CHAPTER

How to detect progression

in glaucoma

Jayme R. Vianna, Balwantray C. Chauhan1

7
Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, NS, Canada
1
Corresponding author: Tel.: 902-473-3202; Fax: 902-473-2839, e-mail address: bal@dal.ca

Abstract
Detecting glaucoma progression remains one of the most challenging aspects of glaucoma
management, since it can be hard to distinguish disease progression from exam variability
and changes due to aging. In this review article, we discuss the use of perimetry, confocal scan-
ning laser tomography and optical coherence tomography to detect glaucoma progression, and
the techniques available to evaluate change with these modalities. Currently, there is no con-
sensus on the best technique or criteria to detect glaucoma progression, or what amount of
change would be clinically meaningful. New techniques have been developed to assess glau-
coma progression, which make more comprehensive and complex use of data. They have the
potential of detecting progression with better accuracy, with shorter follow-up periods, and
generating better prognostics. Further validation of these new techniques is still required,
but their incorporation into clinical practice is likely to yield significant benefits.

Keywords
Glaucoma, Progression, Rate of change, Perimetry, Confocal scanning laser tomography,
Optical coherence tomography, Aging, Optic nerve head, Retinal nerve fiber layer

1 INTRODUCTION
Detecting progression is an essential task that helps clinicians make appropriate
treatment and follow-up decisions to minimize the likelihood of glaucoma-related
visual disability. At the same time, it remains one of the most challenging aspects
of glaucoma management. Progression due to glaucoma can be hard to distinguish
from variability or changes due to aging and media opacities. Additionally, while
several examination methods and criteria for progression have been used to define
progression, there is no consensus on a best method or magnitude of change that rep-
resents meaningful clinical change. Results in the literature are frequently conflicting
and research in glaucoma progression has been poorly translated for the clinician.
Progress in Brain Research, Volume 221, ISSN 0079-6123, http://dx.doi.org/10.1016/bs.pbr.2015.04.011
© 2015 Elsevier B.V. All rights reserved.
135
136 CHAPTER 7 How to detect progression in glaucoma

Given the importance and complexity of detecting glaucoma progression, much

research has been published on this topic in the past years, including comprehensive
reviews (Brusini, 2008; Leung, 2014; Nouri-Mahdavi and Caprioli, 2014;
Nouri-Mahdavi et al., 2011). The purpose of this review is to summarize the current
knowledge, enabling better understanding and interpretation of the several methods
to assess glaucoma progression, with focus on the most used and the most recently
described methods.

2 GENERAL CONCEPTS
2.1 EVENT- VERSUS TREND-BASED ANALYSES
Methods used to detect glaucoma progression, either with functional or structural
testing, can be grouped in two categories according to the type of analysis: event-
based or trend-based. In event-based analysis, each new measurement is compared
with a baseline. Changes are considered significant if they exceed the expected test–
retest variability in the absence of clinical progression, or another predefined
threshold. This technique has the advantage of possibly detecting change faster than
trend-based analysis (Casas-Llera et al., 2009; Vesti et al., 2003). One example is the
guided progression analysis (GPA) of the Humphrey field analyzer (HFA, Carl Zeiss
Meditec, Dublin, CA).
In trend-based analysis, a series of measurements are evaluated with linear or
other form of regression analysis to estimate rates of change and statistical signifi-
cance. Thresholds for the magnitude of the rate of change and/or its statistical
significance are used to define significant change. The main advantage of this
technique, for example, Progressor (Medisoft Ltd., Leeds, UK) is that it utilizes
all measurements and provides a rate of change estimate.

2.2 GLOBAL VERSUS POINTWISE ANALYSES

Most methods can also be classified according to the unit of analysis, into global or
pointwise. Usually any single examination, such as standard automated perimetry
(SAP), consists of several individual measurements (i.e., sensitivity measurement
at each point). In global analysis, an average of all individual measurements in a
single examination (such as the mean deviation, MD) is used for analysis.
A single global indicator has the advantage of providing a concise description of
the examination, which may be easier to interpret. However, highly localized
changes might not be detected with global analysis, since change in a few points
can be masked by computing global means.
In pointwise analysis, change in each measurement, such as pointwise sensitivity,
is evaluated separately. The advantage of this approach is the ability to evaluate
highly localized change. However, individual measurements are inherently more
variable than averages and it may be more difficult to distinguish measurement var-
iability from true change. Additionally, while there is a change estimate for each
 3 Functional progression 137

point within examination, the information that is sought is if the examination as

a whole suggests progression of glaucomatous damage. Deriving a threshold for
progression based on the individual change estimates can be complex.
In addition to global and pointwise analyses, averaging within sectors or clusters
represents yet another strategy. For example, sectoral analyses of retinal nerve fiber
layer thickness (RNFLT) measured with optical coherence tomography (OCT) could
be more sensitive to localized changes than a global average, but could still fail to
detect highly localized changes (Lee et al., 2009).

2.3 PROGRESSION CRITERIA

Regardless of whether the analysis is event- or trend-based, global or pointwise, a
criterion for making a classification of progression is required. The results of the sta-
tistical tests used are the magnitude of change observed and/or the chance of observ-
ing a change of that magnitude assuming a null hypothesis of no change. Subjective
judgment of these results is required to evaluate if they are clinically meaningful. For
example, a finding of mean global RNFLT loss rate of 0.2 mm/year, with p value of
0.03, could be a marginally significant random finding, a small nonglaucomatous
age-related change, or represent slow but real glaucoma progression. In this case,
other clinical indicators can help the interpretation of such findings.
To help make reproducible decisions, criteria for progression are often defined,
such as minimum thresholds for the amount of observed change, statistical signifi-
cance, number of points with change, or confirmation in repeated examinations.
For example, progression criteria of minimum global RNFLT change could be loss
of more than 0.5 mm/year, with p value <0.05, confirmed in two consecutive exam-
inations. As expected, the chosen criteria can have significant impact on the perfor-
mance of a method, with more conservative criteria usually yielding higher
specificity and lower sensitivity.
Since trend-based analysis estimates the rate of change, its utility can be extended
beyond identifying thresholds for progression. The rates of change can be used to
make predictions, for example, estimating the future status of the visual field in
say, 5 or 10 years at the current progression rate. These predictions can be valuable
for making better individualized clinical decisions.

3 FUNCTIONAL PROGRESSION
3.1 STANDARD AUTOMATED PERIMETRY
3.1.1 Guided Progression Analysis
The GPA of the HFA (Carl Zeiss Meditec, Dublin, CA) is a widely used software tool
for detecting visual field progression. It is based on the criteria employed by the
Early Manifest Glaucoma Trial (Heijl et al., 2003). The GPA compares each new
test result, point by point, with values from two baseline tests. Points with a loss
of sensitivity, as measured by change in pointwise pattern deviation by more than
138 CHAPTER 7 How to detect progression in glaucoma

the expected variability, are flagged. If such changes occur at three or more points in
two consecutive follow-up tests, the GPA raises an alert of “possible progression”; if
they occur in three consecutive tests, an alert of “likely progression” is raised. The
expected variability values are derived from a population of stable glaucoma
patients, and account for initial defect depth, test point location, and general level
of visual field damage (Heijl et al., 2003).
The GPA cannot analyze visual field points with low sensitivity at baseline for
which the expected test–retest variability limit includes 0 dB (Nouri-Mahdavi,
2014). Furthermore, analysis of visual fields with advance damage at baseline
(MD lower than
15 dB) cannot be performed (Wesselink et al., 2009). The GPA
is based on pattern deviation values to avoid the influence of cataracts, which
frequently cause generalized sensitivity loss. However, glaucoma can also induce
generalized sensitivity loss, and the GPA may not detect this pattern of progression
(Artes et al., 2005b). A recent study, in which visual field tests taken 12 times by
stable glaucoma patients were randomly reordered, estimated that the mean false-
positive rate for the “possible progression” alert was 18.5%, and for the “likely
progression” alert was 2.6% (Artes et al., 2014). However, it is important to note that
patients with more variability in the visual field and worse reliability indexes had
significantly more false-positives alerts—up to 80% for “possible progression”
and 20% for “likely progression.”

