View on Glaucoma · The HRT3 model includes the latest software version, called Advanced Glaucoma...

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View on Glaucoma

Advanced imaging technologies for evaluating glaucoma progressionAntonio Ferreras

Dry eye testing in glaucomaJonathan E. Moore and C.B. Tara Moore

Risk factors for visual field progressionRobert T. Chang and Kuldev Singh

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EditorialNew directions in glaucoma management Carlo E. Traverso

Feature articleAdvanced imaging technologies for evaluating glaucoma progression Antonio Ferreras

Review articlesDry eye testing in glaucomaJonathan E. Moore and C.B. Tara Moore

Risk factors for visual field progressionRobert T. Chang and Kuldev Singh

Editor-in-ChiefProf. Carlo E. TraversoDirector, Clinica OculisticaDINOG, University of GenoaViale Benedetto X, 516132 Genoa, Italy

Editorial BoardProf. John ThygesenDepartment of Ophthalmology Copenhagen University Hospital GlostrupDK-2600 Glostrup, Denmark

© 2012 Excerpta Medica BV

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or other-wise, without the prior written permission of the copyright owner.

No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, through negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Because of rapid advances in the medical sciences, the Publisher recommends that independent verification of diagnoses and drug dosages should be made. Opinions expressed in this publication are those of the original authors and do not necessarily reflect those of the Publisher, the sponsor, or the editors. Excerpta Medica assumes no liability for any material published herein.

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Dear Readers,

This fi rst 2012 issue of View on Glaucoma features articles of great practical value. The topics of identifying patients with

worsening disease and of quantifying the risk of such decay are of great interest to clinicians; Antonio Ferreras, Robert

Chang, and Kuldev Singh address these problems, respectively, from both the functional and the morphological viewpoint.

Practical means of guiding the management of patients are currently lacking, and Jonathan and Tara Moore discuss the

steps that are recommended to detect those glaucomatous patients who have – or are prone to – dry eye.

There is an increasing awareness of the adverse consequences of long-term topical treatment – which are probably mainly

related to the inclusion of preservatives – and these and many other clinically relevant topics will be extensively discussed

this year at the European Glaucoma Society Congress (EGS 2012), which will be held in Copenhagen, one of Europe's great

capital cities, on 17–22 June. This meeting, which builds on the previous successful EGS congresses that have set new

standards, off ers a diverse and stimulating scientifi c programme, with extensive audience interaction, as well as a wide range

of instructional courses. With the inclusion of Special Interest Groups, exhibits, and scientifi c posters, attendees will be able

to choose from a variety of components, according to their interests. Trainees, general ophthalmologists, and glaucoma

specialists alike will fi nd topics of interest, and

the friendly, cosmopolitan environment that

typifi es the EGS Congress will make networking

and information exchange a natural occurrence.

The city of Copenhagen itself has much to off er,

and the congress centre and main hotel are at

the border of the fabulous Tivoli Gardens. June is

a perfect month for enjoying the metropolis and

its environs, so EGS Copenhagen 2012 promises

to be an exciting and fun-fi lled meeting. I do

hope you are able to attend and trust you will

enjoy it fully.

Volume 7 Issue 1 2012

New directions in glaucoma management Prof. Carlo E. TraversoEditor-in-Chief

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Advanced imaging technologies for evaluating glaucoma progressionAntonio FerrerasMiguel Servet University Hospital, Aragón Health Sciences Institute, University of Zaragoza, Zaragoza, Spain

The risk of developing visual disability and blindness as a consequence of glaucoma varies greatly

among affected individuals. Personalized testing strategies and tailored therapeutic interventions

are required to effectively reduce visual impairment due to glaucoma. Thus, adequate evaluation of

glaucoma progression is one of the main challenges in the management of the disease. A true standard

to define the changes that signify disease progression is currently lacking, but newly developed imaging

technologies that provide objective, quantitative, and reproducible measurements have become decisive

tools for monitoring patients with glaucoma or at risk for the disease.

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Antonio Ferreras

Antonio Ferreras is an Associate Professor of Health Sciences at the University of

Zaragoza and a Consultant Surgeon (Ophthalmology) at the Miguel Servet University

Hospital in Zaragoza (Spain). The University of Zaragoza awarded him his doctorate

in 2003. His main research focus is glaucoma diagnosis technologies. Dr Ferreras has

been the principal investigator for several research projects funded by the Spanish

Health Research Fund and other institutions and companies. He has authored

numerous articles published in major scientific journals of his specialty. In 2010,

Dr Ferreras received the Arruga award from the Spanish Society of Ophthalmology,

which recognizes the best research and professional trajectory of a Spanish

ophthalmologist younger than 40 years of age.

IntroductionPrimary open-angle glaucoma is an acquired,

multifactorial, and progressive optic neuropathy

characterized by atrophy of the optic nerve due to loss

of retinal ganglion cells and their axons in the retina.1,2

Damage to the retinal nerve fibre layer (RNFL) is usually

followed by morphological changes in the optic nerve

head (ONH) and specific visual-field defects. The loss of

retinal ganglion cells does not usually affect quality of

life until late in the course of the disease. Treatment for

glaucoma reduces the rate of vision loss, but individual

responses vary considerably. Therefore, early diagnosis,

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risk stratifi cation, and effi cient follow-up are key to

preventing visual impairment and the consequent loss of

quality of life.

Classically, standard automated perimetry (SAP) has

been considered the gold-standard test for monitoring

patients with glaucoma. New imaging technologies

that provide objective, quantitative, and reproducible

parameters, however, are becoming essential tools for

detecting disease progression. Currently, no specifi c

test is regarded as the perfect reference standard for

the detection of disease progression; thus the right

balance of combining results from psychophysical tests

and imaging instruments could be the best method for

detecting glaucomatous changes.

New imaging technologiesDetection of changes at the RNFL and ONH is key to

the diagnosis and follow-up of glaucoma. Red-free

photographs have been used for decades to qualitatively

assess RNFL status. However, both the highly subjective

nature of this method and the requirement for

experienced evaluators limit its general applicability.

Likewise, ONH evaluation in glaucoma management

has been traditionally based on physician drawings and

photographic documentation. ONH assessment by slit-

lamp examination with a high-power biconvex lens is

subjective and does not allow for comparison between

images, and stereophotographs of the ONH require

experienced technicians and evaluators, so are not always

obtained in clinical practice.

Several devices have recently been designed to

quantitatively assess ONH morphology and RNFL

thickness to improve the accuracy of measurement

and avoid evaluator subjectivity. Confocal scanning

laser ophthalmoscopy, scanning laser polarimetry, and

optical coherence tomography (OCT) are currently the

most informative and widely used objective imaging

technologies for glaucoma diagnosis.

Confocal scanning laser ophthalmoscopyDue to the wide variations in optic disc appearance in the

normal population, the use of scanning laser devices, such

as the Heidelberg Retina Tomograph (HRT), can improve

the accuracy of ONH evaluation. The HRT assessment

is rapid and easy to perform, provides quantitative

and reproducible data,3,4 and does not usually require

mydriasis (depending on the pupil size).

