optical coherence tomography angiography features ...

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FEATURES OF ANGIOID STREAKS ELEONORA CORBELLI, MD,* ADRIANO CARNEVALI, MD,*† ALESSANDRO MARCHESE, MD,* MARIA VITTORIA CICINELLI, MD,* LEA QUERQUES, MD,* RICCARDO SACCONI, MD,*‡ FRANCESCO BANDELLO, MD, FEBO,* GIUSEPPE QUERQUES, MD, PHD* Purpose: To analyze the optical coherence tomography angiography features of eyes affected with angioid streaks (AS) and to evaluate their ability to predict choroidal neovascularization (CNV) activity. Methods: Angioid streaks were individuated from a pool of consecutive patients. Eyes with and without CNV were evaluated by multimodal imaging. Results: Thirty-eight eyes of 19 consecutive patients diagnosed with AS were included. Thirty of 38 eyes with CNV and 8 of 38 eyes without CNV were included. In the majority of cases, CNV showed on optical coherence tomography angiography tangled appearance always associated with signs of neovascular inactivity on multimodal imaging (100%–0%, inactive-active, respectively). Choroidal neovascularization cases showing interlacing appearance were often associated with signs of neovascular activity on multimodal imaging (71.4%–28.6%, active-inactive, respectively). Optical coherence tomography angiography revealed a total of 27 AS, of which 20 appeared as a choriocapillary rarefaction, and in 7 AS, optical coherence tomography angiography choriocapillary segmentation revealed an irregular vascular network, possibly representing fibrovascular tissue over the crack-like breaks in Bruch membrane. Conclusion: Optical coherence tomography angiography is a noninvasive tool to detect the presence of CNV secondary to AS and to evaluate CNV activity. Optical coherence tomography angiography is able to add a novel element to the multimodal imaging characterization of AS. RETINA 0:1–9, 2017

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he first description of angioid streaks (AS) was provided by Doyne1 in 1889 as irregular, bilateral, dark red to gray lines under the retina, radiating from the optic disk head in a spider-like configuration. Histologically, they appear as crack-like breaks in brittle, thickened, and calcified Bruch membrane (BM), associated with atrophy of the overlying retinal pigment epithelium (RPE) and the choriocapillary layer.2 Although the diagnosis of AS is mainly clinical, structural spectral domain optical coher-

ence tomography (SD-OCT) has shown highly reliable correspondence with the histologic findings,3 helping in identifying linear breaks in BM at the site of the AS. Angioid streaks can occur isolated or associated with systemic diseases in approximately 50% of patients, such as pseudoxanthoma elasticum, Ehlers–Danlos syndrome (only Type 6), Paget disease, hemoglobinopathies including sickle cell trait disease and thalassemias.4 Patients with AS are usually asymptomatic unless they develop macular complications, in particular choroidal rupture and choroidal neovascularization (CNV).5 Choroidal neovascularization is the major cause of severe visual loss in patients with AS, occurring in 42% to 86% of patients during follow-up, and most eyes progress to legal blindness.6 Although conventional imaging allows us in identifying CNV in the majority of cases, this condition is sometimes misdiagnosed, precluding the final functional and anatomical macular recovery after anti–vascular endothelial growth factor therapy.7

From the *Department of Ophthalmology, University Vita-Salute, IRCCS Ospedale San Raffaele, Milan, Italy; †Department of Ophthalmology, University of “Magna Graecia,” Catanzaro, Italy; and ‡Department of Ophthalmology, University of Verona, Verona, Italy. None of the authors has any financial/conflicting interests to disclose. Reprint requests: Giuseppe Querques, MD, PhD, Department of Ophthalmology, University Vita-Salute, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy; e-mail: giuseppe. [email protected]

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Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.

