Current Eye Research

ISSN: 0271-3683 (Print) 1460-2202 (Online) Journal homepage: http://www.tandfonline.com/loi/icey20

Progression of Retinal Nerve Fiber Layer Thinning

in Glaucoma Assessed by Cirrus Optical Coherence
Tomography-guided Progression Analysis

Jung Hwa Na, Kyung Rim Sung, Seunghee Baek, Jin Young Lee & Soa Kim

To cite this article: Jung Hwa Na, Kyung Rim Sung, Seunghee Baek, Jin Young Lee & Soa Kim
(2013) Progression of Retinal Nerve Fiber Layer Thinning in Glaucoma Assessed by Cirrus Optical
Coherence Tomography-guided Progression Analysis, Current Eye Research, 38:3, 386-395, DOI:
10.3109/02713683.2012.742913

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Current Eye Research, 2013; 38(3): 386–395
! Informa Healthcare USA, Inc.
ISSN: 0271-3683 print / 1460-2202 online
DOI: 10.3109/02713683.2012.742913

ORIGINAL ARTICLE

Progression of Retinal Nerve Fiber Layer Thinning in

Glaucoma Assessed by Cirrus Optical Coherence
Tomography-guided Progression Analysis
Jung Hwa Na1,2, Kyung Rim Sung1, Seunghee Baek3, Jin Young Lee1, and Soa Kim1

1
Department of Ophthalmology, College of Medicine, Asan Medical Center, University of Ulsan, Seoul, Korea,
2
Department of Ophthalmology, Kim’s Eye Hospital, Myung-Gok Eye Research Institute,
Konyang University, Seoul, Korea, and 3Department of Clinical Epidemiology and Biostatics,
College of Medicine, Asan Medical Center, University of Ulsan, Seoul, Korea

ABSTRACT
Purpose: To evaluate the performance of Cirrus spectral domain optical coherence tomography (SD-OCT)-
guided progression analysis (GPA) software to detect progression of retinal nerve fiber layer (RNFL) thinning in
glaucoma patients.
Materials and methods: This retrospective cohort study included 272 eyes of 154 glaucoma patients. Median
follow-up time was 2.2 years, during which time data from at least four good-quality OCT examinations were
collected. Glaucomatous eyes were classified as either early or advanced group according to visual field (VF)
severity. Reference standard of glaucoma progression was defined by expert assessment of optic disc/RNFL
photographs or VF GPA data, or visual field index (VFI) linear regression analysis. Sensitivity and specificity of
OCT GPA, and agreement between OCT GPA findings and each reference standard strategy were estimated.
Results: Fifty-three eyes (19.5%) showed progression by at least one of the reference standard strategies, while
OCT GPA detected progression in 36 eyes (13.2%). When expert assessment of optic disc/RNFL photographs
and/or VF analysis was used as the reference standard, the sensitivity and specificity of OCT GPA employed to
detect glaucoma progression were 20.8% and 88.6%. Agreement between OCT GPA and either optic disc/RNFL
photographic evaluation or VF analysis was poor ( ¼ 0.12 and 0.03, respectively). RNFL photographic
assessment in early stage glaucoma showed best agreement with OCT GPA in terms of progression detection.
Discussion: The Cirrus OCT GPA detected a considerable number of eyes exhibiting glaucoma progression. OCT
GPA may be useful for progression detection in earlier stage of glaucoma to complement other reference
standard strategies.
Keywords: Glaucoma, progression, OCT
13
20

INTRODUCTION Several major clinical trials evaluating methods

Glaucoma is defined by the presence of characteristic
structural changes in the optic disc and retinal nerve
fiber layer (RNFL), with accompanying functional
visual field (VF) decay. Monitoring of disease pro-
gression is crucial for careful management of glau-
coma patients. However, no gold standard identifying
glaucomatous progression either structurally or func-
tionally has yet been developed.
used to detect glaucoma progression focused on VF
testing.1–4 To assess functional progression, the
Guided Progression Analysis (GPA) mode of the
Humphrey Field Analyzer (HFA) has frequently
been employed in both clinical practice and research,
including the Early Manifest Glaucoma Trial
(EMGT).5 Although several other strategies for the
determination of VF progression have been suggested,
the use of machine-integrated GPA software should

