- Email: [email protected]
OCT Angiography of Treatment-Naïve Quiescent Choroidal Neovascularization in Pachychoroid Neovasculopathy
Optical Coherence Tomography Angiography of Treatment-Naïve Quiescent Choroidal Neovascularization in Pachychoroid Neovasculopathy Adriano Carnevali, MD,1,2 Vittorio Capuano, MD,3 Riccardo Sacconi, MD,1,4 Lea Querques, MD,1 Alessandro Marchese, MD,1 Alessandro Rabiolo, MD,1 Eric Souied, MD, PhD,3 Vincenzo Scorcia, MD,2 Francesco Bandello, MD, FEBO,1 Giuseppe Querques, MD, PhD1 Purpose: To estimate the prevalence of treatment-naïve quiescent choroidal neovascularization (CNV) among eyes with pachychoroid neovasculopathy and to investigate the optical coherence tomography angiography (OCT-A) features. Design: Prospective case series. Participants: From a pool of 55 eyes of 54 patients (mean age, 5210.2 years; 35 male/19 female) with pachychoroid neovasculopathy, we identified 49 eyes of 49 patients previously treated for actively leaking CNV, whereas 6 eyes of 6 patients met the selection criteria for treatment-naïve quiescent CNV. Methods: Treatment-naïve quiescent CNV was identified in a pool of patients with pachychoroid neovasculopathy consecutively presenting between January 2016 and June 2016 at 2 high-volume referral centers. Each enrolled patient underwent a complete ophthalmologic examination that included fluorescein angiography, indocyanine green angiography (ICGA), and OCT-A with the AngioPlex CIRRUS HD-OCT Model 5000 (Carl Zeiss Meditec, Inc, Dublin, CA) or the AngioVue RTVue XR Avanti (Optovue, Freemont, CA). Main Outcome Measures: Prevalence and OCT-A features of treatment-naïve quiescent CNV. Results: We estimate a prevalence of 10.9% (2.7e19.1, 95% confidence intervals) for treatment-naïve quiescent CNV among eyes with pachychoroid neovasculopathy. Type 1 quiescent neovascular networks were clearly visible in all 6 eyes by OCT-A, and there was agreement of 100% between the readers in the correspondence between ICGA and OCT-A images and in the rating of OCT-A imaging features of CNV. The most frequently observed features (well-defined margin and irregular shape) were seen in 4 of 6 eyes. Conclusions: Using OCT-A allows the clinician to noninvasively identify treatment-naive quiescent CNV and may be considered as a useful tool in guiding the frequency of follow-up examinations and treatment decisions in pachychoroid disease. Ophthalmology Retina 2017;-:1e5 ª 2017 by the American Academy of Ophthalmology
The term “pachychoroid-driven spectrum of disease” describes a set of choroidal features shared by a group of related diseases, including pachychoroid pigment epitheliopathy (PPE) and central serous chorioretinopathy (CSC).1 These diseases share similar features, such as thickened choroid on enhanced depth imaging optical coherence tomography (OCT), reddish orange fundus appearance with reduced fundus tessellation, a spectrum of overlying retinal pigment epithelium (RPE) abnormalities including pigment epithelial detachments, and fundus autofluorescence changes.1,2 Pachychoroid pigment epitheliopathy is distinguished from CSC by the lack of clinical or imaging evidence of acute or chronic subretinal fluid. We consider PPE to be a forme fruste of CSC.1 En face imaging with swept-source OCT recently has revealed new findings that refine the definition of the pachychoroid phenotype to emphasize the morphologic characteristics of pathologically dilated choroidal vessels (“pachyvessels”) over absolute choroidal thickness.3 Both long-standing CSC and PPE have been 2017 by the American Academy of Ophthalmology Published by Elsevier Inc.
shown to be associated with type 1 neovascularization.4e6 Pang and Freund4 coined the term “pachychoroid neovasculopathy” to describe a disease characterized by a form of type 1 neovascularization involving dilated choroidal vessels in areas of increased choroidal thickness. The authors support their hypothesis by noting that eyes with long-standing “silent” pachychoroid disease (because asymptomatic) may develop type 1 neovascularization in the absence of an overt CSC manifestation, including submacular exudative detachment or gravitational tracts of chronic subretinal fluid.4 In addition, both type 1 neovascularization associated with CSC and pachychoroid neovasculopathy could progress to polypoidal choroidal vasculopathy (PCV).4,5,7 The many similarities between CSC and PCV suggest that PCV may be included in the “pachychoroiddriven spectrum of disease.”1,4 Treatment-naïve quiescent choroidal neovascularization (CNV) is a finding recently described in the setting of agerelated macular degeneration (AMD) for nonexudative http://dx.doi.org/10.1016/j.oret.2017.01.003 ISSN 2468-6530/17
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Ophthalmology Retina Volume -, Number -, Month 2017 Table 1. Optical Coherence Tomography Angiography Features of Patients with Treatment-Naïve Quiescent Choroidal Neovascularization in the Setting of Pachychoroid Neovasculopathy Patient No.
Eye
Shape
Core
Margin
Location
Device
1 2 3 4 5 6
LE RE RE LE RE LE
CIR IRR IRR IRR IRR CIR
NV NV V V NV V
WD WD WD PD WD WD
FS FS FI FI FS FI
AngioVue (Optovue, Freemont, CA) AngioPlex (Carl Zeiss Meditec, Inc, Dublin, CA) AngioPlex AngioVue AngioPlex AngioPlex
CIR ¼ circular; FI ¼ foveal involving; FS ¼ foveal sparing; IRR ¼ irregular; LE ¼ left eye; NV ¼ not visualized; PD ¼ poorly defined; RE ¼ right eye; V ¼ visualized; WD ¼ well defined.
