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Polypoidal Choroidal Vasculopathy Masquerading asNeovascular Age-Related Macular Degeneration

Refractory to Ranibizumab

ALEXANDROS N. STANGOS, JAGDEEP SINGH GANDHI, JAYASHREE NAIR-SAHNI, HEINRICH HEIMANN,
CONSTANTIN J. POURNARAS, AND SIMON P. HARDING
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PURPOSE: To report a neovascular age-related macularegeneration pattern refractory to ranibizumab.DESIGN: Retrospective, observational case series.METHODS: Between March and May 2009, cases with

eovascular age-related macular degeneration refractoryo ranibizumab were investigated with indocyanine greenngiography. We identified 12 eyes of 12 patients witholypoidal choroidal vasculopathy. Refractory to treat-ent were defined cases with persistent subretinal or

ntraretinal fluid, or both, after 3 or more consecutiveonthly ranibizumab injections regardless of best-cor-

ected visual acuity.RESULTS: All patients identified were white, of whomwere male. Mean age � standard deviation at presen-

ation was 75 � 5.6 years (range, 64 to 81 years);iagnosis, based on fluorescein angiography, comprisedccult choroidal neovascularization (CNV) in 8 eyes,nd 1 case each of classic-no-occult CNV, minimallylassic CNV, predominantly classic CNV, and retinalngiomatous proliferation. Eight cases had switched fromourses of other therapy (5 pegaptanib, 1 photodynamicherapy, 1 photodynamic therapy then pegaptanib, 1evacizumab). After a mean follow-up of 10.2 � 4.8onths (range, 3 to 18 months) and 7.6 � 3.9 ranibi-

umab injections (range, 3 to 14 injections), indocyaninereen angiography revealed polypoidal choroidal vascu-opathy lesions in all cases.

CONCLUSIONS: Neovascular age-related macular de-eneration refractory to a course of ranibizumab injec-ions may harbor polypoidal choroidal vasculopathy. Inuch cases, indocyanine green angiography is a valuableool for revealing polypoidal lesions. (Am J Ophthal-ol 2010;xx:xxx. © 2010 by Elsevier Inc. All rights

eserved.)

ccepted for publication May 26, 2010.From the St. Paul’s Eye Unit, Royal Liverpool University Hospital,

iverpool, United Kingdom (A.N.S., J.S.G., J.N.-S., H.H., S.P.H.); theivision of Ophthalmology, Department of Clinical Neurosciences,niversity Hospitals of Geneva, Geneva, Switzerland (C.J.P.); and thephthalmology Research Unit, School of Clinical Sciences, University

f Liverpool, United Kingdom (S.P.H.).Inquiries to Alexandros N. Stangos, St. Paul’s Eye Unit, Royal

Biverpool University Hospital, Prescot Street, Liverpool, L7 8XP, Unitedingdom; e-mail: [email protected]

© 2010 BY ELSEVIER INC. A002-9394/$36.00oi:10.1016/j.ajo.2010.05.035

ONTHLY ADMINISTERED INTRAVITREOUS PHAR-

macotherapy with ranibizumab, a vascular endo-thelial growth factor (VEGF) inhibitor, has

een shown to improve mean visual acuity safely in eyesith neovascular age-related macular degeneration

AMD).1–3 Similar results to those reported by the ran-omized control trials have been achieved through anptical coherence tomography (OCT)-guided variable-osing regimen, with fewer ranibizumab injections.4 Inlinical practice, however, some patients fail to respond toanibizumab, leading to repeated treatments. Currently,he cause of this poor response is not well understood. Weerein describe a neovascular AMD pattern refractory toanibizumab treatment.

