Choroidal Neovascularization Associated With FocalChoroidal Excavation

JAE HYUNG LEE AND WON KI LEE

� PURPOSE: To describe the clinical and imaging charac-teristics of choroidal neovascularization (CNV) accom-panied by focal choroidal excavation.� DESIGN: Retrospective, interventional case series.� METHODS: The medical records of 16 patients (16eyes) were reviewed. Imaging findings including fluores-cein angiography (FA), indocyanine green angiography,and spectral-domain optical coherence tomography (SDOCT) were analyzed.� RESULTS: CNV complexes were primarily locatedbeneath the retinal pigment epithelium (type 1 CNV) in9 eyes and in the subneurosensory retinal space (type 2CNV) in 7 eyes, as assessed by SD OCT. Seven of 8patients over 50 years old had type 1 CNV, and 6 of 8patients under 50 had type 2 lesions. All 7 eyes with type2 CNV exhibited classic CNV on FA. Additionally, 7 of9 eyes with type 1 CNV had the classic pattern, and inthese eyes, the CNV complexes were confined to theconcavity of choroidal excavation. In 15 patients treatedby anti–vascular endothelial growth factor (anti-VEGF)injections, the mean best-corrected visual acuity improvedfrom 20/44 to 20/26 with a mean of 3.7 injections duringa mean follow-up period of 14.5 months.� CONCLUSIONS: The CNV growth pattern and extentseem to be determined by the degree of damage to theretinal pigment epithelium/Bruch membrane complexresulting from choroidal excavation, as well as age.Neovascular complexes tend to be located within theboundary of choroidal excavation and are revealed asclassic patterns on FA, even in type 1 CNV. Anti-VEGF was notably effective for treating these lesions,with a low rate of recurrence. (Am J Ophthalmol2014;157:710–718. � 2014 by Elsevier Inc. All rightsreserved.)

CHOROIDAL EXCAVATION WAS FIRST REPORTED

as an unusual finding on time-domain opticalcoherence tomography (OCT) by Jampol and

Accepted for publication Dec 4, 2013.From the Department of Ophthalmology, Seoul St. Mary’s Hospital,

College of Medicine, The Catholic University of Korea, Seoul, SouthKorea.

Inquiries to Won Ki Lee, Department of Ophthalmology, Seoul St.Mary’s Hospital, College of Medicine, The Catholic University ofKorea, #505 Banpo-Dong, Seocho-Gu, Seoul, 137-701, South Korea;e-mail: wklee@catholic.ac.kr

710 � 2014 BY ELSEVIER INC.

associates.1 After a few reports of similar cases detectedby spectral-domain optical coherence tomography(SD OCT),2,3 Margolis and associates4 named this entityfocal choroidal excavation. In 2 recent reports, most focalchoroidal excavation lesions were shown to remainstable over a 1- or 3-year follow-up period.4,5 In aportion of patients, there was a history of central serouschorioretinopathy (CSC) or the concomitant presenceof CSC. Cicatrized subretinal neovascularization wasalso noted at initial presentation in certain patients,while in others, secondary choroidal neovascularization(CNV) developed during the follow-up. The authorssuggested a possible association between abnormalchoroidal circulation in focal choroidal excavation andpathologic lesions. However, it has not been determinedwhether CNV develops as a clinical consequence of focalchoroidal excavation or if they are 2 unrelated diseasesthat were coincidentally detected simultaneously. Thepaucity of cases has made it difficult to make conclusionsregarding the role of focal choroidal excavation in CNVdevelopment.There are several characteristic features of focal

choroidal excavation that indicate that it may providethe appropriate milieu for CNV development. Previousstudies showed that focal choroidal thinning and hypoper-fusion was associated with focal choroidal excavation.Additionally, varying degrees of pigmentary disturbancesand retinal pigment epithelium (RPE) alterations werenoted.3–5 It is also possible that the stretching of the RPE/Bruch membrane in the area of choroidal excavation canresult in a focal break in the Bruch membrane, whichinduces neovascular proliferation from the choroid, as inGass type 2 CNV.Gass classified the patterns of choroidal neovascular

growth into the 2 following pathologic types: type 1, thegrowth of new vessels beneath the RPE; and type 2, thegrowth of new vessels in the subsensory retinal space.6

Elderly patients with age-related macular degeneration(AMD), which is associated with diffuse loosening of thefirm attachment of the RPE to the Bruch membrane, areprone to developing type 1 CNV. This form of neovascula-rization is less permeable and proliferates slowly.7,8

Fluorescein angiography (FA) reveals a pattern that is‘‘poorly defined’’ with minimal leakage, which is alsodescribed as occult CNV. In contrast, type 2 CNV occursprimarily in patients younger than 50 years and isassociated with focally destructive lesions affecting the

0002-9394/$36.00http://dx.doi.org/10.1016/j.ajo.2013.12.011

ALL RIGHTS RESERVED.

