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.
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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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lEUROPEAN GLAUCOMA SOCIETYEUROPEAN GLAUCOMA SOCIETY
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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
Volume 7 Issue 1 2012
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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Volume 7 Issue 1 2012
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).
Volume 7 Issue 1 2012
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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Volume 7 Issue 1 2012
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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25. Sung KR, Kim DY, Park SB, et al. Comparison of retinal
nerve fiber layer thickness measured by Cirrus HD and
Stratus optical coherence tomography. Ophthalmology.
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
Ophthalmol Vis Sci. 2008;49:4886-92.
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
Ophthalmol Vis Sci. 2011;52:3338-44.
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Volume 7 Issue 1 2012
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
Volume 7 Issue 1 2012
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
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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
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Volume 7 Issue 1 2012
This publication is sponsored by Santen
www.santen.fi