Optical Coherence Tomography Biomarkers
for Conversion to Exudative Neovascular
Age-related Macular Degeneration
YU WAKATSUKI, KAZUTAKA HIRABAYASHI, HANNAH J. YU, KENNETH M. MARION, GIULIA CORRADETTI,
CHARLES C. WYKOFF, AND SRINIVAS R. SADDA
• PURPOSE: To identify optical coherence tomography
(OCT) biomarkers, including thin and thick double-layer
sign (DLS) for the progression from intermediate AMD
(iAMD) to exudative macular neovascularization (MNV)
over 24 months.
• DESIGN: Retrospective cohort study.
• METHODS: Setting: Retina consultants of Texas. Pa-
tient population: 458 eyes of 458 subjects with iAMD in
at least 1 eye with 24 months of follow-up data. Main
outcomes measures: The following biomarkers were as-
sessed at baseline: high central drusen volume (≥0.03
mm3 ), intraretinal hyper-reflective foci (IHRF), subreti-
nal drusenoid deposits, hyporeflective drusen cores, thick
DLS, thin DLS, and central choroidal thickness. A binary
logistic regression was computed to investigate the asso-
ciation between baseline OCT covariates and the conver-
sion to exudative MNV within 24 months. In addition,
fellow eye status was also included in the model.
• RESULTS: During follow-up, 18.1% (83 of 458) of eyes
with iAMD progressed to exudative MNV. Thick DLS,
IHRF, and fellow eye exudative MNV were found to be
independent predictors for the development of exudative
MNV within 2 years. The baseline frequencies, odds ra-
tios, 95% confidence intervals, and P values for these
biomarkers were as follows: thick DLS (9.6%, 4.339,
2.178-8.644; P < .001), IHRF (36.0%, 2.340, 1.396-
3.922; P = 0.001), and fellow eye exudative MNV
(35.8%, 1.694, 1.012-2.837; P = .045).
• CONCLUSIONS: Thick DLS, IHRF, and fellow eye ex-
udative MNV were associated with an increased risk
of progression from iAMD to exudative MNV. These
biomarkers, which are readily identified by the review of
OCT volume scans, may aid in risk prognostication for
patients and for identifying patients for early interven-
Supplemental Material available at AJO.com.
Accepted for publication September 20, 2022.
From the Doheny Eye Institute, Los Angeles, California (Y.W., K.H.,
K.M.M., G.C., S.R.S.); Retina Consultants of Texas, Retina Consultants
of America, Houston, Texas (H.J.Y., C.C.W.); Department of Ophthal-
mology, David Geffen School of Medicine at UCLA, Los Angeles, Cali-
fornia, USA (Y.W., K.H., G.C., S.R.S.)
Inquiries to Srinivas R. Sadda, Doheny Eye Institute, Pasadena, Califor-
nia, USA; e-mail: ssadda@doheny.org
0002-9394/$36.00 © 2022 ELSEVIER INC. ALL RIGHTS RESERVED.
https://doi.org/10.1016/j.ajo.2022.09.018
tion trials. (Am J Ophthalmol 2023;247: 137–144. ©
2022 Elsevier Inc. All rights reserved.)
A
ge-related macular degeneration (AMD) is
the leading cause of central vision loss in the elderly
in developed countries.1 The risk of developing ad-
vanced AMD (ie, macular neovascularization [MNV], ge-
ographic atrophy [GA], or both) after 5 years increases to
27% for patients with intermediate AMD (iAMD) in both
eyes and 43% for those who have advanced AMD in the
fellow eye.2
In contrast to GA where vision typically diminishes rela-
tively slowly over time, central vision loss may occur rapidly
in patients who develop exudative MNV. Moreover, MNV
lesions are known to grow more rapidly at lesion onset than
in more advanced or chronic cases, and thus can lead to ir-
reversible vision loss before neovascular AMD (nAMD) is
first diagnosed, particularly when the vision is good in the
fellow eye.3 Although antivascular endothelial growth fac-
tor therapy has dramatically improved, visual results among
patients with nAMD, early detection and prompt therapeu-
tic intervention remain vital to achieve the best visual out-
comes.3-5
Optical coherence tomography (OCT) is widely and
commonly used by ophthalmologists as a diagnostic tool,
allowing for noninvasive, 3-dimensional evaluation of reti-
nal morphologic features. Several retrospective studies have
identified features of OCT that may be associated with
a higher risk of AMD progression. These features in-
clude a higher central drusen volume (DV),6 intraretinal
hyper-reflective foci (IHRF),7 , 8 subretinal drusenoid de-
posits (SDD),9-12 and hyporeflective drusen cores.7
A number of studies have shown that these OCT
biomarkers could be associated with a higher risk for pro-
gression to late AMD, though most of these studies fo-
cused on the development of atrophy.13 , 14 In addition to
these common biomarkers, patients with iAMD may de-
velop signs of early type 1 (subretinal pigment epithelial
[sub-RPE]) MNV without evidence of exudation. These le-
sions are termed nonexudative type 1 MNV and are char-
acterized by a shallow irregular RPE elevation,15 more com-
monly termed a double-layer sign (DLS). The 2 “layers”
constituting this DLS sign are the RPE band and Bruch’s
137
membrane, and it is presumed that the separation of these
layers in these cases are caused by interposition of the MNV
lesion.16 However, a thin DLS can also develop as a result
of the accumulation of basal laminar deposits (BLD) in the
absence of MNV and is commonly seen in eyes with at-
rophic AMD.17 , 18 Freund and associates18 suggested that
OCT angiography (OCTA) could be a useful tool to de-
termine which DLSs were vascularized. OCTA is not al-
ways available, however, and is not 100% sensitive and
may be difficult to interpret in some cases. Freund and as-
sociates19 also noted that vascularized DLS lesions tended
to be thicker, and in contrast to BLD, these nonexudative
MNV lesions may exhibit multiple layers of different reflec-
tivity within the sub-RPE space. Importantly, and perhaps
not surprisingly, the presence of nonexudative MNV has
been reported to be associated with a higher risk for con-
version to exudative MNV.20
In the current study, we evaluated these various OCT
biomarkers including a thin and thick DLS as potential in-
dependent risk factors for conversion from iAMD to exuda-
tive MNV over a 2-year period.
METHODS
• STUDY COHORT: Consecutive patients (n = 1128) diag-
nosed with any AMD in at least 1 eye by clinical exami-
nation at the Retina Consultants of Texas, Houston, Texas,
USA, between October 2016 and October 2020 were evalu-