METHODS

HIS WAS A RETROSPECTIVE ANALYSIS OF 12 EYES OF 12

atients with neovascular AMD refractory to ranibizumabn whom polypoidal choroidal vasculopathy (PCV) wasiagnosed between March and May 2009 in St. Paul’s Eyenit. Under our care, patients with 25 letters or more of

est-corrected visual acuity (BCVA) on Early Treatmentiabetic Retinopathy Study charts and subfoveal or jux-

afoveal neovascular AMD of any subtype with signs ofecent disease progression (ie, drop in BCVA; presence ofresh hemorrhage, exudates, or subretinal or intraretinaluid, or both) are eligible for ranibizumab pharmacother-py. After a loading course of 3 consecutive monthlyntravitreal ranibizumab injections, patients are followedp monthly. At each visit, patients undergo BCVA assess-ent, dilated funduscopy, and OCT scanning. BCVA iseasured by externally accredited examiners using thearly Treatment Diabetic Retinopathy Study charts at 4nd 1 m and is recorded as letters read at 1 m. Unlesstherwise indicated, stereo fluorescein angiography (FA) iserformed at baseline and at 3-month intervals thereafter.he decision for retreatment is based on the evidence of

ubretinal or intraretinal fluid on OCT, or both; BCVAoss of 5 letters or more and fewer than 20 Early Treatmentiabetic Retinopathy Study letters compared with therevious visit; and signs of leakage on FA. Regardless of
CVA change, cases are considered refractory to treat-
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ent with evidence of persistent subretinal or intraretinaluid on OCT, or both; fresh hemorrhage; or new serosan-uineous retinal pigment epithelium (RPE) detachmentfter 3 or more consecutive monthly ranibizumab injec-ions. In addition to the standard management, casesefractory to ranibizumab therapy are evaluated with stereondocyanine green angiography (ICGA).

Diagnosis of PCV was established by the presence ofranched vascular network(s) terminating in polypoidal-ike lesions located under the RPE on ICGA.5 Thengiograms of all cases were evaluated independently by 4linicians (A.N.S., C.J.P., H.H., S.P.H.). Final diagnosisas based on the concurrent opinion of 3 of 4 clinicians.CV was classified angiographically, after Cackett andssociates, according to polyp size, location, formation, andumber of discrete polyp areas (foci).6 Size of polyp wasased on the largest diameter of polyp measured in mi-rometers. Location of polyp was divided into 4 categories:eripapillary (within 1 disc diameter from the optic nerveead), subfoveal, juxtafoveal (� 200 �m from the fovea),nd extrafoveal. Lesion formation was classified into 3roups: single, cluster (� 2 polyps in a group configura-ion), string (� 3 polyps in a line), or a combinationhereof. Number of discrete areas (foci) was classified asingle or multiple. Patient data were retrieved, includingender, age at presentation, race, eye laterality, initialtudy eye diagnosis, fellow eye diagnosis, past medical andcular history, BCVA (at presentation, at ranibizumabnitiation, and at PCV diagnosis), OCT findings, number

TABLE 1. Twelve Cases with Ranibizumab-Refractory NeovasVasculop

Case

No. Gender

Age

(yrs) Eye

Study Eye

Diagnosis Fellow Eye Diagnosis

1 M 64 Left MC CNV End-stage nAMD

2 F 75 Left Occult CNV ERM

3 F 76 Right RAP Serous RPE detachme

4 F 65 Left Occult CNV End-stage nAMD

5 M 79 Left Occult CNV End-stage nAMD

6 M 79 Left Occult CNV End-stage nAMD

7 F 79 Right Occult CNV Serous RPE detachme

8 M 77 Left Classic CNV Dry AMD

9 M 81 Left Occult CNV Dry AMD

10 F 75 Right PC CNV Physiologic

11 M 75 Right Occult CNV Dry AMD

12 F 69 Left Occult CNV Dry AMD

AMD � age-related macular degeneration; BCVA � best-correc

Study charts and expressed in number of letters seen); CNV � chor

male; MC � minimally classic; nAMD � neovascular AMD; PC � p

photodynamic therapy; RAP � retinal angiomatous proliferation; RP

f ranibizumab treatments, and follow-up duration. y

AMERICAN JOURNAL OF

RESULTS

HE CHARACTERISTICS AND CLINICAL DATA OF THE 12 PCV

ases are listed in Table 1. All patients were white, ofhom half were male. At presentation, mean age �

tandard deviation was 75 � 5.5 years (range, 64 to 81

Age-Related Macular Degeneration and Polypoidal ChoroidalLesions

BCVA at

resentation Initial Treatment

BCVA at

Ranibizumab

Initiation

No. of

Ranibizumab

Injections

BCVA at

PCV

Diagnosis

49 Pegaptanib 34 14 59

64 Bevacizumab 64 14 61

58 Ranibizumab 58 3 65





40 PDT, Pegaptanib 39 4 27


53 PDT 45 6 59



isual acuity (assessed with Early Treatment Diabetic Retinopathy

neovascularization; ERM � epiretinal membrane; F � female; M �

inately classic; PCV � polypoidal choroidal vasculopathy; PDT �

retinal pigment epithelium; yrs � years.

TABLE 2. Polypoidal Choroidal VasculopathyClassificationa in 12 Cases with Ranibizumab-Refractory

Neovascular Age-Related Macular Degeneration

Case

No. Size (�m) Location Formation

Discrete

Areas

1 400 Extrafoveal Single/cluster 2

2 210 Foveal Single 1


4 380 Extrafoveal Cluster 2

5 770 Extrafoveal Cluster 2

6 420 Foveal/extrafoveal Cluster/string 2

7 340 Foveal Single/cluster 4


9 230 Extrafoveal Single 3



12 330 Extrafoveal Single/cluster 2

aThis classification system for polypoidal choroidal vascu-

lopathy comprises polyp size, location, formation, and number

of discrete polyp areas. Adapted from Cackett P, Wong D, Yeo

I. A classification system for polypoidal choroidal vasculopathy.

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rised occult choroidal neovascularization (CNV) in 8yes, and 1 case each of classic-no-occult CNV, minimallylassic CNV, predominantly classic CNV, and retinalngiomatous proliferation. Four cases were treatment-aïve lesions, whereas 8 cases had switched from courses ofther therapy with a mean follow-up before ranibizumabnitiation of 15 � 12 months (range, 3 to 40 months). Inetail, 5 patients had a course of pegaptanib intravitrealharmacotherapy (mean, 6.4 � 2; range, 3 to 8), 1 patientad 3 photodynamic therapies, 1 patient had 1 photody-amic therapy (PDT) followed by 3 pegaptanib intravitreal

njections, and 1 patient had 1 bevacizumab intravitrealnjection. Fellow eye diagnosis at presentation comprised 4ases with dry AMD, 4 cases with end-stage neovascularMD, 2 cases with isolated serous RPE detachment, 1 with

piretinal membrane, and 1 without any macular disease.Mean BCVA was 52 � 14 letters (range, 25 to 74

etters) and 50 � 13 letters (range, 28 to 68 letters) atresentation and at initiation of ranibizumab treatment,espectively, representing a nonsignificant drop of 2 � 5etters (P � .14, Student t test). After a mean follow-up of0.2 � 4.8 months (range, 3 to 18 months) and 7.6 � 3.9anibizumab injections (range, 3 to 14 injections), meanCVA was 55 � 14 letters (range, 27 to 69 letters). This

IGURE 1. Images of the left eye of Case 1 at baseline with ef minimally classic choroidal neovascularization was establisheate phase of the fluorescein angiogram. (Bottom) Time-domaietachment of the retinal pigment epithelium with subretinal a

epresents an improvement by 5 � 10 letters since initia- s

PCV IN THE RANIBOL. XX, NO. X

ion of ranibizumab (P � .07). Best-corrected visual acuitymproved by 15 letters in 2 patients (17%), whereas 10atients (83%) lost or gained fewer than 15 letters. Noatient lost more than 15 letters with ranibizumabreatment.

