This study compared spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) for grading geographic atrophy (GA) in age-related macular degeneration. Two graders manually measured GA lesion size using SD-OCT and FAF in 81 eyes. SD-OCT measurements of choroidal signal enhancement and loss of outer retinal layers correlated closely with areas of decreased FAF. SD-OCT also more accurately identified foveal involvement than FAF. The study demonstrates SD-OCT can reliably quantify GA lesion size and progression in a reproducible manner.

1. A Systematic Comparison of
Spectral-Domain Optical Coherence
Tomography and Fundus Autofluorescence
in Patients with Geographic Atrophy
Ramzi G. Sayegh, MD,1 Christian Simader, MD,1 Ulrike Scheschy, MD,1 Alessio Montuoro, Dipl.Ing,1
Christopher Kiss, MD,1 Stefan Sacu, MD,1 David P. Kreil, PhD,2 Christian Prünte, MD,1
Ursula Schmidt-Erfurth, MD1
Purpose: To evaluate spectral-domain optical coherence tomography (SD-OCT) in providing reliable and
reproducible parameters for grading geographic atrophy (GA) compared with fundus autofluorescence (FAF)
images acquired by confocal scanning laser ophthalmoscopy (cSLO).
Design: Prospective observational study.
Participants: A total of 81 eyes of 42 patients with GA.
Methods: Patients with atrophic age-related macular degeneration (AMD) were enrolled on the basis of total
GA lesion size ranging from 0.5 to 7 disc areas and best-corrected visual acuity of at least 20/200. A novel
combined cSLO-SD-OCT system (Spectralis HRA-OCT, Heidelberg Engineering, Heidelberg, Germany) was
used to grade foveal involvement and to manually measure disease extent at the level of the outer neurosensory
layers and retinal pigment epithelium (RPE) at the site of GA lesions. Two readers of the Vienna Reading Center
graded all obtained volume stacks (2020 degrees), and the results were correlated to FAF.
Main Outcome Measures: Choroidal signal enhancements and alterations of the RPE, external limiting
membrane (ELM), and outer plexiform layer by SD-OCT. These parameters were compared with the lesion
measured with severely decreased FAF.
Results: Foveal involvement or sparing was definitely identified in 75 of 81 eyes based on SD-OCT by both
graders (inter-grader agreement: 0.6, P 0.01). In FAF, inter-grader agreement regarding foveal involvement
was lower (48/81 eyes, inter-grader agreement: 0.3, P 0.01). Severely decreased FAF was measured over
a mean area of 8.97 mm2 for grader 1 (G1) and 9.54 mm2 for grader 2 (G2), consistent with the mean SD-OCT
quantification of the sub-RPE choroidal signal enhancement (8.9 mm2 [G1] 9.4 mm2 [G2]) and ELM loss with
8.7 mm2 (G1) 10.2 mm2 (G2). In contrast, complete morphologic absence of the RPE layer by SD-OCT was
significantly smaller than the GA size in FAF (R20.400). Inter-reader agreement was highest regarding complete
choroidal signal enhancement (0.98) and ELM loss (0.98).
Conclusions: Absence of FAF in GA lesions is consistent with morphologic RPE loss or advanced RPE
disruption and is associated with alterations of the outer retinal layers as identified by SD-OCT. Lesion size is
precisely determinable by SD-OCT, and foveal involvement is more accurate by SD-OCT than by FAF.
Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.
Ophthalmology 2011;118:1844–1851 © 2011 by the American Academy of Ophthalmology.
Age-related macular degeneration (AMD) affects an esti-mated
30 to 50 million individuals worldwide1 and is the
most common cause of legal blindness among elderly indi-viduals
in developed countries.2,3 Despite the fact that a
minority of patients affected by AMD have the neovascular
form, no effective “treatment for the neovascular form” is
available to reduce or reverse visual loss associated with
atrophic AMD.4,5 Geographic atrophy (GA), a late stage
development of AMD, occurs in 20% of patients with
preexisting clinical hallmarks of this degenerative dis-ease.