AMD eyes complicated by type 1 neovascularization.8 The utility of OCT angiography (OCT-A) in CNV detection in different ocular conditions has been extensively described in the literature and recently reported in quiescent CNV in the setting of AMD.9 To the best of our knowledge, no studies have reported the presence of treatment-naïve quiescent CNV in patients affected by pachychoroid neovasculopathy. In this study, we estimate the prevalence of treatment-naïve quiescent CNV among eyes with pachychoroid neovasculopathy and report the OCT-A features.
Methods Treatment-naïve quiescent CNV was identified in a pool of patients with pachychoroid neovasculopathy consecutively presenting between January 2016 and June 2016 at 2 high-volume referral centers (the Medical Retina & Imaging Unit, University
Vita-Salute San Raffaele in Milan, Italy, and the Department of Ophthalmology of University Paris Est, in Creteil, France). The study was conducted in agreement with the Declaration of Helsinki for research involving human subjects and was approved by the local institutional review board at both sites. Inclusion criteria were: 1) diagnosis of treatment-naïve “quiescent” CNV, defined as a flat irregular elevation of the RPE with moderately reflective material in the sub-RPE space, no intraretinal or subretinal hyporeflective fluid on structural OCT, late-phase ill-defined hyperfluorescent lesion, without late-phase leakage or pooling of dye on fluorescein angiography, and hypercyanescent neovascular network in the earlyemid phases of indocyanin green angiography (ICGA); 2) presence of pachychoroid characteristics, defined as any of the following: choroidal thickness above 270 mm, and presence of pachyvessels on ICGA; 3) sufficiently clear ocular media; and 4) adequate pupillary dilation and fixation to permit high-quality OCT imaging. Ocular exclusion criteria consisted of any disease other than primary pachychoroid neovasculopathy (including history of acute CSC in the study eye) and any previous intervention for CNV.
Figure 1. Indocyanine green angiography (ICGA), spectral-domain optical coherence tomography (SD-OCT) B-scan, and optical coherence tomography angiography (OCT-A) of patient number 3 with quiescent choroidal neovascularization (CNV) secondary to pachychoroid neovasculopathy. Early phase of ICGA (A) shows a hypercyanescent neovascular network, and the late phase (B) is characterized by wash-out of the quiescent CNV. Note the late hypocyanescent lesion grossly corresponding to the neovascular network as visualized by OCT-A (C, arrowhead).
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OCTA of Quiescent CNV in Pachychoroid
Figure 2. Indocyanine green angiography (ICGA), spectral domain optical coherence tomography (SD-OCT) B-scan, and optical coherence tomography angiography (OCT-A) of patient number 4 with quiescent choroidal neovascularization (CNV) secondary to pachychoroid neovasculopathy. Early phase of ICGA (A) shows an hypercyanescent neovascular network (arrowhead), and the late phase (B) is characterized by wash-out of the quiescent CNV. Note the late hypocyanescent lesion grossly corresponding to the neovascular network as visualized by OCT-A (C). Moreover, SD-OCT shows the presence of a pachyvessel below the irregular flat retinal pigment epithelium (RPE) elevation (white asterisk).
Clinical charts and multimodal imaging data were reviewed. As per standard clinical assessment at both sites, all patients had previously undergone a comprehensive ophthalmologic examination, including measurement of best-corrected visual acuity, dilated slit-lamp anterior segment and fundus biomicroscopy, fluorescein angiography, ICGA, spectral-domain OCT (Spectralis þ HRA; Heidelberg Engineering, Heidelberg, Germany), and OCT-A. Each enrolled patient underwent OCT-A with the AngioPlex CIRRUS HD-OCT Model 5000 (Carl Zeiss Meditec, Inc, Dublin, CA) or the AngioVue RTVue XR-Avanti (Optovue, Freemont, CA). Optical coherence tomography angiography was performed in all patients with a scanning area of 33 mm centered on the foveal area. The automatic segmentation provided by the OCT-A software was manually adjusted by 2 expert retina specialists (AC and GQ) for correct visualization of the capillary plexus, outer retinal layers, and choriocapillaris to better identify the CNV plane. The OCT-A images and corresponding structural OCT B-scans were evaluated side by side with ICGA and were assessed for CNV shape, CNV core, CNV margin, and CNV location. The CNV shape was classified as “circular” or “irregular.” The CNV core has been defined as a vessel of greater caliber or a “trunk vessel” from which other smaller vessels branch off. The CNV core was classified as “visible” or “not visible,” depending on its visibility. The CNV margin on OCT-A was classified as “well defined” or “poorly defined” on the basis of its appearance and its borders. The CNV location was classified as “foveal involving” if the lesion involved the foveal center or “foveal sparing” if the CNV lesion spared the foveal center. Disagreement regarding interpretation of the different features was resolved by open adjudication.
Statistical analysis was performed using SPSS software 21 (SPSS, Inc, Chicago, IL). Results of descriptive analyses are expressed as means standard deviations for quantitative variables and as counts and percentages for categoric variables. We also performed an estimation of the prevalence of treatment-naïve quiescent CNV among patients affected by pachychoroid neovasculopathy with 95% confidence intervals. Comparison of mean subfoveal choroidal thickness between the eyes with CNV and the fellow eyes was performed using the Student t test. In all analyses, P values < 0.05 were considered as statistically significant.
