Polypoidal Choroidal Vasculopathy

Definition, Pathogenesis, Diagnosis, and Manageme

nt

Chui Ming Gemmy Cheung, FRCOphth,1,2 Timothy Y. Y. Lai, MD,3 Paisan Ruamviboonsuk, MD,4
Shih-Jen Chen, MD,5 Youxin Chen, MD,6 K. Bailey Freund, MD,7,8 Fomi Gomi, MD,9 Adrian H. Koh, MD,10
Won-Ki Lee, MD,11 Tien Yin Wong, FRCS, PhD1,2

Polypoidal choroidal vasculopathy (PCV) is an age-related macular degeneration (AMD) subtype and is seen
particularly in Asians. Previous studies have suggested disparity in response to intravitreal injections of
antievascular endothelial growth factor (VEGF) agents between PCV and typical AMD, and thus, the preferred
treatment for PCV has remained unclear. Recent research has provided novel insights into the pathogenesis of
PCV, and imaging studies based on OCT suggest that PCV belongs to a spectrum of conditions characterized by
pachychoroid, in which disturbance in the choroidal circulation seems to be central to its pathogenesis. Advances
in imaging, including enhanced depth imaging, swept-source OCT, en face OCT, and OCT angiography, have
facilitated the diagnosis of PCV. Importantly, 2 large, multicenter randomized clinical trials evaluating the safety
and efficacy of anti-VEGF monotherapy and combination with photodynamic therapy (PDT) recently reported
initial first-year outcomes, providing level I evidence to guide clinicians in choosing the most appropriate therapy
for PCV. In this review, we summarize the latest updates in the epidemiologic features, pathogenesis, and ad-
vances in imaging and treatment trials, with a focus on the most recent key clinical trials. Finally, we propose
current management guidelines and recommendations to help clinicians manage patients with PCV. Remaining
gaps in current understanding of PCV, such as significance of polyp closure, high recurrence rate, and hetero-
geneity within PCV, are highlighted where further research is needed. Ophthalmology 2018;125:708-724 ª 2018
by the American Academy of Ophthalmology

708
Age-related macular degeneration (AMD) is a major cause
ª 2018 by the American Academy of Ophthalmolo
of blindness worldwide and is projected to affect 170
gy
million persons by 2040, with 110 million in Asia alone.1 Published by Elsevier Inc.
Polypoidal choroidal vasculopathy (PCV) is believed to be
a subtype of neovascular AMD in which type 1
neovascularization is associated with an abnormal
branching network of vessels (branching vascular network
[BVN]), with aneurysmal dilations referred to as polyps.2
Significant variations in the epidemiologic, clinical, and
imaging features and the natural history between PCV and
typical neovascular AMD have been reported.2,3
Importantly, whereas intravitreal injections of antie
vascular endothelial growth factor (anti-VEGF) agents have
been the standard of care for typical neovascular AMD for
more than a decade, the preferred treatment for PCV has
remained unclear. Recently, the first-year results of 2 major
randomized trials have been released and have provided new
evidence on optimal treatment for PCV: EVEREST-II
compared intravitreal ranibizumab (IVT-R) monotherapy
with combination therapy comprising IVT-R plus photody-
namic therapy (PDT), whereas the PLANET study compared
intravitreal aflibercept (IVT-AFL) monotherapy with or
without rescue PDT.4,5 The aim of this review was to sum-
marize the latest evidence on the diagnosis and management
of PCV, covering epidemiologic and risk factors,

pathogenesis, definition and classification, and management
options and to propose up-to-date management guidelines for
clinicians managing patients with this condition.
Definition
Polypoidal choroidal vasculopathy is a vascular disease of
the choroid first described in the 1990s. Clinically it is
characterized by recurrent serosanguineous maculopathy and
presence of orange nodules.6,7 Currently, there is no uni-
versally accepted definition of PCV. Most investigators base
the diagnosis of PCV on indocyanine green angiography
(ICGA) findings that demonstrate presence of polypoidal
dilatations. In the absence of ICGA, accurately differentiating
PCV from typical AMD remains challenging. As such,
variability in incidence reported in different ethnic groups
will at least in part be influenced by the frequency of ICGA.
Other controversies remain as to whether PCV belongs to the
AMD spectrum, because several hallmarks of AMD,
including drusen, pigmentary changes, and atrophy, are
relatively uncommon in PCV. Recently, the importance of
thick choroid (pachychoroid) in PCV led some investigators
to suggest PCV falls within the pachychoroid spectrum of
conditions that may have a different cause from AMD.
https://doi.org/10.1016/j.ophtha.2017.11.019
ISSN 0161-6420/17
 Cheung et al
Epidemiologic Features and Risk Factors
Prevalence and Incidence
Although there are increasing data on the epidemiologic
features of AMD in Asians, with reported prevalence of
early AMD and late AMD ranging from 1.4% to 37.9% and
0.1% to 7.3%, respectively, there are few population-level
studies on PCV, and accurate estimates of PCV preva-
lence is limited because of difficulties in diagnosing PCV
from clinical examination and fundus photographs. Only 1
study, the Beijing Eye Study, has reported the prevalence of
PCV in the general population at 0.3%, estimated based on
photographic and OCT data. In clinic-based case series of
8
Asian patients with neovascular AMD, the proportion of
PCV based on ICGA findings has been estimated to be
between 20% and 60%. e In contrast, in white European
8 17
patients, the proportion of PCV is only 8% to 13% in cases
in which ICGA were performed. 18
Risk Factors
Whereas risk factors for AMD, including genetic risk fac-
tors, have been investigated extensively, few studies have
evaluated specific risk factors for PCV (Table 1). In general,
these studies suggest that systemic factors for PCV and
typical AMD are similar. For example, a consistent risk
factor for both PCV and typical AMD is cigarette
smoking. e A case-control study in Singapore that
19 22
directly compared risk factors for PCV and typical AMD
showed that cigarette smoking was associated with both
PCV and typical AMD (odds ratios, 4.4 and 4.9, respec-
tively) to a similar extent. Other studies showed that
19
higher body mass index is associated with PCV, as in
typical AMD. Serum levels of inflammatory markers
20
(e.g., C-reactive protein) also have been associated with
PCV (Table 1). Some risk factors, such as chronic
21,23
kidney disease, which has been associated with typical
AMD, may be less important for PCV. 24,25
Unlike typical AMD, the genetics of PCV are relatively
unknown. Existing data suggest some genetic markers are
shared between AMD and PCV, whereas others are more
unique to PCV. e However, many of these associations
26 29
were not found consistently across studies. In a recent meta-
analysis, 31 SNPs in 10 genes and loci exhibited significant
associations with PCV with major pathways implicated in
inflammation, lipid, and complement cascade. Although 29
differences in genetic locus could imply differential
implication on the pathogenesis or treatment outcomes of
PCV and typical AMD, this remains to be determined.
Pathogenesis
Since the first description of PCV,6,7 there has been ongoing
debate regarding the clinical nature and pathogenesis of this
peculiar entity. When PCV was first reported, the authors’
clinical observations and angiographic interpretations led
them to conclude that the vascular lesions were located in the
inner choroid below Bruch’s membrane.30 Subsequently,
several histopathologic studies described conflicting
□ Polypoidal Choroidal Vasculopathy
locations for PCV’s aberrant vessels (intra-Bruch’s
membrane vs. choroid) and also showed evidence for
newly proliferating fibrovascular tissue.31e35 The role of
VEGF in the pathogenesis of PCV also is uncertain. Evidence
of strong VEGF expression was found in vascular endothelial
and retinal pigment epithelium (RPE) cells in some studies
analyzing surgical specimens,36,37 but a lack of VEGF
expression also has been reported.33 The concentration of
VEGF in aqueous humor was found to be higher in eyes
with PCV compared with normal controls, but seems much
lower compared with eyes with typical neovascular
AMD.38,39 Other studies reported elevated proinflammatory
cytokine levels, including interleukin-1b and interleukin-23,
in aqueous and vitreous samples, which support a role
for inflammation in PCV.40,41 Animal studies also demon-
strated that increased expression of serine protease HTRA1
may play a role in the pathogenesis of PCV because trans-
genic mice expressing human HTRA1 were found to develop
retinal features of PCV.42
Clinical and imaging studies also have provided insights
into pathogenesis.43 A paucity of drusen, pigmentary
changes, geographic atrophy, and disciform scar formation
are features that often distinguish PCV from typical AMD.2
On spectral-domain (SD) OCT, the abnormal vasculariza-
tion causing exudation in eyes with PCV (polyps and BVN)
are identified consistently between an elevated RPE and the
thin hyperreflective line representing the outer portion of
Bruch’s membrane (Figs 1e3).44e46 These findings indicate
that the neovascular lesions of PCV develop within Bruch’s
membrane (below the basal lamina of the RPE) as a variant of
type 1 neovascularization.47 However, several studies using
enhanced depth imaging OCT have demonstrated choroidal
thickening and other structural changes of the choroid in
eyes with PCV (Figs 3 and 4). These findings are in contrast
to choroidal thinning that often is observed in eyes with
type 1 neovascularization occurring in typical AMD (occult
CNV), suggesting different pathogenic mechanisms.48e50
There is evolving understanding of the interrelationship
between pachychoroid, type 1 neovascularization, and PCV.
The term pachychoroid originally was conceived to reflect
choroidal congestion and choroidal hyperpermeability
manifested by choroidal thickening, dilated choroidal ves-
sels, and characteristic findings on ICGA. New information
has broadened the original description of pachychoroid to
emphasize additional qualitative features. These features
include focal choroidal thickening that is localized to the
disease focus and attributable to pathologically dilated
Haller layer veins (pachyvessels). Pachyvessels are associ-
ated with focal attenuation of overlying choriocapillaris and
Sattler layers, which brings them closer to the Bruch’s
membraneeRPE complex.51 In patients with PCV, although
the mean choroidal thickness, including the subfoveal area,
is increased, there is pronounced interindividual variability.
In one cohort that included more than 300 eyes with PCV,
the mean subfoveal choroidal thickness was approximately
270 mm, but 40% of eyes showed subfoveal choroidal
thickness of less than 200 mm.52 In these eyes,
pachyvessels and related choroidal changes were
associated topographically with sites of BVN ingrowth,
which suggests that pachychoroid features underlie the
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Table 1. Systemic and Genetic Risk Factors of Polypoidal Choroidal Vasculopathy