5–8 The natural course of GA, unlike the neovascular
form of AMD, progresses slowly and usually involves vi-sual
loss, primarily due to retinal pigment epithelium (RPE)
degeneration and neurosensory retinal atrophy resulting in
absolute and relative scotoma affecting the central vision
field.9–12
Retinal pigment epithelium cell death may result from
the accumulation of lipofuscin, a toxic by-product of pho-toreceptor
shedding, which accumulates in the lysosomal
compartment of RPE cells.11,13 As a part of the aging
process, the clearing ratio of lipofuscin in the RPE cell
diminishes and can impair normal cell metabolism. This
1844 © 2011 by the American Academy of Ophthalmology ISSN 0161-6420/11/$–see front matter
Published by Elsevier Inc. doi:10.1016/j.ophtha.2011.01.043

2. Sayegh et al SD-OCT and Fundus Autofluorescence in GA
eventually leads to cell death by induction of a reductive
chronic inflammatory condition involving complement fac-tor
H.14 Fundus autofluorescence (FAF) is predominantly
based on the fluorescent characteristics and distribution of
lipofuscin within the RPE layer.13 Because metabolically
altered or lost RPE, as in dry AMD or GA, has different
fluorescent properties than physiologic RPE, autofluores-cence
patterns could be used to identify pathophysiologic
mechanisms in dry or atrophic AMD.15 Such changes in the
FAF pattern of the RPE can be captured by a noninvasive in
vivo retinal imaging technique using confocal scanning
laser ophthalmoscopy (cSLO).13,16 The origins of atrophic
processes in AMD and GA, however, are not entirely un-derstood.
17,18
The evolution of optical coherence tomography (OCT)
from time-domain OCT to spectral-domain OCT (SD-OCT)
has greatly influenced AMD research and clinical knowl-edge.
19,20 Currently, the benefit of OCT imaging particu-larly
applies to a realistic analysis of the antiexudative effect
of intravitreal antiangiogenic drugs in neovascular
AMD.21–23
Compared with the diagnostic breakthrough in neovas-cular
AMD, the role of OCT/SD-OCT with regard to GA in
AMD is not clear. Several studies have compared FAF and
SD-OCT with a specific focus on morphologic fea-tures.
24–27 Only limited data are available on the potential
of SD-OCT to determine lesion size and the clinical repro-ducibility
of planimetric measurements. Definite criteria to
assess whether SD-OCT is indeed suitable for precisely
localizing and delineating the lesion area have not yet been
defined, and the predictive value of SD-OCT features in GA
progression remains unclear.25,28 Because the alteration and
loss of neurosensory elements at the retinal level seem to
determine visual prognosis in dry AMD,11 SD-OCT in
patients with GA seems essential if these changes are to be
followed and evaluated. The present study evaluates the
capacity of high-resolution, raster scanning SD-OCT to
provide dependable and reproducible parameters for grad-ing
atrophic disease in comparison with FAF currently in
use as an anatomic end point parameter in several clinical
trials. Such parameters would be of utmost value for diag-nosing
and monitoring disease progression in patients with
GA. Specific SD-OCT protocols would permit clinicians,
investigators, and especially OCT reading centers to reli-ably
evaluate the extent of preexisting lesions and the pro-gression
rate of this late-stage dry AMD and objectively
assess the efficacy of novel treatment strategies.
Patients and Methods
This prospective non-interventional case series was performed at
the Department of Ophthalmology at the Medical University of
Vienna, Austria. The protocol and procedure followed the tenets of
the Declaration of Helsinki. Written informed consent was ob-tained
from each individual before inclusion in the study.
Inclusion/Exclusion Criteria and Follow-Up
Eighty-one eyes of 42 patients with severe vision loss due to GA
secondary to AMD were enrolled in the study and followed ac-cording
to a standardized protocol in a prospective manner. For
inclusion in the study, patients had to be at least 55 years of age
and to have no signs of choroidal neovascularization in biomicros-copy
or OCT in either eye. If there was any doubt, fluorescein
angiography was performed. The macular condition was deter-mined
by biomicroscopy, OCT, and FAF. The study eyes had to
have a minimum GA lesion size of half a disc area and a maximum
lesion size of 7 disc areas, as estimated by biomicroscopy and
FAF, and the lesion had to fit in the SD-OCT volume scan.