Received 25 July 2012; revised 20 September 2012; accepted 15 October 2012

Correspondence: Kyung Rim Sung, MD, PhD, Department of Ophthalmology, College of Medicine, Asan Medical Center, University of Ulsan,
388-1 Pungnap-2-dong, Songpa-gu, Seoul 138-736, Korea. Tel: þ82-2-3010-3680. Fax: þ82-2-470-6440. E-mail: sungeye@gmail.com

386

facilitate objective and efficient detection of glaucoma
progression.
Complete assessment of glaucoma progression
requires both structural and functional evaluation. In
several major clinical trials, including the Ocular
Hypertension Treatment Study and the EMGT, struc-
tural progression assessment based on changes in the
optic disc as assessed by photography was
employed.1,6–9 Although such subjective evaluation
of the disc and the RNFL status is currently the
reference standard for the assessment of glaucomat-
ous structural change, these approaches are qualita-
tive rather than quantitative, and even expert
opinions vary.10,11 Therefore, it would be more effi-
cient for structural progression detection if standar-
dized machine-integrated software can provide the
analysis of RNFL status serially like VF.
The purpose of the present study was to evaluate
the performance of measured changes in RNFL
thickness, as determined using the Cirrus spectral
domain optical coherence tomography (OCT) (Carl
Zeiss Meditec Inc., Dublin, CA) machine-integrated
software termed GPA, to detect glaucoma progres-
sion. Specifically, we compared the glaucoma pro-
gression detection capability of the Cirrus OCT GPA
with that afforded by either expert assessment of optic
disc and RNFL photographs, or VF assessment.
METHODS
Subjects
In this retrospective cohort study, glaucoma patients
evaluated between September 2008 and November
2011 at the glaucoma clinic of the Asan Medical
Center, Seoul, Korea, and who met our inclusion
criteria, were consecutively included via medical
record review.
At initial testing, each participant received a com-
prehensive ophthalmologic examination including a
review of medical history; measurement of best-
corrected visual acuity (BCVA); slit-lamp biomicro-
scopy; Goldmann applanation tonometry (GAT);
gonioscopy; dilated fundoscopic examination using
a 90- or 78-diopter (D) lens; stereoscopic optic disc
photography; RNFL photography; a VF test (using the
HFA running the Swedish Interactive Threshold
Algorithm [SITA] standard 24-2; Carl Zeiss Meditec)
and SD OCT (Cirrus HD-OCT; Carl Zeiss Meditec). VF
test were repeated within 2 weeks interval from initial
examination. First, VF was excluded to obviate the
learning effect.
For inclusion, all participants had to meet the
following criteria: a BCVA of 20/40 or better, with a
spherical refractive error between 6.0 and þ3.0
diopters (D) and a cylinder correction within þ3 D,
and the presence of a normal anterior chamber and
! 2013 Informa Healthcare USA, Inc.
Glaucoma Progression Detection by OCT GPA 387
open-angle on slit-lamp and gonioscopic examin-
ations. Our present study included patients with
glaucomatous optic nerve heads; these patients pre-
sented with enlarged cupping, diffuse or focal neural
rim thinning, disc hemorrhage or RNFL defects that
were confirmed and agreed upon by two glaucoma
specialists (KRS and JHN), regardless of the presence
of any VF abnormality.
Patients with any other ophthalmic or neurologic
condition that could result in a disc change, or with a
history of diabetes mellitus, were excluded. If surgical
or laser treatment was performed during follow-up,
only the data obtained in the period before such
treatment were analyzed. All subjects were followed
up at 6-month intervals via VF testing, stereoscopic
optic disc photography, RNFL photography and
Cirrus SD OCT scanning; all tests were performed at
the same visit or within 2 weeks interval. All subjects
were followed-up for at least 24 months.
Institutional Review Board approval was obtained
from the Asan Medical Center and our study design
followed the principles of the Declaration of Helsinki.
Optic Disc and RNFL Assessment
Progression of optic disc and RNFL defects was
determined by evaluation of stereoscopic optic disc
and red-free RNFL photographs. Serial stereoscopic