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RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2017 VOLUME 0 NUMBER 0

Fig. 1. A and B. MultiColor image, fundus autofluorescence, IR, OCTA, and corresponding structural OCT B-scan of the right eye of patient no. 10 and of the right eye of patient no. 8 with CNV secondary to AS. A. (First, second, and third rows, left panel) MultiColor image, fundus autofluorescence, and IR show AS and pigmentary changes in the macula. (First and second rows, right panel) 3 mm · 3 mm OCTA shows a fovealinvolving, circular, well-defined (yellow dotted lines), interlacing neovascular network, with visible core (white open arrowhead) and large loops (red arrows). The corresponding structural OCT B-scan shows a hypereflective subretinal lesion with sub/intraretinal fluid. B. (First, second, and third rows, left panel) MultiColor image, fundus autofluorescence, and IR show AS and pigmentary changes in the interpapillomacular area. (First and second rows, right panel) 3 mm · 3 mm OCTA shows a foveal-sparing, irregular, poorly defined, tangled neovascular network, without visible core (white open arrowhead). The corresponding structural OCT B-scan shows a hyperreflective subretinal lesion without sub/intraretinal fluid. Note, in some areas of the CNV, it is not possible to visualize flow, because of the poorly defined appearance (white asterisks).

Optical coherence tomography angiography (OCTA) is a relatively new diagnostic device able to provide a rapid and noninvasive three-dimensional reconstruction of perfused vessels of the retina and choroid, using the normal movement of erythrocytes as a contrast medium. Several applications of OCTA have been proposed for improving our understanding of the pathogenesis of different diseases.8–10 Moreover, OCTA has shown good sensitivity and specificity in detecting pathologic neovascular networks in different macular diseases11–14 and may be considered as a potentially useful tool to screen eyes at risk of CNV in AS. The aim of the study was to analyze the OCTA features of CNV secondary to AS and to evaluate their ability to predict CNV activity. As part of this study, we also describe the OCTA appearance of AS, thus adding a novel element to the multimodal imaging characterization of this condition, and possibly gathering insights into their pathogenesis and progression.

Methods Angioid streaks were individuated from a pool of patients consecutively presenting between October 2015 and March 2016 at the Medical Retina & Imag-

ing Unit of the Department of Ophthalmology, University Vita-Salute, San Raffaele Hospital in Milan, Italy. The study was conducted in accordance with the Declaration of Helsinki for research involving human subjects and was approved by the local institutional review board. Included patients signed a written informed consent form to participate in the study. Inclusion criteria were age older than 18 years, diagnosis of AS, defined on the basis of the morphologic and instrumental features previously described in the literature, which includes fundus examination, infrared reflectance (IR), fundus autofluorescence, fluorescein angiography (FA), and indocyanine green angiography, sufficiently clear ocular media, adequate pupillary dilation, and fixation to permit multimodal imaging investigation. Ocular exclusion criteria consisted in any other disease including age-related macular degeneration, pathologic myopia, retinal vascular diseases, vitreoretinal diseases, and history of central serous retinopathy. Each patient underwent a comprehensive ophthalmologic examination, including best-corrected visual acuity, dilated slit-lamp anterior segment and fundus biomicroscopy, ultra widefield retinography (Optos PLC, Dunfermline, Scotland, United Kingdom), MultiColor, IR, fundus autofluorescence, FA, indocyanine


OCTA FEATURES OF ANGIOID STREAKS CORBELLI ET AL

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Fig. 2. A and B. MultiColor image, fundus autofluorescence, IR, OCTA, and corresponding structural OCT B-scan of the left eye of patient no. 8 and of the right eye of patient no. 3 with CNV secondary to AS. A. (First, second, and third rows, left panel) MultiColor image, fundus autofluorescence, and IR show AS and pigmentary changes in the macula. (First and second rows, right panel) 3 mm · 3 mm OCTA shows a foveal-involving, circular, poorly defined, interlacing neovascular network, without visible core (white open arrowhead). The corresponding structural OCT B-scan shows a hyperreflective subretinal lesion with sub/intraretinal fluid. Note, in some areas of the CNV, it is not possible to visualize flow, probably due to the poorly defined appearance (white asterisks). B. (First, second, and third rows, left panel) MultiColor image, fundus autofluorescence, and IR show AS and some pigmentary changes in the macula. (First and second rows, right panel) 3 mm · 3 mm OCTA shows a foveal-involving, irregular, poorly defined (white asterisks), tangled neovascular network, without visible core (white open arrowhead). The corresponding structural OCT B-scan shows a small hyperreflective subretinal lesion without sub/intraretinal fluid.