The HRT3 model includes the latest software version,

called Advanced Glaucoma Analysis 3.0, which is an

enhanced version of the previous HRT II glaucoma

software. The HRT3 calculates diff erent stereometric

parameters from 16 to 64 optical sections to a depth

of 4 mm, centred on the optic disc.5 Nevertheless,

the optic disc margin must be manually defi ned after

acquisition of the images. In addition, the HRT3 provides

two classifi cations: one semiautomatic, the Moorfi elds

Regression Analysis (MRA; Figure 1),6,7 and the other

automatic, the Glaucoma Probability Score (GPS).7,8 Both

the MRA and GPS provide immediate results and colour-

coded classifi cations, which simplifi es interpretation. The

GPS, however, does not rely on reference planes and does

not require prior manual outlining of disc boundaries,

reducing the dependence on operator skill.

The ability of HRT parameters and classifi cations

to detect glaucomatous changes of the ONH is widely

validated.6,7,9–11 Most studies report 80-85% sensitivity

for the best HRT parameters at 90-95% fi xed specifi city.

The primary method of assessing glaucomatous

changes using the HRT3 is Topographic Change Analysis

(TCA), a technique that compares the variability within

a baseline examination (the 3 scan sets in an individual

examination) to that between baseline and follow-up

examinations. The software uses anatomical features such

as blood vessel patterns and other image characteristics to

align the images. TCA is based on the probability of change

in a cluster of pixels within the optic disc margin, and the

stereometric trend analysis reports changes in normalized


New imaging technologies that provide objective, quantitative,

and reproducible parameters are becoming essential tools

for detecting glaucoma progression

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topographic parameters over time.12 Bowd et al.13

reported an acceptable performance of TCA parameters

to discriminate between glaucomatous progressing eyes

and longitudinally observed healthy eyes. They also

observed that a significant number of glaucomatous

and/or suspect eyes that were apparently stable based

on optic-disc stereophotograph assessment and/or SAP

Guided Progression Analysis™ (GPA) showed significant

TCA change. They concluded that this low specificity in

apparently non-progressing patients’ eyes suggests that

TCA can be used to detect early disease progression.

HRT is an imaging technology that allows for the

longest follow-up period because, although HRT II

was introduced more than 10 years ago, the posterior-

segment software upgrades are backwards-compatible

with previously acquired images.

Although agreement between disease progression

identified by HRT and masked stereophotograph

evaluation is reported to be poor,14 there is evidence

that abnormal results obtained on HRT are associated

with worse future outcomes in individuals with ocular

hypertension. Several baseline topographic HRT

Figure 1. The Moorfields Regression Analysis (MRA) of the Heidelberg Retina Tomograph version 3 (HRT3) compares a subject’s

rim area with the predicted rim area for a given disc area and age, based on confidence limits of a regression analysis derived

from an ethnic-selectable database. The optic disc is divided into six colour-coded sectors, and each sector is classified as

“within normal limits” if the percentage of the rim falls within the 95% confidence interval (CI; coloured green), “borderline” if

the percentage of the rim is between the 95% and 99.9% CI (coloured yellow), or “outside normal limits” if the result is greater

than the 99.9% CI (coloured red).

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measurements, such as larger cup-to-disc area ratio,

mean cup depth, mean height contour, cup volume,

reference plane height, and smaller rim area, ratio of

rim area to disc area, and rim volume, were predictive of

future development of visual fi eld loss in a large study

of patients with ocular hypertension followed up for

approximately 6 years.15 Moreover, an outside-normal-

limit MRA classifi cation (overall, global, temporal inferior,

nasal inferior, and superior temporal regions) was

signifi cantly associated with the development of primary

open-angle glaucoma among Ocular Hypertension

Treatment Study participants.15

Scanning laser polarimetryScanning laser polarimetry, developed to detect and

monitor glaucoma, is based on the presumed form of

the birefringence of the microtubules in the RNFL.16

A parallel arrangement of the microtubules leads to a

change in the retardation of passing polarized light.

The amount of retardance exhibited by the RNFL is

proportional to its thickness.17 Typically, in healthy

subjects, larger amounts of retardation are apparent

next to the blood vessels superior and inferior to the

ONH, and decrease with increasing distance from the

optic disc. Nevertheless, anterior-segment birefringence

(cornea and lens) must be neutralized to obtain accurate

RNFL measurements. Scanning laser polarimetry with

variable corneal compensation (GDx-VCC) and the latest

version, scanning laser polarimetry with enhanced

corneal compensation (GDx-ECC), allow for eye-specifi c

neutralization of the magnitude and axis of birefringence

of the anterior segment. The ECC method was developed

to improve neutralization of the atypical retardation

patterns observed in some patients and to increase the

dynamic range of the measurements in the low signal

range. Medeiros et al.18 reported that GDx-ECC performed

signifi cantly better than GDx-VCC for diagnosing

glaucoma in patients with more severe atypical patterns

of retardation and at earlier stages of disease.

The software used to evaluate disease progression

using GDx, called GPA (the same as that for evaluating

visual fi eld progression with Humphrey perimeters),

automatically establishes the fi rst two qualifying

examinations as baselines, and compares measurements

over time to determine if the diff erences are statistically

signifi cant. GPA has two diff erent modes: Fast Mode

and Extended Mode, and the mode selected depends

on the number of images to be obtained. In Fast Mode,

a single image is acquired, while in Extended Mode,

three images are acquired. In Fast Mode, progression is

defi ned as a change outside the variability limits based

on the GDx normative database. In Extended Mode,

progression is defi ned as those changes that exceed the

within-individual variability calculated from the three

baseline images (similar to HRT3 TCA). GPA uses diff erent

algorithms based on event and trend analysis to detect

narrow or broader focal changes, as well as diff use

changes at the follow-up visits. GPA reports “possible

progression” when a signifi cant change is identifi ed and

“likely progression” (95% specifi city) when the change is

confi rmed in one additional visit.

Previous studies19,20 indicated that GDx-VCC could

be used to identify longitudinal RNFL loss in eyes that

showed progression in optic disc stereophotographs and/

or visual fi elds. Moreover, the GDx-VCC more sensitively

detected disease progression during early stages of the

disease. The GDx-GPA recognized only 50% of the eyes

in which disease was progressing, but the test had high

specifi city (96%). Rates of change measured by the GDx-

ECC performed signifi cantly better than those of VCC for

discriminating between disease progressors and non-

progressors.21 For the temporal-superior-nasal-inferior-

temporal average, the area under the receiver operating

characteristic (ROC) curve was 0.89 for ECC compared to

only 0.65 for VCC. When images with atypical patterns of

retardation were excluded, the area under the ROC curve

improved to 0.80 for VCC.