ated for inclusion in this study. This study was reviewed and
approved by the Houston Methodist Hospital Ethics Com-
mittee (Pro00020661:1 “Retrospective prospective analy-
sis of retinal diseases”). As the data collection was retro-
spective, a waiver of informed consent was granted. The
research was conducted in accordance with the tenets set
forth in the Declaration of Helsinki.
As defined by the Beckman scale,21 iAMD is character-
ized by large drusen (>125 μm), and the diagnosis was con-
firmed by the inspection of the examination documentation
in the medical records and corroborated by a review of the
baseline OCT B-scan volumes. Only 1 eye from each pa-
tient was included in the current analysis. If both eyes had
iAMD, either the right or left eye was randomly selected for
potential inclusion in this analysis.
When considering the study eye, the eye with fluid
present in the intraretinal, subretinal, or sub-RPE com-
partment at baseline (suggestive of any type of exudative
MNV), cases with complete RPE and outer retinal atro-
phy (cRORA), and cases with exudative MNV noted at
any point in the previous medical history were excluded.
Eyes with evidence of other macular diseases such as high
myopia, central serous chorioretinopathy, macular hole, or
retinal vascular disease were also excluded. Eyes with vi-
sually insignificant vitreoretinal interface disease, such as
a subtle epiretinal membrane on OCT, were not excluded.
138 AMERICAN JOURNAL OF OPHTHALMOLOGY
After applying these criteria, 763 eyes (763 patients) of the
original 1128 were eligible for further analysis.
However, in order to be included in the primary analysis,
in addition to the baseline OCT, patients were required to
have a follow-up OCT volume scan at 24 ± 2 months after
the baseline visit. This requirement led to an exclusion
of 305 more eyes, yielding 458 eyes of 458 patients in the
primary analysis. The records and OCTs from the inter-
vening visits through the month 24 visit were reviewed
to identify which patients developed exudative AMD
during this interval. For the 305 eyes that did not have a
month 24 visit, the intervening visits were also reviewed
for conversion to exudative AMD, for inclusion in the
time-to-event analysis.
• OCT ACQUISITION PROTOCOL: A consistent OCT ac-
quisition protocol was employed for all subjects, which was
the practice pattern of the clinic. All OCT scans were ac-
quired with the Spectralis HRA+OCT (SPECTRALIS;
Heidelberg Engineering, Inc) using a volume scan protocol
over a 6 × 6 mm area (fovea centered, 49 B-scans spaced
122 μm apart, and automatic real-time tracking = 6). OCT
scans were exported and transmitted to the Doheny Image
Reading and Research Laboratory for masked analysis.
• OCT GRADING PROTOCOL: All OCT data were reviewed
by certified Doheny Image Reading and Research Labora-
tory OCT graders (K.H., Y.W.). The OCT scan from the
patient’s first visit during the period of the study (October
2016 to October 2020) was considered as the baseline. All
49 B-scans were reviewed, and each specific biomarker was
deemed to be present or absent in the volume as a whole.
The presence of a high central DV (≥0.03 mm3 within
the central 3 mm) was determined based on a qualitative
inspection as described by Corvi and associates.22 Briefly,
graders were trained by reviewing Spectralis OCT volumes
from eyes with DVs just above and below the high central
DV threshold (with the ground truth for DV established
from the advanced RPE analysis of the same eye obtained
using Cirrus OCT). By mentally comparing the particular
case against the previous training cases, the graders were
able to subjectively determine whether high central DV
was present or not. This approach has been shown to be ac-
curate and reliable for this determination.22 The presence
of IHRF, hyporeflective drusen core (hDC), and SDD was
graded as detailed previously.14 Briefly, IHRF were defined
as discrete, well-defined hyper-reflective lesions within the
neurosensory retina with a minimum size of 3 pixels and
reflectance greater than or equal to the RPE band.23 Be-
cause a sufficient number of pixels must be present inside
the drusen to identify hDC, the internal reflectance of the
drusen was only evaluated in drusenoid lesions at least 40
μm in height.24 SDD were identified as moderately reflec-
tive hyper-reflective mounds or cones either at the level
of the ellipsoid zone or between the ellipsoid zone and the
RPE surface, and the observation of 3 or more such SDD le-
MARCH 2023
FIGURE 1. Representative optical coherence tomography (OCT) images of thick and thin double-layer signs (DLSs) and 5 other
interests. A. OCT B-scan of a thick DLS. The linear extent of the thick DLS lesion is denoted by the black line below. The inner layer
of the DLS is the highly reflective elevated retinal pigment epithelium (solid yellow arrow) and the outer layer is Bruch’s membrane
(dashed yellow arrow). In between, both bright and dark reflective bands can be seen highlighting the presence of multiple bands or
layers within this thick DLS. B. OCT B-scan of a thin DLS. The linear extent of the thin DLS lesion is denoted by the black line
below. Note that only a single low reflective band can be seen interposed between the retinal pigment epithelial (RPE) and Bruch’s
membrane. C. OCT B-scan of intraretinal hyper-reflective foci (IHRF). Small dot-like lesions with reflectance equal to or greater
than that of the RPE zone can be identified. The minimum size of an IHRF is 3 pixels (yellow arrow). D. OCT B-scan of subretinal
drusenoid deposition (SDD). Granular extracellular deposits can be seen overlying the RPE at the level of the photoreceptor outer
segments. SDD was determined to be present only when at least 3 such SDD lesions were observed (yellow arrow). E. OCT B-scan
of hyporeflective drusen core. Hyporeflective spaces can be seen within the drusen (yellow arrow). A minimum drusen height of
40 µm is required to reliably assess whether areas of low internal reflectivity are present. F. OCT B-scan of high central drusen
volume (DV). Graders were trained to determine if the DV was greater than or less than 0.03 mm3 from cases with premeasured
mechanical DV (yellow arrow).