95% Confidence
Study Sample Size Ethnicity Risk Factors Odds Ratio Interval

Cackett et al, 2011* PCV, n ¼ 123;

Chinese Smoking 4.4 2.5e7.7
controls, n ¼ 1489
Woo et al, 2015* PCV, n ¼ 111; Koreans Smoking, spherical 2.460, 1.187, 2.382 1.359e4.453,
controls, n ¼ 395 equivalent, ARMS2 1.033e1.364,
rs10490924 1.549e3.664
Nakata et al, 2013* PCV, n ¼ 581; Japanese CETP rs3764261 1.50 1.17e1.92
controls, n ¼ 793
Zhang et al, 2013* PCV, n ¼ 250; Chinese CETP rs5882 1.63 1.25e2.12
controls, n ¼ 204
Meng et al, 2015* PCV, n ¼ 291;
controls, n ¼ 221 Chinese CAD, CETP 3.381, 1.444, 1.393 1.377e8.302,
rs3764261, LIPC 1.047e1.991,
Liu et al, 2014* PCV, n ¼ 233; Chinese CETP rs1532085
rs3764261 1.80 1.084e1.789
1.30e2.49
controls, n ¼ 275
Kikuchi et al, 2007* PCV, n ¼ 97; Japanese CRP (>0.95 mg/l) 3.53 1.49e8.40
controls, n ¼ 262
Sakurada et al, 2015* PCV, n ¼ 22; Japanese CRP, IP-10 1.014, 1.13 1.003e1.024,
controls, n ¼ 20 1.04e1.22
Cheung et al, 2017* PCV, n ¼ 241; Singaporeans; Age, BMI, HDL 1.05, 1.07, 1.84, 0.83 1.02e1.08,
controls, n ¼ 1824 predominantly cholesterol, axial 1.01e1.14,
Chinese length 1.02e3.35, 0.71e0.99
PCV, n ¼ 86; Genetics: CFH 0.62, 2.53 0.37e1.02, 1.56e4.11
controls, n ¼ 1267 rs800292, ARMS2
rs10490924

ARMS2 ¼ age-related maculopathy susceptibility protein 2; BMI ¼ body mass index; CAD ¼ coronary artery disease; CETP ¼ cholesteryl ester transfer
protein; CFH ¼ complement factor; CRP ¼ C-reactive protein; HDL ¼ high-density lipoprotein; IP-10 ¼ interferon- g inducible protein; nAMD ¼
neovascular age-related macular degeneration; PCV ¼ polypoidal choroidal vasculopathy.
*As compared with controls.

pathogenesis of the type 1 neovascularization and PCV AMD findings, was reported recently. This condition was
53

lesions, even in eyes with normal or subnormal choroid
thickness.52
Furthermore, although AMD is the most common cause
of type 1 neovascularization, a form of type 1 neo-
termed pachychoroid neovasculopathy and was described as
falling within a spectrum of pachychoroid-related disorders
including pachychoroid pigment epitheliopathy, central
serous chorioretinopathy, and PCV. e These studies
53 57

vascularization associated with choroidal thickening provide further evidence that PCV is a pachychoroid-driven
(pachychoroid), but lacking soft drusen and other typical disorder with findings of similar choroidal features and the

Figure 1. Spectral-domain OCT scan (right) obtained through the polyp imaged in indocyanine green angiography (left) revealing multiple pigment
epithelial detachments (PEDs), PED notch (arrow), and a sharp PED peak (arrowhead) corresponding to the polyp, which can be called a thumb-like
protrusion. Meanwhile, this thumb-like protrusion contains a hyporeflective lumen within hyperreflective lesions adherent to the retinal pigment
epithelium (asterisk).