3.1.2 Global Trend Analysis

In current clinical practice, SAP trend analysis is used mostly with global indexes
such as MD or the visual field index (VFI). The MD is the weighted mean of the
total deviation values, with the weights being inversely proportional to interindivi-
dual variability in healthy subjects (Heijl et al., 1987). The VFI is a weighted mean of
transformed sensitivity values, with central points given more weight than peripheral
ones (Bengtsson and Heijl, 2008). Points with normal pattern deviation probability
values (p > 5%) are given the value 100%, and for the other points the observed
sensitivity at each point is expressed as the percentage of the sensitivity expected
in healthy subjects. However, for severely damaged visual fields (MD worse than

20 dB), the total deviation probability values are used, since the pattern deviation
plot is unreliable in these fields.
The VFI is more resistant to the effects of cataracts compared to MD and is
reported as a comprehendible percentage of intact visual field with 100% equivalent
to a full normal visual field and 0% equivalent to perimetric blindness (Bengtsson
and Heijl, 2008). However, the VFI is encumbered with a “ceiling effect”: for eyes
with MD around
5 dB, representing meaningful visual field damage, the VFI can
be close to its maximum value of 100% (Artes et al., 2011). This suggests that the
VFI is likely insensitive for detecting early visual field loss. Additionally, due to the
change in the VFI algorithm, in visual field series in which MD crosses
20 dB,
there is a stepwise worsening in VFI and an increase in its variability, reducing
the reliability of VFI in these cases (Lee et al., 2014; Rao et al., 2013; Fig. 1).
 3 Functional progression 139

FIGURE 1—Cont’d
140 CHAPTER 7 How to detect progression in glaucoma

FIGURE 1—Cont’d
Example of Humphrey field analyzer guided progression analysis printout. A significant
rate of progression in the visual field index (VFI) is observed (white arrow, panel A). With
pointwise analysis, several locations present significant reduction in sensitivity, indicated with
triangles. The triangles are half-filled when the reduction is present in two consecutive
examinations and filled when it is present in three consecutive examinations (black arrow,
panel B). When three points present significant reduction in three consecutive examinations,
a “likely progression” alert is raised according to the criteria employed in the Early
Manifest Glaucoma Trial.
 3 Functional progression 141

3.1.3 Pointwise Trend Analysis

Pointwise trend analysis of visual field has been used in research settings for decades.
However, it has not been incorporated into HFA perimetry printouts, and it is not
frequently used in clinical practice. In pointwise trend analysis, a regression model
is fitted for each point in the visual field, and an estimate of the rate of change and
statistical significance is calculated. A commonly used progression criteria is the
presence of one point with a rate of
1 dB/year or worse, with a p value of less than
0.01 (Membrey et al., 2000). These criteria aim to identify change of a magnitude
that is clinically significant and with a stricter statistical significance criterion
(p < 0.01) to reduce the likelihood of false-positive changes. However, several other
criteria have been proposed not only with different rates or p value cutoffs but also
with the minimum number of flagged points, their location (clustered or nonclus-
tered; De Moraes et al., 2012), or the requirement of repeatable findings in a consec-
utive number of exams (Gardiner and Crabb, 2002). More strict criteria present less
false positives, but identify less-progressing patients (Kummet et al., 2013); how-
ever, there is lack of a much-required consensus on recommended criteria for pro-
gression. A recently described method uses permutation analyses of pointwise linear
regression to provide a statistical significance estimate of deterioration in the whole
visual field with a false-positive rate that is independent of variability, level of dam-
age, or length of follow-up, and can be useful for analyzing individual visual field
series or comparisons of different techniques (O’Leary et al., 2012).
The most common regression model used for trend analysis is simple linear re-
gression (ordinary least squares). However, pointwise visual field sensitivities have
characteristics that violate the assumptions of this model, increasing the error in the
estimates. The variability of measurements is not constant, with lower sensitivities
presenting higher variability (Artes et al., 2002; Russell et al., 2012a). In fact, a point
with sensitivity of 15 dB has retest limits from 0 to 25 dB, while points with sensi-
tivity below 20 dB may have little value for testing in order to detect progression
(Wall et al., 2009). The variability of measurements is also not constant with time,
since measurements closer in time to each other may be more related than those fur-
ther apart (temporal correlation), and not independent across test locations as points
in closer proximity are more similar than points further away (spatial correlation).
Furthermore, measurements of visual field sensitivity are limited by the device
range, with a 0 dB boundary. Simple linear regression estimates may result in pre-
dictions of negative values that are incompatible with the measurements, as well as
predictions of improving sensitivities that are not universally accepted to occur after
a learning period (Gardiner et al., 2008; Musch et al., 2014). Censoring the estimates
of pointwise analysis by not allowing negative sensitivity values or improving
sensitivities may greatly improve predictions (Chen et al., 2014).
Several regression models have been explored to perform trend-based analysis,
including simple linear regression, censored linear regression, exponential, robust,
quadratic, and logistic (Bryan et al., 2013; Caprioli et al., 2011; Chen et al., 2014;
Pathak et al., 2013). An exponential model could better describe the loss of visual
field sensitivity over a longer period of time, but a linear model may be appropriate
142 CHAPTER 7 How to detect progression in glaucoma

for shorter periods of a few years (Nouri-Mahdavi and Caprioli, 2014). The simple
linear model assumes a constant additive rate of sensitivity loss, meaning that for
each year (or any other time interval) the same amount of sensitivity is lost. The ex-
ponential model assumes a constant multiplicative rate of sensitivity loss, meaning
that for each year a same percentage of the sensitivity is lost. Some reasons for better
fit using exponential models might be the use of a logarithm scale for the measure-
ments of sensitivity (dB) and the presence of a floor effect due to the measurable
range of the perimeter (Pathak et al., 2013). However, the difference between the
exponential and linear model is essentially just a mathematical transformation,
and the low signal-to-noise ratio of SAP is maintained. It is not clear if using expo-
nential models would result in better precision of rates of change estimates and
ultimately better detection of glaucoma progression.

3.1.4 New Modeling Techniques

Recently, more advanced statistical techniques have been applied to detect progres-
sion in SAP that allow to incorporate additional information when estimating a given
patient rate of change. In general, these techniques use data from a previous patient
population, sometimes called training dataset, to identify expected rates of change,
patterns of the rates of change, and predictors influencing the rates of change. When
used to evaluate a new patient, these statistical techniques will combine the informa-
tion in the patient’s examinations, with the information that they obtained from the
training dataset, attempting to generate better estimates.
Medeiros et al. (2012c) used growth mixture model to estimate individual rates of
change of VFI incorporating information from the distribution of observed rates of
change from the whole study population of glaucoma patients. The model estimates
had better prediction of future VFI than ordinary least squares linear regression, es-
pecially when fewer examinations were available for the predictions and in patients
with faster rates of change. Murata et al. (2014) used a variational Bayes linear re-
gression model to predict pointwise and mean total deviation values, incorporating
spatial and temporal patterns of visual fields from a training dataset of 5049
eyes. With this model, they reported prediction errors with one or two examinations
similar to simple linear regression prediction using six to seven examinations. Zhu
et al. (2014) developed a model that incorporates information of spatial correlation of
visual field points and retest variability at different visual field sensitivities. At
equivalent false-positive rates, this model detected change earlier (average 2.4 years
less) and with higher progression detection rates compared with linear regression of
MD or pointwise values.
Overall, these studies suggest that more advanced statistical techniques can sig-
nificantly improve detection of visual field progression, requiring fewer examina-
tions, shorter follow-up, and yield more accurate predictions about the future
visual field. These advantages might have significant clinical benefit given that
the frequency of visual field examinations is well below that required to identify pro-
gression with conventional techniques (Chauhan et al., 2008; Fung et al., 2013;
Quigley et al., 2007). However, it is important for further development and adoption
 3 Functional progression 143

of these new techniques to carry out external validation and comparison studies.
The performance of these techniques depends on the similarity between the evalu-
ated patient and the training dataset. Most of these studies carried out performance or
validation analyses using patients from the same center as the ones included in the
training dataset, therefore likely to present similar characteristics. The performances
reported may be overestimated, when compared to use in a wider population.