The right balance of combining functional and imaging tests could be the best method for detecting

glaucomatous changes

8

Optical coherence tomographyOCT is also, like both of the above techniques, a non-

invasive, quantitative method that provides real-time

in vivo images of the retina. The new spectral-domain

OCTs have increased resolution and acquisition speed

compared with earlier time-domain OCTs, allowing for

the generation of highly detailed three-dimensional

images. Increased scanning speed (more than 20,000

A-scan/s) allows spectral-domain OCT to obtain a three-

dimensional cube of data, and advances in light-source

technology have enhanced axial resolution from 10 μm

to 5 μm. The cube of data enables a far more extensive

assessment of the peripapillary area, including temporal-

superior-nasal-inferior-temporal RNFL profiles, en face

RNFL images (fundus image), and ONH assessment.22

Higher image resolution allows for improved

segmentation of the retinal layers, leading to more

accurate measurements, and the faster scan-acquisition

speed reduces artifacts, which also contributes to

reduced measurement variability. Schuman23 reported

that, compared with earlier time-domain instruments,

spectral-domain OCT has significantly better

reproducibility in most RNFL sectoral measurements.

These results were confirmed by Leung et al.,24 indicating

excellent repeatability and reproducibility of spectral-

domain OCT parameters. The reduced variability

compared to time-domain OCT might improve the

detection of disease progression in glaucoma patients

(Figure 2).

In cross-sectional studies, most authors25–28 agree

that both OCT systems have good sensitivity–specificity

balance to discriminate between healthy people and

Figure 2. The new Guided Progression Analysis™ (GPA) software version 6 of Cirrus™ optical coherence tomography (OCT)

(Carl Zeiss Meditec, Dublin, CA, USA) includes retinal nerve fibre layer (RNFL) and optic nerve head (ONH) evaluation in a single

report. This example illustrates the power of using multiple algorithms to detect disease progression. Other spectral-domain

OCT manufacturers, such as those of the Topcon 3D OCT-2000 (Topcon Corporation, Tokyo, Japan), RTVue (Optovue Inc.,

Fremont, CA, USA), and Spectralis® OCT (Heidelberg Engineering, Germany), also include progression programs for RNFL and/or

ONH trend analysis.

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Currently, spectral-domain OCT is the most polyvalent

imaging technology available in ophthalmology. It

can be used for diagnosing and monitoring retinal and

macular diseases, and glaucoma, as well as neuro-

ophthalmological diseases, such as multiple sclerosis, and

anterior-pole pathologies.

ConclusionsThe 8th World Glaucoma Association Global Consensus

Meeting on glaucoma progression was held at the World

Glaucoma Congress 2011 in Paris. A book was published

in October 2011, based on the experience of diff erent

experts, to serve as a guideline to optimize glaucoma

progression evaluation.31 These experts reported the

main strengths and limitations of HRT, GDx, and OCT in

the evaluation of glaucoma progression. They indicated

that TCA of the HRT3 is the most well-developed and

tested progression-detection analysis technique available

for imaging diagnosis. The limitations of TCA are the

lack of a clinically usable and well-tested cut-off to

defi ne progression and the inability to interpret areas of

improvement (i.e. local increases in retinal height that

may be associated with adjacent decreases in height).


glaucoma patients, even at early stages of the disease.

In a longitudinal study, Medeiros et al.29 found that

time-domain OCT RNFL parameters could discriminate

eyes with progressing disease, based on visual fi elds or

optic disc photographs, from eyes that remained stable

according to these methods (77% sensitivity and 80%

specifi city for average RNFL thickness), and performed

signifi cantly better than ONH and macular thickness

parameters in detecting change over time. Sung et al.30

reported that an abnormal RNFL classifi cation in the

inferior area of the optic disc or an elevated number of

abnormal RNFL sectors in glaucoma-suspect patients,

as determined by the Stratus OCT, was associated with

future visual-fi eld conversion. Approximately 24% of

eyes with abnormal OCT RNFL classifi cations developed

visual-fi eld abnormalities during 4 years of follow-up.

Currently no single test is suff cient to confi dently defi ne mild to moderate dry eye test should be confi rmed by

the evidence from another

Table. Comparison of coeffi cient of variation and intraclass correlation coeffi cient of the main parameters of HRT3, GDx-VCC, time-domain OCT, and spectral-domain OCTs.

ParametersCoeffi cient of variation,

% (lower 95% CI)

Intraclass correlation coeffi cient

(lower 95% CI)

HRT3 (global rim area)32 6.22 (5.57) 0.97 (0.95)

GDx-VCC (TSNIT average)32 3.52 (3.16) 0.98 (0.97)

Time-domain Stratus™ OCT (average RNFL

thickness)324.79 (4.29) 0.97 (0.96)

Spectral-domain Cirrus™ OCT (average RNFL)33 2.7 0.97 (0.93)

Spectral-domain Cirrus™ OCT (rim area)33 6.6 0.96 (0.92)

Spectral-domain Spectralis® OCT (global RNFL)34 1.3 0.99 (0.98)

CI = confi dence interval; GDx-VCC = scanning laser polarimetry with variable corneal compensation; HRT3 = Heidelberg Retina Tomograph version 3; OCT = optical coherence tomography; RNFL = retinal nerve fi bre layer; TSNIT = temporal-superior-nasal-inferior-temporal.

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GDx (VCC and ECC) can detect progression in eyes

with known progression. It seems that the low variability

in measurements allows for the detection of age-related

changes, or alternatively, disease-related changes in

suspect eyes that are apparently stable when evaluated

with other current methods. Additionally, the availability

of Fast-Mode and Extended-Mode GPA allows the change

detection to be applied to archival data, regardless of

the number of images obtained at each visit. There

are, however, some limitations. First, VCC and ECC

measurements are not compatible, so a new baseline is

required for GPA analyses when switching instruments.

Moreover, particularly in GDx-VCC, atypical birefringence

retardation patterns can have a significant effect on the

detection of progressive RNFL loss. Eyes with chronic

atypical patterns, fluctuations of these patterns over

time, or both may show changes in measurements that

can falsely appear as glaucomatous progression or that

mask true changes.19 It is possible that this issue has been

remedied by ECC. Finally, it is likely that the progression-

detection techniques using GDx are not optimized

because the cut-offs to define progression are somewhat

arbitrary.

The strengths of the OCT technology are its ability to

measure structural parameters without the need for a

reference plane or magnification correction and to image

all 3 scanning areas, namely the RNFL, ONH, and macula.

The limitations are the influence of signal strength on

the measurements and the non-compatibility of current

spectral-domain OCT technology with earlier OCT

technologies.

The ability of the imaging technologies to identify

changes due to the disease depends largely on the test-

retest variability of the measurements. When variability is

high, there is little statistical confidence in detecting small

changes over time. If variability is low, however, small

changes can be detected with confidence (Table).32-34

Differences in technologies and scan protocols could

influence the detection of progression even when the

same structure is measured. Measures for equivalent

parameters acquired by different devices cannot be

used interchangeably. The quality of the data obtained

by the imaging devices is influenced by media opacity,

retinal pigment epithelium status, instrument variability,

and positioning and centring of the images. Moreover,

identifying descriptors of clinically significant change is

complicated by the fact that there is no true reference

standard for such change. These limitations must be

taken into account in clinical practice.

A large number of tests have an increased ability to

detect small changes. Thus, frequent examinations should be

KEY MESSAGES

•Early diagnosis, risk stratification, andefficient follow-up are essential steps for preventing visual impairment and a consequent loss of quality of life in patients with glaucoma.

•The ability to identify glaucomatouschanges depends mainly on the test-retest variability of the instruments.

•Frequent examinations are associatedwith increased ability to detect small changes.

