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Study of vessel density in adult-onset foveomacular vitelliform dystrophy with optical coherence tomography angiography
Journal Pre-proof Study of vessel density in adult-onset foveomacular vitelliform dystrophy with Optical Coherence Tomography Angiography Gilda Cennamo, Daniela Montorio, Federica Mirra, Chiara Comune, Anna D’Alessandro, Fausto Tranfa
PII:
S1572-1000(20)30055-7
DOI:
https://doi.org/10.1016/j.pdpdt.2020.101702
Reference:
PDPDT 101702
To appear in:
Photodiagnosis and Photodynamic Therapy
Received Date:
9 December 2019
Revised Date:
20 February 2020
Accepted Date:
28 February 2020
Please cite this article as: Cennamo G, Montorio D, Mirra F, Comune C, D’Alessandro A, Tranfa F, Study of vessel density in adult-onset foveomacular vitelliform dystrophy with Optical Coherence Tomography Angiography, Photodiagnosis and Photodynamic Therapy (2020), doi: https://doi.org/10.1016/j.pdpdt.2020.101702
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier.
Study of vessel density in adult-onset foveomacular vitelliform dystrophy with Optical Coherence Tomography Angiography.
Gilda Cennamo MD1, Daniela Montorio MD2, Federica Mirra MD2, Chiara Comune MD2, Anna D’Alessandro MD2, Fausto Tranfa MD2.
1
Eye Clinic, Public Health Department, University of Naples Federico II, Naples, Italy.
2
Department of Neurosciences, Reproductive Sciences and Dentistry, University of Naples Federico
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II, Naples, Italy.
Corresponding author: Gilda Cennamo MD, Department of Public Health, University Federico II,
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Naples, Italy, University of Naples Federico II, Via S. Pansini 5, 80133 Naples, Italy. Phone:
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00390817143731. Fax: 00390817462383. Email: [email protected]
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Highlights
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OCTA showed retinal and CC vascular features in different AOVFD stages. Foveal VD in CC significantly increased from vitelliform to vitelliruptive
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stages.
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No significant difference in retinal VD among patients in different AOVFD stages.
OCTA provides to better understand the vascular role in physiopathology of AOVFD.
Abstract 1
Background: To evaluate retinal and choriocapillaris (CC) vessel density in macular region in patients affected by adult-onset foveomacular vitelliform dystrophy (AOFVD) using optical coherence tomography angiography (OCTA) Methods: A total forty-four right eyes of 44 AOFVD patients (20 females, 24 males, mean age 69.17 ± 11.57 years) divided in 3 stages (vitelliform, pseudohypopyon and vitelliruptive) and 60 normal right eyes of 60 controls (20 females, 40 males, mean age 66.04 ± 6.40 years) were included in this prospective study. We evaluated the vessel density of superficial capillary plexus (SCP), deep capillary plexus (DCP) and CC in different macular areas (whole image, parafovea and fovea).
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We also analyzed the subfoveal choroidal thickness (SFCT) with Enhanced Depth Image (EDI)OCT.
Results: The vessel density of SCP and of DCP did not differ between patients and controls in all
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macular sectors. The vessel density of CC was lower in patients compared to controls but the
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difference turned out to be statistically significant only in foveal region (p<0.001). We found that the foveal vessel density of the CC was lower in vitelliform stage and significantly increased in
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vitelliruptive stage (p=0.031). At EDI-OCT, the SFCT revealed a statistically significant increase in patients compared to controls (p=0.002) whereas it was similar in the different stages of this
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dystrophy (p=0.276).
Conclusions: In vitelliform stage of AOFVD, OCTA and EDI-OCT can be useful to avoid mistakes
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of evaluation, due to the masking effect artifact. OCTA provides us a better understanding of the
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vascular role in the physiopathology of the macular diseases.
Keywords: Adult-onset foveomacular vitelliform dystrophy, optical coherence tomography angiography, vessel density, choroidal thickness.
Introduction
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Adult-onset foveomacular vitelliform dystrophy (AOFVD) is a relatively uncommon macular disease, first described by Gass in 1974 [1]. It typically occurs between the fourth and sixth decade of life showing bilateral, heterogeneous, yellowish, subfoveal material within the macular area due to altered cellular turnover mechanisms between retinal pigment epithelium (RPE) and photoreceptor cell layer [1,2]. The diagnosis of AOFVD is based on the typical clinical features of the macula displayed by different techniques such as fluorescein angiography (FA), indocyanine green angiography (ICGA), spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) [3,4].