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 Cheung et al □ Polypoidal Choroidal Vasculopathy

Figure 2. Spectral-domain OCT scan (right) with corresponding fluorescein angiography (left) showing a double-layer sign (black arrowhead), pigment
epithelial detachment notch (black arrow), and a thumb-like polyp containing hyperreflective rings with internal hyporeflective lumen (white arrow).

occurrence of polypoidal lesions in eyes lacking typical
AMD features.48e50,53,54,56,58e61
Diagnostic Criteria
Based on both new understanding of its pathogenesis and
increasing data from imaging studies, the current thinking is
that PCV is a variant of a type 1 neovascularization, pre-
senting with clinical and imaging findings that differ from
those of typical neovascular AMD. There are several
traditional classifications of PCV and diagnostic criteria
based on clinical and ICGA findings (Table 2). According to
the Japanese Study Group guidelines,62 PCV may be
diagnosed as definite or probable based on fundus
examination, ICGA, or both. The EVEREST criteria first
were used by the central reading center of the multicenter
randomized clinical trial comparing IVT-R monotherapy,
OCT findings are more accessible and are actually highly
reliable (Figs 1 and 2). Spectral-domain OCT B-scans
commonly show highly protruded RPE with underlying
moderate reflectivity, double-layer hyperreflective lines, and
notched pigment epithelial detachment (PED). Future
diagnostic criteria should aim to include multimodal imag-
ing criteria.
Clinical and Imaging Features
Clinical Features
Polypoidal choroidal vasculopathy presents with a seros-
anguineous exudative maculopathy characterized by a
paucity of drusen, pigmentary changes, geographic atrophy,
and disciform scar formation, with common features of
2
PCV summarized in Table 3. Polypoidal choroidal
9,66

PDT monotherapy, and combination therapy of IVT-R and
PDT.63,64 One study suggested that the Japanese PCV and
EVEREST classification systems of flash fundus camera-
based ICGA and confocal scanning laser ophthalmoscope
based ICGA largely are similar, with the EVEREST study
criteria having slightly higher specificity than the use of
subretinal focal hyperfluorescence alone.65 Although ICGA
traditionally is believed to be essential to diagnose PCV,
vasculopathy should be classified based on the location of
the polyps: subfoveal, juxtafoveal, extrafoveal, peripapil-
lary, or peripheral. Based on the presentation, PCV also can
be classified into quiescent, exudative, or hemorrhagic
subtypes. Quiescent PCV is not associated with subretinal or
intraretinal fluid or hemorrhage. Exudative PCV is associ-
ated with subretinal fluid, neurosensory retinal thickening,
PED, lipid exudation, or a combination thereof, but without

Figure 3. Spectral-domain OCT image (right) with corresponding fluorescein angiography (left) showing the pachychoroid feature of polypoidal choroidal
vasculopathy.

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 Ophthalmology Volume 125, Number 5, May 2018
Figure 4. Spectral-domain OCT image (left) showing a moderate focal choroidal excavation (arrowhead). The position of the line scan is shown (dotted line)
in the corresponding fluorescein angiography ([FA] middle) and indocyanine green angiography ([ICGA] right).
hemorrhage. Polypoidal choroidal vasculopathy has been
reported to have higher incidence of serous retinal detach-
ment, greater serous retinal detachment height, and lower
incidence of intraretinal edema than eyes with typical neo-
vascular AMD.67 Hemorrhagic PCV is associated with
subretinal or sub-RPE hemorrhage, with or without exuda-
tive changes.68,69 Eyes with PCV are more likely than
typical neovascular AMD to demonstrate recurrent serous or
hemorrhage PED, massive macular hemorrhage, break-
through vitreous hemorrhage, or a combination thereof. This
classification has not been validated, and correlation with
visual outcome or treatment response has not been evaluated
in detail.70
OCT Features
The most commonly seen SD OCT features in PCV include
PED, double-layer sign, thickened choroid, and sometimes
focal choroidal excavation (Table 3; Figs 1e5). These
features should alert a clinician of the possibility of PCV
even in populations in which PCV prevalence is low or in
Table 2. Polypoidal Choroidal Vasculopathy Diagnostic Criteria
Japanese Study Group Guidelines
Definite PCV:
Elevated orange-red lesions on fundus examination, and/or
Polypoidal lesions on ICGA
Probable PCV:
Only abnormal BVN seen on ICGA or recurrent hemorrhagic or serous
RPE detachments, or both, without features of definite PCV
EVEREST criteria (based on confocal scanning laser ophthalmoscopy)
Focal hyperfluorescent lesions appearing before 6 minutes on ICGA, plus
at least 1 of the following:
BVN on ICGA
Pulsatility on dynamic ICGA
Nodular appearance when ICGA viewed stereoscopically
Hypofluorescent halo on ICGA
Orange subretinal nodule on color photograph
Associated massive submacular hemorrhage
BVN ¼ branching vascular network; ICGA ¼ indocyanine green angi-
ography; PCV ¼ polypoidal choroidal vasculopathy; RPE ¼ retinal
pigment epithelium.
712
which ICGA is not performed routinely. In addition to
assisting the diagnosis of PCV, SD OCT also is useful in
monitoring the changes in subretinal fluid, PED, or both
after therapy.
Presence of subretinal fluid and intraretinal fluid are
markers of active exudative activity and often correlate to
areas of leakage on fluorescein angiography (FA). In PCV,
different parts of the lesion complex may have different
levels of activity. The predominant active component often
can be determined by colocalization of the area of fluid with
polyps, BVN, or both on ICGA or by colocalization of PED,
BVN, or both on OCT. This detail may have impact on the
choice of treatment method.
OCT angiography (OCTA) is a new imaging method to
visualize the vasculature noninvasively and has been
suggested to be a possible replacement for FA for diagnosis
of typical neovascular AMD. OCT angiography depicts the
abnormal vessels of PCV in 2 dimensions, like ICGA.
However, the consistency of findings between OCTA and
ICGA needs further investigation.71e74 Although the BVN
generally could be visualized using OCTA, the detection
rates of polyps using OCTA have been found to be
considerably lower compared with ICGA.72,73,75 Possible
reasons for an incomplete detection rate of polypoidal
lesions with OCTA are signal attenuation from overlying
structures and low blood flow speed within the polyps.
Therefore, with the present technology, OCTA is unable to
replace ICGA in the assessment of PCV.
Indocyanine Green Angiography Features
Indocyanine green angiography traditionally has been the
gold standard investigation tool used to diagnose PCV. Single
or multiple polyps can be seen in the early phase of ICGA. As
noted, both flash digital fundus photography ICGA or the
confocal scanning laser ophthalmoscope systems can detect at
least 80% of the typical nodular lesions of the PCV, although
the BVN and other features may be visualized better with
confocal scanning laser ophthalmoscopy. Some groups 76
have proposed to classify PCV further into different
subtypes according to the appearances on ICGA (Table 3).
However, there is no universal agreement on the visual
prognosis related to these subclassifications. It has been
suggested further that pulsatile polyps tend to rupture and
 Cheung et al □ Polypoidal Choroidal Vasculopathy

Table 3. Summary of Common Clinical and Imaging Features of Polypoidal Choroidal Vasculopathy
Clinical features
Reddish-orange nodular structure s beneath the retina
Serous neurosensory detachment
Submacular hemorrhage
Serous or hemorrhagic pigment epithelial detachment, or both
RPE atrophy
Subretinal fibrosis
SD OCT features
PED
May be sharp PED peak, PED notch, septae, M-shaped PED.
When corresponding to the polyps on ICGA images, polyps frequently appear as sharp inverted V-shaped anterior protrusions or dome-shaped elevations
of RPE on SD OCT, and they have been called thumb-like polyps or PED peaks (Fig 1).
May contain hyperreflective rings with internal hyporeflective lumens.
Double-layer sign
Presence of 2 highly reflective layers (the RPE and a sub-RPE layer) within the area of the network of vessels
Although it can be detected in several fundus diseases, approximately 85% to 95% of the eyes within PCV showed double-layer sign (Fig 2).
Pachychoroid (enhanced depth imaging OCT or swept-source OCT)
Thickened choroid (often >300 mm).
May be associated with choroidal vascular hyperpermeability on ICGA.
Choriocapillaris and Sattler layers usually are attenuated at sites of polypoidal disease, but Haller vessels are markedly dilated.
May exhibit focal choroidal excavation (Fig 4), which can be associated with choroidal diseases, including PCV, as well as CSC, AMD, and CNV, but it
is most prevalent in PCV (6.0%).
En face OCT
PCV lesions and the lesions are seen as RPE rings with inner reflectivity with or without a BVN (Fig 5).
The polypoidal lesions detected on en face OCT generally correlate well with the lesions seen in ICGA.
ICGA
See Table 2.
May be used to classify into subtypes:
Polyps: single, cluster, string configuration, pulsatile vs. nonpulsatile
Type 1 (type A): ICGA fill abnormal choroidal vasculature simultaneously with other choroidal vessels to form BVN and polyps.
Type 2 (types B and C): feeding vessels are common and on fill with ICGA after the filling of choroidal arterioles and are emptied rapidly. Type 2 PCV
generally have larger lesion size on ICGA and significantly thinner choroid compared with type 1.
FA
Usually appear as occult NV
Classic NV pattern can be seen in a small proportion of cases. PCV appearing as classic CNV on FA may be associated with poorer visual prognosis.

