaminar and lamina cribrosa regions, most of the vasculature is composed of capillaries derived from the posterior ciliary circulation. It is generally believed that the laminar region is the site of insult in glaucomatous optic nerve disease. The central retinal artery has a minimal contribution to this region, and most of the capillary beds are oriented in a lamellar fashion, running parallel to the posterior sclera. In fact, most of the anterior optic nerve is supplied by either direct or secondary branches of the PCAs. Branches from either the circle of ZinnHaller (an anastomotic ring surrounding the optic nerve) or the short posterior ciliary arteries provide the arterial supply to the capillary beds within the prelaminar and laminar regions. In vascular castings from normal eyes (n = 5), the average number of feeding vessels supplying to the anterior optic nerve is 9.6 ± 1.5 and 10.8 ± 1.9 in the superior and inferior quadrant of anterior optic nerve, respectively.

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Anterior optic nerve microvasculature in glaucomatous optic neuropathy A summary of the clinical visual field data of the glaucoma patients can be seen in Table 1. The time from the diagnosis of glaucoma to the time of death in this group of individuals ranged between seven and 19 years. The correlation between visual field changes and the arteriolar supply vessels to the anterior optic nerve is presented in Table 2. The six glaucomatous eyes with complete vascular filling were included in this analysis, in order to allow for quantification of the entire optic nerve. The total number of feeding vessels was diminished to between three and six in the superior and inferior quadrants, which correlated with the most severe visual function loss (Table 2). Capillary dropout mainly occurred within the prelaminar and laminar regions of the anterior optic nerve in the glaucomatous eyes.

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Table 1. Clinical data of the glaucomatous eyes Age (years)

Sex

C/D ratio

Visual fields

70 70 74 74 83 83 81 81 88

M M M M F F F F M

0.6 0.7 0.9 0.5 0.6 0.7 >0.95 0.9 0.7

inferior arcuate loss inferior arcuate loss small central island within normal limitations within normal limitations superior and inferior arcuate loss blind general constriction superior and inferior nasal loss

Table 2. Comparison of the number of feeding vessels with average threshold deviation (dB) on visual field testing in the glaucomatous eyes Feeding vessels (stumps)

1L 3R 6L 9R 9L 10L

VF changes

superior

inferior

5 3 11 4 6 4

8 3 6 5 6 6

inferior central island superior blind constriction superior and inferior nasal

Mean total deviation (dB)/stimulus superior

inferior

total

3.4 23.3 2.7 27.2 9.0 19.2

5.7 24.4 2.5 25.5 7.9 17.8

9.1 47.6 5.2* 52.6 17 37

Using total threshold deviation except for * using pattern threshold deviation

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Discussion Selective microvascular casting studies in normal and glaucomatous anterior optic nerves demonstrate changes in the vasculature, consistent with a variety of previous reports.2-5,13,14,18 In addition, this technique allows precise anatomical description of the microvasculature and quantification of the arterial supply vessels to the anterior optic nerve. The arteriolar supply vessels to the anterior optic nerve can be quantified and compared to pre-mortem optic nerve function. As clinical observations support the theory that arterial insufficiency and decreased blood flow in the anterior portions of the optic nerve are involved in the production of visual field loss in glaucoma,1,15 this technique may allow identification of anatomical anomalies that correlate with functional deficits. In experimental glaucoma, François and Neetens reported that there was a significant reduction in the filling of the capillaries of the retina and choroid, and, in the optic nerve, the reduction was greater on the temporal side of the nerve.5 The results of experimental glaucoma studies are indicative of an alteration of blood flow pattern as one cause of the pathological changes in the optic nerve.5,16 Likewise, Hayreh and colleagues17 found that 70% of choriocapillaris and 67% of temporal peripapillary

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choroids showed moderate to severe atrophy. Using quantitative methods, Quigley and coworkers19 found that loss of nerve fibers leads to capillary loss, and a constant relationship is maintained between the tissue and capillaries in the optic nerve head following complete transection of the optic nerve. This finding was also confirmed in human glaucomatous eyes.13 Jonas and colleagues found that the diameter of the retrobulbar optic nerve decreases with optic nerve atrophy.20 It was suggested that greater retrobulbar optic nerve caliber may indicate a greater structural reserve capacity. Grunwald and associates21 showed that glaucoma patients have a reduced optic nerve blood flow that correlates with the degree of glaucomatous damage. As glaucoma damage is believed to occur at the level of the lamina cribrosa,22,23 alterations in the laminal arterial supply (either anatomical or physiological) may lead to structural laminal changes or direct axonal ischemia. The correlation of a decreased number of arteriolar supply vessels in the quadrant of the optic nerve exhibiting the greatest amount of damage, as determined by visual function loss, suggests that anatomical alterations may proceed function loss. While we would expect loss of the capillaries within a region of neuronal atrophy, retrograde closure of larger supply vessels may represent pre-existing regions at risk for vascular insufficiency. In conclusion, microvascular corrosion castings seem to be an ideal method for studying the three-dimensional microvasculature of the anterior optic nerve. Microvascular changes were found in the anterior optic nerve as well as in the juxtapapillary choroid and retina of glaucomatous eyes. It is possible that hemodynamic changes result from anomalous vascular anatomy and contribute to the pathogenesis of glaucomatous optic neuropathy. Acknowledgments This study was supported by grant No. EY 05231 from the NIH.

References Copyright © 2003. Kugler Publications. All rights reserved.

1. Van Buskirk EM, Cioffi GA: Glaucomatous optic neuropathy. Am J Ophthalmol 113:447542, 1992 2. Zhao DY, Cioffi GA: Microvasculature of the human glaucomatous anterior optic nerve. Eye 14:445-449, 2000 3. Michelson G, Langhans MJ, Groh MJM: Perfusion of the juxtapapillary retina and neuroretinal rim area in primary open-angle glaucoma. J Glaucoma 5:91-98, 1996 4. Nicolela MT, Hnik P, Drance SM: Scanning laser Doppler flowmeter study of retinal and optic disk flow in glaucomatous patients. Am J Ophthalmol 122:775-783, 1996 5. François J, Neetens A: Vascularity of the eye and the optic nerve in glaucoma. Arch Ophthalmol 71:219-225, 1964 6. Wang L, Cioffi GA, Van Buskirk EM: The vascular pattern of the optic nerve and its potential relevance in glaucoma. Curr Opin Ophthalmol 9(2):24-29, 1998 7. Onda E, Cioffi GA, Bacon DR, Van Buskirk EM: Microvasculature of the human optic nerve. Am J Ophthalmol 120:92-102, 1995 8. Hayreh SS: The optic nerve head circulation in health and disease: the 1994 Von Sallman lecture. Exp Eye Res 61:259-272, 1995 9. Zhao Y, Li F: Microangioarchitecture of the optic papilla. Jpn J Ophthalmol 31:147-159, 1987

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10. Olver JM, Spalton DJ, McCartney ACE: Quantitative morphology of human retrolaminar optic nerve vasculature. Invest Ophthalmol Vis Sci 35:3858-3866, 1994 11. Lieberman MF, Maumenee AE, Green WR: Histologic study of the vasculature of the anterior optic nerve. Am J Ophthalmol 82:405-423, 19876 12. Fahrenbach WH, Bacon DR, Morrison JC, Van Buskirk EM: Controlled vascular corrosion casting of the rabbit eye. J Electron Microsci Tech 10:15-26, 1988 13. Quigley HA, Hohman RM, Addicks EM, Green WR: Blood vessels of the glaucomatous optic disc in experimental primate and human eyes. Invest Ophthalmol Vis Sci 25:918-931, 1984 14. Hayreh SS: Blood supply of the optic nerve head and its role in optic nerve atrophy, glaucoma, and oedema of the optic disc. Br J Ophthalmol 53:721-748, 1969 15. Harrington DO: The pathogenesis of the glaucoma field: clinical evidence that circulatory insufficiency in the optic nerve is the primary cause of visual field loss in glaucoma. Am J Ophthalmol 47:177-185, 1959 16. Kalvin NH, Hamasaki DI, Gass JDM: Experimental glaucoma in monkeys. II. Studies of intraocular vascularity during glaucoma. Arch Ophthalmol 76:94-103, 1966 17. Hayreh SS, Pe’er J, Zimmerman MB: Morphologic changes in chronic high-pressure experimental glaucoma in rhesus monkeys. J Glaucoma 8:56-71, 1999 18. Radius RL, Anderson DR: Breakdown of the normal optic nerve head blood-brain barrier following acute elevation of intraocular pressure in experimental animals. Invest Ophthalmol Vis Sci 19:244-255, 1980 19. Quigley HA, Hohman RM, Addicks EM: Quantitative study of optic nerve head capillaries in experimental optic disk pallor. Am J Ophthalmol 93:689-699, 1982 20. Jonas JB, Schmidt AM, Müller-Bergh JA, Naumann GO: Optic nerve fiber count and diameter of the retrobulbar optic nerve in normal and glaucomatous eyes. Graefe’s Arch Clin Exp Ophthalmol 233(7):421-424, 1995 21. Grunwald JE, Piltz J, Hariprasad SM, Dupont J, Maguire MG: Optic nerve blood flow in glaucoma: effect of systemic hypertension. Am J Ophthalmol 127:516-522, 1999 22. Anderson DR, Hendrickson A: Effect of intraocular pressure on rapid axoplasmic transport in monkey optic nerve. Invest Ophthalmol Vis Sci 13:771-783, 1974 23. Quigley HA, Addicks EM, Green WR, Maumenee AE: Optic nerve damage in human glaucoma. II. The site of injury and susceptibility to damage. Arch Ophthalmol 99:635-649, 1981

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Neuroprotection and glaucoma

43

Neuroprotection and glaucoma How do I tell if a drug is neuroprotective?

George A. Cioffi Devers Eye Institute, Portland, OR, USA

Defining neuroprotection While a variety of complex definitions of neuroprotection exist, a simple diagram (Fig. 1) illustrates the concept best. Neuroprotection in glaucoma refers to the ability of a therapeutic modality to prevent the loss, or decrease the rate of loss, of retinal ganglion cells, thereby preventing subsequent loss of visual function. Many drugs have laid claim to being neuroprotective, however, other than lowering the intraocular pressure (IOP), no therapeutic interventions currently used in the treatment of glaucoma have been proven. Proof of neuroprotection requires three important scientific hurdles to be crossed before therapeutic application in humans, as follows: proof of concept; adequacy of drug delivery; and human clinical trials (Table 1). Until these investigative hurdles are overcome, the claim of neuroprotection in the treatment of glaucoma remains suspect.

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Intrinsic and extrinsic factors A multitude of factors, either intrinsic or extrinsic to the optic nerve, alone or in combination, may adversely affect the health and function of the optic nerve.1-8 Potential extrinsic factors that may contribute to the development of glaucomatous optic neuropathy include elevated IOP and aberrations of the systemic cardiovascular status. Factors intrinsic to the optic nerve that potentially contribute to axonal loss, include abnormalities of the composition of the support tissues of the optic nerve, or anomalies of the microcirculatory physiology within the nerve. Some individuals may have optic nerves with particular anomalies of these intrinsic factors, which result in heightened susceptibility to glaucomatous optic neuropathy. Other individuals may possess optic nerves that develop glaucomatous damage primarily as a result of extrinsic insult. Thus, a spectrum of factors should be considered in each individual case of glaucoma. Address for correspondence: George A. Cioffi, MD, Devers Eye Institute, 1040 NW 22nd Avenue, Suite 200, Portland, OR 97210, USA Glaucoma in the New Millennium, pp. 43–48 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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Fig. 1. Neuroprotection changes the slope of retinal ganglion cell (RGC) death. Drug X: any therapeutic modality. Table 1. Three criteria for neuroprotection 1 2 3

Proof of concept cell death pathways and models of ‘glaucoma’ Drug delivery site of action and pharmacological doses Human clinical trials endpoints, progression rate, study population

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IOP plays a major role in the development of glaucomatous optic neuropathy in many subjects. One hypothesis of the etiology of glaucoma proposes that neuronal damage results from mechanical pressure on the optic nerve. This hypothesis focuses primarily on the potential deleterious effects that elevated IOP has on the extracellular matrix and glial support structures of the anterior optic nerve. It suggests that there is direct, mechanical insult, which results from IOP being increased above a tolerable threshold. The IOP causes backward bowing, stretching, and compression of the laminar plates within the lamina cribrosa. Misalignment of the fenestrations within the lamina cribrosa and compression of the connective tissue plates results in the inhibition of axoplasmic flow within the axons of the ganglion cells. Interruption of axoplasmic flow or direct mechanical compression of the neural axons causes death of the nerve cells and results in glaucomatous optic neuropathy. This extrinsic, pressure-induced hypothesis of glaucomatous optic neuropathy is supported by both laboratory models of glaucoma and clinical observations. Increased IOP in non-human primate models causes obstruction of axoplasmic flow in the laminar region. Histology of such primate eyes demonstrates posterior bowing of the lamina cribrosa, with compression of the connective tissue plates and distortion of the laminar fenestrae. Transverse sections through the lamina cribrosa have documented the increased size of laminar fenestrae in the superior and inferior poles of the optic nerve. These regional differences of the lamina cribrosa may account for asymmetric mechanical damage to the axons within the various regions. In early glaucomatous optic neuropathy, damage to the ganglion cell axons primarily occurs in the superior and inferior regions of the optic nerve.

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Histology shows non-uniform distribution with increased numbers of large ganglion cell axons in the inferior and superior poles of the optic nerve. Large ganglion cell axons appear to be preferentially damaged early in glaucomatous optic neuropathy. This apparent increased susceptibility of the large cell axons may be due to the relative distribution of these axons within the regions of the optic nerve, which are primarily distorted by mechanical forces. Other glial support tissues within the optic nerve also show changes in glaucomatous optic neuropathy. Extracellular matrix components, including elastin fibers of the lamina cribrosa, are altered in glaucomatous eyes and in experimental models of glaucoma. These changes may be the result of increased IOP with concomitant mechanical stress, and may be associated with axonal death in glaucoma. However, accumulating epidemiological and laboratory evidence demonstrates that elevated IOP is not the sole cause of optic nerve injury in glaucoma. As many as 20-30% of individuals with glaucoma never exhibit statistically elevated IOP, and among individuals treated for glaucoma, approximately 20-30% continue to lose vision despite maximal IOP-lowering therapy. These findings highlight the need for neuroprotection and have stimulated the investigation of alternative hypotheses. A commonly cited hypothesis proposes that intraneural ischemia leads to the development of glaucomatous optic neuropathy. This hypothesis proposes that vascular perfusion of the neural tissue within the optic nerve is deficient in glaucoma. Vascular perfusion is dependent upon arterial blood pressure, venous outflow, tissue pressure surrounding the vasculature, autoregulation, and local and regional vasomodulators. Insufficiency or abnormality of any or all of these components may result in regional ischemia. In laboratory studies, axoplasmic flow of the ganglion cell axons is obstructed by interrupting the short posterior ciliary artery circulation to the optic nerve. This may lead to ganglion cell death similar to that found with mechanical compression. Autoregulatory mechanisms within the regional vascular beds are believed to accommodate changes in arterial blood pressure in normal individuals. However, deficient autoregulation of the optic nerve vasculature would result in decreased optic nerve perfusion. The vascular hypothesis suggests that elevated IOP results in increased tissue pressure within the optic nerve tissue surrounding the vasculature. This causes vascular collapse and decreased neural perfusion, resulting in glaucomatous optic neuropathy. Increased tissue pressure from elevated IOP is only one possible cause of decreased vascular perfusion of the optic nerve. Individuals with glaucoma are more likely to have systemic vascular disorders, including diabetes mellitus, systemic hypertension, peripheral vascular disease, and vasospastic syndromes. These associations between extrinsic vascular factors and glaucoma support a vascular etiology in the development of glaucomatous optic neuropathy. Glaucomatous optic neuropathy likely derives from many potential insults working independently or in concert. A combination of the various intrinsic and extrinsic factors may contribute to varying degrees in each individual. Many possible scenarios can be considered. Increases in IOP with mechanical distortion of the optic nerve may result in increased tissue pressure on the microvasculature of the optic nerve and decreased perfusion of the neuronal tissue. Mechanical distortion of the lamina cribrosa fenestrae could directly compromise ganglion cell axons, rendering them more susceptible to damage from an insufficient vascular supply. Further studies examining changes in the compliance and structure of the optic nerve resulting from increased IOP should increase our understanding of the

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mechanical component of the development of glaucomatous optic neuropathy. Beyond these studies, investigations into potential neuroprotective therapies offer the promise of halting progressive vision loss in glaucoma. Perhaps the most important contribution of these types of investigations is that novel targets for therapeutic intervention can be developed and investigated. These potential therapies must then meet each of the three criteria (Table 1) in order to prove their therapeutic benefit. Three important considerations Proof of concept, drug delivery and clinical trials

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With advances in molecular and cellular biology, understanding of the mechanisms that may lead to neural damage has expanded enormously. Apoptosis (programmed cell death without necrosis) has been cited as a potential pathway of retinal ganglion cell death in both human glaucoma and experimental primate glaucoma associated with elevated IOP.9-11 Apoptosis is a cell death pathway in which a complex cascade of cellular events occurs (including nuclear clumping, DNA condensation, cellular shrinkage and involution, and finally macrophage engulfment without inflammation).12-15 As the genetic information necessary for apoptosis exists in neural cells, the question arises as to what is the initiating signal that leads to this terminal cascade of events. Potential initiating signals of apoptosis in central nervous system diseases include growth factor deprivation (Fig. 2), excitotoxicity (Fig. 3), oxygen-free radical production, nitric oxide synthesis, and abnormalities of calcium metabolism. In the eye, growth factor deprivation of retinal ganglion cells (the ‘neurotrophic hypothesis’) results from blockade of retrograde transport at the lamina cribrosa preventing growth factors from reaching their site of action in the cell body.16,17 Calcium and oxygen-free radicals influence biological pathways that can damage the optic nerve. Increased levels of intracellular calcium may damage neurons by stimulating catabolic enzymes or oxygenfree radical production.18 Oxygen-free radicals, such as superoxide ion and hydroperoxyl radical, have unpaired electrons that make them highly reactive.19 Following transient ischemia, these molecules are commonly liberated resulting in ‘re-perfusion injury’. Oxygen-free radicals preferentially damage the mostly unsaturated lipid cell membranes of neural tissues. Aberrant nitric oxide synthesis has also been demonstrated within the glaucomatous anterior optic nerve.20 Neuroscience has provided us with a variety of novel targets to aim our potential therapeutic agents at. Claims of neuroprotection that do not focus on one of the known pathways of neuronal cell death should be viewed with skepticism. “Does the therapy make sense, given our current knowledge of neuronal cell death pathways?” should be the first question when determining whether a new claim of neuroprotection is valid. Caution should be used when extrapolating from in vitro or animal experiments and clinically applying the findings to human disease. Proof of concept allows selection of the most promising drugs for further investigation and human clinical trials. The adequacy of drug delivery is the next important issue that should be considered when determining whether a drug is neuroprotective. Does the drug reach the target tissue? It is commonly assumed that topically applied medication reaches the posterior segment of the eye and exerts effects (either beneficial or detrimental)

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Fig. 2. Neurotrophic hypothesis. RGC: retinal ganglion cells; GF: growth factor.

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Fig. 3. Glutamate excitotoxicity.

on the retina and optic nerve. However, evidence that topical medications reach the posterior segment in pharmacologically appropriate dosages is lacking and, at times, conflicting. Most available evidence indicates that topically applied medications have highly variable penetration to the posterior pole, while many systemic medications reach the optic nerve and retina. However, the integrity of the bloodretinal barrier and the blood-brain barrier may limit the amount of drug present in the target tissues, even following systemic administration. Drug concentrations sufficient for the proposed mechanism of action at the site of action must be demonstrated. Human clinical trials are the final hurdle that must be cleared in order to establish proof of neuroprotection. Due to high costs, long duration, large sample sizes, difficulties of study protocols, and ill-defined endpoints, this hurdle is by far the most difficult to overcome. While traditional pharmaceutical trials in glaucoma

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have used the surrogate marker of IOP to assess the adequacy of therapy, definitions of optic nerve structural and functional endpoints have lagged behind. Regulatory agencies and pharmaceutical companies alike have struggled to establish appropriate and meaningful guidelines for these trials. In addition, glaucoma is a very slowly progressive disease. This slow rate of progression mandates large study populations and lengthy study durations in order to test potential neuroprotectants. This translates into very expensive investigations, and limits the number of agents that can be examined. While basic science proof of concept and adequate drug delivery are important considerations in determining the potential of a neuroprotective agent, human clinical trials remain the gold standard for determining efficacy. References

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1. Schumer RA, Podos SM: The nerve of glaucoma. Arch Ophthalmol 112:37-44, 1994 2. Cartwright MJ, Crajewski AL, Friedberg ML et al: Immune-related disease and normal tension glaucoma: a case control study. Arch Ophthalmol 110:500, 1992 3. Drance SM: Some factors in the production of low tension glaucoma. Br J Ophthalmol 56:229, 1972 4. Hayreh SS: Pathogenesis of optic nerve damage and visual field defects in glaucoma. Doc Ophthalmol Proc Ser 22:89, 1980 5. Hernandez MR, Luo XX, Igoe F et al: Extracellular matrix of the human lamina cribrosa. Am J Ophthalmol 104:567, 1987 6. Quigley HA, Hohman RM, Addicks EM et al: Morphologic changes in the lamina cribrosa correlated with neural loss in open-angle glaucoma. Am J Ophthalmol 95:673, 1983 7. Quigley HA, Addicks EM: Chronic experimental glaucoma in primates. II. Effect of extended intraocular pressure elevation on optic nerve head and axonal transport. Invest Ophthalmol Vis Sci 19:137, 1980 8. Quigley HA, Addicks EM: Regional differences in the structure of the lamina cribrosa and their relation to glaucomatous optic nerve damage. Arch Ophthalmol 99:137, 1982 9. Quigley HA, Nickells RW, Kerrigan LA, Pease ME, Thibault DJ, Zack DJ: Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci 36:774-786, 1995 10. Quigley HA: Neuronal death in glaucoma. Progr Retin Eye Res 18:39-57, 1999 11. Kerrigan LA, Zack DJ, Quigley HA, Smith SD, Pease ME: TUNEL-positive ganglion cells in human primary open-angle glaucoma. Arch Ophthalmol 115:1031-1035, 1997 12. Wyllie AH: Apoptosis: an overview. Br Med Bull 53:451-465, 1997 13. Wyllie AH, Kerr JF, Currie AR: Cell death: the significance of apoptosis. Int Rev Cytol 68:251306, 1980 14. Kerr JF, Gobe GC, Winterford CM, Harmon BV: Anatomical methods in cell death. Methods Cell Biol 46:1-27, 1995 15. Kerr J, Nelson P, O’Brien C: A comparison of ocular blood flow in untreated primary openangle glaucoma and ocular hypertension. Am J Ophthalmol 126:42-51, 1998 16. Olney JW, Sharpe LG: Brain lesions in an infant rhesus monkey treated with monosodium glutamate. Science 166:386-388, 1969 17. Sucher NJ, Lipton SA, Dreyer EB: Molecular basis of glutamate toxicity in retinal ganglion cells. Vision Res 37:3483-3493, 1997 18. Choi DW: Glutamate neurotoxicity and disease of the nervous system. Neuron 1:623-634, 1988 19. Kontos HA: Oxygen radicals in CNS damage. Chem Biol Interact 72:229-255, 1989 20. Neufeld AH, Hernandez MR, Gonzalez M: Nitric oxide synthase in the human glaucomatous optic nerve head. Arch Ophthalmol 115:497-503, 1997

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The true nature of angle-closure glaucoma

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The Angle

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The true nature of angle-closure glaucoma Harry A. Quigley Glaucoma Service and Dana Center for Preventive Ophthalmology, Wilmer Ophthalmological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Introduction It is only during the last 100 years that we have begun to differentiate the various types of glaucoma. Important insights into angle-closure glaucoma came from E.J. Curran, a Kansas eye physician, who proposed the concept that pupillary block led to high eye pressure, and described how small holes in the iris would alleviate it.1 In 1931, Rosengren noted that there were two populations among those with glaucoma: one group had high intraocular pressure (IOP), pain, and shallow anterior chambers; the second had normal chamber depth, what was considered normal IOP, and were asymptomatic.2 Through his development of gonioscopic observation, Otto Barkan supported the idea that narrowness of anatomical structure predisposes to outflow obstruction in angle closure.3 Most ophthalmologists have a sense of confidence that we understand angle-closure glaucoma, and, with laser iridotomy, we have a rapid cure.

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So, what is the problem? This essay questions our understanding of the pathogenesis of primary angleclosure glaucoma (PACG). In the simplest terms, I propose that the events leading to pupillary block include forces that move the vitreous and lens forward, and that are additive to relative pupillary block. Observations of the behavior of angleclosure eyes at later cataract surgery show that these forces are still present after iridotomy, but most often they fail to cause a recurrence of acute angle closure. The nature and contribution of this ‘extra-pupillary’ mechanism requires further research. Study of PACG is timely, since it has recently been recognized to represent as much as half the glaucoma in the world4 – and, it causes proportionately more visual disability than its open-angle cousin.5,6

Address for correspondence: Harry A. Quigley, MD, Wilmer 122, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287, USA. e-mail: [email protected]

Glaucoma in the New Millennium, pp. 51–63 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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Definitions for angle closure

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Here, I will use some newer definitions for angle closure that were recently suggested at Worldwide Glaucoma 2000, a meeting co-sponsored by the World Health Organization (Baltimore, MD; May, 2000). The meeting summary is available on the Wilmer web site (www.wilmerinstitute.net). In the formulation proposed, there are three categories of angle-closure: narrow-angle, primary angleclosure, and primary angle-closure glaucoma. Narrow-angle (NA) is defined as a bilateral condition in which the gonioscopic view of the angle with a Goldmann-type lens shows no view of the posterior (pigmented) trabecular meshwork through three-fourths or more of the angle. The gonioscopy is conducted with the eye in the primary position and without any attempted indentation of the cornea artificially to deepen the angle. In order to be classified as narrow-angle only, the person must not have an abnormality of the IOP, optic disc, visual field, or have peripheral anterior synechiae or other signs of past acute attacks (iris atrophy, iris spiralling of vessels, or anterior lens opacity). For this definition, abnormality in IOP or cup/disc is defined as the value that exceeds the 97.5th percentile value for the population to which the person belongs. For European-derived people, this would be 21 mmHg, or a cup of 0.7. Visual field abnormality is defined by the Zeiss-Humphrey threshold test with ‘outside normal limits’ on the glaucoma hemifield test (GHT) or a pattern standard deviation (PSD) probability < 5%. Primary angle-closure (PAC) is defined as a person with bilateral narrow angle (as above) and at least one of the following: C IOP above the 97.5th percentile for the population C peripheral anterior synechiae for at least one clock hour C history of, or observed past, acute attacks, defined as bilateral narrow-angle with an episode of documented IOP more than twice as high as the 97.5th percentile value for the population in one eye, often but not necessarily associated with ocular pain, decrease in vision, and conjunctival redness C signs of past acute attacks (iris atrophy, spiralling, anterior lens opacity) C cup/disc ratio exceeding the 97.5th percentile for the population, but a normal visual field Primary angle-closure glaucoma (PACG) is defined as a person with bilateral narrow angle and glaucomatous optic nerve damage in at least one eye, which is defined as a cup/disc exceeding the 97.5th percentile and the presence of a ZeissHumphrey visual field defect as described above. These definitions adhere to two basic ideas. Firstly, that primary glaucoma is a term only applied to eyes with damage to the optic nerve (field loss with a compatible disc change). Secondly, that qualifying terms for PACG such as intermittent, chronic, plateau iris, creeping, or subacute, imply more knowledge of the natural history than we have at this time; hence, they are not to be used. The tyranny of gonioscopy While gonioscopy confirmed the dichotomy between PACG and open-angle glaucoma, we have become slaves to angle observation, which has limited clinical predictive value and provided almost no pathogenic information. When the angle

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is closed by peripheral anterior synechiae, higher IOP can be expected. But, none of our present clinical tools allows the differentiation of persons who will develop a disease from persons who will not, among all those with NA. There are ten persons with narrow angles for every one with PACG.5 Gonioscopy is only moderately successful in specifying the angle associated with a future disease, regardless of which grading system is used. Shaffer’s gonioscopic grades give a single value for angle width, while Spaeth’s system separately describes the position of iris insertion, the angle width, and the shape of the peripheral iris. How likely is it that a Shaffer Grade 1 angle will occlude? Does it matter whether we describe the position of iris insertion as in Spaeth’s system? This might be determined by longitudinal follow-up of a large number of persons thought to be at risk for PAC or PACG, who could be followed without therapy after gonioscopic grading. There have been few prospective studies of the power of gonioscopy to predict the development of PACG.7,8 Gonioscopy is all we have, but it is inherently anatomical and static, when we need to predict the physiological behavior of the eye. As an analogy, imagine that someone you cannot see is pushing a car over a cliff. You are down below trying to determine if it will fall, but all you are measuring is the amount of car hanging over the edge at that time. To be sure, the more car you can see, the more likely disaster is to strike, but it is the unseen force pushing the car that will determine the outcome. It is the unseen forces that are behind the angle that we should be attempting to estimate, and gonioscopy does not provide that information. The risk factors for PACG include smaller axial length, smaller cornea, shallower anterior chamber, larger lens diameter, and hyperopia. These all logically fit with a predisposition for crowding of the anterior ocular structures. Some investigators have tried to improve on gonioscopy with newer technology to measure critical anatomical features. These include ultrasonic biomicrosopy, Scheimpflug photography, and pachymetry of the anterior chamber by ultrasound and optical methods. To date, these are only fancier methods to measure how much of the car is hanging over the cliff. In his lecture to the Worldwide Glaucoma 2000 meeting, the noted observer of angle closure, Poul Helge Alsbirk quoted Ronald Lowe, one of those who spent his life on this disorder, as saying: “I believe that the big remaining problems of angle-closure glaucoma will be little assisted by further biometry, as they have a disturbed physiological basis.” It isn’t all acute attacks An acute attack of angle closure is impressive, with its pain, vision loss, corneal edema, and high IOP. Yet, in population-based studies, acute angle-closure attacks are far less common than asymptomatic PACG.5,8,10 But, these surveys looked at a group at one point in time. It could be that there are more acute attacks that are missed in population surveys. How might these unrecognized acute cases of PACG have been missed? Firstly, if the attacks were associated with some fatal condition, persons who suffered attacks might be ‘missing’ from the population due to selective death. However, a selectively greater mortality than the general rate is not found among those with glaucoma. Secondly, acute attacks could go undetected. But, attacks typically leave visible scarring and atrophy. If attacks occur without symptoms, and resolve without detectable iris or lens damage, the eye would

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have asymptomatic peripheral anterior synechiae and, ultimate nerve damage in a quiet eye. This merely describes the mechanism of PACG, and becomes a circular argument. Since there are many more persons with PACG than there are those who have had an acute attack (considered here a form of PAC), screening for PACG could be effectively carried out by looking for optic nerve damage. This means that methods being tested to screen for open-angle glaucoma will identify many of those with PACG as well – a welcome bonus. There is more to PACG than meets the eye-ridotomy

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We were taught that pupillary block explains all the important aspects of PAC and PACG. After all, a hole in the iris has some benefit in these conditions. Laser iridotomy is relatively easy to perform and has few long-term complications. But, if all persons with NA were given iridotomy, and the relative proportion of NA to PACG is really 10:1, then iridotomy would look as if it had a 90% cure rate, even if it were totally worthless. As described above, a longitudinal study of at-risk eyes is needed to determine who will benefit from iridotomy. It is interesting to speculate on how many iridotomies are needed for the USA, based on a population at the last census of 76.7 million persons over the age of 50 years. A recent population study in Europeans can be used to calculate the incidence of PACG from its prevalence.9 The estimate of 29 new cases/100,000/year leads to the suggestion that 44,000 iridotomies would be appropriate to cover all those with PACG (two eyes per person). Additional iridotomies might be appropriate for those whose risk was sufficiently high. Medicare data suggest an estimated 57,000 iridotomies in 1999 among those over the age of 65 years in the USA (unpublished data kindly provided by Anne Coleman, MD, PhD). Yet, as we evaluate those who have been ‘cured’ by iridotomy, there are bothersome observations that indicate that everything is not normalized. These observations can be placed in three groups: C 1. some eyes continue to get worse, despite iridotomy; C 2. some eyes still have acute attacks with a patent iris hole; C 3. some eyes, particularly PAC eyes, even those that have had iridotomy, have a tendency for forward iris-lens movement during cataract removal. A progressive course after iridotomy could result from a variety of circumstances. The diagnosis could have been incorrect, and the subject has open-angle glaucoma, or the subject could have both types of glaucoma. Secondly, many of those who have iridotomy for an acute attack need subsequent trabeculectomy.11 Most likely, these eyes had permanent angle damage and iridotomy came too late. But, some observers propose that the angle continues to form permanent, new synechiae despite iridotomy, referred to as ‘creeping’ angle closure. There are no well-documented gonioscopic follow-ups of PAC patients that show what proportion have increasing synechiae after iridotomy. Since the same IOP control problem could arise from damage sustained prior to iridotomy, specific evidence for progressively more synechiae is needed to support this mechanism. It is not enough to cite that there is sometimes poor IOP control or the perceived need for trabeculectomy. The impetus leading to more angle closure

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could be forces leading the iris and lens to move anteriorly, despite elimination of relative pupillary block (see below). I examined 140 consecutive eyes that underwent iridotomy and found that the angle grade had widened in 68% of eyes.12 Subsequently, with much better quantification, Lee et al.13 found that the peripheral chamber deepens after iridectomy, i.e., the peripheral iris convexity flattens. But, they and others14 have conclusively shown that the position of the lens relative to the cornea does not change with iridotomy. In other words, the central chamber depth is unchanged by iridotomy. While 30 of the eyes in my follow-up study had had past acute attacks, and others had had positive mydriatic provocative testing, none had IOP elevations when the pupil was dilated after iridotomy. So, iridotomy did eliminate the component of their disease related to the iris, without changing the lens position. As we will see, the position of the lens in the antero-posterior axis is very important in generating critical pupil block. The flattening of the peripheral iris does not happen in every NA, PAC, or PACG eye after iridotomy. In my experience, most eyes that retain a narrow appearance after iridotomy do not have recurrent acute attacks. Some refer to such eyes as having a plateau iris configuration. One possible explanation for this appearance is ciliary processes that are more anterior than normal, and this has been observed by ultrasound biomicroscopy.15 Among those with plateau iris configuration after iridotomy, an even smaller number develops repeat attacks of high IOP with pupil dilation. These are referred to as plateau iris syndrome. No detailed study of these eyes compared to other plateau iris eyes has demonstrated risk factors that explain this behavioral difference. While some claim that plateau iris syndrome is common, my experience is that it is not. In general, iridotomy prevents sudden, episodic IOP increase in eyes that have NA. How does it do this? Tiedeman16 wrote a most lucid description of the reasons that the iris assumes a convex shape. He assumed that the forces acting on the iris derived from five basic structural/physiologic facts: 1. the iris is fixed at its root; 2. the iris sphincter produces a force acting inward (perpendicular to the optical axis and toward it); 3. the iris dilator produces a force acting outward (opposite the sphincter); 4. there is a hydrostatic pressure both in front and behind the iris; and 5. position of the lens antero-posteriorly determines the corresponding position of the pupil. By using fairly elementary physics, he modeled the likely shape of the iris in two and three dimensions. He stated that the pressure in the posterior chamber would be higher than that in the anterior chamber (otherwise no fluid would move through the pupil from back to front). This pressure differential combined with the resistance to flow through the pupil would determine the aqueous flow rate. His model for iris shape led to several important facts. Under nearly every condition in which there is a lens in the eye and in which the iris has only the pupil opening (no iridectomy), the iris assumes a convex shape. Using the imaging method called Scheimpflug photography, Anderson et al.17 found that the predictions of Tiedeman’s model fit the actual shape of the iris under a variety of conditions in real eyes. Furthermore, Tiedeman predicted that the more anterior the position of the pupil relative to the iris root, the more convex its shape. The most convex profile would occur at mid-dilation, with flatter shapes at both a smaller and a larger pupil diameter. He stated some facts that are clearly true, but which may surprise many ophthalmologists. We frequently hear that the iris ‘rests on the