photographs were displayed on an LCD monitor. Two
glaucoma experts (KRS and JHN) independently
assessed all photographs to estimate glaucoma pro-
gression between the first and last visits. The most
recent photography was compared to the baseline one
in each patient. Either grader was masked to the
progression assessments rendered by the other and to
all clinical, OCT and VF information. Photographs
were presented in chronological order, with masking
of patient identification, age, and test date. Each
grader viewed all photographs of each eye before
making an assessment, and each was asked to
determine glaucomatous optic disc or RNFL progres-
sion, as revealed by an increase in the extent of
neuroretinal rim thinning, enhancement of disc exca-
vation, and/or any widening or deepening of an
RNFL defect. Each grader classified each glaucomat-
ous eye as either stable or progressing. If the opinions
of the two observers differed, a third examiner (JYL)
made a final decision.
SD OCT Assessment
SD OCT images were obtained using the Cirrus HD-
OCT system. The image acquisition procedure has
been described in detail elsewhere.12–14 Our Cirrus
HD-OCT platform is calibrated on a regular basis by
a technician employed by the manufacturer.
388 J. H. Na et al.
FIGURE 1. Cirrus Optical coherence tomography GPA printouts. Changes in the RNFL thickness map during follow-up (A), RNFL
thickness values in overall, superior, and inferior (B), and RNFL thickness profiles (C).
RNFL thickness measurements were obtained using
the optic disc cube mode. Optic disc cube data are
obtained from a three-dimensional dataset composed
of 200 A-scans derived in turn from 200 B-scans that
cover a 6  6 mm area centered on the optic disc. After
the creation of an RNFL thickness map from the cube
dataset, the inbuilt software automatically determines
the center of the disc and next extracts a circumpa-
pillary circle (1.73 mm in radius) from the dataset,
prior to calculation of RNFL thickness measurements.
Pupil dilatation was performed in all subjects. All
accepted images exhibited a centered optic disc; were
well-focused, with even and adequate illumination;
exhibited no eye motion within the measurement
circle; exhibited no segmentation error; and had a
signal strength (SS) 7.
The RNFL thicknesses of the four quadrants (tem-
poral, superior, nasal and inferior), those of the 12
clock-hours, and average RNFL thickness, were
employed as RNFL thickness parameters. For inclu-
sion in the analysis, at least four acceptable OCT
images, taken at separate visits, were required.
The Cirrus OCT GPA software analyzes data
yielded upon the use of the optic disc cube
200  200 mode. Three RNFL parameters are
employed to detect progression of reduction in
RNFL thickness; these are the RNFL thickness map,
the RNFL thickness profile and average RNFL thick-
ness (Figure 1). Using any such parameter,
progression is identified if the observed change from
baseline to a test value exceeds the test–retest vari-
ability of the system. For example, if data from only
three examinations were available (a baseline and two
follow-up tests), a ‘‘Possible Loss’’ was identified
when the differences between baseline and both the
first and second follow-up values exceeded the test–
retest variability. If the results of four examinations
were available (thus those of two baseline and two
follow-up tests), three of four such comparisons had
to meet our criterion. If the ‘‘Possible Loss’’ criterion
was met on two successive visits, that patient was
considered to show ‘‘Likely Loss’’. Both the RNFL
thickness maps and RNFL thickness profiles carry
spatial criteria; at least 20 adjacent pixels in any pixel
cluster must be affected if loss is to be identified using
either modality, or at least 14 adjacent profile points
must be affected if the loss of any sort is to be
identified. If follow-up data revealed a significant
increased change, a ‘‘Possible Increase’’ was
identified.
We considered that ‘‘Likely Loss’’ and ‘‘Possible
Loss’’ reflected glaucomatous progression.
VF Assessment
Only reliable VF test results (false-positive errors
515%, false-negative errors 515% and fixation loss
Current Eye Research