RPE/Bruch membrane. The firm attachment betweenthe surrounding RPE and Bruch membrane in youngindividuals was postulated to explain the type 2 growthpattern. Type 2 CNV tends to proliferate rapidly, andFA typically exhibits a ‘‘well-defined’’ pattern withintense leakage, also referred to as classic CNV.7,8 SDOCT enables us to observe the details of retinalstructures and the level of retinal involvement in CNV.Studies using SD OCT demonstrated a relatively goodcorrelation between the angiographic classification(occult vs classic) and the anatomic classification ofCNV (type 1 vs type 2).9,10

The purpose of this study was to evaluate the detailedclinical and imaging characteristics in patients withCNV accompanied by focal choroidal excavation, focusingparticularly on the association between the angiographicpattern and the anatomic pattern on OCT.We also suggesta hypothetical angiogenic process in this newly describeddisease entity.

METHODS

WE ANALYZED THE MEDICAL RECORDS AND IMAGING

studies of 689 eyes from 653 consecutive patients withCNV or polypoidal choroidal vasculopathy who werereferred to the ophthalmology department of Seoul St.Mary’s Hospital, The Catholic University of Korea,between the beginning of January 2009 and the end ofMarch 2013. Sixteen patients were diagnosed as havingCNV accompanied by focal choroidal excavation. Detailedclinical and imaging characteristics were evaluated in thesepatients. This retrospective study was approved by theInstitutional Review Board of the Catholic Medical Centerand conducted in accordance with the tenets of the Decla-ration of Helsinki.

All patients received a complete ocular examination,including best-corrected visual acuity (BCVA) measure-ment using a Snellen visual acuity chart, slit-lamp bio-microscopy with a noncontact or contact lens, and OCTat baseline and at each follow-up visit. Spectralis OCT(Heidelberg Engineering, Heidelberg, Germany) was usedfor SDOCT examinations after November 2011. The rasterscan of Spectralis OCTwas performed on each eye centeredat the fovea using 2 scan protocols: a conventional protocoland an enhanced depth imaging (EDI) protocol.11 Beforethat time, Cirrus OCT (Carl Zeiss Meditec, Dublin,California, USA) with macular cube program consistingof 128 horizontal lines of 512 A-scans was used. All 16patients underwent EDI OCT using Spectralis OCT at leastonce during their follow-up. FA and indocyanine greenangiography (Heidelberg Retina Angiograph; HeidelbergEngineering, Heidelberg, Germany) were performed atbaseline and on a patient-by-patient basis thereafter. How-ever, indocyanine green angiography (ICGA) was not

VOL. 157, NO. 3 FOCAL CHOROIDAL EXCAVATION AND C

performed in 4 eyes at baseline. The Topcon IMAGEnetDigital Imaging System (Topcon, Tokyo, Japan) was usedfor FA examination in some patients.The diagnosis of focal choroidal excavation was based on

SDOCT findings of local excavation of the RPE and Bruchmembrane line. Staphylomatous excavation of the sclero-choroidal junction was ruled out with EDI OCT. EDIOCT was used to determine choroidal thickness at thebase of the focal choroidal excavation and the unaffectedsites near the excavation by measuring the distance fromthe outer portion of the hyperreflective RPE line to theinner surface of the sclera with the digital calipers includedin the review software. The ratio of the choroidal thick-nesses of the 2 sites was calculated.The diagnosis and classification of CNVwere based on the

FA and SD OCT findings. According to FA, CNVs werelabeled classic or occult based on the Treatment of Age-RelatedMacularDegenerationWith Photodynamic Therapy(TAP) protocol.12 The anatomic classification of CNV wasmade based on the location of the CNV membrane appear-ing as a highly reflective lesion on SD OCT with respect tothe RPE band. CNV was classified as type 1 when the highlyreflective lesion was primarily identified in the sub-RPE spaceand as type 2 when it was predominantly localized in thesubretinal space. The topographic association betweenchoroidal excavation and the hyperreflective lesion wasalso evaluated. The ICGA images were analyzed to identifyaberrant vessels or polypoidal lesions and any abnormalhypofluorescent or hyperfluoresecnt areas.All patients were treated with intravitreal anti–vascular

endothelial growth factor (anti-VEGF) injection witheither bevacizumab (Avastin; Genentech, Inc, San Fran-cisco, California, USA) or ranibizumab (Lucentis; Genen-tech Inc), except for 1 patient who was lost to follow-up.Anti-VEGF treatment was performed on an as-neededbasis, after either an initial 2 or 3 consecutive injectionsor a single injection. Repeated injections were givenwhenever either intraretinal or subretinal fluid involvingthe fovea was detected on follow-up OCT. The patientswere followed up regularly at 1- to 6-month intervals,depending on lesion activity, but the intervals did notexceed 3 months in patients over 50 years old.