Best-corrected visual acuity (BCVA) had to be 20/200. Clear
ocular media were required to provide good imaging quality.
Patients with history of any ocular disease that might confound
assessment of the retina were excluded. At each visit, patients
underwent BCVA testing obtained using Early Treatment Diabetic
Retinopathy Study charts, slit-lamp examination, biomicroscopy,
color fundus photography, SD-OCT, and FAF.
Spectral-Domain Optical Coherence
Tomography and Fundus Autofluorescence
Imaging Procedures
Imaging modalities analyzed in this study included SD-OCT and a
cSLO visualizing FAF, both integrated in the Spectralis HRA-OCT
(Heidelberg Engineering, Heidelberg, Germany). The cSLO
device uses blue light with excitation at 488 nm to illuminate the
fundus and detects emitted fluorescence signals from cellular ele-ments
of retinal and RPE layers between 500 and 700 nm. A
grayscale FAF image with a frame size of 3030 degrees was
acquired in a high-speed mode with a resolution of 768768
pixels. For this specific study, non-normalized FAF data acquisi-tion
was used and brightness and contrast were manually adjusted
during data acquisition for better visualization of the intensity
distribution in the posterior pole. Fundus autofluorescence imaging
was obtained by recording a 7-second video in the FAF mode of
the Spectralis HRA-OCT. One image comprising a mean FAF
intensity was calculated out of 15 frames.
The SD-OCT device uses a superluminescence diode emitting
a scan beam at a wavelength of 870 nm. The retina is scanned at
a speed of 40 000 A-scans per second with an axial resolution of
3.9 m and a transversal resolution of 14 m. The eye tracker and
automatic real-time averaging modes of the Spectralis SD-OCT
system were used throughout the study. The eye tracker enables
each OCT scan to be registered and locked to a reference image.
Therefore, the Spectralis-OCT software can identify the previous
scan location and scan the identical area. The automatic real-time
averaging mode, when activated, allows for adjustment of the
recorded frames to obtain averaged B-scans, which enhances im-age
quality by reducing movement artifacts and optimizes the
signal-to-noise ratio. The SD-OCT imaging protocol comprised 49
B-scans per volume scan of 2020 degrees, and each scan was
averaged with 30 frames per B-scan. If the lesion size was not
entirely displayed in the volume scan, the protocol allowed for
enlarging the scan area. If acquisition of the scan was not possible
because of the patient’s inability to comply, both the number of
frames acquired for each B-scan and the number of B-scans in the
volume scan were reduced. A minimum of 25 B-scans per volume
scan with a minimum of 20 frames per B-scan were obtained. The
distance between the SD-OCT B-scans is 120 m when acquiring
a volume stack of 49 scans and 240 m when acquiring a volume
stack of 25 B-scans. These distances are automatically registered
in the XML file generated by the Spectralis SD-OCT software. The
raster scan position for SD-OCT was centered in a manner anal-ogous
to the FAF imaging to delineate the complete extent of the
lesion.