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Previous studies have evaluated the choroidal thickness mainly in subfoveal region in AOVFD
patients using SD-OCT with enhanced depth image (EDI) technique that provides more accurate assessments of the choroidal morphology [5]. In order to better understand the pathophysiology of
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this disease, retinal and choriocapillaris (CC) vascular networks must be carefully analyzed. The
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oxidative damage, due to accumulation of the vitelliform material, could involve these vascular plexa [6-9]. The introduction of optical coherence tomography angiography (OCTA), a novel and
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non-invasive diagnostic technique, has allowed a detailed and objective quantitative analysis of the retinal and CC vessel density [10,11].
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The purpose of this study was to analyze the macular vessel density in the superficial capillary
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plexus (SCP), deep capillary plexus (DCP) and in CC in patients affected by AOVFD using OCTA.
Materials and Methods
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In this prospective study, we enrolled a total of 44 right eyes of 44 patients (20 females, 24 males, mean age 69.17 ± 11.57 years) affected by adult-onset foveomacular vitelliform dystrophy (AOVFD) divided in 3 different stages (18 eyes were in vitelliform, 16 eyes in pseudohypopyon and 10 eyes in vitelliruptive) who consecutively presented to the Eye Clinic of the University of Naples “Federico II”.
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The criteria for diagnosis of AOVFD were: 1) age older than 40 years; 2) presence of macular yellowish deposits on fundus examination; 3) hyper-autofluorescence spots in fundus autofluorescence images; 4) fluorescein angiography exhibiting late staining, without leakage; 5) indocyanine green angiography without any sign of choroidal neovascularization. In this study, the patients with AOVFD presented different stages: vitelliform (the presence of hyper-reflective material located between the photoreceptor layer and the retinal pigment epithelium); pseudohypopyon (a partial resorption of the vitelliform material occurred); vitelliruptive (a progressive resorption of the fluid). Eyes with the atrophic/fibrotic stage of the
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disease were not included in this study.
Each patient underwent evaluation of best corrected visual acuity (BCVA) according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) [12], slit-lamp biomicroscopy, intraocular
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pressure measurement, fundus examination with a +90 D lens, FA, ICGA, SD-OCT and OCTA.
Engineering, Heidelberg, Germany).
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The SFCT was measured using Spectralis Heidelberg with EDI mode (Spectralis, Heidelberg
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Sixty healthy subjects (20 females, 40 males) for a total of 60 right eyes with a normal ophthalmic examination, no history of intraocular surgery or retinal pathologic features were included in the
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control group and were underwent SD-OCT and OCTA. Exclusion criteria included history of choroidal neovascularization, central serous
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chorioretinopathy, geographical atrophy, subretinal fibrosis, retinal vascular diseases, vitreoretinal disease, myopia greater than 6 diopters, history of ocular surgery and significant lens opacities.
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The study was approved by the Institutional Review Board of the University of Naples “Federico II” and all investigations adhered to the tenets of the Declaration of Helsinki. Written informed consents were obtained from the patients enrolled in the study.
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EDI-OCT measurement The SFCT was measured using the Spectralis OCT device in EDI mode (Spectralis, Heidelberg Engineering, Heidelberg, Germany). The choroidal thickness was evaluated in the subfoveal region as a manual linear measurement between the outer border of Bruch’s membrane and the most posterior identifiable aspect of the choroidal-scleral interface, which is seen as a hyper-reflective layer in the posterior margin of the
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choroid in EDI mode [9].
Optical Coherence Tomography Angiography
We obtained OCTA images with the Optovue Angiovue System (software ReVue version
2017.1.0.151, Optovue Inc., Fremont, CA, USA) which is based on split-spectrum amplitude de-
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correlation algorithm (SSADA). The instrument has an A-scan rate of 70,000 scans per seconds
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with a tissue axial resolution of 5 µm and a 15-µm beam width. Each B-scan contained 304 Ascans. Two consecutive B-scans were captured at a fixed position before proceeding to the next
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sampling location. Blood flowing through vessels causes a change in reflectance over time and results in localized areas of flow de-correlation between frames. The spectrum of the light source
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was split into multiple component parts to decrease the noise present in the image; each part was used to perform the de-correlation step and the results of all the split spectra were averaged. In any
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given region of tissue, the projection image can be viewed to obtain an image of the contained blood flow [13].