RESULTS

THE PATIENT CHARACTERISTICS ARE SUMMARIZED IN THE

Table. We studied 16 eyes in 16 Korean patients, 9 ofwhom were women. The mean age was 49.6 years (range,28-86 years). Eight patients were under 50 years old; 2among them had a history of CSC in the affected eyesand 1 patient had high myopia. Soft drusen was only notedin 1 of 8 patients over 50. None of the patients had a historyof medical illness, medication use, or a family history ofretinal disease. None of the cases were bilaterally affected,

711HOROIDAL NEOVASCULARIZATION

TABLE. Clinical Characteristics of Patients With Choroidal Neovascularization Associated With Focal Choroidal Excavation

Case

No. Age/Sex Eye SE

OCT FA ICGA

Ratio of Choroidal

ThicknessaF/U

(Months) Anti-VEGF (Nb)

Additional

Injectionc

BCVA

OthersCNV Pattern Extent of CNV

CNV

Pattern

Focal

Hypofluoresence

Late

Hyperfluoresence Initial Final

1 39/M Left �12.5 Subsensory Within the

concavity

Classic NA NA 0.50 (114/228) 19 Bevacizumab (1) � 20/32 20/25 Subsequent

development of

CNV

2 71/M Left �1.125 Sub-RPE Within the

concavity

Classic þ þ 0.25 (54/216) 35 Ranibizumab (7) þ 20/200 20/25

3 86/F Left 0.625 Sub-RPE Over the margin Occult þ þ 0.60 (168/282) 32 Bevacizumab (8) þ 20/63 20/32 CNV in the other eye

4 28/M Right �4.5 Subsensory Over the margin Classic þ � 0.56 (120/214) � F/U loss 20/200 Subsequent

development of

CNV

5 69/F Left 1.125 Sub-RPE Within the

concavity

Classic NA NA 0.41 (83/203) 19 Ranibizumab (5) þ 20/200 20/100

6 45/M Right �2.125 Subsensory Within the

concavity

Classic þ þ 0.29 (62/217) 17 Bevacizumab (3) � 20/25 20/20 History of CSC

7 47/F Left �6.5 Subsensory Within the

concavity

Classic NA NA 0.69 (154/224) 17 Bevacizumab (3) � 20/40 20/20 History of CSC

8 55/M Right �0.5 Sub-RPE Within the

concavity

Classic þ � 0.35 (134/383) 14 Ranibizumab (5) þ 20/32 20/20

9 40/F Right �2.75 Sub RPE Within the

concavity

Classic þ þ 0.46 (148/324) 13 Bevacizumab (2) � 20/50 20/32

10 53/F Right �3.125 Subsensory Within the

concavity

Classic þ þ 0.74 (265/356) 13 Ranibizumab (3) � 20/25 20/20

11 29/F Right �7.125 Subsensory Over the margin Classic NA NA 0.44 (118/259) 7 Bevacizumab (2) � 20/32 20/25 Subsequent

development of

CNV

12 53/M Left �0.5 Sub-RPE Within the

concavity

Classic þ � 0.34 (76/221) 8 Bevacizumab (5) þ 20/80 20/63

13 66/M Right 0.875 Sub-RPE Over the margin Occult þ þ 0.46 (124/272) 8 Bevacizumab (3) � 20/100 20/32 CNV in the other eye

14 54/F Right �4.0 Sub-RPE Within the

concavity

Classic þ þ 0.76 (297/389) 7 Bevacizumab (4) þ 20/40 20/20

15 28/F Left �4.0 Sub-RPE Within the

concavity

Classic þ þ 0.85 (353/413) 6 Bevacizumab (3) � 20/25 20/25

16 30/F Right �9.5 Subsensory Within the

concavity

Classic � � 0.78 (197/250) 3 Bevacizumab (1) � 20/100 20/25

Anti-VEGF ¼ anti–vascular endothelial growth factor; BCVA ¼ best-corrected visual acuity; CNV ¼ choroidal neovascularization; CSC ¼ central serous chorioretinopathy; FA ¼ fluorescein

angiography; F/U ¼ follow-up; ICGA ¼ indocyanine green angiography; NA ¼ not available; OCT ¼ optical coherence tomography; RPE ¼ retinal pigment epithelium; SE ¼ spherical equivalent.aRatio of choroidal thickness at the base of the focal choroidal excavation and unaffected sites near the excavation.bTotal number of injections.cAdditional injection after initial 1-3 injections.