3.2 OTHER PERIMETRIC TECHNIQUES

3.2.1 Short-Wavelength Automated Perimetry
Older longitudinal studies suggested that short-wavelength automated perimetry
(SWAP, or blue-on-yellow perimetry) could detect visual field deterioration earlier
than SAP Demirel and Johnson, 2001; Johnson et al., 1993a,b); however, more recent
studies failed to confirm these findings (Havvas et al., 2013; Van der Schoot et al.,
2010). Differences in methodology could influence the conflicting findings: earlier
studies used custom normative databases and performed individual adjustments by
lens opacities, while the most recent studies used the device built-in normative da-
tabase without lens opacities adjustments. Technical specifications of the perimeters
and progression criteria also varied between studies. Additionally, with the exception
of one study in glaucoma patients ( Johnson et al., 1993b), these studies were
performed in ocular hypertensive patients, selected with baseline normal SAP, but
possibly abnormal SWAP, inducing a selection bias that could favor the detection
of defects with SWAP.
SWAP is more influenced by lens opacities than SAP (Sample et al., 1994) and
has higher measurement variability (Blumenthal et al., 2000) characteristics that are
likely to impair its performance to detect glaucoma progression. The most recent ver-
sion of SWAP utilizing the SITA algorithm reduces test time and variability
(Bengtsson and Heijl, 2006); however, its utility has not been evaluated in longitu-
dinal studies. Given the absence of solid evidence supporting the value of SWAP, in
a clinical settings with limited resources, it is likely more beneficial to perform more
SAP examinations than to divide resources with SWAP.

3.2.2 Frequency-Doubling Technology Perimetry

The first generation of frequency-doubling technology perimetry (FDT, Welch Allyn
Inc., Skaneateles, NY; Carl Zeiss Meditec, Dublin, CA) was evaluated in very few
longitudinal studies (Bayer and Erb, 2002; Haymes et al., 2005; Nakagawa et al.,
2012) that suggested the potential of FDT to identify more patients progressing than
SAP, but this result varied with different progression criteria (Haymes et al., 2005).
This version of FDT has larger and fewer stimuli compared to SAP (19 locations
compared to 54 locations in the 24-2 program of SAP) and complicated the defini-
tions of progression criteria. The most recent generation of FDT (Humphrey Matrix,
Carl Zeiss Meditec, Inc.) has an identical test pattern to SAP and test–retest
variability that does not increase with decreasing sensitivity, as is the case
with SAP (Artes et al., 2005a; Wall et al., 2009). Furthermore, this version of
144 CHAPTER 7 How to detect progression in glaucoma

FDT had higher signal-to-noise ratio (Artes and Chauhan, 2009). Theoretically,
these attributes should have resulted in more accurate and efficient detection of
perimetry.
There are still very few longitudinal studies with the Matrix FDT. In glaucoma
suspects, Meira-Freitas et al. (2014) reported that faster rates of increase of FDT pat-
tern deviation were related to higher chance of progression in SAP, and Liu et al.
(2014b) reported that approximately the same number of suspects developed repro-
ducible defects in FDT or in SAP. In glaucoma patients, Liu et al. (2014a) identified
more progressing patients with FDT than SAP; however, Redmond et al. (2013)
identified more progressing patients with SAP than FDT. While some studies suggest
that FDT may be useful to evaluate progression of glaucoma functional damage,
further research is required to better assess its additional value to SAP, before recom-
mending frequent clinical use.

4 STRUCTURAL PROGRESSION
4.1 CONFOCAL SCANNING LASER TOMOGRAPHY
The Heidelberg retina tomograph (HRT; Heidelberg Engineering GmbH, Heidelberg,
Germany) has been used to image and monitor the optic nerve head (ONH) since the
early 1990s. One advantage of the device is the backward compatibility with earlier
versions allowing evaluations of a long follow-up. Two methods for progression
assessment are available in the current HRT software: a trend analysis of stereometric
parameters (Strouthidis and Garway-Heath, 2008) and the topographic change anal-
ysis (TCA; Chauhan et al., 2000).
The trend analysis available in the device software presents changes of the stereo-
metric parameters using normalized values, obtained with the ratio of the difference
between follow-up measurement and baseline to the difference between average
measurement in a normal eye and in an eye with advanced glaucoma (Strouthidis
and Garway-Heath, 2008), without testing for statistical significance of the changes.
We did not find any published report using the device trend analysis, but several
studies evaluate the linear regression of rim area measured with HRT.
Patients with progressive damage observed in visual field and/or optic disc
photos present faster reduction rates of rim area than stable ones (Medeiros et al.,
2014; Zangwill et al., 2013). However, a wide range of rim area reduction rates
has also been observed in healthy subjects (Alencar et al., 2010; See et al., 2009),
with magnitude that could be similar to glaucoma patients with progressive visual
field damage (Alencar et al., 2010), what can lead to difficulty in differentiating
age-related loss from glaucomatous loss. Nevertheless, some studies classified all
statistically significant negative slopes of rim area (rate of change less than 0) as
glaucoma progression (Leung et al., 2011b; O’Leary et al., 2010), while a criterion
of slope faster than
1%/year has also been used to avoid incorrect classification of
patients presenting age-related loss (Strouthidis et al., 2006).
 4 Structural progression 145

The measurement of rim area with HRT depends on a reference plane used to
define “rim,” the structures above it, and “cup,” the structures below it, both within
an operator-delineated optic disc margin contour. The standard positioning of the
reference plane is 50 mm posterior to the temporal disc margin, and this position
is estimated for each examination. Variability in the reference plane height is related
to variability in the rim area measurements (Strouthidis et al., 2005; Tan et al., 2003),
and other algorithms to define the position of the reference plane have been evaluated
(Poli et al., 2008). The Moorfields reference plane, which consists in estimating the
standard reference plane for the baseline examination and keeping the plane position
fixed for follow-up examinations, presented the best performance for longitudinal
evaluation of rim area (Asaoka et al., 2009; Poli et al., 2008).
The TCA is a pointwise event-based method to evaluate change in the topo-
graphic height of the ONH and peripapillary region (Chauhan et al., 2000). The
topography image is grouped into 96  96 superpixels (1 superpixel ¼ 4  4 pixels),
and the first exam is used as baseline reference. For each superpixel, the height in
subsequent exams is compared to the baseline with an analysis of variance. Such
analysis does not require a contour line to define the optic disc margin or a refer-
ence plane to define the dimensions of the neuroretinal rim. Instead, the expected
variability is modeled from the individual baseline, not relying on normative var-
iability databases from other patients. The TCA printout presents the ONH image
with an overlay where superpixels with statistically significant elevation are
marked in green, and depression in red. It is also possible to evaluate the area,
depth, volume, and statistical significance of the observed changes with the super-
pixel clusters.
Similar to other pointwise analyses, several criteria to detect progression with the
TCA have been described, from more conservative to more liberal (Chauhan et al.,
2009). In research settings or with access to the device software, a possible moderate
criterion (specificity of 94%) is the presence of a cluster of superpixels with statis-
tically significant depression in which area is more than 1% of the disc area and mean
change depth is more than 50 mm (Chauhan et al., 2009). In clinical settings, the
result of the TCA is frequently limited to the printout, which must be evaluated sub-
jectively by the physician. To date, there is no consensus on the optimal progression
criteria for the TCA (Fig. 2).
Recent studies in experimental glaucoma in nonhuman primates found ONH
surface depression before a reduction in retinal nerve fiber layer (RNFL) thickness
(Fortune et al., 2012, 2013; He et al., 2013; Strouthidis et al., 2011). Xu et al. (2014)
investigated this temporal relationship in glaucoma patients with the HRT TCA
and Cirrus OCT GPA of RNFL (GPA, Cirrus HD-OCT; Carl Zeiss Meditec AG,
Dublin, CA). They found that 45.7% of eyes had ONH depression at the detection
of RNFL thinning, whereas only 7% of eyes had RNFL thinning at detection of
ONH depression. Also, from the eyes that presented both changes during the study
follow-up, 82.6% had ONH surface depression detected before RNFL thinning.
The results of these studies suggest that changes in the connective tissues of the
ONH (such as the lamina cribrosa and non-axonal components of the neuroretinal
146 CHAPTER 7 How to detect progression in glaucoma

FIGURE 2
Example of Heidelberg retina tomograph topographic change analysis (TCA) printout.
Clusters of superpixels with significant reduction in topographic height, highlighted in red
(dark gray in the print version), can be seen at the temporal superior (white arrow) and
temporal inferior (black arrow) optic nerve head neuroretinal rim, suggesting progression of
glaucomatous damage.
 4 Structural progression 147

rim and prelaminar tissue) may precede the loss of axons during development
or progression of glaucoma.
One caveat of the assessment of glaucoma progression with HRT is the ONH sur-
face change induced by intraocular pressure (IOP; Alencar et al., 2010). Increase in
the rim area and reduction of the cup depth measured with HRT have been reported
after surgical (Irak et al., 1996; Lesk et al., 1999) or clinical (Bowd et al., 2000; Tan
and Hitchings, 2004) reduction of IOP in glaucoma patients. These changes in HRT
parameters are probably only significant if the magnitude of IOP reduction is higher
than 7 mmHg or 40% (Bowd et al., 2000; Lesk et al., 1999; Nicolela et al., 2006), and
in such cases, new baselines for assessment of progression should be acquired.
RNFLT measured with OCT is not significantly altered by IOP (Chang et al.,
2007; Rebolleda et al., 2007) and, in this aspect, may be a more robust parameter
for long-term glaucoma follow-up. However, since the usual question of interest
is if the patient is undergoing progression with the current treatment, new baselines
for any progression evaluation should be obtained whenever there is a treatment
change.