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Cross-sectional registered reflectance intensity images and flow images were summarized and viewed as an en face maximum flow projection from the inner limiting layer to the retinal epithelial pigment. Macular capillary network was visualized in scans centered on the fovea by performing a 6 mm × 6 mm scan over the macular region. Vessel density was defined as the percentage area occupied by the large vessels and microvasculature in the analyzed region [14]. The OCT software, according to the ETDRS classification of diabetic retinopathy, applies to all angiograms a grid 5
centered on fovea, which divides macular region in foveal and parafoveal area. For each eye analyzed, the software automatically calculates vessel density in whole scan area and in all sections of applied grid in different vascular networks of the retina (SCP, DCP) and in CC, as previously described [15,16]. Poor-quality images with a signal strength index less than 40 or registered image sets with residual motion artefacts were excluded from the analysis.
Statistical Analysis
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Statistical analysis was performed with the Statistical Package for Social Sciences (Version 20.0 for Windows; SPSS Inc, Chicago, Ill, USA). The Chi-squared test was used to determine differences in term of sex. The Mann–Whitney U test was used to evaluate differences in vessel density of each
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capillary plexus and in SFCT between controls and patients. Kruskal-Wallis test was used to
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compare retinal, choriocapillaris vessel density and SFCT among the patients divided according to
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disease stages. A p value of < 0.05 was considered statistically significant.
Results
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Forty-four patients (20 females, 24 males, mean age 69.17 ± 11.57 years) for a total of 44 right eyes were included in this study. The control group was constituted by 60 healthy subjects (20 females,
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40 males, mean age 66.04 ± 6.40 years). There were no significative differences for age (p=0.094) and sex (p=0.907) between patients and controls. Regarding disease stages, 18 eyes presented the
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vitelliform stage (figure 1), 16 eyes the pseudohypopyon stage (figure 2) and 10 eyes the vitelliruptive stage (figure 3). The demographic and clinical characteristics of the controls and patients were reported in table 1.
Regarding the vessel density of the SCP we did not find statistically significant differences between controls and AOFVD patients in whole image (47.28 ± 4.08% vs 46.97 ± 4.32%; p=0.856), 6
parafoveal area (49.32 ± 6.16% vs 47.06 ± 5.88%; p=0.274) and foveal area (18.99 ± 6.63 vs 22.17 ± 10.70; p=0.158). Similar findings for the vessel density of DCP when compared between the two groups in whole image (48.84 ± 7.04% vs 49.42 ± 6.17%; p=0.861), parafoveal area (53.30 ± 5.67% vs 51.83 ± 6.18%; p=0.523) and foveal area (36.19 ± 6.87% vs 34.47 ± 12.47%; p=0.465). The vessel density of the choriocapillaris resulted reduced in patients compared to controls in whole image (69.19 ± 5.06% vs 70.87 ± 3.5% p=0.239) and parafoveal area (66.72 ± 7.36% vs 69.09 ± 4.27% p=0.106) but the difference turned out to be statistically significant only in foveal area (50.15 ± 15.55% vs 69.58 ± 4.82%; p<0.001).
to controls (328.25 ± 60.86 vs 295.78 ± 29.93; p=0.002) (table 2).
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With EDI-OCT evaluation, SFCT revealed a statistically significant increase in patients compared
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Analyzing the patients according to disease staging, we found that the retinal vessel density and
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SFCT were similar among the different groups (p=0.276) while the foveal vessel density in CC
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significantly increased from vitelliform to vitelliruptive stage (p=0.031) (table 3).
Discussion
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In this prospective study, we performed a quantitative analysis of retinal, choriocapillaris vessel density and SFCT in patients with AOFVD compared with controls. We also analyzed the vascular features of the capillary plexa in the different stages of this disease.
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Previous studies have performed only a morphological analysis on retinal and choriocapillaris
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microvascular networks, other studies have not evaluated the patients according to disease stage [17-20].