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lens’. In fact, the lack of exfoliative deposits on the middle of the lens (compared to its central polar area or its periphery, where the deposits do collect) is often cited as evidence that the iris rubs off the deposits here. Certainly, the iris could, and probably does, come into contact with the lens at some time. A further illustration of this is the transillumination defects seen in pigment dispersion syndrome, which result from iris contact with the zonule in eyes predisposed to this phenomenon. But, under normal conditions and even in angle-closure glaucoma eyes, there is always flow through the pupil and no iris lens contact. The narrow zone between the iris and lens contributes to the resistance to aqueous flow through the normal pupil. If there were no resistance to flow, or if the pressure in the anterior and posterior chambers were equal, the iris would not be bowed forward (convex). Under what conditions might the pressure in the anterior and posterior chambers be equal? With an iris hole somewhere away from the pupil, this would occur. Clinical experience cited above confirms that this is true, and Jin and Anderson showed it to be the case photographically.18 Interestingly, we might consider what happens during an acute attack of angle closure. In this setting, the iris configuration becomes convex forward to such an extent that the iris contacts the trabecular meshwork, obstructing it to varying degrees. The degree of contact needed to produce a significant IOP rise must differ among eyes, but there is not reason to think that all the meshwork must be occluded, or that flow stops completely. In fact, if flow did stop, pressure in the posterior and anterior chamber would become equal, the iris would assume a flat configuration, and the attack would be broken. Hence, in the middle of a continuing attack, it is quite likely that flow does not stop completely, and that some outflow is ongoing (not 100% angle closure). One prediction of Tiedeman’s model that is not intuitively obvious is that the shape of the iris is not dependent upon the actual tension in the iris dilator and sphincter, nor, probably, is it dependent upon the thickness of the iris stroma. Tiedeman assumed for the model that the iris stroma exerted no relevant force to determine iris shape, and only the iris musculature contributed. This seems to be a reasonable judgment, considering how loose the iris connective tissue is. In reality, the model predicts that, if the iris components of the model are strengthened (e.g., if the stroma is thicker and exerts itself into the equation), the convex shape of the iris is unaffected, but the pressure differential between posterior and anterior chamber increases proportionately. While this has not been measured in vivo in an eye, a laboratory model of iris, pupil and lens was studied by Wyatt and Ghosh,19 using a latex membrane simulating the iris and a ball for the lens. The behavior of this model fits in every way with the Tiedeman equations. Moreover, they tried doubling the thickness of the latex membrane and found that, as predicted, the shape of the convexity did not change, but that the measured difference in pressure from posterior to anterior did. This may have relevance to the differences among human eyes of various thicknesses, relative to angle-closure glaucoma. It has been a frequently expressed anecdote that angle closure and acute attacks are less frequent in black persons. Population-based data do not support this idea,4,10 indicating that African- and European-derived persons have similar rates of PACG. In addition, if thicker irises made PACG less likely to happen because the iris did not bow forward as readily, then why would Chinese persons, with thicker brown irises, have so much PACG?5 It is interesting to speculate on the behavior of the lens at the pupil, given the

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Tiedeman model. Moses20 may have been the first to realize that the lens has forces acting on it that would move its position more anteriorly. Firstly, he recognized that, in the area of the pupil, the lens has a lower hydrostatic pressure on its anterior surface (the ambient anterior chamber pressure), but on its posterior surface, it has the higher posterior chamber pressure. This would tend to move the lens toward a more anterior position. In addition, there might be a Venturi-like effect moving the lens forward, which would be induced by the flow of aqueous through the pupil. We cannot measure these forces in total, but their combined effects must be relatively small in the living human eye. I base this conclusion on the fact that the resting position of the anterior surface of the lens does not move posteriorly when iridotomy is performed.13 Iridotomy not only equalizes anterior and posterior chamber pressure, but also decreases flow through the pupil to at least some degree. Despite the removal of both forces that would lead to anterior lens position, there is no net posterior lens movement. It is not true that the lens cannot move forward in the angle-closure eye; on the contrary, as we discuss below, it is all too common to see it move forward when the anterior chamber is opened. But, the resting anterior position of the lens in PACG eyes is unaffected when an iris hole is made. Then, what forces do lead the lens to assume a more anterior position in the resting state of eyes with PACG? Every cataract surgeon has observed that some eyes have a disturbing tendency for the iris and lens to move toward the cornea when a corneal or limbal incision is made. This dramatic ‘positive pressure’ phenomenon results from equating the hydrostatic pressure in the anterior chamber with that ambient in the operating room. In this condition, the pressure in the vitreous cavity behind the iris and lens is equal to the prevailing IOP just prior to the incision (say 15 mmHg higher than atmospheric). It would be expected that movement of the lens toward the cornea would always occur, and it is interesting that this is not the case in most eyes. Working to keep the iris and lens from moving forward is their resistance to movement, which must be higher in the supine position (in the operating room) than in the sitting position. Not only does forward lens movement occur in PAC eyes with an iridotomy, but also it seems (anecdotally) to be more frequent than in other eyes. When large incision cataract surgery was the norm, eyes with positive pressure caused the iris to prolapse continuously and the nucleus practically delivered itself (sometimes followed by vitreous). This would continue to occur during the entire procedure, despite an existing iridotomy (and the production of new iris holes). Obviously, positive pressure does not result from pupillary block. It occurs even during ‘small incision’ phacoemulsification lens removal. Those who try to remove the lens in angle-closure eyes cannot fail to be impressed that some residual force is attempting to move the iris and lens forward. A second clinical observation indicates that PAC eyes have a tendency for forward lens movement when there is an increased pressure differential between the anterior and posterior lens surfaces. Most glaucoma surgeons would agree that PAC eyes have a greater tendency to develop flat anterior chambers after trabeculectomy. Since they always have an iridotomy performed at the time of trabeculectomy, pupillary block cannot be a factor. The tendency toward forward lens movement seems to be a regular feature of the angle-closure eye. This could be part of the explanation for the PAC

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eye developing abnormal IOP and trabecular obstruction. As Tiedeman pointed out, the more anterior the lens, the more the forward bowing of the iris (convexity). Many eyes may have the same small dimensions of cornea, axial length, and the same larger than average lens size. But, only a minority develop full-blown PAC or PACG. I propose that, in these eyes, there is an additional feature or features causing anterior lens position in the resting state (further bowing these irises forward to the point of meshwork obstruction). Surgeons have discovered that preoperative digital or instrumented pressure on the closed lid for a period of minutes decreased the problems of positive pressure. These techniques reduce the prevailing IOP by removing aqueous humor from the anterior and posterior chamber, as well as by removing volume from the fluid in the vitreous cavity, via the retinal and choroidal vasculature. Reducing the IOP would make the instantaneous pressure differential across the lens smaller, reducing the tendency for it to move forward. It is quite remarkable that more eyes do not develop positive pressure. Seemingly, they rapidly equilibrate the anterio-posterior pressure differential by loss of vitreous volume. To do so, fluid might exit the vitreous cavity, either going forward into the anterior chamber or exiting through the retina/choroid. Anteriorly, the vitreous gel is in direct contact with the lens. The area through which water could diffuse to leave the gel is shaped like a doughnut with the lens occluding the central area (Fig. 1). In PAC eyes, there are two reasons why this anterior fluid diffusion would be slower. Their axial length is smaller, making the outer diameter of the doughnut smaller, and the lens is larger, making the inner, blocked area bigger. In the illustration in Figure 1, the dimensions of a typical PACG eye lead to the anterior diffusional area decreasing by nearly one half. This could contribute to forward movement of the iris and lens within the eye, not only in the extreme case of paracentesis, but also in the closed eye with various other situations (e.g., the prone position). A second region for fluid to exit from the vitreous cavity (to minimize positive pressure) is across the surface of the retina. In a smaller eye with an axial length of 21 mm, the retinal surface area is 25% less than in an eye of 24 mm. Thus, for both exit pathways for fluid from the vitreous cavity, the small eye is at a disadvantage. If as described above, water must diffuse from the vitreous cavity into the anterior chamber to equilibrate the induced pressure differential with paracentesis, water molecules are passing through the vitreous body to do so. The vitreous has a high water content, but there are hydrogen bonds and other chemical interactions that limit water diffusion through vitreous. Fatt21 measured the fluid conductivity of the vitreous in vitro. He determined that the fluid conductivity decreases as a pressure differential is induced across the vitreous gel. This suggests the intriguing idea that a risk factor for positive pressure is poor vitreous fluid conductivity. This could be either high baseline resistance, or a more than average rise in resistance with induced pressure differential. Hence, a risk factor for positive pressure would be a vitreous with a greater collapsibility under pressure (similar to poor outflow facility). Note that the eye with highly collapsible and compressible vitreous would be prone to a disequilibrium (vicious cycle), with initial higher pressure behind the vitreous gel leading to greater compression and higher resistance, further decreasing diffusional flow. The extreme case of severe positive pressure on opening the anterior chamber is identical to what has been called malignant glaucoma (Fig. 2). The clinical observations of this condition describe

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Fig. 1. In an eye with an axial length of 24 mm and a lens diameter of 9 mm, the anterior area for fluid to diffuse from the vitreous cavity to the posterior chamber is a doughnut-shaped zone, with an area of 113.1 mm2. A typical PACG eye has an axial length of 21 mm and the lens is slightly larger, say 9.5 mm in diameter. These changes alone would lead the diffusional doughnut-shaped area of the PACG eye to decrease to 64.3 mm2, nearly twice as small.

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lakes of fluid behind a forward, compressed appearing vitreous gel,22 which flattens the anterior chamber. In my view, the eye with malignant glaucoma results from high resistance to vitreous fluid diffusion and/or highly collapsible vitreous. This is more logical than the idea of ‘misdirected aqueous’, a proposed mechanism, that appears to violate the laws of physics. If aqueous humor could move in a so-called misdirected way from the ciliary body through the vitreous gel to the fluid compartment behind it, it would be able to move back the opposite way. A functional ball valve would somehow need to be invented to propose a one-way movement of aqueous humor, and none has ever been documented. Shaffer and Hoskins suggested the possibility that the vitreous was detached at its base in a way that allowed such a ball valve or one-way flow. Instead, I propose that the inciting event for malignant glaucoma is a transiently higher hydrostatic pressure in the fluid vitreous cavity than that in front of the gel. Most commonly, this happens iatrogenically during ocular surgery when the anterior chamber is opened to the air. It can happen spontaneously if there was a higher IOP behind the vitreous. With Jonathan Pederson, I made observations in aphakic eyebank eyes in which such differential pressures were induced using two needles inserted into the eye, one through the optic nerve and the other in the anterior chamber. It takes less than a 5 mmHg difference in pressure to cause forward vitreous movement, as in malignant glaucoma, even in normal eyebank eyes. The therapies for malignant glaucoma all fit in well with this hypothesis. Cycloplegia widens the ciliary body diameter, increasing forward diffusional area for fluid to leave the eye. Osmotic agents remove fluid from the entire eye, but have a disproportionately greater effect on the vitreous cavity, thereby lowering the pressure differential across the vitreous body. Vitrectomy as a definitive therapy logically removes the resistance to fluid movement entirely, though if only partial vitrectomy is performed, the flow may not be fully sufficient to allow normal intraocular fluid dynamics (not enough collapsible vitreous removed). In addition to vitreous block of aqueous flow, a second additional feature that may lead to positive pressure is expansion of choroidal volume. The choroid is a highly vascular structure whose choriocapillaries are permeable to a variety of proteins. The choroid has one of the highest ratios of blood flow to tissue volume in the body. The thickness of the choroid is about 400 µm in the human eye when measured histologically; however, its volume in vivo would seem to be determined by a group of variables. These include arterial and venous pressure in choroidal vessels and colloid osmotic pressure of the choroidal extracellular space. The choroidal venous pressure would have to be higher than IOP in order to keep the vessels open to carry blood out of the vortex vein outlets. Consider what would happen to the choroid’s extracellular space if the eye pressure were quickly to fall from 15 mmHg to zero. The hydrostatic force driving water into choroidal veins would fall by that amount, leading to an expansion of the choroidal volume. The same would result from increase in choroidal venous pressure (or increased pressure in any distal drainage site, the orbital or jugular veins). There was an empirical demonstration of this expansion in a recent report by Schumann and colleagues. They documented increased choroidal thickness with the higher venous pressure generated by the vigorous playing of a wind instrument.23 A 20% increase in choroidal thickness was measured. Presumably, the degree to which a given change in IOP or choroidal venous pressure leads to a change in choroidal thickness would vary among eyes, based on various features of the choroidal tissue, such as its elasticity,

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Fig. 2. Transiently higher hydrostatic pressure in the fluid cavity behind a posteriorly detached vitreous body (P2) compared with the posterior/anterior chamber zone (P1) causes a requirement for increased fluid movement through the vitreous. If baseline fluid conductivity is low, or if the fall in conductivity due to the increased pressure is high, fluid movement is insufficient to equilibrate the pressure, and a vicious cycle is initiated. The vitreous gel further condenses, decreasing its conductivity even more, eventually causing a forward movement of the lens and iris. The anterior chamber shallows until there is iris contact with the trabecular meshwork, typically not until the anterior chamber is nearly flat. The clinical syndrome of malignant glaucoma is proposed to follow this pathophysiological path.

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vascular permeability, and protein concentration. If this feature were called choroidal elasticity, it might be proposed that some persons have greater choroidal elasticity than others, so that their choroid expanded more for a given change in hydrostatic forces. At one extreme, a change in IOP might lead the vortex veins to collapse completely at their exit from the eye. This has been proposed as a mechanism in nanophthalmos, a condition in which small eye size leads to a disorder of fluid movements in the eye. Increases in choroidal volume have potentially dramatic effects on anterior ocular structural positions. The estimated vitreous cavity volume of an eye with axial diameter of 23 mm can be calculated as about 5000 µl. The choroidal volume in this eye is about 480 µl and the anterior chamber volume about 150 µl. If an incision opens the anterior chamber, and the choroid expands by 20%, its increase is equal to two-thirds of the anterior chamber volume. In an eye with a relatively smaller chamber, all aqueous would exit, with the iris forced against the cornea (positive pressure). Since the IOP changes during these events, the alteration in the sclera that would occur are predictable.24 If the IOP fell, the sclera would contract somewhat, accentuating the flattening of the anterior chamber. If the choroid expanded and the incision in the eye were closed temporarily, then the IOP might rise, even higher than the original IOP. In this case, some of the expansion of the choroid would generate an expansion of the scleral diameter and the rise in IOP would be mitigated, though there would still be an impressive loss of anterior chamber volume. There have been past attempts to codify the entities that comprise pupillary block or angle-closure glaucoma. In large part, these consisted of efforts to divide cases into specific types of mechanisms that were considered to be separate from each other and not occurring simultaneously. I have referred above to the observations that comprise the scenario of malignant glaucoma or nanophthalmos as they are typically seen. However, in more recent investigations, the coexistence of a picture identical to malignant glaucoma with annular uveal swelling has been observed by ultrasonic biomicroscopy.25 This seems illogical, since IOP is typically high in malignant glaucoma, and ciliary detachment by serous fluid is more often a sign of low IOP. It appears more likely that the so-called choroidal detachments seen in this setting represent relative expansions of the choroidal thickness (whether ‘serous’ or not), and are examples of high choroidal elasticity. In summary, past analysis stressed two major elements in angle-closure glaucoma: an anatomically small eye and blockade of aqueous movement at the pupil. I propose that there is more to the mechanism of angle closure than these two elements. These additional features are evident after relative pupil block has been eliminated by iridotomy. They could include forces generated by poor exchange of fluid or collapsibility of the vitreous body and over-vigorous expansion of the choroid. These elements unify the concepts of malignant glaucoma and nanophthalmos with angle closure, suggesting that features that dominate one condition could be contributory to the others. References 1. Curran EJ: A new operation for glaucoma involving a new principle in the aetiology and treatment of chronic primary glaucoma. Arch Ophthalmol 49:131-155, 1920

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2. Rosengren B: Studies in depth of the anterior chamber of the eye in primary glaucoma. Arch Ophthalmol 44:523-538, 1950 3. Barkan O: Glaucoma: classification, causes, and surgical control: results of microgonioscopic research. Am J Ophthalmol 21:1099-1114, 1938 4. Quigley HA: The number of persons with glaucoma worldwide. Br J Ophthalmol 80:389393, 1996 5. Foster PJ, Oen FTS, Machin D, Ng T-P, Devereux JG, Johnson GJ, Khaw PT, Seah SKL: The prevalence of glaucoma in Chinese residents of Singapore. Arch Ophthalmol 118:1105-1111, 2000 6. Dandona L, Dandona R, Mandal P, Srinivas M, John RK, McCarty CA, Rao GN: Angleclosure glaucoma in an urban population in southern India: the Andhra Pradesh Eye Disease Study. Ophthalmology 107:1710-1716, 2000 7. Alsbirk PH: Primary angle-closure glaucoma: oculometry, epidemiology, and genetics in a high risk population. Acta Ophthalmol (Kbh) 54:5-31, 1976 8. Wilensky JT, Kaufman PL, Frohlichstein D, Gieser DK, Kass MA, Ritch R, Anderson R: Follow-up of angle-closure glaucoma suspects. Am J Ophthalmol 115:338-346, 1993 9. Bonomi L, Marchini G, Marrafa M, Bernardi P, De Franco I, Perfetti S, Varotto A: Epidemiology of angle-closure glaucoma: prevalence, clinical types, and association with peripheral anterior chamber depth in the Egna-Neumarkt Glaucoma Study. Ophthalmology 107:9981003, 2000 10. Buhrmann RR, Quigley HA, Barron Y, West SK, Oliva MS, Mmbaga BBO: The prevalence of glaucoma in a rural east African population. Invest Ophthalmol Vis Sci 41:40-48, 2000 11. Aung T, Ang LP, Chan S-P, Chew PTK: Acute primary angle-closure: long-term intraocular pressure outcome in Asian eyes. Am J Ophthalmol 131:7-12, 2001 12. Quigley HA: Long term follow-up of laser iridotomy. Ophthalmology 88:218-224, 1981 13. Lee DA, Brubaker RF, Ilstrup DM: Anterior chamber dimensions in patients with narrow angles and angle-closure glaucoma. Arch Ophthalmol 102:46-50, 1984 14. Jacobs IH, Krohn DL: Central anterior chamber depth after laser iridectomy. Am J Ophthalmol 89:865-867, 1980 15. Pavlin CJ, Ritch R, Foster FS: Ultrasound biomicroscopy in plateau iris syndrome. Am J Ophthalmol 113:390-395, 1992 16. Tiedeman JS: A physical analysis of the factors that determine the contour of the iris. Am J Ophthalmol 111:338-343, 1991 17. Anderson DR, Jin JC, Wright MM: The physiologic characteristics of relative pupillary block. Am J Ophthalmol 111:344-350, 1991 18. Jin JC, Anderson DR: The effect of iridotomy on iris contour. Am J Ophthalmol 110:260-263, 1990 19. Wyatt H, Ghosh J: Behaviour of an iris model and the pupil block hypothesis. Br J Ophthalmol 54:177-185, 1970 20. Moses RA: Intra-ocular circulation and pressure. In: Sorsby A (ed) Modern Ophthalmology, Vol 1, p 296, London: Butterworths 1963 21. Fatt I: Hydraulic flow conductivity of the vitreous gel. Invest Ophthalmol Vis Sci 16:565568, 1977 22. Shaffer RN, Hoskins HD: Ciliary block (malignant) glaucoma. Ophthalmology 85:215-221, 1985 23. Schumann JS, Massicotte EC, Connolly S, Hertzmark E, Mukerji B, Kunen MX: Increased intraocular pressure and visual field defects in high resistance wind instrument players. Ophthalmology 107:127-133, 2000 24. Silver DM, Geyer O: Pressure-volume relation for the living human eye. Curr Eye Res 20:115120, 2000 25. Liebmann JM, Weinreb RN, Ritch R: Angle-closure glaucoma associated with occult annular ciliary body detachment. Arch Ophthalmol 116:731-735, 1998

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Gonioscopy in the laser age Paul Palmberg Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, USA

Introduction The performance of gonioscopy in cases of glaucoma or in those with a suspicion of glaucoma will often yield vital information that can be obtained in no other way. Consider these cases: • A 35-year-old Haitian pediatrician with uveitic glaucoma presented with no signs or symptoms of uveitus other than keratic precipitates (KP) seen in the trabecular meshwork (Fig. 1a). Topical steroids brought the pressure from 35 to 14, eliminated the KP, and avoided progressive synechial angle closure from developing. • Findings of angle recession (Fig. 1b) explained a case of unilateral glaucoma and prompted careful examination for zonular and retinal tears. • Subtle signs of angle neovascularization (Fig. 1c) in both eyes of a diabetic patient led to prompt panretinal photocoagulation and a reduction of IOP from the 40s to the mid-20s, with medical control then being achieved in this patient referred with an incorrect diagnosis of primary open-angle glaucoma. • Discovery of a ciliary body melanoma (Fig. 1d) with unilateral glaucoma due to an increase in angle pigmentation or tumor seeding called for an ocular oncology consultation. Also, even in cases already suspected of having angle closure, it is important to differentiate appositional from synechial angle closure, and to differentiate appositional closure due to pupillary block from that due to plateau iris syndrome.1

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Gonioprisms and techniques Audience surveys indicate that about 65% of general ophthalmologists use a Goldmann type of gonioprism when looking for angle-closure glaucoma, and 35% use a Zeiss 4-mirror or similar gonioprism. Among glaucoma specialists, 5% use the Goldmann and 95% the Zeiss. Why is there such a difference in lens preference between generalists and glaucoma specialists, and what difference does it make? Address for correspondence: Paul Palmberg, MD, PhD, Bascom Palmer Eye Institute, University of Miami School of Medicine, P.O. Box 016880, Miami, FL 33101, USA Glaucoma in the New Millennium, pp. 65–76 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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a. b.

d.

c.

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Fig. 1. Important causes of secondary glaucoma only revealed by gonioscopic examination. a. Keratic precipitates of uveitic glaucoma. b. Traumatic angle recession, posterior displacement of the insertion of the ciliary body. c. Angle neovascularization, with new vessels from the iris passing over the scleral spur and arborizing over the trabecular meshwork. d. A ciliary body melanoma visible in the peripheral iris and angle.

The Goldmann single-mirror gonioprism has an inner diameter of 11 mm (which fits over the cornea) and a second, outer diameter of 14 mm, which sits on the sclera (Fig. 2). The vault of the lens is filled with a viscous solution for optical coupling. When the lens is quickly placed on the eye (as it should be to avoid loss of the fluid), some of the fluid is expelled by the pressure applied and a suctioncup effect is created. This has the advantage of holding the lens in place. It gives a steady view since it will not slide from side to side. However, the suction cup also increases the IOP, resulting in a stretching of the scleral-corneal ring, and also resulting in a backward rotation of the iris and ciliary body, potentially opening a closed angle. The Zeiss gonioprism has 4 mirrors, a diameter of 9 mm, and fits on the cornea (Fig. 2). Optical coupling can be achieved with tears or saline. There is no suctioncup effect, so to keep the lens in place for steady viewing and to avoid inadvert-

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Fig. 2. Goldmann (round) and Zeiss (square) gonioprisms.

Fig. 3. a and b. Proper support for the elbow, use of two fingers on the cheek to steady the hand, and gentle application of the Zeiss lens using the thumb and second and third fingers, with avoidance of inadvertent pressure on the cornea.

ently pressing on the cornea, which would also increase the IOP and potentially open a closed angle, the examiner should adequately support his elbow, and can rest the side of the hand (fourth and fifth fingers) on the side of the cheek (Fig. 3a). The lens is then held between the thumb and first and second fingers, and gently allowed to contact the cornea (Fig. 3b).

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Identifying angle structures

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When viewing the drainage angle through a gonioprism, three techniques are quite reliable in proper feature identification. The first is the use of a projected thin line of light in the corneal light wedge or parallelepiped method. The beam penetrates the transparent cornea, forming a three-dimensional figure of light, but, as we move our point of attention to the border between the cornea and the trabecular meshwork, the reflected beam is seen to collapse to a two-dimensional figure of light (Fig. 4). This border, at which there is also a slight transition of curvature, is called the Schwalbe line. If the examiner were to see a three-dimensional figure of light all the way to the point where the iris meets the wall of the eye, this would mean that the angle was closed. The second technique is to look at the character and distribution of pigment particles in pigmented lines in the angle. When the pigment particles are large, gray-brown, and form a discontinuous line, giving a ‘salt and pepper’ appearance, look out! This may be a Sampaolasi line of pigment on or near the Schwalbe line, and not the pigmented portion of a true trabecular meshwork. When the trabecular meshwork has a pigmented region (over Schlemm’s canal), as it usually does to some degree, the pigment particles are light brown and are distributed as a continuous line (at least for a few clock hours). This has the appearance of ‘fine powdered brown sugar’ (Fig. 5). The third technique is indentation gonioscopy, which can be performed with a Zeiss-type lens, but not with a Goldmann lens.2 The examiner first views the angle in its undisturbed state (Fig. 6a), having the patient look in the direction of the

b.

a. Fig. 4. a. The parallelepiped method of identifying the transition from peripheral cornea to the trabecular meshwork. b. An arrow points to the Schwalbe line.

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Fig. 5. Recognizing the coarse and discontinuous pigmentation of a Sampaolasi line (upper arrow, at or near the Schwalbe line) and the fine, powdered brown-sugar appearance of pigment on the functional portion of the trabecular meshwork (lower arrow). The pigment deposits are dense in this case of pigmentary glaucoma.

b. a. Fig. 6. a and b. An appositionally closed angle is pushed open with indentation gonioscopy. The arrows in 6b point to low PAS.

mirror, and then instructs the patient to look only slightly in the direction of the mirror for indentation gonioscopy. To view the superior angle, the examiner has the patient now look only slightly down, and both pushes in and lifts on the Zeiss lens, selectively pushing inwards on the inferior cornea. As a result, the IOP increases in the eye and the iris and ciliary body rotate backwards, and the examiner allows selective deepening of the superior angle (since the cornea is not being pushed in there). Angle structures that were not visible due to appositional angle

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closure now come into view (Fig. 6b). The iris in the region of any peripheral anterior synechias (PAS) is tethered and cannot fully rotate backwards, while the iris in adjacent regions does bow backwards (Fig. 7). When the only visible pigmented line is composed of coarse granules in a discontinuous line, indentation gonioscopy may then reveal the true trabecular meshwork. In Figure 8a there is a seemingly wide approach to a pigmented line, but this is a Sampaolasi line, and indentation reveals extensive PAS to the true trabecular meshwork, seen in Figure 8b. In Figure 9a there are two lines with discontinuous pigment, and in Figure 9b, with indentation gonioscopy, the angle that was appositionally closed is pushed open, revealing a continuous line of pigment on the true trabecular meshwork.

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Fig. 7. Indentation gonioscopy accentuates the PAS. The rise of IOP produced by the indentation causes the iris to each side of the PAS to rotate posteriorly (white arrow), while the tethering of the iris by adhesions holds it in place in the region of the PAS (black arrow).

a.

b.

Fig. 8. a. A Sampaolasi line (arrow) mimicking a true trabecular meshwork in an angle with a wide angle of approach. b. With indentation gonioscopy, the angle opens and the previously seen Sampaolasi line (upper arrow) is visible, as well as extensive PAS to the trabecular meshwork (lower arrow).

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b.

Fig. 9. a. A patient with a Sampaolasi line (arrow) and a second line of pigment in the peripheral cornea. b. Upon indentation gonioscopy, the Sampaolasi line is visible (upper arrow) and the continuous line of pigment on the trabecular meshwork can now be seen, resembling fine powdered brown sugar.

Artifacts to avoid1 •

•

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•

If light is allowed to pass through the pupil or if the patient is looking at a fixation target during gonioscopy, the pupil will constrict and an angle that is actually closed in the dark will open. Therefore, gonioscopy should also be done in a dark room. The examiner can use a widening and narrowing of the slit beam during gonioscopy to dynamically open and close angles, for confirmation of a diagnosis (Figs. 10a and b). The use of a Goldmann lens (Fig. 11a) artifactually opens closed angles created by means of a suction-cup effect that increases the IOP (Fig. 11b). Inadvertent indentation with a Zeiss lens can open closed angles. Conversely, inadvertent pressure over the portion of the angle being viewed can push closed a narrow, but open angle.

a.

b.

Fig. 10. The effect of the pupillary light response upon an appositional closed angle. a. The angle is closed when light is not allowed to pass through the pupil. b. The angle opens with pupillary constriction to light.

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a. b. Fig. 11. a. The appositionally closed angle opens as a result of the use of: b. a Goldmann lens, which produces a suction-cup effect that elevates IOP, resulting in stretching of the corneascleral ring and posterior rotation of the ciliary body and iris.

a.

b.

c.

d.

Fig. 12. After performance of an adequate laser iridotomy (a), an angle appositionally closed on the basis of plateau iris syndrome (b) can be seen to open with indentation gonioscopy, with the peripheral iris draped over a prominent last roll of the iris (c). Following peripheral iridoplasty, the angle is opened to grade III (d).

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Plateau iris syndrome Angle-closure glaucoma can also be produced by a forward rotation of the ciliary body processes, which occurs spontaneously for unknown reasons in plateau iris syndrome, and which also occurs in a variety of conditions in which the ciliary body is congested, as may occur due to, and complicate the management of, a pupillary block angle-closure glaucoma attack, or due to the application of extensive panretinal photocoagulation, or due to placement of a tight scleral buckle, or to a fresh central retinal vein occlusion. Upon gonioscopy in such cases, the iris plane is usually flat, without the characteristic forward bowing of a pupillary block mechanism, and there is a prominent last roll of the iris. During indentation gonioscopy, and in the presence of a patent iridotomy, the iris moves backwards over the peripheral lens, and is then draped even more prominently over the ciliary body processes, such that the outline of the individual processes can be detected (Figs. 12a, b and c). After peripheral iridoplasty, the angle is opened to grade III (Fig. 12d). In 1989, I encountered the following case: A woman who had undergone an adequate surgical iridectomy in each eye in 1979 for angle-closure glaucoma again presented with angle-closure symptoms. Gonioscopy showed angle closure, and indentation gonioscopy revealed that the closure was only appositional and that there was a prominent last roll of the iris (Figs. 13a and b). Looking through the iridectomy, the forward rolled ciliary processes lifting the peripheral iris against the trabecular meshwork could be seen (Fig. 13c). In the site of the iridectomy, the ciliary processes were seen to be directly rolled up to the trabecular meshwork (Fig. 13d). During indentation gonioscopy, the ciliary processes rolled backwards, opening the angle (Fig. 13e). Peripheral iridoplasty (24 applications of a 500 µm argon spot through an iridotomy lens at 0.18 W in a brown eye and 0.22 W in a blue one, with one-second duration) opened the angles. (This case resolved a longrunning debate I had been having with Bob Ritch since the early 1980s as to the mechanism of plateau iris syndrome.) In 1992, Ritch and colleagues published ultrasound biomicroscopy images that confirmed the mechanism and documented the effect of his technique of peripheral iridoplasty (Figs. 14a and b).3 Ritch also realized that Paul Chandler had beaten both of us to discovering the mechanism, since he had reported and properly understood a case similar to mine.4 Gonioscopy for trabeculoplasty When performing trabeculoplasty, the suction-cup effect of the Goldmann lens is an advantage, since it steadies the eye and even allows the surgeon to achieve a fine focus of the beam on the trabecular meshwork by allowing him to pull the eye side to side, up and down, and in or out, in order to bring the eye to the laser beam. The surgeon instructs the patient to look away from the beam (Figs. 15a and b) in order to obtain as perpendicular an application as possible, and thus a round, focused spot, and since this also helps to avoid having the energy skim backwards and hitting and inflaming the ciliary body.

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b. a.

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c.

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Fig. 13. a. The patient had recurrent angle-closure glaucoma in the presence of a large surgical iridectomy. b. The angle has been appositionally closed. c. When the angle is pushed open by indentation gonioscopy, a prominent last roll of the iris can be seen. d. Looking through the surgical iridectomy, the ciliary processes can be seen to be rotated forwards, lifting the peripheral iris against the angle. e. In the area of the iridectomy, the forward rotation of the ciliary body processes can be seen. f. Those processes rotate posteriorly with indentation.

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a.

b. Fig. 14. a. Ultrasound biomicroscopy illustrates forward rotation of the ciliary processes, lifting the peripheral iris against the trabecular meshwork. b. The angle is open after peripheral iridoplasty heat has shrunk the peripheral iris. (Reproduced by courtesy of Robert Ritch, MD.3)

a.

b.

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Fig. 15. a. The trabecular meshwork is seen at an oblique angle through a Goldmann lens when the patient looks straight ahead. b. A more perpendicular view of the meshwork is obtained when the patient looks away from the direction of the mirror, an advantage when applying laser trabeculoplasty.

Summary Gonioscopy is essential in the diagnosis of any suspected case of glaucoma, since the examiner must know the cause of glaucoma before he can decide upon the most appropriate treatment. The use of a Zeiss-type of lens, with a proper arm and hand support, the use of the parallelepiped method, recognition of the character and distribution of angle pigment, control of the pupil response to light, and the use of indentation gonioscopy allow the surgeon confidently to assess the type of glaucoma present.

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References

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1. Palmberg P: Gonioscopy. In: Ritch R, Shields MB, Krupin T (eds) The Glaucomas, 2nd Edn. St Louis, MO: CV Mosby 1996 2. Forbes M: Gonioscopy with corneal indentation: a method for distinguishing between appositional closure and synechial closure. Arch Ophthalmol 76:488-492, 1966 3. Pavlin CJ, Ritch R, Foster FS: Ultrasound biomicroscopy in plateau iris syndrome. Am J Ophthalmol 113:381, 1992 4. Chandler PA, Grant M: Lecture Notes in Glaucoma. Philadelphia, PA: Lea and Febiger 1965

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Round table How I make the decision to do a peripheral iridotomy: my laser, lens and settings Paul Palmberg, MD, PhD, presiding Panel: George A. (Jack) Cioffi, MD Harry A. Quigley, MD Dr Palmberg: Welcome to the rectangular table discussion, as somebody pointed out. First, I’d like to ask what lens you are using to do your laser iridotomies. I would point out, just as an historical footnote, that Irvin Pollack of Baltimore, I think, was the first to put a +66 lens on top of a fundus contact lens and to use it to make laser iridotomies, and really pioneered that. At that point, Charles Munderland, who was with a company, wanted to make a lens commercially, so he went to Dr Pollack and said, “Can I call this the Pollack lens?” and Pollack said, “No, I don’t think I really want to do that”. So they went to Dr Wise, who said, “Sure”. At any rate, I am not sure where the idea came from, but maybe they both independently did it. The question is, what lens do you use. Do you use an Abraham, a Wise, or what’s your favorite? Do you have any pearls on that?