4.2 OPTICAL COHERENCE TOMOGRAPHY

OCT evaluation of the RNFLT is an important diagnostic procedure glaucoma man-
agement. The current generation of OCT, spectral domain OCT (SD-OCT), allows
higher resolution, faster image acquisition, and higher reproducibility compared to
the previous generation time-domain OCT(Leung et al., 2009; Pierro et al., 2012),
resulting in better assessment of longitudinal changes (Leung et al., 2011a). There
are several commercial SD-OCT devices in use and it is important to note that their
measurements are not interchangeable (Leite et al., 2011; Pierro et al., 2012; Seibold
et al., 2010), therefore progression assessment with the same device is essential. Each
device software contains different progression assessment tools that have been de-
scribed in detail elsewhere (Grewal and Tanna, 2013). Briefly, the results of a series
of examinations are usually presented side-by-side, allowing visual comparison, and
changes in global and sectoral indexes are computed. In some devices, there is no
statistical evaluation of the significance of the observed changes, while other devices
present linear regression or event-based analysis.
The Cirrus OCT assesses RNFLT change with the GPA. The Cirrus GPA per-
forms pointwise event-based change analysis of the RNFLT map and RNFLT profile
(TSNIT plot), and also event-based change analysis of global and sectoral RNFLT
averages. The first two examinations are used as baseline and change in follow-up
examinations exceeding test–retest variability is highlighted. The variability limits
are derived from a reproducibility study in healthy subjects tested over a short period
of time (Cirrus HD-OCT User Manual). Linear regression analyses of global and
sectoral averages are also performed (Fig. 3).
Significant change in RNFLT and glaucoma progression are not equivalent en-
tities. While faster reduction of rates of RNFLT are related to visual field deteriora-
tion or rim thinning (Alencar et al., 2010; Grewal et al., 2012; Lee et al., 2011;
148 CHAPTER 7 How to detect progression in glaucoma

FIGURE 3
Example of Cirrus HD-OCT guided progression analysis printout. A significant reduction in
the retinal nerve fiber layer thickness (RNFLT) map is indicated with yellow-colored pixels
(light gray in the print version) in the first follow-up examination (white arrow). Pixels
highlighted in purple (dark gray in the print version) indicate increase in RNFLT. Additionally,
the Cirrus GPA printout also presents evaluation of changes in the RNFLT profile (arrow,
dashed line), and trend analyses of average and sectoral indexes (black arrows).
 6 Conclusion 149

Medeiros et al., 2009; Miki et al., 2014; Wessel et al., 2013), healthy subjects also
have significant age-related loss of RNFLT (Leung et al., 2012). There is no consen-
sus on thresholds to separate age-related decline from glaucoma progression.
A possible approach could be using rate of change normative limits estimated from
age-related change observed in longitudinal cohorts of control subjects (Leung et al.,
2013), but potentially long and expensive studies are required to define and evaluate
the performance of such limits.
SD-OCT macular thickness measurements have potential for the detection of
glaucoma progression (Na et al., 2012, 2013; Naghizadeh et al., 2014). In advanced
glaucoma (MD <
10 dB), average macular thickness may identify progressing
patients better than RNFLT (Sung et al., 2012). However, changes in macular
parameters due to early age-related macular degeneration are similar to those due
to glaucoma (Garas et al., 2012), limiting utility in patients with these common
morbidities.

5 COMBINING PROGRESSION TECHNIQUES

When evaluating glaucoma progression with several techniques, it is common to ob-
serve patients with significant changes with some techniques but not others (Artes
and Chauhan, 2005; Medeiros et al., 2009; Strouthidis et al., 2006). Integrating these
findings into a single conclusion to guide management decisions can be a difficult
task for clinicians. To assist in this task, newer statistical analyses have been de-
scribed to combine the information of different techniques. For example, information
on RNFLT change can be used to make better estimates of visual field change
(Medeiros et al., 2011). Bayesian regression models have been used to integrate
the results of HFA GPA (Medeiros et al., 2012a), ONH photography (Medeiros
et al., 2012d), RNFL (Medeiros et al., 2011), or rim area (Medeiros et al., 2012e;
Russell et al., 2012b), with visual field measurements achieving better estimates
of rates of change. Another approach used to integrate results of different examina-
tions is the development of combined indexes. Visual field measurements have been
combined with RNFLT to produce estimates of the number of retinal ganglion cells
(Medeiros et al., 2012b).

6 CONCLUSION
Several different devices and analyses are currently available to evaluate change in
structural and functional measurements. At the moment, there is no consensus on a
best technique or criteria to detect glaucoma progression, or what amount of change
would be clinically meaningful. Considering this uncertainty in interpreting the re-
sult of some techniques and the cost to perform each examination, clinicians should
appraise which tests provide the most useful information for their specific decision.
Assessment of glaucoma progression is frequently problematic because of test
150 CHAPTER 7 How to detect progression in glaucoma

variability that leads to imprecision in rate estimates. Examinations whose results are
unlikely to influence clinical decisions should be replaced with more frequent exam-
inations of tests that do influence clinical decisions. It is unlikely that any theoretical
merit of one test over another outweighs the benefits of frequent examinations
with a single test, even it is proven to be less meritorious than an infrequently
performed test.
New techniques have been developed to assess glaucoma progression, which
make more comprehensive and complex use of data. They have the potential of
detecting progression with better accuracy, with shorter follow-up periods, and gen-
erating better prognostics. Further validation of these new techniques is still required,
but their incorporation into clinical practice is likely to yield significant benefits.

ACKNOWLEDGMENTS
Supported by Grant MOP-11357 from the Canadian Institutes of Health Research (B.C.C.) and
the Mathers Fellowship (J.R.V.).

REFERENCES
Alencar, L.M., Zangwill, L.M., Weinreb, R.N., Bowd, C., Sample, P.A., Girkin, C.A.,
Liebmann, J.M., Medeiros, F.A., 2010. A comparison of rates of change in neuroretinal
rim area and retinal nerve fiber layer thickness in progressive glaucoma. Invest. Ophthal-
mol. Vis. Sci. 51, 3531–3539. http://dx.doi.org/10.1167/iovs.09-4350.
Artes, P.H., Chauhan, B.C., 2005. Longitudinal changes in the visual field and optic disc in
glaucoma. Prog. Retin. Eye Res. 24, 333–354. http://dx.doi.org/10.1016/j.preteyeres.
2004.10.002.
Artes, P.H., Chauhan, B.C., 2009. Signal/noise analysis to compare tests for measuring visual
field loss and its progression. Invest. Ophthalmol. Vis. Sci. 50, 4700–4708. http://dx.doi.
org/10.1167/iovs.09-3601.
Artes, P.H., Iwase, A., Ohno, Y., Kitazawa, Y., Chauhan, B.C., 2002. Properties of perimetric
threshold estimates from full threshold, SITA standard, and SITA fast strategies. Invest.
Ophthalmol. Vis. Sci. 43, 2654–2659.
Artes, P.H., Hutchison, D.M., Nicolela, M.T., Leblanc, R.P., Chauhan, B.C., 2005a. Threshold
and variability properties of matrix frequency-doubling technology and standard auto-
mated perimetry in glaucoma. Invest. Ophthalmol. Vis. Sci. 46, 2451–2457. http://dx.
doi.org/10.1167/iovs.05-0135.
Artes, P.H., Nicolela, M.T., LeBlanc, R.P., Chauhan, B.C., 2005b. Visual field progression
in glaucoma: total versus pattern deviation analyses. Invest. Ophthalmol. Vis. Sci.
46, 4600–4606. http://dx.doi.org/10.1167/iovs.05-0827.
Artes, P.H., O’Leary, N., Hutchison, D.M., Heckler, L., Sharpe, G.P., Nicolela, M.T.,
Chauhan, B.C., 2011. Properties of the statpac visual field index. Invest. Ophthalmol.
Vis. Sci. 52, 4030–4038. http://dx.doi.org/10.1167/iovs.10-6905.
Artes, P.H., O’Leary, N., Nicolela, M.T., Chauhan, B.C., Crabb, D.P., 2014. Visual field pro-
gression in glaucoma: what is the specificity of the guided progression analysis?
Ophthalmology 121, 1–5. http://dx.doi.org/10.1016/j.ophtha.2014.04.015.
 References 151