We found, using OCTA and EDI-OCT, a different behavior of retinal and choroid vasculature. Regarding the retinal vascular network, we found that vessel density did not differ significantly between patients and controls in all macular sectors of SCP and DCP. In accordance with our results, the study, conducted by Toto et al, showed that superficial and deep vessel density were not statistically different in AOFVD group compared to controls except for the 7
parafoveal deep vessel density that appeared increased due to a possible inflammatory response aimed to reabsorb vitelliform material [17]. In agreement with previous studies [18-20], we found a reduction in choriocapillaris vessel density in different macular sectors comparing patients to controls but this difference was statistically significant only in foveal region that represents the main site of vitelliform material accumulation [20]. Regarding the different disease stages, we observed a reduced choriocapillaris vessel density in vitelliform stage and a progressive, statistically significant increase in vitelliruptive stage. These findings could be researched in the changes of the vascular network secondary to the
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vitelliform material accumulation in the outer retina. It is possible that the deposition of waste
materials in outer retina causes oxidative damages between RPE and the underlying CC resulting in hypoxia with consequent reduced perfusion density.
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On the other hand, the size of areas of reduced vessel density in CC at OCTA images corresponded
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with the size of vitelliform material detected on structural OCT B scans in vitelliform and pseudohypopyon stages, as shown in figures 1 and 2. Instead, in the vitelliruptive stage,
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characterized by reabsorption of this material followed by fluid accumulation, we did not observe this artifact.
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We hypothesized that our findings at OCTA may be related to shadowing effect of subfoveal vitelliform lesion rather than a true absence of flow.
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As previously shown in other studies, using EDI-OCT, we noted that the SFCT turned out to be thicker in AOVFD patients compared with controls, [8,22-24,25].
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The increased choroidal thickness was thought to be associated to choroidal vasodilatation and to increased blood flow due. A compensatory vascular mechanism to the metabolic overload of the RPE and photoreceptor layer occurs in the attempt to remove the vitelliform material. In our study the SFCT was similar in different stages of the disease because patients presented vitelliform, pseudohypopyon and vitelliruptive stages and no eyes was in atrophic/fibrotic phase of disease.
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Our results could be useful in clinical practice. We believe that the vitelliform lesion could be considered an important artifact that influences the visualization of the vascular network and therefore the measurements of the vessel density in macular region. The present study has several limitations, especially the relatively small sample size of the groups, the impaired visualization of the CC due to masking effect at OCTA, the EDI-OCT software inability to measure automatically the choroidal thickness and the difficulty to identify its precise boundaries because of shadowing of the vitelliform material.
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In conclusion, our study, using OCT-A and EDI-OCT, provides detailed evaluation about the vascular features of the retina, CC and choroid in AOVFD patients divided according to disease stages. OCTA is a new technique that allows us a better understanding of the possible vascular role
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in physiopathology of macular diseases.
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Declarations of interest: none
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commercial, or not-for-profit sectors.
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Funding: This research did not receive any specific grant from funding agencies in the public,
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10. MC. Savastano, B. Lumbroso, M. Rispoli, In vivo characterization of retinal vascularization morphology using optical coherence tomography angiography, Retina. 35 (2015):21962203. 11. RF. Spaide, Choriocapillaris Flow Features Follow a Power Law Distribution: Implications for Characterization and Mechanisms of Disease Progression, Am J Ophthalmol. 170 (2016):58-67. 12. C. Kniestedt and RL. Stamper, Visual acuity and its measurement, Ophthalmol Clin North Am. 16 (2003):155-170.
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angiography using the optovue device, Dev Ophthalmol. 56 (2016):6-12.
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15. Tarakcioglu HN, Yilmaz S, Kara T, Mavi Yildiz A, Yigit U, Ozkaya A. Foveal avascular zone and vessel density in children with attention deficit hyperactivity disorder. Int
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Optical coherence tomography angiography to assess vascular remodeling of the choriocapillaris after low-fluence photodynamic therapy for chronic central serous
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chorioretinopathy. Photodiagnosis and Photodynamic Therapy 27 (2019):162–166. 17. L. Toto, E. Borrelli, R. Mastropasqua, Adult-onset foveomacular vitelifform dystrophy
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evaluated by means of optical coherence tomography angiography: A Comparison With Dry Age-Related Macular Degeneration and Healthy Eyes. Retina. 38 (2018):731-738.