520%) were included in the analysis. The first set of
VF test data was excluded to obviate any learning
effect. Glaucomatous VF defects were identified when
at least two of the following criteria were met: (1) a
cluster of three points with a probability of less than
5% on a pattern deviation map in at least one
hemifield, including at least one point with a prob-
ability of less than 1%, or a cluster of two points with a
probability of less than 1%; (2) glaucoma hemifield
test (GHT) results outside normal limits and/or (3) a
pattern standard deviation (PSD) less than 5%. VF
progression was determined using two methods:
event-based analysis (EA) and trend-based analysis
(TA). To conduct EA, commercial software (HFA GPA;
Carl Zeiss Meditec) was employed. VF EA progres-
sion was defined as a significant deterioration from
the baseline pattern deviation at three or more of the
same test points evaluated on three consecutive
examinations.5 The other VF progression criterion
employed linear TA regression using visual field
index (VFI) data. A significantly negative slope
(p50.05) indicated VF TA progression.
Analysis
Descriptive statistics presented as mean and standard
deviation (SD) for normally distributed variables and
as median, first quartile and third quartile values for
non-normally distributed variables. A generalized
estimating equation (GEE) approach was used to
compare characteristics.
Employing expert assessment of optic disc and
RNFL photographs and/or VF analysis as the refer-
ence standard, the sensitivity and specificity of
detection of glaucoma progression using Cirrus OCT
GPA software were assessed using a GEE approach
for adjusting correlation between two eyes within one
subject. The confidence intervals (CIs) were estimated
from the bootstrapping method (N ¼ 499). The extent
of agreement between Cirrus OCT GPA data and optic
disc/RNFL photographs or VF analysis in terms of
progression detection was measured using  statistics.
A  value 0.00–0.20 indicates slight agreement, a value
0.21–0.40 fair agreement, a value 0.41–0.60 moderate
agreement, a value 0.61–0.80 substantial agreement
and a value 0.81–1.00 almost perfect agreement.15
Standard error (SE) was described with the  value.
To explore the extent of agreement between the
reference standard and OCT GPA at different stages of
glaucoma, we divided subjects into two groups, an
early glaucomatous group (EG) and a moderate-to-
advanced glaucomatous group (AG), according to the
Hodapp–Anderson–Parrish (HAP) grading scale of
VF severity. This staging system has been described in
detail elsewhere.16,17 Briefly, the system assigns glau-
coma patients to different stages of disease progres-
sion using a combination of mean deviation (MD)
! 2013 Informa Healthcare USA, Inc.
Glaucoma Progression Detection by OCT GPA 389
score and one of the following: pattern deviation
probability plot score, dB plot and either corrected
pattern standard deviation/pattern standard devi-
ation (CPSD/PSD) or GHT data.16,17
All statistical analyses were performed using
R.2.13.1 and SPSS version 15.0 (SPSS Inc, Chicago, IL).
RESULTS
A total of 272 eyes from 154 subjects were included;
the median duration of follow-up was 2.2 (range,
2.0–3.2) years. Of these 154 subjects, 75 (48.7%) were
female. Interval period of each visit was median 0.62
(range, 0.60, 0.68) years. Total number of OCT tests
was 1185, optic disc stereophotographs and red-free
RNFL photographs was 1180, VF tests was 1178,
average number of OCT test per eye was 4.3  0.5
(range, 4–6), photographs per eye was 4.3  0.5 (range,
4–6) and VF tests per eye was 4.3  0.8 (range, 4–6).
Table 1 showed the demographic and baseline char-
acteristics of all participants and subgroups according
to glaucoma severity. Corneal thickness showed
significant difference between two groups.
Progression estimated by reference
standards
Overall, 53 eyes (19.5%) of 46 subjects showed
progression upon expert assessment of stereoscopic
optic disc and RNFL photographs, VF GPA and/or
VFI regression analysis. Among these 53 progressing
eyes, 15 (28%) showed progression based only on
optic disc and/or RNFL changes, 25 (47%) based only
on VF changes and 13 (25%) based on both changes.
Of the 28 eyes (24 subjects) in which progression was
detected by stereoscopic optic disc/RNFL photog-
raphy, 21 eyes showed widening or deepening of an
RNFL defect and the remaining 7 eyes showed
neuroretinal rim thinning upon evaluation of photo-
graphs. Of the 38 eyes in which progression was
detected by VF analysis, 34 eyes of 30 patients
progressed by VF GPA and 4 eyes (4 patients) by
VFI trend analysis (Figure 2).
Progression Estimated by OCT GPA
Cirrus OCT GPA detected progression in 36 eyes
(13.2%) of 34 subjects. Twenty-tree eyes progressed by
RNFL thickness mapping, 9 eyes by RNFL thickness
profiles and 16 by average RNFL thickness assess-
ment. Five eyes were detected by all three strategies.
Thus, of the three strategies tested, RNFL thickness
mapping most frequently detected progression. In the
mean time, 18 eyes showed ‘‘possible increase’’ in
OCT GPA.
390 J. H. Na et al.