Results From a pool of 55 eyes of 54 patients (mean age, 5210.2 years; 35 male/19 female) with pachychoroid neovasculopathy, we identified 49 eyes of 49 patients previously treated for actively leaking CNV, and 6 eyes of 6 patients met the selection criteria for treatment-naïve quiescent CNV (a subject presented pachychoroid neovasculopathy in both eyes with a quiescent CNV in the right eye and a type 1 neovascularization treated for active leaking in the fellow eye). The cases in the current study were all consecutive patients with pachychoroid neovasculopathy, and no cases were excluded. This accounts for an estimated prevalence of 10.9% (2.7e19.1, 95% confidence intervals) for treatment-naïve quiescent CNV among eyes with pachychoroid neovasculopathy; the mean age of the patients with quiescent pachychoroid neovasculopathy was 61.19.0 years. Four patients were male, and 2 patients were female. Four patients (4 eyes) with treatment-naïve quiescent CNV
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Ophthalmology Retina Volume -, Number -, Month 2017 were enrolled at University Vita-Salute San Raffaele in Milan, and 2 patients (2 eyes) were enrolled at University Paris Est in Creteil. Among all 55 eyes, 18 presented intraretinal or subretinal hyporeflective fluid on structural OCT and were classified as actively leaking and thus received previous treatments (10 photodynamic therapy [PDT], 5 antievascular endothelial growth factor [VEGF] [ranibizumab], 3 combination of PDT and anti-VEGF [aflibercept]). Among 37 eyes presenting with no intraretinal or subretinal hyporeflective fluid on structural OCT, 31 eyes received previous treatments (19 PDT, 8 anti-VEGF [ranibizumab], 4 combination of PDT and anti-VEGF [aflibercept]) for actively leaking CNV. Mean subfoveal choroidal thickness in eyes with treatment-naïve quiescent CNV, measured as the distance between the RPE-Bruch’s membrane complex and the chorioscleral border, was 39972 mm (37569 mm in fellow eyes, P ¼ 0.57). The CNV shape on OCT-A was rated as circular in 2 of 6 eyes and irregular in 4 of 6 eyes. The CNV core was visible in 3 of 6 eyes and was not visible in 3 of 6 eyes; in the 3 eyes with a visible core, the core position was considered as central in 2 cases and as eccentric in the other case. The CNV margin was considered as well defined in 5 of 6 eyes and poorly defined in 1 of 6 eyes. The CNV location was foveal sparing in 3 of 6 eyes and foveal involving in 3 of 6 eyes. The most frequently observed features (well-defined margin and irregular shape) were seen in 4 of 6 eyes. In all 49 treated eyes with active or inactive CNV, OCT-A disclosed the type 1 neovascular networks. In addition, type 1 quiescent neovascular networks were clearly visible in all 6 eyes by OCT-A, and there was agreement of 100% between the readers in the correspondence between ICGA images and OCT-A images and in the rating of OCT-A images features of CNV (Table 1). There was good correspondence between the late-phase ill-defined hyperfluorescent lesion, without late-phase leakage or pooling of dye on fluorescein angiography, and the quiescent CNV as visualized by OCT-A. Of note, the CNV appearing as a hypercyanescent neovascular network in earlyemid phases of ICGA was characterized by wash-out in the late phase; also, the late hypocyanescent lesion grossly corresponded to the neovascular network as visualized by OCT-A (Fig 1 and Fig 2).
In AMD, quiescent CNV appeared to enlarge over time on ICGA, as described by Querques et al8 without any detectable retinal thickening on OCT. It is generally accepted in clinical practice that asymptomatic CNVs do not have associated intraretinal and subretinal exudation on structural OCT and do not meet the criteria for antiVEGF therapy.13 The precise location of the lesion on OCT-A and the precise measurement of the CNV area, together with detection of intraretinal and subretinal exudation on structural OCT, could be useful tools to monitor nonexudative CNV in pachychoroid neovasculopathy and to support the treatment decision. Future studies will investigate whether repeated scans on the neovascular membrane may allow early detection of its growth in a faster and safer fashion than dye angiography. It is noteworthy that in our cases the most frequently observed features (irregular shape and well-defined margin) were all detected in 4 of 6 eyes (66.6%), and the core was visualized in 50% of the cases. Instead, our group recently analyzed the OCT-A features in quiescent CNV secondary to AMD and showed that the most frequently observed features (irregular shape, not visible core, well-defined margin, foveal-sparing location) were all detected in 6 of 18 eyes (33.3%), and the core was visualized only in 2 of 18 eyes (11%).9 In quiescent CNV secondary to AMD, our group suggested that the absence of a detectable core vessel may represent a protective factor against increased activity from quiescent CNV,9 and thus the higher prevalence of a detectable core vessel in quiescent pachychoroid neovasculopathy may be associated with a higher tendency to activation in pachychoroid neovasculopathy than AMD. This hypothesis should be investigated in further studies with relevant follow-up.
Discussion
The main limitation of this study is the relatively small cohort of patients; however, quiescent CNV is not as common as active neovascularization.