sions in a single B-scan was a condition for establishing the
presence of SDD.14 The companion infrared reflectance im-
age available with the OCT data was also evaluated for the
presence of SDD. The topographic configuration of SDD,
with multiple deposits commonly present at regular inter-
vals within a region of the retina, was also useful for recog-
nizing these lesions (Figure 1).
A double-layer sign was defined by a visible separation
of 2 highly reflective layers, in this case the RPE band and
Bruch’s membrane. If only a single zone of low-to-medium
reflectivity occupied the area between Bruch’s membrane
and the RPE, the lesion was classified as a thin DLS. A thin
DLS was distinguished from a drusen by its relatively shal-
low and flat contour. In contrast, if multiple layers (ie, at
least 2) of different reflectivity could be identified between
the RPE and Bruch’s, the lesion was classified as a thick
DLS. In other words, a thin DLS has a single layer of re-
flectivity between RPE and Bruch’s, whereas a thick DLS
has 2 or more layers with differing reflectivity between the
RPE and Bruch’s (Figure 1).
The central choroidal thickness (CCT) was measured at
the foveal center from the outer RPE band to the choroid-
scleral interface using the caliper function of OCT re-
view software. As the OCT B-scans were not acquired in
enhanced depth imaging mode and the outer choroidal
boundary could not be visualized in all eyes with thicker
choroids, the CCT was recorded in a binary fashion as <200
µm or ≥200 µm.
Finally, the fellow eye at baseline was evaluated for
the presence of 2 categories of late AMD as defined in
the Beckman classification:21 exudative MNV (determined
from medical records and OCT scans according to Consen-
sus on Neovascular AMD Nomenclature (CONAN) crite-
ria)25 and atrophy (determined from medical records and
OCT scans according to Classification of Atrophy Meet-
ing (CAM) criteria for cRORA).26 Per CONAN criteria,
exudative MNV was defined by the presence of fluid in
the intraretinal, subretinal, and/or sub-RPE compartments
that was associated with pigment epithelial detachment
with heterogeneous internal reflectivity (suggestive of type