Asaoka, R., Strouthidis, N.G., Kappou, V., Gardiner, S.K., Garway-Heath, D.F., 2009. HRT-3
Moorfields reference plane: effect on rim area repeatability and identification of progres-
sion. Br. J. Ophthalmol. 93, 1510–1513. http://dx.doi.org/10.1136/bjo.2008.148031.
Bayer, A.U., Erb, C., 2002. Short wavelength automated perimetry, frequency doubling
technology perimetry, and pattern electroretinography for prediction of progressive glau-
comatous standard visual field defects. Ophthalmology 109, 1009–1017. http://dx.doi.org/
10.1016/S0161-6420(02)01015-1.
Bengtsson, B., Heijl, A., 2006. Diagnostic sensitivity of fast blue-yellow and standard auto-
mated perimetry in early glaucoma. A comparison between different test programs.
Ophthalmology 113, 1092–1097. http://dx.doi.org/10.1016/j.ophtha.2005.12.028.
Bengtsson, B., Heijl, A., 2008. A visual field index for calculation of glaucoma rate
of progression. Am J. Ophthalmol. 145, 343–353. http://dx.doi.org/10.1016/j.ajo.
2007.09.038.
Blumenthal, E.Z., Blumenthal, E.Z., Sample, P.A., Zangwill, L., Lee, A.C., Kono, Y.,
Weinreb, R.N., 2000. Comparison of long-term variability for standard and short-
wavelength automated perimetry in stable glaucoma patients. Am J. Ophthalmol.
129, 309–313. http://dx.doi.org/10.1016/S0002-9394(99)00432-8.
Bowd, C., Weinreb, R.N., Lee, B., Emdadi, A., Zangwill, L.M., 2000. Optic disk topography
after medical treatment to reduce intraocular pressure. Am J. Ophthalmol. 130, 280–286.
Brusini, P., 2008. Monitoring glaucoma progression. Prog. Brain Res. 173, 59–73. http://dx.
doi.org/10.1016/S0079-6123(08)01106-0.
Bryan, S.R., Vermeer, K.A., Eilers, P.H.C., Lemij, H.G., Lesaffre, E.M.E.H., 2013. Robust
and censored modeling and prediction of progression in glaucomatous visual fields. Invest.
Ophthalmol. Vis. Sci. 54, 6694–6700. http://dx.doi.org/10.1167/iovs.12-11185.
Caprioli, J., Mock, D., Bitrian, E., Afifi, A.A., Yu, F., Nouri-Mahdavi, K., Coleman, A.L.,
2011. A method to measure and predict rates of regional visual field decay in glaucoma.
Invest. Ophthalmol. Vis. Sci. 52, 4765–4773. http://dx.doi.org/10.1167/iovs.10-6414.
Casas-Llera, P., Rebolleda, G., Muñoz-Negrete, F.J., Arnalich-Montiel, F., Pérez-López, M.,
Fernández-Buenaga, R., 2009. Visual field index rate and event-based glaucoma progres-
sion analysis: comparison in a glaucoma population. Br. J. Ophthalmol. 93, 1576–1579.
http://dx.doi.org/10.1136/bjo.2009.158097.
Chang, P.T., Sekhon, N., Budenz, D.L., Feuer, W.J., Park, P.W., Anderson, D.R., 2007. Effect
of lowering intraocular pressure on optical coherence tomography measurement of peri-
papillary retinal nerve fiber layer thickness. Ophthalmology 114, 2252–2258. http://dx.
doi.org/10.1016/j.ophtha.2007.02.012.
Chauhan, B.C., Blanchard, J.W., Hamilton, D.C., LeBlanc, R.P., 2000. Technique for detect-
ing serial topographic changes in the optic disc and peripapillary retina using scanning
laser tomography. Invest. Ophthalmol. Vis. Sci. 41, 775–782.
Chauhan, B.C., Garway-Heath, D.F., Goñi, F.J., Rossetti, L., Bengtsson, B., Viswanathan, A.C.,
Heijl, A., 2008. Practical recommendations for measuring rates of visual field change in
glaucoma. Br. J. Ophthalmol. 92, 569–573. http://dx.doi.org/10.1136/bjo.2007.135012.
Chauhan, B.C., Hutchison, D.M., Artes, P.H., Caprioli, J., Jonas, J.B., LeBlanc, R.P.,
Nicolela, M.T., 2009. Optic disc progression in glaucoma: comparison of confocal scan-
ning laser tomography to optic disc photographs in a prospective study. Invest. Ophthal-
mol. Vis. Sci. 50, 1682–1691. http://dx.doi.org/10.1167/iovs.08-2457.
Chen, A., Nouri-Mahdavi, K., Otarola, F.J., Yu, F., Afifi, A.A., Caprioli, J., 2014. Models of
glaucomatous visual field loss. Invest. Ophthalmol. Vis. Sci. 55, 7881–7887. http://dx.doi.
org/10.1167/iovs.14-15435.
152 CHAPTER 7 How to detect progression in glaucoma

Demirel, S., Johnson, C.A., 2001. Incidence and prevalence of short wavelength automated
perimetry deficits in ocular hypertensive patients. Am J. Ophthalmol. 131, 709–715.
http://dx.doi.org/10.1016/S0002-9394(00)00946-6.
De Moraes, C.G., Liebmann, C.A., Susanna, R.J., Ritch, R., Liebmann, J.M., 2012. Examina-
tion of the performance of different pointwise linear regression progression criteria to
detect glaucomatous visual field change. Clin. Exp. Ophthalmol. 40, 190–197. http://
dx.doi.org/10.1111/j.1442-9071.2011.02680.x.
Fortune, B., Burgoyne, C.F., Cull, G.A., Reynaud, J., Wang, L., 2012. Structural and
functional abnormalities of retinal ganglion cells measured in vivo at the onset of optic
nerve head surface change in experimental glaucoma. Invest. Ophthalmol. Vis. Sci.
53, 3939–3950. http://dx.doi.org/10.1167/iovs.12-9979.
Fortune, B., Reynaud, J., Wang, L., Burgoyne, C.F., 2013. Does optic nerve head surface to-
pography change prior to loss of retinal nerve fiber layer thickness: a test of the site of
injury hypothesis in experimental glaucoma. PLoS One 8, e77831. http://dx.doi.org/
10.1371/journal.pone.0077831.
Fung, S.S.M., Lemer, C., Russell, R.A., Malik, R., Crabb, D.P., 2013. Are practical recommen-
dations practiced? A national multi-centre cross-sectional study on frequency of visual
field testing in glaucoma. Br. J. Ophthalmol. 97, 843–847. http://dx.doi.org/10.1136/
bjophthalmol-2012-302903.
Garas, A., Papp, A., Holló, G., 2012. Influence of age-related macular degeneration on mac-
ular thickness measurement made with fourier-domain optical coherence tomography.
J. Glaucoma 22, 195–200. http://dx.doi.org/10.1097/IJG.0b013e31824083e6.
Gardiner, S.K., Crabb, D.P., 2002. Examination of different pointwise linear regression
methods for determining visual field progression. Invest. Ophthalmol. Vis. Sci.
43, 1400–1407.
Gardiner, S.K., Demirel, S., Johnson, C.A., 2008. Is there evidence for continued learning over
multiple years in perimetry? Optom. Vis. Sci. 85, 1043–1048. http://dx.doi.org/10.1097/
OPX.0b013e31818b9b40.
Grewal, D.S., Tanna, A.P., 2013. Diagnosis of glaucoma and detection of glaucoma progres-
sion using spectral domain optical coherence tomography. Curr. Opin. Ophthalmol.
24, 150–161. http://dx.doi.org/10.1097/ICU.0b013e32835d9e27.
Grewal, D.S., Sehi, M., Paauw, J.D., Greenfield, D.S., 2012. Detection of progressive retinal nerve
fiber layer thickness loss with optical coherence tomography using 4 criteria for functional
progression. J. Glaucoma 21, 214–220. http://dx.doi.org/10.1097/IJG.0b013e3182071cc7.
Havvas, I., Papaconstantinou, D., Moschos, M.M., Theodossiadis, P.G., Andreanos, V.,
Ekatomatis, P., Vergados, I., Andreanos, D., 2013. Comparison of SWAP and SAP on
the point of glaucoma conversion. Clin. Ophthalmol. 7, 1805–1810. http://dx.doi.org/
10.2147/OPTH.S50231.
Haymes, S.A., Hutchison, D.M., McCormick, T.A., Varma, D.K., Nicolela, M.T.,
Leblanc, R.P., Chauhan, B.C., 2005. Glaucomatous visual field progression with
frequency-doubling technology and standard automated perimetry in a longitudinal pro-
spective study. Invest. Ophthalmol. Vis. Sci. 46, 547–554. http://dx.doi.org/10.1167/
iovs.04-0973.
He, L., Yang, H., Gardiner, S.K., Williams, G., Hardin, C., Strouthidis, N.G., Fortune, B.,
Burgoyne, C.F., 2013. Longitudinal detection of optic nerve head changes by spectral
domain optical coherence tomography in early experimental glaucoma. Invest.
Ophthalmol. Vis. Sci. 55, 574–586. http://dx.doi.org/10.1167/iovs.13-13245.
 References 153