green angiography, structural SD-OCT (Spectralis + HRA; Heidelberg Engineering, Heidelberg, Germany), and OCTA. Optical coherence tomography angiography was performed on the same day of FA through AngioPlex CIRRUS HD-OCT Model 5000 (Carl Zeiss Meditec, Inc, Dublin, OH) in all patients with a scanning area of at least 3 mm · 3 mm, centered on the lesions. AngioPlex uses optical microangiography, a recently developed imaging technique that produces 3D images of dynamic blood perfusion within microcirculatory tissue beds at an imaging depth up to 2.0 mm.15–17 AngioPlex CIRRUS HD-OCT Model 5000 contains A-scan rate of 68,000 scans per second, using a superluminescent diode centered on 840 nm. A three by three angio cube contains 245 B-scan slices repeated up to 4· at each B-scan position. Each B-scan is made of 245 A-scans; each A-scan is 1,024 pixels deep. The pool of patients was investigated according to eye characteristics: eyes with and without CNV, as evaluated by multimodal imaging, which included dye angiography (FA and indocyanine green angiography) and structural SD-OCT. We analyzed the possible correlation between the different OCTA features and the CNV activity. The automatic segmentation provided by the OCTA software was manually adjusted by two expert retina

specialists (A.C. and G.Q.) modulating the segmentation lines for correct visualization of the capillary plexus, outer retinal layer, and choriocapillaris to better identify the CNV plane and for correct visualization of the choriocapillaris in correspondence with AS. In eyes with CNV, the OCTA images and corresponding OCT B-scans were assessed for CNV shape, CNV core, CNV margin and margin loops, and CNV location. The CNV shape was classified as “circular” or “irregular.” The CNV core was classified as “visible” or “not visible”; if the core was visible, CNV was classified as “central core” or “eccentric core.” The CNV margin on OCTA was classified as “well defined” or “poorly defined” on the basis of its appearance and its borders; moreover, the CNV margin was classified as “large loops” or “small loops” when the margin was well defined. 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 area. Examples of CNV shape, core, margin, location, and appearance are presented in Figures 1–3. In eyes without CNV, we conduced a qualitative analysis in the choriocapillary segmentation of OCTA in correspondence with the AS (the distance below


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Fig. 3. A and B. MultiColor image, fundus autofluorescence, IR, OCTA, and corresponding structural OCT B-scan of the right eye of patient no. 16 and of the left eye of patient no. 6 with CNV secondary to AS. A. (First, second, and third rows, left panel) MultiColor image, fundus autofluorescence, and IR show AS and pigmentary changes in the macula. (First and second rows, right panel) 3 mm · 3 mm OCTA shows a foveal-involving, irregular, poorly defined (white asterisks), tangled neovascular network, with visible core (white open arrowhead). The corresponding structural OCT B-scan shows a hyperreflective subretinal lesion without sub/intraretinal fluid. B. (First, second, and third rows, left panel) MultiColor image, fundus autofluorescence, and IR show AS and pigmentary changes in the posterior pole with a small area of retinal atrophy. (First and second rows, right panel) 3 mm · 3 mm OCTA shows a foveal-involving, circular, well-defined (yellow dotted lines), interlacing neovascular network, with visible core (white open arrowhead) and small loops (red arrows). The corresponding structural OCT B-scan shows a hyperreflective subretinal lesion with intraretinal fluid.