TABLE 1. Baseline characteristics of subjects (means  standard deviations).

Total EG AG

N (Eyes) 272 220 52

Progressor (%) 53 (19.5%) 28 (12.7%) 25 (48.1%)
Age (years) 56.8  12.5 57.3  11.6 54.7  15.9
SE (diopters) 0.8  1.9 0.6  1.9 1.5  2.0
Initial IOP (mmHg) 16.9  4.1 16.8  3.8 17.0  4.5
CCT (mm) (progressors/ 540.7  35.2 541.9  34.1 536.1  39.4
non-progressors) (520.7  36.4/545.7  33.3)* (524.3  29.6/544.4  34.1)* (517.2  42.7/554.1  26.2)*
Follw-up IOP (progressors/ 14.2  2.4 14.2  2.4 14.1  2.4
non-progressors) (13.8  2.0/14.3  2.5) (13.9  1.9/14.2  2.5) (13.7  2.2/14.5  2.5)
VFI median (%) (first/last quartiles) 99 (96, 100) 99 (98, 100) 72 (55, 82)
MD median (dB) (first/last quartiles) 1.20 (3.91, 0.07) 0.73 (0.73, 0.12) 10.94 (14.12, 8.47)
PSD median (dB) (first/last quartiles) 1.82 (1.45, 4.62) 1.50 (1.37, 1.63) 11.72 (8.40, 13.29)
Average RNFL thickness (mm) 81.4  13.8 85.2  11.2 65.7  12.6
at baseline (progressors/ (75.9  14.3/82.5  12.9)* (83.9  12.0/85.6  11.1) (63.6  9.7/66.2  13.6)
non-progressors)
Average RNFL thickness (mm) at last 79.6  13.6 82.9  11.1 63.5  12.9
follow up (progressors/ (74.0  14.1/81.2  13.0)* (80.6  11.3/83.5  11.0) (63.4  11.6/63.6  14.3)
non-progressors)

AG ¼ moderate to advanced glaucomatous eyes; CCT ¼central corneal thickness; EG ¼ early glaucomatous eyes; IOP ¼ intraocular
pressure; MD ¼ mean deviation; N ¼ numbers; Progressor ¼ progressed eye detected by reference standard method; PSD ¼ pattern
standard deviation; RNFL ¼ retinal nerve fiber layer; SE ¼ spherical equivalent.
*Statistically significant difference (p50.05) between progressors and nonprogressors

Of the 38 eyes in which progression was detected

FIGURE 2. A Venn diagram showing progression detection by
each four reference standard method, VFI linear regression, VF
GPA, optic disc (Disc) and RNFL.
Agreement Between Reference Standards
and OCT GPA
When expert assessment of stereoscopic optic disc
and RNFL photographs was employed as the refer-
ence standard, the overall sensitivity and specificity of
Cirrus OCT GPA in terms of progression detection
were 25.0% (95% CI, 10.1–44.9%) and 88.1% (95% CI,
50.0–92.0%), respectively.  between OCT GPA and
expert assessment of photographs was 0.12 (SE 0.07,
p ¼ 0.08) (Figure 3A, Table 2).  values between OCT
GPA three strategies and assessment of photographs
were 0.11 (SE 0.079, p ¼ 0.06), 0.12 (SE 0.08, p ¼ 0.02)
and 0.07 (SE 0.07, p ¼ 0.25) in RNFL map, profile and
average RNFL thickness, respectively (Figure 4).
Among 21 eyes that showed widening or deepening
of an RNFL defect, 6 eyes were also detected as
progressors by Cirrus OCT GPA. Among 7 eyes that
showed rim changes, only one eye was also detected
as progressor by OCT GPA.
by VF analysis, 6 exhibited progression by Cirrus OCT
GPA. When VF analyses were employed as the
reference standard, the overall sensitivity and speci-
ficity of Cirrus OCT GPA in terms of progression
detection were 15.8% (95% CI, 4.8–29.6%) and 87.2%
(95% CI, 50.0–91.1%), respectively. Agreement in
terms of progression detection between the Cirrus
OCT GPA data and VF analysis was not good, with a 
value of 0.03 (SE 0.06, p ¼ 0.62) (Figure 3B, Table 2).
In subgroup analysis, agreement between each
reference strategy and OCT GPA was not good in
both EG and AG. Among them, agreement between
RNFL photographic assessment and OCT GPA in EG
was best ( ¼ 0.12 (SE 0.07, p ¼ 0.08), Table 2). Eyes that
were detected as progressing only by reference
standards showed worse disease status at baseline
compared to eyes progressing only by the OCT GPA
(Table 3).
DISCUSSION
In the time since Stratus time-domain OCT (Carl Zeiss
Meditec Inc) data were incorporated into glaucoma
assessment, many cross-sectional studies have con-
firmed that this approach can discriminate between
glaucomatous and healthy eyes.18–26 As glaucoma is a
progressive disease, it is more important that the
valuable diagnostic capability of OCT should be
further utilized as a longitudinal method of detecting
progression. Several approaches toward progression
detection, using RNFL data obtained by OCT, have
been developed. Some studies27,28 found that the
ability of OCT to detect progression was optimal
Current Eye Research
 Glaucoma Progression Detection by OCT GPA 391