Heijl, A., Lindgren, G., Olsson, J., 1987. A package for the statistical analysis of visual fields.
Doc. Ophthalmol. Proc. Ser. 49, 153–168.
Heijl, A., Leske, M.C., Bengtsson, B., Bengtsson, B., Hussein, M., 2003. Measuring visual
field progression in the Early Manifest Glaucoma Trial. Acta Ophthalmol. Scand.
81, 286–293.
Irak, I., Zangwill, L., Garden, V., Shakiba, S., Weinreb, R.N., 1996. Change in optic disk to-
pography after trabeculectomy. Am J. Ophthalmol. 122, 690–695.
Johnson, C.A., Adams, A.J., Casson, E.J., Brandt, J.D., 1993a. Progression of early glaucoma-
tous visual field loss as detected by blue-on-yellow and standard white-on-white auto-
mated perimetry. Arch. Ophthalmol. 111, 651–656. http://dx.doi.org/10.1001/
archopht.1993.01090050085035.
Johnson, C.A., Adams, A.J., Casson, E.J., Brandt, J.D., 1993b. Blue-on-yellow perimetry can
predict the development of glaucomatous visual field loss. Arch. Ophthalmol.
111, 645–650. http://dx.doi.org/10.1001/archopht.1993.01090050079034.
Kummet, C.M., Zamba, K.D., Doyle, C.K., Johnson, C.A., Wall, M., 2013. Refinement of
pointwise linear regression criteria for determining glaucoma progression. Invest.
Ophthalmol. Vis. Sci. 54, 6234–6241. http://dx.doi.org/10.1167/iovs.13-11680.
Lee, E.J., Kim, T.W., Park, K.H., Seong, M., Kim, H., Kim, D.M., 2009. Ability of stratus OCT
to detect progressive retinal nerve fiber layer atrophy in glaucoma. Invest. Ophthalmol.
Vis. Sci. 50, 662–668. http://dx.doi.org/10.1167/iovs.08-1682.
Lee, E.J., Kim, T.-W., Weinreb, R.N., Park, K.H., Kim, S.H., Kim, D.M., 2011. Trend-based
analysis of retinal nerve fiber layer thickness measured by optical coherence tomography
in eyes with localized nerve fiber layer defects. Invest. Ophthalmol. Vis. Sci.
52, 1138–1144. http://dx.doi.org/10.1167/iovs.10-5975.
Lee, J.M., Cirineo, N., Ramanathan, M., Nouri-Mahdavi, K., Morales, E., Coleman, A.L.,
Caprioli, J., 2014. Performance of the visual field index in glaucoma patients with mod-
erately advanced visual field loss. Am J. Ophthalmol. 157, 39–43. http://dx.doi.org/
10.1016/j.ajo.2013.09.003.
Leite, M.T., Rao, H.L., Weinreb, R.N., Zangwill, L.M., Bowd, C., Sample, P.A., Tafreshi, A.,
Medeiros, F.A., 2011. Agreement among spectral-domain optical coherence tomography
instruments for assessing retinal nerve fiber layer thickness. Am J. Ophthalmol. 151, http://
dx.doi.org/10.1016/j.ajo.2010.06.041, 85.e1–92.e1.
Lesk, M.R., Spaeth, G.L., Azuara-Blanco, A., Araujo, S.V., Katz, L.J., Terebuh, A.K.,
Wilson, R.P., Moster, M.R., Schmidt, C.M., 1999. Reversal of optic disc cupping after
glaucoma surgery analyzed with a scanning laser tomograph. Ophthalmology
106, 1013–1018. http://dx.doi.org/10.1016/S0161-6420(99)00526-6.
Leung, C.K.S., 2014. Diagnosing glaucoma progression with optical coherence tomography.
Curr. Opin. Ophthalmol. 25, 104–111. http://dx.doi.org/10.1097/ICU.0000000000000024.
Leung, C.K.-S.S., Cheung, C.Y.-L., Weinreb, R.N., Qiu, Q., Liu, S., Li, H., Xu, G., Fan, N.,
Huang, L., Pang, C.-P., Lam, D.S.C., 2009. Retinal nerve fiber layer imaging with spectral-
domain optical coherence tomography: a variability and diagnostic performance study.
Ophthalmology 116, 1257–1263. http://dx.doi.org/10.1016/j.ophtha.2009.04.013, 1263.
e1–1263.e2.
Leung, C.K.S., Chiu, V., Weinreb, R.N., Liu, S., Ye, C., Yu, M., Cheung, C.Y.-L., Lai, G.,
Lam, D.S.-C., 2011a. Evaluation of retinal nerve fiber layer progression in glaucoma: a
comparison between spectral-domain and time-domain optical coherence tomography.
Ophthalmology 118, 1558–1562. http://dx.doi.org/10.1016/j.ophtha.2011.01.026.
154 CHAPTER 7 How to detect progression in glaucoma

Leung, C.K.S., Liu, S., Weinreb, R.N., Lai, G., Ye, C., Cheung, C.Y.L., Pang, C.P., Tse, K.K.,
Lam, D.S.C., 2011b. Evaluation of retinal nerve fiber layer progression in glaucoma a pro-
spective analysis with neuroretinal rim and visual field progression. Ophthalmology
118, 1551–1557. http://dx.doi.org/10.1016/j.ophtha.2010.12.035.
Leung, C.K.S., Yu, M., Weinreb, R.N., Ye, C., Liu, S., Lai, G., Lam, D.S.C., 2012. Retinal
nerve fiber layer imaging with spectral-domain optical coherence tomography: a prospec-
tive analysis of age-related loss. Ophthalmology 119, 731–737. http://dx.doi.org/10.1016/
j.ophtha.2011.10.010.
Leung, C.K.S., Ye, C., Weinreb, R.N., Yu, M., Lai, G., Lam, D.S., 2013. Impact of age-
related change of retinal nerve fiber layer and macular thicknesses on evaluation of
glaucoma progression. Ophthalmology 120, 2485–2492. http://dx.doi.org/10.1016/
j.ophtha.2013.07.021.
Liu, S., Yu, M., Weinreb, R.N., Lai, G., Lam, D.S.-C., Leung, C.K.-S., 2014a. Frequency-
doubling technology perimetry for detection of the development of visual field defects
in glaucoma suspect eyes: a prospective study. JAMA Ophthalmol. 132, 77–83. http://
dx.doi.org/10.1001/jamaophthalmol.2013.5511.
Liu, S., Yu, M., Weinreb, R.N., Lai, G., Lam, D.S.-C., Leung, C.K.-S., 2014b. Frequency
doubling technology perimetry for detection of visual field progression in glaucoma:
a pointwise linear regression analysis. Invest. Ophthalmol. Vis. Sci. 55, 2862–2869.
http://dx.doi.org/10.1167/iovs.13-13225.
Medeiros, F.A., Zangwill, L.M., Alencar, L.M., Bowd, C., Sample, P.A., Susanna, R.,
Weinreb, R.N., 2009. Detection of glaucoma progression with stratus OCT retinal nerve
fiber layer, optic nerve head, and macular thickness measurements. Invest. Ophthalmol.
Vis. Sci. 50, 5741–5748. http://dx.doi.org/10.1167/iovs.09-3715.
Medeiros, F.A., Leite, M.T., Zangwill, L.M., Weinreb, R.N., 2011. Combining structural and
functional measurements to improve detection of glaucoma progression using Bayesian
hierarchical models. Investig. Ophthalmol. Vis. Sci. 52, 5794–5803. http://dx.doi.org/
10.1167/iovs.10-7111.
Medeiros, F.A., Weinreb, R.N., Moore, G., Liebmann, J.M., Girkin, C.A., Zangwill, L.M.,
2012a. Integrating event- and trend-based analyses to improve detection of glaucomatous
visual field progression. Ophthalmology 119, 458–467. http://dx.doi.org/10.1016/
j.ophtha.2011.10.003.
Medeiros, F.A., Zangwill, L.M., Anderson, D.R., Liebmann, J.M., Girkin, C.A., Harwerth, R.S.,
Fredette, M.-J., Weinreb, R.N., 2012b. Estimating the rate of retinal ganglion cell loss
in glaucoma. Am J. Ophthalmol. 154, http://dx.doi.org/10.1016/j.ajo.2012.04.022 814.
e1–824.e1.
Medeiros, F.A., Zangwill, L.M., Weinreb, R.N., 2012c. Improved prediction of rates of visual
field loss in glaucoma using empirical Bayes estimates of slopes of change. J. Glaucoma
21, 147–154. http://dx.doi.org/10.1097/IJG.0b013e31820bd1fd.
Medeiros, F.A., Zangwill, L.M., Mansouri, K., Lisboa, R., Tafreshi, A., Weinreb, R.N., 2012d.
Incorporating risk factors to improve the assessment of rates of glaucomatous progression.
Invest. Ophthalmol. Vis. Sci. 53, 2199–2207. http://dx.doi.org/10.1167/iovs.11-8639.
Medeiros, F.A., Zangwill, L.M., Girkin, C.A., Liebmann, J.M., Weinreb, R.N., 2012e.
Combining structural and functional measurements to improve estimates of rates
of glaucomatous progression. Am J. Ophthalmol. 153, http://dx.doi.org/10.1016/
j.ajo.2011.11.015. 1197.e1–205.e1.
 References 155