BM to form the choriocapillaris images was 31 mm) with the help of MultiColor and IR to localize the streaks. All features analyzed on both conventional imaging and OCTA were subjectively evaluated by two expert retinal specialists (E.C. and L.Q.); disagreement was resolved by an open adjudication. Calculations were performed using SPSS software 21 (SPSS, Inc, Chicago, IL). All data were expressed as mean ± SD. Fisher’s exact test was used to estimate the association of the different OCTA features according to neovascular activity. P , 0.05 was considered statistically significant.

Results Study Population Thirty-eight eyes of 19 consecutive patients (8 women and 11 men; mean age 57.2 ± 12.4 years, range 26–75 years) diagnosed with AS were included. Angioid streaks were associated with pseudoxanthoma elasticum in 15 of 19 patients, with sickle cell disease in 1 of 19 patients, and were idiopathic in 3 of 19 patients. Thirty of 38 eyes (17 patients) presented

CNV; in 8 of 38 eyes without CNV (6 patients), the qualitative features of AS were investigated. Demographic data and angiographic features are listed in Tables 1 and 2. Analysis of Choroidal Neovascularization Features Dye angiography and structural SD-OCT demonstrated the presence of Type 2 (classic) neovascularization, located above the RPE, in all 30 eyes with CNV; 24 of 30 CNVs were foveal involving and 6 of 30 were foveal sparing. Five of 30 eyes presented active CNVs on the basis of the angiographic (FA leakage) and structural SD-OCT features, whereas 25 of 30 CNVs resulted inactive. All eyes with CNVs had previously received intravitreal anti–vascular endothelial growth factor (ranibizumab Lucentis; Novartis Pharma AG, Basel, Switzerland, and Genentech Inc, South San Francisco, CA, in all eyes; a mean of 7.9 ± 5.9 intravitreal injections). Manual adjustment of the automatic segmentation improved the visualization of the CNV using OCTA, although in no case it accounted for detection of vascular network not identified on OCT. Ten of 30 eyes with CNV were excluded by OCTA analysis because the presence of large subretinal


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Table 1. Demographic Characteristics and OCTA Features of Patients With CNV Secondary to AS Pt No

Age, years

Sex

Eye

Shape

Core

Margin

Margin Loops

Location

CNV Appearance

1

54

M

2

58

F

3

57

F

4

75

M

5 6

73 52

M M

7

62

M

8

70

M

9

65

F

10

51

F

11 12

58 74

M F

13

58

M

14 15

63 54

M F

16

54

F

17

48

F

RE LE RE LE RE LE RE LE RE RE LE RE LE RE LE RE LE RE LE LE RE LE RE LE LE RE LE RE LE RE

NC NC IRR IRR IRR IRR CIR NC IRR NC CIR IRR CIR IRR CIR NC IRR CIR IRR IRR NC NC NC CIR IRR IRR NC IRR NC CIR

NC NC NV NV NV V V NC NV NC V NV NV NV NV NC NV V NV NV NC NC NC NV NV V NC V NC NV

NC NC PD WD PD PD WD NC WD NC WD WD WD PD PD NC WD WD PD PD NC NC NC PD PD PD NC PD NC WD

NC NC NC SL NC NC LL NC LL NC SL SL SL NC NC NC LL LL NC NC NC NC NC NC NC NC NC NC NC LL

NC NC FI FI FI FI FI NC FI NC FI FI FS FS FI NC FI FI FS FI NC NC NC FI FS FI NC FI NC FI

NC NC Tangled Tangled Tangled Tangled Tangled NC Tangled NC Interlacing Tangled Interlacing Tangled Interlacing NC Interlacing Interlacing Tangled Tangled NC NC NC Interlacing Tangled Tangled NC Tangled NC Interlacing