•No specific test can be considered thereference standard for detecting disease progression.

Consensus statements: 1. Automated quality indices vary by instrument

and are often proprietary, with little information

available regarding their construction.

2. Image quality can influence the ability to detect

structural changes.

3. Poor-quality images can lead to either false-

positive or false-negative results.

4. For patient management decisions, clinicians

should review the quality of images included in

the glaucomatous progression assessment.

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performed whenever possible, although the increased cost

due to repeated testing as well as patient and operator time

mean that this is not always realistic in clinical practice.

While newer imaging technologies and selective visual

function tests are promising toward providing better

ways to monitor glaucoma, well-designed studies

demonstrating the clinical relevance of progression

detected by these technologies are still lacking for most

instruments. Multicentre studies with longer follow-up

time and larger image series comparing the accuracy

of structural and functional tests to detect glaucoma

progression are necessary to further elucidate the ability

of new techniques to detect glaucomatous changes at the

RNFL and ONH. In this direction, the Advanced Imaging

for Glaucoma (AIG) project is a longitudinal clinical trial

that included glaucoma suspects, glaucoma patients, and

normal subjects, and aimed to develop advanced imaging

technologies to improve the detection and management

of glaucoma. Originally designed as a 5-year study, the

AIG Study was recently renewed for a second 5-year

term. This study may provide additional information to

enhance imaging-assisted management of glaucoma.

(See http://coollab.net/index.php?id=833).

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2009;116:1264-70.

26. Chang RT, Knight OJ, Feuer WJ, et al. Sensitivity and

specificity of time-domain versus spectral-domain optical

coherence tomography in diagnosing early to moderate

glaucoma. Ophthalmology. 2009;116:2294-9.

27. Moreno-Montañés J, Olmo N, Alvarez A, et al. Cirrus

high-definition optical coherence tomography compared

with Stratus optical coherence tomography in glaucoma

diagnosis. Invest Ophthalmol Vis Sci. 2010;51:335-43.

28. Jeoung JW, Park KH. Comparison of Cirrus OCT and Stratus

OCT on the ability to detect localized retinal nerve fiber

layer defects in preperimetric glaucoma. Invest Ophthalmol

Vis Sci. 2010;51:938-45.

29. Medeiros FA, Zangwill LM, Alencar LM, et al. Detection

of glaucoma progression with Stratus OCT retinal nerve

fiber layer, optic nerve head, and macular thickness

measurements. Invest Ophthalmol Vis Sci. 2009;50:5741-8.

30. Sung R, Kim S, Lee Y, et al. Retinal nerve fiber layer

normative classification by optical coherence tomography

for prediction of future visual field loss. Invest Ophthalmol

Vis Sci. 2011;52:2634-9.

31. Weinreb RN, Garway-Heath DF, Leung C, et al., editors.

Progression of glaucoma. WGA Consensus Series 8.

Amsterdam: Kugler Publications; 2011.

32. Leung CK, Cheung CY, Lin D, et al. Longitudinal variability of

optic disc and retinal nerve fiber layer measurements. Invest


33. Mwanza JC, Chang RT, Budenz DL, et al. Reproducibility

of peripapillary retinal nerve fiber layer thickness and

optic nerve head parameters measured with Cirrus HD-

OCT in glaucomatous eyes. Invest Ophthalmol Vis Sci.

2010;51:5724-30.

34. Langenegger SJ, Funk J, Töteberg-Harms M. Reproducibility

of retinal nerve fiber layer thickness measurements using

the eye tracker and the retest function of Spectralis SD-

OCT in glaucomatous and healthy control eyes. Invest


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Dry eye testing in glaucomaJonathan E. Moore1,2 and C.B. Tara Moore2

1Cathedral Eye Clinic, University of Ulster, Belfast, Northern Ireland2School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland

Chronic topical therapeutic management of glaucoma has the potential to deleteriously alter an ocular

surface if medication is given at a high enough concentration for a suffi ciently long period of time.

Some ocular surfaces such, as those accompanying dry eye disease, are more susceptible to the eff ects

of benzalkonium chloride and other preservatives. This review highlights the importance of considering

and carefully assessing the ocular surface for evidence of dry eye or other problems, with the aim of

enabling clinical intervention to prevent or retard the deleterious eff ect and exacerbation of ocular

surface disease by topical glaucoma medication.

Medical management of glaucomaGlaucoma is a common condition usually aff ecting an older

age group. The main treatment options for the condition

involve topical medication, laser treatment or surgical

intervention. Topical medications have well-recognized

toxicity reactions associated with prolonged usage and it is

well recognized that chronic topical therapy can potentially

deleteriously aff ect subsequent glaucoma shunt surgery.1

Many of the ocular surface reactions secondary to topical

medication are in fact due to the drug’s formulation, such as

the preservative used, rather than the active drug component.

Benzalkonium chloride (BAK), traditionally the most common

preservative for all eye drops, has been shown to be highly

toxic to conjunctival epithelial and goblet cells as evidenced

through treatment of primary cultured conjunctival cells

with BAK.1 Additionally, prolonged treatment of the ocular

surface with BAK-containing drops has been shown to result

in up-regulation of infl ammatory cytokines, adhesion factors,

and destructive enzymes.2,3 Recognition of this problem has

prompted signifi cant research, and eff orts by pharmaceutical

companies to enhance and improve biocompatibility of these

formulations with the introduction of both single-dose

preservative-free eye drops and preservatives non-toxic to

mammalian cells. The long-term benefi cial eff ects upon the

ocular surface of some of these changes in drop formulation

are still to be assessed.4

Dry eye syndrome aff ects the ocular surface and tear fi lmA healthy tear fi lm and ocular surface constitutes a signifi cant

protective barrier against all forms of insult to the eye,

which is therefore much less likely to suff er from any early

deleterious eff ects induced by chronic topical medication.5

The corollary, however, is that a defi cient tear fi lm and

compromised ocular surface has a greatly reduced capacity

to withstand any form of challenge or stress.6 It is particularly

important that clinicians prescribing and administering topical

glaucoma medications are able to both test for and recognize

pathologically altered ocular surfaces and dry eye states prior

to instituting their defi nitive treatment plan.7

Dry eye syndrome is a recognized group of disorders

that culminate in the production of common signs and

symptoms aff ecting the ocular surface and tear fi lm.5

Ocular infl ammation is one of the single most common

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accompanying findings.8 The term “ocular surface”

recognizes the close interaction and interdependence

of conjunctiva, cornea, lids, tears, and tear-producing

glands.9 Defects or damage to one of its components can

rapidly spill over to affect the whole eye environment.10

As dry eye syndrome comprises a spectrum of

disease severity, it is important that clinicians are able

to recognize early evidence of disease or potential

precipitating factors, in addition to more established

disease. The tear film is traditionally regarded as a

trilaminar structure comprising a predominantly aqueous

layer overlying a mucous layer attached to the underlying

epithelium and coated by an overlying lipid layer.11 The

regulation of the tear film is beyond the scope of this

review but suffice to say there is evidence for regulation

via both sensory and autonomic pathways,12 and defects

in either may contribute to disease states. The mucin

layer is predominantly produced by goblet cells and has

been shown to be affected early in dry eye disease,13,14

which allows specialist clinics to grade dry eye disease

based upon cytological examination of ocular surface

impression cytology samples (Figure). Dry eye syndrome

has been classically subdivided into aqueous deficiency

and evaporative dry eye. However, both these types of

Figure. A–C: Photographs showing impression cytology sampling of an eye. D: Photomicrograph of representative impression

cytology specimen stained with periodic acid and Schiff reagent (PAS) to show goblet cells. This is representative of a normal

cytological specimen post-PAS staining: the presence of goblet cells embedded in the epithelial sheet represented by the pink

colour against conjunctival epithelia, counterstained purple with haematoxylin, with round-shaped epithelial cells, dense staining

around the nuclei, and abundant goblet cells stained bright pink (original magnification, ×400).