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Dr Cioffi: I use a YAG Abraham and I think there are probably about ten lenses out there that you can use. I don’t know how much difference it makes, to be honest. I think we will talk about that in a second. But I often, in a congested eye, will pretreat with argon prior to doing YAG, but I use a YAG Abraham on a straightforward PI. Dr Palmberg: That was the next question, is anybody here doing argon laser iridotomies, just argon for the whole thing? Maybe we should ask the audience too. How many are using argon laser to do your laser iridotomies, not YAGs? A few. And it certainly works. Dr Quigley: We can talk about the lens thing. Some of you may have been around long enough that you did iridotomies without a lens. We did that initially. Clearly, some lens is beneficial because it holds the eye open. You go into tetany after a while trying to hold somebody’s eyelids open to get them in focus. So the lens helps hold the eyelid open. The extra button magnification lens is useful, but not absolutely necessary. The way it helps you is twofold. First, it probably does concentrate the energy so that there is a tighter, smaller area within which the energy is delivered, so you have a greater effect on the iris. Second, when you have one Glaucoma in the New Millennium, pp. 77–87 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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of these with the button lens glued on the more peripheral aspect of the lens that you are using, you can actually see better into the periphery. I flunked optics, but there is some sort of prismatic effect whereby you can see further in, and you will produce an iridotomy with the button iridotomy lens and then later you will look at the patient with the slit lamp and you will think, how the heck did I get out that far in the periphery. I can hardly even see the darned thing. Partly that is because you used pilocarpine during the treatment to pull the pupil down, and after the pilocarpine wears off, the iris moves back out more peripherally. But part of it is because the prismatic effect of the lens takes you more into the periphery. I think the advantage of that is to be sure that you keep the iridotomy as far out peripherally as possible and as superior as possible, especially if you had one or two of these folks complaining of double vision, and it’s a real phenomenon. Dr Palmberg: That leads to the next question, which has to do with the location of the iridotomy. Dr Cioffi: Actually, Paul, before we go on to that, I agree with both of Harry’s points, and the third thing I would add is that the magnification button often allows you to identify nice iris crypts much more easily, where you are going to find that you can poke through with a single or two shots from your YAG. I always try to find a thin point if I can, which just makes the procedure quicker and easier, and less of an issue for the patient.

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Dr Palmberg: When using YAGs, I want to ask, if many of you, as I do, generally like to do some argon pretreatment. I put in a 500-micron spot of basically an iridoplasty burn where I am going to go through with the YAG laser later, for a couple of reasons. It deepens the angle so that what you are treating is farther away from the edematous cornea, if it is edematous; and secondly, it contracts the blood vessels in that region so that you don’t get that annoying bleeding that can develop while you are making the laser iridotomy, and it keeps the tissue from fracturing into little pieces. So I always like to put one iridoplasty burn with about a 0.2-watt 500-micron spot applied for about 0.2 to 0.5 seconds, and then go on down to the YAG laser and punch through. I usually use 3 to 7 millijoules, one or two pulses per burst. Any markedly different way of doing that? What kind of YAG laser settings do you use? Dr Cioffi: I don’t routinely pretreat on a quiet eye. But I do routinely pretreat an acute angle closure eye for all the reasons Paul just mentioned – stops bleeding. You essentially do a little sector iridoplasty. It deepens things, it may pull the angle open a bit, and it makes it easier to do the YAG afterwards. But on a quiet eye, I generally will not pretreat with argon. I use settings very similar to yours. I usually start at about 3 to 3.5 millijoules and work up if I need to, but usually you don’t have to go over 4 to 5, if it’s not a really thick iris. Dr Quigley: I think it depends on whether you’ve got both lasers in the same room. If you have to walk over to the hospital to get to the continuous wave laser, but the YAG is sitting in your office, there is a tendency to do the thing where you and the patient don’t have to walk 100 miles to do it, or buy into a facility charge. I would routinely not pretreat an eye that is blue or green, because the chance you

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are going to be able to make a hole with fewer than three shots is so high that there is really no value to further inflame an eye with pretreatment. Dr Palmberg: What is a blue eye?

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Dr Quigley: It’s anything that doesn’t look brown. When I went to visit in Singapore, and I told my colleagues there why I never use argon pretreatment, and they said, “Why don’t you come and look at a couple of eyes here, Chinese folk, and why don’t you try what you do at home in Baltimore.” And I learned why they pretreat eyes there. If it’s uniform brown and all you see is uniform brown, you are probably going to be better off pretreating. Look all around the superior iris and see somewhere where it looks thinner. You can tell it’s thinner if you can see the white blood vessel lines. So it’s a thick iris, it doesn’t have a thin spot, but why not, if you want, if you would have to walk across the street to find the argon laser and the YAG is sitting right here, why not take two shots with the YAG. Tell the patient, “I’m going to do a preliminary treatment. If I get through, great; otherwise, we are going across the street.” And if you happen to make a hole with three shots, fine; but if you don’t, you’re going to say, “Okay, now we’re going to go across the street.” What have I done, though? I have inflamed the eye ahead of the argon, then I have to do argon and come back for YAG. Dr Palmberg: I want to share one little pearl with you. It’s something I call the shuffle technique. If, as you are doing this, a lot of pigment starts coming through and blocking your view, if you have been doing the YAG, that can sometimes happen; it happens certainly more with the argon. I had a patient who came in with Parkinson’s disease, and as the guy was shaking back and forth and I was holding the lens in place, I noticed that fluid would exchange between the anterior and posterior chambers with each one of these thrusts, and cleared all the pigment out of the way. So you can actually do this on purpose. If, as you are making a hole, you get bubbles or pigment, and it is blocking your view, you can just push in and out gently on the lens a few times, which I call the shuffle, if you’ve already got a little bit of a hole, it will spit out pigment and other things, and then you can see clearly to go ahead and complete it. Let’s discuss the location of the iridotomy. One of the things that Doug Anderson and other people who think about optics have brought out is that if you can put it under the upper eyelid and the upper eyelid covers the limbus, and you put a hole there, the patient is not going to have the complaint of double vision from light going out and around through a more peripheral portion of the lens. But if the patient has kind of a retracted stare appearance, and their lid happens to be just a bit above and they have the meniscus of the tear film over the superior 12 o’clock position, they will have an annoying blue line across their vision. So that if you look at the natural position of the lid of the patient, that is kind of helpful in deciding where to put the iridotomy. It may be that, in somebody whose lid is retracted up just above the edge, you should actually put it off to one side a clock hour or two to avoid getting the second image. Are there thoughts on that? We’ve all seen patients complaining about this. Dr Cioffi: I agree entirely, and as Harry mentioned, all you need is one or two of these patients in your practice. They are non-symptomatic when they come in and

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they have a bit of appositional closure and you tell them they need an iridotomy to protect them, and then they have diplopia or a line or glare, and they complain to you for the rest of your and their lives. So, it is pretty annoying. In addition to Harry’s comment about the Asian eye, our population in Portland is about ten percent Asian, and it is a much more difficult iris to put a hole in. I pretreat virtually all those patients. Dr Quigley: How many spots would you normally hit with for the pretreatment? With our colleagues in Singapore, it was 50, 60, or even 70 spots sometimes. Dr Cioffi: I don’t do that many. I was in Australia recently and there was a woman there from Singapore who was talking about iridoplasty on virtually everybody, and extensive pretreatment. Usually, I try to do five to six shots and I will surround the area where I am going to put my hole to make it taut like a drum top, and then I will pretreat with a larger spot right in the middle for cauterization, and then I will take them over to the YAG laser. Dr Palmberg: Let me go on to another thing. Let’s say you get somebody in who has had a kind of neglected attack, the eye is really congested, there is a lot of corneal edema, and it is kind of difficult to get that laser iridotomy in there. Do you have any other things that you find are pearls to help you get those cases done?

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Dr Quigley: The usual one is that somebody has had an acute attack while having an eye exam and the doctor recognized it and tried to break it medically for much of the day, and then treated with the laser for a while and didn’t get through, and it is usually Friday afternoon. They are worried and the patient is worried, and then you get to see the patient and wind up by that point of having quite a lot of corneal edema. I have tried all sorts of things, none of which really work, but you try to get the pressure lower. I would try to take a shot at the patient, but sometimes you just have to wait overnight for things to clear, and even use osmotic agents. And on two occasions in the last four or five years, I have actually done surgical iridectomies on people in whom we could not get through, there was no way. One of the reasons for this, and it is not the doctor’s fault, and it is often not the patient’s fault either, is that there is a coincidence of corneal disease in angle closure, and there is more than one pretty good epidemiological report that guttata and angle closure go together. So these are corneas that have fallen apart. It is okay to make a hole in the iris initially out nearer to the pupil than you ultimately would want to, in the setting of the middle of an acute attack when you really have to make the hole. If later that doesn’t turn out to be something that is going to be a useful hole, because it is directly overlying the lens, you can then make a second hole out peripherally. Dr Cioffi: Now is the most frequent time that I will use osmotics and I will hit them with virtually everything in the cabinet, but I will use isosorbide as well, Osmoglyn, one of the two. Often, waiting overnight is the secret. You put them on everything, you give them some isosorbide. It’s always Friday night, as far as I can tell. You see them back the next morning, you give them another dose of isosorbide, and then go ahead and do your treatment.

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Dr Palmberg: One thing I think is really under-utilized in these circumstances is iridoplasty. You can do iridoplasty for two or three clock hours, which will, temporarily, because it does not alleviate the pupil block, open two or three clock hours of the angle. This may first of all move the iris far enough away from the cornea that you can focus on it without having the energy taken up by the cornea, and second, briefly open a portion of the angle. It may decompress the eye down to a pressure quite a bit lower, and for a few minutes, until that pupil block fills up again, the pressure may be lower and there will really be less congestion. In some desperate cases, you can put a few shots of iridoplasty right near the pupil, because you could break the attack either by making a hole in the iris or by distorting the pupil enough that you get it away from that mid-dilated position. You may, by making a few shots of iridoplasty near the pupil, get it open enough that you will see a spurt of fluid, and the pressure in the eye comes down, then you can do the iridotomy. On a couple of occasions, I have given the patient a retrobulbar block, because then they stop hurting, stop retching, and hold still so you can see what you are doing, and this lets you provide treatment. On a couple of occasions, I have used a 30-gauge needle, and this is not a technique you start doing the first thing you do with 30-gauge needles, but you can take a 30-gauge needle iris plane parallel and go into the inferior angle, well in the periphery so you are not going to hit the lens, and let a little fluid out of the eye. It doesn’t fix the block, but it gets the pressure down enough in the eye that the cornea immediately becomes less cloudy and you can then do iridoplasty and shoot a hole through.

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Dr Cioffi: Glycerin works and often, as my coupling agent for the lens, I will actually fill it with glycerin instead of Goniosol, and as you are doing your procedure, it is actually working for you. I usually pre-dose them with glycerin a few times over a half hour or 45 minutes, but then I will put it in my lens as well. Dr Palmberg: Let’s go onto to criteria for doing a laser iridotomy. Surely not every patient with a narrow angle requires a laser iridotomy. We could start out with what the history elements are that would make you do a laser iridotomy, if there was no pressure elevation in the office, no peripheral anterior synechia, nothing else. What would you like to have heard? A colored rainbow about lights, pain, coupled with a family history? What sorts of things will convince you that somebody has had angle-closure glaucoma? Dr Quigley: We are going to go into the clinical mode now instead of what you can prove with epidemiological data. Because this is seat of the pants, “What am I going to do?” If somebody’s mother went blind from narrow-angle glaucoma and they walk in with a narrow angle, you are going to put a hole in their irides. Next question. Because that person is going to go through life saying, “My mom went blind from this disease”. Even if you can’t be sure, I think that’s the sort of business. You want to be sure that his mother really had angle-closure glaucoma. One of the things we are studying right now is how credible is the family history you get from patients. Lou Pasquali had that experience in Boston when patients who were nurses reported that they themselves had been diagnosed with glaucoma, and then they got the charts and only 50% of the time did they actually have glaucoma. So saying, “My mom had glaucoma and she went blind from this dis-

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ease”, may or may not actually be accurate. So you would like to hear, “She saw this guy George Spaeth in Philadelphia and he did something with a laser to her, and after that it was too late and her vision had gone.” So you query people’s histories in more detail than you might otherwise. Someone who says, “Oh, I’m having halos around lights”. “Is it in both eyes?” “Oh, yeah.” It’s a cataract. Most of the time, visual symptoms aren’t angle-closure glaucoma. It has to be a really good story. It has to be, “I covered one eye and then I covered the other one and it was only the eye that was red that was blurry, and boy did I have a headache, and it was on that side.” It has to be that sort of striking history, because there are too many other non-specific symptoms. And a colored rainbow around a light, and I had not just been in a chlorinated pool, or any other cause for corneal edema. What about somebody who is going to go off and be a missionary in a remote area, they have a very narrow angle, and they are not going to be able to get to medical care, is that an indication? Dr Cioffi: I think Harry’s point is right on. I think that it is an accumulation, just like when you decide to treat a glaucoma patient. It is an accumulation on an open-angle glaucoma patient, an accumulation of what you see, and it’s putting all the pieces together and the blind patient going off to a place where they are not going to have medical care or be looked after. All those things add to your concern and, rightfully, to the patient’s concern, that they could get into trouble. So, if the story is not that good, but the mother went blind and they are going to Indonesia for the next six years, you may put a laser hole in their iris. It is an accumulation of not just what you see, but what is going on for the patient.

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Dr Quigley: I’ve treated somebody who is a state department employee who was going to Kazakhstan for two years, and I put holes in irises I would not have put them in otherwise. But, we take appendices out of people who are going to be astronauts. There are some interesting things we do that aren’t necessarily the typical clinical setting. I have a patient who is a mountain climber. He knows he is going to be in Tibet or Nepal for periods of time, and had occludable-looking angles with negative provocative testing and no PAS and no pressure elevation. Had he been somebody who was a sedentary guy who lived in Baltimore, I would have said, “Come on in if you have symptoms, but I’m not going to put holes in your irides”. But for this fellow, it was probably the appropriate thing to do. I will give you one other setting. There are increasing numbers of patients reading the Internet these days, who have gotten themselves a bottle of Glyrol and a bottle of pilocarpine and are carrying them around worried they are going to have the attack tonight. And a doctor has told them, “Don’t ever be without that Glyrol in your purse because you could have the attack tomorrow”. In that case, what you are doing is curing a neurosis by doing an iridotomy. A neurosis generated either by the patient or aided and abetted by us in the medical care system. And I think those patients will do very well too, unless they have a complication from the iridotomy. Dr Palmberg: Let’s go on to people with findings. Somebody has pressures of 23 and 28, and one eye is slit to close with 23, but not quite closed, no synechiae, and no history of an attack, and the other has pressure of about 28, grade 1 angle, so there is some correspondence to it, but you don’t actually see the angle closed. We

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know this is a dynamic situation. It could change from day to day, hour to hour. Is that somebody in whom you put a hole in the iris in the higher-pressure eye and see what happens? Dr Cioffi: Maybe.

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Dr Quigley: You have to do a full eye exam here. I’m always disappointed when I don’t see a visual field test that was done on a patient who is in that setting, because there is no reason not to do a visual field test on someone in that situation. They are either an open-angle glaucoma suspect or an angle-closure suspect, and either way you ought to be doing a field test. Moreover, you are going to dilate their pupil, as I said, in order to find out what is true in their fundus, because their pressure could be elevated from a variety of other things, their narrowness, as Paul showed, could be a lot of stuff, things pushing from behind the iris. Therefore, I do a mydriatic provocative test. If, in this case, Paul, I thought there was a very high chance that dilating the pupil was going to cause an acute attack, then I would use a darkroom test, which we do in a glaucoma service about once a month maybe. So it’s not something that most average practices are going to do, but you can put somebody with their face down for 30 or 40 minutes in a room, and if their eye pressure rises 10 or 15 points that, to me, is very significant. It adds credence to the fact that I should be doing an iridotomy in the patient you just described. If I dilate them and the angle becomes even narrower, and the pressure rises more than 10 points, and I just picked out 10 here because we are talking clinically, then I would definitely feel much better about doing the iridotomy on that patient. In the setting you just presented, if both the darkroom test and the mydriatic provocative test are negative, then I won’t do an iridotomy unless somebody is in one of those other situations like trekking to Nepal, or “My mom went blind from glaucoma”. I say to them, “I can’t prove you have a disease. You have ocular hypertension. It may be due to that narrow angle. I’d like to follow you and see.” And I tell them what the symptoms of an acute attack are in case they have one. I would be seeing that patient that first year twice or three times. Dr Palmberg: Irvin Pollack took such patients who had elevated pressures, did iridotomies on them, and found that, in most of them, the pressure would then come down to normal. But, we are emphasizing those people who had rather narrow angles, not quite closed, very narrow, but a pressure elevation. Let’s go on then to patients who don’t have a pressure elevation spontaneously, who come into your office just for a routine exam, or who saw someone and come to you for a second opinion, and they have slit angles nearly all the way around, no history of anything, no family history of anything, no damage to their nerve, they are just very narrow, and you do a darkroom provocative test, or you dilate them with Mydriacyl and the pressure goes up to 25, and half or two-thirds of the angle closes temporarily. Is that predictive of something in the real world, what would happen to them later, or if they don’t need dilation for diabetic retinopathy or retinal exams for ARMD or something, could you just watch and they would be fine without you? Dr Cioffi: A fair number of people go up with dilation, even open angles, and if in the normal state they don’t have appositional closure, they don’t have synechiae,

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they don’t have any history of attacks, without a significant pressure rise (I don’t know if 10 is the number or 8 or 15), without any other signs of disease, I probably would not do anything. I would just watch them. I look after hundreds of patients with narrow angles that I have followed over time, and they do fine. The majority of them do just fine and you just have to look at them intermittently. Dr Palmberg: Ralph Kirsch looked at 20 people who had positive dilatation provocative tests, followed them for 20 years, and I believe that either none or only one of them ever had any spontaneous glaucoma, and even in that one nothing really happened, we just treated them. So, unless the person has to be dilated on a regular basis for some other reason, I don’t think the dilatation provocative test is really a compelling reason for doing it, but the patient is so fearful, as we brought up before, after you have told them this and done the test, maybe that would be a reason to do it.

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Dr Quigley: It has been too quiet here this morning; we have been agreeing with each other all over the place. What we need, though, is a study in which a group of glaucoma people finally get their act together and say, “We want to do a prospective study to evaluate mydriatic provocative testing”. We are setting this up at the moment in Singapore, which is the place where you can get a lot of suspects for narrow angle all in one place. Our colleagues there are going to help us out with a longitudinal follow-up of people, what Paul was just talking about, in which you do a provocative test, but you don’t do an iridectomy on anybody except the most dramatically positive people who have actually had an acute attack. There’s an ethics issue here, but Paul just made it possible for us to do this trial. Because I think you ought to do an iridotomy on people who have a mydriatic provocative test that leads to a narrower angle and a pressure rise of, let’s say, 10 points. Paul thinks you shouldn’t. So now we have the ethics for doing a trial in which we don’t do the iridotomy on people until they actually develop symptoms, and we find out how good provocative testing is. Mydriatic provocative testing stinks. Why does it stink? Because it does not answer the question you want to ask. You are looking at an end point pressure rise. People could actually have intensified pupillary block without having a pressure rise. So, ultrasonic biomicroscopy or some other method is a way of doing that. We are trying to devise some new provocative testing, for example, provoking people by accommodation, to see if the internal configuration of the eye changes. We need better provocative tests. Based on what I know now, though, if Mrs Jones came to my office and, in a darkroom, her pressure rose 10 points, I would say to her, “You know what, I’ll bet lots of times you go dancing. I bet you occasionally hang out in bars. You go to the movies, don’t you?” Her eye pressure is rising during that time and darkroom provocative tests actually get better when you do an iridotomy on more people than not. Not everyone. So I am in favor of doing something when there is a positive provocative test, and I am the first to admit to you that I don’t have data to support that, and as Jack just said, I don’t yet know how many points of pressure rise is an important rise. I think there is a real difference of opinion among people, but more people agree with Paul than with me. Dr Palmberg: I just wanted to point something out. I don’t know what the right answer is. I am just saying that somebody who did the experiment, which was to

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not treat them, could get an answer. Somebody who makes a laser iridotomy, and they all do well, tells us nothing. Perhaps those people were going to do fine anyway. Certainly, it is a lot safer now that we do laser iridotomies than in the days when we would have done a surgical iridectomy on them. Dr Quigley: Is one of your questions downside risk? Are you going to be talking about complications of iridotomy? Dr Palmberg: Well, we could do that. I have two minutes, so I was going to ask two things. One, what about just appositional closure. Is it enough to do it without a pressure rise. What about a few synechiae starting to form. I would do it for either one of those and our panel at the American Academy, all nine of us, agreed that that’s when we were going to do it, because we thought that trabecular meshwork nutrition is being compromised when it doesn’t get aqueous, and certainly when synechiae start forming, you have anatomical changes, that iridotomy has a low downside, and we were in favor of doing it. Unless somebody disagrees, I will move on. Dr Cioffi: Synechiae without a doubt, and appositional closure... Dr Palmberg: Of a quadrant or more, or something.

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Dr Quigley: Be very careful, because synechiae can have been made by something else. The most common cause of peripheral anterior synechiae in the USA is argon laser trabeculoplasty. And so, if somebody has had ALT, and then someone looks in and says, “Gee, they look a little narrow and they have PAS, now I am going to blow a hole in the iris”, probably not the correct mechanism. Or inflammatory PAS or PAS related to trauma, both things that you can sometimes get a history of, and both things that are much more often asymmetric, one eye compared to the other, narrow angle with PAS on one side, wide open angle on the other with no PAS, be thinking that it is not a primary-angle closure. Dr Palmberg: And if your PAS are from angle closure, they are usually above, and if they are from inflammation, they are usually below, where the inflammation will settle. Okay, iridoplasty indications. Appositional closure after a laser iridotomy. I would do it. If you had a plateau configuration. Dr Cioffi: The incidence of plateau is very low. Dr Palmberg: 3%. Dr Cioffi: I have been in Portland for over ten years now and have only seen a handful of patients with it, or who I would suspect, and while it should be one of the things on your list, I doubt that any of us are going to see large numbers of plateau iris. Dr Quigley: I have done a total of two iridoplasties, which is an extreme viewpoint about iridoplasty. Paul does a lot more of them, and he showed you beautiful results, shown by UBM, in the case of someone who benefited from it. So I don’t

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think we are expressing anything other than two facts. The first is, I have a bias against doing gonioplasty because I don’t think it is permanent, as he showed you, though it can be helpful. The second is, I think it is overdone. I think everybody thinks, well maybe I’ll improve that narrow angle some, and what do you cost the patient? You cost him 24 deliveries, inflammation, pigment release, iris atrophy, possible increased risk of cataract, a whole lot of things. So, I don’t disagree with Paul’s use of iridoplasty. I think, though, that there are extremes in the use of it, and I am down at one end. Dr Cioffi: I think that, even in Paul’s series, though, as you pointed out, over 20 years it was 40 patients in a very busy glaucoma practice. Three percent of the laser iridotomies went on to iridoplasty. Dr Quigley: Whereas some of our colleagues will tell you that one-third of angleclosure patients ought to get an iridoplasty. If you are somewhere in a very large city between Philadelphia and Rhode Island, you are going to get an iridoplasty if you walk in the door. Dr Palmberg: One-third of our iridoplasties were done in eyes that were congested after an angle-closure attack, and they weren’t plateau iris syndrome. Gonioplasty was used to break a continuing attack. We are talking about two to three percent, that’s all. But I do think that if you have real appositional closure, and I have shown you photographs, then I would perform gonioplasty. Dr Quigley: It can be cosmetically disfiguring as well. Consider that some blueeyed people really don’t like their eyes looking like a clock face.

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Dr Palmberg: Two other things came up that I just wanted to comment on briefly. One was nanophthalmos, because you were mentioning de-roofing veins. It turns out that what is of benefit in that situation is making a scleral window. It could even be a posterior sclerotomy. In nanophthalmos, people with glaucoma from uveal scleral increased episcleral pressure, and in people with Sturge-Weber, it really is helpful in avoiding exudative retinal detachments to do a window. Doug Anderson and Don Gass, I think, finally worked this out very well. We have done about 20 cases of nanophthalmos now, with no catastrophes afterwards, whereas otherwise it would be about 50% of patients who have that problem. You don’t need to de-roof vortex veins. For goodness sake, don’t do that. You destroy vortex veins. All you need is a hole in the sclera. It doesn’t have to be a window all the way through the sclera, a posterior sclerotomy works very well. It lets albumin out of the suprachoroidal space, keeps it from building up in that way. And one other thing... Dr Quigley: Can I propose that its real mechanism is that you are reducing to atmospheric pressure the space between the choroid and the sclera, so the choroid doesn’t have the tendency to expand that it did before against a sclera that is rigid. We can differ about the mechanism. It works. Dr Palmberg: It does work, and any nanophthalmic eye you go into should have it.

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Dr Quigley: Do you know what we are talking about, nanophthalmos? Does everybody know? How small does an eye have to be to be nanophthalmic? I hear 17. Anybody bid 20? Dr Palmberg: Could be 20. Dr Quigley: Somewhere in the high teens axial length measurement, and you will know them when you see them, especially if you open the anterior chamber. Dr Cioffi: Actually, the word to the wise is, stay out of a nanophthalmic eye for as long as possible.

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Dr Palmberg: If you do a window, you don’t have any trouble. Malignant glaucoma – mention was made about pars plana vitrectomy and you were talking about the mechanism, I just want to throw in one thing. Doing a pars plana vitrectomy is not going to cure all cases of malignant glaucoma, if you don’t disrupt the anterior vitreous face. In pseudophakic eyes, our retina people buzz all the way through the zonular diaphragm, all the way through the iris, into the anterior chamber. When you have a real communication all the way from the anterior chamber to the posterior chamber, zero out of 33 had any more attacks. Just doing a pars plana vitrectomy, about half of them would recur. So, it’s that compressed anterior vitreous fibrin, choroidal swelling, whatever it is, you’ve got to get rid of that by having a communication. The other way out of it, which is brilliant, and which came out of Wills, is to put a Baerveldt into the vitrectomized posterior chamber, because, if the fluid wants to misdirect, or whatever you want to call it, it can go out in the tube. So, I just wanted to throw in those pearls of wisdom, and hand over to Harry, because we are going on to his part of the session.

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Round table How I make the decision to do an argon laser trabeculoplasty: my laser, lens and settings Claude F. Burgoyne, presiding Panel: George A. (Jack) Cioffi, MD Paul Palmberg, MD, PhD Harry A. Quigley, MD

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Dr Quigley: Can you really spend 25 minutes talking about argon laser trabeculoplasty (ALT)? Sure you can. Actually, we will cut it short if we don’t get into anything controversial. To start with maybe the most controversial, during the last year and a half there was a publication that suggested that argon laser angle treatment should be done differently, depending upon whether the person is European derived or African derived. A lot of my patients have read that work. It was quoted widely in the press. So I am going to ask my two colleagues, to start with – one of them at least was involved in the AGIS study, the advanced glaucoma intervention study. I’d like to hear what their view is on that particular issue, and then we will get to the issue of argon laser angle treatment and in whom should we do it, or better said, how do you present it to a patient. But first, let’s talk about the AGIS study results. Dr Palmberg: The AGIS study randomized patients in whom, in 1988, medicine didn’t work well enough, and in whom something had to be done. They were randomized to have 360° ALT in one or two sessions, or to undergo a non-antimetabolite filtering procedure, adding medications as they came on the market. By the time you got to five years, if you had had laser trabeculoplasty first and then went on to surgery, and met with certain criteria failure, 34% of the white patients demonstrated further progression of visual field. If they first had filtering surgery, 20% demonstrated progression. And so without doing any analysis as to who failed and for what reason, a recommendation was made in white patients to skip doing laser trabeculoplasty and go on to surgery. In black patients, it was about 26% and 27% who lost more visual field during that period of time, regardless of their treatment group, and so it was recommended to use laser first, it was safer. As a member of the monitoring committee, I was apoplectic that this recommendation was made without looking at the results, because what if you had done a laser trabeculoplasty and the pressure had come down nine points, the patient was doing great, and if you had found in looking at your data that was a very good thing to do, but what if you did laser and it went down two points, and you didn’t Glaucoma in the New Millennium, pp. 89–104 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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meet the criterion for going over to the other side of the study and doing the filter, that’s where all your trouble was, then the clinical recommendation should be to do laser. If it works well, stick with it, and if not go on to surgery, which is what I do. Now that the analysis has been carried out and paper seven is out, it turns out that if your pressure, by whatever means, has come down very nicely, you don’t lose more visual field very often, and that’s the better strategy. The investigators have yet to come out and reverse the recommendation. Fortunately, when I asked audiences, let’s ask the audience here, how many people skip laser trabeculoplasty and go on to surgery in medically compliant patients? OK, either you don’t understand the question or you’re using laser first. You are using laser first in a medically compliant patient. So it seems that very little harm was done by that recommendation.

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Dr Quigley: One of the great joys, actually, is that it has been conclusively shown that doctors pay no attention whatever to clinical trial results, and carry on doing whatever they were doing in the first place. But if you look at the results of argon laser angle treatment, it was about 60% successful in achieving the target as set in both white persons and black persons who participated in that study. It turned out that the surgery, trabeculectomy, in the persons who participated in the study, worked better in the white group than in the black one, which, in that study, made surgery for white people look better. But I think I am correct in saying to my patients, “If I were to do an argon laser angle treatment for you and you have just been on medicines and now you are up to two kinds of medicine and you are failing to achieve what I am setting as a target, I’ve got about a two out of three chance that, in five years from now, you will have achieved the targets we set without having surgery, and a one in three chance that you won’t”. Then I look at the patient and see their face and see what they are thinking. And they are going, well that sounds pretty good to me, fine. No matter what the race of the person is, let’s go ahead and do that treatment. The study you just heard about was one in which we still don’t know what would happen if they took account of how severe the glaucoma was in both the white and black persons, and we know that the black persons in that study had a different severity of glaucoma from their white counterparts. So, I have a bone to pick with how some of the statistics were done, and certainly how the politics was done, of reporting to you and the public that we ought to do one thing in black people and another in whites. There are ethnic differences, but that study didn’t do us a favor for ALT in that case. It did us a tremendous favor because it says that ALT isn’t great but it isn’t terrible either; it is somewhere in the middle. My two colleagues – you have a patient who comes to you for a routine exam who was found to have a cup-to-disc ratio of 0.9 in one eye and 0.8 in the other, and they have visual field defects on a Humphrey, and you establish what their baseline eye pressure is through a couple of visits, and you decide to set a target number. How do you propose to the patient that you are going to lower their eye pressure? What do you tell them? Jack, what do you tell them regarding the options they now have for pressure lowering? George A. (Jack) Cioffi, MD: It hasn’t really changed all that much for me over the last decade. I offer them medical, laser, and surgical therapy. I describe each of them in some detail, normally starting with medical therapy. I think I still hold

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with that. I think of argon laser later in my treatment course. I was discouraged by the AGIS report, more by its form than what the data actually showed. I think the data were somewhat encouraging, but the way they came out with this racial difference really didn’t help us. I generally don’t offer argon laser trabeculoplasty as an initial therapy, only because I realize that, in the vast majority of patients, it is time-limited, especially in younger patients. It is not going to be there forever. On that note, though, I will tell you that I have a very mature practice. I joined Mike van Buskirk and so I have patients who have been followed by him or me for 25 years, and I will tell you that argon laser trabeculoplasty can be redone, and in patients in whom it works well initially, and I am talking about a substantial pressure-lowering of 25, 30, 40%, and lasts for a number of years, you can redo it, even if you treated the entire angle initially, or you can treat the second half of the angle. We have patients in our practice who have been treated three and four times. Because I don’t believe this is a mechanical event. I believe it is a biological process that you are kicking into action which helps to clean out, if you will, the extracellular matrix component of the trabecular meshwork. So you can retreat. I talk with the patient and give them numbers along the lines of 80% of people with argon laser trabeculoplasty will have some response. Of that group, approximately 10% will lose that response per year. The 60-65%, or the two-thirds that Harry just listed at over four or five years, is pretty close to what I would expect, so I wasn’t that surprised by the AGIS results. I don’t generally offer argon laser trabeculoplasty as a first line. Dr Palmberg: I sit down and tell the patients that we have these three options, and I tell them that they successively have more effectiveness in some ways perhaps, but also more risk, and I also look into what the family history is, whether there is a lot of blindness, the level of understanding of the patient. We have some immigrants from some parts of the Caribbean who believe in voodoo and who don’t believe in taking more than one bottle of medicine if it hasn’t fixed them, and who really need surgery from the beginning because there is very little cultural chance that medicine is going to work for them. Also, who have no money and no insurance in the USA. There are also people who George Spaeth would say can’t be team players. Someone shows up the first time in a doctor’s office complaining that they are nearly blind in both eyes, isn’t very observant and probably not very reliable, and probably ought to be filtered in both eyes. But aside from that, a patient who shows up with lesser degrees of glaucoma, and you have reason to think that they will comply, I tell them, “This is likely to be a progressive disease in the drain of your eye. We are going to start some treatment and it is probably going to work for a while, but then we will have to do something more, and then we may need to do something more again, but it won’t matter as long as your nerve and your vision aren’t getting worse”. So at least they are prepared for this, it is not a defeat every time we go on. There are some people who say, “Doctor, I just don’t think I can take medication. It’s not natural. I don’t want to do it”, on whom I will start with laser, but it is rather rare. I usually find that I am going to go with medicine, then with laser, then with surgery. It depends on how desperate the situation is, what kind of a team player they are, and how strong their feeling is that they prefer one of these, if it is really a rational reason that they prefer one or the other.

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Dr Quigley: The audience probably knows, and I am sure you follow what is considered to be the standard of care, the Academy’s publications, for example, if you feel they are authoritative, suggest that you are obligated to tell the patient what methods of pressure-lowering are available. It would be like holding out on a woman with a breast lump that she has a variety of options for surgery, and you just told her there was one kind of surgery that you do and that’s it. So you should tell them that there is laser treatment, surgery, and medicines. We have a little brochure that we hand out to patients which includes frequently asked questions about glaucoma. By the time they get in after they have waited two hours to see me, or have been dilated and other stuff, they have had a chance to read through the stuff, so some of them will say, “Yes, I read over your little brochure. I’ve seen what it says about the laser.” But you should go over it with them. There is a very small downside risk when doing argon laser angle treatment. I guess by the time Jack gets to his fourth one, he could possibly have scarred up so much of the angle that the pressure is actually going to wind up being higher, but I have had the same experience he has, of patients who had a dramatically good effect, and it worked for five years, I will present them with the option of a repeat treatment. You will have to tell them that it’s not going to work with the same frequency that the standard first treatment does, but it can be a way of them having a continued effect from the treatment. You also have to tell them no, and here’s where you can look at a clinical trial, and have a result, and nobody behaves like the clinical trial suggests they should. The glaucoma laser trial, the GLT study, found that initial laser treatment had the same result at about five years as initial medical treatment, with the proviso that almost half the people who underwent laser had to use eye drops in addition in order to achieve the target pressure by the time point of follow-up of five years. Now the medically treated people, did they start using a drop and it always kept on working? You mean eye drops never wear off in their effect? People never wind up needing two drops in two years instead of the one that worked so well at first? I disagree that laser treatment should be presented to patients as a time-limited treatment. You mean filters aren’t time-limited too? Oh yes. Everything we do for a glaucoma patient is time-limited. So I don’t think that’s a particular downside for laser treatment as opposed to something else, until and if I am shown that the wearing-off effect is dramatically greater for one of our treatments than the other. We probably have 5% of patients who pick laser first, after what I think is probably a pretty aggressive presentation of how good laser sounds. To give you an idea, I don’t think that your patients are going to be jumping into laser, or jumping into surgery first, although I had another patient choose surgery first just the other day, after having presented him with the idea that filtering surgery is often done in some countries, even developed countries, the UK being considered a developed country I think still. Dr Cioffi: Harry, I don’t quite agree on the front of time-limitless. I think that a significant portion of ALT patients does fall out of control. I think there is substantial evidence that at least 10% of patients who respond initially (and they don’t all respond initially) lose some if not all of that control on a year basis. That’s not my experience with filters. Dr Quigley: Let’s look at the 5-fluorouracil study. Paul, didn’t you guys do...