Mean central foveal thickness (CFT) on OCT was49 � 141 �m and 316 � 136 �m at presentation and atnitiation of ranibizumab treatment, respectively. At diag-osis of PCV, mean CFT was 370 � 140 �m, indicative ofesistance to ranibizumab treatment. Because CFT waseasured with different OCT machines, we cannot quan-

ify CFT changes precisely. However, qualitative analysisf OCT scanning revealed persistent retinal exudationespite continuous ranibizumab treatments.The average size of the largest polyp was 340 � 160 �m

range, 120 to 770 �m). Polypoidal choroidal vasculopathyesions were found in multiple discrete areas (foci) in 9yes (75%). The breakdown of formation of lesion was:ingle polyp in 9 eyes (75%), cluster of polyps in 6 eyes50%), and a string of polyps in 1 eye (8%). In this cohort,e did not detect any peripapillary PCV lesions. In 6 eyes

50%), we detected foveal PCV lesions, whereas in 5 eyes42%), we detected extrafoveal PCV lesions. One eye hadoth foveal and extrafoveal polyps. Details on PCV clas-

ce of neovascular age-related macular degeneration. Diagnosised on fluorescein angiography: (Top left) early and (Top right)ical coherence tomography of the same eye showed a shallowtraretinal fluid.

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esions on the fellow eye were found in 5 cases (42%). Fourf those eyes were diagnosed clinically with end-stageeovascular AMD and 1 eye was diagnosed with serousPE detachment.

CASE 1: A 64-year-old white man with hypertensionas referred by his optician for left eye suspected neovas-ular AMD. The patient reported metamorphopsia withoncomitant vision drop of few weeks’ duration. Onresentation, BCVA was 49 letters (20/100 Snellen equiv-lent). CFT was 379 �m. He was diagnosed with mini-ally classic CNV lesion (Figure 1) and started with

egaptanib intravitreal pharmacotherapy. The fellow eyehowed signs of end-stage neovascular AMD. After 6onsecutive pegaptanib injections, BCVA dropped to 34etters (20/200) with evidence of leakage on FA andersistent subretinal and intraretinal fluid on OCT (CFT,48 �m). He then was switched to ranibizumab intravit-

IGURE 2. Images of the left eye of Case 1 after 6 consecutivnjections for neovascular age-related macular degeneration. (Tolassic choroidal neovascularization, (Top right) with leakageerformed the same day revealing a single extrafoveal polypoidan extrafoveal cluster of 4 PCV lesions (white arrow). (Middllustered PCV lesion and (Bottom right) the single PCV lespithelium detachment, suggestive of the polypoidal lesions, w

eal pharmacotherapy. After 14 consecutive monthly z

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anibizumab injections, BCVA improved to 59 letters20/63 Snellen); FA showed leakage with concomitantersistent exudation on OCT (CFT, 288 �m). He subse-uently underwent ICGA, which revealed PCV lesionsFigure 2). The size of the largest polyp was 400 �m. Twoiscrete areas of PCV lesions (foci) were identified (aingle PCV lesion and a cluster of 4 polyps), both beingxtrafoveal in location. Spectral-domain OCT showed aelative hypereflectivity under the RPE detachment, sug-estive of the PCV lesions, with concomitant intraretinalnd subretinal fluid (Figure 2).

CASE 2: A 75-year-old white woman was referred for leftye neovascular AMD with concomitant progressive visionoss. On presentation, BCVA was 64 letters (20/50).entral foveal thickness was 234 �m. She was diagnosedith occult CNV lesion (Figure 3). After receiving 1evacizumab intravitreous injection, funding for ranibi-

gaptanib and 14 consecutive monthly ranibizumab intravitrealt) Early phase of the fluorescein angiogram showing minimallyhe late phase. (Bottom left) Indocyanine green angiographyroidal vasculopathy (PCV) lesion (white arrowhead) as well ast) Spectral-domain optical coherence tomography scan of thehowing a relative hypereflectivity under the retinal pigmentncomitant intraretinal and subretinal fluid.

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ew treatment. The fellow eye showed signs of epiretinalembrane. After 18 months of follow-up and 14 ranibi-

umab injections, BCVA dropped to 61 letters (20/63)ith evidence of leakage on FA and persistent subretinalnd intraretinal fluid on OCT (CFT, 450 �m). Sheubsequently underwent ICGA, which revealed the pres-nce of a branched vascular network and a foveal PCVesion (Figure 4). The size of the polyp was 210 �m.pectral-domain OCT scanning over the branched vascu-

ar network and the single PCV lesion showed areas ofoderate reflectivity under the RPE detachment with

oncomitant subretinal fluid (Figure 4).