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3. Ophthalmology Volume 118, Number 9, September 2011
Planimetric Measurements of Geographic
Atrophy Lesions by Spectral-Domain
Optical Coherence Tomography
To planimetrically measure areas in SD-OCT scans and subse-quently
compare them with FAF, we developed a program (OCT-Tool
Kit) that is able to read and display data generated by the
Spectralis XML Data Export Interface. Marking an area of interest
is performed by manually drawing a line in the B-scan image and
projecting it to the en face image. The mean distance from 1
B-scan to the next was used as the width of the line when
projecting it to the en face image. The software uses the calibration
(XML file) and the manually marked data to calculate the size of
the areas marked in the B-scans. Defined neurosensory retinal and
RPE layers were measured individually and included choroidal
signal enhancement below the RPE layer, the presence or absence
of the RPE cell layer, the outer plexiform layer (OPL), and the
external limiting membrane (ELM). The nomenclature of the ret-inal
layers in the SD-OCT B-scans is in accordance with Schmidt-
Erfurth et al.19
Comparison of Geographic Atrophy
Features Between Spectral-Domain Optical
Coherence Tomography and Fundus
Autofluorescence
To correlate SD-OCT with FAF findings, the same 2 independent
readers from the Vienna Reading Center (VRC) measuring the
lesion size in FAF separately graded the obtained SD-OCT B-scan
baseline data obtained from the entire lesion area using the OCT
planimetric protocol according to the areas of interest: For each
OCT B-scan, the complete and questionable presence of choroidal
signal enhancement, referred to as area 1 and area 2, respectively,
were graded. Complete choroidal signal enhancement was defined
as a consistent signal enhancement throughout the choroidea that
can be definitively determined by the reader; questionable choroi-dal
signal enhancement was defined as choroidal signal enhance-ment
that cannot be graded as choroidal signal enhancement with
certainty. Furthermore, the sum of both areas was referred to as
area 1/2 (Figs 1–3). Complete loss of the RPE was defined as area
3, incomplete loss of the RPE layer was defined as area 4, and
complete loss of both areas was defined as area 3/4 (Figs 1–3).
Complete loss of the RPE was defined as a complete reduction of
the RPE layer to a thin line with no hyperreflective elements in the
RPE layer. Incomplete loss of the RPE was defined as a partial
reduction of the RPE layer when compared with normal RPE
appearance.
With regard to atrophy of the neurosensory layers of the retina,
a thinning and shifting of the OPL toward the RPE layer was
labeled as area 5, and loss of the OPL was defined as area 6. Loss
of the ELM was defined as area 7 (Fig 2).
The OCT-Tool Kit summarizes the measurements and indicates
planimetric values for each specific area of interest, which can then
be compared and correlated to the FAF measurement values. The
defined areas demonstrating GA features were then correlated with
BCVA.
Evaluation of Lesion Size by Fundus
Autofluorescence
The GA lesion size in the FAF images was measured manually by
2 readers from the VRC using the Spectralis software “Heidelberg
Eye Explorer” region overlay device. Fundus autofluorescence
images were enlarged, and the GA area, represented as an area of
hypofluorescence in FAF, was delineated using an external stylus
(Wacom Bamboo Pen Touch; Wacom Technology Corp., Van-couver,
WA). Those results served as reference values when
comparing the dimension of GA in FAF with the areas of interest
in SD-OCT B-scans.
Identification of Foveal Sparing in Fundus
Autofluorescence and Spectral-Domain
Optical Coherence Tomography
Furthermore, we examined whether SD-OCT and FAF were equiv-alent
with respect to identifying foveal sparing or foveal involve-ment
in the GA process. An adequate grading system was estab-lished,
and the 2 readers from the VRC independently graded the
SD-OCT B-scans and FAF images at baseline according to this
predetermined grading system.
The grading system was established according to the level of
disease progression: grade 1 fovea definitely involved; grade
2 fovea probably involved; grade 3 fovea probably spared;
and grade 4 fovea definitely spared. In SD-OCT, the fovea was
graded as fovea definitely involved when the RPE in the fovea was
altered causing choroidal signal enhancement. In FAF, the fovea
was defined as definitely involved when the grayscale image in
FAF had similar intensity values in the region of the supposed
fovea and in the region of GA in the rest of the posterior pole.
When in doubt, the graders were asked to grade the fovea as
probably involved or spared.
Statistical Analysis
Data analysis was performed in an established statistical environ-ment
(R version 2.9.2). First-order descriptive statistics were com-puted
to provide a simple characterization of the measured values.