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Dr Cioffi: I’m not sure I want to look at that one to make my case. Dr Quigley: Oh, because it was well controlled and documented? Dr Cioffi: Because I think it had other problems. At any rate, we follow our trabs on an ongoing basis and without subsequent surgery or a subsequent inflammatory event, there is very little loss over time of filtering. If they are up and running at three months, in my experience they have a decent long term, and certainly I’m not losing 10% per year. I’m not losing it in the same order that you lose with ALT, so I think it is larger with ALT. Dr Palmberg: You talk about time-limited and about doing laser and going back and doing it again. It makes an awful lot of difference in my mind when you are thinking about going back and doing a laser if all that has happened is that, after five or six years, the pressure is back up but the field has been stable all this time, versus they have dribbled away another third of their field and I’m thinking of doing it again, I am more likely to jump and do an operation. Dr Cioffi: I agree.

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Dr Quigley: I would agree with that too. I think the choices for therapy are going to depend very much on how you perceive the patient’s initial severity and how you perceive the rapidity with which they are progressing, if at all. Because, as we’ve also learned in the last few years, the majority of patients with glaucoma do not progress under mild therapy, under your observation. In fact, half the patients in the normal-tension glaucoma study didn’t progress with no treatment. So it’s those who are progressing, and especially those who Paul is describing who are apparently progressing rapidly, who you would want to be presenting with the option of the most aggressive and risky treatment, getting their eye pressure down to the 12 range probably with surgery, although in the normal-tension study, a lot of patients got to that low target range with medicine or laser treatment. Dr Cioffi: I do urge you – the point that Harry made about listing the options. We actually have a similar handout that is called ‘Options for Therapy’. This lists the three options. It discusses the upside and downside of each option. I think it should be given to the patient initially. You also describe it, but it gives them the chance to take something home and think about the options as well, because the decision is often not made at that first visit when you are starting your dialogue with the patient. Dr Palmberg: In explaining the course of the disease to patients, I think it is terribly important – patients aren’t used to chronic diseases or thinking about them, and the fact that you are going to have to do something more after time. Harry’s point about time-limitless is true, even of mitofilter. 15 or 20% of them are going to fail after five to ten years. I think that, if you prepare people in advance for this sort of thing, they are much better able to cooperate and not to lose faith in the system if there are no unanticipated bad surprises as you are going along, and they understand their role. Most people are used to going to the doctor and getting something to treat an illness and getting over it. I certainly commend the idea that there

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should be a booklet and an explanation at the first visit. Answer those questions, explain what is going on. There are some nice booklets from the Glaucoma Foundation in California and some other places that help out. Dr Quigley: The data show, though, that ophthalmologists in the USA are presently doing fewer glaucoma surgeries, laser and surgery, than you were three, four or five years ago. Does that surprise you? It surprised me. The majority of trabeculectomies being done are combined procedures with cataract surgery. Does that surprise you? It surprised me. Dr Palmberg: I think that every time a new drug comes out – when Timoptic came out in 1978 or 1979, there was a three- or four-year hiatus. When dorzolamide came out, when brimonidine came out, now with the prostaglandin drugs, it is always going to buy two or three years for a lot of patients. When laser trabeculoplasty came out, it bought some years, and then they get back on the ladder. You can expect that unless a new wonderful drug comes out, marijuana derivative or something in the next few years, that we are probably going to catch up and get back to the same numbers, because the population is aging and they are living longer and there is going to be more glaucoma out there. Dr Cioffi: My feeling is the same; it’s just a hiatus right now, and we have had some nice drugs that have been introduced over the last decade. They have made a substantial difference. It is really the first edition medically since the 1970s with beta-blockers that has made a big difference in the last few years. This has been an explosion if you look at how many drugs we had 20, 30 years ago, and how many drugs we have now. Dr Quigley: Mechanistically, 180° treatment or 360° treatment, and why? Paul? Dr Palmberg: I do 360 because, when we do 180, it fails more quickly if you don’t, and you put the patient through another period of lack of control. I don’t like to have periods of lack of control. I am not going to see this person for three or four months between visits, so I do 360. Other people will have different strategies. Copyright © 2003. Kugler Publications. All rights reserved.

Dr Cioffi: I do 180 and I don’t have an absolutely good reason for it. I will re-treat the other half some years later if the response is good. Dr Palmberg: Does it depend on the degree of damage? You’re more likely to play the whole card if there were more damage? Dr Cioffi: Yes, possibly. Often, if they are that damaged, I am going on to surgery anyway because I am not willing even to wait the five to six weeks that you really need to get your full therapy. So in general I do 180. Dr Quigley: I do 360 for the same reason Paul does, and I would add that, if the treatment worked so well that I only needed do half of it to get what I wanted a lot of the time, then I would do 180, but unfortunately, ALT, despite the fact I just said something very positive, that I think it is better than what people are using it for, it doesn’t work as well as I’d like. I am going to give it the full shot, “This

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is the laser, this is my best shot. If it gets you to your target, wonderful, if it doesn’t, let’s move on.” Then we are either going to move on to the medicines you didn’t choose first, or we’re going to move on to surgery, if the patient was a medical failure and that’s why they were getting the laser. There is a variety of lasers that you can do this treatment with. Argon is the standard, diode laser, and so-called selective laser therapy. Paul, do you want to comment on what you use and why? Dr Palmberg: I’m using argon, because it is what I have. The data show that the diode seems to work as well, even krypton apparently works as well for up to two or three years. I am intrigued by selective laser trabeculoplasty because of the fact that it does less damage to the tissue, at least as far as microscopy is concerned, and maybe would have the opportunity of being used over and over and over again. That’s exciting if it’s true. What is your take on it? I’m still learning about it. Dr Cioffi: I use argon as well because I have it. We have a diode in the OR. I use a diode in the lab, but I don’t have access to it in my treatment lanes. Dr Quigley: If you use a diode and deliver it through a slit lamp, does it have any disadvantages? Does anyone know? Are any of you using a diode? I believe it has a different spot size, so that might make a difference. Dr Cioffi: I think the smallest diode spot size is 75 µm instead of 50 µm. Dr Quigley: Do either of you actually use the selective laser treatment?

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Dr Palmberg: I don’t have it yet. Dr Quigley: We don’t have any specific experience with it and we can’t comment on it. I don’t think that the literature presently contains any overwhelming reason for me to think it is actually better, and I look forward to those who are either selling it or working with those who sell it to do more research, so that we can figure a better way. We need a better way to do laser treatment, no question about that. Does the lens matter? Dr Palmberg: One thing that I think is very helpful is to have the patient look away from the direction of the mirror as you are treating, because we are not shooting perpendicular to trabecular meshwork, we’re shooting at an angle, and the more perpendicular you can get, the rounder the spot size, the less it goes down to the iris and ciliary body, and does things that are probably not helpful. When you are looking to see if an angle is open or closed, you have the patient look in the direction of the mirror so that you can get over the iris and look down the crack, but here you want to get perpendicular to the wall, so I find it very helpful to tell the patient, “Look away from the direction of the mirror”, as this gives a much clearer, nicer view. Dr Quigley: Any other pearls, Jack, on ALT?

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Dr Cioffi: I agree with Paul. I teach this and, every five weeks, I get to have another young person do their first ALT in front of me, and one of the things they have to learn is the mechanics of holding everything, and they are still learning gonioscopy. Frankly, I think ALT was the best thing that ever happened to gonioscopy, because I don’t think ophthalmologists did gonioscopy, certainly not of the nasal and temporal angle, because it is harder, until they had to do an ALT, and then they had to realize, “I’ve got to see every single little hour of the clock going around, so I’d better learn how to do this”. All of us learn gonioscopy well, thanks to this treatment. But, as you start doing it, you will sometimes look and think it was an open angle and you get at the laser and everything looks narrow, and there is a tendency to say, “Well, I guess I’ll probably have to do iridoplasty so I can see better”. I am going to urge you not to do that. But rather, do what Paul just said. Ask the patient to look a little bit to the left, a little bit to the right. Interestingly, having them look in the direction of where the mirror is, if there is only one mirror, turns out to be much more often than random chance the right way to suddenly produce a wide open angle. Because what the patient is doing is holding the other eye closed, the eye is rolled up, and you want them to look down, or you want them to look left or right. As you go around the angle, have them re-fixate (it really helps if they have vision in the other eye), to move the other eye a little bit left, a little bit right, to make it easier for you to see the angle clearly. It is really quite rare that you need to destroy the peripheral iris in order to treat the eye to do ALT. I don’t know that it is actually bad to do iridoplasty. I just don’t like the idea if I don’t have to do it, because I think it is doing more than I need to do. So, fixation of the patient during ALT is an extremely important thing for making your life easy and for seeing better. Actually figuring out a way, as Harry alluded to, of holding the lens so that you are not constantly having to use two hands, because there is a little bit of an art to holding the lens. I actually talk about putting my middle finger underneath the lens as a support so that I can spin it on top of my middle finger, and that helps. Then you can use one hand to spin the entire angle, and so often what happens is that we’re just used to using our index finger and thumb to hold the lens. You get up there in place, you do ten spots and all of a sudden you have to readjust, your fingers are flying off, and you have to use your other hand. So bring your middle finger down underneath the lens as a support that it just rides on, then you can spin it for the whole 360°. Dr Palmberg: One other thing is that the suction of the Goldmann lens that is your enemy for finding angle closure is your friend for doing laser trabeculoplasty, because that increase in pressure deepens the angle and gives you that wider view, which is good, and also that suction lets you move the eye left, right, up and down, and the final little focus before you shoot is not moving the slit lamp. You get close with that and then you move the eye to the beam because of the suction, and that’s when you get it right on the spot and shoot it. Dr Quigley: During ALT, is the power set and you forget it, or do you change the power during the treatment? Jack?

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Dr Cioffi: I start at 800 and look for a little bit of a cavitation bubble. If I’m getting lots of cavitation bubbles, I usually back off a little. So I will bring it up and will end up as high as 1200 milliwatts in a non-pigmented trabecular meshwork sometimes. Dr Palmberg: I usually use 800, but I have almost a uniform 2+ trabecular pigmentation population. And if I had some that are pigmentary, I frequently go on down to 500 because I am already getting plenty of blanching and possibly even starting into bubbles, which I would rather not see much of. I like seeing a little contraction of the tissue at the spot. If you see that, I kind of feel that I’m doing enough. Dr Quigley: A little white spot is really nice. We’re aiming at the top of the trabecular meshwork, the top of what we call the pigmented trabecular meshwork, because that whole area is trabecular meshwork. The pigmented part is simply the area where the macrophages pick up the most pigment. Dr Cioffi: A point with this is that you only have to watch a few residents do ALTs, and you realize that they are hitting cornea, they are hitting iris, they are hitting trabecular meshwork, cornea, cornea, trabecular meshwork, and often they still work. Dr Quigley: And it works just as well as ours. Dr Cioffi: So the placement may not make a big difference, and so it comes back to why it works in the first place, and I believe that biological cascade that the burns initiate, and as long as you are in the area, it may not make any difference.

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Question and Answer Session Dr Loftfield: I have several questions, and we will start with this one. It’s primarily addressed to Dr Quigley, but then to everyone. If the pressure is always, as you say, higher in the posterior chamber so that the aqueous is flowing, do you then not believe in the theory of reverse pupillary block and pigmentary dispersion glaucoma, or is that an exception? And how do you feel about iridectomy for pigmentary dispersion glaucoma, and just pigmentary dispersion without glaucoma? Dr Quigley: All eyes have reverse pupillary block. If you were to put a needle in the anterior chamber and you attempt to flush fluid back stream into the posterior chamber in an eye that does not have an iridotomy, it won’t go. The reason for this is that the iris is plastered against the front surface of the lens in that situation. So, start with the assumption that all eyes have reverse pupillary block, but eyes with pigment dispersion syndrome have something more dramatic happen when the iris, for whatever reason, drapes backward. Now why would it drape backward more? Well, perhaps it starts closer to the zonule in the first place. This is true of eyes with deep chambers, with posterior placed lenses that are myopic, so it is the set-up, it is the pigment dispersion eye that you know and love, it’s the big myopic eye. The iris is already starting out in a position where it is near the

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zonule. What happens when Paul does dynamic gonioscopy? The iris goes back, right? What happens when you blink? The iris goes back. It goes back in all of us. Because you have raised the pressure in the anterior chamber by pushing in on the cornea, and that means that instead of convex forward, the iris goes concave. These folks probably have a set-up that their iris is already in a position near the zonule and they probably have a thinner peripheral iris than do persons who don’t get this syndrome. That is total speculation on my part. I can’t back it up at all. I just think it is probably true. Do you think it is true? Dr Palmberg: There’s no question. Dr Quigley: So, the reason why folks have pigment dispersion syndrome is a variety of the aspects of their eye, some of which are anatomical and some of which are physiological. Now, would it help to make a hole in the iris? Well, if I make a hole in the iris of many eyes, the eye is actually going to have the iris get closer to the zonule. Is that really what I want to do? I heard from my colleague, George Spaeth, that he did a number of those and it didn’t seem to affect the course of the pigmentary glaucoma. Our experience has been negative in a few cases in which we made holes in the iris, and while I think making a hole in the iris is relatively benign, it is not totally benign. The eye ought to have fluid flowing through the pupil to bathe the entire lens in aqueous humor. The aqueous humor is the blood flow of the lens. If you make a circuit breaker hole in the iris, aqueous is preferentially going to go through the hole, not through the pupils. Posterior synechiae are more likely to form, the lens is more likely, almost surely, mildly perhaps, but almost surely more likely to develop cataract earlier in life. So, if you think you are going to help someone with pigment dispersion by making a hole in their iris, in my opinion, you should also tell them that you are likely going to speed up the development of cataract, though we can’t prove either the benefit or the risk at the moment. It is a wide open area for a clinical trial, and why the glaucoma group hasn’t done it yet, I don’t know. We designed it, we handed it to our colleagues, and nobody will do it.

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Dr Cioffi: Harry, I think the reason nobody will do it is because it gets back to the ethics of it, and a number of us tried a handful of cases and weren’t terribly impressed, and to enter one of these trials, you have to say to the patient, “I don’t know the answer to this and I don’t feel that I know if it’s better or worse one way or the other”, and for the reasons you just listed that an iridotomy is not totally benign, I’m not sure that I can offer this to my patients with good conscience. I think that’s why the trial hasn’t happened. My findings are the same as yours. I don’t see the dramatic change that often is described by some of our colleagues in the convexity or concavity of the iris, and in the patients I have done it in, I just haven’t seen a marked change. Dr Palmberg: I have spent a lot of time talking to Bob Ritch and Dave Campbell about this. It turns out that there is probably a bulk transfer of fluid from the posterior to the anterior chambers when you blink. That is what is getting trapped in these eyes and pushing the iris back. I think Bob Ritch has shown very clearly that, if you have a patient not blink, this posterior bowing goes away, and if you make a large laser iridotomy, it goes away. But the little 50 µm, very small laser

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iridotomy that you make for pupillary block angle closure, and that is fine for this slow, continuous flow, apparently will not stop that posterior bowing. Apparently you need quite a bit larger iridotomy. So I don’t know of anyone who has done this up until now who has useful data. I have done about 30 eyes, one eye and not the other, and I must say that, in only about four or five of them, did the pigment preferentially go away and the pressure get better. It took four or five years. So it has been disappointing. The use of pilocarpine in the past, and the Ocusert or pilocarpine that Dave Campbell used, really did clear up pigment on that side, really did improve aqueous dynamics. There has to be some way of blocking this mechanism, but apparently making a small iridotomy isn’t it. We don’t know yet. Dr Loftfield: The next questions are about iridoplasty. First, should an iridoplasty be performed before an iridotomy in plateau iris, and secondly, can an iridoplasty cause enough inflammation to hasten and cause peripheral anterior synechiae? Lets start with Dr Palmberg.

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Dr Palmberg: I don’t think it causes synechiae. I have never seen a case where I thought it did. I think it actually opens up the angle so well right away, the problem is the decay of the effect over time. In my brown-eyed patients, it doesn’t make them look ugly or cause much of a problem. In a blue-eyed patient, as Harry points out, if we had any of those people in Miami, some of them would probably be unhappy with having gray spots on their iris. So it’s not an innocuous thing that I think you should do. In a plateau iris patient, who is really plateau iris, they have an absolutely flat iris, no pupillary block, and a very clear hump over peripheral...the ciliary body rolled forward, and you push and you can see that. All that patient needs is probably an iridoplasty and Doug Anderson has actually done a couple of these when he didn’t do the iridotomies, as he was absolutely sure that this is what it was. I still haven’t got enough confidence to be absolutely sure what was going on, and I put a laser iridotomy in all those people, and in some of the ones I was quite convinced were only a plateau iris mechanism, when I put the iridotomy in, they actually opened enough so that I didn’t have to do the iridoplasty. I don’t think you can tell. I would always put the iridotomy in first and then re-evaluate. Dr Quigley: I think that unless God told you, you don’t know whether they have plateau iris syndrome until you make an iridotomy and prove that they still get a pressure rise on dilation. Therefore, I can’t imagine that it would help very often, much as I love Doug Anderson, to think about doing iridoplasty without iridotomy, except in that pure circumstance with his kind of experience. Dr Loftfield: The next questions are about ALT, are there any downsides to it, and do you think it is less effective after cataract surgery, and does it increase bleb failure? Dr Cioffi: It is my impression, sitting next to Paul, that ALT does not hinder future filtration surgery, and that would have been my clinical impression. Before or after cataract surgery is an interesting question. Most of the data that talk about whether or not to do ALT first and then cataract surgery, or the reverse, come from the days of ECCE and not from modern cataract surgery.

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Dr Palmberg: Or even ICCE. Dr Cioffi: Actually, the initial report was ICCE, so I don’t know that those studies necessarily apply. Clinically, I am not impressed that there is much difference in response, whether I do it in a pseudophakic or a phakic eye. But that is just my clinical gut impression. Dr Palmberg: I don’t know of it, but I don’t think it is going to change what you do. It works well enough. Dr Quigley: It is not a fair comparison, because eyes that have had cataract surgery are not the same. So, does it work as well. What you care about is what the success rate is in a pseudophakic eye. So that when you are presented with a patient who is pseudophakic and you need a lower target pressure, the question is, does ALT lower it, and if so, how often. That’s true, we don’t know after phaco...what I say to patients is that it normally works two out of three times. You have already had surgery on your eye, so I think it is going to be a lower chance than that, but if it is 40% chance that it works for five years, would you take it? I think it is a reasonable approach, even though it is not backed up by huge numbers. Dr Loftfield: The next question is, assuming that 10% of extremely narrow angles go on to angle closure and that it is a really bad thing when that happens and it is much worse than an iridotomy, why not do prophylactic iridotomy on all very narrow angles? Dr Cioffi: Because of the 90% that don’t need it.

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Dr Quigley: The downside risk of iridotomy – we didn’t really talk about this, so we ought to. There are eyes that develop posterior synechiae. There is probably a higher rate of cataract in persons who have iridotomy. Of course, cataract is no where near as bad as having an acute attack. But I think there is a cost-risk benefit, a trade-off here that you would have to weigh up. One of my colleagues who is a little cynical said, “Well, we ought to go to the newborn nursery and put a hole in every kid. You know, you do circumcision, you give them the Credé prophylaxis, and then you blow a hole in each iris, and you have basically cured angleclosure glaucoma in our lifetime, isn’t that wonderful”. I said, “Well, yes, but you know we vaccinate the population, but I’m not sure whether we’re talking here about vaccinating all persons with narrow angles”. It really matters which angle you’re talking about. A little bit narrow? Kind of narrow? Dr Loftfield: They said extremely narrow. Dr Quigley: Extremely narrow. Well, I think then that we’re back to the group of persons we were talking about here in whom it looks so narrow that you think they have a disease. And that’s a clinical judgment, isn’t it? I am not sure that we all agree about this. Dr Palmberg: The only one I’m really sure about doing is the fellow eye of one that

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has had angle closure and now this one is appositionally closed a little, or is very narrow. This has been clearly shown, that 50% of these people are going to go on. And Harry, as you say, these would be the eyes to study, to try to figure out what the difference is about them, that they are the ones who go on? Dr Quigley: Do you know that is what we are doing, or did you guess that? Dr Palmberg: What, 50%? That was shown. Dr Quigley: No, that we are studying fellow eyes? The study David Friedman is engaged in right now with our Singapore colleagues is that the patient comes in with an acute attack in one eye, and in the 24 hours before they do the iridotomy in the fellow eye, we studied the heck out of the fellow eye. Dr Palmberg: It makes me feel smaller just to know I had a similar thought. Dr Quigley: I would not say that, at the present time, Medicare or anyone else would look favorably upon ophthalmologists suddenly deciding to do iridotomies on the indication that the angle looked narrow a little. So, I would say that you would have to have an extremely narrow angle. If that is the questioner’s question, then I think you are getting into an area of clinical judgment where, if you want to do that and you called it extremely narrow, I wouldn’t disagree with you.

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Dr Loftfield: The next question goes back to the nanophthalmic eye. Do you make posterior scleral windows when you operate on these eyes during cataract surgery, or only when you do a trabeculectomy, or not at all? Dr Cioffi: I do it for any surgery. I do a scleral window at six o’clock down below, I’ll do a cut-down through the conjunctiva, I’ll do a radial incision so that I get into the suprachoroidal space, and then actually I take my cautery and cauterize back the sides of that scleral wound a little so that it stays open, and then I put a single Vicryl in the conjunctiva over the top of it. I do that whenever I am entering a nanophthalmic, a true nanophthalmic, eye. I have operated on an eye as short as 14 mm and have got away with it. I also had one patient with a scleral window that I am fairly certain bled out through the window postoperatively after a trabeculectomy, and had a large tan-colored collection of fluid about four or five days after trabeculectomy. So I think they work. I think they make your case a lot easier for cataract surgery while you are doing it, because you can keep a chamber more easily. It is still not always easy, but I urge you to do it on any eye. Dr Palmberg: It doesn’t need to be a window. An L-shaped sclerotomy and maybe a little cautery on the edge, as he says, that you don’t close, is the answer. This is less likely to allow an expulsive hemorrhage of the choroid to come out. As I say, we have had zero out of 20 in Miami since we first started making windows, but now getting simpler and just simply putting in an L-shaped sclerotomy, just as you would do to drain choroidals. Dr Cioffi: In fact, what sometimes happens is that you see a patient, you know they are a bit of a hyperope with a slightly shallow chamber, and they are scheduled

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for cataract surgery. You go through risks and benefits, etc., and then a week before cataract surgery, they have their A scan and you are looking over this scan and all of a sudden you realize it is a 16.5-mm eye. I call those patients back prior to surgery, and say, “Look, you know, we found something on your scan. You have to realize this increases your risk.” I talk to them. I bring them back for a second visit. Dr Palmberg: And you ordered the 45 lens. Dr Cioffi: Yes, exactly. Dr Quigley: Doing trabeculectomy on those eyes, you may want to do some things that we do for anybody who has had a past expulsive hemorrhage in the other eye, or someone who you know has had severe positive pressure, and that is, you can pre-place the 10-0 suture on the trabeculectomy scleral flap and put Healon in the anterior chamber. For example, you put the 10-0 through the two corners of a square flap, but you don’t tie the knots down. You just have the 10-0 there. If you actually want to loop a slip knot, but not tie it up on each one of those. Now you have Healon in the chamber and you say to the nurse, “I would like to do this trabeculectomy in the next ten seconds, so you are going to hand me the Kelly punch and the iris scissors. Are you ready?” And we enter the chamber, Kelly punch, Kelly punch, iridectomy, and you close the two 10-0s. Healon is running out of the eye while you are doing that, but you probably haven’t generated an atmospheric pressure in the anterior chamber before you are done. In that way, you avoid as much as possible the situation where the pressure is very low at the front of the eye and is normal or higher at the back of the eye, and whatever bad is going to happen, such as an expulsive or other things, it had a very short time to happen. You are aware that, in trabeculectomy, it will sometimes take you a while between the time you do the trabeculectomy and you do the iridectomy, give me the 10-0, you drop it, you do this, you try to put it through and there is some blood, you have to clear it, it could take you a couple, three, four, five minutes to do that.

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Dr Palmberg: There is another way, and it takes two seconds. When you are putting your Baerveldt in, you pull the 23-gauge needle out and stick the ligated Baerveldt in, it takes two seconds to pull one out and put the other in. You have no decompression at all. I have started doing this on Sturge-Weber cases because it was even happening with the posterior sclerotomy, some small exudative retinal detachments. If you angle this tube quite nasally and in the far periphery it will never touch the lens, no matter how dilated they are, and you are not going to have an explosive decompression. I have not seen, so far in a small series, any of these kinds of problems. So that is another potential approach. Dr Cioffi: Then you put them on prayer q.i.d. afterwards. Dr Palmberg: All my patients are on prayer q.i.d. Dr Loftfield: In those patients, those rare patients who do have visual complaints after iridotomies with either double vision or a white line, and can be quite mis-

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erable, what do you have to offer them in the way of treatment to make them happier? Dr Cioffi: I haven’t actually found a good solution, to be honest. You could talk about colored contact lenses and things like that, but avoidance, in this case, is your best hope. I have a couple of them that let me know it each time they come in. Dr Quigley: I had a patient who got to the point of almost ordering a contact lens with an artificial pupil in the center of it, and then he didn’t do it because he said his symptoms got better. He was a contact lens wearer, so it would have simply been a matter of changing to a different contact lens. Dr Palmberg: Yes, all these colored contact lenses for changing iris color would be ideal for it if the person wanted and needed to wear a contact lens. Doug Anderson says that, if you make the laser iridotomy somewhat larger, it is less of a problem. I have never done that. I offer you that. I have one patient in whom I was going to sew it shut....They decided not to do it. Dr Loftfield: The next goes to the physiological and provocative testing. What test do you use and, specifically, what about the water drinking test? Dr Quigley: Who remembers water drinking tonography? Congratulations. You’re not that old. Actually, water drinking was predictive of open-angle glaucoma, development of field loss, but it is not something you would do pragmatically. A liter of water in 15 minutes is not something that we are doing now. I use a mydriatic provocative test in everyone, except in those I think are extremely narrow, as we talked about earlier, and I also perform darkroom tests. I don’t think my colleagues probably do. Dr Loftfield: Actually, they were asking what mydriatic you use for that?

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Dr Quigley: I use 1% mydriacyl, one drop. Dr Palmberg: My darkroom provocative test is to do gonioscopy in the dark, and as you sit there watching, in about nine or ten seconds some of these narrow angles just simply close, and if they have appositional closure, I do it. I do this because of a patient who came over from Miami Beach one time for a fifth opinion, said “It is two to two, you’re going to decide.” And after I said, “Well, I think it is narrow but open”; she said, “How about a darkroom provocative test?” I just watched it in a dark room and it closed, and that is when I realized that not putting light through the pupil was important. Dr Cioffi: I use 1% mydriacyl as well. I don’t use a darkroom provocative test. If I am that worried, I will probably put an iridotomy in. Dr Loftfield: The last question before we break for lunch. In the last five years, have you been able to treat all acute angle closures with laser iridotomies, or have you had to do a surgical iridectomy?

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Dr Cioffi: I have done one surgical iridectomy in the last five years. Dr Palmberg: I haven’t done any in 20 years, but I think this is because the people in the community solve all these. Dr Quigley: I have done two surgical iridectomies in a decade. Dr George Ellis: My question is related to the role forward of the ciliary body. Last year, we heard some talks about scleral expansion in order to treat presbyopia, and I am wondering if there is any kind of relationship with this rolling forward of the ciliary body with presbyopia, and does this fit in anyway? Dr Palmberg: At least the refractive error of these patients is not usually the high hyperopic values that you see in people with angle closure. Their amount of presbyopia did not impress us as being unusual for people between the ages of 30 and 60. We did not test their accommodative ability, but, for example, none of the people aged from 30 up to 40 required bifocals prematurely. Dr Quigley: Did the folks who gave the lecture on scleral surgery for presbyopia give you all kinds of data, or was it mostly theory? Because I think our worry is that we don’t know enough about what would happen if large numbers of people underwent some sort of procedure. I take it they were talking about the scleral surgical procedure? Dr Ellis: A scleral surgery procedure, yes. But I don’t think there were large controlled studies. I think this was theory and a couple of examples.

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Dr Quigley: Yes, there are a couple of really smart people who proposed that, George, and when you look at what they are talking about, it really sounds plausible. So you have a plausible hypothesis. You just don’t know what is going to happen to a lot of eyes if you do it. If you told me that LASIK would work and a million people would be getting LASIK, I would have said no, so that shows you, don’t bet on what I say about the stock market. I would bet on data, though, on that procedure, and I don’t have any. It could very well change the position of the choroid and the ciliary body. For all I know, it could help. We talked about scleral windows here. I think if you thin the sclera and you allow fluid to flow faster out of the suprachoroidal space, you are probably going to help all sorts of glaucomas. Dr Ellis: It would be interesting if people who had the ciliary body role forward had a diminished accommodative range, their ability to accommodate was less than, say, age norms or age-matched controls. Dr Palmberg: We will check it on our next 24 patients and, when I am 96, I will come back and tell you, because it would take me 30 years to get enough patients. Dr Loftfield: Thank you for all the questions.

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The Optic Nerve Head

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Evaluation of optic disc and nerve fiber layer in glaucoma Clinical techniques

Joseph Caprioli

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Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, CA, USA This is a review of the clinical evaluation of the optic nerve and nerve fiber layer. Figure 1 shows a pair of optic nerve photos from a 40-year-old patient. He is a bricklayer and he has had pressures in the right eye in the mid-thirties and pressures in the left in the mid-twenties for some years. Despite acquired cupping in the right eye, this patient’s visual fields remain normal in both eyes. The next example is of a different patient, the same eye imaged over a two-year interval (Fig. 2). Let me draw your attention to the inferotemporal rim and I think you will see that there has been a significant change there, a notch developed with thinning of the neural rim, and you can look at this vessel and see how this vessel has dipped into that notch. The vessels will give you clues as to where to look for changes in the neural rim. Despite this progressive change over that two-year period, this patient’s visual fields remain normal, at least to standard automated perimetry with white stimuli and a white background. These examples demonstrate how the visual field and disc can progress over time in some patients with glaucoma. In general, we first detect structural change up to some threshold, at which point our psychophysical functional measurements become abnormal. As the disease progresses, both the functional and structural abnormalities tend to get worse. Later in the disease, there may not be much left of the disc (Fig. 3). The disc can be pretty bad, almost totally cupped, and we can see continued changes over time in the visual field as the patient gets worse. Early on in glaucoma, it makes sense to pay particular attention to the structural characteristics of the eye, the disc and the nerve fiber layer, and later on in the disease, to follow functional tests as a more sensitive measure of progression. We are going to focus on this early part of the disease and on different ways of evaluating structural characteristics of the nerve. The direct ophthalmoscope is sometimes useful when you have patients with miotic fixed pupils, but whenever I want to have a good look at a nerve, I dilate the eye and perform a good stereoscopic examination using a hand-held lens at the slit lamp, in addition to disc photographs. The worst way to look at a disc is with Address for correspondence: Joseph Caprioli, MD, Jules Stein Eye Institute, UCLA School of Medicine, 100 Stein Plaza, Suite 2-118, Los Angeles, CA 90095, USA. e-mail: [email protected] Glaucoma in the New Millennium, pp. 107–114 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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Fig. 1.

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Fig. 2.

Fig. 3.

an indirect ophthalmoscope. Discs usually look better than they really are with an indirect. The disc is small and has better color when you use an indirect ophthalmoscope, and I think this is because you are illuminating a large portion of the surrounding choroid and the ‘redness’ bleeds into the disc.

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Fig. 4.

Particularly in the early stages of glaucoma when you are looking for early or small structural changes, it is mandatory to use a magnified stereoscopic view at the slit lamp. Cup-to-disc ratio estimates are not sensitive or specific indicators for the presence or progression of glaucoma. We may think that, “Well, if I’m looking at this disc every time once a year and I’m making the same estimate, then I’m pretty good at these estimates and I can detect small changes.” It has been shown that we are quite variable in our estimates, even those of us who do this for a living. Finally, in clinics where there may be different doctors, particularly in a fellow or resident clinic where there may be different practitioners seeing the same patient over time, cup-to-disc ratios are useless and counter-productive. Photographs are the best way to document the appearance of the optic nerve. Second best would be careful drawings; a drawing is much better than a cup-todisc ratio estimate because you can show where the neural rim may be thin, where there may be a disc hemorrhage, where there may be some undermining of the edge of the disc, where the lamina is there, etc. (Fig. 4). So, drawings are second best to photographs. The best sign of glaucomatous damage is progressive loss of the disc rim. In Figure 5 a few examples of progression are shown which I think we should all be able to detect in our practices. There is sometimes a sentinel vessel sign, and if you go back and examine the rim on the right, you will see that a new notch has developed between 6:00 and 7:00, and that this vessel has fallen into that notch, and that there is a real change for the worse. You would not be able to pick this up with a cup-to-disc ratio estimate. In the next example, the neural rim in follow-up has become much thinner and in this area the disc is cupped right to the edge (Fig. 6). This is a real change which I think is clinically significant and one that we should detect. A very careful drawing might detect this change. A cup-to-disc ratio estimate by the best of us would probably not suggest a change, but clearly a comparison of photographs will show it very nicely.

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Fig. 5.

Fig. 6.

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Next is an example of a patient with a disc hemorrhage with follow-up showing some progressive loss of the neural rim in the same area (Fig. 7). This loss of the neural rim is not huge, it is fairly subtle, and if this disc hemorrhage was not here, perhaps we would not even pick it up. You certainly would not pick it up without the use of photographs. I usually get photographs at baseline and occasionally during the course of caring for the patient. I do not think you need to get them every six months and maybe not even every year, but comparing your examination to the photograph is certainly better than not having a photograph at baseline. I think you can pick up small changes if you are comparing photographs with photographs. I recommend, particularly in patients you might be concerned about, getting sequential photographs. Disc asymmetry is a very useful sign. Of course, disc asymmetry does not have to be present in order to have glaucoma, but glaucoma is often asymmetrical, and you will see differences between left and right eyes. One little caveat is that if you are going to compare the appearance between left and right eyes, the size of the disc should be the same in both eyes since larger discs will typically have larger cups (Fig. 8). If you have a situation in which the two eyes have different-sized discs, which is rather unusual but certainly happens, then your evaluation of disc asymmetry should take this into account.

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New focal loss

Fig. 7.

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Fig. 8.

Disc hemorrhages only occur where there is nerve tissue left to bleed. Disc hemorrhages will not occur at a sharp edge of the scleral canal where all neural tissue has been lost. There is nothing there to bleed, but right next to that area, where there is presumably ongoing damage and some neural tissue being fed by vessels, there can be breakdown of the vessels and a disc hemorrhage can occur (Fig. 9). We know that the presence of a disc hemorrhage is a sign of poor prognosis. Individuals with disc hemorrhages are more likely to progress over the next few years than those without, and this has been shown in a number of studies. Peripapillary atrophy is another non-specific sign of glaucomatous damage. This kind of atrophy is the irregular area of hyper- and hypo-pigmentation. Peripapillary atrophy tends to be greatest where the neural rim is thinnest (Fig. 10). Whether this is a precursor of neural damage to the disc or a consequence thereof, we really do not know; in a prognostic sense, it may be similar to a disc hemorrhage. There

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Fig. 9.