AMD ¼ age-related macular degeneration; BVN ¼ branching vascular network; CNV ¼ choroidal neovascularization; CSC ¼ central serous
chorioretinopathy; FA ¼ fluorescence angiography; ICGA ¼ indocyanine green angiography; NV ¼ neovascularization; PCV ¼ polypoidal choroidal
vasculopathy; PED ¼ pigment epithelial detachment; RPE ¼ retinal pigment epithelium; SD ¼ spectral-domain.

cause severe hemorrhage,77 whereas grape-like cluster polyps
tend to require more intravitreal anti-VEGF injections.78
Another group has proposed to classify PCV into 2
subtypes according to appearances on ICGA and
pathophysiologic features.79e82 Polypoidal choroidal vas-
culopathy type 1 was proposed to be caused by abnormalities
of the choroidal vasculature, whereas type 2 was believed to
relatively limited because of the inability of FA to visualize
sub-RPE structures, including polyps. Furthermore, greater
leakage with fluorescein dye, compared with ICGA, makes
the lesions of PCV visualized on FA appear larger than
those visualized on ICGA. Therefore, if FA is used as
guidance for the use of PDT in PCV, an unnecessarily larger
spot size may be applied. However, FA may be superior to
85

be associated with choroidal neovascularization. A study
using a similar classification reported that type A (corre-
sponding to type 1) had the best visual outcome over 5 years.
Recently, a study based on choroidal vascular features on SD
OCT also supported there may be 2 subtypes of PCV: typical
ICGA for detecting and monitoring leakage of BVN.
Although ICGA is considered by many as the most
reliable means for diagnosing PCV, it is not performed
routinely in many parts of the world, particularly in areas
where PCV is uncommon. De Salvo et al reported that 86

PCV with increased choroidal vascularity, as opposed to
polypoidal choroidal neovascularization with low choroidal
vascularity.83 More studies are needed to validate further the
impact of this and other classification on visual prognosis and
treatment strategies.84
Fluorescein Angiography Features
Although FA is useful for diagnosis and classification of
typical neovascular AMD, the use of FA in PCV is
based on a combination of 3 of the following 4 OCT-
based signsdmultiple PEDs, sharp PED peak, PED notch,
and rounded sub-RPE hyporeflective areadthey were able
to diagnose PCV based on OCT with a sensitivity of 94.6%
and specificity of 92.9% from a cohort of 51 patients from
the United Kingdom. In another study comparing 113 eyes
with PCV and 75 eyes with neovascular AMD, a combi-
nation of 2 of the following 3 signsdPED, double-layer
sign, and thumb-like protrusiondwas reported to detect
PCV with sensitivity of 89.4% and specificity of 85.3%.