VOL. 247 OCT RISK FACTORS FOR EXUDATING NEOVASCULAR AMD 139
1 MNV) and/or subretinal hyper-reflective material (sug-
gestive of type 2 MNV), and/or intraretinal hyper-reflective TABLE 1. Baseline Variables and Frequencies
foci with cystoid macular edema at the apex of an under-
lying pigment epithelial detachment (suggestive of type 3 Frequency (%)

MNV). Eyes 458

Medical records and OCT data through month 24 were Central DV ≥ 0.03 mm3 221 (48.3)
reviewed to determine the development of exudative MNV IHRF presence 165 (36.0)
at any point during the 24-month period from the baseline SDD presence 143 (31.2)
OCT. hDC presence 56 (12.2)
Thick double-layer sign 44 (9.6)
• STATISTICAL ANALYSIS: All analyses were performed us- Thin double-layer sign 52 (11.4)
ing IBM SPSS Statistics Ver. 28 (IBM). CCT >200 μm 244 (53.3)
The frequency of each biomarker in the cohort at base- MNV in the fellow eye 164 (35.8)
cRORA in the fellow eye 33 (7.2)
line was computed. Univariate regression was first per-
formed to determine whether each of the 7 OCT biomark- CCT = central choroidal thickness, cRORA = complete reti-
ers and the fellow eye AMD stage at baseline were associ- nal pigment epithelial and outer retinal atrophy, DV = drusen
ated with progression to exudative MNV within 24 months. volume, hDC = hyporeflective drusen cores, IHRF = intrareti-
Unadjusted odds ratios [ORs] and 95% confidence inter- nal hyper-reflective foci, MNV = macular neovascularization,
vals [CIs] for risk factors were calculated (Pearson’s χ 2 test). SDD = subretinal drusenoid deposits.