DISCUSSION

N THE PRESENT RETROSPECTIVE CASE SERIES, WE DESCRIBE

pattern of neovascular AMD refractory to treatment.welve eyes of 12 patients with various types of neovas-ular AMD showed evidence of resistance to a course ofanibizumab intravitreal pharmacotherapy. Investigationith ICGA revealed the presence of PCV lesions.Ranibizumab currently is the mainstay of treatment for

eovascular AMD. Both the Ophthalmic Assessmentechnology Committee of the American Academy of

IGURE 3. Images of the left eye of Case 2 at baseline with evarly and (Top right) late phase of the fluorescein angiogram shptical coherence tomography of the same eye depicted a detac

phthalmology and the European Society for Retina t


pecialists’ Guidelines Committee have recommendedanibizumab pharmacotherapy for all subtypes of neovas-ular AMD.7,8 Ranibizumab has proven to be effective inecreasing the angiographic lesion size and the amount ofeakage from CNV.1–3 Seventy percent of ranibizumab-reated patients had a resolution of all macular edemaithin 1 month after their first injection, whereas more

han 90% of treated patients had a resolution of all fluidfter 3 consecutive injections.9 Our cohort representsatients with a poor response (ie, eyes showed persistentubretinal or intraretinal fluid, or both), despite receivingt least 3 consecutive monthly ranibizumab injections.

The cause of a poor anatomic response to ranibizumabharmacotherapy is not well understood. On the basis ofurrent experience with anti-VEGF therapies, it is evidenthat there is a differential response to treatment in patientsith neovascular AMD. For instance, the extent of vascu-

ar maturation can affect the therapeutic response. Imma-ure vessels respond better to VEGF inhibitors comparedith mature vessels, which appear to respond better toombined therapy with VEGF and platelet-derived growthactor inhibitors.10 It is tempting to assume that CNV isore mature and thus resistant to ranibizumab treatment

n eyes with neovascular AMD of longer duration or inyes with a history of previous treatment. In our cohort,

ce of neovascular age-related macular degeneration. (Top left)g occult choroidal neovascularization. (Bottom ) Time-domain

nt of the retinal pigment epithelium with subretinal fluid.

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mean follow-up before initiation of ranibizumab treat-ent of 15 � 12 months.Another reason for recalcitrant retinal exudation after

nti-VEGF pharmacotherapy is the presence of PCV. Al-hough ranibizumab and bevacizumab showed good short-erm results in reducing subretinal or intraretinal fluid, oroth, in eyes with PCV, it seems that VEGF inhibitors aloneay be ineffective in restoring the choroidal vascular changes

elated to this peculiar variant of neovascular AMD.11,12

ersistent PCV lesions under treatment with VEGF inhibi-ors could induce further subretinal or intraretinal exudation,r both, leading to disease progression. In our cohort, at theoint at which poor response was identified, ICGA revealedCV lesions. Cho and associates were the first to report thisorrelation.13 They also showed control of the disease processith combined anti-VEGF and PDT. As previously reported,DT frequently leads to occlusion of polypoidal lesions.14,15

ost recently, a study evaluating verteporfin PDT andanibizumab combination therapy for symptomatic macularCV (EVEREST study) showed that PDT with or without

IGURE 4. Images of the left eye of Case 2 after 1 bevacizge-related macular degeneration. (Top left) Early and (Top righeovascularization. (Bottom left) Indocyanine green angiograpwhite arrowhead) terminating in a single foveal polypoidal chpectral-domain optical coherence tomography scanning of the bhowing subretinal fluid as well as areas of moderate reflectivit

anibizumab intravitreal pharmacotherapy is superior to t

AMERICAN JOURNAL OF

anibizumab alone in achieving complete regression of theolypoidal lesions (Lai TY, et al. IOVS 2010;51:ARVO-Abstract 2228).Other causes of poor response to anti-VEGF treatment

nclude vitreomacular traction and other non-AMD dis-ases, such as retinal vascular occlusion or central seroushorioretinopathy. We could not identify, however, suchorrelations in our cohort, and we believe that the resis-ance to ranibizumab treatment was related to the PCVesions found during follow-up.