18. M. Battaglia Parodi, A. Rabiolo, MV. Cicinelli, P. Iacono, F. Romano, F. Bandello, Quantitative analysis of optical coherence tomography angiography in adult-onset foveomacular vitelliform dystrophy, Retina. 38 (2018):237-244.
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19. M. Treder, JL. Lauermann, M. Alnawaiseh, P. Heiduschka, N. Eter, Quantitative changes in flow density in patients with adult-onset foveomacular vitelliform dystrophy: an OCT angiography study, Graefes Arch Clin Exp Ophthalmol. 256 (2018):23-28. 20. G. Querques, O. Zambrowski, F. Corvi, et al. Optical coherence tomography angiography in adult-onset foveomacular vitelliform dystrophy, Br J Ophthalmol, 100 (2016):1724-1730. 21. JJ. Arnold, JP. Sarks, MC. Killingsworth, EK. Kettle, SH. Sarks, Adult vitelliform macular degeneration: a clinicopathological study, Eye. 17 (2003):717-726. 22. M. Battaglia Parodi, R. Sacconi, P. Iacono, C. Del Turco, F. Bandello, Choroidal thickness
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optical coherence tomography in adult-onset foveomacular vitelliform dystrophy, Eur J
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24. Eriş E. Association between choroidal vascular density, age and sex: A prospective study. Photodiagnosis Photodyn Ther. 27 (2019):452-454.
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25. Eriş E, Aydin E, Özçift SG. The effect of the smoking on choroidal thickness, central macular vascular and optic disc perfusion. Photodiagnosis Photodyn Ther. 28 (2019):142-
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Figure Legends
Figure 1. Right eye of a patient with adult-onset foveomacular vitelliform dystrophy at the vitelliform stage. (a) Multicolor image shows a yellowish macular lesion. (b) Fundus
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autofluorescence shows a central area hyper/hypoautofluorescence. (c) Spectral-domain optical coherence tomography reveals subfoveal accumulation of hyperreflective material between retinal
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pigment epithelium and the ellipsoid zone of the photoreceptors. (d,e) In the early phase of
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fluorescein angiography the vitelliform lesion appears hypofluorescent while in the later phase becomes hyperfluorescent. (f,g) In the early of indocyanine green angiography the lesion appears
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hypocyanescent with hypercyanescent border in the late phase. (h,i) OCTA of the superficial capillary plexus and deep capillary plexus shows no significative changes in vessel density. (j)
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OCTA of the choriocapillaris shows a reduction of the vessel density below the corresponding
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vitelliform lesion in foveal region.
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Figure 2. Right eye of a patient with adult-onset foveomacular vitelliform dystrophy at the
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pseudohypopyon stage. (a) Multicolor image is characterized by the yellow material that accumulates centrally and inferiorly. (b) Fundus autofluorescence shows loss of autofluorescence, particularly in the upper part of the lesion. (c) Spectral-domain optical coherence tomography
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reveals a partial reabsorption of the material resulting in some hyporeflective areas with clumping of hyperreflective material on the posterior retinal surface located between the retinal pigment
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epithelium (RPE) and the ellipsoid zone of the photoreceptors. There is also a hyperreflective area corresponding to vitelliform material still visible. (d,f) In the early phase of fluorescein angiography
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and indocyanine green angiography the lesion shows a central hypofluorescence/hypocyanescent (e,g) with areas of hyperfluorescence/hypercyanescence in the late stages due to window defect and
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staining. (h,i) OCTA of the superficial capillary plexus and deep capillary plexus show no significative changes in vessel density. (j) OCTA of the choriocapillaris shows a reduction of the
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vessel density below the corresponding vitelliform lesion in foveal region.