Then, adjusted ORs for the risk of MNV progression in

iAMD were calculated by including those with P < .05
univariate regression analysis. The results of the model X2
from the univariate regression analysis in the multivariate
test were P < .05, and each variable was significant, and
logistic regression analysis. In addition, a correlation ma-
the results of the Hosmer-Lemeshow test also showed a good
trix was created before the introduction of the independent
model fit with P = .692 and a discriminant accuracy of 82.5.
variables to ensure that there were no coarse and strong
There were no outliers where the predicted value exceeded
correlations between the independent variables with r >
±3 standard deviation relative to the measured value. Sig-
0.8 (Spearman’s rank correlation coefficient). In addition, a
nificant independent predictors from this analysis included
time to even analysis was performed including the primary
IHRF (OR = 2.340; 95% CI, 1.396-3.922; P = .001), thick
cohort with 2 years of follow-up as well as the additional
DLS (OR = 4.339; 95% CI, 2.178-8.644; P < .001), and
305 eyes with baseline data who may have converted in the
fellow eye exudative MNV (OR = 1.694; 95% CI, 1.012-
interval but did not have a 2-year follow-up visit. Cox pro-
2.837; P = .045).
portional hazards were performed as a multivariate analysis
Because the risk accorded with fellow eye disease is high
of survival regression.
according to the AREDS study,27 we also conducted a sen-
sitivity analysis for all patients (N = 375), adjusting for the
history of the MNV in the fellow eye in our final regres-
sion model. All analyses were repeated excluding MNV in
RESULTS the fellow eye. Results from the sensitivity analysis yielded
similar findings (Table 3).
The final analysis cohort includes 458 iAMD eyes from 458
In addition, as the primary analysis did not consider the
patients. The mean age was 74.4 ± 9.5 years, and 63.5%
time to conversion, and there were eyes that converted be-
were female. At baseline, 48.3% of eyes had a high central
fore 2 years but did not complete the 2-year follow-up visit,
DV, 36.0% had IHRF 36.0%, 31.2% had SDD, 12.2% had
the absence of these eyes from the primary analysis may
hDC, 53.3% had a CCT < 200 µm, 9.6% had a thick DLS,
have potentially introduced ascertainment bias. To miti-
and 11.4% had a thin DLS. The fellow eye was graded as
gate this potential bias, we also analyzed Cox proportional
showing evidence of exudative MNV in 35.8% and cRORA
hazards as a multivariate analysis of survival regression, in-
in 7.2% (Table 1).
cluding these additional eyes without 2 years of follow-up
Over 24 months, 83 (18.1%) eyes progressed to exudative
(N = 305). The overall findings (for a total of 763 eyes)
MNV.
were similar to the primary analysis (Table 4).
Univariate regression analysis (Table 2) revealed that
baseline high central DV, IHRF, hDC, and a thick DLS were
all associated with an increased risk for progression to ex-
udative AMD (P < .05). Fellow eye exudative MNV and
fellow eye cRORA were also associated with a higher risk DISCUSSION
for progression to exudative MNV (P < .05).
Multivariate logistic regression analysis was performed In this study, we evaluated multiple OCT biomarkers in
including these variables that demonstrated P < .05 in the eyes with iAMD to determine if they were associated with

140 AMERICAN JOURNAL OF OPHTHALMOLOGY MARCH 2023

 TABLE 2. Baseline Biomarkers for Intermediate Age-related macular degeneration Progression to Exudative Macular
Neovascularization (MNV) Over 24 Months

Univariate Analysis Multiple Logistic Regression

Risk Factor Unadjusted Odds Ratios 95% CI P Value Adjusted Odds Ratios 95% CI P Value

Central DV ≥ 0.03 mm3 2.177 1.331-3.560 .002 1.603 0.946-2.715 .079

IHRF presence 3.024 1.858-4.923 <.001 2.340 1.396-3.922 .001
SDD presence 0.939 0.560-1.574 .811 — — —
hDC presence 2.219 1.185-4.157 .011 1.017 0.491-2.108 .964
Thick double layer 5.787 3.020-11.090 <.001 4.339 2.178-8.644 <.001
Thin double layer 1.600 0.812-3.153 .171 — — —
CCT > 200 μm 0.780 0.484-1.255 .305 — — —
Exudative MNV (fellow eye) 2.000 1.236-3.236 .004 1.694 1.012-2.837 .045
cRORA (fellow eye) 2.451 1.139-5.278 .019 1.694 0.735-3.902 .216

CCT = central choroidal thickness, CI = confidence interval, cRORA = complete retinal pigment epithelial and outer retinal atrophy,
DV = drusen volume, hDC = hyporeflective drusen cores, IHRF = intraretinal hyper-reflective foci, SDD = subretinal drusenoid deposits.

TABLE 3. Baseline Biomarkers Exclude Exudative Macular Neovascularization (MNV) on Fellow Eye for Intermediate Age-related
macular degeneration Progression to Exudative MNV Over 24 Months

Univariate Analysis Multiple Logistic Regression

Risk Factor Unadjusted Odds Ratios 95% CI P Value Adjusted Odds Ratios 95% CI P Value

Central DV ≥ 0.03 mm3 2.177 1.331-3.560 .002 1.569 1.525-2.239 .092

IHRF presence 3.024 1.858-4.923 <.001 2.538 1.525-4.222 <.001
SDD presence 0.939 0.560-1.574 .811 — — —
hDC presence 2.219 1.185-4.157 .011 1.016 0.489-2.111 .966
Thick double layer 5.787 3.020-11.090 <.001 4.432 2.239-8.771 <.001
Thin double layer 1.600 0.812-3.153 .171 — — —
CCT > 200 μm 0.780 0.484-1.255 .305 — — —
cRORA (fellow eye) 2.451 1.139-5.278 .019 1.694 0.735-3.902 .216

CCT = central choroidal thickness, CI; confidence interval, cRORA = complete retinal pigment epithelial and outer retinal atrophy, DV = drusen
volume, hDC = hyporeflective drusen cores, IHRF = intraretinal hyper-reflective foci, SDD = subretinal drusenoid deposits.