CIR, circular; FI, foveal involving; FS, foveal sparing; IRR, irregular; LE, left eye; LL, large loops; NC, not classified; NV, not visualized; PD, poorly defined; Pt No, patient number; RE, right eye; SL, small loops; V, visualized; WD, well defined.

fibrosis did not permit an accurate visualization of CNV, and thus, it was not possible classifying CNV “shape,” presence of “core,” and “margin.” The CNV shape on OCTA was rated as circular in 7 of 20 included eyes and as irregular in 13 of 20 eyes. The CNV core was visible in 6 of 20 eyes and was not visible in 14 of 20 eyes; in all 6 eyes with visible core, the core position was considered as central. The CNV margin was considered as well defined in 9 of 20 eyes Table 2. Demographic Characteristics and OCTA Features of AS Pt No

Age, years

Sex

Eye

N° AS

OCTA

1

26

M

2 3 4 5

58 63 73 35

M M M M

48

F

RE LE RE RE LE RE LE RE

5 4 1 3 3 3 5 3

Rarefaction Rarefaction Fibrovascular Fibrovascular Fibrovascular Rarefaction Rarefaction Rarefaction

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LE, left eye; Pt No, patient number; RE, right eye.

and poorly defined in 11 of 20 eyes. Because of poorly defined margins, in 11 eyes, it was not possible to classify margin loops. CNV margin loops were rated as small loops in four eyes and large loops in five eyes. The CNV location was foveal sparing in 4 of 20 eyes and foveal involving in 16 of 20 eyes. The “tangled” vascular network was defined on OCTA by a loose lace appearance with filamentous vessels and few large branches with a thick vessel wall. This appearance was found in 13 of 20 eyes. The “interlacing” vascular network appeared on OCTA as a dense vascular hyperintensity with a cobweb shape, multiple and tortuous vessels, and a perilesional halo; 7 of 20 CNVs were classified as interlacing. The interlacing appearance was more often associated with signs of Table 3. Association Between Tangled and Interlacing Appearance With CNV Activity

Active CNV (N = 5) Inactive CNV (N = 15)

Tangled CNV

Interlacing CNV

0 13

5 2


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neovascular activity on multimodal imaging (5 eyes vs. 2 eyes [71.4% vs. 28.6%], active vs. inactive, respectively). The tangled appearance was always associated with the absence of neovascular activity on multimodal imaging (13 eyes vs. 0 eyes [100% vs. 0%], inactive vs. active, respectively) (Table 3). There was a significant association between the described OCTA features and CNV activity (P = 0.0014). The most frequently observed features (irregular, not visible core, poorly defined margin, and foveal involving) were all collectively detected in 3 of 20 eyes (15%) (Figure 2B). Analysis of Angioid Streak Features Eight of 38 eyes without CNV were collected, and the AS appearance was studied. A total of 8 eyes affected by AS with mean 3.75 ± 1.9 of AS per eye (a total of 27 AS) were analyzed by means of OCTA. Most AS (20 of 27 AS) appeared as choriocapillary rarefaction, corresponding to hyporeflective lines over background reflectivity on MultiColor and IR imaging and to the hyporeflective area of the RPE–BM complex on structural OCT (Figures 4 and 5). In 7 of 27 AS, choriocapillary segmentation of OCTA revealed an irregular vascular network, possibly representing the development of fibrovascular tissue over the crack-like breaks in calcified BM (Figures 6 and 7); in this series, AS appeared as hyperreflective

lines over background reflectivity on MultiColor and IR imaging, contiguous to hyporeflective lines over background reflectivity. Interestingly, the area affected with an irregular vascular network appeared on structural SD-OCT as a flat elevation of the RPE, with hyperreflective accumulations above the BM, without intra/subretinal fluid accumulation. Discussion In this study, we analyzed the OCTA features of CNV in patients affected by AS, and we evaluate their ability to predict CNV activity. In the majority of cases, CNV showed foveal involvement and appeared on OCTA as an irregular, with poorly defined margin, without visible core. The CNV shape was classified as tangled (loose lace appearance with filamentous vessels and few branches with a thick vessel wall) more often than as interlacing (dense vascular hyperintensity with a cobweb shape, multiple and tortuous vessels, and a perilesional halo). By investigating the correspondence between the two different CNV appearances on OCTA and the clinical behavior, we found the interlacing appearance to be more often associated with signs of neovascular activity on multimodal imaging. These findings suggest the possible application of OCTA as a tool for the evaluation of CNV activity in AS. Interestingly,