A B

C D

15


Table 1. Biomicroscopic grading of dry eye based on assessment of meibomian glands, lids, conjunctiva, and tear fi lm debris.

Grading score Meibomian glands Lid and lid margin Conjunctiva (palpebral and bulbar)

Tear fi lm debris

Erythema Erythema/ Hyperaemia

None (0) No glands plugged

Normal Normal Absence of debris

Mild (+1) 1–2 glands plugged

Redness localized to a small region of the lid margin or skin

Slight localized infection

Presence of debris in inferior tear meniscus

Moderate (+2) 1–3 glands plugged

Redness of most or all lid margin or skin

Pink colour, confi ned to palpebral or bulbar conjunctiva

Presence of debris in inferior tear meniscus and in tear fi lm overlying the cornea

Severe (+3) All 5 glands plugged

Redness of most or all lid margin and skin

Red colour of the palpebral and/or bulbar conjunctiva

Presence of debris in inferior tear meniscus and in tear fi lm overlying the cornea. Presence of mucus strands in inferior fornix or on bulbar conjunctiva

Very Severe (+4) Marked diff use redness of both lid margin and skin

Marked dark redness of the palpebral and/or bulbar conjunctiva

Presence of debris in inferior tear meniscus and in tear fi lm overlying the cornea. Presence of numerous and/or adherent mucus strands in inferior fornix and on bulbar conjunctiva, or fi lamentary keratitis

dry eye produce very similar signs and symptoms, and

separation into two specifi c types is somewhat artifi cial,

as fi nding one aspect in total isolation is highly unlikely

due to the physiologically integrated ocular surface. The

aim of clinical testing, however, has been to try, fi rstly,

to diagnose the presence of dry eye and, secondly, to

classify it if possible into one or another major subtype, in

order to enable further specifi c treatments.15

Osmolarity testingThere is great variation in which diagnostic criteria16 are

currently used, and a signifi cant problem faced by the

clinician is that many of the tests used do not agree, and

can even be at odds with each other. This problem is most

prevalent in patients with mild-to-moderate dry eye,17,18

while in more severe dry eye states the common clinical

tests appear to concur well with each other. Several new

diagnostic tools have started to enter the clinical arena

and are helping to defi ne specifi c aspects of the condition

in more reproducible and eff ective ways. Osmolarity

testing was initially proposed as a standard test at the

First International Conference on the Lacrimal Gland, Tear

Film, and Dry Eye in 1992.19 Tear hyperosmolarity has been

regarded as a central mechanism causing ocular surface

infl ammation, damage, and symptoms, and the initiation of

compensatory events in dry eye.5 The ease of testing tear

osmolarity and the purported pathomechanistic role of

hyperosmolarity in dry eye makes it an attractive prospect

for positive diagnosis of the condition and it has been

proposed as a possible biomarker for disease severity.20,21

16

Defining a specific osmolarity number to correlate with

or define mild dry eye is difficult. Based upon population

studies, the manufacturers of the product have classified

the mild dry eye spectrum commencing at 308–320

mOsmol/L. The range of 320–340 mOsmol/L has been

classified as moderate dry eye, with anything greater being

more severe. In early dry eye, fluctuation of osmolarity has

also been described as early evidence of dry eye syndrome.

There is significant elegance to this form of testing where

a numerical factor can be used to define the severity

of a condition. However, in mild-to-moderate disease,

care should be taken prior to defining with certainty the

diagnosis of dry eye without other confirmatory evidence.

Other diagnostic tools to detect presence and severity of dry eye symptomsFor clinicians, the key aspect required is to know

which tests are both easy to carry out and effective

in determining the presence, type, and severity of

the condition. Several basic concepts already alluded

to underpin the need for examination of the ocular

surface for evidence of dry eye. Firstly, if dry eye is

severe, all aspects of the ocular surface will be affected,

inflammation will be apparent, and multiple dry eye

tests will positively confirm the diagnosis.15 In mild-

to-moderate dry eye disease, inter-test concordance

is often low,15 and therefore it is important to perform

combinations of tests, some of which are outlined in

Tables 1 and 2, including assessment of symptoms, which

is often best formalized through the use of specific

questionnaires.22 A general principle for accuracy in dry

eye testing is that the less invasive tests should be carried

out prior to the more invasive to reduce the likelihood

of altering the underlying baseline state. Table 2 gives a

reasonable stepwise test regimen to improve repeatability

in results. Newer non-invasive interferometric techniques,

together with topographic methods, have been developed

to assess tear film thickness and stability.23

One of the principal aims of dry eye testing is to

determine those patients at increased risk of inflammatory

reactions to chronic glaucoma drop usage and to direct

prophylactic management where appropriate to the

patients on glaucoma medication. The recognition and

management of structural lid abnormalities, treatment

of atopy or meibomian gland dysfunction, replacement

of aqueous tears, or management of overt inflammation

can greatly enhance patient comfort and enable the

continued tolerance of glaucoma medication, particularly

in mild-to-moderate dry eye.24

ConclusionThe ocular surface can be deleteriously affected by

treatment with long-term topical anti-glaucoma

medication. Ophthalmologists should be proficient in

detecting and managing dry eye and other ocular surface

problems both before and after the introduction of

antiglaucoma medication.

References1. Cvenkel B, Kopitar AN, Ihan A. Correlation between filtering

bleb morphology, expression of inflammatory marker

HLA-DR by ocular surface, and outcome of trabeculectomy.

J Glaucoma. [Epub ahead of print. 2011 Jul 5].

2. Mantelli F, Tranchina L, Lambiase A, et al. Ocular surface

damage by ophthalmic compounds. Curr Opin Allergy Clin

Immunol. 2011;11:464-70.

Table 2. Potential sequence and types of tests to determine presence and severity of dry eye.

Dry eye test sequence Tool or test used

Questionnaire Preclinical examination

Tear osmolarity TearLab®

Tear meniscus Slit lamp

Lid margin/meibomian glands Slit lamp

Fluorescein tear film break-up time (FTBUT)

Slit lamp/fluorescein

Corneal/conjunctival staining Slit lamp/fluorescein

Schirmer test Schirmer paper

Currently no single test is suffcient to confidently define mild to moderate dry eye test should be confirmed by

the evidence from another


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3. Baudouin C, Labbé A, Liang H, et al. Preservatives in

eyedrops: the good, the bad and the ugly. Prog Retin Eye

Res. 2010;29:312-34.