712

MARCH

2014

AMER

ICANJO

URNALOFO

PHTHALM

OLO

GY

FIGURE 1. Type 1 choroidal neovascularization (CNV)with classic pattern in a 40-year-old woman (Case 9). The patient presentedwith decreased visual acuity of 20/50 in the right eye. (Top left) Biomicroscopic examination demonstrated a subfoveal gray-yellowishlesion suspicious for CNV. The white line corresponds to the section examined with spectral-domain optical coherence tomography(SDOCT). (Middle, left and right) Fluorescein angiography revealed classic pattern CNVwith intense leakage in the late phase. (Topmiddle) Indocyanine green angiography (ICGA) in the early phase revealed choroidal venous dilation and focal hypofluorescence,corresponding to the area of focal choroidal excavation. (Top right) A relatively well defined hyperfluorescence was observed inthe late phase of ICGA. (Bottom left) SD OCT showed focal excavation involving the outer retinal layers up to the external limitingmembrane (ELM). Irregular elevation of the retinal pigment epithelium (RPE) line with a minimal amount of fluid collection wasnoted in the macula. A hyperreflective lesion was located beneath the RPE line (type 1 CNV), and this was confined within the con-cavity of the focal choroidal excavation. (Bottom right) After 2 consecutive injections of bevacizumab, the patient’s best-correctedvisual acuity recovered to 20/32 and the fluid was completely absorbed. The regression of the hyperreflective lesion was noted, alongwith the complete restoration of the ELM and inner segment/outer segment line. After the treatment, SD OCT revealed the focalchoroidal excavation more clearly as the RPE band followed the contour of the choroidal excavation.

while 2 cases showed type 1 CNV in their contralateral eye.The spherical equivalent of the refractive error ranged from�12.50 diopters (D) to 1.125 D (mean, �3.48 D).

At initial presentation, CNV was accompanied by focalchoroidal excavation in 13 of 16 patients. CNV had devel-oped in 3 patients at 2, 11, and 21 months of follow-up, and2 of them showed a nonconforming pattern. Fifteen CNVsinvolved the subfoveal area and 1 CNV was juxtafoveal(within 200 mm from the center of the fovea). The meanbaseline BCVA was 20/46 (range, 20/200-20/25). Thefocal choroidal excavation lesions were located subfoveallyin 14 of 16 eyes (87.5%) and juxtafoveally in 2 eyes

VOL. 157, NO. 3 FOCAL CHOROIDAL EXCAVATION AND C

(12.5%). The mean choroidal thickness was 160 mm(range, 54-353 mm) at the base of the excavation and272 mm (range, 203-413 mm) at the unaffected sites nearthe excavation. The ratio of the choroidal thicknesses ofthe 2 sites varied from 0.25-0.85 (mean, 0.53).According to FA, 14 eyes exhibited a classic appearance

with profuse leakage through the mid and late phase(Figures 1-4). The other 2 CNVs were purely occult(Figure 5). All 8 patients under 50 years had classicCNV. Six of 8 patients over 50 years old showed a classicpattern, and the other 2 had occult pattern CNV. ICGArevealed abnormal vasculature consistent with CNV, but

713HOROIDAL NEOVASCULARIZATION

FIGURE 2. Type 2 choroidal neovascularization (CNV) with classic pattern in a 28-year-old man (Case 4). The patient presentedwith an abrupt reduction in vision in his right eye. (Top left) His best-corrected visual acuity was 20/200 in the right eye and thefundus photograph demonstrated a subfoveal exudative lesion with serous retinal detachment. The white line corresponds to the sec-tion examined with spectral-domain optical coherence tomography (SD OCT). (Top right) Fluorescein angiography showed classicCNV. (Bottom left) Indocyanine green angiography revealed focal hypofluorescence at the area of focal choroidal excavation andabnormal vessels representing CNV that extended over the margin of the hypofluorescent area (white arrows). (Bottom right) SDOCT demonstrated focal choroidal excavation in the macula and a distinct layer of hyperreflective material located above the retinalpigment epithelium line (type 2 CNV). The hyperreflective tissue extended over the boundary of focal choroidal excavation, andsubretinal and intraretinal fluid accumulation was noted.

no polypoidal lesions. Eleven of 12 eyes (91.7%) showedfocal hypofluorescence at the corresponding focal choroidalexcavation area, and 8 of 12 eyes (66.7%) showed choroidalvenous dilation and diffuse hyperfluorescence in the latephase.