Fig. 4. MultiColor image (A), IR with corresponding structural OCT B-scan (B) and OCTA (C) of the right eye of patient no. 1 with AS. (First row) MultiColor image and corresponding 3 mm · 3 mm OCTA showing rarefaction of choriocapillary along the AS (white arrowheads). (Second row) IR and corresponding structural OCT B-scan revealing a hyporeflective area of the RPE–BM complex in correspondence with AS (arrows).



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Fig. 5. MultiColor image (A), IR with corresponding structural OCT B-scan (B) and OCTA (C) of the left eye of patient no. 1 with AS. (First row) MultiColor image and corresponding 3 mm · 3 mm OCTA showing rarefaction of choriocapillary along the AS (white arrowheads). (Second row) IR and corresponding structural OCT B-scan revealing a hyporeflective area of the RPE–BM complex in correspondence with AS (arrows).

similar behaviors have been shown for CNV secondary to age-related macular degeneration,10 where the presence of a well-defined CNV shape (lacy-wheel or sea-fan shaped) with many anastomoses and loops,

peripheral vascular arcades, and perilesional hypointense halo was associated with a major activity of the CNV on conventional imaging compared with CNV made of long filamentous linear vessels. Nevertheless,

Fig. 6. MultiColor image (A), IR with corresponding structural OCT B-scan (B) and OCTA (C) of the right eye of patient no. 2 and of the left eye of patient no. 4 with AS. (First row) MultiColor image and corresponding 3 mm · 3 mm OCTA showing fibrovascular tissue along the AS (white arrowheads). (Second row) IR and corresponding structural OCT B-scan revealing a flat elevation of the RPE with hyperreflective accumulations above the BM in correspondence with AS (arrows).


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Fig. 7. MultiColor image (A), IR with corresponding structural OCT B-scan (B) and OCTA (C) of the left eye of patient no. 4 with AS. (First row) Magnified central view of ultra widefield fundus photograph and corresponding 6 mm · 6 mm OCTA showing fibrovascular tissue along the AS (white arrowheads). (Second row) IR and corresponding structural OCT B-scan revealing a flat elevation of the RPE with hyperreflective accumulations above the BM in correspondence with AS (arrows).

standard cross-sectional OCT could be a more direct indicator of CNV activity, whereas the OCTA-derived CNV morphology could represent a complementary examination. In this study, we also described the OCTA features of AS. Optical coherence tomography angiography can potentially add new information compared with traditional dye imaging modalities, thanks to its ability of segmentation of different vascular plexa. In most cases, AS appeared as choriocapillary rarefaction on OCTA. This may be interpreted as atrophy of the choriocapillary associated with overlying crack-like breaks in thickened BM.2 In some cases, choriocapillary segmentation of OCTA revealed an irregular vascular network in the areas affected with AS; interestingly, these areas appeared on structural SDOCT as a flat elevation of the RPE, with hyperreflective accumulations above the BM. The irregular vascular network may represent fibrovascular tissue over the crack-like breaks in calcified BM, which, differently from leaking CNV, is not associated with intra/ subretinal fluid accumulation. We hypothesize that the development of fibrovascular tissue could represent a natural attempt to repair the damaged BM and the overlying atrophy of the choriocapillary and RPE. Defects in BM have been implicated in the pathogenesis of CNV in AS. BM serves an important mechanical separation between the choroidal circulation and the outer retina that maintains the physiologic