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Fig. 10.

is a correlation between progressive peripapillary atrophy and progressive disc damage. In a study we conducted a couple of years ago, we were able to show that progressive enlargement of peripapillary atrophy was correlated with progressive disc and field damage. There is a loose correlation between loss of the neural rim and enlargement in this area of peripapillary atrophy, but we cannot say anything about cause and effect. Another sign of glaucomatous damage which I am interested in is so-called ‘focal ischemic glaucoma’. Spaeth was the first to coin this term, which describes a very focal change in the optic nerve, which I would consider a subset of a notch. It is probably a form of a notch, but it is slightly different in that it occurs very focally, either at the slightly temporal inferior pole of the disc or at the superior, slightly temporal pole of the disc. It can be very deep, so if you imagine that this neural tissue is made of soft butter and you stick your finger straight into it and take it out, this is what would be left, this very focal deep, for lack of a better word,

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Fig. 11.

pit (Fig. 11). It should not be confused with a congenital pit, but is rather an acquired pit from glaucoma. A true acquired pit is separated from the central cup by some intervening tissue which differentiates it from a notch. At the bottom of this pit, the lamina cribosa looks altered and has a grayish appearance, and the laminar pores may be stretched and large. The pit has peculiar characteristics and it has been described by various names. The use of the word ischemic is, I think, unfortunate. We have no idea whether or not it is ischemic in nature, but it is similar to the presence of a disc hemorrhage, in that we were able to show that the presence of a pit is a poor prognostic factor. We match patients for the stage of glaucoma, pressures, and other variables, except for the presence or absence of an acquired pit. Those with acquired pits had a much higher rate of disc and visual field progression over a five-year period than those without.1 We think that this is probably a sign of progressive damage, and it may very well be an indicator of poor prognosis. A frequently asked question is, “Should I examine the nerve fiber layer in glaucoma and, if I do, how should I do it?” There are diffuse and localized types of nerve fiber layer loss. In Figure 12, we can see large wedge-shaped defects both superiorly and inferiorly which we would classify as a focal type of defect. In addition, there is probably diffuse nerve fiber loss throughout as well, which is harder to call in the early stages, but is probably more specific when it is more advanced. You can detect nerve fiber layer loss with dilated direct ophthalmoscopy and a red-free light. The easiest way to detect nerve fiber layer loss is to take photographs utilizing a special narrow-band filter in your camera and a highcontrast film and development process. Figure 13 is an example of a patient with no glaucoma in the right eye, angle recession glaucoma in the left eye, and diffuse nerve fiber loss in the affected eye. The thin striations that can be seen in these bundles in the normal eye are really quite normal. Defects should be wedge-shaped and point to the disc. In the left eye, rather diffuse severe loss can be seen, which is fairly extensive. The striations that are normally there are lost. The fundus looks a little bland because the structure from the internal retina is missing, and the small vessels actually stand out in

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Fig. 12.

Fig. 13.

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relief because they are now more visible. They are not buried by the nerve fiber layer. In younger patients, glaucoma suspects, ocular hypertensives, or if the disc does not quite look normal and we really need better evidence to say that it may be abnormal, I would look for nerve fiber layer loss. I pick and choose patients to do a careful nerve fiber layer examination. Careful structural evaluation of the optic nerve and nerve fiber layer is an important diagnostic step and should be performed in all patients suspected of having early glaucomatous damage. References 1. Ugurlu S, Weitzman M, Nduaguba C, Caprioli J: Acquired pit of the optic nerve: a risk factor for glaucoma. Am J Ophthalmol 125:457-464, 1998

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Round table How I follow the optic nerve head and nerve fiber layer: my step by step approach Claude F. Burgoyne, MD, presiding Panel: Joseph Caprioli, MD George A. (Jack) Cioffi, MD Harry A. Quigley, MD

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Dr Caprioli: We have a round table discussion on how I follow the optic nerve and nerve fiber layer, and there may be some diversity of opinions here, and I think that would be useful to explore. After this session, we will have a question and answer session. Dr Quigley: Looking at the nerve fiber layer for me is something I do more often because it is something we began doing a long time ago and did a bunch of studies on, and it’s free. You are looking at the stereo appearance of the optic disc in white light, and all you have to do on your slit lamp is to flick a green filter in and look. The situations in which it is really helpful include the discs where you are looking at somebody with a 0.6 cup bilaterally. The question is, is that a physiological cup or is it early glaucoma? If there is nerve fiber atrophy, it would really swing you in favor of either following the patient more closely or starting treatment on someone if they had normal fields. If they have a field defect, obviously you don’t necessarily need the nerve fiber layer, except as confirmation that it is not a phoney field, and there are people who have a field defect that goes away with practice. The second is an asymmetric case where you have a 0.7 cup on one side and 0.4 on the other. That is beyond the population frequency of asymmetry, enough that you would say, “Boy, 0.7 and 0.4”. Could somebody have that physiologically? They could, but if the nerve fiber layer is poorly seen on the side of the 0.7 cup and beautifully seen on the 0.4 side, you have just had confirmation that there is early damage in one eye. If nerve fiber loss corresponds to the field defect, and that is also where the notch is, again, it is a situation where it is helpful. The question is, how do you do it? How do you look at it? For some years, I tried to teach this in lectures showing people, and everybody said, “Yes, the pictures are kind of pretty, but I went home and tried to do it in the office and I couldn’t”. So I wrote a book on the subject. The book sold out. Nobody seems to be doing it. So, I am glad there are machines that are now doing it, or at least attempting to, because I think it will help you.

Glaucoma in the New Millennium, pp. 115–128 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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Dr Caprioli: Jack, your view on where the nerve fiber layer exam fits in to your practice. Dr Cioffi: I think it fits in even more often perhaps than Harry suggested. I examine the nerve fiber layer in virtually all patients, because it is one more clue about progression. I don’t take photographs of the nerve fiber layer because we don’t have a photographer who really gets reliable, reproducible photos to the extent that Harry has been able to do. As he said, it’s free. You are sitting there. All it takes is to flick the light over to green, and you can do it on virtually any patient. His examples are right on, but I think that in any patient in whom you are questioning progression, you can add it to the drawing of the optic nerve as you are taking notes. It is hard to get reproducible numbers, just as Joe mentioned, with the cup-to-disc ratio without having the photographs, but you can get an idea. And certainly the presence or absence of a new wedge defect you can recognize if you look each time. So, I would urge you to do it more often than not, and even if you can’t take the photographs, the beautiful photographs that we are showing, you have the green light on your slit lamp.

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Dr Quigley: In trying to teach it, we found that one of the ways you can learn to do it yourself is to look at eyes in which the patient has definite damage in one eye and has a normal eye on the other side. This lets you try to see some of the things that were being illustrated here, that there is a dense pattern in the normal – but it looks like a mat finish when they are not there. The blood vessels are very clearly seen when the nerve fiber layer is gone, because they are not buried in nerve fibers. So, when somebody has bad field loss on one side and a normal eye on the other, do try to look at the nerve fiber layer in both eyes. What you will see is the normal pattern in the left eye and what atrophy looks like on the other side, live. As we have tried to evaluate in studies, the photographs are extremely helpful, and in fact you can see the pattern much better in pictures than you can clinically. I don’t mean to say that it is an easy thing to do, and the photographs do help. The problem with the photographs is that you have to dial the Zeiss flash fundus camera up to flash 6, and it is really bright and patients don’t like it and that’s why they like the GDx Nerve Fiber Analyzer (GDx, scanning laser polarimetry) and Heidelberg Retina Tomography (HRT, confocal scanning laser tomography). The laser images don’t have a big flash. Dr Caprioli: Claude, do you have anything to add to that? How do you mesh those two techniques, optic nerve and nerve fiber layer exams? Dr Burgoyne: Joe is asking me a tough question. Having trained with Harry, I got wonderful experience with the nerve fiber layer, and at LSU we had a hard time getting consistent photographs. However, clinically, I use it to confirm nerve fiber layer loss in patients in whom I am confused by the appearance, and in addition to the ways that have been outlined, I believe that sometimes you have change in the rim or loss of nerve fiber layer that isn’t associated with change in the rim. You might look for pallor, but nerve fiber layer dropout can occur before the pallor, and I use it in that situation as well, in addition, of course, to the others that have been outlined.

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Dr Caprioli: To get an idea about how important you think it is, if you took, let’s say, 100 patients with glaucomatous damage, let’s leave it at that, a fairly broad category of patients, and you’ve done a careful optic nerve exam and a careful nerve fiber layer exam, and you have the field in front of you, in how many of those 100 would you think that adding the nerve fiber layer exam really added to your ability to follow that patient over time or to detect something different that you didn’t detect in the nerve? Dr Quigley: I read a paper once by Caprioli which said that the nerve fiber layer didn’t add much, although its information was almost as useful. Is that a summary of the manuscript? Dr Caprioli: Yes.

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Dr Quigley: So you could get the information from the nerve fiber layer, you could get it from the disc. There were some additive features that were good. We followed a group of 800 glaucoma suspects for 11 years and took pictures of all of them, and we looked as they went from no field loss to field loss, going back up to 5 years prior to the time that they developed their field loss. The idea was, which technique would best predict which person was going to get their first field defect. We looked at both color disc photos and at the nerve fiber layer pictures in a masked fashion, and were a little disappointed that the cup change was not detectable to us except in about 20 or 25% of eyes before there was field loss. They had suspicious discs. If you just looked at a basic disc, the basic disc was a 0.6, 0.7 cup, you would have been suspicious. That was a high level suspect. But the disc didn’t change as often as I would have thought. The nerve fiber layer changed 50% of the time before there was a field defect, in our readings of these ideal photographs that we are talking about. So, I think that instruments, or an experienced human who can detect the nerve fiber layer, can detect persons who are actually progressing to the early stage of initial white-on-white visual field loss. Dr Cioffi: I think we are all saying the same thing. I just think it is one more piece of the pie. It gives you a little more confidence in the difficult patient. I don’t think most of us have the availability of photographs. I don’t think it is easy for patients or easy to get reproducible photographs, and so we have to rely on our clinical abilities, and I think it is worth adding, especially in the difficult nerve where you are up in the air with the asymmetry that Harry talked about, or the Clairol patient – does she have glaucoma or doesn’t she? Those are the patients in whom it is most helpful. Dr Caprioli: Let me just add one comment, if I may. And that is, we’re talking about these two exams as if we are looking at different things. We are looking at the same thing in two different places, of course. We are looking at the nerve fibers as they are crowded toward the disc, or we are looking at them once they are splayed out over the retina. The way I often think about it is that small, early defects, particularly if they are focal, can be lost in the mass of fibers once they have congregated at the disc, but if you take them and you spread them out over the surface of the retina, they are more often detected as a nerve fiber layer defect. So, my opinion is that, in early disease, you can substantially add to your detection rate of abnormalities by adding the nerve fiber layer exam, whereas later in the

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disease, it is often not all that helpful. That is my view. Dr Quigley: By the time there is moderate field loss, you can’t see the nerve fiber layer at all clinically. Ask yourself, when is the nerve fiber layer exam not helpful? By the time you have a mean defect of –10 dB in a Humphrey, the nerve fiber layer has gone, forget it and the disc is blown. Well, that is Joe’s point. By the time you are halfway into the damage pattern of glaucoma, which is really 75% of the way into the optic disc, you are on fields entirely. Dr Caprioli: I would assume that every one of the panel members gets photographs of the optic nerve at least at baseline. Let’s say in a patient that we are going to continue to see in the future. Am I correct in that assumption? Yes. Now what I would like to know, and I think what the audience would like to know, is how do you use those baseline photographs? Do you examine the patient ever so often, sequentially compare your exam to those photographs? Do you re-photograph the patients? If so, how frequently do you do it and what kinds of patients do you do, and so forth? Claude, why don’t we start on this end with you.

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Dr Burgoyne: Joe is being nice enough to include me in the discussions. We have a tradition here of the local presenter chairman staying out of the discussions, and I think maybe I’ll do just that... I know that Harry tends to be a bit of a junkyard dog and he is the kind of person you want on your side. I am actually glad you brought it up, Joe, because I feel strongly about photographs as opposed to the newer imaging modalities, which we are all excited about and which we hope will come into clinical practice. The one thing that we should all be doing is taking good photographs. I do it at baseline, and then I do it subsequently whenever I am concerned about change. Sometimes it is to confirm a change. Sometimes it is because the visual field has changed, I don’t see anything in the nerve and I want to know. Sometimes it is because, as Joe mentioned at the end of his talk, you just think it is about time to reassess, because there are two levels of variability in the assessment. First, you are looking at the optic nerve through the slit lamp through a dilated view, and it doesn’t correspond to the 2X photo. The views are different. Second, photos don’t correspond to one another, and so sometimes I get nervous and I’ll just get another set of photos and look and see how much variability is present in the photos, illumination, clarity, stereo, compared to the original ones. These are the ways I use photos, not on a routine basis, but when I feel I need them. Dr Cioffi: I actually do very much the same as Claude. I get them at baseline for a couple of reason. One is for the baseline measurement so that I can look later. The other is that we have an HRT which we will touch on later, and I believe to draw the contour line on an HRT at baseline, you actually need a stereo disc photograph. You can’t draw without it because, if you are going to be consistent in getting the line at the scleral exit, then you have to have something to go by. Often the image on the HRT itself isn’t sufficient. We literally have thousands of patients in various studies, following them over long periods of time, and you can’t just draw those circles without it. So back to clinically, I get them at baseline. I don’t have a set pattern of when I get them. Similarly to what Claude just said, I get them when I am concerned about change. When I see something that alerts

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me to look in an area more carefully. But what we never talk about is how we actually use them. What I do is – the technician who is working up the patient actually pulls out the disc photographs and, in my top drawer on my writing table is a light box in each room, and I pull out the light box and so that the photos are there ready for me when I walk into the room, it forces me to acknowledge them. I use them as I look at the patient. I will look at the photographs and then I will look at the patient and then I’ll go back to the photographs, sometimes three or four times even. I’ll say, “Sit back a second”, and I will look for a particular feature. I actually do use them quite intensely when I am looking at patients. It’s not all patients whose optic nerve you can get a look at every time you see them, but I make a point of getting a very good look, dilated if need be, at least once a year, as I am following the patient for the optic nerve. I try every time, but sometimes because of cataract you can’t, and I certainly don’t dilate patients on every three- or four-month visit. I use photos constantly, it is part of the routine in my clinic.

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Dr Caprioli: Harry, do you do anything differently? Dr Quigley: Yes, a little bit differently. I did a study in which I asked if I took pictures every year, so that I had annual photography, and then I played the game of only using the information from every fifth year, would I actually have decreased my ability to see change in these glaucoma patients? And the truth is that glaucoma moves slowly enough that we proved in that study to my satisfaction that, in most cases, I wouldn’t have lost a lot if I hadn’t done the photos every year. If you feel comfortable doing them every year and you think you might get information, you are probably giving Cadillac care. But the pictures are very uncomfortable and they are expensive. I am not sure that annual photography is something that I could justify. I take pictures every five years, and, as these gentleman said, I examine with a 90-diopter lens every single time the patient is in, which is typically twice a year. On one of those annual visits, they get dilated for the rest of their exam. The other time, you can use a 90 and look through most pupils very nicely. It was one of the nice things about the hand-held indirect lenses when they came into use. You are looking for a disc hemorrhage, or for some dramatic event that has happened in the back of the eye. Bear in mind that the clinical exam, as Claude said, doesn’t look like the photographs. Clinical stereophotographs do not have the depth of field that the live human does when you look at them at the slit lamp. Often you will look and you will say, “Oh my God, the disc looks much more cupped than in that photograph”. And you take some more photographs, then you lay the photographs side by side and darn it if they don’t look identical. The difference was the beautiful depth of field you get live on the human compared to the photo. So don’t be fooled by that particular aspect of it. I agree with the comment about the HRT. We have a technician who does the HRT exam, and then I look at the HRT and I compare it with what the patient looks like, and have the technician redraw the line so that the baseline HRT will more closely match the patient’s real disc. Dr Cioffi: One other practical note is, in a busy clinic, if you are trying to take photographs more often and to judge your treatment on it, it becomes a bit of an issue because you don’t get the photographs back for a few days or a week, and

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so you have to carve out a portion of time to actually look at them and compare them with the old photographs. It is reassuring to hear Harry’s one-to-five year jump, because I think it is true. On a practical note, I don’t know if you can do it much more often than that. Dr Caprioli: If I may add two cents to this too. I think it is difficult to compare your exam to a photograph for the reason that Harry mentions. For that reason, I actually get serial photographs. The frequency is variable and I absolutely believe what Harry just said that one year is probably overdoing it. I probably do it every one or two or three years, depending on the patient, and I agree that that is probably overdoing it, but I think if you wait until you are suspicious on a clinical exam, you may already have missed something you could have picked up much earlier. For that reason, I tend to do them sequentially and to compare photographs over time. If you are going to do that, you have to make it easy on yourself, the practical aspect of it. What I do is to put the slides in these plastic sheets and organize them left and right stereo for the left eye, left and right stereo for the right eye, the oldest ones at the top, and then go down chronologically. You should have a light box in every examining room. You can rapidly compare those discs over time by using a magnifier or viewer and compare them one to the other. Unless I am particularly worried about someone, I don’t actually look at the photos until the patient comes back the next time, which may be after six months or a year. It sounds like I am not missing too much if Harry’s five year figure is right. Dr Cioffi: If you are taking them every two years and they are not coming back for another six months to a year, you have really lost the benefit of taking them more often because there is another year delay before you evaluate the photo. Dr Caprioli: I think there is some value to taking sequential photographs and I think the interval is up for grabs. Thank you very much for this round table discussion, gentleman, and I think Dr Burgoyne would like us to move into the question and answer session, so I will turn it over to him.

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Question and Answer Session Dr Burgoyne: I am sorry to have to move in this direction, and the only reason I pushed it was because we have a lot of questions and they are really good, and I think they will prompt a lot of interesting discussion. In routine glaucoma suspect patients, what screening visual field test are you using? Dr Caprioli: Is this a patient with risk factors for glaucoma but a normal disc? Dr Burgoyne: I think a glaucoma suspect. So let’s throw out the idea that they have no risk factors other than that their nerve is suspicious. Dr Caprioli: First, we obtain a Humphrey 24-2 SITA-standard white-on-white. If that is normal, I would now generally add a blue-on-yellow to that, at least at baseline.

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Dr Cioffi: That is exactly what I do. I may not add the short-wavelength at that visit. If I am suspicious enough then I am going to see them back in six months and if the white-on-white is totally clean, then I will just possibly do it at the next visit. It depends on my level of suspicion about the patient. When SITA (Swedish Interactive Threshold Algorithm) came out, we had to make a decision as to whether we were going to do SITA-standard or SITA-fast on everyone who came in. The decision in our glaucoma group was to use SITA-fast. We save two to three minutes per patient. We potentially lose some form of detectable glaucoma which is as yet unknown. Our patients are, in general, extremely happy with SITA, and I think it was a good decision on the part of Humphrey to go that way. We hardly use blue-on-yellow perimetry. The chief reasons for that are that it is arduous, extremely difficult, and in my opinion, the normative database is inadequate for representing the general population. As a result, nearly everyone has an abnormal blue-on-yellow field in some way or another. I think that, under ideal conditions, the blue-on-yellow test, in Chris Johnson’s prospective study, shows that the test is able to detect abnormality, and almost surely does so before white-on-white does, under the right conditions. But I don’t think we have a practical way of using SWAP (Short-Wavelength Automated Perimetry) yet, and until there is a SITA-SWAP and we have a better database for it, I am not going to be using it. Dr Cioffi: I actually disagree on two points. The first is SITA-fast. I don’t think it buys you that much. These are generally younger patients, they take fields fairly quickly, and I am not willing to accept the increased variability on a patient on whom I am trying to pick up new disease for saving a minute per eye. I don’t think you save two or three minutes; I think it is less than that. I actually use SITAstandard and never SITA-fast. On the blue and yellow front, the normative database (I guess we were part of it so I like the normative database), especially in younger patients without cataracts, I don’t believe it is that difficult a test, and I don’t believe that the normative database is that insufficient. In fact, if you look at just the gray scale, all the gray scales look bad, but the pattern deviation plots don’t actually look bad. I think it is a valuable test. That said, we sorely need two things with SWAP. We need SITA-SWAP, and Humphrey has that message and I think they will develop that. It needs to be a quicker test, so it is easier. Another thing is we need is a Statpac type format where we can follow SWAP over time, and we don’t have that availability right now. Dr Caprioli: I have become sufficiently comfortable with SWAP. Actually my initial opinion about this was much like Harry’s, but I have used it despite that to try to get some experience with it, and it is a very noisy test. There’s no question about that. But if you do have a patient whose abnormality exceeds the noise, and occasionally you have those with normal standard perimetry and a suspicious disc, that finding of a scotoma on SWAP can actually change the way I take care of the patient or the way I follow that patient. So, I think it is a useful addition in selected patients. My opinion about following for change over time with SWAP is that it is going to be very difficult, simply because of the huge noise and fluctuation of the test. Dr Quigley: Just quickly, and Jack may want to comment again, when we said to Humphrey, “You are doing a standard algorithm test that is much too long and

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what is happening is the patients get tired and you are getting unreliable information, make the test faster”, “Oh, my God, we can’t do that, it will change everything”. I think those of us who have been using SITA fields for some time, and I think Jack agrees with me, have realized that patients give more reliable answers and therefore, in a faster time you get a better answer. He and I can sit here and talk about which one we like, SITA-fast or SITA-standard. The truth is they are relatively close to each other. One is a little faster. I am opting for a slightly quicker test. He is hoping that, by spending a little more time, it is more reliable. You should do what you want. Dr Burgoyne: Let me jump in and ask the next question. Do you consider the SITAstandard or SITA-fast test to be adequate for following glaucoma patients for progression? Since you have already said that you are using it, what is it you are using as criteria?

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Dr Quigley: We have a real problem in that we have a situation where there is no new software being provided by the company, and the company will not allow us to get the data output in a usable computerized format from SITA-standard or SITA-fast. It has been encoded in a way that they won’t let us touch. This is particularly unfortunate because what we could do from our center in less than six months would be to provide you, through the Internet, with software that monitored progression in a variety of ways, and I would do it through free shareware. It is pretty clear that this is not going to happen anytime soon until we can crack what is coming out of the SITA data stream. Therefore, we are left sitting there laying them out on a table comparing them, almost as we were eight or nine years ago. Because you don’t have the kinds of regression comparisons and glaucoma change probability comparisons that we used to have. What you can do is look at the pattern standard deviation (PSD) and look for changes like the loss of a decibel per year. That in linear regression in the previous fields was a serious loss measure. So, a PSD, if it is going down by one or more per year, that is way beyond the standard that would occur in anyone of age, and is equivalent to what was going on, we hope, in the standard algorithm. The second is we look for individual points that have become statistically abnormal in the total deviation plot, particularly when it is the same point more than once in consecutive three fields, when it is a cluster of more than one point, but you are doing it manually, you are doing it by looking at it, and that is really pretty arduous. So I think we, at the moment, are stuck doing things like this. Maybe my colleagues have better ways. Dr Caprioli: There is no statistical test that has been shown to be any better than just looking at a series of visual fields. The point-wise linear regression approach may turn out to be the best approach, setting some standards for minimum change, as well as statistical significance. But until that has been developed and has been tested in sort of a rigorous and longitudinal way, I think we are stuck with just evaluating fields over time. Just a couple of basic points about how to do that without getting into too much trouble. You need a large number of fields in order to deal with the noise of the test. You need to establish, at least in your mind, some magnitude of what the long-term fluctuation and of what the noise of the test is, and then you need to demand that any change you are going to call progressive

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damage needs to exceed that magnitude of long-term fluctuation. This is how I actually evaluate fields over time and in a sort of qualitative semi-quantitative way. Until we get better and validate a statistical test, I am afraid we’re stuck with that approach. Dr Burgoyne: What conditions other than glaucoma lead to nerve fiber layer loss, and how does the pattern of nerve fiber layer loss differ, for example, a disc drusen? Dr Quigley: Anything that kills a ganglion cell is going to lead to nerve fiber loss. So, multiple sclerosis, brain tumors that affect the anterior visual pathway, ischemic optic neuropathy, they all lead to nerve fiber layer atrophy. They don’t lead to excavation of the optic disc, although they do lead to disc pallor. Now, the disc drusen can give you a disc change that looks like glaucoma, usually because it is a small disc and is full of drusen. Drusen can cause almost anything, and almost always confuse me as being something that could look like glaucoma. Not only in nerve fiber loss, but also in the visual field. They can be progressive as well. So, what you are left with, with a patient who has disc drusen, if they have a progressive disorder and you think it might also be glaucoma, is setting a very low target pressure. There are those who have been advocating lowering the eye pressure in eyes with disc drusen in whom you don’t have any reason to think the patient has glaucoma, but they are progressively getting worse, and it is something that I have offered to a number of patients, and that is what we have done in a couple of them. I have no idea whether it is beneficial.

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Dr Cioffi: I’d say disc drusen, in particular, of all the ones that have been listed by you, are the most confusing, because they can produce almost anything, including an arcuate loss of nerve fiber layer bundle, and it can be difficult. But all the rest look different, especially based on the excavation. Dr Caprioli: Can I tell you about an interesting case? This was a patient who had a diagnosis of glaucoma and her field looked a little glaucomatous, not quite typical, but there was some superior loss. If you used your imagination, it looked like a little bit of an arcuate pattern, some nasal loss, in both eyes, fairly symmetrical. She underwent LASIK and immediately after noticed a huge decrease in her vision, and her visual fields then tested like small tunnel fields, and she had extensive peripheral loss and small 5-10° central fields. When I finally got hold of her and examined her, it turned out she had disc drusen. She had small discs with disc drusen. I don’t think she had ever had glaucoma, but after LASIK, what I guess happened was with the high pressures and those little rocks sitting in the anterior optic nerve pressed against her nerve fibers and knocked them off. Dr Burgoyne: In Ophthalmology this month is another first case report for a glaucomatous-like optic neuropathy occurring following LASIK. Dr Cioffi: There are four refractive surgeons in the back row that just passed out. Dr Burgoyne: Does the appearance of the nerve fiber layer differ with age and race, in your experience, or in the literature?

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Dr Cioffi: I think the nerve fiber layer is easier to see in children and in darker pigmented fundi. It is just more evident on examination. Dr Quigley: We lose some nerve fibers with age, so in addition to the fact that older persons like me are less pigmented in the posterior pole, you have a lighter background which makes it harder to see the nerve fiber there, you also have fewer nerve fibers. Our recent work suggested that nerve fiber loss, which is pretty modest through the first 50 years of life, accelerates between the ages of 50 and 90, so you are losing in the order of about 7000 fibers a year later on, so I am hoping for the best here. Dr Caprioli: Also, I think in really young patients, you get this sheen off the internal limiting membrane which is a bit thicker, and it looks a little shiny. I think it sometimes makes the evaluation of the nerve fiber layer directly under it a little more difficult. Dr Burgoyne: Do you start treatment in the glaucoma suspect with normal whiteon-white fields but repeatable abnormal SWAP fields? How do you make that decision, Joe? Dr Caprioli: I guess that would depend on how the nerve looked. I am not willing to put all my eggs in that one basket, that SWAP basket, without some corroborating information. If there was asymmetry that agreed with the SWAP, either within that optic nerve, it’s a superior versus inferior pole, or asymmetry compared to the other eye, and the other sort of social/medical factors favor treatment, age, and so forth, yes, I would consider treatment in that patient. But only if there were some corroborative structural damage as well. Dr Cioffi: Yes, I think you have to put it, of course, as Joe mentioned, in the context of the patient. An 80-year-old with a SWAP defect and maybe suspicious nerves, I may choose not to treat. A 35- or 45-year-old with SWAP defects and a little bit of elevated pressure, yes, I probably would treat. So, in the context of the patient and everything else built around it, I would treat based on repeatable SWAP loss. Copyright © 2003. Kugler Publications. All rights reserved.

Dr Burgoyne: A very practical question. One, do any of you use digital photos as opposed to 35-mm slides, and two, concerning your stereo-photos of the nerve, how do you view them in a stereo fashion? Dr Caprioli: I still use film. Dr Quigley: One of the things that is interesting is that we are probably entering an era where we will all switch over to some form of digital information, and yet I have photos of patients taken in our service in the 1950s, and you can still see the photos. You can still compare them with the old photos. I wonder how many of the technologies we are purchasing or seeing on the floor out here will still be there in 35 years. So the photos are going to have a longevity and an information content and value that is going to far exceed some of the software packages, even some of the companies that are selling these now.

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Dr Cioffi: You can take the same type of photograph. You can have the same lenses up front. It is the capturing technology. I don’t think it has quite arrived yet. Layer on top of that the problems with storage. There was actually a fairly lengthy article on the plane out here yesterday in the New York Times about which storage media will survive and which won’t, and it is anyone’s guess. Finally, without going to extreme cost in digital, you are really hampered because silver grain still provides better resolution. Dr Burgoyne: General question. Do you change treatment or make an intervention based on nerve fiber layer hemorrhage alone? Is a disc hemorrhage evidence enough of glaucomatous progression? Dr Quigley: I change follow-up always. When someone has a disc hemorrhage, this means that we completely repeat everything about the patient that we hadn’t done recently. So, if we haven’t done a field recently, even if it wasn’t a visual field time, we will repeat it then. We will then see the patient every three months for a period of time. Because it is a sign that the patient is going to be progressive or is possibly progressive. We will also sit down with the patient, talk to him about cooperation with therapy. We might re-evaluate his pressure, his treatment. A lot of things happen. Do you always change the target at that point? No, I wouldn’t change the target to a lower number until I saw that something functional had changed. Saying that the disc hemorrhage is a sign of progression doesn’t mean that they all progress. There are a lot of patients who have a disc hemorrhage who don’t progress. So you don’t necessarily want to change the game, in my opinion, until you see that they have actually changed. But I start gathering a lot more information. They are waving red flags at you. Dr Cioffi: I agree, structurally and functionally. I will take photographs shortly thereafter, maybe a couple of months later.

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Dr Burgoyne: This has to do with the nerve fiber layer hemorrhage. Do any of you have an opinion about the increased incidence of disc hemorrhages in patients on anti-coagulants? Dr Cioffi: I am not aware of any data on the increased incidence of disc hemorrhages with anti-coagulation, and I haven’t noticed it, off the cuff. Dr Caprioli: I would agree. I think the incidence of disc hemorrhage is probably no different. Perhaps they are bigger if the patient is on anti-coagulation, but I think they probably occur at the same rate. But I don’t have any evidence to support this; it’s my clinical opinion. Dr Burgoyne: Practically speaking, how do each of you measure, how do you assess the size of the disc in your clinical practices? What do you do, and how quantitative is it? Dr Caprioli: We have quantitative techniques to measure this and we will be talking about this after the break, but to be very honest with you, I really don’t use these in most cases to make clinical decisions. With respect to evaluating how large

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the optic nerve is in terms of interpreting what the width of the neural rim means, I sort of just look at it in a Gestalt kind of way and say this is a small nerve, this is an average nerve, this is a nerve that is a little big or a lot big, and I have maybe four or five categories, but I actually don’t measure them at the time of our clinical exam. As a back-up, we have these other quantitative techniques, but to be honest, I don’t use them to correct my examination of the nerve. Dr Cioffi: I think the one thing I do, as was mentioned earlier, is that I make a note of asymmetry in nerve size. I don’t project a micrometer or any of that.

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Dr Quigley: I have a micrometer scale which you can buy from Fischer Scientific that you can put inside the eye piece, certainly the Zeiss eye pieces in my slit lamp, and I wager you could probably do it in most other slit lamps as well. For about 12 years I have been measuring the size of every disc I see, in arbitrary units. Now, if you do that on the next hundred people you see, you will have established your own sort of normative database, and you will start to get an idea that the average size disc is, let’s say, 13, and one that is 11 is kind of small, and one that is 15 is rather large. Bear in mind that there is an optical magnification effect of high refractive error, so if someone is more than –4D or more than +4D, then there is going to be a magnification or minification that starts becoming important. But, in the general range of normal refraction, you don’t actually have to take account of anything, other than what it looks like on the measurement system. I have at least one referral a week for someone who is sent to me for asymmetric cupping. Or the patient has already been started on therapy when the asymmetry is explained by the size of the disc. Either both discs are large or one is larger than the other one, and that explains the asymmetry. In all these cases, we look at the nerve fiber layer and field, history, pressure, and everything else. And it is rare for me to tell them, “I’m sure you don’t have glaucoma”. But I can certainly reassure them that their findings are likely to be due to the fact that their disc diameter is large. Now the HRT actually gives you a disc area. It makes the same kinds of assumptions I just told you about in doing its calculation for disc area. We are noticing dramatic cases of patients with large physiological cups. They are particularly true in African Americans who are known from our population and other population studies to have larger diameter discs. The disc area is worth measuring, and you can do this with an optic nerve head analyzer, or you can do it with a cheap and dirty method similar to what I just described. Dr Caprioli: We get lots of patients who are referred for: is this a glaucoma patient with large disc and large cups? A reminder, it is always useful to examine family members when you see discs like that. So, if you can find another first-degree relative who has the same size disc and the same looking cup and so forth, I think you need to worry less about the glaucoma. Dr Burgoyne: One additional point I would make is that this brings us back to the discussion on the nerve fiber layer, because this is the kind of patient in whom the clinical nerve fiber layer exam really helps you feel confident when it looks healthy and abundant in the setting of a large central cup. I have to ask a question for myself. I always harp on to the residents that it is not the cup-to-disc ratio, much like Joe said earlier, rather it is the health of the remaining rim that leads me to

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decide whether someone has damage or not. However, certainly the notion that the central cup enlarges in all directions without any change in the remaining rim has been described as part of glaucomatous damage. Do you guys know what I am talking about? Just the central cup getting bigger without the remaining rim tissue looking what I call thinned, bowed back, eventually excavated? How real is that in your experience? Dr Cioffi: Are you talking about generalized cup enlargement? Dr Burgoyne: Yes. Dr Cioffi: I think it is real. Dr Burgoyne: Where do you see it most commonly? Dr Cioffi: I think there is some evidence in the literature that maybe up to 50% of early glaucomatous loss is diffuse. It is not only notching or dense nerve fiber layer bundle loss, but also you can have generalized cup enlargement. That said, I don’t actually even write cup-to-disc ratios on my chart. I think they are generally worthless, and so I make detailed drawings and take photographs. I think diffuse nerve loss and generalized cup enlargement occurs.

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Dr Caprioli: I’d go one step further. I think there is probably some component of diffuse loss in every patient with progressive damage from glaucoma. Sometimes this may be vastly overshadowed by relative focal loss at one of the poles, but almost invariably, if you look carefully as the patient progresses, there is some temporal thinning and some nasal thinning which is often overlooked because of the rather glaring defects at the poles. Dr Quigley: Claude, we did a study of progressive change in the disc and we had annual photographs. We looked at 100 people who got worse. In something like 50% of them, there was a highly localized loss which disappeared and merged into a more diffuse pattern within the two years after it first appeared. So, they often had a notch or a wedge-shaped defect of the nerve fiber layer, sometimes with a hemorrhage, and they would go from a 0.5 cup to the localized defect over a period of time, but if you didn’t see the patient during that period of time and two years later you looked, you would see a diffuse 0.7 looking cup. The second comment I would make is that we now know that there is something called secondary degeneration in the visual system, as there is in the brain, which means that when some ganglion cells die, they take out some buddies as they go, from the production of some sort of toxic environment. The extent to which this is going to occur in a broader area around the retina, maybe even diffusely across to the other side of the retina, means, as Joe says, that there is always going to be diffuse loss, not just highly focal local loss. Our histological studies never showed an eye that had loss in only one place, within the limits that you can measure that stuff in laboratory studies. Dr Cioffi: I want to make a point. In collecting these eyebank eyes, we get a fair number of them, I am stunned to see, because we get the full medical record of

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these patients, I am stunned to see how infrequently optic nerve photographs are taken. I would urge you, if you are not taking them, to start using them. I think you will really find them to be a nice addition to the care of your glaucoma patient. In fact, in the last two weeks, I just received the first chart with a set of photographs. I don’t know, maybe it is our particular area, but these are patients being taken care of in a metropolitan environment and they are not getting photographs. So I really urge you to start using them.

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Dr Burgoyne: I think that brings this part of the program to a close. I wish it could keep going. Thank you very much to all the participants.