FIGURE 3. (A) Venn diagrams showing detection of glaucoma progression by employing the Cirrus Optical coherence tomography
GPA and by stereoscopic disc and RNFL photography (Photo) in early glaucoma group (EG) and moderate to advanced glaucoma
group (AG). (B) Venn diagrams showing detection of glaucoma progression by employing the Cirrus OCT GPA and by VF analysis in
EG and AG.

TABLE 2. The agreement between the reference standards and Cirrus OCT GPA. ( [SE]).
Photographs assessment
Disc or RNFL Disc RNFL VF analysis

Total subject (n ¼ 272) 0.12 (0.08) 0.00 (0.04) 0.13 (0.08) 0.03 (0.06)
Subgroup analysis
EG (n ¼ 220) 0.17 (0.09) 0.03 (0.02) 0.21 (0.09) 0.10 (0.08)
AG (n ¼ 52) 0.04 (0.12) 0.16 (0.19) 0.15 (0.04) 0.06 (0.09)

AG ¼ advanced glaucomatous eyes; EA ¼ event-based analysis; EG ¼ early glaucomatous eyes;

RNFL ¼ retinal nerve fiber layer; SE ¼ standard error; VF ¼ visual field

FIGURE 4. Venn diagrams showing detection of glaucoma progression by stereoscopic disc and RNFL photography (Photo) and by
employing the three strategies of Cirrus Optical coherence tomography GPA (OCT GPA); RNFL thickness map (Map) (A), average
RNFL thickness (AVG) (B) and RNFL thickness profiles (Profile) (C).

when an event-based approach was employed,
whereas other reports12,29–31 detected progression
using trend-based analysis. Medeiros et al.31 reported
that RNFL thickness parameter evaluation could
reliably detect progression as determined by both
standard automated perimetry (SAP) and optic disc
stereophotography. The various approaches that have
! 2013 Informa Healthcare USA, Inc.
been developed have both advantages and disadvan-
tages in terms of progression detection capability.
Thus, it is important to formulate standardized
criteria that define progression.
Theoretically, the use of Cirrus SD OCT GPA might
afford several predictive advantages. SD technology
affords a much higher scan speed than that of
392 J. H. Na et al.

TABLE 3. Comparison of baseline characteristics between eyes detected only by Cirrus OCT GPA and those detected only by
stereoscopic optic disc and RNFL photographs and/or VF analysis (means  standard deviations).