growth factor gradients across these two compartments. Interruption in the mechanical integrity of BM can result in dysregulation of these gradients and can culminate in CNV.18 Bruch membrane defects act as “loci minoris resistentiae” where new blood vessels easily diffuse toward the retina. The irregular vascular network in areas affected with AS appeared between the RPE and BM (i.e., a flat elevation of the RPE, with hyperreflective accumulations above the BM), differently from CNVs, which in the current series were classified as Type 2 neovascularization, always located above the RPE. Although we hypothesize that CNV and the irregular vascular network actually represent two different entities in the pathologic findings associated with AS, we cannot exclude that the irregular vascular network may predispose to the development of active CNV. In this view, OCTA may be particularly contributive in detecting not only typical CNV but also the irregular vascular network located between the RPE and BM, possibly representing fibrovascular tissue in areas affected with AS. However, OCTA may be considered a useful tool for the evaluation of AS characterized by areas of choriocapillaris atrophy, thus requiring a strict follow-up because at high risk to develop CNV. Limitations of this study include the retrospective design, the small number of patients included, the absence of follow-up, and the use of a shorted wavelength 840 nm device rather than 1,050 nm swept



source OCTA providing improved visualization of CNV lesions.19–21 Moreover, all CNVs have been previously treated by anti–vascular endothelial growth factor injections, resulting in CNV network remodeling with a partial regression of the new vessels and even their disappearance.22,23 Optical coherence tomography angiography image classification of CNV was not possible in 33.3% of eyes (10 of 30 eyes). However, our analysis is the first to describe and provide valuable information on the characterization of AS and on the pathogenesis of CNV associated with AS. In conclusion, we described the characteristics of AS by OCTA, and we evaluate their ability to predict CNV activity. Optical coherence tomography angiography appears as a useful tool not only identifying the presence of CNV but also evaluating its activity in AS. Moreover, OCTA is able to add new information to characterize AS thanks to its ability of segmentation of different vascular networks. Key words: angioid streaks, choroidal neovascularization, optical coherence tomography angiography, pseudoxanthoma elasticum, retinal imaging. Acknowledgments F. Bandello consultant for: Alcon (Fort Worth, TX), Alimera Sciences (Alpharetta, GA), Allergan Inc (Irvine, CA), Farmila-Thea (Clermont-Ferrand, France), Bayer Schering Pharma (Berlin, Germany), Bausch and Lomb (Rochester, NY), Genentech (San Francisco, CA), Hoffmann-La Roche (Basel, Switzerland), Novagali Pharma (Évry, France), Novartis (Basel, Switzerland), Sanofi-Aventis (Paris, France), Thrombogenics (Heverlee, Belgium), and Zeiss (Dublin, OH). G. Querques consultant for: Alimera Sciences (Alpharetta, GA), Allergan Inc (Irvine, CA), Heidelberg (Germany), Novartis (Basel, Switzerland), Bayer Schering Pharma (Berlin, Germany), and Zeiss (Dublin, OH). References 1. Doyne RW. Choroidal and retinal changes. The result of blows on the eyes. Trans Ophthalmol Sok U K 1889;9:128. 2. Domke H, Tost M. On the histology of “Angioid Streaks” [in German]. Klin Monbl Augenheilkd 1964;145:18–29. 3. Charbel Issa P, Finger RP, Holz FG, Scholl HP. Multimodal imaging including spectral domain OCT and confocal near infrared reflectance for characterization of outer retinal pathology in pseudoxanthoma elasticum. Invest Ophthalmol Vis Sci 2009;50:5913–5984. 4. Gurwood AS, Mastrangelo DL. Understanding angioid streaks. J Am Optom Assoc 1997;68:309–324. 5. Georgalas I, Papaconstantinou D, Koutsandrea C, et al. Angioid streaks, clinical course, complications, and current therapeutic management. Ther Clin Risk Manag 2009;5:81–89.

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