4. Ammar DA, Noecker RJ, Kahook MY. Eff ects of benzalkonium

chloride-preserved, polyquad-preserved, and sofZia-preserved

topical glaucoma medications on human ocular epithelial cells.

Adv Ther. 2010;27:837-45.

5. Gipson IK, Argüeso P, Beuerman R, et al. Research in dry eye:

report of the Research Subcommittee of the International

Dry Eye WorkShop (2007). Ocul Surf. 2007;5:179-93.

6. Servat JJ, Bernardino CR. Eff ects of common topical

antiglaucoma medications on the ocular surface, eyelids and

periorbital tissue. Drugs Aging. 2011;28:267-82.

7. Monaco G, Cacioppo V, Consonni D, et al. Eff ects of

osmoprotection on symptoms, ocular surface damage, and

tear fi lm modifi cations caused by glaucoma therapy. Eur J

Ophthalmol. 2011;21:243-50.

8. Tavares F de P, Fernandes RS, Bernardes TF, et al. Dry eye

disease. Semin Ophthalmol. 2010;25:84-93.

9. Thoft RA, Friend J, Kenyon KR. Ocular surface response to

trauma. Int Ophthalmol Clin. 1979;19:111-31.

10. Paiva CS, Pfl ugfelder SC. Rationale for anti-infl ammatory

therapy in dry eye syndrome. Arq Bras Oftalmol. 2008;71(6

Suppl):89-95. Review.

11. Johnson ME, Murphy PJ. Changes in the tear fi lm and

ocular surface from dry eye syndrome. Prog Retin Eye Res.

2004;23:449-74.

12. Dartt DA. Neural regulation of lacrimal gland secretory

processes: relevance in dry eye diseases. Prog Retin Eye Res.

2009;28:155-77. Review.

13. Albertsmeyer AC, Kakkassery V, Spurr-Michaud S, et al. Eff ect

of pro-infl ammatory mediators on membrane-associated

mucins expressed by human ocular surface epithelial cells.

Exp Eye Res. 2010;90:444-51.

14. Moore JE, Vasey GT, Dartt DA, et al. Eff ect of tear

hyperosmolarity and signs of clinical ocular surface

pathology upon conjunctival goblet cell function in

the human ocular surface. Invest Ophthalmol Vis Sci.

2011;52:6174-80.

15. Moore JE, Graham JE, Goodall EA, et al. Concordance

between common dry eye diagnostic tests. Br J Ophthalmol.

2009;93:66-72.

16. Lemp M, Baudoin C, Baum J, et al. The defi nition and

classifi cation of dry eye disease: report of the Defi nition and

Classifi cation Subcommittee of the International Dry Eye

WorkShop (2007). Ocul Surf. 2007;5:75-92.

17. Goren MB, Goren SB. Diagnostic tests in patients with

symptoms of keratoconjunctivitis sicca. Am J Ophthalmol.

1988;106:570-4.

18. Kallarackal GU, Ansari EA, Amos N, et al. A comparative study

to assess the clinical use of Fluorescein Meniscus Time (FMT)

with Tear Break up Time (TBUT) and Schirmer's tests (ST) in the

diagnosis of dry eyes. Eye (Lond). 2002;16:594-600.

19. Farris RL. Tear osmolarity: a new gold standard? Adv Exp

Med Biol. 1994;350:495-503.

20. Suzuki M, Massingale ML, Ye F, et al. Tear osmolarity as a

biomarker for dry eye disease severity. Invest Ophthalmol

Vis Sci. 2010;51:4557-61.

21. Sullivan BD, Whitmer D, Nichols KK, et al. An objective

approach to dry eye disease severity. Invest Ophthalmol Vis

Sci. 2010;51:6125-30.

22. Gothwal VK, Pesudovs K, Wright TA, et al. McMonnies

questionnaire: enhancing screening for dry eye syndromes with

Rasch analysis. Invest Ophthalmol Vis Sci. 2010;51:1401-7.

23. Szczesna DH, Kasprzak HT, Jaronski J, et al. An

interferometric method for the dynamic evaluation of the

tear fi lm. Acta Ophthalmol Scand. 2007;85:202-8.

24. Lemp MA, Bron AJ, Baudouin C, et al. Tear osmolarity in

the diagnosis and management of dry eye disease. Am J

Ophthalmol. 2011;151:792-8.e1.

KEY MESSAGES

•Clinicians prescribing topical lenti-glaucoma medications should recognise pathologically altered ocular surfaces and dry eye states prior to instituting their defi nitive treatment plan.

•A general principle for accuarcy in dryeye testing is that the less invasive tests should be carried out prior to the more invasive to reduce the likelihood of perturbing the underlying baseline state.

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Risk factors for visual field progressionRobert T. Chang and Kuldev SinghGlaucoma Service, Stanford University School of Medicine, Palo Alto, CA, USA

The current, gold-standard functional outcome measure for monitoring glaucomatous disease is the visual

field (VF) examination. Detecting the rate of VF progression is key to developing a therapeutic plan.

However, identifying definitive progression may be a challenging task due to the subjective nature of

perimetric testing. Thus, risk factor assessment can help determine the required frequency of VF testing.

The evaluation of glaucomatous disease generally involves the combination of structural optic nerve

assessment and functional VF testing. Because progressive disease may necessitate escalation of therapy

with the potential for accompanying side-effects, a thorough understanding of VF results as well as risk

factors that may affect VF loss is critical for optimal glaucoma care. These risk factors may be categorized

as being either intraocular pressure (IOP)-dependent or IOP-independent.

Types of visual field testingThe most commonly performed visual field (VF) test in

clinical practice is white-on-white standard automated

perimetry (SAP), which is generally considered the

preferred tool for measuring VF progression. The Swedish

interactive threshold algorithm (SITA) on the Humphrey

perimeter is optimized to reduce testing time without

sacrificing accuracy. The stimulus default is size III, but

size V stimuli can be used for advanced glaucoma with

poor visual acuity. The Humphrey VF test currently

includes Glaucoma Progression Analysis (GPA) with

a visual field index (VFI) parameter for monitoring

progression. The Octopus perimeter, an alternate SAP

with a model that includes kinetic perimetry, also has

EyeSuite progression analysis software.

Blue-on-yellow perimetry, also known as short-

wavelength automated perimetry (SWAP), is similar to

SAP but employs a specially chosen blue-light stimulus

on a yellow illumination background to isolate the blue-

yellow ganglion cells, which are thought to be damaged

first in early glaucoma. Another method for selectively

isolating the M ganglion cell pathway to detect early

glaucoma is known as frequency-doubling technology

(FDT). This high-frequency flicker perimeter is frequently

used for glaucoma screening.

When automated static perimetry fails due to patient-

related testing problems, kinetic perimetric techniques,

such as Goldmann VF tests, are often utilized. Novel

computerized methods, such as high-pass resolution

perimetry, rarebit perimetry, and motion detection

perimetry, are currently under investigation.

Why risk factors matterThe earlier glaucoma progression is detected, the

greater the likelihood that glaucoma treatment will be

successful in preserving vision during an individual’s


19

lifetime. Unfortunately, VF testing is limited by subject

and test variability, as well as by long-term fl uctuation.