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 Ophthalmology
Figure 5. Hyperreflective signal of retinal pigment epithelium shown on en face OCT image (right) delineating the similar structure of polypoidal choroidal
vasculopathy seen on indocyanine green angiography (ICGA) image (left).
These studies suggest that SD OCT signs can be very
helpful as a screening tool in areas where ICGA is not
performed routinely. However, for planning of PDT treat-
ment, information from ICGA remains essential.87
Treatment Options
Unlike typical neovascular AMD, where intravitreal anti-
VEGF therapy has been the mainstay of care for over a
decade, currently a wide spectrum of treatment options for
PCV exists. These include focal laser photocoagulation,
verteporfin PDT, anti-VEGF therapy (aflibercept, ranibizu-
mab, and bevacizumab), and various combinations of these
therapies. Advantages and disadvantages of individual
methods have been summarized in Table 4.
Focal Laser Therapy
Focal laser long has been used to ablate extrafoveal and
extramacular polyps identified on ICGA. e Stabili- 7,82,88
zation or even improvement of vision has been described in
these reports. However, limitations include scarring and
recurrence. Focal laser therapy largely has been superseded
by newer therapeutic options, but nevertheless remains a
useful therapeutic option for extrafoveal polyps. Combina-
tion with anti-VEGF therapy has been described to be
effective in eyes with extrafoveal PCV in which exudation
or hemorrhage extends to the fovea. A combination with
93
anti-VEGF, selective PDT, or both has been described to
be effective in recurrent PCV. 94
Verteporfin Photodynamic Therapy
Monotherapy
Before the advent of anti-VEGF therapy, PDT was used
widely for PCV, and favorable results have been publishe
d in many clinical studies. e However, as further
2,22,63,95 99
experience with PDT accumulated, reports with longer
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Volume 125, Number 5, May 2018
follow-up showed less favorable results. A meta-analysis 100
of 29 studies with 3-year visual outcomes reported mean
best-corrected visual acuity (BCVA) improvement at years
1 and 2, but returned to baseline after 3 years or more. 101
Other concerns include persistence of the BVN and 13,102
rare incidences of complications, including subretinal
hemorrhage, choroidal infarction, and RPE tear. e 43,68,103 105
This experience has somewhat dampened the initial enthu-
siasm for PDT as monotherapy for PCV, particularly in eyes
with good presenting vision. Modifications to the settings of
PDT, such as limitation of spot size to include only active
polyps, but not the BVN, and reduced-fluence PDT,
94 106,107
have been proposed to reduce the frequency of these rare
adverse events.
AntieVascular Endothelial Growth Factor
Monotherapy
After reports from the pivotal clinical trials in typical neo-
vascular AMD, anti-VEGF therapy has superseded PDT as
92
the first line of therapy. e Early studies suggested that
108 110
despite a limited polyp regression rate with anti-VEGF
monotherapy (25%e40%), e anti-VEGF mono-
111 114
therapy has favorable visual outcomes. The PEARL
studies consisted of 2 open-label studies of PCV using
115
monthly IVT-R 0.5 mg (PEARL 1 study) or 2.0 mg
(PEARL 2 study). In both studies, significant improvement
in mean BCVA was accompanied by reduction in subretinal
hemorrhage, subretinal fluid, or both. The LAPTOP 115
study is a phase 4 prospective, multicenter, randomized
116
trial comparing the effect of PDT and IVT-R in PCV us-
ing a pro re nata retreatment regimen (Table 5). At both
month 12 and month 24, patients in the IVT-R arm ach-
ieved better visual outcomes than patients in the PDT
arm. However, angiographic results were not evaluated in
116
these studies.
Another anti-VEGF agent, aflibercept, also has been
approved for the treatment of typical neovascular AMD.
 Cheung et al □ Polypoidal Choroidal Vasculopathy
Table 4. Summary of Advantages and Disadvantages of Commonly Used Treatment Methods in Polypoidal Choroidal Vasculopathy
Method Advantages
Disadvantages Focal laser
For extrafoveal and extramacular polyps: stabilization or
improvement of vision
Combination with anti-VEGF may be effective for
extrafoveal PCV with exudation or hemorrhage
extending to fovea
Combination with anti-VEGF, selective PDT, or both may
limit PDT exposure in recurrent cases
Low cost
Few re-treatments needed
Photodynamic therapy Effective in stabilization of vision in 80%
Improvement of vision (3 lines) reported in 25%e55%
High rate of polyp regression noted on ICGA
Possibility of reducing fluence to improve safety profile
Limited re-treatments needed
Anti-VEGF therapy Favorable visual outcome
Requires minimal equipment
Not dependent on availability of ICGA
BVN ¼ branching vascular network; ICGA ¼ indocyanine green angiography; PCV ¼ polypoidal choroidal vasculopathy; PDT ¼ photodynamic therapy;
RPE ¼ retinal pigment epithelium; VEGF ¼ vascular endothelial growth factor.
The efficacy of IVT-AFL administered every 8 weeks after
3 monthly loading doses in neovascular AMD has been
demonstrated in the VIEW studies, which compared the
110
efficacy and safety of IVT-AFL and IVT-R in patients
with neovascular AMD. Within the VIEW study population,
baseline ICGA was available in 88 of 101 Japanese patients,
among whom PCV was confirmed in 29 eyes (33%). A post
hoc analysis reported that the visual acuity and retinal
thickness outcomes in the PCV and non-PCV eyes receiving
IVT-AFL were comparable. However, angiographic
117
changes were not available in this post hoc analysis.
Several other case series have reported favorable visual
outcome and polyp regression rate ranging from 48% to
75% in patients with PCV treated with IVT-AFL. e 118 121
There have been fewer studies reporting the results of
bevacizumab for PCV. Favorable outcomes in improving
vision and macular exudation, but limited polyp regression,
have been reported. e 122 125
Key Clinical Trials
The EVEREST-I study was the first randomized controlled
trial in PCV that compared the efficacy and safety of IVT-R
monotherapy, PDT monotherapy, and combination therapy
with IVT-R and PDT in 61 patients. The primary end63
point was polyp regression based on ICGA results at
month 6. The results demonstrated PDT alone or
combined with IVT-R achieved a significantly higher
polyp regression rate (71.4% and 77.8%, respectively)
compared with IVT-R monotherapy (28.6%). Despite the
lower polyp closure rate, IVT-R monotherapy achieved
higher visual gain than PDT monotherapy (þ9.2 letters
Laser limited to polyps: treating BVN may result in large
scar and paracentral scotoma
Scar enlargement and late RPE atrophy
Residual untreated BVN may be a source of recurrent polyps
or persistent exudation
High recurrence rate
Less favorable long-term vision: return to baseline or drop to
less than baseline after 2 yrs or more
Repeated PDT may cause cumulative damage to the normal
choroidal vasculature and RPE
BVN usually persists despite PDT and acts as a source of
recurrent polyps or persistent exudation
Rare cases of acute vision loss resulting from subretinal
hemorrhage, choroidal infarct, and RPE tear
High cost
Limited polyp regression (25%e40%)
Multiple injections may be needed
Possible differences between individual agents
Relatively high cost
Small risk related to intravitreal injection procedure and
exposure to anti-VEGF agents
vs. þ7.5 letters), although the difference was not statistically
significant. The results of EVEREST suggested the need for
larger studies with longer follow-up with visual acuity as the
primary end point.
This gap was addressed in 2 pivotal randomized
controlled trials (EVEREST-II and PLANET) evaluating
anti-VEGF and combination therapy (Tables 5 and 6)
providing level 1 evidence to help guide clinicians in the
optimal management of PCV. EVEREST-II compared
IVT-R monotherapy with combination therapy of IVT-R
plus PDT at baseline, whereas PLANET compared IVT-
AFL monotherapy with or without rescue PDT, which
was available after 3 months. Both studies reported signif-
icant visual acuity gain in the anti-VEGF monotherapy arms
at 1 year (þ5.1 letters in EVEREST-II; þ10.8 letters in
PLANET). Polyp closure rates were 34.7% (EVEREST-II)
and 38.9% (PLANET). Fifty-one percent of eyes in
EVEREST-II had no disease activity (defined as absence of
persistent or new polyps based on OCT, FA, ICGA, and
color fundus examinations) at 12 months, whereas 81.7% of
eyes in PLANET had no active polyps (active polyps
defined as polyps with leakage on FA, subretinal or intra-
retinal fluid on OCT, or presence of new hemorrhage). The
mean number of injections was 7.3 (EVEREST-II) and 8.1
(PLANET). 4,5
These results were corroborated further by the DRAGON
study, a phase 4 randomized, double-masked, multicenter
126
trial based in China comparing the efficacy of IVT-R
monotherapy using a monthly fixed dosing regimen versus
a pro re nata regimen. At baseline, 41.7% of the 334
126
enrolled patients were diagnosed with PCV based on
ICGA results. Significant improvement in BCVA was
715
716

Table 5. Updated Randomized Trials in Polypoidal Choroidal Vasculopathy

Best-Corrected Visual No. of A

Acuity (Early Photodyn
No. of
Treatment Diabetic
AntieVascular Baseline Gain AntieVascular
Retinopathy Study Letters)
Endothelial Growth Duration Polyp Closure
Endothelia l Growth
Study Factoyr Treatments
Therap Agent Treatment Arms (mos) RatreTreatments
Facto (%)
EVEREST I63 Ranibizumab PRN Ranibizumab 3 þ PRN 6 49.0 9.2
28.6* 5.2NA
Verteporfin PDT 57.2 7.5 71.4*
4.2 1.7
Ranibizumab PRN þ PDT 56.6 10.9 77.8*
1.43.9
EVEREST-II Ranibizumab PRN
4

RanibizumabRanibizumab
monthly vs. 24 68 12.7 Not reported
k
11.2 NA
Ranibizumab 3 þ PRN 12 y
61.2
Ranibizuma b PRN
monthly/PRN 69 9.4 k
8.4 NA
5.1 z
34.7 7.3 z
NA
Ranibizumab PRN þ PDT 61.1 8.3 z

FUJISAN 130
Ranibizumab PRN 69Ranibizumab
12
z
54.33þ PRN þ Ophthalmolog
8.1 {y62.1
5.2 Volume 125, 4.5 Number 5, May 2018
1.5 1.14
initial PDT LAPTOP Ranibizumab PRN
116,x

Ranibizumab 3þ PRN þ Ranibizumab 3 þ PRN 12 y

84 deferred PRN PDT # 4 Not reported 5.8

NA
Verteporfin PDT 88 □2 (loss)
NA 2.2
DRAGON subgroup
analysis (41.7%
126

of enrolled patients
with PCV)