Recent studies have shown that OCT-A is able to precisely identify microvascular structures and that it can be used to assess the morphology of type 1, type 2, and type 3 CNV.10e12 In this study, we investigated the features of treatment-naïve quiescent CNV in 6 pachychoroid eyes with OCT-A. The most frequently observed features (irregular shape and well-defined margin) were all detected in 4 of 6 eyes (66.6%). In addition, OCT-A allowed us to visualize the presence of a neovascular network in all eyes enrolled (100%), and we estimated a prevalence of quiescent CNV in pachychoroid neovasculopathy of 10.9%. Given the difficulty in visualizing quiescent type 1 neovascularization in pachychoroid eyes using conventional retinal imaging, the identification of quiescent CNV with OCT-A in a large proportion of eyes with flat irregular pigment epithelial detachments can be a useful method to diagnose this particular entity. In fact, unlike quiescent CNV in AMD characterized by late plaque hyperfluorescence, in pachychoroid eyes only the earlyemid phases of ICGA can show the quiescent neovascular network (which is characterized then by late wash-out), thus making proper diagnosis challenging.
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Study Limitation
Conclusions We describe the OCT-A features in a series of patients with treatment-naïve quiescent CNV secondary to pachychoroid neovasculopathy. Quiescent CNV in pachychoroid disease may be suspected by structural OCT as a flat irregular elevation of the RPE with moderately reflective material in the sub-RPE space and by earlyemid phases of ICGA that show the neovascular network, then characterized by late wash-out. In the current series, OCT-A was able to clearly visualize treatment-naïve quiescent CNV in all cases. Using OCT-A allows the clinician to identify noninvasively treatment-naive quiescent CNV and may be considered as a useful tool in guiding the frequency of follow-up examinations and treatment decisions in pachychoroid disease. References 1. Warrow DJ, Hoang QV, Freund KB. Pachychoroid pigment epitheliopathy. Retina. 2013;33:1659e1672.
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OCTA of Quiescent CNV in Pachychoroid
2. Guyer DR, Yannuzzi LA, Slakter JS, et al. Digital indocyanine green videoangiography of central serous chorioretinopathy. Arch Ophthalmol. 1994;112:1057e1062. 3. Dansingani KK, Balaratnasingam C, Naysan J, Freund KB. En face imaging of pachychoroid spectrum disease with sweptsource optical coherence tomography. Retina. 2016;36:499e516. 4. Pang CE, Freund KB. Pachychoroid neovasculopathy. Retina. 2015;35:1e9. 5. Fung AT, Yannuzzi LA, Freund KB. Type 1 (sub-retinal pigment epithelial) neovascularization in central serous chorioretinopathy masquerading as neovascular age-related macular degeneration. Retina. 2012;32:1829e1837. 6. Freund KB, Zweifel SA, Engelbert M. Do we need a new classification for choroidal neovascularization in age-related macular degeneration? Retina. 2010;30:1333e1349. 7. Ueta T, Obata R, Inoue Y, et al. Background comparison of typical age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese patients. Ophthalmology. 2009;116:2400e2406. 8. Querques G, Srour M, Massamba N, et al. Functional characterization and multimodal imaging of treatment-naive
9.
10. 11.
12. 13.
“quiescent” choroidal neovascularization. Invest Ophthalmol Vis Sci. 2013;54:6886e6892. Carnevali A, Cicinelli MV, Capuano V, et al. Optical coherence tomography angiography: a useful tool for diagnosis of treatment-naïve quiescent choroidal neovascularization. Am J Ophthalmol. 2016;169:189e198. de Carlo TE, Bonini Filho MA, Chin AT, et al. Spectral-domain optical coherence tomography angiography of choroidal neovascularization. Ophthalmology. 2015;122:1228e1238. Coscas GJ, Lupidi M, Coscas F, et al. Optical coherence tomography angiography versus traditional multimodal imaging in assessing the activity of exudative age-related macular degeneration: a new diagnostic challenge. Retina. 2015;35: 2219e2228. Miere A, Querques G, Semoun O, et al. Optical coherence tomography angiography in early type 3 neovascularization. Retina. 2015;35:2236e2241. Jia Y, Bailey ST, Wilson DJ, et al. Quantitative optical coherence tomography angiography of choroidal neovascularization in age-related macular degeneration. Ophthalmology. 2014;121:1435e1444.
Footnotes and Financial Disclosures Originally received: October 31, 2016. Final revision: January 6, 2017. Accepted: January 6, 2017. Available online: ---. Manuscript no. ORET_2016_148. 1
Department of Ophthalmology, University Vita-Salute, IRCCS Ospedale San Raffaele, Milan, Italy.
Author Contributions: Research design: Carnevali, Capuano, Sacconi, Querques, Marchese, Rabiolo, Souied, Scorcia, Bandello, Querques Data acquisition and/or research execution: Carnevali, Capuano, Sacconi, Querques, Marchese, Rabiolo, Souied, Scorcia, Bandello, Querques
2
Data analysis and/or interpretation: Carnevali, Sacconi, Querques, Scorcia, Bandello, Querques
3
Manuscript preparation: Carnevali, Sacconi, Querques, Scorcia, Bandello, Querques
Department of Ophthalmology, University of “Magna Graecia ,” Catanzaro, Italy. Department of Ophthalmology, Centre Hospitalier Intercommunal de Créteil, Université Paris Est Créteil, Créteil, France.