Progression
both by Progression
OCT GPA Progression only by
and reference only by reference
standards OCT GPA standards p Value*

N (Eyes) 11 25 42
Follw-up (year) 2.1  0.3 2.2  0.4 2.1  0.3 0.290
N of OCT tests per eye 4.3  0.5 4.4  0.6 4.4  0.5 0.984
Mean signal strength of OCT tests per eye 7.5  0.7 7.6  0.9 7.5  0.5 0.712
Age (years) 62.8  9.9 56.2  14.6 57.8  12.4 0.656
Spherical equivalent (diopters) 0.4  2.2 0.9  0.2 0.9  0.1 0.711
Initial IOP (mmHg) 16.6  2.8 17.8  6.6 16.9  4.2 0.530
Central corneal thickness (mm) 526.7  30.6 546.0  30.7 519.3  38.0 0.023
Mean follow up IOP (mmHg) 14.4  3.0 14.8  3.1 13.9  2.2 0.274
VFI (%) 95.7  5.6 94.8  8.9 78.6  20.4 50.001
MD (dB) 3.6  3.6 2.0  3.9 7.7  6.34 50.001
PSD (dB) 3.2  2.7 2.7  2.0 7.9  4.6 50.001
Average RNFL thickness (mm) 78.2  10.1 88.1  12.9 72.6  13.7 50.001

IOP ¼ intraocular pressure; MD ¼ mean deviation; N ¼ numbers; OCT GPA ¼ optical coherence tomography guided progression
analysis; PSD ¼ pattern standard deviation; RNFL ¼ retinal nerve fiber layer.
*Comparison between progression only by OCT GPA and progression only by reference standard

time-domain Stratus OCT; Cirrus SD OCT collects
three-dimensional data from an area around the optic
disc, and en-face images are next derived from such
datasets. Through registration of serial images by
comparing blood vessel configuration among the en-
face images, the test–retest variability caused by the
use of differing scan circle locations at each visit
during which Stratus OCT is employed can be
decreased.
To the best of our knowledge, our present work is
the first study to evaluate the glaucoma progression
detection capability of the Cirrus OCT GPA software.
We found that the Cirrus OCT GPA detected a
considerable number of progressing glaucomatous
eyes using three strategies: peripapillary RNFL thick-
ness mapping, RNFL thickness profiling and assess-
ment of average RNFL thickness. Of the three
approaches, RNFL thickness mapping most fre-
quently detected progression. Conventionally, OCT
RNFL thickness is determined by processing of data
from a 360 peripapillary scan of diameter 3.4 mm.
Thus, in both RNFL thickness profiles and average
RNFL thickness measurements, minor RNFL change
that is not apparent on that scan circle may be missed.
However, a deviation map displays abnormal RNFL
changes, expressed in pixel units, over a three-
dimensional 6  6 mm-sized peripapillary RNFL
area. Hence, RNFL thickness mapping may provide
more information on peripapillary structure. Recently,
it has been reported that abnormal findings upon
RNFL thickness mapping were more useful in terms
of glaucoma detection than were RNFL thickness
values per se.32,33 In the mean time, the Cirrus OCT
GPA rather frequently detected ‘‘Possible Increases’’
(in 18 eyes). Generally, no significant increase in RNFL
thickness is noted over time in either healthy or
glaucomatous eyes. The reasons for such increases in
thickness are not known; variability in instrumenta-
tion is presumed to be responsible. Measurement
variability is one of the obstacles which prevent
progression detection capability in OCT. Different
scan circle placement at each follow-up test has been
known as the source of measurement variability in
time-domain Stratus OCT. However, Cirrus OCT GPA
employed image registration technique using en-face
image to resolve this issue. Thus, our result of
increased RNFL thickness which may be induced by
measurement variability suggested that either image
registration technique were insufficient to resolve this
issue or other sources of measurement variability still
existed. For example, SS is known to be important in
this regard. In previous publications, SS of OCT
images was reported to affect RNFL thickness meas-
urement.34–37 The current version of Cirrus OCT GPA
does not consider SS differences upon longitudinal
analysis, and thus SS variation among images may
contribute to the variability of measurements, result-
ing in reported artifactual increases in RNFL thickness
during follow-up.
When expert assessment of stereoscopic optic disc
and RNFL photographs was chosen as the reference
standard, the sensitivity of Cirrus OCT GPA was not
high, and agreement between Cirrus OCT GPA and
expert assessment was not good ( ¼ 0.12). When
compared between optic disc and RNFL photographs,
the agreement with Cirrus OCT GPA was better in
RNFL photograph ( ¼ 0.13 versus 0.00, Table 2). That
result might be explained by the fact that Cirrus OCT
GPA assesses only peripapillary RNFL changes and
does not detect optic disc change in the current version.
Current Eye Research