In all 16 eyes, a hyperreflective subretinal or sub-RPElesion, representing a CNV complex, was observed onOCT. The location and extent of the lesion was well corre-lated with the area of hyperfluorescence on FA or abnormalvessels on ICGA. Type 1 CNVwas identified in 9 eyes, andtype 2 CNV was found in 7 eyes. Among the 8 patientsunder 50 years old, 2 and 6 patients had type 1 (Figure 1)and type 2 CNV (Figures 2 and 3), respectively. Seven of8 patients over 50 years old had type 1 CNV (Figures 4and 5), and the remaining patient had type 2 CNV. Avariable amount of subretinal fluid accumulationwas observedin all 16 eyes and intraretinal fluid was noted in 5 eyes.

714 AMERICAN JOURNAL OF

All 7 eyes with type 2 CNV on OCT exhibited a classicpattern on FA. Among the 9 eyes with type 1 CNV, 2 eyesexhibited an occult pattern on FA and 7 eyes showed aclassic pattern. Hyperreflective lesions on OCT wereconfined to the boundary of the focal choroidal excavationin 12 eyes. These eyes had a classic appearance on FA, evenin type 1 CNV (Figures 1 and 4). In 2 eyes with type 2CNV, the hyperreflective lesion extended slightly overthe margin of excavation with a corresponding classicpattern on FA (Figures 2 and 3). In 2 eyes with type 1CNV, highly reflective tissue beneath the RPE extendedfar away from the excavation, corresponding to an occultpattern with irregular RPE elevation (Figure 5).The mean follow-up period was 14.5 months (range:

3-35 months) and all but 1 patient were treated withanti-VEGF injections. A total of 11 eyes were treated withbevacizumab and 4 eyes were treated with ranibizumab,

MARCH 2014OPHTHALMOLOGY

FIGURE 3. Type 2 choroidal neovascularization (CNV) with classic pattern in a 29-year-old woman (Case 11). The patientpresented with vague visual disturbance and her best-corrected visual acuity (BCVA) was 20/25 in the right eye. (Top left) Initialspectral-domain optical coherence tomography (SDOCT) scan through the fovea revealed focal choroidal excavation with slight sep-aration between sensory retina and retinal pigment epithelium (RPE). (Top right) Initial fluorescein angiography (FA) showednonspecific RPE mottling with no leakage. Two months later, her BCVA decreased to 20/32. (Middle left) SD OCT showed subre-tinal fluid with hyperreflective material located above the RPE line (type 2CNV). (Bottom right) At that time, FA demonstrated well-defined CNV with progressive leakage. After 2 consecutive injections of bevacizumab, her BCVA recovered to 20/25. (Bottom left)Follow-up SD OCT disclosed regressed CNV.

with a mean of 3.7 injections. The mean BCVA in theseeyes improved from 20/44 (range: 20/200-20/25) at baselineto 20/26 (range: 20/100-20/20) at the last visit. Fluid collec-tion in the macular area was not observed in any patient atthe last visit.All 7 patients under 50years old achieved a finalBCVA of 20/32 or better with a mean of 2.1 (range: 1-3)injections during the mean follow-up period of 11.7 months(range: 3-19months).Additional treatmentwas not requiredafter the 1-3 initial injections (Figures 1 and3).All 8 patientsover 50 years old attainedvisual improvementwith ameanof5.0 injections (range: 3-8) during the mean follow-up periodof 17.0 months (range: 7-35 months), and 6 had a finalBCVA better than 20/32. Complete absorption of fluid wasobserved after 3 initial loading injections in all eyes. Addi-tional treatment of 1-5 injections was given in 6 eyes forrecurrent fluid collection (Figure 4).

DISCUSSION

IN OUR SERIES, ALL 16 CHOROIDAL NEOVASCULAR COM-

plexes involved the area of choroidal excavation on

VOL. 157, NO. 3 FOCAL CHOROIDAL EXCAVATION AND C

OCT, with 12 being located within the boundary of exca-vation and 4 extending over the margin. This close topo-graphic relationship supports the notion that choroidalexcavation plays a role in the development of CNV.Choroidal thinning at the area of excavation was observedin nearly all patients, which is consistent with the resultsof other studies.4,5 By ICGA, focal hypofluorescencewas observed in this area, which indicates choroidalhypoperfusion. The results of numerous studies stronglysupport the role of choroidal hypoperfusion and possibleischemia as an inciting factor for CNV formation inAMD.13–18 We postulated that mechanical stretchingof the RPE/Bruch membrane complex in the areacorresponding to choroidal excavation can result in afocal defect in the Bruch membrane through which newvessels can extend from the choroid. Additionally,in vitro, the stretching of the RPE cells has been reportedto induce the production and secretion of VEGF.19