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Eye Clinic, Department of Neurological, Biomedical and Movement Sciences, University of Verona, Italy. Financial Disclosure(s): The author(s) have made the following disclosure(s): E.S.: Financial relationships d Alcon, Alimera Sciences, Allergan Inc, Farmila-Thea, Bayer Shering-Pharma, Bausch & Lomb, Genentech, Heidelberg, and Novartis. F.B.: Consultant d Alcon, Alimera Sciences, Allergan Inc, Farmila-Thea, Bayer Shering-Pharma, Bausch & Lomb, Genentech, Hoffmann-La-Roche, NovagaliPharma, Novartis, Sanofi-Aventis, Thrombogenics, and Zeiss. G.Q.: Consultant d Alimera Sciences, Allergan Inc, Heidelberg, Novartis, Bayer Shering-Pharma, and Zeiss.
Abbreviations and Acronyms: AMD ¼ age-related macular degeneration; CNV ¼ choroidal neovascularization; CSC ¼ central serous chorioretinopathy; ICGA ¼ indocyanine angiography; OCT ¼ optical coherence tomography; OCT-A ¼ optical coherence tomography angiography; PCV ¼ polypoidal choroidal vasculopathy; PDT ¼ photodynamic therapy; PPE ¼ pachychoroid pigment epitheliopathy; RPE ¼ retinal pigment epithelium; SD-OCT ¼ spectral-domain optical coherence tomography; VEGF ¼ vascular endothelial growth factor. Correspondence: Giuseppe Querques, MD, PhD, Department of Ophthalmology, University Vita-Salute, IRCCS Ospedale San Raffaele, Via Olgettina 60, Milan 20132, Italy. E-mail: [email protected].
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The term “pachychoroid-driven spectrum of disease” describes a set of choroidal features shared by a group of related diseases, including pachychoroid pigment epitheliopathy (PPE) and central serous chorioretinopathy (CSC).1 These diseases share similar features, such as thickened choroid on enhanced depth imaging optical coherence tomography (OCT), reddish orange fundus appearance with reduced fundus tessellation, a spectrum of overlying retinal pigment epithelium (RPE) abnormalities including pigment epithelial detachments, and fundus autofluorescence changes.1,2 Pachychoroid pigment epitheliopathy is distinguished from CSC by the lack of clinical or imaging evidence of acute or chronic subretinal fluid. We consider PPE to be a forme fruste of CSC.1 En face imaging with swept-source OCT recently has revealed new findings that refine the definition of the pachychoroid phenotype to emphasize the morphologic characteristics of pathologically dilated choroidal vessels (“pachyvessels”) over absolute choroidal thickness.3 Both long-standing CSC and PPE have been 2017 by the American Academy of Ophthalmology Published by Elsevier Inc.
shown to be associated with type 1 neovascularization.4e6 Pang and Freund4 coined the term “pachychoroid neovasculopathy” to describe a disease characterized by a form of type 1 neovascularization involving dilated choroidal vessels in areas of increased choroidal thickness. The authors support their hypothesis by noting that eyes with long-standing “silent” pachychoroid disease (because asymptomatic) may develop type 1 neovascularization in the absence of an overt CSC manifestation, including submacular exudative detachment or gravitational tracts of chronic subretinal fluid.4 In addition, both type 1 neovascularization associated with CSC and pachychoroid neovasculopathy could progress to polypoidal choroidal vasculopathy (PCV).4,5,7 The many similarities between CSC and PCV suggest that PCV may be included in the “pachychoroiddriven spectrum of disease.”1,4 Treatment-naïve quiescent choroidal neovascularization (CNV) is a finding recently described in the setting of agerelated macular degeneration (AMD) for nonexudative http://dx.doi.org/10.1016/j.oret.2017.01.003 ISSN 2468-6530/17
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Ophthalmology Retina Volume -, Number -, Month 2017 Table 1. Optical Coherence Tomography Angiography Features of Patients with Treatment-Naïve Quiescent Choroidal Neovascularization in the Setting of Pachychoroid Neovasculopathy Patient No.
Eye
Shape
Core
Margin
Location
Device
1 2 3 4 5 6
LE RE RE LE RE LE
CIR IRR IRR IRR IRR CIR
NV NV V V NV V
WD WD WD PD WD WD
FS FS FI FI FS FI
AngioVue (Optovue, Freemont, CA) AngioPlex (Carl Zeiss Meditec, Inc, Dublin, CA) AngioPlex AngioVue AngioPlex AngioPlex
CIR ¼ circular; FI ¼ foveal involving; FS ¼ foveal sparing; IRR ¼ irregular; LE ¼ left eye; NV ¼ not visualized; PD ¼ poorly defined; RE ¼ right eye; V ¼ visualized; WD ¼ well defined.
AMD eyes complicated by type 1 neovascularization.8 The utility of OCT angiography (OCT-A) in CNV detection in different ocular conditions has been extensively described in the literature and recently reported in quiescent CNV in the setting of AMD.9 To the best of our knowledge, no studies have reported the presence of treatment-naïve quiescent CNV in patients affected by pachychoroid neovasculopathy. In this study, we estimate the prevalence of treatment-naïve quiescent CNV among eyes with pachychoroid neovasculopathy and report the OCT-A features.