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Workshop Imaging the optic nerve head and nerve fiber layer in glaucoma J. Caprioli, MD and Harry Quigley, MD

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Dr Quigley: We were just privileged to be at the Glaucoma Society Meeting and Jeff Liebmann did a study in which he looked at a group of patients before and after LASIK and imaged them with three different machines: the GDx Nerve Fiber Analyzer (GDx, scanning laser polarimetry), Heidelberg Retina Tomography (HRT, confocal scanning laser tomography), and Optical Coherence Tomograph (OCT). There was no statistical difference before or after LASIK when imaging was performed with either the OCT or HRT. However, there was a difference when imagining was performed with the GDx. We think this is because the corneal polarization shift would be changed if you thin the cornea by a certain amount, or the healing response in the cornea somehow changed the cornea’s response, but the nerve fiber layer was the same. So, an instrument that has a corneal component might very well be changed, but probably the other images aren’t bothered by it. Dr Caprioli: Let us explain a little bit more about what we mean by this corneal artifact. The GDx deals with corneal birefringence by using a compensator, which is fixed. In other words, it assumes a population average for the magnitude and the direction of the polarization in the cornea, and applies this to every single patient. As a first approximation, it probably wasn’t too bad an assumption, but it turns out that the corneal birefringence really represents somewhat of a bellshaped curve, both with respect to the magnitude and the direction of the polarization, and that a single standard correction just doesn’t work for everyone. One size does not fit all. We have come to the conclusion, and I know GDx has also, that there needs to be individual compensation for each patient, based on his or her corneal birefringence in each eye. I think Harry and I are both hopeful that this will correct a large part of the problem and get back to the original results, where Harry Quigley and Bob Weinreb found good correlation between the anatomy and the change in polarization properties. Dr Quigley: I don’t mean to beat on only one instrument. We can talk about good and bad. OCT has shown some really beautiful images of a variety of retinal conditions. For it to be useful to us in glaucoma, though, as Joe Caprioli said, it has to be a little more user-friendly. The OCT instrument judges the nerve fiber layer

Glaucoma in the New Millennium, pp. 129–132 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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thickness almost by a kind of arbitrary choice as to, “Well, this is a different color here and it has different optical properties, so that is probably where the nerve fiber layer is”. But there is no particular reason to think that this was a good judgment, except that it worked. Joel Schuman went to the extent of producing nerve fiber loss in a monkey model of glaucoma and then OCT’d those eyes and measured them histologically, and the choices they made with the OCT for what is arbitrarily the nerve fiber layer really looked pretty good. In ideal circumstances, the OCT has also been validated as something that shows how much nerve fiber layer there is. It remains to be seen whether the commercial models that you are getting of that machine are going to do it that well, and whether they are going to continue to update and upgrade software in the kinds of ways that maybe we were suggesting, or in brighter ways than we can think of today for using the machine more effectively. Dr Caprioli: As long as we are pointing out negatives, let me do one for the HRT so that we are fair about it. As I mentioned, the HRT measures the surface, the position of the surface. In terms of its axial resolution, it is the poorest of these instruments. It cannot measure thickness, and its ability to discriminate two points separated in the Z axis, away from you as you are looking into the eye, is actually pretty poor. It is only about 300 µm, and in an eye with good optical characteristics. These instruments are all trying to come up with ways of measuring early damage, but by very different approaches. Each has its good points and its bad points. Remember those ROC curves I showed you comparing the results from the different instruments with respect to the relative sensitivities and specificities? We actually get something very close to that top left-hand corner with a 99% area under the curve. It is right up at the top left-hand corner, if we add the results of all three instruments. Now that’s not a very practical approach because it is so time-consuming, but it does indicate that each of these instruments is measuring something a little different. Question: When you look at your GDx printout, what parameters do you rely on?

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Dr Quigley: In analyzing study data, when we know that one group is glaucomatous and the other is normal, the actual absolute values of the nerve fiber layer thickness from the machine are not terribly useful to me. If you look at which thing is the best single identifier, or which group of information, first the absolute nerve fiber layer thickness is what the machine is trying to measure. However, this is probably not your best indicator. It would be like saying, “In the Humphrey machine, how good is the gray scale?” The gray scale is the absolute decibel. That is the sensitivity of the patient measured in decibels. But what we have learned with the Humphrey is that you have to compare it to a normative database, and do statistics to find out how likely it is that that value for that patient is abnormal. For me, the number that is most useful is the neural network number in each patient. In general, the value I was showing you here is that the cut point in two large studies we have done, and I think that this is similar in other people’s data, is somewhere in the twenties. So that someone with their number in the 10, 12, 15 range is much more likely to be normal than not. Someone whose number is 40 or 50 is much more likely to have glaucoma.

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Question: If the number is abnormal in the glaucoma suspect, with borderline intraocular pressure, normal visual fields, would you start him on treatment? Dr Quigley: No. I would not simply rely on one instrument’s number. Dr Caprioli: I think one of the questions I have seen written down somewhere, perhaps to us as speakers, was do we really use any of these instruments to make diagnostic or clinical decisions? I assume that means alone, or does it modify what we would have done otherwise if we didn’t have the results from that instrument? I have, and, of course, Dr Quigley has, research interests in these, and we make these measurements all the time in patients. To be honest, I fall back on standard clinical examinations of the optic nerve and the disc photos for making the vast majority of clinical decisions. I certainly would not make a clinical decision based on a measurement from any of these instruments alone. Dr Quigley: I couldn’t agree with you more, and I think that, when someone buys an instrument, you tend to say, “Well gee, I invested my energy in this and the patient went through the examination, so I really ought to act on it”. Use everything you know about the patient when making your decision. If you were on the fence and you thought there was a suspicious disc and there is an iffy field defect and it is an ocular hypertensive and one of these machines is also screaming abnormal, that may be the thing that pushes you over into finally putting the picture together as a definite person you suggest therapy to. But, if you are looking at a normal disc and nerve fiber layer and a normal visual field, and one of these instruments is screaming ‘abnormal’, don’t necessarily buy the farm on that one.

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Question: One of the things that is uppermost in most practitioners’ offices is that the reps are bombarding all the practices to buy the GDx or one of these machines. The insurance companies are reimbursing these machines. I know quite a few practices that are considering stopping taking the disc photography because it is so time-consuming to dilate the pupil, etc., and using the HRT or the GDx instead. Is this something that you would advise practices to do, or is the technology not there right now for general practice? Dr Caprioli: The first part of that question I might just address by saying that, if you don’t have one of these things, you are really not missing out on very much. As long as you are looking at the disc and the nerve fiber layer, and so forth, you are going to be taking good care of that glaucoma patient, and you are not missing out on something that one of these instruments is going to tell you. The second part of the question, based on what I just said, I wouldn’t run out and get one of these things. You are under a lot of pressure from the commercial interests to go ahead and do it. If you have an interest in the technique, I think it is a lot of fun to use, it is very interesting, it is an interesting approach. You may even want to do some research with it within your own practice, to see how it compares with other techniques. I think that’s great, but you have to use it like any other laboratory result or test. You have to take it with the caveats that come along with it. Dr Quigley: I am going to add a couple of things. If a doctor is taking care of his or her patients based on pressure from a commercial sales person, I think that is

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deplorable. It happens to all of us, and it works, but it shouldn’t work. So, think that over. Think over your relationship with the detail person and the sales person, and think about what you know and what they know. You know best what you want to do for your patients. The truth is, from the point of view of these instruments right now, because there is reimbursement from some of the carriers and from Medicare for this, you are in the enviable position that you won’t lose money imaging people. So when I say ‘enviable position’, this means that you can either recommend it for your patient or not, without your patient necessarily having to pay a lot of money for it, although they are going to get nailed for deductibles in some insurance situations, and you are not going to make a lot of money out of imaging patients. One of the reasons you’re not going to is, if you begin thinking in your mind, “Gee, I am going to buy one of these and make a million by imaging everyone who walks in”, be sure you cost out how much the color printer costs to print these images. Because we are spending several hundred dollars a month on color printer cartridges. There are a lot of hidden costs that you’d better look at before you think you’ll make a lot of money. But I think you should have some way of documenting the patient’s disc. As Joe said, you can take care of people in a lot of good ways. The HRT, for example, produces a very usable image of the disc quickly and effectively. The GDx produces a pseudo-color image of the optic disc. It is not stereo. It probably doesn’t have the quality or ability to detect excavation change and a notch, and that sort of thing, but it is better than nothing. If you are presently not doing fundus photography, and you don’t intend to, then owning one of these instruments is better. Dr Caprioli: The second part I wanted to address was whether you can change from doing disc photos to getting one of these instruments instead. I have been using these sorts of approaches for a long time now. It has been a major interest of mine. I would not feel comfortable, having been doing disc photographs and continuing to do disc photographs, just switching to HRT or GDx, or any of these things, alone without the disc photograph. Certainly, as Harry said, if you are not doing it and now you’re doing HRT, I think that’s a big step up. But I wouldn’t feel comfortable switching from disc photographs to one of these techniques, and omitting the disc photograph. Copyright © 2003. Kugler Publications. All rights reserved.

Dr Quigley: As a matter of practice management, the New York Times news service carried an article on the GDx within the last month. How many patients carried that article into your office? They bring it to me all the time. They say, “Why aren’t you doing this test, Doctor?” It can make you feel like, “Maybe I’m behind the times.” “Maybe I should have something like this.” As Joe said, you don’t necessarily have to do it, but you wouldn’t be losing money if you did. And there is value in it. My guess is that, among these instruments, one or more is going to be a good long-term addition to glaucoma management. We just can’t tell you yet. You have heard an awful lot today, so you have a pretty good idea of what we think about them. I think we are being fair about it, plus or minus.

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Round table My most confusing optic nerve head Jonathan Nussdorf, MD, presiding Panel: George A. (Jack) Cioffi, MD Paul Palmberg, MD, PhD Harry A. Quigley, MD

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Dr Cioffi: This round table focuses on my most difficult optic nerve. I didn’t think I could do this round table without a few pictures, so I thought, for Harry and Paul, I would present a few patients and let them comment, because these are the type of folks you will be seeing in your office. This patient is a 31-year-old Japanese American who came in about eight years ago (Figs. 1a and b). He is a –8.00 D in both eyes, and is 20/20 in each eye. He has had exams by a variety of different people. He saw Steve Drance at one point. He is a VP with a computer company. He has never had a pressure above 20. His

Fig. 1. Right optic disc image of a 31-year-old Japanese American with myopia (-8.00 D OU, 20/ 20 OU) and kissing inferior and superior visual field defects in this eye. a. The appearance of an ‘oblique exit disc’ with nerve fiber layer loss. b. Comparison between the right and left discs demonstrates relative disc size asymmetry within a given patient.

pressures in my office on a diurnal ran between 16 and 20. His angles are open. His visual field in this eye (OD) has about a 22-decibel mean deviation loss, and in the other eye (OS) about a 10 or 12. My question for the panelists is, how do you go about following and treating and prognosticating about such patients? Paul? Glaucoma in the New Millennium, pp. 133–147 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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Dr Palmberg: I think it clearly is glaucoma, and it is someone whose nerves are abnormally susceptible. The right optic nerve head looks a little large too (Fig. 1a). I don’t know if that plays any role in it. We saw laminar dots going all the way out almost to the superior pole. We get some peripapillary atrophy in which you can see choroidal vessels through missing retinal pigment epithelium and I think Doug Anderson has shown that, in people who are called normal-tension glaucoma, you see that four times more often than you do in people in the general population of the same age. He has speculated that such eyes may be at greater risk for loss of autoregulation since they are being exposed to vasoactive substances through the choroid there. But after you put all that together, you are just saying, this is somebody for whom 20 is too high and we’d like to lower it a lot, because they have a lot of damage. Dr Cioffi: Now this was in 1992, Paul. What were you doing in 1992? Dr Palmberg: For these people with a pressure of 20, in 1992 I was giving whatever drugs we had and if that didn’t work... This is a 31-year-old, so I probably would not have done laser. Let’s just say that, with the drugs available in 1992, which would have been beta-blockers, miotics, Diamox, we would probably eventually have ended up doing a filtering procedure with either 5-FU or mitomycin to try to get that pressure down 30%.

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Dr Quigley: Let’s go back to the actual disc appearance, because if you contrast... why did Paul think this disc was big? Compare the two discs. Flick back and forth if you would, Jack, between the two (Figs. 1a and b). The actual disc margin of the right eye is from there to approximately there, if you were marking it with the HRT. This is the beginning of the choroid. You are looking at choroid over here. That’s the end of the retinal pigmented epithelium. This is a little bit of downsloping temporal rim, so the disc horizontally goes from here to there, and what I am marking is the actual outlet for axons out of the eye. Let’s think mentally. How big is this from here to here and we will go back to the preceding picture. In this eye, that is the 12 o’clock position and that’s the 6 o’clock. The right disc is probably 50 or 60% larger in diameter than the left disc. So, discs can vary, not only from one human to the next, but also often between both eyes of the same person. Second, you see this sloping crescent over on this side, quite typically seen in high myopes, though moderate myopes don’t necessarily have it. What is going on is that the disc has an optic nerve leaving the back of the eye, not straight out the back of the eye, at a 90° angle, but at a severe tilt, so we call them oblique exit discs. That gives you a royal pain trying to figure out what the cup to disc ratio is, because you won’t see a sharp margin on the cup. The first question you might ask yourself is, “Am I sure I am looking at glaucoma?”, because it could simply be an oblique exit disc in a high myope and you pass it. Now the asymmetry would be very striking to you, but the asymmetry is due to the difference in disc size. It isn’t that this disc is really damaged because the cup is so much bigger, because it started out life with a bigger cup than the other eye. However, in this color picture, there is a striking absence of the nerve fiber layer (Fig. 1a). In fact, there is a focal loss in here that is quite dramatic. See the nerve fibers there, but you don’t see them here (look between 7 and 8 o’clock). You ought to see them in both places. There are no nerve fibers at all down here. This guy is going to have

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field loss. He has field loss in his upper field corresponding to this zone, and probably has field loss in the lower zone as well. He probably has kissing defects above and below around his 20/20 vision. Dr Cioffi: Actually, that’s right on. I don’t have the fields. They are on my computer, but that is exactly right on. Dr Quigley: The other eye probably has an iffy early field defect. So what tells us that this is a glaucomatous disc? It is the absence of the nerve fiber layer and the field defect. You would have gotten a field on this patient and say, okay, it’s more than an oblique exit disc because simple oblique exit discs don’t get double arcuate scotomas. Dr Palmberg: The other thing that correlates exactly with what Harry is saying, is that these laminar dots are pale. This temporal sloping crescent is never going to look as pink as it would if the nerve was coming straight up at you, but you have laminar dots here that come almost all the way to the inferior rim and some up here as well. As George Spaeth pointed out a long time ago, that’s also a sign of missing tissue, that there used to be nerve tissue coming through and obscuring these dots, and now you can see them clearly. There is no tissue there to obscure the lamina structure. So what’s missing here in the nerve fiber layer is also missing in the laminar dots. Dr Quigley: The next thing that occurs to me in evaluating this fellow is the fact that he is Japanese. We know that, on a population basis, persons from Japan have an average eye pressure of 13. So, a fellow with a diurnal that is averaging between 16 and 20 is approximately four to five points above the average person, as measured in his ethnicity. This is equivalent to a European person having pressure in the low twenties. This person is actually a higher pressure glaucoma subject compared to the average person with glaucoma in Japan, whose ‘high’ eye pressure is more like 15.

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Dr Cioffi: What would you have done here? Dr Quigley: I agree with everything Paul said. You want to lower the eye pressure. The target for a guy who is running 16 to 20, his baseline is 18, so 50% lowering would be 12. I would try to put him in the 12-13-14 range. If you could get him there, now you probably could get him there medically, but you would probably wind up heading in the direction of a surgery. You are terrorized doing that, by the way, because he has a bunch of risk factors for being the person who is going to get hypotony, maculopathy, or nasty consequences from getting a filtering operation with a big bleb. Is he a contact lens wearer? Dr Cioffi: Of course. Dr Quigley: Yes, okay, so now you are even more in the soup, because you have someone who doesn’t want to have a bleb or whom you are forced to tell, “You keep wearing contact lenses and you are at somewhat greater risk of a leak and bleb-associated endophthalmitis”. He is also going to ask you the question, “Doc-

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tor, how long is this filtering operation going to last? I am 31 years old. Is it going to last for 50 years. I am planning to live to be 85. My mom is 90.” The answer I give to that question, by the way, and I don’t know if it’s a smart answer, but it is that, every five years since I have been in practice in glaucoma, we have had a fair improvement in some major aspect of how we take care of glaucoma, whether this was laser treatment or trabeculectomy or mitomycin added to what we do. I don’t know what is going to be true in 50 years’ time and neither does he, but I know that if he doesn’t get his pressure lowered pretty soon, it’s not going to matter. He ought to take his best shot with our best therapy at this time, and not worry about what is going to happen in 50 years if we don’t take care of it now. I don’t know if that would help you in dealing with this. If your patients don’t ask that question, you’re lucky. Mine ask it all the time. Dr Cioffi: That’s great. That is exactly what we did. We did a filter on his right eye in, I think, 1992. He has had a pressure running around 10 ever since and has had absolutely stable visual fields, no change. About two to three years ago, I ended up doing his left eye because of change. He wouldn’t tolerate beta-blockers at the time. Of course, we didn’t have the other drugs. Dr Quigley: How did you deal with his contact lenses in the filter? Dr Cioffi: You know, there’s no way around that and actually we had some discussion the other day about whether this is a LASIK patient, or a photorefractive patient at all. He now wears lenses intermittently with blebs in both eyes, and understands the risk, and I try to get him to wear his glasses as much as possible, but his vision is just so much better with his contact lenses. This is a high-powered guy. He is a mover and a shaker. Let me tell you one thing he did in about 1994; he learned Braille. There is a realist. He came in one day with his wife who is about the same age. They had two or three young children. He announces to me with the whole family standing there, “Oh by the way, I just started learning Braille”. There’s a stroke for your confidence.

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Dr Palmberg: I’m such an upbeat guy, I probably would have told him, “Well, look, our filters are probably going to accelerate cataracts, and when they do, we could put an intraocular lens in and you won’t have to wear your contacts any more”. Dr Cioffi: We haven’t operated on his lenses yet. Dr Quigley: By the way, be sure that you remember to tell this guy that all his family members, including his children, ought to get examined. One of my favorite patients is a gentleman just like this, with pressures actually in the 40 range, who was in his late thirties. He had bilateral filters and fortunately they were going well and, therefore, he kept coming back, and I said, “Do you have any brothers or sisters?” “No.” “How old are your kids?” “Well, they are 11 and 8, two boys.” He said, “Well, should they get examined?” I said, “Why don’t you bring them in?” So the 11-year-old had a pressure of 32 and the 8-year-old a pressure of 26. Subsequently, before they were 20 years old, both of those boys wound up being filtered, and I probably would find a Glc 1a gene defect in that family if we were to look for it. We didn’t know about that then.

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Dr Cioffi: That’s a very nice point. Let me add to the discussion. This guy obviously became quite concerned with young children. He wanted to do something. He became sort of one of our poster children for a capital campaign for raising money, and his parents came into town for the talks, and he said, “You know, why don’t we just screen my dad. He can be part of your normative population for some visual field test.” Guess what. He had actually much worse field defects in both eyes and was unrecognized. Dr Quigley: The Academy is presently working on a program through which we are going to be surveying ophthalmologists to see how aggressively they chase down the family history of their glaucoma patients. If we made it easier for patients to get their family members examined, we would have a very good yield of persons like this guy’s father and the children of my patient, who were detected earlier and got better therapy. We are investigating that process right now, and I can tell you that it looks as if there is a less than ideal ascertainment of family members who might have glaucoma.

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Dr Cioffi: Let me move on to the next patient so that we get a few nerves here. This is a 30-year-old Caucasian female. She is a +3.00 D in both eyes, 20/20 OU. She has pressures of 22 mmHg in both eyes and she has this disc on the right (Fig. 2a) and the left (Fig. 2b). She has just a little bit of far peripheral loss on her fields that were repeatable, but not really arcuate in nature, inferior in both eyes.

Fig. 2. Images from a 30-year-old Caucasian female with hyperopia (+3.00 D) and bilateral visual field defects illustrate asymmetric cupping in the presence of optic nerve drusen which are: a. more apparent in the right eye; and b. slightly buried and hidden from view in the left eye. Optic nerve drusen are relatively more common in small optic nerve heads.

Dr Palmberg: It looks to me as though there is an odd coloration to this disc. You have what looks like white balls up there at about 11 o’clock and at about three or four o’clock (Fig. 2a), so I am beginning to wonder if the pressure of 22 is sort of a red herring and maybe we’re looking at optic nerve drusen. I would like to get an ultrasound and see if there is some calcium there. Dr Cioffi: So I got an ultrasound, and yes, in fact, she does have optic nerve drusen. Dr Quigley: Get used to the fact that, when you look at a disc in a patient, you say

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to yourself, is it a big disc or a small disc, or an average size one? Look at that photograph. Assume that it is not an optical illusion that is going on here, but you really could judge whether that is a large or a small disc. Very small discs are more likely to have disc drusen. So the 0.4 or 0.5 cup in the left eye (we are trying to guess depth here from the position of the vessels in a single image) – but perhaps even bigger because it looks as if there may be undermined rim right there – so, maybe this cup is even as big as 0.6 or 0.7. That’s huge in a person who has a small disc, way out of proportion to what would ever be physiological. So we have to be concerned. The arterioles are also narrow here. If you read nerve fiber layer, there is very little nerve fiber layer there. This is somebody who probably has two optic neuropathies, without question disc drusen, as Paul noticed. I don’t see drusen in this eye (Fig. 2b). Dr Cioffi: She actually has some on ultrasound in this eye as well. Dr Quigley: They are kind of buried, but I am really worried that you have somebody now who has two other risk factors for glaucoma. The eye pressure being 22 is a risk factor. It doesn’t mean she has the disease. I am looking at asymmetric cup size with the cup size in the left eye being way out of proportion to what ought to be there in a small disc. Dr Palmberg: Could it be the other way? The other cup to disc ratio would have been 0.3 or 0.4 if you hadn’t had the drusen. Dr Quigley: Yes, the drusen fills everything in. Dr Cioffi: Both eyes had sort of nondescript peripheral visual field changes. The right eye was a little worse than the left in terms of the field, but nothing that make you say, “Ah ah, that’s glaucoma!” Dr Quigley: And you did gonioscope the patient?

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Dr Cioffi: She is open in both eyes. What do you do with drusen patients with nondescript visual fields and a pressure of 22? Do you treat them all? Dr Quigley: Yes, I do. Dr Palmberg: I do because I’m not going to know if they get worse due to pressure. The whole idea of not treating ocular hypertensives is based on the idea that this patient is normal now and I will be able to detect it before they change in any important amount. So if a patient has a cataract and ocular hypertension or other disc findings and you can’t figure out what is going on, then I would treat it mildly. Dr Cioffi: We do exactly that same thing. The patient is on beta-blockers, her pressures have come down into the mid to low teens. I agree with both of you, and that is exactly what we do in practice, we treat these patients. An ocular hypertensive with drusen I always treat. This gentleman is 35 years old. He has a past medical history that is significant

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Fig. 3. Image of the right ‘tomato ketchup’ fundus of a 35-year-old male with unilateral glaucoma OD and a history of seizures associated with Sturge-Weber syndrome.

for seizures. He is –2.00 D myope in both eyes, and 20/20 OU. In his right eye, he has had pressures ranging anywhere from 24 to 34 (Fig. 3). In his left eye, he is always 16 to 18. He really can’t do automated visual fields, and confrontational fields are grossly normal. That is all I have to go on. Dr Palmberg: Afferent defect? Dr Cioffi: He doesn’t have an afferent defect. I don’t actually have a picture of his left eye. Dr Palmberg: If you showed him a flashlight, would he say that it looked only 80% as bright in this eye as the other?

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Dr Cioffi: No, he doesn’t give subjective or objective afferent findings. Dr Quigley: Does the fundus on this side look more tomato-colored than on the other side? Dr Cioffi: Oh, this guy is good. I don’t know, what do you think? Dr Quigley: Well, this is kind of red. There is a little bit of torturous vascularity. You have a fellow who has central nervous system disease with seizures. He has a monocular glaucoma. You’d be thinking, do his episcleral vessels look kind of funny? Perhaps he has a red splotch on the side of his face, something like that. Dr Cioffi: So-called tomato ketchup fundus. I can’t put anything past this guy. Dr Quigley: This is an interesting issue, because they can have glaucoma on both sides, and I have a couple where the red splotch is only on one side and the

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glaucoma is on both. And very interesting questions about how to manage this particular issue. Dr Cioffi: What do you do with these, Paul? Dr Palmberg: Well, you try to lower the pressure with about the same kind of criteria. If you do get to filtering surgery, you would be darn sure to do a posterior sclerotomy or use a Baerveldt implant so that you have a very minimal time of lowered pressures. Harry mentioned the other day that if you are going to use a scleral flap, have stitches in place to pull up immediately. You don’t want a low pressure in this eye for more than a few seconds. Dr Cioffi: It seems to be the exception that I can treat these guys with medicine, and I think a lot of them end up with surgical intervention, as this fellow did, and he had a trabeculectomy. I find that often when you operate on episcleral venous pressure patients, their blebs don’t look too great, but they often work very well. Dr Palmberg: When you see vessels on the conjunctiva, like a rete mirabile, that layer is under the conjunctiva separated from it, and when you cauterize it, it doesn’t bleed. It is amazing. You would think that you were going to have a lot of trouble with surface bleeding affecting your bleb, but it doesn’t seem to happen. Dr Cioffi: This is an 84-year-old Caucasian male. He is pseudophakic bilaterally. He is NLP in his right eye from glaucoma. He is 20/40 in this left eye. His pressures are 14 to 16. He is on three topical medications. He has had ALT for 360° in this eye, and he has a 5° central field. How do you follow these guys? He is 14 to 16, so he is starting to get down into Paul’s window. I know everybody in Miami has pressures of 12. Dr Quigley: What was his baseline IOP? Dr Cioffi: It was in the mid to high twenties. Copyright © 2003. Kugler Publications. All rights reserved.

Dr Quigley: One of the difficulties is that, if you acquire a patient who has been under therapy from someone else, you don’t actually know what their baseline eye pressure is. If the fellow’s pressure is 16, it could be that this is what it always was. My first move is usually to try to talk the patient into stopping their medicine in one eye. That is not often easy. Not only do they not comply with therapy, but also they will refuse to stop it, even though they are not taking it half the time. Dr Cioffi: Harry, if this was your eye and you were 84 and on three medicines and blind in the other eye, would you stop your three medicines? Dr Quigley: No, our approach to this patient would be to start doing a 10-2 Humphrey field with foveal sensitivity measurements about every two months for a year, and if the person had absolutely no change during that time, I’d say, “Damn, I’m smart that I didn’t operate on this man”. I would continue 10-2 testing, and extend the time interval to maybe every four months for the next year

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after that. If there were signs after three or four of those that he was losing it further, then you have to bite the bullet and do the filter. Dr Palmberg: You might be able to stop the medication in the other eye that is already NLP, just to see how high that would go. You would like to know whether the fields have been progressing. Get the records and find out. Dr Cioffi: It’s tough with a 5° field on a Humphrey 24-2 or a 30-2, and I actually do exactly what Harry does. I move on to a Humphrey 10-2 with the fovea sensitivity on, and that is how I follow these sort of end-stage visual fields where the optic nerve itself isn’t going to tell you much. Dr Cioffi: I think that’s it for the optic nerves. Regrettably, I have to go catch a plane. Thank you again all for your hospitality and I am sure that Harry and Paul can handle all the questions. Thanks. Dr Palmberg: While we are waiting for the question session to start, I’d like to chime in as the others did and thank you for the honor of being invited here and for the incredible hospitality of the hosts, and to say how much I have enjoyed being part of this. Question and Answer Session

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Dr Nussdorf: What causes a disc hemorrhage? Is it due to ischemia or is it a precursor to ischemia, and is the blood toxic to the never fibers? Dr Palmberg: Well, neither one of us knows, but if the problem in glaucoma is a problem with autoregulation or blood flow, then it might be that, as in people with migraine headaches, they have a constriction followed by a dilation. It could be that, after an episode of vasospasm followed by vasodilation, you might have a rush of blood and your surge protectors aren’t working very well and you would get a little hemorrhage in that location. I saw a patient not too long ago, and I am sure all of us have, who at the time following filtering surgery when the pressure is lower, developed an absolutely classic disc hemorrhage at the time that the eye’s pressure was lowered from about 26 down to 12 or 13. Again, the idea of perhaps a constriction followed by a surge, you might get a hemorrhage. I think there is another odd thing about people with normal-tension glaucoma, corrected for age and everything, they are more likely to have suprachoroidal hemorrhages than people who have primary open-angle glaucoma, but their pressures were around 18 and they were progressing. So I kind of wonder about vascular spasm followed by dilation. All of this is total speculation. Dr Quigley: The question about disc hemorrhage could be added to a little bit by saying that if you take a monkey’s eye and raise the eye pressure to 40, you will sometimes see a disc hemorrhage appear during the time the monkey is losing nerve fibers. I have no reason to think that a healthy young monkey has an autoregulatory problem. So, at least in that artificial laboratory model setting, it is something to do with losing nerve fibers and the process of glaucoma that causes

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the hemorrhage. Now I have speculated in some diagrams in print that there is a continuous meshwork of capillaries that goes from the retina down into the disc and into the optic nerve, and as that whole structure recedes out of the eye in the process of excavation, the capillaries are put on a stretch because they pull backwards by about half a millimeter, the whole capillary network is on a strain from being physically pulled on. In addition to this stretch, the thing that is in between all the capillaries is nerve fibers and they are being lost. So there is less support for them to be sitting there. It makes some sense then that you could just have a tearing of a capillary leading to a flame-shaped hemorrhage. It is absolutely not good to have an open blood vessel leaking serum into the nerve fiber layer. When God built the retina and the central nervous system, she made sure there was an intact blood-brain barrier and that there was no serum protein getting in loose among the neurons. It is probably bad for the neurons to have that happen, absolutely. Of course, the whole process is bad. We know that from a practical standpoint, from a clinical management point of view, that is a patient you have to watch more closely. It could be ischemic too, I don’t know. Dr Nussdorf: If the blood is bad, why don’t patients with bad diabetic retinopathy get horrible optic neuropathies? Dr Quigley: Diabetic retinopathy patients do get horrible neuropathies. Some years ago we began counting the optic nerve axonal number in human eyes. And we would get eyes from the eye bank. One of the things we learned very quickly was that if we used eyes from persons who had a history of diabetes, even without visible retinopathy in the retina that we got in the fixed state, and we looked at the eyes with diabetes, they invariably had lower optic nerve counts than control nondiabetic eyes. It is my opinion, without having published this and documenting it in a tight way, that diabetics lose ganglion cells and inner retina at a much higher rate than other people do. But they get retinal neuropathies that are sometimes worse than you would expect from their lack of diabetic retinopathy, as we see it. Dr Nussdorf: What else do you tell your patients to do, other than to control their intraocular pressures? Do you tell them not to eat Chinese food? Copyright © 2003. Kugler Publications. All rights reserved.

Dr Quigley: Actually, the ingestion of monosodium glutamate is a terrifically bad thing for you to do, in part because of the salt load. There is a tremendous amount of sodium in MSG, so I would tell patients, go and enjoy Chinese cooked food, but tell them no MSG, and the chef will have heard that a thousand times and will abide by it. Ingesting oral glutamate is almost certainly not going to cause any damage to your eye from the glutamate itself, because your eye has a beautiful set of systems for getting rid of glutamate. It is one of the reasons why it is unlikely we’re actually going to confirm that there are high glutamate levels in the vitreous in experimental glaucoma. We have just finished studies of more than 100 rats with experimental glaucoma, and while there is some elevation of glutamate in the vitreous cavity of eyes of rats with glaucoma, there is elevation of a bunch of other amino acids as well. It is not a specific spike of glutamate, and it doesn’t seem to correlate with a lot of things regarding the damage in the eyes of those rats. I think it is a relatively non-specific elevation of a bunch of amino acids. That doesn’t mean that glutamate excitotoxicity isn’t related to glaucoma. It simply means it is

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unlikely that you are going to be able to have the simple result that, “Hey, there’s a lot of glutamate floating around in the eye”. It is going to be more complex than that. To answer the question specifically, I tell all my patients to exercise. There is a clear relationship between someone’s aerobic activity and their eye pressure. There are two studies, one in normals and one in older persons who were ocular hypertensive, that show that you can lower your eye pressure with some regularity by another point or two with aerobic exercise, not necessarily jogging or running five miles. But this was a group of mature persons who had a walking program where they raised their pulse to an aerobic level for 20 minutes four times a week. People respond to that very well. They want something to do other than simply lowering the eye pressure. Beyond that, altering any other aspect of your life, use of the eyes is irrelevant, caffeine or alcohol in moderation is irrelevant. God knows how people live in New Orleans. Most of the other things that people do, I can’t tell them one way or the other. There is this whole pharmacopeia of Echinacea, St John’s Wort, Ginkgo Biloba, which I tell them to stay away from because they are expensive and a waste of time.

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Dr Palmberg: The only other thing I tell people who have rather advanced damage is to think about not drinking more than one or two glasses of fluid in an hour. Occasionally somebody will come in and their pressure is like 28, and it has always been 20. And you say, what were you doing in the last hour? And they say well, just sitting out there waiting, and I drank an entire liter bottle of Coca-Cola or something. I don’t know that having the pressure up for half an hour or an hour until the kidney catches up is a bad thing. I tell them the total amount of fluid you take in during the day is not harmful, but it is probably better not to drink more than one or two glasses in an hour in people who have rather advanced glaucoma, because you can raise the eye pressure that way. Dr Quigley: There are some other things we have in a brochure that we hand out to patients. It deals with those whose exercise will very often be weight-lifting, and you do not want them to lift weights with a closed glottis. You don’t want them doing (strains here) kinds of activities. They can breathe through weight-lifting just fine. Some of them are on the decline bench. Their head is below their heart. There should be no activity for a glaucoma patient in which their head is below their heart. Everything that is fun that you want to do can be done in the horizontal position, or with your head above your heart. And so, go right ahead and do all the exercise in the world. Dr Palmberg: I tell them that, as far as we know, Viagra is not a problem. Dr Quigley: Steroids are a huge issue. Please do ask your patients what drugs they are taking, and you want to know everything. You want to know the nasal sprays and the inhalers. These have now been proven through epidemiological evidence to be associated with the onset of glaucoma in persons in a large study in Canada. So you should minimize the use of those. It is fine for someone to use them, as long as you are monitoring them and you know whether they are having a pressureelevating effect. You shouldn’t say, “Don’t ever use anything with steroids”,

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rather you should say, “If you start using steroids, I want to recheck your eye pressure to see if it has changed”.