54.9 8.8 {
54.8
6.8 1.45 #

PLANET5
Aflibercept 3 þ Q8 12 y
57.7 10.7** 38.9
A 8.1 NA
fli Aflibercept þ rescue PDT yy
59 10.9** 44.8
b 8.0 0.2
er
c
e
pt
8-
w
k
fi
x
e
d

d
o
si
n
g

NA ¼ not applicable; PCV ¼ polypoidal choroidal vasculopathy; PDT ¼ photodynamic therapy; PRN ¼ pro re nata.
*Primary end point: verteporfin PDT combined with ranibizumab or verteporfin PDT alone was superior to ranibizumab monotherapy in achiev
ing complete polyp regression; P < 0.01.
y
Primary end point was reported at month 12 although these studies had follow-up after 12 months.
z
Primary end points at month 12: ranibizumab with PDT achieved superior best-
corrected visual acuity gain (P ¼ 0.013) and polyp regression (P < 0.001) compared with ranibizumab monotherapy.
x
Primary end point: more patients in ranibizumab arm had a visual acuity gain of □0.2 logarithm of the minimum angle of resolution compared wi
th vertepor
Visua l acuitfiyn conversio
PDT (31% vs. 17%
n based on; PEarl
¼ y0.039 ) at mont
Treatmen h 12.c Retinopathy Study letters ¼ 100 □ 50 □ log10 (decimal).
t Diabeti
k
Primary end point: not reported in subgroup analysis.
#
Only 14 of 31 patients required PDT.
{
Primary end point: no significant difference in change in best-
correcte
**Primaryd visual acuit
end poinyt afro
tm h 12e
baselin
mont toibercep
: afl montht2monotherap
between initia
y wa l PD T with ranibizuma
s noninferio b andt deferre
r to aflibercep d PD
plus rescu eTPD
with change inb best-
T inranibizuma group (P ¼ 0.70).
corrected visual acuity at week 52 from baseline (P ¼ 0.548).
yy
Only 15% of patients met rescue PDT criteria.
 Cheung et al □ Polypoidal Choroidal Vasculopathy

Table 6. Summary of Study Designs of EVEREST-II Study and PLANET Study

EVEREST-II PLANET
Study description A 24-month, phase 4, randomized, double-masked, A randomized, double-masked, sham-controlled phase
multicenter study comparing ranibizumab 3b/4 study that compared the efficacy and safety of
monotherapy with ranibizumab in combination with aflibercept monotherapy versus aflibercept with PDT
PDT. rescue therapy.
Study objective To demonstrate that ranibizumab combined with vPDT To explore whether intravitreally administered
is superior to ranibizumab monotherapy with respect aflibercept monotherapy is noninferior to that of
to: (1) change in mean BCVA (letters) from baseline aflibercept plus PDT (as indicated) based on BCVA.
at month 12 and (2) complete polyp regression
assessed by ICGA at month 12.
Anti-VEGF agent Ranibizumab Aflibercept
Anti-VEGF dosing Three initial monthly followed by PRN if retreatment Three initial monthly followed by every 8 wks.
criteria are met*
PDT in combination arm Performed at baseline in all cases randomized to Prohibited during first 3 months, allowed from week 12
combination arm and repeated according to onward if rescue criteriay are met.
retreatment criteria*
No. of participants 322 318

BCVA ¼ best-corrected visual acuity; ETDRS ¼ Early Treatment Diabetic Retinopathy Study; FA ¼ fluorescence angiography; ICGA ¼ indocyanine green
angiography; PCV ¼ polypoidal choroidal vasculopathy; PDT ¼ photodynamic therapy; VEGF ¼ vascular endothelial growth factor; vPDT ¼ verteporfin
photodynamic therapy.
*EVEREST II retreatmen t criteria:
4

1. Loss of BCVA because of condition under study or disease activity seen on OCT.
2. Only ranibizumab will be given if last PDT treatment is <3 mos earlier.
3. If □3 mos since last PDT treatment, ICGA or FA should be performed.
a. If ICGA or FA shows active PCV (PCV and leakage) involving macula with greatest linear dimension of total lesion area <5400 mm,
ranibizumab plus vPDT or sham PDT will be administered according to randomization.
b. If ICGA or FA does not show active PCV (PCV and leakage) involving macula with greatest linear dimension of total lesion area <5400 mm,
ranibizumab monotherapy will be administered.
y 5
PLANET study rescue criteria:
1. BCVA □73 ETDRS letters.
2. New or persistent fluid on OCT.
3. Evidence of active polyps on ICGA.
4. Deterioration, no change, or insufficient gain in BCVA (<5-letter gain).
5. BCVA improvement of more than 5 letters but less than 10 letters, and investigator determines PDT may be of additional benefit.
Rescue PDT could be performed if criteria 1, 2, 3, and 4 or criteria 1, 2, 3, and 5 were met.

achieved in both PCV and non-PCV patients in the monthly
arm (þ12.7 letters vs. 11.2 letters) and the pro re nata arm
(9.4 letters vs. 8.4 letters) at 24 months (Table 5).
Based on these clinical trial data, anti-VEGF mono-
therapy with either ranibizumab or aflibercept can achieve
visual improvement and reduction in disease activity and
can be considered as first-line treatment in patients with
PCV. Direct comparison between studies based on the ab-
solute number of letters gained may suggest some advantage
using aflibercept (þ10.8 letters in PLANET) compared with
ranibizumab (5.1 letters in EVEREST-II) when used as
monotherapy. However, differences in baseline BCVA
should be considered, because eyes with lower baseline
BCVA (as in PLANET) generally can be expected to ach-
ieve a larger magnitude of improvement (Table 5).
Differences in dosing regimens (Tables 5 and 6) also
should be considered a potential factor underlying any
differences in absolute BCVA change reported.
Combination Therapy
Combination therapy of PDT and anti-VEGF therapy has
been reported to achieve significantly better visual outcomes
than PDT alone and to reduce the rate of PDT-related hem-
orrhages. e In
101,107,127
the EVEREST-I study, the
129
combination therapy arm achieved slightly higher polyp
closure rate compared with PDT monotherapy, but the dif-
ference was not statistically significant. Patients in the com-
bination arm also achieved the highest BCVA gain
numerically (10.9 letters) compared with patients in the
ranibizumab monotherapy arm (9.2 letters) or the PDT
monotherapy arm (7.5 letters) at month 6, but these differ-
ences were not statistically significant.63 In the EVEREST-II
study, the combination arm achieved superior BCVA gain
(8.3 vs. 5.1 letters; P ¼ 0.013), a higher proportion of patients
with BCVA of 69 letters or more (69.0% vs. 58.8%), a higher
polyp closure rate (69.3% vs. 34.7%; P < 0.01), and a higher
proportion with absence of disease activity (79.5% vs. 50.0%)
at month 12 compared with ranibizumab monotherapy. The
combination arm also required fewer injections (mean, 5.2 vs.
7.3 injections over 12 months), with 50.6% of patients in the
combination arm requiring only 3 to 4 injections over 12
months, which was significantly lower than that in the mono-
therapy arm (26.2%). However, currently there are no clear
criteria to identify this subgroup at baseline. These results
suggest that although ranibizumab monotherapy is safe and
achieves moderate BCVA gains in PCV, combination therapy
with PDT is superior in terms of BCVA gain and polyp
closure and can reduce the number of ranibizumab injections
required in the first year of treatment.