Seven of 16 patients in our series had type 2 CNV on SDOCT and 6 of them were under the age of 50. Margolis andassociates suggested that the elasticity of the retina wouldinitially allow the photoreceptors to remain attached tothe RPE (conforming pattern).4 With time, stress on the

715HOROIDAL NEOVASCULARIZATION

FIGURE 4. Type 1 choroidal neovascularization (CNV) with classic pattern in a 71-year-old man (Case 2). The patient was referredfor evaluation of exudative age-related macular degeneration in his left eye. The best-corrected visual acuity (BCVA) was 20/200 atinitial presentation. (Top left) Biomicroscopic examination demonstrated suspicious CNV surrounded by hemorrhage. A few softdrusen were noted in the extramacular area. The white line corresponds to the section examined with spectral-domain optical coher-ence tomography (SD OCT). (Top second) Fluorescein angiography showed an area of discrete hyperfluorescence in the early phase.(Top third) Awell-defined neovascular network was noted in the early phase of indocyanine green angiography. (Top right) Initial SDOCT taken at the previous hospital showed subretinal fluid with a hyperreflective lesion, mostly located beneath the retinal pigmentepithelium (RPE) line. After 3 loading injections of ranibizumab, the BCVA improved to 20/25. (Bottom left) A fundus photographtaken 12 months after initial presentation demonstrated the regression of CNV. Atrophic changes of the RPE were noted in the areaof the focal choroidal excavation. (Bottommiddle) Complete absorption of subretinal fluid and regression of the hyperreflective lesionwas observed on follow-up SD OCT. Focal choroidal excavation was more obvious on SD OCT after the regression of the hyperre-flective lesion. (Bottom right) Fifteen months after presentation, CNV recurrence was noted with subretinal fluid accumulation onfollow-up SD OCT. A hyperreflective lesion was observed again beneath the RPE line. Additional injections with ranibizumab wereperformed, resulting in complete absorption of fluid again. Final BCVA was 20/25.

outer retina could result in the separation of the photore-ceptor tips from the apical surface of the RPE, leading tothe formation of a subretinal space (nonconformingpattern). New vessels then can grow into this space withoutany resistance. Furthermore, the potential metabolic stressand ischemic insult to the outer retina and RPE after long-standing disintegrationmay also serve as a potential drivingforce for the ingrowth of neovascularization in a noncon-forming pattern. Nonconforming choroidal excavationmay have a greater tendency to develop secondary CNV,compared to the conforming pattern. However, thisremains speculative because most of the CNV in this studywas already present at initial examination.

Type 1 CNV was observed in 9 patients, 7 of whom wereover the age of 50. The age profile of our patients is compat-ible with the pathogenesis of CNV proposed by Gass.6 Gasssuggested that the growth pattern of neovascular prolifera-tion is determined primarily by preexisting disease, as wellas by the patient’s age. Given that most of the olderpatients in our study did not have soft drusen, a commonsign of early AMD, and 2 younger patients demonstratedtype 1 lesions, anatomic changes of the overlying retinallayers induced by choroidal excavation may also affect

716 AMERICAN JOURNAL OF

the growth pattern. According to the degree and extentof loosening of the adhesion between the surroundingRPE and Bruch membrane, new vessels extending fromthe choroid through the focal defects in the Bruch mem-brane may grow laterally, beneath the RPE layer, or anteri-orly, beneath the sensory retina.It is notable that in our series, 7 of 9 patients with type 1

CNV onOCT had a classic pattern with profuse leakage onFA. In these 7 eyes, entire abnormal vascular complexeswere located within the concavity of the focal choroidalexcavation (Figures 1 and 4). In contrast, in 2 eyes withan occult appearance, the neovascular complexes extendedbeyond the margin of excavation with irregular RPE eleva-tion on OCT. It is likely that a healthy RPE and the rela-tively firm adhesion of the RPE and Bruch membranesurrounding the focal choroidal excavation may limitactive CNV proliferation within the focal choroidal exca-vation boundary. We postulated that this characteristiccontributed to the well-defined, classic appearance on FAeven though the CNV is located beneath the RPE layer.Owing to the small number of cases and different follow-

up periods, our interpretation of the prognosis of this disor-der is currently limited. Nonetheless, the visual prognosis