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Dr Palmberg: I also try a couple of things. Tell patients who are using medications a couple of times a day not to look at the clock, but to take this medication with meals – breakfast and dinner – because I think people remember to eat meals, and I don’t think they think about looking at clocks. Of course, I also instruct them to space their drops out over time. I also show them how to put drops in. I find it is really surprising how many people who have had glaucoma for 10 or 15 years have no clue how to get a drop in their eye. And you watch them and they are actually missing. So I tell them to take one hand, put it on their cheek just below the eye, pull down the lid to make a little sack, bunch up their knuckles, take the bottle upside down with the cap off in the other hand and put their knuckles right on top and tilt the head back and lay the palm of the hand that is holding the bottle on top of the knuckles from the other and lean back, and by golly you can’t miss. Because the hand knows where it is. The other hand is in contact with this one, and you have made a sack, and then it will go in, and not worry that most of the drop will run down your cheek. This doesn’t mean you have missed, because most of the drop can’t be held in the eye anyway. If your eye feels wet, it didn’t bounce off, it got in, and that’s enough. Then, just let your eye close gently for two or three minutes afterwards, because it is the pumping and squeezing that gets it to go down the nasal lacrimal duct into your nose. People who try to put their finger over the punctum, it just doesn’t work, and it isn’t necessary. Thom Zimmerman, I think now, who studied this and who is convinced about it, says you do just about as well by letting your eyes fall shut with the force of gravity. But do be sure to wait, as was pointed out very well in one of the lectures, at least we tell them five minutes, a couple of songs on the radio, whatever that is, if they are using more than one drug. I do like the idea, as brought up by Eve, of things like Cosopt and other drugs that are coming in combination where you are not going to have to worry about washing one drug out with another. I think those are the things that are worth telling people to do. And also, set up in your office to make sure that, if they don’t come back, if they miss a visit, you have some mechanism of noticing this and notifying them. My dentist does this, and it helps a whole lot, because I would probably be non-compliant half the time with my visits. Dr Nussdorf: This meeting has brought up a number of questions about what we should be doing in our general eye clinic setting. You have a general ophthalmologist who doesn’t have prescreened patients sent to him. What is the best way to identify a glaucoma patient if you can’t screen them on the basis of intraocular pressure, a cup or even a normal visual field in a suspect? What do you use? Dr Quigley: I assume that everybody in general practice has a perimeter. Since the older Humphrey perimeters are very unlikely to continue to be serviced, you are going to be forced to buy something new. I think that, in order to take care of most glaucoma patients, you are going to want to have an instrument that can perform SITA visual field testing. SITA-fast, even in someone who hasn’t done a field before, takes four minutes or less per eye. So, what I would urge you to do in general practice is that anyone with a risk factor should get a SITA-fast visual field

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test in each eye along with your dilated examination of the disc. I wager that, if you do that, you are going to miss less than 5-10% of those who have early glaucoma. At the present time, I can’t tell you that there is a test worth doing on every patient who comes to see you. The frequency doubling technology is good, but you would have to buy that separate free-standing piece of equipment. Whether they will produce one that is less expensive is problematic. At the moment we are trying to determine whether or not we can produce one that is less expensive and is simply head-mounted. I would think that, if there is a risk factor of any kind, a SITA-fast visual field should be added to your exam. The problem there is that you would probably have to define that the patient is a glaucoma suspect after a dilated exam and bring them back on another day for a field.

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Dr Palmberg: Since I am very handy with it, I love the Zeiss gonioprism. If I were in general practice, I would pop it on everyone and take a look at their angle and nerve. You have a stereoscopic magnified view and you are not going to miss important glaucoma if you have looked at the nerve and at the angle. Dr Quigley: We might ask, what is a risk factor for glaucoma? That is a family member that has been affected. What do you think are the chances of an African American over the age of 65 having glaucoma? It is about one in four. So you ought to be doing field testing on a large number of these persons. If there is an ocular hypertensive situation, if the disc is suspicious, and what is the cup-to-disc ratio that should knee-jerk a field test? In the population of the USA, a cup of 0.7 is extremely unusual. Only 2.5% of people have a cup as big as 0.7. I think all 0.7 and greater cups ought to have a field test as a way of not missing glaucoma. This doesn’t mean that we aren’t missing glaucoma. It doesn’t mean that there aren’t suspicious discs with notches that only have a total cup to disc ratio of 0.5, and those should also have a field test. Now having said they should get a SITA-fast field test, 50% of initial field tests are unreliable. So you are actually buying them into two field tests a lot of the time. If they can do a normal field test, great. It is nearly impossible to do a normal field test the first time. So, if someone does that, you can believe it; it’s real. But, if their test is abnormal the first time, smile and say, “Well, you know that test, I’ll bet it was a little tricky to do, even the three-minute version. We are going to bring you back.” Now, if the patient is terribly anxious, you are going to bring her back next week, because you don’t want her staying up every night for the next six months waiting to find out if she has glaucoma. But, if the patient is not particularly worried about it and says, “Gee, doctor, I am really busy. I’ll come back in six months and we will do it then”, that’s fine, as long as it gets done. Dr Nussdorf: Going back to the patient with Sturge-Weber and placing a seton in the eye, there was a question about lysing or pulling the ripcord and having a period of hypotony afterwards, which you have told us is important to guard against. Dr Palmberg: If the pressure is particularly high, such as 40 or 50, and you have a Sturge-Weber with a large hemangioma, those are eyes that I really do favor these

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days going in with a Baerveldt, and the minute I pull a 23-gauge needle out, I push a ligated tube in. It’s ligated with Vicryl and it is going to be three to five weeks before it opens. I don’t pull any cords or anything. By three to five weeks, you have a pretty good cocoon of tissue out around that plate. At that time, when the tube opens, the pressure doesn’t go to zero. If you do pull a cord, the first time you can measure with a Tono-Pen within a minute or so, you will find pressures of something like 8 to 10. So I don’t think it is as severe as if you were doing a filtering procedure. I have not yet seen someone with Sturge-Weber have one of these exudative detachments at that time. But is always going to be a concern. The same thing with nanophthalmos and people who have increased episcleral venous pressure. Dr Quigley: I have seen a lot more folks with very prominent episcleral blood vessels, big ones, not pulsatile, not arterialized, not CC fistula, but simply prominent episcleral vessels and moderately high eye pressures, and they have pretty recalcitrant glaucoma. So, when somebody has very prominent blood vessels on the episclera, think about the possibility of glaucoma. Dr Nussdorf: Do you think the studies concerning the genetics of glaucoma will lead to a vast improvement in diagnosis and eventual treatment?

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Dr Palmberg: I sure do. Paul Nepra in Chicago, with whom we collaborated, did some work and found a biochemical defect that seems to be present in 60% of primary open-angle glaucoma. This could be something secondary and we will have to see where it leads. But, if we know who is at risk, if we knew the biochemical defect, and were able to detect genes and clone genes, I think this would be a great improvement. Perhaps these discoveries will lead to some ability to modify the trabecular meshwork by inserting a gene in the anterior chamber, which Don Gudenz did years ago in rabbits and now Paul Kaufman has been able to duplicate. I think we ought at least to be able to do things in the front of the eye genetically within 10 years. It will take more clever people to try to correct some problems at the back of the eye. Harry may very well be right, that we will have pills, and once we have made the genetic diagnosis and know the problem, we will be able to target some systemic therapy for that person. So, yes, I have a great deal of optimism. I am a very optimistic person, I am very optimistic that we will be treating glaucoma differently in 10-20 years from now. We will be far more successful and people will look back and say, “Gee, I used to do it that way”. Dr Quigley: I’m spending a lot of time right now attempting to do gene therapy in experimental glaucoma models, and those who have done this in a variety of diseases outside ophthalmology have not been terribly successful yet. There have been some real disasters. It is probably going to be more challenging than anyone thinks. As Paul says, it may be that the most important genetic information we get is diagnostic. If you know that one of two or three mutations in three or four different loci throughout the genome are more often associated with glaucoma, when you find the 31-year-old Japanese with the glaucoma, you might find out if he has one of those mutations and then look for it in his family members. Even if his two kids, aged 11 and 8, don’t have risk factors for glaucoma right now, if they

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are carrying that mutation, it provides you with information to protect them better in the long term. I think the first thing we are going to find useful from genetic studies is diagnostic information for who is at risk for disease. We have not yet been very successful, though we have implanted genes into retinal ganglion cells in the rat eye, genes that should be neuroprotective, and that experiment will be analyzed in about 6 weeks. There is no question that gene insertion can be done. The question is, are we going to be doing it, is it going to be practical, and you can’t guess like that with research.

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Dr Nussdorf: I want to thank our quest speakers for a wonderful morning discussion, and I am sorry to have to bring this session to end.

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Psychophysics

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J. Caprioli

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Update on psychophysical tests for glaucoma Joseph Caprioli

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Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, CA, USA

As far back as the 1800s, psychophysics was defined as measuring the responses of the mind. We tend to equate what comes out on the Humphrey visual field print-out with what is going on in the eye. It is not just the eye, of course. It is the eye, it is the brain, it is all those connections that end up triggering the thumb to press that button, and so it is really what is going on in the mind and not just in the eye. What are some of the drawbacks of standard perimetry? It is well established that standard automated perimetry (SAP) is relatively insensitive to the earliest loss of retinal ganglion cells. If you believe that early detection of glaucomatous damage is important, then standard white-on-white perimetry is not going to provide you with that information. Automated perimetry and other visual psychophysical techniques are susceptible to many artifacts, ocular media being one of the important ones. In addition, the greatest problem that faces us when following patients over time, is the magnitude of long-term fluctuation or variability of the measurement over time. Long-term fluctuation is the largest confounding variable in the detection of the occurrence of glaucomatous progression. How can we deal with some of these problems? Figure 1 shows a 56-year-old male with ocular hypertension and a glaucomatous disc. SAP demonstrates a few isolated defects in the superior field. This is not a very robust measure of damage. However, as an alternative, if we measure motion sensitivity in the part of the retina that is involved with this defect, we get a very abnormal result (Fig. 2). In the adjacent retina, in an area served by the relatively normal nerve fiber layer and optic nerve, it can be seen that motion sensitivity is normal. Part of the problem with glaucoma detection is the compromise we make in terms of visual field testing grid density. We currently use a grid which has 6° spacing, at least with the Humphrey. The Octopus fields had program G1 with variable spacing, depending on field location, and slightly higher resolution in the central part of the field where we were looking for early glaucomatous defects. One approach would be to increase the resolution of our test. This costs time and the 6° grid is a compromise. With some of the new algorithms, particularly the SITA algorithm which shortens test time, it may now be reasonable to increase test Address for correspondence: Joseph Caprioli, MD, Jules Stein Eye Institute, UCLA School of Medicine, 100 Stein Plaza, Suite 2-118, Los Angeles, CA 90095, USA. e-mail: [email protected] Glaucoma in the New Millennium, pp. 151–164 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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Fig. 1.

grid density. The Humphrey perimeter can be used to merge two 10° fields to obtain 1° resolution. This is not a practical thing to do in all patients, but it might be worthwhile in some cases when applied with some thought. As an example, the detection performance of a low resolution SAP 24-2 pattern can be improved by increasing the density of the test grid (Fig. 3). What are some of the advantages of this type of high resolution approach? It can be applied to specific areas of the field of concern. If we are relatively selective about applying this technique with the newer testing algorithms, then the increase in test time is relatively modest. Finally, it may improve our understanding of how scotomas enlarge and deepen in glaucoma. Useful sites might be in suspicious areas of the original field, along the nasal step area, or after structural evaluation has suggested suspicious locations.

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Fig. 2.

If the standard field does not come up with anything, you could tune that field slightly to the area of suspicion, which would correspond with the area of the structural defect (Fig. 4). What other future developments in glaucoma psychophysics are there? One is the departure from the fixed grid to the development of adaptive testing strategies individualized for a particular patient, so that areas of scotomas or around edges of scotomas will be tested with higher resolution. We know that clinically detectable structural damage can occur before functional loss. Quigley’s histological studies have shown us that areas with a 40% loss of ganglion cells correspond to about one logarithmic unit of decrease in visual sensitivity, or a 10-dB loss with SAP. Twenty percent ganglion cell loss corresponds to about 5 dB, and so forth. We have psychophysical tests that detect glaucomatous loss with greater sensitivity than SAP. For example, motion perimetry and short wavelength automated perimetry (SWAP), and frequency doubling perimetry (FDP). The rationale for using some of these other tests depends upon the selective stimulation of retinal ganglion cell (RGC) subclasses. These RGC subclasses differ in size, shape, distribution, connectivity, and information processing capabilities. In the simplest terms, we can divide the majority of RGCs into magnocellular and parvocellular subclasses (Fig. 5). Magnocellular RGCs project to the magnocellular layer of the lateral geniculate nucleus and tend to transmit achromatic luminance information, and exhibit greater sensitivity to lower spatial and higher temporal frequencies, i.e., they are more sensitive to motion. Parvocellular RGCs project to the parvocellular layer of the lateral geniculate nucleus and exhibit higher sensitivity to higher spatial frequency and lower temporal frequency tasks and color vision. Relative to the distribution of magnocellular RGCs, parvocellular RGCs are more highly concentrated in the macular region. Parvocellular RGCs are more tuned to central vision (Fig. 6). Quigley’s work suggested that magnocellular RGCs could be preferentially affected and damaged early on in glaucoma. Thus, psychophysical tests designed

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Fig. 3.

to stimulate and stress the magnocellular pathway could demonstrate greater sensitivity in detecting early glaucoma. In addition, Johnson has developed an alternative hypothesis called the ‘reduced redundancy theory’ (Fig. 7). If we select a relatively narrow channel of visual function to test, we are more likely to detect a functional abnormality early on with relatively few cells lost from this discrete cell population, rather than detecting cell loss from the entire population of RGCs. Whichever theory is correct, they both provide a rationale for the testing of individual RGC channels. What are the selective psychophysical tests? SAP is the non-selective luminance channel test, the brightness test of white-on-white. More selective tests might be

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Fig. 4.

SWAP, motion perimetry, flicker, high pass spatial frequency perimetry, and FDP. It has been well established that SWAP defects occur at an early stage in glaucoma. In other words, fewer losses of ganglion cells can be detected with this particular psychophysical test. The problem with SWAP is that there is high variability in test results. The long-term fluctuation in SWAP is even greater than with SAP, and this makes detecting glaucomatous progression difficult. SWAP detects early glaucomatous damage (Fig. 8). Motion detection testing uses a line stimulus, and the endpoint is when the patient can actually detect motion of the stimulus. It is the amplitude of the motion that is changed over the course of the test, and when the patient can actually detect

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Fig. 5.

movement, he or she presses a button. There is a frequency-of-seeing curve which is developed for normals and the threshold is, by definition, when the patient can detect that motion 50% of the time. Motion detection may detect early abnormalities (Fig. 9). This is an area that needs a great deal of further work. FDP is a technology that is now commercially available. It is sometimes used as a screening test. The endpoint is when the patient detects an optical illusion of the fusion of two alternating patterns, and the frequency of those stripes, if you will, becomes double (Fig. 10). This is the endpoint and this is when the patient clicks the button. Patients like this test better because there is less uncertainty about the endpoint. It is fairly rapid, at least when relatively few points are being tested. The commercially available program tests about 16 points in the visual field compared to 50 or so with SAP. There is relatively good agreement with SAP, at least for

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Fig. 6.

glaucomatous defects that are fairly well developed (Fig. 11). Defects with FDP may precede standard white-on-white testing, but we have many questions to answer before we can recommend its use wholesale for following glaucoma patients (Fig. 12). For example, we do not yet know its sensitivity for detecting glaucoma or glaucomatous progression (Fig. 13). Fortunately for the patient and the practitioner, glaucoma is a very slow disease. However, the slow pace of this disease makes it difficult for the psychophysicist studying glaucoma, the only way to validate a psychophysical test is to follow patients over a long period of time and to determine whether early defects correspond to the presence and progression of disease. Future challenges in psychophysical tests for glaucoma are listed in Figure 14.

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Fig. 7.

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Fig. 8.

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Fig. 9.

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Fig. 10. Frequency doubling perimetry.

Fig. 11. Case example 3.

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Fig. 12.

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Fig. 13.

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Fig. 14.

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The variability of perimetry

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The variability of perimetry Reassessing an important clinical tool

Eve J. Higginbotham, Nancy Ellish and Rani Kalsi Department of Ophthalmology, University of Maryland School of Medicine, Baltimore, MD, USA

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Introduction Every ophthalmologist who has managed glaucoma patients has faced the challenge of judging the validity of a patient’s visual field in the context of making a diagnosis of glaucoma. Perimetry is particularly tedious for a patient who has never undergone visual field testing, or if the last visual field was far enough in the past that the patient is essentially starting the learning curve again. As is true for any diagnostic test in this era of managed care, it has become difficult to obtain approval to perform the necessary repetitive testing in order to confirm or disprove whether the visual field is truly abnormal. Although the learning curve associated with perimetry has been well documented in the medical literature,1-3 visual field tests that have been repeated within two or three months of an initial field examination are often denied payment. Thus, to the extent that the clinician can improve the accuracy of the test on an initial trial, both the patient and the physician can benefit. This study focused on the initial visual field test of naive patients (those who have either never previously undergone perimetric testing or who underwent testing more than two years earlier). Therefore, its purpose was to determine whether the ‘inferred validity’ of a patient’s first visual field data can be enhanced by having that patient undergo a simple screening field test before undergoing his or her first threshold test. Before discussing the study, the following introductory topics will be reviewed: 1. factors that influence perimetric performance in patients; 2. variability of perimetric testing; 3. importance of clinical evaluation; and 4. rationale for the study.

Address for correspondence: Eve J. Higginbotham, MD, Department of Ophthalmology, University of Maryland School of Medicine, 419 W Redwood Street, Suite 580, Baltimore, MD 21201, USA. e-mail: [email protected]

Glaucoma in the New Millennium, pp. 165–181 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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Variables that influence perimetric performance To a large extent, perimetry depends on several factors, including specific patient characteristics and cooperation, involvement of the technician, and the environment. For the purposes of discussion, these factors will be divided into two categories: anatomical and non-anatomical factors. Anatomical factors that influence perimetry

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Refractive error In his article, Standardizing the Measurement of Visual Fields, Johnson noted the importance of using the appropriate lens correction during perimetric testing. Failure to use adequate correction can result in increased variability of fields, refractive scotomas, and a variety of spurious test results.4 Thus, the appropriate lens must be used to ensure that the patient clearly sees the stimuli. However, some investigators have noted a relationship between the magnitude of refractive error and a decrease in differential light sensitivity in specific areas of the visual field. In one series, 120 eyes of 86 patients with normal-tension glaucoma and 197 eyes of 138 patients with primary open-angle glaucoma underwent visual field examination using the 30-2 and 10-2 programs of the Humphrey visual field analyzer. All patients had clear ocular media, refractive error of less than +1.00 diopter (D), and no retinal abnormalities. Myopic power was noted to be significantly and positively correlated with a depression in sensitivity in the lower cecocentral area in eyes with normal-tension glaucoma, as well as in those with primary open-angle glaucoma. Interestingly, only eyes that carried the diagnosis of normal-tension glaucoma showed a statistically significant negative correlation with the depression in the upper arcuate area.5 Corallo and coworkers6 also noted the occurrence of perimetric defects which correlated with refractive error. In their study, they included highly myopic patients (myopia greater than or equal to 7 D) with or without glaucoma. Patients were examined using the 30-2 program of the Humphrey visual field analyzer. Defects that could be ascribed to myopia included modification of the blind spot, peripheral absolute defects, and modifications of perimetric indexes such as mean deviation, pattern standard deviation, and short-term fluctuation. (Mean deviation is a weighted average of deviations compared with a normal database. Pattern standard deviation (PSD) takes into account factors which may diffusely influence the hill of vision, and short-term fluctuation refers to the variation that may occur at individual points.) These findings suggest that the refractive error, even if it has been properly corrected, can influence specific findings in the visual field. Pupil size Both pupillary dilation and pupillary constriction have been noted to influence the results of perimetric testing. Lindenmuth and coworkers7 examined the effects of pupillary dilation on automated visual field testing in 18 healthy volunteers. The subjects underwent baseline, non-dilated field testing, and dilated testing using the 30-2 program of the Humphrey visual field analyzer. The investigators noted that the mean deviation worsened by 0.83 dB (SD 0.92 dB) in dilated visual fields compared with baseline fields. This difference was statistically significant (p =

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0.001). Mendivil8 reported a decrease in threshold sensitivities in glaucomatous patients whose pupils had been dilated; these patients were tested with the Octopus 1-2-3 perimeter using the G1X program. He noted a difference in the mean defect of 3.01 dB (SD 1.52), which was statistically significant (p < 0.001). The PSD and corrected pattern standard deviation (CPSD) were altered as much as 1.51 dB (p < 0.01) and 1.73 dB (p < 0.05), respectively. The peripheral field was more affected than the central field. Constriction of the pupil can also affect automated perimetry. Lindenmuth et al.9 assessed this effect in 20 healthy volunteers. Patients underwent baseline testing and were then re-tested with 2% pilocarpine. The mean defect worsened by an average of 0.67 dB (SD 0.67 dB). These artifactual decreases are due to variations in the retinal profile, which can be as steep as -0.62 dB/degree for a 3-mm pupil versus -0.34 dB/degree for an 8-mm pupil.10 Thus, it is important to maintain a consistent pupil size throughout visual field testing, both during and between the tests. Lens opacification Given that glaucoma typically occurs in an aging population, it is no surprise that the influence of lens opacification on perimetry has been exhaustively evaluated in the medical literature. Some investigators have noted a lack of a change in visual field indexes after cataract surgery,11 while others have noted improvement in the mean deviation.12 It appears that some of the differences that have been reported are related to specific characteristics of the patients in the series. Lam et al.3 performed visual field testing using program 30-2 of the Humphrey visual field analyzer in 24 patients before and after cataract extraction. The mean defect improved from -6.14 to -2.22 dB. There was no difference in short-term fluctuation (1.43 versus 1.43 dB) and little difference in PSD (2.54 versus 2.66). Only the presence of posterior subcapsular opacification in the visual axis correlated significantly with postoperative central threshold recovery. Similarly, Smith et al.12 noted a mean improvement in mean deviation of 1.68 dB; however, there was a worsening of 0.54 dB in CPSD. Gillies and Brooks13 also noted a statistically significant improvement in mean deviation following cataract extraction, but there was worsening in the PSD. Chen and Budenz14 reported improvements in the foveal threshold and mean deviation, whereas the mean PSD and CPSD worsened. The different results between the studies of Lam et al.,3 Smith et al.12 and Gillies and Brooks13 may be related to a greater number of patients with moderate to advanced glaucoma in the latter studies, as well as to a variation in the specific types of cataract. Results of the studies of Smith12 and Gillies13 suggest that there may worsening of glaucoma following cataract extraction. On the other hand, in a series of patients reported by Stewart and coworkers,11 no difference was noted with regard to average mean defect, PSD, and total decibel loss among 24 consecutive patients who underwent cataract extraction. It is important to point out that these patients evidenced nuclear sclerotic cataracts. Nevertheless, it is surprising that the study by Stewart and coworkers11 failed to demonstrate a statistically significant change in mean deviation, particularly when considering the studies by Budenz, Feur and Anderson,15 who used a simulated cataract device to quantify the effect of lens opacification. Glaucomatous patients with relative scotomas and healthy individuals underwent testing using a lightdiffusing piece of ground glass, which was positioned in front of the eye during

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testing. This glass resulted in a mean decrease in perimetric threshold of 5.7 dB (SD 3.3 dB) within the area of the relative scotoma, 6.1 dB (SD 2.4 dB) in the unaffected areas, and 4.4 dB (SD 2.25.dB) at the fovea. CPSD was not affected. Considering that no statistically significant difference was noted between these areas, the investigators concluded that the simulated cataract resulted in a diffuse reduction in sensitivity. Considering these findings, it may be that the study by Stewart et al.11 did not have an adequate number of patients to be able to detect a difference. All the above-mentioned studies used full threshold testing programs, either the 24-2 or 30-2 of the Humphrey visual field analyzer. Costagliola and coworkers16 used the G1 program of the Octopus system, and noted that the presence of cataract influenced visual field indexes that correspond to diffuse loss of sensitivity. Visual field indexes such as loss variance and corrected loss variance were not greatly affected since these indexes are influenced more by local defects in the visual field. A population survey, the Blue Mountains Eye Study, failed to find a correlation between cataract and visual field loss. However, it is important to note that suprathreshold screening visual fields were used in this study, and that lenses were assessed using photographs. Thus, the level of sensitivity was possibly not present in order to adequately detect any influence that the lens may have had on the visual field.17 The influence of lens opacification was noted in the era before automated perimetry. Lyne and Phillips18 pointed out the difference in the effect on the visual field when the opacification is in the lens rather than the cornea. These investigators noted that opacities in the posterior layers of the lens result in defects in the visual field on the side opposite the opacification, as opposed to corneal opacities which cause defects ipsilateral to the opacification. Thus, both the lens and the cornea can influence the assessment of the visual field.

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Other anatomical factors Other anatomical factors include posture and dermatochalasis. Recognizing that the body position can influence blood flow in the optic nerve head, Lietz and coworkers19 evaluated the influence that posture may have on the visual field. They noted that, among patients with either high- or low-tension glaucoma, there was a deterioration in the visual field when patients were tested in the sitting position, which was not present when patients were in the supine position, or in controls. There are probably few clinicians who perform perimetry with patients in the supine position. However, practitioners should be aware that some patients may have an alteration in their ocular blood flow due to other reasons, and that this alteration can influence the visual field. Dermatochalasis is a common occurrence in the aged population of patients with glaucoma. Fifteen visual fields of nine ocular hypertensive patients were evaluated and noted to poorly correlate with the clinical examination of the patients. Visual field testing was repeated either after the patient’s upper eyelid had been taped, or following blepharoplasty, and the spurious defects were noted to disappear. All the defects were superior in location. Thus, it is important for either the clinician or the technician, or both, to recognize the potential confounding factor of dermatochalasis and to consider taping the eyelid before perimetric testing.20

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Non-anatomical influences on perimetric testing In an editorial, Colm O’Brien21 noted that the “single most important factor influencing the quality of the visual field examination, and yet largely ignored by current perimetric software, is the interaction of the nature of the patient response with the demands of the examination procedure.” He mentioned motivation and anxiety as being contributing factors to performance. These ‘soft’ factors may be difficult to quantify; however, reasonable investigations have addressed factors such as patient experience, supervision, and drugs. Other factors that will be discussed here include lens holder, stimulus size, and diabetes. There has been greater appreciation in recent years of the importance of perimetric experience in patients with and without glaucoma. Twenty-five naive patients underwent visual field testing five times at one-week intervals in one study. With repeated testing, visual field results improved in 21 of 37 eyes. Means of mean deviation improved significantly by 2.81 dB (p < 0.001) between the first two tests. However, when the improvement over tests 2 through 5 was quantified, it was difficult to measure any significant difference. The investigators noted a learning effect that was greater peripherally compared to centrally. They also noted that points with greater sensitivity improved more than ‘disturbed’ points did. Thus, confirmatory testing is very important.22 It is important to note that early disturbances at any given point in a visual field may indicate early progression of glaucoma. Werner and Drance23 examined 22 eyes of 22 patients, in whom visual field defects developed after they initially had normal field test results. In 13 of these patients, there was a disturbance in the visual field before development of the defects. This is in marked contrast to only six of 22 eyes with ocular hypertension that demonstrated disturbances. However, the challenge that clinicians face is distinguishing between fluctuation of the visual field and actual disease-related change in the field. The potential influence of a patient’s fatigue on perimetric results cannot be underestimated. Two studies deserve mention. With the use of a customized 30point central threshold visual field program, 38 healthy subjects were repeatedly tested, three times in each eye with tests separated by two weeks. The investigators noted a decrease in mean sensitivity of 2.0 dB whenever the second eye was treated, suggesting a greater fatigue effect when the second eye was tested compared with the first eye.24 Gonzalez de la Rosa and Paraja25 examined healthy subjects as well as glaucomatous and ocular hypertensive patients. Patients with glaucoma and ocular hypertension showed a longer testing time compared with healthy subjects. The former group required 13.88 ± 1.25 minutes versus 13.26 ± 2.91 minutes for the control group. This study used a modified Delphi program on the Humphrey visual field analyzer, which made it possible to register consecutive measurements of mean deviation. In the abnormal eyes, there was a decrease of 2.98 dB on average from the beginning to the end of the test, compared with normal eyes in which there was a decrease of 2.22 dB. This finding suggests that the decline was not related to the severity of the visual fields, but it was noted that age was a more important factor than the severity of the defects. In reviewing the guidelines for ensuring the validity of visual fields, Johnson underscored the importance of allowing the patient to rest for five to 15 minutes if fatigue appeared to be playing a factor in the perimetric results.4 One sign of fatigue can be fixation loss. However, Henson and coworkers26

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determined that fixation losses, although contributors to variability, do not significantly affect increased variability at locations where sensitivity is reduced. Thus, variability is likely attributed to several factors besides the number of fixation losses. Some investigators have emphasized that the performance of visual fields according to strict protocols, as is done in clinical trials, should be supervised by certified ophthalmic technicians.4 However, a study by Van Coevorden and coworkers27 noted a benefit associated with supervision only when there were risk factors present for unreliable perimetric results. The investigators noted these risk factors to be advanced age, a low level of formal education, and previous results with high false positives and false negatives. Given the difficulty in determining a patient’s level of risk of an unreliable visual field result on the first visit, it is reasonable to consider supervision of all patients, rather than only a subset. Supervision can only help those patients undergoing perimetry, even patients who do not have risk factors for unreliable visual field results. Other factors that may be influence perimetric results include the size of the stimulus,28 lens holder,29 diabetes,30 and alcohol and drug use.31,32 When patients with glaucoma were tested with stimuli ranging from I to V, Wall and coworkers28 noted that testing with stimulus V resulted in less variability in the visual fields compared to dimmer stimuli. These investigators noted a standard deviation of only 1-2 dB centrally versus 4-6 dB in the periphery (27°). Donahue29 noted a mild cecocentral depression in the visual field, which was related to an ill-positioned lens holder. Zucca et al.30 reported depression in the inferior temporal quadrant in diabetic patients compared to glaucomatous patients. Investigators failed to note a change in differential light sensitivity or short-term fluctuation when patients were under the influence of either alcohol31 or diazepam32 while undergoing testing with the Octopus 201 perimeter. The results of these studies differed from studies performed with the Humphrey perimeter (San Leandro, CA). In another study, patients were tested after receiving either alcohol or triprolidine, an antihistamine that can depress the central nervous system, and their visual fields were adversely affected.33 In their review, Zulauf and Caprioli34 noted that the difference between these studies may be due to the perimeter. Since the Octopus presents its stimuli following a click, the patient receives warning. Therefore, even a subject who is inebriated may be able to ‘game’ the program and stay alert throughout the study. The Humphrey perimeter, on the other hand, does not give a click before presenting the stimulus. Variability of fields Regardless of whether the factors that influence the reliability of visual fields are anatomical or non-anatomical, the result of these factors is a visual field test that does not necessarily provide an indication of disease progression, but instead a reflection of ‘noise’ in perimetric testing. The challenge to the clinician is to determine the difference between the two phenomena. The variability of visual fields has been assessed by several investigators.35-38 Wilensky and Joondeph35 tested 12 eyes of six normal volunteers with the 30-2 program of the Octopus 201 perimeter. These subjects were tested on four separate occasions during a four-week period. This testing was preceded by at least two

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practice sessions in order to minimize a learning effect. In 11 of the 12 eyes, at least one of the 76 points tested in the visual field varied more than 4 dB between tests. Three of the 12 eyes showed adjacent points with a variance of 4 dB. This latter finding is significant, considering the importance of defining a relative scotoma based on the depression of adjacent points in a visual field. Also using the Octopus 201 perimeter, but with the G1 program, Boeglin et al.36 assessed the long-term fluctuation of visual fields in patients with glaucoma. They examined 756 automated threshold fields of 167 eyes. These investigators discovered a strong relationship between the magnitude of fluctuation and sensitivity. When the initial sensitivity was 25-30 dB the 5th-95th percentile value for subsequent measurements was ±4 dB. When the initial sensitivity was 15 dB or less, the 90% range of subsequent values was a large magnitude, zero to near normal values. Boeglin et al.36 separated their cohort into two groups: patients with stable and unstable glaucoma. It was noted that mean fluctuation, as measured by the mean of the individual pointwise variances, was 7.0 dB2 in the stable group and 9.7 dB2 in the non-stable group. Moreover, there was greater fluctuation in the points as eccentricity increased.36 Similarly, Heijl and coworkers37 noted that variability was lowest in the most central visual field and at points that were initially normal on testing. This study was conducted in glaucomatous eyes using the 30-2 program of the Humphrey visual field analyzer. Zulauf and Caprioli34 noted that long-term fluctuation at a single test location generally increased by 0.2 dB for each 1-dB decrease in sensitivity. Because of the degree of fluctuation noted in these studies, it is important to base the assessment of either abnormality or progression on more than one visual field. The importance of performing a confirmatory visual field test has been addressed in the medical literature. Katz and coworkers38 defined field loss in three different ways within a cohort of patients who underwent annual visual field testing for a period ranging from five to nine years. When incident field loss was defined as one or more normal fields followed by an abnormal field, the incidence of field loss was 63.6 per 1000 person-years of follow-up. This ratio was reduced when either two (27.6 per 1000 person-years of follow-up) or three visual fields (19.2 per 1000 person-years of follow-up) were used as the definition. For those patients who had one, two, and three consecutive abnormal results with the glaucoma hemifield test at the beginning of the study, 59.2%, 83.6%, and 89.1%, respectively, had an abnormal field three years later. In a series of normal, ocular hypertensive individuals, and patients with glaucoma, specificity was improved if two rather than one test were required. For example, when two tests were used to establish a normal visual field among ocular hypertensive individuals, specificity increased from 84.2 to 89.5% for one test versus two tests, respectively.39 In an effort to quantify visual field data and to provide the clinician with potential predictors of glaucoma field loss, indexes such as mean deviation, CPSD, and the glaucoma hemifield test have been developed. As mentioned earlier, the mean deviation, which is age-adjusted, is a weighted-average of deviations compared with a normal database. CPSD takes into account the variation that is inherent in normal subjects. An estimate of variation of the test locations is made, and adjustments are considered for measurement error. The glaucoma hemifield test compares groups of selected locations above and below the horizontal meridian. Visual fields that fall outside the specified p value, based on a prediction model derived from normal data, are considered abnormal.40

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Indexes for reliability also have been developed: fixation losses, false negatives, and false positives. The blind spot is mapped near the beginning of the test, and throughout the test, stimuli are presented within the mapped blind spot. If the individual responds to the stimulus, a fixation loss is registered. At other times during the test, the machine will prepare to project a stimulus, but does not do so; if the patient responds nonetheless, then a false-positive response is registered. Alternatively, if a stimulus is presented in an area that previously yielded a response from the patient, and the patient fails to respond, a false-negative response is registered. Usually, test results are flagged as unreliable if the fixation losses are 20% or greater, or if the false-positive and false-negative rates are 33% or greater. In one series, patients with glaucoma were more likely to have unreliable visual field test results than were healthy individuals; the tests were performed using the 30-2 program of the Humphrey visual field analyzer. There was a higher degree of rejection among patients with glaucoma, due to the number of false-negative responses.41 Bickler-Bluth and coworkers42 also used the Humphrey 30-2 program to examine visual fields at baseline, and at six and 12 months, in 120 patients with established ocular hypertension. These investigators noted that 35% of patients exhibited low reliability field test results at baseline. This number decreased to 25% by 12 months. Fixation losses greater than 20% were the major reason for the unreliable results of full threshold tests. Substantial defects were identified more readily using CPSD than with mean deviation. The authors concluded that raising the fixation loss error to 33% would reduce the number of unreliable fields without sacrificing, to any great extent, the sensitivity or specificity of the perimetric test. Thus, these quantitative indexes can be helpful, but must be judged within the context of the experience of the patient, the probable diagnosis, and the appropriateness of the index. Importance of clinical evaluation

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Considering the high degree of variability of perimetry, the clinical examination of the patient is important. From the history of the patient, including family history and consideration of topical and systemic medications, to a careful examination of the optic nerve, the clinician needs to consider the relevance of an initial abnormal result of automated perimetry within the context of the entire scope of available clinical data. Considering that optic nerve damage can occur before evidence of perimetric defects,43 the optic nerve provides not only objective evidence of nerve damage, but also important evidence of early glaucoma. However, even this objective measure must be judged within the context of systemic disease and heredity. Because of the diurnal variation of intraocular pressure and the influence of corneal thickness and astigmatism on the accuracy of applanation tonometry,44,45 the pressure within the eye should be repeatedly and appropriately measured. It is also necessary to consider patients who have elevated intraocular pressure but never experience glaucoma, as well as those patients who never have elevated intraocular pressure but in whom glaucoma does develop. Neither intraocular pressure, perimetry, nor the optic nerve can be judged in isolation.