Methods Treatment-naïve quiescent CNV was identified in a pool of patients with pachychoroid neovasculopathy consecutively presenting between January 2016 and June 2016 at 2 high-volume referral centers (the Medical Retina & Imaging Unit, University
Vita-Salute San Raffaele in Milan, Italy, and the Department of Ophthalmology of University Paris Est, in Creteil, France). The study was conducted in agreement with the Declaration of Helsinki for research involving human subjects and was approved by the local institutional review board at both sites. Inclusion criteria were: 1) diagnosis of treatment-naïve “quiescent” CNV, defined as a flat irregular elevation of the RPE with moderately reflective material in the sub-RPE space, no intraretinal or subretinal hyporeflective fluid on structural OCT, late-phase ill-defined hyperfluorescent lesion, without late-phase leakage or pooling of dye on fluorescein angiography, and hypercyanescent neovascular network in the earlyemid phases of indocyanin green angiography (ICGA); 2) presence of pachychoroid characteristics, defined as any of the following: choroidal thickness above 270 mm, and presence of pachyvessels on ICGA; 3) sufficiently clear ocular media; and 4) adequate pupillary dilation and fixation to permit high-quality OCT imaging. Ocular exclusion criteria consisted of any disease other than primary pachychoroid neovasculopathy (including history of acute CSC in the study eye) and any previous intervention for CNV.
Figure 1. Indocyanine green angiography (ICGA), spectral-domain optical coherence tomography (SD-OCT) B-scan, and optical coherence tomography angiography (OCT-A) of patient number 3 with quiescent choroidal neovascularization (CNV) secondary to pachychoroid neovasculopathy. Early phase of ICGA (A) shows a hypercyanescent neovascular network, and the late phase (B) is characterized by wash-out of the quiescent CNV. Note the late hypocyanescent lesion grossly corresponding to the neovascular network as visualized by OCT-A (C, arrowhead).
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OCTA of Quiescent CNV in Pachychoroid
Figure 2. Indocyanine green angiography (ICGA), spectral domain optical coherence tomography (SD-OCT) B-scan, and optical coherence tomography angiography (OCT-A) of patient number 4 with quiescent choroidal neovascularization (CNV) secondary to pachychoroid neovasculopathy. Early phase of ICGA (A) shows an hypercyanescent neovascular network (arrowhead), and the late phase (B) is characterized by wash-out of the quiescent CNV. Note the late hypocyanescent lesion grossly corresponding to the neovascular network as visualized by OCT-A (C). Moreover, SD-OCT shows the presence of a pachyvessel below the irregular flat retinal pigment epithelium (RPE) elevation (white asterisk).
Clinical charts and multimodal imaging data were reviewed. As per standard clinical assessment at both sites, all patients had previously undergone a comprehensive ophthalmologic examination, including measurement of best-corrected visual acuity, dilated slit-lamp anterior segment and fundus biomicroscopy, fluorescein angiography, ICGA, spectral-domain OCT (Spectralis þ HRA; Heidelberg Engineering, Heidelberg, Germany), and OCT-A. Each enrolled patient underwent OCT-A with the AngioPlex CIRRUS HD-OCT Model 5000 (Carl Zeiss Meditec, Inc, Dublin, CA) or the AngioVue RTVue XR-Avanti (Optovue, Freemont, CA). Optical coherence tomography angiography was performed in all patients with a scanning area of 33 mm centered on the foveal area. The automatic segmentation provided by the OCT-A software was manually adjusted by 2 expert retina specialists (AC and GQ) for correct visualization of the capillary plexus, outer retinal layers, and choriocapillaris to better identify the CNV plane. The OCT-A images and corresponding structural OCT B-scans were evaluated side by side with ICGA and were assessed for CNV shape, CNV core, CNV margin, and CNV location. The CNV shape was classified as “circular” or “irregular.” The CNV core has been defined as a vessel of greater caliber or a “trunk vessel” from which other smaller vessels branch off. The CNV core was classified as “visible” or “not visible,” depending on its visibility. The CNV margin on OCT-A was classified as “well defined” or “poorly defined” on the basis of its appearance and its borders. The CNV location was classified as “foveal involving” if the lesion involved the foveal center or “foveal sparing” if the CNV lesion spared the foveal center. Disagreement regarding interpretation of the different features was resolved by open adjudication.
Statistical analysis was performed using SPSS software 21 (SPSS, Inc, Chicago, IL). Results of descriptive analyses are expressed as means standard deviations for quantitative variables and as counts and percentages for categoric variables. We also performed an estimation of the prevalence of treatment-naïve quiescent CNV among patients affected by pachychoroid neovasculopathy with 95% confidence intervals. Comparison of mean subfoveal choroidal thickness between the eyes with CNV and the fellow eyes was performed using the Student t test. In all analyses, P values < 0.05 were considered as statistically significant.