MARCH 2014OPHTHALMOLOGY

FIGURE 5. Type 1 choroidal neovascularization (CNV) with occult pattern in a 66-year-old man (Case 13). The patient presentedwith decreased visual acuity of 20/100 in the right eye. (Left column, top) Fluorescein angiography (FA) showed occult CNV withirregular and diffuse leakage. (Left column, bottom) A well-defined hyperfluorescence, so-called plaque lesion, was observed in thelate phase of indocyanine green angiography. Hypofluorescence corresponds to the area of focal choroidal excavation. (Right column)The 3 spectral-domain optical coherence tomography (SDOCT) images were arranged in order from the lowest white line (top) to thehighest (bottom) in the FA image (Left column, top). (Right column, top) On SD OCT, hyperreflective materials beneath the retinalpigment epithelium (RPE) line were noted at the base of the focal choroidal excavation. These extended over the margin of the focalchoroidal excavation associated with irregular RPE elevation. (Right column, middle and bottom) There was an accumulation ofintraretinal fluid and a minimal amount of subretinal fluid. The disruption of the external limiting membrane and inner segment/outersegment line was noted.

with anti-VEGF treatment in our patients was seeminglyfavorable. Less frequent injection was required even inpatients over 50 years compared with typical neovascularAMD.20

Our study has limitations inherent to a small retrospec-tive analysis performed at a single institution. We carefullyreviewed the OCT images of all patients who were diag-nosed with CNV over the study period, which lasted longerthan 4 years, and collected a relatively large number ofcases that were uncommon. Despite the close topographicrelationship observed, it is possible that focal choroidalexcavation was detected coincidentally with CNV, espe-cially in 2 eyes with a large occult pattern. Angiographicclassification of CNV can vary between observers. Also,anatomic classification may vary between different modelsof OCT. However, 14 of 16 CNVs were obvious classic-only pattern. Both OCTs used in this study were SDOCT, which had enough resolution to identify CNV andits location. Finally, the precise determination of CNVtype on OCT may be hindered by other pathologicchanges, such as exudates or clusters of fibrin and hemor-rhage that may also appear as highly reflective lesions.

VOL. 157, NO. 3 FOCAL CHOROIDAL EXCAVATION AND C

Nonetheless, the comparison between serial OCT andangiograms showed good co-localization of the neovascularlesions in this study.In summary, taking into consideration all of the imaging

and clinical features observed in this study, as well as theresults of previous reports, a direct causal relationshipbetween focal choroidal excavation and CNV developmentseems plausible. Focal choroidal ischemia, overlying RPEchanges, and occasional separation of the sensory retinafrom the RPE layer in focal choroidal excavation may serveas a predisposition for CNV development. It is highlypossible that mechanical stretching of the overlying retinallayer may result in a focal break in the Bruch membrane,inducing neovascular proliferation from the choroid. TheCNV growth pattern (type 1 or type 2 CNV) may be deter-mined by the anatomic changes in retinal layers associatedwith focal choroidal excavation, as well as age. Specifically,the growth pattern is dependent on the degree and extentof loosening of the adhesion between the RPE and Bruchmembrane. Because the CNV is frequently located withinthe concavity of the focal choroidal excavation, FA seemsto indicate a well-defined classic pattern, even in type 1

717HOROIDAL NEOVASCULARIZATION

CNV. Smaller lesion size within the focal choroidal exca-vation cavity, younger age of onset, and a relatively healthysurrounding RPE seem to contribute to notable, favorable

718 AMERICAN JOURNAL OF

visual outcomes. Further long-term studies with largerpatient cohorts are required to elucidate the exact patho-physiology and visual prognosis of this novel disease.

ALL AUTHORSHAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSUREOF POTENTIAL CONFLICTS OF INTEREST.Won Ki Lee has served on advisory boards for Novartis and Bayer, and has received consultancy fees from these companies. He has received payments forlectures from Novartis, Bayer, and Allergan. Jae Hyung Lee has no financial disclosure to report. The authors indicate no funding or financial support.Contributions of authors: design and conduct of the study (W.K.L., J.H.L.); collection and management of data (J.H.L., W.K.L.); analysis and interpre-tation of the data (W.K.L., J.H.L.); preparation of the manuscript (J.H.L., W.K.L.); review or approval of the manuscript (W.K.L., J.H.L.).

REFERENCES

1. Jampol LM, Shankle J, Schroeder R, Tornambe P, Spaide RF,Hee MR. Diagnostic and therapeutic challenges. Retina 2006;26(9):1072–1076.

2. Katome T, Mitamura Y, Hotta F, Niki M, Naito T. Two casesof focal choroidal excavation detected by spectral-domainoptical coherence tomography. Case Rep Ophthalmol 2012;3(1):96–103.

3. Wakabayashi Y, Nishimura A, Higashide T, Ijiri S,Sugiyama K. Unilateral choroidal excavation in the maculadetected by spectral-domain optical coherence tomography.Acta Ophthalmol 2010;88(3):e87–91.