Apparent VF changes may often be due to artifact rather

than glaucomatous disease. Traditionally, progression

detection methods incorporate a combination of trend-

based and event-based analyses.

One of the most important goals of glaucoma

management, given the wide range of inter-patient

variability in glaucoma progression rates, is to identify

“fast progressors” who are at greatest risk of severe

vision loss.1 Chauhan and colleagues have reported that

a VF progression rate of –2 dB loss per year or greater

is associated with a high risk of visual disability in an

individual’s lifetime, when starting at a mean deviation

(MD) baseline of –4 dB.2 Frequent VF testing with 5–6

tests over the fi rst 2–3 years (or at least 3 in 2 years)

following initial diagnosis may aid in identifying “fast

progressors”.

Clinical risk-factor assessment and the relative risk

of visual impairment are the basis for prognosis and

treatment. At present, the most widely studied and

primary modifi able risk factor for glaucomatous disease

is intraocular pressure (IOP).3 It is well recognized,

however, that what constitutes a “normal” IOP for one

individual may be abnormal for another. In addition, there

is growing evidence regarding other IOP-independent

risk factors associated with glaucoma progression, and

therefore it is not surprising that lowering IOP is not

enough to signifi cantly slow glaucoma progression in

all patients. Predictive factors for glaucoma progression

from major clinical trials are shown in Table 1.

IOP as a risk factorMany major clinical trials, such as the Ocular

Hypertension Treatment Study (OHTS), the Collaborative

Normal-Tension Glaucoma Study (CNTGS), and the Early

Manifest Glaucoma Trial (EMGT),4 have confi rmed that

lowering IOP can slow the development of glaucoma

and the rate of disease progression. Unfortunately, there

is no defi nitive glaucoma treatment end-point as there

is no consensus on how low is safe enough for a given

patient. Typically, IOP is lowered with medications, laser

treatment, or surgery until VF or other testing is deemed

“minimally progressive or stable.” Essentially, the goal of

IOP-lowering therapy is to maintain quality of life and

visual function, ideally at a reasonable cost.5

A current IOP glaucoma-risk calculator combines data

from the OHTS and the European Glaucoma Prevention

Study (EGPS).6 It was designed to aid the management of

ocular-hypertensive subjects by estimating their 5-year

conversion rate to glaucoma based upon age, IOP, central

corneal thickness (CCT), vertical cup-to-disc ratio, and VF

pattern standard deviation (PSD). Its usefulness is limited

because parameters that defi ne glaucomatous disease are

not included in the calculator, and factors other than IOP

are not modifi able. A calculator for estimating the risk

Table 1. Predictive factors for glaucoma progression from major clinical trials.

Clinical trials for open-angle glaucoma

Risk factors for glaucomatous progression

Hazard ratio (95% CI)

CNTGSMigraine 2.58 (1.32–5.07)

Disc haemorrhages 2.72 (1.39–5.32)

AGIS

Increasing age (per 5 years)

1.28 (1.10–1.49)

Mean IOP 1.07 (0.97–1.18)

Large IOP fl uctuation 1.31 (1.11–1.53)

EMGT

Older age (> 68 years) 1.51 (1.11–2.07)

Higher IOP (> 21 mmHg) 1.77 (1.29–2.43)

Thinner CCT per 40 μm 1.25 (1.01–1.55)

VF MD worse than–0.4 dB

1.38 (1.00–1.91)

Lower systolic blood pressure (< 125 mmHg)

1.42 (1.04–1.94)

Pseudo-exfoliation 2.12 (1.30–3.46)

Adapted from Coleman AL. et al.3

AGIS = Advanced Glaucoma Intervention Study; CCT = central corneal thickness; CI = confi dence interval; CNTGS = Collaborative Normal-Tension Glaucoma Study; EMGT = Early Manifest Glaucoma Trial; IOP = intraocular pressure; MD = mean deviation; VF = visual fi eld.

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of blindness in those who have established perimetric

disease has not been available to date.

IOP-dependent risk factorsIt remains controversial which IOP parameters are most

relevant in predicting glaucoma progression. The mean,

peak, and variability of IOP have all been assessed

as predictors in various clinical trials. The Advanced

Glaucoma Intervention Study (AGIS), in a post hoc

analysis, revealed that those with an IOP reduced below

18 mmHg at all visits did better with regard to slowing

glaucomatous disease than those who had occasional or

frequent IOP readings above this arbitrary cut-off.7,8 In

cases of very advanced disease, the IOP range is typically

lowered to a greater extent than in those with mild-to-

moderate disease, due to the higher risk of blindness in

the former group.

A recent retrospective review by De Moraes and

colleagues assessed baseline VF MD, mean follow-up IOP,

peak IOP, and IOP fluctuation in a cohort of patients who

had 8 or more fields with progression, evaluated using

automated pointwise linear regression.9 In the time-

adjusted logistic regression, all IOP-related parameters

were significantly associated with progression, but in the

multivariate model, only peak IOP remained significantly

associated with progression.9 At present, there is no

consensus opinion regarding whether or not long-

term IOP variability or short-term IOP fluctuation are

independent risk factors for glaucoma progression.

IOP-independent risk factorsAlthough many glaucoma studies have confirmed

that increasing age and IOP are major risk factors for

glaucoma and glaucoma progression, less is known about

the relevance of IOP-independent risk factors. Currently,

there is much research interest in cardiac health history,

systemic blood pressure, and ocular perfusion pressure

(OPP). A recent review has covered the many large

population-based studies that have found an association

between low OPP and glaucoma prevalence.10

The pathophysiology of glaucoma appears to be

multifactorial, with a genetic predisposition and a

combination of mechanical damage, vascular regulatory

dysfunction, and possible neurosusceptibility.11 Risk

factors such as age, gender, ethnicity, heritability, CCT,

and beta parapapillary atrophy are all recognized as being

non-modifiable. In contrast, there is significant interest

in the potential for altering vascular dysfunction and for

neuroprotection as potential new therapeutic approaches

for glaucoma care. The recent Canadian Glaucoma

Study was designed to evaluate systemic risk factors for

glaucoma VF progression.12 The investigators examined

peripheral vasospasm and haematological, coagulation,

and immunopathological variables under a strict protocol

for IOP control. The most interesting finding was that an

abnormal baseline anticardiolipin antibody (ACA) level,

though in a relatively small group of patients, conferred

a hazard ratio of 3.86 times (95% confidence interval

1.60–9.31) greater likelihood of VF progression. This result

raises the possibility that there may be an association

between microthrombotic infarctions at the nerve head,

disc haemorrhages, and VF progression with normal

pressure.