Medeiros, F.A., Lisboa, R., Zangwill, L.M., Liebmann, J.M., Girkin, C.A., Bowd, C.,
Weinreb, R.N., 2014. Evaluation of progressive neuroretinal rim loss as a surrogate end
point for development of visual field loss in glaucoma. Ophthalmology 121, 100–109.
http://dx.doi.org/10.1016/j.ophtha.2013.06.026.
Meira-Freitas, D., Tatham, A.J., Lisboa, R., Kuang, T.-M., Zangwill, L.M., Weinreb, R.N.,
Girkin, C.A., Liebmann, J.M., Medeiros, F.A., 2014. Predicting progression of glaucoma
from rates of frequency doubling technology perimetry change. Ophthalmology
121, 498–507. http://dx.doi.org/10.1016/j.ophtha.2013.09.016.
Membrey, W.L., Poinoosawmy, D.P., Bunce, C., Fitzke, F.W., Hitchings, R.A., 2000.
Comparison of visual field progression in patients with normal pressure glaucoma between
eyes with and without visual field loss that threatens fixation. Br. J. Ophthalmol.
84, 1154–1158. http://dx.doi.org/10.1136/bjo.84.10.1154.
Miki, A., Medeiros, F.A., Weinreb, R.N., Jain, S., He, F., Sharpsten, L., Khachatryan, N.,
Hammel, N., Liebmann, J.M., Girkin, C.A., Sample, P.A., Zangwill, L.M., 2014. Rates
of retinal nerve fiber layer thinning in glaucoma suspect eyes. Ophthalmology
121, 1350–1358. http://dx.doi.org/10.1016/j.ophtha.2014.01.017.
Murata, H., Araie, M., Asaoka, R., 2014. A new approach to measure visual field progression
in glaucoma patients using variational bayes linear regression. Invest. Ophthalmol. Vis.
Sci. 55, 8386–8392. http://dx.doi.org/10.1167/iovs.14-14625.
Musch, D.C., Gillespie, B.W., Palmberg, P.F., Spaeth, G., Niziol, L.M., Lichter, P.R., 2014.
Visual field improvement in the collaborative initial glaucoma treatment study. Am J.
Ophthalmol. 158, http://dx.doi.org/10.1016/j.ajo.2014.04.003, 96.e2–104.e2.
Na, J.H., Sung, K.R., Baek, S., Kim, Y.J., Durbin, M.K., Lee, H.J., Kim, H.K., Sohn, Y.H.,
2012. Detection of glaucoma progression by assessment of segmented macular thickness
data obtained using spectral domain optical coherence tomography. Invest. Ophthalmol.
Vis. Sci. 53, 3817–3826. http://dx.doi.org/10.1167/iovs.11-9369.
Na, J.H., Sung, K.R., Lee, J.R., Lee, K.S., Baek, S., Kim, H.K., Sohn, Y.H., 2013. Detection of
glaucomatous progression by spectral-domain optical coherence tomography.
Ophthalmology 120, 1388–1395. http://dx.doi.org/10.1016/j.ophtha.2012.12.014.
Naghizadeh, F., Garas, A., Vargha, P.P., Holló, G., Hollo, G., 2014. Detection of early
glaucomatous progression with different parameters of the RTVue optical coherence
tomograph. J. Glaucoma 23, 195–198. http://dx.doi.org/10.1097/IJG.0b013e31826a9707.
Nakagawa, S., Murata, H., Saito, H., Nakahara, H., Mataki, N., Tomidokoro, A., Iwase, A.,
Araie, M., 2012. Frequency doubling technology for earlier detection of functional dam-
age in standard automated perimetry-normal hemifield in glaucoma with low-to-normal
pressure. J. Glaucoma 21, 22–26. http://dx.doi.org/10.1097/IJG.0b013e318202777e.
Nicolela, M.T., Soares, A.S., Carrillo, M.M., Chauhan, B.C., LeBlanc, R.P., Artes, P.H., 2006.
Effect of moderate intraocular pressure changes on topographic measurements with con-
focal scanning laser tomography in patients with glaucoma. Arch. Ophthalmol.
124, 633–640. http://dx.doi.org/10.1001/archopht.124.5.633.
Nouri-Mahdavi, K., 2014. Selecting visual field tests and assessing visual field deterioration in
glaucoma. Can. J. Ophthalmol. 49, 497–505. http://dx.doi.org/10.1016/j.jcjo.2014.10.002.
Nouri-Mahdavi, K., Caprioli, J., 2014. Measuring rates of structural and functional change in
glaucoma. Br. J. Ophthalmol. http://dx.doi.org/10.1136/bjophthalmol-2014-305210.
Nouri-Mahdavi, K., Nassiri, N., Giangiacomo, A., Caprioli, J., 2011. Detection of visual field
progression in glaucoma with standard achromatic perimetry: a review and practical
156 CHAPTER 7 How to detect progression in glaucoma

implications. Graefes Arch. Clin. Exp. Ophthalmol. 249, 1593–1616. http://dx.doi.org/