To relate grader classifications of SD-OCT or FAF images to
BCVA values, a linear logistic model was fit, also testing for a
grader effect and any left/right bias. Left/right bias was insignifi-cant
for all tests and was thus removed from the models. To
quantify inter-grader concordance concerning the grading of the
foveal involvement, coefficients for the reliability of nominal
data were computed. The original coefficient as computed by
Cohen29 and the = coefficient for pooled classification propor-tions30
were similar and significant with comparable P values. In
addition, we report the coefficient adjusted for prevalence
according to Byrt et al.31
Linear regression analysis was used to examine alternative
potential relationships of the different areas of interest in SD-OCT
compared with FAF. Non-transformed measurements were used,
because they yielded better model fits than models of square-root
or log-transformed data. In multivariate analysis of variance, the
least significant factors were trimmed iteratively until all remain-ing
factors were significant (P 0.05). Univariate regression
achieved only a marginally worse model fit; therefore, the focus
was set on reporting the best univariate models.
For the correlation of graded GA areas with BCVA, all visual
acuity values were converted to logarithm of minimal angle of
resolution for statistical analysis. Univariate models on linear and
log scales, with arbitrary and zero offsets, were considered. The
best model fit for area 3 was achieved on a linear scale with zero
offset, and for all other variables, best model fits were achieved on
the log scale with zero offset, that is, by fitting a power law with
no scaling factor. Correlation values are each given for the linear
regression fit of the linear or log-transformed data.
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4. Sayegh et al SD-OCT and Fundus Autofluorescence in GA
Figure 1. Graded area of hypofluorescence measured in fundus autofluo-rescence
(FAF) representing the area of geographic atrophy (GA).
Results
Included Study Eyes
Eighty-one eyes of 42 patients (16 men and 26 women; mean age 80
years, range 55–89 years) were included in this prospective study. All
patients presented bilateral GA. Of the potential total number of 84
study eyes, 3 fellow eyes were excluded because of poor retinal
imaging quality due to advanced cataract. Of the 81 included eyes, 41
were right eyes and 40 were left eyes. Mean BCVA at baseline among
the 81 study eyes was 20/51 Snellen equivalents.
Determination of Foveal Sparing by
Spectral-Domain Optical Coherence
Tomography and Fundus Autofluorescence, and
Correlation with Best-Corrected Visual Acuity
For all 81 eyes, foveal involvement by the atrophic process was
independently assessed from SD-OCT and FAF images. Grading
results for both imaging methods are summarized in Table 1 (avail-able
at http://aaojournal.org), and examples are shown in Figure 4.
Logistic regression indicated a highly significant relation between the
BCVA and the grading of SD-OCT measurements (P2108). This
finding shows that clear results could be obtained by SD-OCT.
Independence of the results of the operators was tested by including a
grader effect in the logistic regression model. There was no significant
grader bias (P0.54) and little random variation (’0.6, P0.01;
’’0.9). This is reflected in the high inter-individual agreement between
graders (Table 2, available at http://aaojournal.org), where congruent
SD-OCT gradings were obtained for 75 of 81 eyes: grade 1 (definite
involvement) for 70 eyes and grade 4 (definite sparing) for 5 eyes. In
these groups, mean BCVA values were 20/61 and 20/26, respectively. In
6 eyes, graders were discordant regarding involvement or sparing of the
fovea by the atrophic process. Mean BCVA was 20/27 in this group.
Figure 2. Areas of interest graded in spectral-domain optical coherence
tomography (SD-OCT) (from top to bottom): area 1 complete choroi-dal
signal enhancement; area 2 questionable choroidal signal enhance-ment;
area 3 complete absence of retinal pigment epithelium (RPE);
area 4 incomplete loss of RPE; area 5 subsidence of the outer
plexiform layer (OPL); area 6 loss of the OPL; area 7 loss of the
external limiting membrane (ELM).
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5. Ophthalmology Volume 118, Number 9, September 2011
Figure 3. Combined areas of interest in spectral-domain optical coherence tomography (SD-OCT). A, Combined areas 1 and 2 representing complete
and questionable choroidal signal enhancement. B, Combined areas 3 and 4 representing complete absence of retinal pigment epithelium (RPE) and
incomplete loss of RPE.