Disc haemorrhages have long been associated with

glaucoma, and studies have shown VF progression to

be faster when they are present, though it is not clear

whether this is a cause or an effect.13 Furthermore, it is

not known whether there is an association between

disc haemorrhages and OPP, largely because there

are currently no standardized methods for accurately

measuring optic nerve head (ONH) blood flow. The

importance of IOP-independent risk factors undoubtedly

varies among individuals and ethnicities. The presence

of a disc haemorrhage has been demonstrated to be a

strong negative prognostic factor for “normal- or low-

tension glaucoma”, particularly in Japanese people.14

A visual-field progression rate of –2 dB loss per year or greater is

associated with a high risk of visual disability in an individual’s lifetime, when starting at a mean-deviation

baseline of –4 dB


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However, some hypothesize that “normal IOP” is harmful

if cerebrospinal fl uid (CSF) pressure is low, due to the

impact on translaminar gradient pressure.15

Eff orts at fi nding a neuroprotective agent in glaucoma

have not been successful to date. While memantine, a

glutamate antagonist, did not meet its study end-points,

there is still much interest in preventing apoptosis of

retinal ganglion cells. Alpha-2-adrenergic agonists are

neuroprotective in experimental glaucoma models,

and the Low Pressure Glaucoma Treatment Study

(LoGTS) collaborators demonstrated that brimonidine-

treated patients had signifi cantly less VF progression by

pointwise linear regression than timolol-treated patients

(9.1% vs 39.2%).16 In a randomized, double-masked,

placebo-controlled clinical trial, an oral calcium-channel

blocker has also been shown to slow VF progression as

represented by MD on SAP.17 While it has been theorized

that increasing ONH perfusion may slow low-pressure

glaucoma, an alternative explanation is that there may be

some direct neuronal benefi t from the action of a calcium

antagonist. Whether or not these IOP-independent risk

factors have a larger role than IOP in the onset and

progression of VF loss is yet to be determined.

Risk factor impact and clinical practiceThe EGS has listed in the third edition of the guidelines

risk factors for both the onset of PAOG and for its

progression.18

The World Glaucoma Association produced a consensus

statement in 2011 on risk factors for glaucoma

progression.19 These risk factors can be grouped into

those that aff ect glaucoma prognosis and those that

aff ect treatment. It is important to weigh the strength

of evidence for each risk factor and the relative stage

of disease. Risk factors are most useful when there is

a select population that is at increased risk, and when

a patient fi ts the baseline characteristics of the current

available risk calculator. Ideally, risk factors can be

modifi ed to reduce the rate of visual disability but, if not,

they may help in deciding whether to institute or escalate

glaucoma therapy, as well as in determining the frequency

of follow-up. Lack of patient education, late detection

of disease, and non-compliance are all additional risk

factors for blindness that are recognized by clinicians

in daily practice. Ocular hypertension is the strongest

risk factor in addition to being the primary treatable

glaucoma parameter, but some patients still progress

despite pressure lowering. Thus, it is important to look

at IOP-independent risk factors in such circumstances.

Further research is needed to better understand the

complex interplay between risk factors for mechanical

KEY MESSAGES

•Frequent visual field testing with 5–6tests over the fi rst 2–3 years (or at least 3 in 2 years) following initial diagnosis may aid in identifying “fast progressors”.

•In cases where visual field progressionoccurs despite lowering IOP, look at IOP-independent risk factors including low ocular perfusion pressure and disc haemorrhages.

•The pathogenesis of glaucomatousvisual fi eld progression involves a complex interplay between pressure-dependent mechanical damage, pressure-independent vascular dysregulation, and neurosusceptibility.

•www.worldglaucoma.org/pages/consensus/C7.htm

•www.eugs.org/eng/EGS-guidelines.asp

From the Canadian Glaucoma Study, an abnormal baseline anticardiolipin antibody level

conferred a hazard ratio of 3.86 times (95% CI 1.60–9.31) greater likelihood

of visual fi eld progression

22

Revi

ew a

rtic

le damage, vascular dysregulation, and neurosusceptibility

in glaucomatous VF progression.

ConclusionIn conclusion, risk factor calculators are important tools

impacting therapeutic decisions. For glaucoma, there are

currently few adequate studies that are prospectively

assessing risk factors for predetermined functional visual

loss. Future studies that longitudinally assess risk factors

for visual field progression, through the use of electronic

health records, will be key to the early identification of

glaucoma patients at highest risk for blindness.19

References1. Susanna R Jr. Unpredictability of glaucoma progression.

Curr Med Res Opin. 2009;25:2167-77. Review.

2. Chauhan BC, Garway-Heath DF, Goñi FJ, et al. Practical

recommendations for measuring rates of visual field change

in glaucoma. Br J Ophthalmol. 2008;92:569-73. Review.

3. Coleman AL, Miglior S. Risk factors for glaucoma onset

and progression. Surv Ophthalmol. 2008;53 Suppl 1:S3-10.

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4. Heijl A, Leske MC, Bengtsson B, et al. Reduction of

intraocular pressure and glaucoma progression: results

from the Early Manifest Glaucoma Trial. Arch Ophthalmol.

2002;120:1268-79.

5. Rossetti L, Goni F, Denis P, et al. Focusing on glaucoma

progression and the clinical importance of progression rate

measurement: a review. Eye (Lond). 2010;24 Suppl 1:S1-7.

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6. Miglior S, Zeyen T, Pfeiffer N, et al. Results of the European

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with long-term progression or stability in primary open-

angle glaucoma. Am J Ophthalmol. 2000;130:274-9.

8. Palmberg P. What is it about pressure that really matters in

glaucoma? Ophthalmology. 2007;114:203-4.

9. De Moraes CG, Juthani VJ, Liebmann JM, et al. Risk factors

for visual field progression in treated glaucoma. Arch

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10. Grover DS, Budenz DL. Ocular perfusion pressure and

glaucoma. Int Ophthalmol Clin. 2011;51:19-25. Review.

11. Moore D, Harris A, Wudunn D, et al. Dysfunctional regulation

of ocular blood flow: A risk factor for glaucoma? Clin

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12. Chauhan BC, Mikelberg FS, Artes PH, et al. Canadian Glaucoma

Study: 3. Impact of risk factors and intraocular pressure

reduction on the rates of visual field change. Arch Ophthalmol.

2010;128:1249-55. Erratum in: Arch Ophthalmol. 2010;128:1633.

13. Medeiros FA, Alencar LM, Sample PA, et al. The relationship

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14. Ishida K, Yamamoto T, Sugiyama K, et al. Disk hemorrhage is

a significantly negative prognostic factor in normal-tension

glaucoma. Am J Ophthalmol. 2000;129:707-14.

15. Ren R, Jonas JB, Tian G, et al. Cerebrospinal fluid pressure

in glaucoma: a prospective study. Ophthalmology.

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16. Krupin T, Liebmann JM, Greenfield DS, et al. A randomized

trial of brimonidine versus timolol in preserving visual

function: results from the Low-Pressure Glaucoma

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Erratum in: Am J Ophthalmol. 2011;151:1108.

17. Koseki N, Araie M, Tomidokoro A, et al. A placebo-controlled

3-year study of a calcium blocker on visual field and

ocular circulation in glaucoma with low-normal pressure.


18. European Glaucoma Society. Terminology and Guidelines for

Glaucoma. Ch 2, page 5. Dogma, Savona Italy 2008.

19. Weinreb RN, Garway-Heath D, Leung C, et al., editors.

Progression of glaucoma. WGA Consensus Series 8.

Amsterdam: Kugler Publications; 2011.

This publication is sponsored by Santen

www.santen.fi

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