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Rationale for the study The unreliability of visual fields is a challenge for both the patient and the practitioner. In an era of managed care, it is particularly challenging to wrestle with a series of unreliable visual field test results when attempting to make the diagnosis of glaucoma. Insurance carriers will limit the number of field examinations that can be performed, and when subsequent field examinations are performed, the reimbursement is below the cost of performing these tests. Much progress has been made within the last three years in automated perimetry, and the introduction of a perimetric device using frequency doubling technology (FDT) offers a portable and easy method to screen for perimetric abnormalities. However, it is unclear whether this device can be used as a method to train patients before they undergo their first automated test, or to reintroduce them to automated testing after a long gap. Zulauf and Caprioli34 noted that the first visual field result may often need to be eliminated and considered a ‘practice field’.38 Werner and colleagues39 did not note a learning curve when 20 glaucomatous patients underwent automated testing. These patients had previously been tested with manual perimetry. Thus, the question arises as to whether FDT can be used as a method of improving the reliability of initial visual field results. If this is possible, it would be feasible for patients to undergo FDT testing in the waiting room of a practice, or elsewhere as part of a screening program, before undergoing threshold testing.

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Methods This study was approved by the Institutional Review Board of our Institution. Patients were recruited from the glaucoma division of our ophthalmology department over a two-year period, 1998-1999, and were included in the study regardless of their diagnosis. Inclusion criteria included no prior perimetric experience or no visual field testing for more than two years before the study. Patients were excluded if a Humphrey visual field threshold test had been performed within the preceding two years. A list of randomized assignments was generated and technicians were instructed to consecutively assign patients to the list. Participants were randomized to one of two groups: 1. FDT before threshold testing, or 2. no FDT testing before threshold testing. Patients underwent testing using either SITA-standard or full threshold testing using the Humphrey visual field analyzer (San Leandro, CA). Patients were tested using either the 24-2 program or the macula threshold, if the glaucoma was extremely advanced. The right eye was always tested first, and the technician remained in the room at all times. All subjects underwent a comprehensive ophthalmic evaluation, which included history, measurement of visual acuity, examination of the pupils, slit-lamp examination, gonioscopy, and dilated fundoscopic examination. A subset of patients underwent optic nerve fiber analysis using the GDx nerve fiber analyzer (Laser Diagnostic Technologies, San Diego, CA) as part of a comprehensive ophthalmic evaluation. Student’s t test, or Wilcoxon rank-sum test, the non-parametric equivalent of the t test, were used to compare continuous variables. Fisher’s exact test was used to compare categorical variables.

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Results Initially, 66 patients were listed on the randomization list. Some patients were included non-consecutively and others had been added from a previous protocol. This previous protocol enrolled patients who had undergone FDT before threshold testing. This group was further refined as follows: There was one line which was not assigned to a patient, three lines which contained names of patients already listed (duplicates), and six patients were ineligible because they either underwent FDT testing after the Humphrey visual field test or had undergone a Humphrey visual field threshold test within two years of entering the study. Thus, 56 individuals were included in this non-randomized group. A second group of 19 individuals was randomized as the study was initially designed. Two patients were eliminated, one due to a lost medical chart, and the other to the patient’s departure before completing the visual field examination. This group of 17 patients was labeled the randomized group (Table 1). Thus, a total of 73 individuals was included in the study. The age range for the entire group was 11-89 years. All but two patients were tested using the 24-2 software program in both eyes. One patient underwent testing with the 24-2 program in one eye and the macula threshold program in the fellow eye. One other patient underwent testing using the macula threshold program in both eyes. The non-randomized and randomized groups were compared with regard to Table 1. Comparison of randomized and non-randomized groups

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Non-randomized group (n=56)

Randomized group (n=17)

Variable

Mean±SD

Median

Mean±SD

Age, years Time, seconds Right eye Left eye Diameter Right eye Left eye Mean deviation Right eye Left eye Pattern SD Right eye Left eye Fixation loss Right eye Left eye False positive Right eye Left eye False negative Right eye Left eye

54.7±18.4

55.5

54.6±11.5

50

488.3±173.1 462.8±179.3

433.5 410.0

375.1±67.3 375.2±90.2

363 366

4.6±0.9 4.2±0.8

4.6 4.0

4.2±1.0 4.0±0.7

4.2 4.0

-4.6±5.6 -3.2±3.8

-3.0 -2.4

-2.9±2.9 -3.8±3.4

-2.1 -2.6

3.4±2.2 3.2±2.7

2.8 2.1

3.4±2.9 3.5±2.2

2.1 2.3

0.12±0.16 0.11±0.16

0.06 0.07

0.06±0.08 0.08±0.09

0.0 0.06

0.04±0.07 0.03±0.05

0.01 0.0

0.04±0.06 0.03±0.03

0.02 0.01

0.08±0.12 0.05±0.06

0.05 0.01

0.05±0.06 0.05±0.08

0.02 0.04

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Table 2. Number and percent of patients with no misses for each reliability variable Reliability variable

No. (%) of patients

Fixation losses Right eye Left eye False positives Right eye Left eye False negatives Right eye Left eye

28 (41.2) 27 (50.9) 30 (41.1) 37 (52.9) 27 (38.0) 29 (42.6)

Table 3. Comparison of mean time between full threshold and SITA tests* Eye

Full threshold

SITA-standard

P**

Right Left

651.2 (10.8) 627.3 (10.5)

385.5 (6.4) 361.9 (6.0)

0.0001 0.0001

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*SITA indicates Swedish interactive threshold algorithm. Time is given as seconds (minutes). ** Student’s t test.

age, total testing time, pupillary diameter, mean deviation, PSD, false positives and negatives. All parameters were analyzed for right and left eyes separately. There was no significant difference between the groups, except for testing time in the right eye (p = 0.0195). There was a statistically significant association (p = 0.026) between the type of visual field test and the non-random versus random group. Of the 21 individuals who had a full threshold Humphrey visual field analyzer, 20 were in the non-random group. Thus, this difference most likely accounts for the longer time for Humphrey visual field testing in the non-random compared to the random group. Because of the similarities in the non-random and random groups, both groups were combined for further analyses. Of the 73 patients in the study population, 35 (47.9%) underwent FDT testing first and 38 (52.1%) underwent Humphrey visual field testing only. Overall, 21 (29%) of the patients underwent full threshold testing, 51 (70%) had SITA-standard testing, and one (1.4%) underwent SITA testing in the right eye and full threshold testing in the left. Overall, the group demonstrated reliable visual field results. When the number of fixation losses, false positives, and false negatives is examined, the percentage of patients with no misses in any category is remarkable (Table 2). Comparison between full threshold and SITA tests demonstrated a statistically significant difference in the mean time to complete the two tests. SITA test took an average of 6.4 minutes in the right eye compared to 10.8 minutes for the full threshold (p = 0.0001). Similar results were found in the left eye (Table 3). The reliability variables, i.e., fixation losses, false positives, and false negatives, were examined separately for the SITA and full threshold tests. During full threshold testing with the Humphrey 24-2 program, there was no difference between the

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Table 4. Sensitivity and specificity of HVF using GDx as gold standard by group* Right eye No FDT Type of visual field test

Sens

All HVFs Excludes borderline Borderline as abnormal Full threshold** Excludes borderline Borderline as abnormal SITA-standard Excludes borderline Borderline as abnormal

Spec

Left eye

FDT first Sens

Spec

No FDT Sens

FDT first

Spec

Sens

Spec

42.9 50.0

70.0 70.0

75.0 80.0

57.1 53.3

70.0 70.0

75.0 66.7

80.0 81.8

64.3 60.0

100.0 100.0

100.0 100.0

75.0 80.0

100.0 100.0

100.0 100.0

100.0 100.0

75.0 80.0

100.0 100.0

33.3 33.3

66.7 66.7

75.0 80.0

14.3 12.5

57.1 57.1

71.4 62.5

83.3 83.3

28.6 25.0

*HVF indicates Humphrey visual field; FDT, frequency doubling technology; Sens, sensitivity; Spec, specificity; and SITA, Swedish interactive threshold algorithm. ** For the right eye, only three people were in the full threshold, no FDT (Humphrey visual fields only) group. For the left eye, only four people were in the full threshold, no FDT group.

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FDT-first group and the Humphrey visual field-only group. Neither was there a difference within the SITA group when we examined the FDT-first group compared to the no-FDT group for the right eye. There was no difference between groups for fixation losses or false negatives for the left eye. However, there was a statistically significant difference between groups for false positives regarding the left eye (p = 0.04). We categorized the false-negative and false-positive variables as being reliable if there were no misses when the points were tested. If there was even one miss, the variable was considered ‘unreliable’. When the eyes that received full threshold testing were examined, there was no association between reliability variables and group for either the right or left eyes using a two-tailed Fisher’s exact test. With regard to SITA-standard, there was no association between reliability variables and group for the right eye. However, for the left eye, there was an association between false-positive rate and group (p = 0.04). Of the 21 subjects with SITA tests who had FDT first, 13 (62%) had reliable results. Of the 28 subjects with SITA tests but no FDT, only eight (29%) had reliable results. There was no association between false-negative rate and group for the left eye. Forty-three (59%) of the individuals underwent optic nerve fiber analysis using GDx (Laser Diagnostic Technologies, San Diego, CA). GDx was considered normal if the neural net number was less than or equal to 30. A neural net number greater than 30 was considered abnormal. For the purposes of this analysis, we considered GDx as the gold standard, and defined the visual fields as abnormal based on the glaucoma hemifield test. Thus, we can determine that, when FDT was performed first among patients who underwent SITA, there was a trend towards greater sensitivity for both eyes. However, the specificity was poor. This trend was also noted when all fields were grouped together, but no such advantage was seen for

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Table 5. Sample size calculations Detectable difference between means Power Right eye

Mean deviation All visual fields SITA* subset Full threshold subset

Left eye

90%

80%

90%

80%

4.1 5.3 5.7

3.5 4.6 4.9

3.0 3.4 6.3

2.6 3.0 5.5

Detectable difference between proportions Subgroups by reliability parameter

Power Right eye

False positive All visual fields SITA subset Full threshold subset False negative All visual fields SITA subset Full threshold subset

Left eye

90%

80%

90%

80%

37% 42% 69%

32% 36% 60%

38% 45% 62%

33% 39% 53%

37% 41% 77%

32% 35% 66%

38% 43% 74%

33% 37% 64%

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*SITA indicates Swedish interactive threshold algorithm.

the full threshold fields. It should be noted that the number of patients who underwent both full threshold field testing and optic nerve fiber analysis was very small. For the right eye, only three eyes were in the full threshold group with no FDT and for the left eye, only four eyes were in the full threshold group with no FDT (Table 4). With the current sample size, we were able to detect differences between the means for mean deviation, and differences between proportion for the number of false positives and false negatives at the levels of power indicated in Table 5. This analysis was carried out for three categories of data: all visual fields, SITA subset, and full threshold subset. Conclusions This study did not show a clear advantage in performing FDT before threshold testing. However, there appeared to be a trend in favor of the FDT group, but this trend did not achieve statistical significance (Table 4). Nevertheless, the study did

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reaffirm the findings of other studies, such as the reliability of SITA fields and the shorter testing times for SITA fields compared to full threshold testing. As noted, a significant number of reliable visual field results were obtained. Using a lofty criterion of no misses for reliable field results, our data indicate that a large number of patients achieved this goal, ranging from 38.0-52.9%. The high degree of reliability could be related to the large proportion of visual fields performed with SITA. As mentioned earlier, SITA fields have been shown to demonstrate less inter-subject variability than full threshold fields.40 Moreover, when examining those patients who underwent SITA testing, a greater percentage of patients who underwent FDT first showed reliable results compared to no FDT. This finding may suggest a positive effect related to prior FDT testing. However, our current sample size may not be sufficient to detect small differences in the reliability parameters. Furthermore, it is of interest that the left eyes for each of the parameters tended to demonstrate higher values than the right eyes. Because the left eye was always tested second, this improvement may be related to a very small learning effect. Other investigators2,28 have noted the improved performance of the second eye. The results of this study, as of others,46-50 demonstrated shorter testing times for SITA compared with full threshold testing. In the right eye, there was a reduction of 40.7% compared with full threshold testing, and 42.9% for the left eye. This reduction is greater than that described in previous reports. The difference is probably related to two factors: 1. Ours was a naive patient population and the calculations were only based on the initial visual field. 2. The socioeconomic mix of this study population may differ from other reported studies. This study aimed to determine whether testing with FDT before automated perimetry provided a greater level of ‘inferred validity’ to initial automated field testing. The measure by which a ‘gold standard’ is determined in glaucoma is often difficult, given the difference in opinions that clinicians may have regarding the assessment of the optic nerve and nerve fiber layer. Thus, the GDx nerve fiber analyzer was arbitrarily chosen as a ‘gold standard’ to assess the sensitivity and specificity of these visual fields. The GDx can suffer from its own set of artifacts.51,52 However, at least it offers an unbiased estimate of the nerve fiber thickness which could be an indication of glaucoma. In order to determine whether FDT may reduce the length of the learning curve, patients would need to undergo serial visual fields. Given that SITA testing results in less intersubject variability compared to other programs,40 a greater number of patients would have to be recruited in order to detect even smaller differences between groups, as noted previously. SITA testing has provided the profession with a shorter version of this tedious test, and it may be that serial testing using this program will demonstrate a reduced learning effect which has not been experienced previously with full threshold testing. In conclusion, perimetric testing remains an ongoing challenge for patients and clinicians. However, SITA has provided patients with welcome relief from the long testing times associated with full threshold testing. Future studies will need to correlate confirmatory SITA testing with clinical findings before we can be sure that this algorithm offers a greater level of inferred validity compared to full threshold testing. Nevertheless, perimetric testing, because of its subjective nature must always be considered in the context of both anatomical and non-anatomical influences on its accuracy. Until more objective measures are available, the importance of a carefully performed clinical evaluation remains paramount.

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Acknowledgment This study was supported in part by an unrestricted grant from Research to Prevent Blindness (New York, NY).

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References 1. Wood JM, Wild JM, Hussey MK, Crews SJ: Serial examination of the normal visual field using Octopus automated projection perimetry: evidence for a learning effect. Acta Ophthalmol (Kbh) 65:326-333, 1987 2. Low F: Some characteristics of peripheral visual performance. Am J Physiol 146:573-584, 1946 3. Lam BL, Alward WLM, Kolder HE: Effect of cataract on automated perimetry. Ophthalmology 98:1066-1070, 1991 4. Johnson C: Standardizing the measurement of visual fields. Ophthalmology 103:186-189, 1996 5. Araie M, Arai M, Koseki N, Suzuki Y: Influence of myopic refraction on visual field defects in normal tension and primary open angle glaucoma. Jpn J Ophthalmol 39:60-64, 1995 6. Corallo G, Capris P, Zingirian M: Perimetric findings in subjects with elevated myopia and glaucoma. Acta Ophthalmol Scand Suppl 224:30-31, 1997 7. Lindenmuth KA, Skuta GL, Rabbani R, Musch D, Bergstrom TJ: Effects of pupillary dilation on automated perimetry in normal patients. Ophthalmology 97:367-370, 1990 8. Mendivil A: Influence of a dilated pupil on the visual field in glaucoma. J Glaucoma 6(4):217220, 1997 9. Lindenmuth KA, Skuta GL, Rabbani R, Musch DC: Effects of pupillary constriction on automated perimetry in normal eyes. Ophthalmology 96:1298-1301, 1989 10. Herse PR: Factors influencing normal perimetric thresholds obtained using the Humphrey field analyzer. Invest Ophthalmol Vis Sci 33:611-617, 1992 11. Stewart WC, Rogers GM, Crinkley CMC, Carlson AN: Effect of cataract extraction on automated fields in chronic open-angle glaucoma. Arch Ophthalmol 113:875-879, 1995 12. Smith S, Katz J, Quigley HA: Effect of cataract extraction on the results of automated perimetry in glaucoma. Arch Ophthalmol 115:1515-1519, 1997 13. Gillies WE, Brooks AMV: Effect of lens opacity on the glaucomatous field of vision. Aust NZ J Ophthalmol 26(Suppl):S19-S21, 1998 14. Chen PP, Budenz DL: The effects of cataract extraction on the visual field of eyes with chronic open-angle glaucoma. Am J Ophthalmol 125:325-333, 1998 15. Budenz DL, Feuer WJ, Anderson DR: The effect of simulated cataract on the glaucomatous visual field. Ophthalmology 100:511-517, 1993 16. Costagliola C, De Simone C, Giacoia A, Iuliano G, Landolfo V: Influence of lens opacities on visual field indices. Ophthalmologica 201:180-186, 1990 17. Ivers RQ, Mitchell P, Cumming RG: Lack of association between localized cataract and visual field loss: The Blue Mountains Eye Study. Aust NZ J Ophthalmol 25:193-198, 1997 18. Lyne AJ, Phillips CI: Visual field defects due to opacities in the optical media. Br J Ophthalmol 53:119-122, 1969 19. Lietz A, Kaiser HJ, Stumpfig D, Flammer J: Influence of posture on the visual field in glaucoma patients and controls. Ophthalmologica 209:129-131, 1995 20. Kosmin AS, Wishart PK, Birch MK: Apparent glaucomatous visual field defects caused by dermatochalasis. Eye 11:682-686, 1997 21. O’Brien C, Wild JM: Automated perimetry in glaucoma: room for improvement? Br J Ophthalmol 79:200-201, 1995 22. Heijl A, Bengtsson B: The effect of perimetric experience in patients with glaucoma. Arch Ophthalmol 114:19-22, 1996 23. Werner EB, Drance SM: Early visual field disturbances in glaucoma. Arch Ophthalmol 95:1173-1175, 1977

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24. Searle AET, Wild JM, Shaw DE, O’Neill EC: Time-related variation in normal automated static perimetry. Ophthalmology 98:701-707, 1991 25. Gonzalez de la Rosa M, Pareja A: Influence of the ‘fatigue effect’ on the mean deviation measurement in perimetry. Eur J Ophthalmol 7(1):29-34, 1997 26. Henson DB, Evans J, Chauhan BC, Lane C: Influence of fixation accuracy on threshold variability in patients with open angle glaucoma. Invest Ophthalmol Vis Sci 37:444-450, 1996 27. Van Coevorden RE, Mills RP, Chen YY, Barneby HS: Continuous visual field test supervision may not always be necessary. Ophthalmology 106:178-181, 1999 28. Wall M, Kutzko KE, Chauhan B: Variability in patients with glaucomatous visual field damage is reduced using size V stimuli. Invest Ophthalmol Vis Sci 38:426-435, 1997 29. Donahue SP: Lens holder artifact simulating glaucomatous defect in automated perimetry. Arch Ophthalmol 116:1681-1683, 1998 30. Zucca I, Tanda A, Piras V et al: The influence of diabetes mellitus on primary open angle glaucoma perimetry. Acta Ophthalmol Suppl 224:49-50, 1997 31. Zulauf M, Flammer J, Signer C: The influence of alcohol on the outcome of automated static perimetry. Graefe’s Arch Clin Exp Ophthalmol 224:525-528, 1986 32. Haas A, Flammer J, Schneider U: Influence of diazepam on differential light sensitivity. Doc Ophthalmol Proc Ser 42:527-532, 1985 33. Wild JM, Betts TA, Ross K et al: Influence of antihistamines on central visual field assessment. In: Heijl A (ed) Perimetry Update, 1988/89, Proceedings of the 7th International Perimetric Society Meeting, pp 439-444. Amsterdam: Kugler & Ghedini 1988 34. Zulauf M, Caprioli J: Fluctuation of the visual field in glaucoma. Ophthalmol Clin N Am 4(4):671-697, 1991 35. Wilensky JT, Joondeph BC: Variation in visual field measurements with an automated perimeter. Am J Ophthalmol 97:328-331, 1984 36. Boeglin RJ, Caprioli J, Zulauf M: Long-term fluctuation of the visual field in glaucoma. Am J Ophthalmol 113:396-400, 1992 37. Heijl A, Lindgren A, Lindgren G: Test-retest variability in glaucomatous visual fields. Am J Ophthalmol 108:130-135, 1989 38. Katz J, Quigley HA, Sommer A: Repeatability of the glaucoma hemifield test in automated perimetry. Invest Ophthalmol Vis Sci 36:1658-1664, 1995 39. Werner EB, Adelson A, Krupin T: Effect of patient experience on the results of automated perimetry in clinically stable glaucoma patients. Ophthalmology 95:764-767, 1988 40. Hilton S, Katz J, Zeger S: Classifying visual field data. Statistics in Medicine 15:1349-1364, 1996 41. Katz J, Sommer A: Reliability indexes of automated perimetric tests. Arch Ophthalmol 106:1252-1254, 1988 42. Bickler-Bluth M, Trick GL, Kolker AE, Cooper DG: Assessing the utility of reliability indices for automated visual fields, testing ocular hypertensives. Ophthalmology 96:616-619, 1989 43. Quigley HA, Addicks EM, Green WR: Optic nerve damage in human glaucoma. III. Quantitative correlation of nerve fiber loss and visual field defect in glaucoma, ischemic neuropathy, papilledema and toxic neuropathy. Arch Ophthalmol 100:135-146, 1982 44. Mark HH: Corneal curvature in applanation tonometry. Am J Ophthalmol 76:223-224, 1973 45. Ehlers N, Bramsen T, Sperling S: Applanation tonometry and central corneal thickness. Acta Ophthalmol (Kbh) 53:34-43, 1975 46. Bengtsson B, Olsson J, Heijl A, Rootzen H: A new generation of algorithms for computerized threshold perimetry, SITA. Acta Ophthalmol Scand 75:368-375, 1997 47. Bengtsson B, Heijl A: Comparing significance and magnitude of glaucomatous visual field defects using the SITA and full threshold strategies. Acta Ophthalmol Scand 77:143-146, 1999 48. Bengtsson B, Heijl A: Evaluation of a new perimetric threshold strategy, SITA, in patients with manifest and suspect glaucoma. Acta Ophthalmol Scand 76:268-272, 1998 49. Bengtsson B, Heijl A, Olsson J: Evaluation of a new threshold visual field strategy, SITA, in normal subjects. Acta Ophthalmol Scand 76:165-169, 1998 50. Bengtsson B, Heijl A: SITA Fast, a new rapid perimetric threshold test: description of methods and evaluation in patients with manifest and suspect glaucoma. Acta Ophthalmol Scand 76:431-437, 1998

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51. Shirato S, Inoue R, Fukushima K, Suzuki Y: Clinical evaluation of SITA: a new family of perimetric testing strategies. Graefe’s Arch Clin Exp Ophthalmol 237:29-34, 1999 52. Lee DA, Committee on Ophthalmic Procedures Assessment Glaucoma Panel: Optic nerve head and retinal nerve fiber layer analysis. Ophthalmology 106:1414-1424, 1999 53. Hoh ST, Greenfield, DS, Ishikawa H, Liebman JM, Ches SJ, Maw R, Titch R: Factors affecting image acquisition during scanning laser polarimetry. Ophthalmic Surg Lasers 29:545-551, 1998

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Questions & answers 4/7/01

183

Round table Visual field Eve J. Higginbotham, MD, presiding Panel: Alan S. Crandall, MD George A. (Jack) Cioffi, MD Dr Higginbotham: Maybe I could pose a question to the other panelists while we are waiting for questions from the audience. Do you have a preference in new patients for using the 24-2 SITA-standard or SITA-fast? What are you using in your practice, Alan? Dr Crandall: I use the SITA-standard. Dr Cioffi: We mentioned this yesterday. I use SITA-standard as well. Harry Quigley said he was using SITA-fast as his initial test, which surprised me. Again, I don’t think the time saving is that great over SITA-standard, and the variability goes up. Dr Higginbotham: I guess one of the things I didn’t mention about the SITA-standard in terms of the difference between standard and fast is that the SITA-standard will threshold selective points if they fall outside the predicted range of error, whereas with the SITA-fast, you are going to miss that opportunity. So, like my two colleagues, I use the SITA-standard as my first field.

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Question from the audience: I wanted to ask the panel if there were studies to show an increased variability with higher refractive errors. I was interested in that because, for a number of years having very liberal access to disposable contact lenses, I frequently put, as I mentioned once to Eve, contact lenses on eyes with higher refractive errors, and it seemed to me that it increased the accuracy of the Humphrey full threshold. Dr Cioffi: With Humphrey full threshold you have to correct high refractive errors. It doesn’t tolerate much in the way of blur and you also have to correct for the testing distance in a presbyopic patient, and probably what you were eliminating were optical aberrations of the periphery of lenses with a contact lens on. Dr Higginbotham: Yes, I remember our conversation. That was over a decade ago, I think. Certainly, as I reviewed the literature, particularly of myopes, it makes a big difference, and in this one particular study that I referenced, the magnitude Glaucoma in the New Millennium, pp. 183–184 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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was extraordinary. I have a question for the audience. How many people, if any out there, have listened to all these lectures about SITA and SWAP and are leaving confused about which test you are getting in your own offices? We have a question from the audience. Many patients with multiple reproducible standard automated perimetry test defects appear to improve markedly when switched to SITA-fast. What is the cause, and how can they be followed? Do you need to switch back to standard testing in these patients? Dr Cioffi: I would. I think this is exactly what we were talking about earlier. If you have an abnormality – I get a lot of referrals based on SITA-fast because there are weird changes on it and it is a variability factor. You have more variability and the best referral is the old Fastpac, because it was used all over the place. It was quick, but it was just so variable that, from time to time, you could get almost anything, and so it is that function that I talked about. If the test time goes down, the variability generally goes up. Dr Higginbotham: I only use the SITA-fast in those instances in which I am getting very variable fields on the SITA-standard. If I have an elderly patient, then I will switch to the SITA–fast. Fastpac is similar to the SITA-fast and I consider the SITAstandard in the same ballpark as the full threshold. So, I think I would use the SITA-fast as an exception to the rule. Dr Cioffi: Some patients can’t take fields. Some of the patients we see, we just mark on their charts, “don’t give fields”. Some patients are simply incapable of it, and you have to follow them with other parameters.

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Dr Higginbotham: In those patients, I just follow as if they were babies, disc photos and periodic exams, but mostly disc photos.

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Update on perimetry New developments

Chris A. Johnson Discoveries in Sight/Devers Eye Institute, Legacy Health Systems, Portland, OR, USA

Introduction In recent years, there have been a number of advances in perimetry and visual field testing. Most of these new developments have been directed toward two primary areas: 1. test procedures that are more sensitive and are therefore better able to detect pathological changes in the visual pathways, and 2. efficient test strategies that are able to obtain the same amount of information as conventional test procedures, but in a fraction of the time. This chapter provides a brief review of a new efficient test strategy, the Swedish Interactive Threshold Algorithms (SITA), as well as two new perimetric test procedures, Short Wavelength Automated Perimetry (SWAP) and Frequency Doubling Technology (FDT) perimetry. Additionally, it will briefly discuss methods for detecting progression of visual field loss, which is currently one of the major challenges in the management of glaucoma patients.

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The Swedish Interactive Threshold Algorithms The objective of conventional automated perimetry is to provide valid, reliable visual field information within a reasonable time period. Although the staircase procedures originally designed for conventional automated perimetry were able to provide high quality information, these test procedures are rather time-consuming. In addition to taxing clinical resources, long perimetric testing times result in greater errors and variability on the part of the patient, as well as sensitivity reductions due to fatigue. It is possible to make staircase procedures more efficient (such as the FASTPAC procedure), but only at the expense of increased variability.1 The family of Swedish Interactive Threshold Algorithms (SITA) were designed to provide more efficient threshold testing strategies while maintaining the same Address for correspondence: Chris A. Johnson, PhD, Discoveries in Sight/Devers Eye Institute, Legacy Health Systems, 1040 NW 22nd Avenue, Portland, OR 97210, USA. e-mail: [email protected] Glaucoma in the New Millennium, pp. 185–206 Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001 edited by Jonathan Nussdorf © 2003 Kugler Publications, The Hague, The Netherlands

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accuracy and reliability of conventional test procedures. SITA-standard was designed to replace the Full Threshold test procedure and SITA-fast was designed to replace FASTPAC. Recent investigations have verified that SITA-standard and SITAfast are 35-50% faster than their Full Threshold and FASTPAC counterparts, respectively, while maintaining equivalent accuracy and reliability characteristics.2-8 The SITA strategy is based on Bayesian statistics that are used as part of a maximum likelihood estimation procedure to provide forecasting of threshold sensitivities for individual visual field locations. For readers interested in obtaining more detailed information, Vingrys and Pianta9 have published an excellent overview of the application of maximum likelihood techniques for threshold determinations in automated perimetry. The SITA strategy consists of three main components: 1. probability density functions (pdfs) at each visual field location for normal and glaucomatous visual fields; 2. likelihood functions, also known as frequency-of-seeing curves; and 3. neighborhood analysis of visual field results for locations surrounding each visual field location. A probability density function (pdf) is essentially a frequency distribution of threshold sensitivity values at a given visual field location for the population at large. For example, Figure 1 presents an illustrative example of a pdf for normal persons (age-adjusted) for an individual visual field location. In this example, a sensitivity of 34 dB is the most frequent value found in the normal population. Progressively higher and lower sensitivity values become successively less frequent. The frequency of sensitivity values higher than 39 or lower than 29 is very low. Typically, a maximum likelihood procedure begins testing at the mean value of the a priori pdf, which in the illustrative case presented in Figure 1 would be 34 dB. For example, if the stimulus is seen, then threshold is most likely to be in the upper portion of the distribution. The lower portion of the distribution is truncated (except for a small allowance for false positive responses), and a revised pdf is generated by multiplying the adjusted distribution by a likelihood function (frequency of seeing curve). This revised distribution is then used to establish the value of the next stimulus presentation. The process continues until there is a small interval between the upper and lower bounds of the revised pdf distribution. It can readily be appreciated that this method is capable of producing an accurate estimate of threshold within a few presentations. The primary difference between SITA-standard and SITA-fast is that SITA-fast accepts a greater amount of error in the threshold estimate than SITA-standard, and therefore a fewer number of stimulus trials are needed to establish the threshold estimate. Upon completion of the test procedure, each location is compared to its immediate neighbors and a final adjustment of the threshold estimate is made on the basis of these comparisons. SITA is currently limited to programs 10-2, 24-2, 30-2 and 60-4 on the HFA II (700 series) and can only be used with white, size III stimuli. Threshold sensitivity values obtained by SITA are analyzed by the internal statistical package, STATPAC,6 in the same manner as the traditional Full Threshold staircase strategies. STATPAC has been revised such that patients tested with SITA are compared with normative SITA data from 330 age-corrected individuals.7 For each test location and global index, STATPAC indicates when the patient has a low probability of falling within the normal range. Single field analysis printouts derived from SITA examinations are highly similar to those from Full Threshold and FASTPAC examinations and are presented in

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Update on perimetry

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30

32

34

36

38

40

SENSITIVITY (dB)

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Fig. 1. An illustrative example of a normal probability density function (pdf) for an individual visual field location. In this example, the mean of the pdf is 34 dB.

the same format. An example of the printout for SITA-standard is shown in Figure 2 for a glaucoma patient with superior visual field loss. SITA-fast results for the same eye are presented in Figure 3. The benefits of shorter test times and less fatigue provided by using SITA make it highly suitable for routine clinical use, both for defect detection and for monitoring progression. Although longitudinal clinical trials are still required to validate SITA’s performance for monitoring progression, the results of such investigations are likely to be positive. The differences in accuracy and reliability between SITA-standard and SITAfast should be considered when deciding on their use. SITA-fast appears suitable for populations likely to be predominantly normal, or where traditional perimetry tests may be too difficult. However, if diagnosis and monitoring of visual field loss are most important, the greater accuracy and reliability of SITA-standard is probably desirable. How do we go about comparing new SITA results to previous findings using the traditional staircase test strategies? Comparisons among visual field test results are always the most informative when all tests are performed using the same strategy. For this reason, when attempting to identify progressive loss, it is inappropriate to switch back and forth between staircase and SITA strategies, or between SITA-standard and SITA-fast. It has been suggested that comparisons based on pointwise total and pattern deviation probability plots, rather than decibel values, may be employed for comparing the results obtained with SITA to those acquired using traditional staircase strategies, although establishing a new baseline is the most desirable alternative.10 The time to switch test strategies and establish a new baseline is when the patient’s visual field appears to be stable. If the patient’s recent visual field history suggests that there is progressive loss or visual field results are unstable, it is not a good time to change testing strategies.

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Fig. 2. An example of the printed output for SITA-standard. Results for the right eye of a patient with superior glaucomatous visual field loss is presented.

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Fig. 3. An example of the printed output for SITA-fast for the same eye as that shown in Figure 2.

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Short Wavelength Automated Perimetry

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Short Wavelength Automated Perimetry (SWAP) uses a bright yellow background and a large (Goldmann size V) blue stimulus to isolate and measure the sensitivity of the short-wavelength-sensitive (blue) visual pathways. The bright yellow background suppresses the sensitivity of the middle (green) and long (red) wavelength mechanisms and permits the sensitivity of the short wavelength sensitive mechanisms to be evaluated. Using the optimum stimulus conditions for SWAP (implemented on the Humphrey Field Analyzer II – Model 750), approximately 17 dB of isolation of the short-wavelength-sensitive pathways can be achieved.11 These optimal stimulus conditions consist of a 100 cd/m2 (315 asb) yellow background (Schott OG 530 filter) and a size V blue stimulus (Omega 440-nm interference filter). Several investigators have reported that isolation of short-wavelength-sensitive mechanisms is maintained over the entire operating range of SWAP, even in areas of severe glaucomatous visual field loss.12,13 Large scale prospective longitudinal evaluations conducted at two independent laboratories have shown that SWAP losses in glaucoma are larger and progress at a greater rate than conventional automated perimetry deficits.14-22 In patients at risk of developing glaucoma, SWAP losses appear earlier than standard visual field defects and are predictive of future glaucomatous visual field loss that develops for conventional automated perimetry.16,18 SWAP deficits can be detected approximately three to five years prior to the development of visual field loss with conventional white-on-white perimetry. Results from these and other laboratories confirm that SWAP provides the earliest and most sensitive indication of glaucomatous visual field loss.11,13,16,17,23-35 SWAP deficits have also been reported to be correlated with glaucomatous optic disc abnormalities and retinal nerve fiber layer losses16,18,22,25,31,32,36-38 early in the glaucomatous disease process. An example of SWAP’s earlier detection of glaucomatous visual field loss is shown in Figure 4, which presents a comparison of conventional automated perimetry (top) and SWAP (bottom) in the right eye of a glaucoma suspect over a fiveyear period of time. For both tests, locations with normal sensitivity are indicated by open circles, locations with sensitivity lower than the normal 5% probability level are shaded gray, and locations with sensitivity below the normal 1% probability level are solid black circles. It can be observed that a SWAP deficit in the form of a superior nasal step begins to appear in year 1 and then progresses over the next four years. Conventional automated perimetry results begin to show the appearance of the superior nasal step about four years after it appears for SWAP. Progression of glaucomatous visual field loss occurs more rapidly for SWAP than for conventional automated perimetry. An example of standard (white-onwhite) and SWAP perimetry results obtained over a five-year period in the right eye of a patient with progressive glaucomatous visual field loss is presented in Figure 5. For SWAP, superior and inferior defects are present in year 1 and progress rapidly over the next four years. For standard automated perimetry, the defect appears in year 3 and then progresses more gradually in years 4 and 5. An example of the printed output for SWAP on the Humphrey Field Analyzer II Model 750 is presented in Figure 6. Similar to conventional white-on-white automated perimetry, SWAP results present the sensitivity values in dB, a gray scale representation of test results, total and pattern deviation probability plots, visual field indices, reliability indices and other relevant information. When assess-

Glaucoma in the New Millennium, Kugler Publications, 2003. ProQuest Ebook Central,

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