TABLE 4. Baseline Biomarkers for Intermediate Age-related macular degeneration Progression to Exudative Macular
Neovascularization (MNV) Within 24 Months

Univariate Analysis Multiple Logistic Regression

Risk Factor Unadjusted Odds Ratios 95% CI P Value Adjusted Odds Ratios 95% CI P Value

Central DV ≥ 0.03 mm3 1.903 1.337-2.710 <.001 1.268 0.908-1.771 .163

IHRF presence 3.234 2.264-4.621 <.001 1.913 1.373-2.666 <.001
SDD presence 1.103 0.762-1.595 .604 — — —
hDC presence 2.062 1.269-3.350 .003 0.923 0.600-1.419 .714
Thick double layer 5.077 3.092-8.338 <.001 2.284 1.540-3.385 <.001
Thin double layer 1.495 0.874-2.558 .140 — — —
CCT > 200 μm 0.628 0.444-0.890 .010 0.836 0.610-1.145 .264
Exudative MNV (fellow eye) 2.460 1.723-3.513 <.001 1.576 1.147-2.164 .005
cRORA (fellow eye) 1.870 1.002-3.490 .046 1.145 0.679-1.931 .611

CCT = central choroidal thickness, CI = confidence interval, cRORA = complete retinal pigment epithelial and outer retinal atrophy,
DV = drusen volume, hDC = hyporeflective drusen cores, IHRF = intraretinal hyper-reflective foci, SDD = subretinal drusenoid deposits.

VOL. 247 OCT RISK FACTORS FOR EXUDATING NEOVASCULAR AMD 141
increased risk for progression to exudative MNV within a
2-year period. IHRF, a thick DLS, and fellow eye exudative
MNV were independent risk factors for progression to ex-
udative MNV.
Among the biomarkers, a thick DLS was the strongest
predictor, though it was only evident in 9.6% of cases at
baseline. A thin DLS, however, was not a risk factor for
exudative MNV. In our analysis, we used qualitative reflec-
tivity criteria to distinguish between thick and thin DLSs
as we could not a priori define a consensus thickness cri-
teria to distinguish these lesions. Our overall objective for
differentiating thin and thick DLS lesions was to distin-
guish nonexudative type 1 MNV lesions from regions of
BLD without the benefit of OCTA. Specifically, we defined
a thin DLS by the presence of only a single low-to-medium
reflective layer between the RPE and Bruch’s membrane
bands. This interposed material in a thin DLS is presum-
ably BLD.17 In contrast, a thick DLS was identified by the
presence of more than 1 layer of different reflectivity be-
tween the RPE and Bruch’s membrane. The requirement for
multiple layers meant that the “thick DLS” was invariably
thicker than a “thin DLS” without needing to specify an ab-
solute thickness value. Moreover, the presence of multiple
layers of reflectivity indicated that some material aside from
just BLD was likely present in the sub-RPE space, increas-
ing the probability that MNV may be present.17 , 18 , 28-30 Of
course without OCTA, the specificity of a thick DLS for the FIGURE 2. A case of intermediate age-related macular degen-
presence of nonexudative MNV cannot be assured. eration that progressed to exudative macular neovasculariza-
tion (MNV). A. Optical coherence tomography (OCT) B-scan
Previous reports have shown IHRF, high DV, hyporeflec-
at baseline when the eye was classified as intermediate age-
tive foci within drusenoid lesions, and SDD as risk factors related macular degeneration. Note that a thick double-layer
for progression from iAMD to late AMD (atrophy and/or sign (DLS) is observed at the fovea. B. OCT B-scan 1 year af-
MNV alone),13 , 14 but to our knowledge, this is the first ter baseline. The internal reflectivity of the thick DLS in the
analysis to report thick DLS defined in this manner on fovea is slightly altered, but no fluid is apparent. C. OCT im-
structural OCT alone as a biomarker for progression from age 2 years after baseline. Subretinal hyper-reflective material
iAMD to exudative MNV (Figure 2). This is of clinical rel- and subretinal fluid (yellow arrow) are now evidently overlying
evance, as this determination is easy to make by the review the areas of retinal pigment epithelial elevation. The eye was
of OCT B-scans and does not require OCTA or indocya- determined to have progressed to exudative MNV, and an in-
nine green angiography (ICGA). travitreal anti-vascular endothelial growth factor injection was
DLS was first reported as a feature of polypoidal choroidal performed.
vasculopathy (PCV) and has been extensively studied in
the context of pachychoroid spectrum disease, and these deed, among the various biomarkers evaluated in our analy-
DLS lesions were thought to likely harbor type 1 MNV.16 , 28 sis, a thick DLS was the most important predictor of conver-
More recently, DLS has been reported as a feature of type 1 sion to exudative MNV. However, unlike previous studies
MNV in the context of AMD.15 , 29 that used OCTA and/or ICGA to diagnose these lesions,
The limitation of using DLS as a marker for MNV, how- we demonstrated that using structural OCT alone with our
ever, is that it is apparent that DLS can arise due to the definition of thick DLS could aid in identifying patients at
accumulation BLD alone in the absence of vascularization, higher risk for conversion.
and this BLD accumulation can become quite thick.17 This Importantly, even accounting for the presence of a thick
is the reason why we chose not to use an absolute measure- DLS, our study highlights that IHRF and fellow eye MNV
ment but rather the number of layers and the reflectivity are independently associated with a higher risk for the de-
profile to distinguish thick and thin DLS lesions. This is velopment of MNV. This is perhaps not surprising as a thick
an important distinction, as BLD may be associated with DLS or nonexudative type 1 MNV lesion likely increases
a higher risk for atrophy,17 whereas presuming that most the risk for conversion to exudative type 1 MNV, but may
thick DLS lesions were regions of nonexudative MNV, the not be relevant to other types of MNV. On the other hand,
presence of nonexudative MNV is known to be associated IHRF are known to be precursor lesions for the develop-
with a higher risk for progression to exudative MNV.20 In- ment of type 3 MNV.31