The BCVA was significantly related to grading of FAF mea-surements
(P 5104). For FAF, the grader effect in the logis-tic
regression model was marginally significant (P 0.08), sug-gesting
a possible operator bias. Little random variation was
observed (’0.3, P 0.01; ’’0.4). Inter-individual agree-ment
between graders, with consistent FAF gradings, was obtained
for 48 of 81 eyes. In 40 eyes, definite foveal involvement (grade 1)
was identified, with a mean BCVA of 20/74, whereas in 5 eyes the
fovea was identified as probably involved (grade 2, BCVA
20/38). Finally, in 3 eyes the graders considered the fovea to be
probably spared (grade 3, mean BCVA of 20/27). For the remain-ing
33 eyes, there was inter-grader disagreement: grade 1 versus
grade 2 for 18 eyes (mean BCVA 20/42), grade 1 versus grade
3 for 8 eyes (BCVA 20/77), and grade 2 versus grade 3 for 7
eyes (BCVA 20/29). In general, there was an inconclusive
relationship between the FAF-based identification of foveal in-volvement
and BCVA within each group and between groups
(Table 2, available at http://aaojournal.org).
Determination of Geographic Atrophy Lesion Size
Based on Spectral-Domain Optical Coherence
Tomography Grading and Fundus
Autofluorescence Planimetry
The results of the evaluation of GA features in absolute planim-etric
values (Table 3, available at http://aaojournal.org) were sim-ilar
for both graders regarding complete choroidal signal enhance-ment
through increased transmission of light in the absence of
melanin (area 1),32 subsidence of the OPL (area 5), loss of the
ELM (area 7) by SD-OCT, and absence of FAF by cSLO. Lesion
size values referring to complete loss of RPE (area 3) were
approximately half the dimension of the areas mentioned above,
including absence of FAF. For areas 3 and 4, comprising complete
and incomplete RPE loss from SD-OCT measurements, similar
FAF results indicating GA with complete loss of RPE fluorescence
were obtained.
Complete choroidal signal enhancement was probably closest
to representing the area of GA in SD-OCT B-scans measured in a
larger area than complete RPE loss or advanced alteration of the
RPE based on RPE morphology in SD-OCT. The total extent of
complete and incomplete RPE loss, however, was consistent with
the size of the area of complete choroidal signal enhancement and
complete loss of FAF. The areas of ELM loss and OPL shifting
were consistent with the sum of the areas of complete RPE loss
and advanced alteration of RPE morphology (Table 3, available at
http://aaojournal.org). In all eyes, both graders were able to pre-cisely
measure a larger area of complete (area 1) and a smaller area
of questionable choroidal signal enhancement of incomplete loss
of RPE and loss of the ELM.
Comparison of Fundus Autofluorescence and
Spectral-Domain Optical Coherence Tomography
Values
We tested a multivariate model relating the area measured in FAF
by the graders to the areas graded in SD-OCT. The least significant
factors were trimmed iteratively until all remaining analysis of
variance factors were significant (P 0.05). The obtained multi-variate
model explaining FAF as a function of the graded area 1
(complete choroidal signal enhancement) and area 7 (loss of the
ELM) achieved an adjusted R20.961. The best univariate model
for the FAF was with area 1, obtaining a comparable fit quality
with an adjusted R20.958. These findings justify focusing on the
presentation of the correlations corresponding to multiple univar-iate
models (Table 4, available at http://aaojournal.org). The
matching scatter plots comparing the results of SD-OCT gradings
with the FAF are shown in Figure 5. Although all areas exhibited
a significant non-zero correlation, only the graded area 1 (complete
1848

6. Sayegh et al SD-OCT and Fundus Autofluorescence in GA
Figure 4. Grading of the foveal involvement of the atrophic process in fundus autofluorescence (FAF) and spectral-domain optical coherence tomography
(SD-OCT). A, In FAF fovea probably involved, in SD-OCT fovea definitely spared. B, In FAF fovea probably spared, in SD-OCT fovea definitely spared.