Results From a pool of 55 eyes of 54 patients (mean age, 5210.2 years; 35 male/19 female) with pachychoroid neovasculopathy, we identified 49 eyes of 49 patients previously treated for actively leaking CNV, and 6 eyes of 6 patients met the selection criteria for treatment-naïve quiescent CNV (a subject presented pachychoroid neovasculopathy in both eyes with a quiescent CNV in the right eye and a type 1 neovascularization treated for active leaking in the fellow eye). The cases in the current study were all consecutive patients with pachychoroid neovasculopathy, and no cases were excluded. This accounts for an estimated prevalence of 10.9% (2.7e19.1, 95% confidence intervals) for treatment-naïve quiescent CNV among eyes with pachychoroid neovasculopathy; the mean age of the patients with quiescent pachychoroid neovasculopathy was 61.19.0 years. Four patients were male, and 2 patients were female. Four patients (4 eyes) with treatment-naïve quiescent CNV
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Ophthalmology Retina Volume -, Number -, Month 2017 were enrolled at University Vita-Salute San Raffaele in Milan, and 2 patients (2 eyes) were enrolled at University Paris Est in Creteil. Among all 55 eyes, 18 presented intraretinal or subretinal hyporeflective fluid on structural OCT and were classified as actively leaking and thus received previous treatments (10 photodynamic therapy [PDT], 5 antievascular endothelial growth factor [VEGF] [ranibizumab], 3 combination of PDT and anti-VEGF [aflibercept]). Among 37 eyes presenting with no intraretinal or subretinal hyporeflective fluid on structural OCT, 31 eyes received previous treatments (19 PDT, 8 anti-VEGF [ranibizumab], 4 combination of PDT and anti-VEGF [aflibercept]) for actively leaking CNV. Mean subfoveal choroidal thickness in eyes with treatment-naïve quiescent CNV, measured as the distance between the RPE-Bruch’s membrane complex and the chorioscleral border, was 39972 mm (37569 mm in fellow eyes, P ¼ 0.57). The CNV shape on OCT-A was rated as circular in 2 of 6 eyes and irregular in 4 of 6 eyes. The CNV core was visible in 3 of 6 eyes and was not visible in 3 of 6 eyes; in the 3 eyes with a visible core, the core position was considered as central in 2 cases and as eccentric in the other case. The CNV margin was considered as well defined in 5 of 6 eyes and poorly defined in 1 of 6 eyes. The CNV location was foveal sparing in 3 of 6 eyes and foveal involving in 3 of 6 eyes. The most frequently observed features (well-defined margin and irregular shape) were seen in 4 of 6 eyes. In all 49 treated eyes with active or inactive CNV, OCT-A disclosed the type 1 neovascular networks. In addition, type 1 quiescent neovascular networks were clearly visible in all 6 eyes by OCT-A, and there was agreement of 100% between the readers in the correspondence between ICGA images and OCT-A images and in the rating of OCT-A images features of CNV (Table 1). There was good correspondence between the late-phase ill-defined hyperfluorescent lesion, without late-phase leakage or pooling of dye on fluorescein angiography, and the quiescent CNV as visualized by OCT-A. Of note, the CNV appearing as a hypercyanescent neovascular network in earlyemid phases of ICGA was characterized by wash-out in the late phase; also, the late hypocyanescent lesion grossly corresponded to the neovascular network as visualized by OCT-A (Fig 1 and Fig 2).
In AMD, quiescent CNV appeared to enlarge over time on ICGA, as described by Querques et al8 without any detectable retinal thickening on OCT. It is generally accepted in clinical practice that asymptomatic CNVs do not have associated intraretinal and subretinal exudation on structural OCT and do not meet the criteria for antiVEGF therapy.13 The precise location of the lesion on OCT-A and the precise measurement of the CNV area, together with detection of intraretinal and subretinal exudation on structural OCT, could be useful tools to monitor nonexudative CNV in pachychoroid neovasculopathy and to support the treatment decision. Future studies will investigate whether repeated scans on the neovascular membrane may allow early detection of its growth in a faster and safer fashion than dye angiography. It is noteworthy that in our cases the most frequently observed features (irregular shape and well-defined margin) were all detected in 4 of 6 eyes (66.6%), and the core was visualized in 50% of the cases. Instead, our group recently analyzed the OCT-A features in quiescent CNV secondary to AMD and showed that the most frequently observed features (irregular shape, not visible core, well-defined margin, foveal-sparing location) were all detected in 6 of 18 eyes (33.3%), and the core was visualized only in 2 of 18 eyes (11%).9 In quiescent CNV secondary to AMD, our group suggested that the absence of a detectable core vessel may represent a protective factor against increased activity from quiescent CNV,9 and thus the higher prevalence of a detectable core vessel in quiescent pachychoroid neovasculopathy may be associated with a higher tendency to activation in pachychoroid neovasculopathy than AMD. This hypothesis should be investigated in further studies with relevant follow-up.
Discussion
The main limitation of this study is the relatively small cohort of patients; however, quiescent CNV is not as common as active neovascularization.
Recent studies have shown that OCT-A is able to precisely identify microvascular structures and that it can be used to assess the morphology of type 1, type 2, and type 3 CNV.10e12 In this study, we investigated the features of treatment-naïve quiescent CNV in 6 pachychoroid eyes with OCT-A. The most frequently observed features (irregular shape and well-defined margin) were all detected in 4 of 6 eyes (66.6%). In addition, OCT-A allowed us to visualize the presence of a neovascular network in all eyes enrolled (100%), and we estimated a prevalence of quiescent CNV in pachychoroid neovasculopathy of 10.9%. Given the difficulty in visualizing quiescent type 1 neovascularization in pachychoroid eyes using conventional retinal imaging, the identification of quiescent CNV with OCT-A in a large proportion of eyes with flat irregular pigment epithelial detachments can be a useful method to diagnose this particular entity. In fact, unlike quiescent CNV in AMD characterized by late plaque hyperfluorescence, in pachychoroid eyes only the earlyemid phases of ICGA can show the quiescent neovascular network (which is characterized then by late wash-out), thus making proper diagnosis challenging.
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Study Limitation
Conclusions We describe the OCT-A features in a series of patients with treatment-naïve quiescent CNV secondary to pachychoroid neovasculopathy. Quiescent CNV in pachychoroid disease may be suspected by structural OCT as a flat irregular elevation of the RPE with moderately reflective material in the sub-RPE space and by earlyemid phases of ICGA that show the neovascular network, then characterized by late wash-out. In the current series, OCT-A was able to clearly visualize treatment-naïve quiescent CNV in all cases. Using OCT-A allows the clinician to identify noninvasively treatment-naive quiescent CNV and may be considered as a useful tool in guiding the frequency of follow-up examinations and treatment decisions in pachychoroid disease. References 1. Warrow DJ, Hoang QV, Freund KB. Pachychoroid pigment epitheliopathy. Retina. 2013;33:1659e1672.