10.1007/s00417-011-1787-5.
O’Leary, N., Crabb, D.P., Mansberger, S.L., Fortune, B., Twa, M.D., Lloyd, M.J., Kotecha, A.,
Garway-Heath, D.F., Cioffi, G.A., Johnson, C.A., 2010. Glaucomatous progression in se-
ries of stereoscopic photographs and Heidelberg retina tomograph images. Arch. Ophthal-
mol. 128, 560–568. http://dx.doi.org/10.1001/archophthalmol.2010.52.
O’Leary, N., Chauhan, B.C., Artes, P.H., 2012. Visual field progression in glaucoma: estimat-
ing the overall significance of deterioration with permutation analyses of pointwise linear
regression (PoPLR). Invest. Ophthalmol. Vis. Sci. 53, 6776–6784. http://dx.doi.org/
10.1167/iovs.12-10049.
Pathak, M., Demirel, S., Gardiner, S.K., 2013. Nonlinear, multilevel mixed-effects approach
for modeling longitudinal standard automated perimetry data in glaucoma. Invest.
Ophthalmol. Vis. Sci. 54, 5505–5513. http://dx.doi.org/10.1167/iovs.13-12236.
Pierro, L., Gagliardi, M., Iuliano, L., Ambrosi, A., Bandello, F., 2012. Retinal nerve fiber layer
thickness reproducibility using seven different OCT instruments. Invest. Ophthalmol. Vis.
Sci. 53, 5912–5920. http://dx.doi.org/10.1167/iovs.11-8644.
Poli, A., Strouthidis, N.G., Ho, T.A., Garway-Heath, D.F., 2008. Analysis of HRT images:
comparison of reference planes. Invest. Ophthalmol. Vis. Sci. 49, 3970–3975. http://dx.
doi.org/10.1167/iovs.08-1764.
Quigley, H.A., Friedman, D.S., Hahn, S.R., 2007. Evaluation of practice patterns for the
care of open-angle glaucoma compared with claims data: the Glaucoma Adherence and
Persistency Study. Ophthalmology 114, 1599–1606. http://dx.doi.org/10.1016/
j.ophtha.2007.03.042.
Rao, H.L., Senthil, S., Choudhari, N.S., Mandal, A.K., Garudadri, C.S., 2013. Behavior of
visual field index in advanced glaucoma. Invest. Ophthalmol. Vis. Sci. 54, 307–312.
http://dx.doi.org/10.1167/iovs.12-10836.
Rebolleda, G., Muñoz-Negrete, F.J., Noval, S., 2007. Evaluation of changes in peripapillary
nerve fiber layer thickness after deep sclerectomy with optical coherence tomography.
Ophthalmology 114, 488–493. http://dx.doi.org/10.1016/j.ophtha.2006.06.051.
Redmond, T., O’Leary, N., Hutchison, D.M., Nicolela, M.T., Artes, P.H., Chauhan, B.C.,
2013. Visual field progression with frequency-doubling matrix perimetry and standard au-
tomated perimetry in patients with glaucoma and in healthy controls. JAMA Ophthalmol.
131, 1565–1572. http://dx.doi.org/10.1001/jamaophthalmol.2013.4382.
Russell, R.A., Crabb, D.P., Malik, R., Garway-Heath, D.F., 2012a. The relationship between
variability and sensitivity in large-scale longitudinal visual field data. Invest. Ophthalmol.
Vis. Sci. 53, 5985–5990. http://dx.doi.org/10.1167/iovs.12-10428.
Russell, R.A., Malik, R., Chauhan, B.C., Crabb, D.P., Garway-Heath, D.F., 2012b. Improved
estimates of visual field progression using bayesian linear regression to integrate struc-
tural information in patients with ocular hypertension. Invest. Ophthalmol. Vis. Sci.
53, 2760–2769. http://dx.doi.org/10.1167/iovs.11-7976.
Sample, P.A., Martinez, G.A., Weinreb, R.N., 1994. Short-wavelength automated perimetry
without lens density testing. Am J. Ophthalmol. 118, 632–641.
See, J.L.S., Nicolela, M.T., Chauhan, B.C., 2009. Rates of neuroretinal rim and peripapillary
atrophy area change: a comparative study of glaucoma patients and normal controls.
Ophthalmology 116, 840–847. http://dx.doi.org/10.1016/j.ophtha.2008.12.005.
 References 157

Seibold, L.K., Mandava, N., Kahook, M.Y., 2010. Comparison of retinal nerve fiber
layer thickness in normal eyes using time-domain and spectral-domain optical coherence
tomography. Am J. Ophthalmol. 150, 807–814. http://dx.doi.org/10.1016/j.ajo.2010.06.024.
Strouthidis, N.G., Garway-Heath, D.F., 2008. New developments in Heidelberg retina tomo-
graph for glaucoma. Curr. Opin. Ophthalmol. 19, 141–148. http://dx.doi.org/10.1097/
ICU.0b013e3282f4450b.
Strouthidis, N.G., White, E.T., Owen, V.M.F., Ho, T.A., Hammond, C.J., Garway-Heath, D.F.,
2005. Factors affecting the test-retest variability of Heidelberg retina tomograph and
Heidelberg retina tomograph II measurements. Br. J. Ophthalmol. 89, 1427–1432.
http://dx.doi.org/10.1136/bjo.2005.067298.
Strouthidis, N.G., Scott, A., Peter, N.M., Garway-Heath, D.F., 2006. Optic disc and visual
field progression in ocular hypertensive subjects: detection rates, specificity, and
agreement. Invest. Ophthalmol. Vis. Sci. 47, 2904–2910. http://dx.doi.org/10.1167/
iovs.05-1584.
Strouthidis, N.G., Fortune, B., Yang, H., Sigal, I.A., Burgoyne, C.F., 2011. Longitudinal
change detected by spectral domain optical coherence tomography in the optic nerve head
and peripapillary retina in experimental glaucoma. Invest. Ophthalmol. Vis. Sci.
52, 1206–1219. http://dx.doi.org/10.1167/iovs.10-5599.
Sung, K.R., Sun, J.H., Na, J.H., Lee, J.Y., Lee, Y., 2012. Progression detection capability of
macular thickness in advanced glaucomatous eyes. Ophthalmology 119, 308–313. http://
dx.doi.org/10.1016/j.ophtha.2011.08.022.
Tan, J.C.H., Hitchings, R.A., 2004. Reversal of disc cupping after intraocular pressure
reduction in topographic image series. J. Glaucoma 13, 351–355. http://dx.doi.org/
10.1097/01.ijg.0000133151.82804.e3.
Tan, J.C.H., Garway-Heath, D.F., Hitchings, R.A., 2003. Variability across the optic nerve
head in scanning laser tomography. Br. J. Ophthalmol. 87, 557–559. http://dx.doi.org/
10.1136/bjo.87.5.557.
Van der Schoot, J., Reus, N.J., Colen, T.P., Lemij, H.G., 2010. The ability of short-wavelength
automated perimetry to predict conversion to glaucoma. Ophthalmology 117, 30–34.
http://dx.doi.org/10.1016/j.ophtha.2009.06.046.
Vesti, E., Johnson, C.A., Chauhan, B.C., 2003. Comparison of different methods for detecting
glaucomatous visual field progression. Invest. Ophthalmol. Vis. Sci. 44, 3873–3879.
http://dx.doi.org/10.1167/iovs.02-1171.
Wall, M., Woodward, K.R., Doyle, C.K., Artes, P.H., 2009. Repeatability of automated peri-
metry: a comparison between standard automated perimetry with stimulus size III and V,
matrix, and motion perimetry. Invest. Ophthalmol. Vis. Sci. 50, 974–979. http://dx.doi.
org/10.1167/iovs.08-1789.
Wessel, J.M., Horn, F.K., Tornow, R.P., Schmid, M., Mardin, C.Y., Kruse, F.E.,
Juenemann, A.G., Laemmer, R., 2013. Longitudinal analysis of progression in glaucoma
using spectral-domain optical coherence tomography. Invest. Ophthalmol. Vis. Sci.
54, 3613–3620. http://dx.doi.org/10.1167/iovs.12-9786.
Wesselink, C., Heeg, G.P., Jansonius, N.M., 2009. Glaucoma monitoring in a clinical setting:
glaucoma progression analysis vs nonparametric progression analysis in the Groningen
Longitudinal Glaucoma Study. Arch. Ophthalmol. 127, 270–274. http://dx.doi.org/
10.1001/archophthalmol.2008.585.
158 CHAPTER 7 How to detect progression in glaucoma

Xu, G., Weinreb, R.N., Leung, C.K.S., 2014. Optic nerve head deformation in glaucoma: the tem-
poral relationship between optic nerve head surface depression and retinal nerve fiber layer
thinning. Ophthalmology 121, 1–9. http://dx.doi.org/10.1016/j.ophtha.2014.06.035.
Zangwill, L.M., Jain, S., Dirkes, K., He, F., Medeiros, F.A., Trick, G.L., Brandt, J.D.,
Cioffi, G.A., Coleman, A.L., Liebmann, J.M., Piltz-Seymour, J.R., Gordon, M.O.,
Kass, M.A., Weinreb, R.N., 2013. The rate of structural change: the confocal scanning
laser ophthalmoscopy ancillary study to the ocular hypertension treatment study. Am J.
Ophthalmol. 155, 971–982. http://dx.doi.org/10.1016/j.ajo.2013.01.020.
Zhu, H., Russell, R.A., Saunders, L.J., Ceccon, S., Garway-Heath, D.F., Crabb, D.P., 2014.
Detecting changes in retinal function: analysis with non-stationary Weibull error regres-
sion and spatial enhancement (ANSWERS). PLoS One 9, 1–11. http://dx.doi.org/10.1371/
journal.pone.0085654.