C, In FAF fovea definitely involved, in SD-OCT fovea definitely involved.
choroidal signal enhancement), area 5 (OPL shifting), and area 7
(loss of the ELM) in SD-OCT had a strong correlation with the
hypofluorescent area measured in FAF. In particular, area 1 rep-resenting
the area of complete choroidal signal enhancement in the
SD-OCT B-scans correlated best and was also less dependant on
grader variability (data not shown).
The area of complete choroidal signal enhancement in SD-OCT
B-scans correlated strongly with the area of OPL shifting and with
ELM loss. Moreover, the sum of the areas of complete and
questionable choroidal signal enhancement correlated highly with
the sum of the areas of complete and incomplete RPE loss (Table
5, available at http://aaojournal.org).
Inter-grader Reproducibility of Grading
Measurements
The inter-grader reproducibility of the FAF and SD-OCT measure-ments
of lesion size were best for FAF, followed closely by
complete choroidal signal enhancement and loss of the ELM
(Table 6 and Fig 6, available at http://aaojournal.org).
Correlation of Best-Corrected Visual Acuity,
Fundus Autofluorescence, and Spectral-Domain
Optical Coherence Tomography Lesion Size
Between the Two Graders
The BCVA correlated significantly with all graded areas as shown
in Table 7 (available at http://aaojournal.org).
Discussion
This prospective study represents the first analysis of com-plete
SD-OCT volume stacks to determine the potential of
SD-OCT versus FAF for monitoring patients with GA, partic-
Figure 5. Agreement between area of hypofluorescence measured in fundus autofluorescence (FAF) representing the area of geographic atrophy (GA) and the
graded areas of interest in spectral-domain optical coherence tomography (SD-OCT). Area 1 represents the area of complete choroidal signal enhancement, area
3 represents the area of complete absence of retinal pigment epithelium (RPE), Area 4 (A4) represents the area of incomplete loss of RPE, area 5 represents the
area of outer plexiform layer (OPL) subsidence, and area 7 represents the area of loss of the external limiting membrane (ELM). FAF fundus autofluorescence.
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7. Ophthalmology Volume 118, Number 9, September 2011
ularly with respect to identifying the foveal condition and
relevant grading parameters for precisely measuring GA.
Lujan et al28 compared the size of GA in SD-OCT and
FAF in 5 eyes by superimposing both imaging modalities
and delineating the borders of the disease without analyzing
the retinal layer morphology. The findings indicated that it
is in principle possible to assess the size of an atrophic GA
lesion in SD-OCT, but retinal morphology was not an issue.
Choroidal signal enhancements and alterations at the
level of RPE, ELM, and OPL are characteristic morphologic
changes in GA that we assumed might be helpful in accurately
measuring the lesion size. The aim of our study was to deter-mine
which of these pathologic changes should be graded to
obtain equivalent planimetric measurements in FAF.
Although general grading reproducibility was good for both
methods, foveal sparing was identified by SD-OCT with a
higher certainty and inter-grader agreement than with FAF.
This could be due to the presence of yellow macular pigment
in the neurosensory retina at the fovea that blocks the blue
excitation light of FAF imaging. Moreover, the grayscale im-ages
obtained by FAF merely reflect the overall autofluores-cence
of the RPE and the quantity of fluorophores within the
RPE cells, if present. Neither the resolution nor the quantifi-cation
of FAF values allow for precise delineation regarding
the parameter “foveal localization,” and the fovea is frequently
located within the junctional zone of RPE disease, which, as
our study also shows, is generally problematic for FAF eval-uation.
Furthermore, foveal depression can easily be deter-mined
by SD-OCT. Therefore, screening for decreased FAF in
the central fovea may be difficult without complementary
extensions, such as near-infrared reflectance imaging. Conclu-sions
regarding foveal involvement or sparing based on FAF
alone must therefore be drawn cautiously.27
The agreement of outcomes between grader 1 and grader 2
regarding the parameters graded by SD-OCT highlight the
feasibility of objectively grading well-defined parameters in
SD-OCT. A significant correlation of these SD-OCT–based
results with the GA area measured in FAF proves that both
methods can be used to consistently quantify the extent of this
disease.