Diagnosis of AMD relies on stereoscopic fundus exam-nation. The evaluation of the retinal and choroidalasculature by fundus FA is integral to the diagnosis andanagement of this sight-threatening condition.16,17 The

iagnostic properties of FA, however, can be limited by theresence of hemorrhage, RPE abnormalities, or both.lthough not being used routinely in clinical practice,

CGA is a valuable tool for identifying certain neovascularMD patterns.18,19 Because of the inherent properties of

he indocyanine green molecule, ICGA lends itself well to

b and 14 ranibizumab intravitreal injections for neovascularte phase of the fluorescein angiogram showing occult choroidalrformed the same day revealing a branched vascular networkdal vasculopathy (PCV) lesion (white arrow). (Middle right)hed vascular network and (Bottom right) the single PCV lesionder the retinal pigment epithelium detachment.

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he delineation of PCV. A recent study reported that


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eovascular AMD lesions classified as occult disease usingA are evident as PCV when examined with ICGA.20 Inur cohort, two thirds were diagnosed with occult CNVesions. In Cho and associates’ cohort, none of the patientshowed clinical evidence of PCV at baseline, whereas twohirds showed absence of PCV on ICGA at baseline.13 Theame authors hypothesized that the chronic use of VEGFnhibitors could disrupt the fine balance between VEGFnd pigment epithelium-derived factor, leading to theevelopment of new PCV lesions. Our study did notermit a consideration of PCV pathogenesis because base-ine ICGA images were not available. The number ofatients also was insufficient to allow identification ofatterns in clinical behavior. Certainly, the premise thatodulation of VEGF may affect neovascular AMD mor-

hologic features is intriguing. However, the question ofhether anti-VEGF drugs favor conversion of baselineeovascular AMD lesion into the subtype of PCV awaits

urther exploration. A

486 – 494.

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Given the increasing familiarity with PCV, baselineeovascular AMD angiographic assessments now ideallyhould include ICGA to screen for this peculiar choroidalasculopathy. The recommendation is specifically applica-le where FA shows a lesion that incorporates occult (type) CNV, as well as instances where the lesion is associatedith the optic nerve head.Despite such recommendation, it is important to ac-

nowledge that not all AMD services currently have theacilities to accommodate routine ICGA. In such a clinicalnvironment, ICGA may be invoked selectively for thoseesions that manifest a suboptimal response after a stan-ardized initial treatment sequence. Identification of PCVs early as possible in the therapeutic sequence providesimely information on longer-term disease behavior andften prompts a change treatment strategy. In conclusion,ur study forms part of the nascent literature that alertslinicians to the presence of PCV in a clinical service for
MD.
R HEIMANN HAS RECEIVED LECTURE FEES FROM NOVARTIS AG. DR HARDING HAS RECEIVED CONSULTING FEES FROMovartis AG and Chameleon and receives grant support from Quinitles and National Coordinating Centre for Health Technology assessment (UK NHS&D). Involved in Conception and design of study (A.N.S.); Analysis and interpretation of data (A.N.S., J.S.G., J.N.-S., H.H., C.J.P., S.P.H.); Writing

he article (A.N.S.); Critical revision of manuscript (J.S.G., J.N.-S., H.H., C.J.P., S.P.H.); Final approval of manuscript (A.N.S., J.S.G., J.N.-S., H.H.,.J.P., S.P.H.); Data collection (A.N.S.); and Literature research (A.N.S.). Ethics Committee approval was obtained from the Royal Liverpoolniversity Hospital Review Board. All investigations adhered to the principles of the Declaration of Helsinki.

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0. Squirrell DM, Bacon JF, Brand CS. To investigate theprevalence of polypoidal choroidal vasculopathy in presumedage-related peripapillary subretinal neovascular membranes.
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