717
 Ophthalmology Volume 125, Number 5, May 2018
In addition to combination therapy performed at baseline,
deferred combination has been evaluated in the FUJISAN
study130 (Table 5), which compared the outcomes of initial or
deferred PDT combined with IVT-R. In this study, patients
were evaluated after 3 monthly IVT-R injections. In pa-
tients who met the retreatment criteria, deferred combination
treatment was performed. The study reported similar BCVA
and polyp closure outcomes at 1 year between patients with
initial PDT and those with deferred PDT. With this approach,
more than half of the patients in the deferred arm (17 of 31
patients) did not require PDT, although patients in this arm
had significantly more injections (3.8 vs. 1.5 injections in
addition to 3 loading doses).
The PLANET study evaluated deferred, rescue PDT
combination therapy. Qualification for rescue PDT was based
on insufficient gain in BCVA and evidence of leakage from
active polyps (Table 6). A large majority of patients did not
meet these rescue criteria after 3 initial monthly IVT-AFL
injections (94.9% and 93.2% in the IVT-AFL monotherapy
arm and combination arm, respectively), and less than 15% of
patients in either arm met rescue criteria over the course of 12
months (P ¼ 0.84). Both treatment arms achieved similar
BCVA gains (10.7 letters vs. 10.9 letters, respectively),
and polyp regression rates (38.9% vs. 44.8%, respectively;
P ¼ 0.32). More than 80% of patients had no signs of polyp
activity at week 52. The PLANET study thus concluded that
if anti-VEGF monotherapy was selected for treatment of
PCV, aflibercept monotherapy achieved significant BCVA
gains in more than 85% of patients with PCV and no sig-
nificant additional benefit could be demonstrated at week 52
by adding rescue PDT based on their criteria. There are
ongoing studies to evaluate the safety and efficacy of afli-
bercept combined with prompt PDT.
Current Management Guidelines and
Recommendations for Clinicians
The most important goal of treatment of treatment-naïve
PCV, as in typical neovascular AMD, should be achieving
the best possible visual outcome while minimizing the
treatment burden. In this respect, results of both the
EVEREST-II and PLANET studies showed that anti-VEGF
monotherapy as well as combination therapy with PDT give
excellent functional visual outcomes at 1 year, similar to
results of typical neovascular AMD, and thus are acceptable
initial treatment options in patients with symptomatic PCV.
Therefore, when deciding on the best treatment option for
each patient, differences in individual patients and settings
(such as prevalence of PCV and accessibility of ICGA and
PDT), lesion characteristics, and presenting visual acuity
should be considered (Table 7). Advantages of anti-VEGF
monotherapy include eliminating the need for access to
ICGA and PDT, thus potentially simplifying logistics and
lowering financial burden. The risk of uncommon compli-
cations related to PDT also were eliminated. However, the
number of anti-VEGF injections when given as monotherapy
can be expected to be higher than when given in combination
with PDT, as demonstrated in EVEREST-II. Thus, patients
who are not committed to regular follow-up and multiple
injections (average, 7e8 over 12 months) may not achieve
718
the same visual benefit as described in clinical trials.
Although the risk related to intravitreal injection is low, the
cumulative risk does increase in patients undergoing repeated
injections. In contrast, initial combination therapy may
reduce the need for retreatment up to 1 year based on
currently available evidence. In contrast, the need for special
equipment and the high cost of verteporfin PDT in many
countries remain major barriers to the use of combination
therapy as first-line treatment. In patients with very good
presenting vision, there is also concern of worsening of
vision after combination therapy. There are suggestions that
certain features of the PCV lesion, such as size and config-
uration of polyps or choroidal hyperpermeability, thickness,
or both may help to predict eyes with a more favorable
response to combination therapy. However, these factors
have yet to be evaluated in clinical trials.
Future Research and Gaps
As this review has shown, significant advances in our un-
derstanding of various management approaches have been
made, and recent results from the large randomized
controlled trials described herein have better informed the
risks and benefits of various treatment options for PCV.
A key gap in our understanding of optimal management
for PCV is the importance of polyp closure. One of the
major advantages of combination therapy seems to be
achievement of higher polyp closure rates. However, there is
no clear evidence for a direct association between higher
polyp closure rate and better visual outcome. Neither is there
clear evidence of a direct association between higher polyp
closure rates and lower recurrences during extended follow-
up. Recurrence rates are reported to be as high as 40% to
78.6% after 3 years. In recurrent cases, repeated ses-
101,131
sions of PDT have been postulated to damage chorioca-
pillaris and retinal pigment epithelium, leading to long-term
visual loss. e
132
The 1-year data from trials reported
135
above are unable to detect these changes. Thus, studies with
longer follow-up will be required to evaluate recurrence
rates and long-term visual outcomes.
Another important gap is the lack of patient, clinical, and
imaging biomarkers that may predict response to therapy.
As demonstrated in the EVEREST-II study, half of the pa-
tients responded very well to combination therapy and
required only 3 to 4 ranibizumab injections over 12 months.
Similarly, in the FUJISAN study, more than 50% of patients
were treated with ranibizumab monotherapy and did not
require additional deferred PDT. These results suggest sig-
nificant heterogeneity within PCV, which may be reflected
in differences in choroidal thickness, and
48,50,136,137
choroidal vascular hyperpermeability. These differ-
52,59,138
ences in turn may be explained at least partially by differ-
ences in genetic background. Some clinical studies have
suggested that eyes with thicker choroids may respond
poorly to anti-VEGF monotherapy. e 139
Other results
141
suggest that the presence of choroidal vascular hyper-
permeability may predict more favorable response to com-
bination therapy. However, these biomarkers have been
142
evaluated in just small clinical case series. The current
 Cheung et al □ Polypoidal Choroidal Vasculopathy

Table 7. Current Management Guidelines and Recommendations for Clinicians

1 Diagnosis of PCV: PCV should be diagnosed by ICGA at presentation in all cases.
Rationale: There are many macular disorders that mimic PCV, such as central serous chorioretinopathy, vascularized PED, and type 3
neovascularization (retinal angiomatous proliferation). It is important to treat based on an accurate diagnosis.
SD OCT and OCTA may complement ICGA in the diagnosis of PCV, but the current gold standard for identifying polyps is still ICGA.
2 Treatment goal: The most important goal of treatment of treatment-naïve PCV should be achieving the best possible visual outcome while
minimizing the treatment burden.
The secondary goals are achieving complete polyp closure and minimizing adverse events, RPE atrophy, and recurrence.
3 Initial treatment: both anti-VEGF monotherapy as well as combination anti-VEGF therapy and PDT* are acceptable initial treatment options in
patients presenting with symptomatic PCV.
Rationale: EVEREST-II and PLANET studies demonstrated level I evidence that anti-VEGF monotherapy as well as combination therapy
give excellent functional visual outcomes at 1 year. Current evidence suggests that anti-VEGF monotherapy and combination therapy
achieve comparably favorable outcomes up to 1 year; therefore, the choice between these 2 methods may depend on other factors, including
Accessibility to ICGA diagnosis and confirmation of PCV;
Accessibility to and expertise with verteporfin PDT laser equipment;
Presenting visual acuity;
Lesion characteristics: number, size, and location of polyps;
Affordability and availability of reimbursement for treatments; and
Ability of patients to return for regular and long-term follow up at frequent intervals.
When discussing anti-VEGF monotherapy, please note there may be differences between anti-VEGF agents:
There are no head-to-head studies to compare directly between different anti-VEGF agents. There is currently no evidence to support
extrapolation of the above study results to off-label use of bevacizumab.
If ranibizumab is used, the EVEREST-II study demonstrated clearly that combination therapy with PDT is preferred to ranibizumab
monotherapy and is supported by superior visual and angiographic outcomes and reduced need for repeat injections during the first year of
treatment.
If aflibercept is used, the PLANET study suggests there is no additional benefit in combining with PDT as a rescue therapy. However, there
are currently no data as to whether combination at baseline has any additional benefit to aflibercept. Patients who opt for aflibercept
monotherapy should be prepared to adhere to fixed dosing as used in the PLANET study.
3A Commencing treatment with anti-VEGF monotherapy** may be preferred under the following circumstances:
Lack of access to ICGA, PDT or both (logistically, financially, or both).
ICGA features are uncertain or equivocal for PCV, for example, when massive submacular hemorrhage masks definitive diagnosis of PCV.
Ocular features that limit effective application of PDT, e.g., location of polyps in proximity to optic disc, poor view such as that resulting from
presence of thick or vitreous hemorrhage or dense cataract, and multifocal location or lesions with greatest linear dimension of >5400 mm.
Systemic contraindications to PDT, e.g., drug sensitivity, porphyria, or photosensitive dermatitis.
Clinical features suggest low probability of PCV (e.g., patient from ethnic groups with lower PCV prevalence, lack of serosanguineous
maculopathy clinically).
3B Commencing treatment with combination therapy may be preferred if:
Commitment to adhere to monitoring and retreatmen t is a concern.
Combination therapy results in significant reduction in total number of ranibizumab injections over 12 months without compromising visual
outcome or safety. The main reason behind reduced need for treatment is thought to be related to higher rate of complete polyp closure when
using combination therapy compared with monotherapy with either aflibercept or ranibizumab.
4 Treatment regimen: patients who start with anti-VEGF monotherapy should either be treated using fixed dosing following the PLANET study (3
initial monthly aflibercept injections followed by 8 weekly injections) or be monitored monthly if following a PRN regimen as in the EVEREST-II
study (3 initial monthly ranibizumab injections followed by monthly monitoring and PRN re-treatment).
Premature cessation of treatment, particularly if monitoring is irregular, may lead to less favorable results than those reported above. There is
concern that sudden hemorrhage may occur in cases with residual polyps after discontinuation of anti-VEGF therapy.
The second year of the PLANET study will assess the efficacy of aflibercept using a treat-and-extend regimen.
There is currently no evidence to support extrapolation of the above study results to off-label use of bevacizumab.
5 Monitoring of treatment response:
After initial therapy, patients should be monitored for adequate response based on BCVA and OCT results.
Particularly in patients who are receiving anti-VEGF monotherapy, ICGA should be considered if there is suboptimal response based on BCVA
and OCT monitoring. In these cases, addition of PDT to the anti-VEGF regimen should be considered if active polyps are identified on
ICGA.
Note: The rescue criteria used in the PLANET study are based on the hypothesis that aflibercept monotherapy is noninferior to aflibercept plus
PDT. Thus, the PLANET study cannot address what would be the outcome of combination therapy if PDT were used in the same ways as in
the EVEREST-II study.