142 AMERICAN JOURNAL OF OPHTHALMOLOGY MARCH 2023

 The importance of late AMD in the fellow eye in predict-
ing conversion to exudative MNV is not surprising as eyes
with late AMD in the fellow eye were shown to be more
likely to convert to late AMD in the AREDS study.27
Importantly, a high central DV was not significantly asso-
ciated with the development of exudative MNV. In a prior
report, we observed that high central DV was a risk factor
for the development of atrophy but not exudative MNV
that appears consistent with the present study.13 Other
studies have also highlighted the importance of DV as a
predictor of progression to late AMD, but did not neces-
sarily focus on exudative MNV.32 , 33 Contrary to our re-
sults, de Sisternes and associates34 reported an automated
prediction model for the development of nAMD based on
a number of morphologic features and reflectivity proper-
ties of the drusen, including DV that was reported to be of
importance. DV on its own, however, may not be a stable
biomarker for risk prediction because drusen can appear and
disappear,32 , 33 and commonly DV will decrease before the
conversion to late AMD.35
The current study has limitations that must be consid-
ered when evaluating the results. First, our analysis is ret-
rospective and as such is subject to ascertainment bias. We
cannot establish whether our findings would extrapolate to
other populations that may have different frequencies of
baseline features. Second, our follow-up interval was lim-
ited to 2 years. It is possible that other risk factors may
have proven to be associated with risk over a longer period.
Moreover, we considered conversion within a 2-year period,
Funding/Support: No funding was obtained for this study.
Financial Disclosures: G.C.: Nidek (F). C.C.W.: Apellis (C), Genentech/Roche (C), Iveric Bio (C), Novartis (C), NGM (C), Gyroscope (C), Janssen
(C), S.R.S.: Amgen (C), Allergan (C), Genentech/Roche (C), Iveric (C), Oxurion (C), Novartis (C), Regeneron (C), Bayer (C), 4DMT (C), Centervue
(C,F), Heidelberg (C,F), Optos (C,F), Merck (C), Apellis (C), Astellas (C), Carl Zeiss Meditec (F), Nidek (F), Topcon (F). The other authors have no
conflict of interest to disclose. All authors attest that they meet the current ICMJE criteria for authorship.
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MARCH 2023