There were significant correlations of varying strength
between the area of interest and the visual acuity, which can
be explained by the fact that the size of the GA does not
entirely determine the BCVA in GA, because there is often
foveal sparing. As the GA area expands, the probability of
foveal involvement increases.17,27 Furthermore, the results
obtained and presented in Table 1 (available at http://aao-journal.
org) show that mean BCVA among patients with
definite fovea involvement ranged between 20/57 and 20/
77. This indicates that BCVA in patients with central GA
may be higher than generally assumed.
The results of our study showed that the definite RPE
loss graded in SD-OCT and FAF was only weakly corre-lated
(R240%; Table 4, available at http://aaojournal.org).
This correlation increased to 97% when we added the areas
of definite RPE loss to that of uncertain RPE alteration with
moderate RPE loss. We presume that this issue underlines
the importance of the junctional zone in GA because this
zone is the site of disease activity and will be the target for
any effective therapeutic strategy. The interest in this area is
reflected by the large number of scientific publica-tions.
25,26,33,34 In the study by Bearelly et al,25 SD-OCT
images of the junction zone in patients with GA were
analyzed to determine whether RPE loss or photoreceptor
loss is the first sign of GA progression. The authors stated
that if this were the case, then the frequency of photorecep-tor
loss outside the GA margin would have been higher. In
the present study, we analyzed the alterations of the photo-receptor
layer in complete B-scans and concluded that pho-toreceptor
alterations seem to be more extensive than com-plete
RPE alterations. A longitudinal study in this field is
necessary to provide more detailed insight, and the lack of
longitudinal data is a limitation of this study. Fundus auto-fluorescence
does not allow for accurate mapping of the fine
borders of a disease that is characterized by different stages
of progression and cannot differentiate between an absent or
a diseased RPE in the same manner as SD-OCT, which
allows for viewing and grading all retinal layers.
Most noteworthy is the finding that not only RPE absence
correlates closely with neurosensory alterations, but that even
in junctional zones where RPE cells are still present but are
beginning to undergo morphologic changes, retinal layers such
as the ELM and OPL are severely affected. It remains contro-versial
whether the primary origin of atrophic AMD is the RPE
or neuronal elements such as photoreceptors.35,36 The fact that
RPE atrophy occurs at the novel macular site after 360-degree
translocation36 suggests that photoreceptor disease is the pri-mary
stimulus for subsequent RPE death.
In conclusion, spectral-domain OCT seems to be an
appropriate imaging modality for evaluating the extent of
GA lesions. The retinal scanning time in SD-OCT and FAF
relevant to obtaining gradable material is dependent on the
patient and physician. Manual grading of the B-scans, how-ever,
is time-consuming and should be replaced by auto-mated
algorithms delineating choroidal signal enhancement
for accurate GA lesion size determination.
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Footnotes and Financial Disclosures
Originally received: January 8, 2010.
Final revision: January 13, 2011.
Accepted: January 13, 2011.
Available online: April 15, 2011. Manuscript no. 2010-46.
1 Department of Ophthalmology, Medical University of Vienna, Austria.
2 Chair of Bioinformatics, Department of Biotechnology, Boku University
Vienna, Austria.
Financial Disclosure(s):
The author(s) have made the following disclosure(s): Christian Prünte,
MD, has a financial relationship with Novartis Pharma, Alcon Pharma, and
Bayer. None of the authors have a proprietary interest in any of the
products mentioned in this study.
Parts of the study were presented at: the DOG annual meeting, September
26, 2009, Leipzig, Germany (paper presentation)
Correspondence:
Christian Simader, MD, Department of Ophthalmology, Medical Uni-versity
of Vienna, Austria, Waehringer Guertel 18-20, Vienna, Austria.
E-mail: chrisitan.simader@meduniwien.ac.at
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