In the mean time, 29 eyes that showed progression
only by Cirrus OCT GPA did not do so when
stereoscopic optic disc and RNFL photographs were
examined. Fundus photographic assessment in terms
of progression detection depends on the quality of
photographs. Furthermore, in the case of diffuse RNFL
atrophy or lightly pigmented fundus which obscures
RNFL visibility, photographic assessment can be dif-
ficult or inaccurate. Additionally, the result of photo-
graphic assessment is prone to be subjective because
even experts showed different opinions in this regard
in previous publication.10,11 Therefore, OCT GPA may
have advantage over photographic assessment in those
cases. However, detection only by OCT GPA not by
photo may suggest false positive of OCT GPA, thus
further longitudinal follow up of these eyes is war-
ranted for confirmation of true progression.
As reported in previous studies, agreement in
terms of progression detection between VF data and
OCT results was also poor in our current
analysis. 27,29,38–42 The discordance in progression
between structure and function might be related to the
fundamental differences in instrument variability.
And it is also speculated that structural change and
functional decay may not happen at the same time.
The appearance of RNFL defects has been reported to
precede the development of apparent VF abnormal-
ities in glaucomatous eyes,43,44 and the progression
rates of structural and functional changes might thus
be different.39,41 Additionally, different scales between
VF MD (decibel, log scale) and OCT RNFL thick-
ness(micron, linear scale) may contribute to
disagreement.
In subgroup analysis, EG showed better agreement
between the RNFL photographic assessment and OCT
GPA than AG did (Table 2). Additionally, eyes that
progressed only by reference standards had more
advanced glaucoma at baseline than those progressed
only by the OCT GPA (Table 3). Thus, OCT GPA
which assesses change of circumpapillary RNFL
thickness can be useful for detection of progression
of earlier stage of glaucoma than for advanced
glaucoma. This could represent a floor effect for
detection of RNFL loss with OCT, or it could reflect
the natural history of progression in glaucoma, with
greater detectable rates of RNFL loss in the earlier
stages of disease.41
Progressor showed thinner CCT compared with
that of nonprogressor in our result. This observation
coincided with that of previous publication. Different
biomechanical properties of cornea may affect glau-
comatous progression. Or, although the IOP which
was measured by applanation tonometer in this study
did not show difference statistically between progres-
sor and nonprogressor, actual IOP might be different
between progressor and nonprogrssors.45
The present study had several limitations including
a short follow-up period. Additionally, we used disc
! 2013 Informa Healthcare USA, Inc.
Glaucoma Progression Detection by OCT GPA 393
and RNFL photography, or VF analysis, as reference
standards; although these tests are currently reference
standards for glaucoma diagnostic modality, none of
them are perfect in terms of detection of progression.
Supposed ‘‘progression’’ detected only by Cirrus OCT
GPA, thus not by using the two tests described above,
remains controversial and requires longer follow-up
to determine whether Cirrus OCT GPA can identify
early disease progression before the occurrence of
progressive change in optic disc and RNFL photog-
raphy and VF.
In conclusion, the Cirrus OCT GPA software
detected glaucomatous progression in a significant
number of eyes. Generally, agreement between Cirrus
OCT GPA data on the one hand, and expert assess-
ment of optic disc and RNFL photographs or the
results of VF examinations, on the other, was not
good. Among several reference standard strategies,
RNFL photographic assessment in early stage
glaucoma showed better agreement with Cirrus
OCT GPA. Glaucomatous progression may not be
reliably detected using a single method; all three
established approaches should be used, in a
complementary manner, in clinical practice.
Therefore, Cirrus OCT GPA may serve as a useful
tool for detection of progression, but it cannot replace
stereoscopic optic disc and RNFL photograph assess-
ment; the techniques are best regarded as
complementary.
Declaration of Interest: The authors report no con-
flicts of interest. The authors alone are responsible for
the content and writing of the paper.
This study was supported by a grant of the Basic
Science Research Program through the National
Research Foundation of Korea (NRF) funded by the
Ministry of Education, Science and Technology
(MEST) (NRF-2011-0013802).
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