4. Margolis R, Mukkamala SK, Jampol LM, et al. The expandedspectrum of focal choroidal excavation. Arch Ophthalmol2011;129(10):1320–1325.

5. Obata R, Takahashi H, Ueta T, Yuda K, Kure K, Yanagi Y.Tomographic and angiographic characteristics of eyes withmacular focal choroidal excavation. Retina 2013;33(6):1201–1210.

6. Gass JDM. Stereoscopic atlas of macular disease: diagnosisand treatment. 4th ed. St Louis: Mosby; 1997:26–37.

7. Freund KB, Ho IV, Barbazetto IA, et al. Type 3 neovasculari-zation: the expanded spectrum of retinal angiomatous prolif-eration. Retina 2008;28(2):201–211.

8. Subfoveal neovascular lesions in age-related maculardegeneration. Guidelines for evaluation and treatment inthe macular photocoagulation study. Macular Photocoagu-lation Study Group. Arch Ophthalmol 1991;109(9):1242–1257.

9. Malamos P, Sacu S, Georgopoulos M, Kiss C, Pruente C,Schmidt-Erfurth U. Correlation of high-definition opticalcoherence tomography and fluorescein angiography imagingin neovascular macular degeneration. Invest Ophthalmol VisSci 2009;50(10):4926–4933.

10. Park SS, Truong SN, Zawadzki RJ, et al. High-resolutionFourier-domain optical coherence tomography of choroidalneovascular membranes associated with age-related maculardegeneration. Invest Ophthalmol Vis Sci 2010;51(8):4200–4206.

11. Spaide RF, Koizumi H, PozzoniMC. Enhanced depth imagingspectral-domain optical coherence tomography. Am JOphthalmol 2008;146(4):496–500.

12. Photodynamic therapy of subfoveal choroidal neovasculariza-tion in age-related macular degeneration with verteporfin:one-year results of 2 randomized clinical trials—TAP report.Treatment of age-related macular degeneration with photo-dynamic therapy (TAP) Study Group. Arch Ophthalmol1999;117(10):1329–1345.

13. Chung SE, Kang SW, Lee JH, Kim YT. Choroidal thickness inpolypoidal choroidal vasculopathy and exudative age-relatedmacular degeneration. Ophthalmology 2011;118(5):840–845.

14. Metelitsina TI, Grunwald JE, DuPont JC, Ying GS,Brucker AJ, Dunaief JL. Foveolar choroidal circulation andchoroidal neovascularization in age-related macular degener-ation. Invest Ophthalmol Vis Sci 2008;49(1):358–363.

15. Ramrattan RS, van der Schaft TL, Mooy CM, de Bruijn WC,Mulder PG, de Jong PT. Morphometric analysis of Bruch’smembrane, the choriocapillaris, and the choroid in aging.Invest Ophthalmol Vis Sci 1994;35(6):2857–2864.

16. Spaide RF. Age-related choroidal atrophy. Am J Ophthalmol2009;147(5):801–810.

17. McLeod DS, Grebe R, Bhutto I, Merges C, Baba T, Lutty GA.Relationship between RPE and choriocapillaris in age-relatedmacular degeneration. Invest Ophthalmol Vis Sci 2009;50(10):4982–4991.

18. Hayashi K, de Laey JJ. Indocyanine green angiography ofchoroidal neovascular membranes. Ophthalmologica 1985;190(1):30–39.

19. Seko Y, Seko Y, Fujikura H, Pang J, Tokoro T,Shimokawa H. Induction of vascular endothelial growthfactor after application of mechanical stress to retinalpigment epithelium of the rat in vitro. Invest OphthalmolVis Sci 1999;40(13):3287–3291.

20. Comparison of Age-Related Macular Degeneration Treat-ments Trials Research Group; Martin DF, Maguire MG,Fine SL, et al. Ranibizumab and bevacizumab for treatment ofneovascular age-relatedmacular degeneration: two-year results.Comparison of Age-relatedMacular Degeneration TreatmentsTrials (CATT). Ophthalmology 2012;119(7):1388–1398.

MARCH 2014OPHTHALMOLOGY

Biosketch

Jae Hyung Lee, MD, graduated from Catholic University of Korea, College of Medicine in 2008 where he completed

internship and residency in 2013. He is currently pursuing his first year of retinal fellowship in Seoul St. Mary’s

Hospital. His research interests include age-related macular degeneration and polypoidal choroidal vasculopathy.

VOL. 157, NO. 3 718.e1FOCAL CHOROIDAL EXCAVATION AND CHOROIDAL NEOVASCULARIZATION