Carnevali et al
OCTA of Quiescent CNV in Pachychoroid
2. Guyer DR, Yannuzzi LA, Slakter JS, et al. Digital indocyanine green videoangiography of central serous chorioretinopathy. Arch Ophthalmol. 1994;112:1057e1062. 3. Dansingani KK, Balaratnasingam C, Naysan J, Freund KB. En face imaging of pachychoroid spectrum disease with sweptsource optical coherence tomography. Retina. 2016;36:499e516. 4. Pang CE, Freund KB. Pachychoroid neovasculopathy. Retina. 2015;35:1e9. 5. Fung AT, Yannuzzi LA, Freund KB. Type 1 (sub-retinal pigment epithelial) neovascularization in central serous chorioretinopathy masquerading as neovascular age-related macular degeneration. Retina. 2012;32:1829e1837. 6. Freund KB, Zweifel SA, Engelbert M. Do we need a new classification for choroidal neovascularization in age-related macular degeneration? Retina. 2010;30:1333e1349. 7. Ueta T, Obata R, Inoue Y, et al. Background comparison of typical age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese patients. Ophthalmology. 2009;116:2400e2406. 8. Querques G, Srour M, Massamba N, et al. Functional characterization and multimodal imaging of treatment-naive
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“quiescent” choroidal neovascularization. Invest Ophthalmol Vis Sci. 2013;54:6886e6892. Carnevali A, Cicinelli MV, Capuano V, et al. Optical coherence tomography angiography: a useful tool for diagnosis of treatment-naïve quiescent choroidal neovascularization. Am J Ophthalmol. 2016;169:189e198. de Carlo TE, Bonini Filho MA, Chin AT, et al. Spectral-domain optical coherence tomography angiography of choroidal neovascularization. Ophthalmology. 2015;122:1228e1238. Coscas GJ, Lupidi M, Coscas F, et al. Optical coherence tomography angiography versus traditional multimodal imaging in assessing the activity of exudative age-related macular degeneration: a new diagnostic challenge. Retina. 2015;35: 2219e2228. Miere A, Querques G, Semoun O, et al. Optical coherence tomography angiography in early type 3 neovascularization. Retina. 2015;35:2236e2241. Jia Y, Bailey ST, Wilson DJ, et al. Quantitative optical coherence tomography angiography of choroidal neovascularization in age-related macular degeneration. Ophthalmology. 2014;121:1435e1444.
Footnotes and Financial Disclosures Originally received: October 31, 2016. Final revision: January 6, 2017. Accepted: January 6, 2017. Available online: ---. Manuscript no. ORET_2016_148. 1
Department of Ophthalmology, University Vita-Salute, IRCCS Ospedale San Raffaele, Milan, Italy.
Author Contributions: Research design: Carnevali, Capuano, Sacconi, Querques, Marchese, Rabiolo, Souied, Scorcia, Bandello, Querques Data acquisition and/or research execution: Carnevali, Capuano, Sacconi, Querques, Marchese, Rabiolo, Souied, Scorcia, Bandello, Querques
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Data analysis and/or interpretation: Carnevali, Sacconi, Querques, Scorcia, Bandello, Querques
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Manuscript preparation: Carnevali, Sacconi, Querques, Scorcia, Bandello, Querques
Department of Ophthalmology, University of “Magna Graecia ,” Catanzaro, Italy. Department of Ophthalmology, Centre Hospitalier Intercommunal de Créteil, Université Paris Est Créteil, Créteil, France.
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Eye Clinic, Department of Neurological, Biomedical and Movement Sciences, University of Verona, Italy. Financial Disclosure(s): The author(s) have made the following disclosure(s): E.S.: Financial relationships d Alcon, Alimera Sciences, Allergan Inc, Farmila-Thea, Bayer Shering-Pharma, Bausch & Lomb, Genentech, Heidelberg, and Novartis. F.B.: Consultant d Alcon, Alimera Sciences, Allergan Inc, Farmila-Thea, Bayer Shering-Pharma, Bausch & Lomb, Genentech, Hoffmann-La-Roche, NovagaliPharma, Novartis, Sanofi-Aventis, Thrombogenics, and Zeiss. G.Q.: Consultant d Alimera Sciences, Allergan Inc, Heidelberg, Novartis, Bayer Shering-Pharma, and Zeiss.
Abbreviations and Acronyms: AMD ¼ age-related macular degeneration; CNV ¼ choroidal neovascularization; CSC ¼ central serous chorioretinopathy; ICGA ¼ indocyanine angiography; OCT ¼ optical coherence tomography; OCT-A ¼ optical coherence tomography angiography; PCV ¼ polypoidal choroidal vasculopathy; PDT ¼ photodynamic therapy; PPE ¼ pachychoroid pigment epitheliopathy; RPE ¼ retinal pigment epithelium; SD-OCT ¼ spectral-domain optical coherence tomography; VEGF ¼ vascular endothelial growth factor. Correspondence: Giuseppe Querques, MD, PhD, Department of Ophthalmology, University Vita-Salute, IRCCS Ospedale San Raffaele, Via Olgettina 60, Milan 20132, Italy. E-mail: [email protected].
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