BCVA ¼ best-corrected visual acuity; ICGA ¼ indocyanine green angiography; OCTA ¼ OCT angiography; PCV ¼ polypoidal choroidal vasculopathy;
PDT ¼ photodynamic therapy; PED ¼ pigment epithelial detachment; PRN ¼ pro re nata; RPE ¼ retinal pigment epithelium; SD ¼ spectral-domain;
VEGF ¼ vascular endothelial growth factor.
*Current evidence on PDT is based predominantly on studies using full-fluence PDT.

body of evidence is insufficient to allow us to provide In conclusion, PCV is a common subtype of neovascular
recommendations and guidance in these aspects of AMD, particularly in Asian populations. In this review, we
management. Future clinical trials will be needed to proposed guidelines and recommendations to help clinicians
address each of these knowledge gaps. manage patients with PCV, based on the latest available

719
 Ophthalmology Volume 125, Number 5, May 2018

evidence from clinical studies and randomized trials. There Japanese and French Patients: multicenter diagnosis with
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18. Ciardella AP, Donsoff IM, Huang SJ, et al. Polypoidal
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19. Cackett P, Yeo I, Cheung CM, et al. Relationship of smoking
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Footnotes and Financial Disclosures

Originally received: September 19, 2017.
Final revision: November 9, 2017. K.B.F.: Consultant e Optovue, Optos, Heidelberg Engineering, Genentech,
Accepted: November 9, 2017.
GrayBug Vision; Financial support e Genentech/Roche
Available online: January 10, 2018. Manuscript no. 2017-2142.
F.G.: Consultant, Financial support, and Lecturere Bayer, Novartis Pfizer,
1
Singapore Eye Research Institute, Singapore National Eye Centre,
Singapore, Republic of Singapore. Santen; Nonfinancial support e Topcon
2
Duke-NUS Medical School, National University of Singapore, Singapore, A.H.K.: Financial and Nonfinancial support e Bayer Healthcare, Allergan,
Republic of Singapore.
Alcon, Boeringher Ingelheim, Bayer, Carl Zeiss Meditec, Heidelberg,
3
Department of Ophthalmology and Visual Sciences, The Chinese Uni- Novartis, Topcon, Santen
versity of Hong Kong, Hong Kong Eye Hospital, Hong Kong, China.
4 W.-K.L.: Financial and Nonfinancial support e Bayer Healthcare, Novartis
Department of Ophthalmology, Rajavithi Hospital, Bangkok, Thailand.
5 T.Y.W.: Consultant and Financial support e Bayer, Novartis, Abbott,
Department of Ophthalmology, Taipei Veterans General Hospital, and
School of Medicine, National Yang-Ming University, Taipei, Taiwan. Allergan, Bayer, Genentech, Novartis, Roche, Pfizer
6
Department of Ophthalmology, Peking Union Medical College Hospital, Supported by the National Medical Research Council Singapore, Republic
Peking Union Medical College and Chinese Academy of Medical Sciences,
of Singapore. The sponsor or funding organization had no role in the design
Beijing, China.
7 or conduct of this research.
Vitreous Retina Macula Consultants of New York, and The LuEsther T.
Mertz Retinal Research Center, New York, New York. HUMAN SUBJECTS: No human subjects were included in this study.
8 Author Contributions:
Department of Ophthalmology, New York University School of Medi-
cine, New York, New York.
9
Conception and design: Cheung, Wong
Department of Ophthalmology, Hyogo College of Medicine, Hyogo,
Japan. Analysis and interpretation: Cheung, Lai, Ruamviboonsuk, S.-J.Chen,
10
Eye & Retina Surgeons, Camden Medical Centre, Singapore, Republic of Y.X.Chen, Freund, Gomi, Koh, Lee
Singapore.
Data collection: Cheung, Lai, Ruamviboonsuk, S.-J.Chen, Freund, Gomi, Koh
11
Department of Ophthalmology, Seoul St. Mary’s Hospital, College of Obtained funding: none
Medicine, The Catholic University of Korea, Seoul, South Korea.
Financial Disclosure(s): Overall responsibility: Cheung, Lee, Wong
The author(s) made the following disclosure(s): C.M.C.: Consultant e Abbreviations and Acronyms:
Bayer, Novartis; Financial support e Bayer, Novartis, Roche, GlaxoSmith AMD ¼ age-related macular degeneration; BCVA ¼ best-corrected visual
Kline; Nonfinancial support e Bayer, Allergan, Topcon acuity; BVN ¼ branching vascular network; FA ¼ fluorescein angiog-
raphy; ICGA ¼ indocyanine green angiography; IVT-AFL ¼ intravitreal
T.Y.L.: Consultant e Bayer, Novartis, Allergan, AbbVie, Genentech;
aflibercept; IVT-R ¼ intravitreal ranibizumab; OCTA ¼ OCT angiog-
Financial support e Bayer, Novartis, Allergan, AbbVie, Genentech
raphy; PCV ¼ polypoidal choroidal vasculopathy; PDT ¼ photodynamic
P.R.: Consultant and Financial support e Bayer, Novartis, Allergan therapy; PED ¼ pigment epithelial detachment; RPE ¼ retinal pigment
S.-J.C.: Consultant and Financial support e Bayer, Novartis, Allergan, epithelium; SD ¼ spectral-domain; VEGF ¼ vascular endothelial growth
Medical Image Integration factor.
Y.X.C.: Consultant and Financial support e Bayer, Novartis; Nonfinancial
Correspondence:
support e Topcon Chui Ming Gemmy Cheung, FRCOphth, Singapore Eye Research Institute,
Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore
168751, Republic of Singapore. E-mail: gemmy.cheung.c.m@singhealth.
com.sg.

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