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Figure 3. Right eye of a patient with adult-onset foveomacular vitelliform dystrophy at the vitelliruptive stage. (a) Multicolor image reveals partial reabsorption of the vitelliform material with typical scrambled-egg appearance and dispersion of the material. (b) Fundus autofluorescence
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shows a central area of hypoautofluorescence surrounded by an area of slight
hyperautofluorescence. (c) Spectral-domain optical coherence tomography reveals optically empty
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lesion between the retinal pigment epithelium (RPE) and the photoreceptor ellipsoid zone, with clumping of hyperreflective material on the posterior retinal surface and with some zones of
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hyperreflective mottling on the RPE layer corresponding to areas of focal hypertrophy. (d,e,f,g) In the early and late phases, the fluorescein angiography and indocyanine green angiography show
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central hypofluorescence with some areas of hyperfluorescence due to staining and window defects linked to RPE and chorioretinal atrophy. (h,i) Optical coherence tomography angiography (OCTA)
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of the superficial capillary plexus and deep capillary plexus shows no significative changes in
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vessel density. (j) OCTA of the choriocapillaris shows some areas of reduced vessel density below the previous vitelliform lesion in foveal region.
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Table 1. Demographic and clinical characteristics in controls and AOFVD patients. Controls
Patients
Eyes (n.)
60
44
Female/Male
20 / 40
20 / 24
Age (years; mean ± SD)
66.04 ± 6.40
69.17 ± 11.57
Vitelliform
-
18
Pseudohypopyon
-
16
Vitelliruptive
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AOVFD stage, (eyes n.)
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SD: Standard Deviation; AOVFD:Adult-Onset Foveomacular Vitelliform Dystrophy
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Table 2. Differences in OCT angiography vessel density and subfoveal choroidal thickness between controls and AOFVD patients. Controls
Patients
p value
Whole image
47.28 ± 4.08
46.97 ± 4.32
0.856
Parafovea
49.32 ± 6.16
47.06 ± 5.88
0.274
Fovea
18.99 ± 6.63
22.17 ± 10.70
0.158
Whole image
48.84 ± 7.04
49.42 ± 6.17
0.861
Parafovea
53.30 ± 5.67
51.83 ± 6.18
0.523
Fovea
36.19 ± 6.87
34.47 ± 12.47
0.465
70.87 ± 3.5
69.19 ± 5.06
0.239
69.09 ± 4.27
66.72 ± 7.36
0.106
69.58 ± 4.82
50.15 ± 15.55
<0.001
328.25 ± 60.86
0.002
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Deep Capillary Plexus (%)
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Superficial Capillary Plexus (%)
Choriocapillaris (%)
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Whole image Parafovea
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Fovea
Subfoveval Choroidal Thickness (µm)
295.78 ± 29.93
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Data expressed as mean ± SD The Mann-Whitney U test, p <0.05
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Table 3. Differences in OCT angiography vessel density and subfobveal choroidal thickness among patients divided according to AOFVD stages. Vitelliform
Pseudohypopyon
Vitellirupture
P value
Whole image
45.85 ± 4.41
48.35 ± 4.56
46.80 ± 3.41
0.256
Parafovea
46.23 ± 3.20
49.96 ± 5.78
43.92 ± 7.92
0.243
Fovea
20.10 ± 8.46
23.55 ± 11.62
23.69 ± 13.14
0.765
Whole image
47.11 ± 4.69
51.68 ± 6.94
49.96 ± 6.33
0.194
Parafovea
50.45 ± 3.78
53.98 ± 6.62
50.87 ± 8.32
0.329
Fovea
33.24 ± 14.41
34.01 ± 10.93
37.40 ± 11.77
0.521
Superficial Capillary Plexus
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(%)
Whole image
re 69.01 ± 4.72
68.78 ± 5.25
70.18 ± 5.73
0.891
64.22 ± 8.01
65.19 ± 7.36
69.27 ± 5.30
0.543
47.02 ± 16.28
53.35 ± 17.20
57.37 ± 14.11
0.031
328.83 ± 75.73
321.25 ± 67.46
318.40 ± 54.01
0.276
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Parafovea
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Choriocapillaris (%)
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Fovea
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Deep Capillary Plexus (%)
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Subfoveal Choroidal Thickness (µm)
Data expressed as mean ± SD Kruskal-Wallis test, p <0.05
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PII:
S1572-1000(20)30055-7
DOI:
https://doi.org/10.1016/j.pdpdt.2020.101702
Reference:
PDPDT 101702
To appear in:
Photodiagnosis and Photodynamic Therapy
Received Date:
9 December 2019
Revised Date:
20 February 2020
Accepted Date:
28 February 2020
Please cite this article as: Cennamo G, Montorio D, Mirra F, Comune C, D’Alessandro A, Tranfa F, Study of vessel density in adult-onset foveomacular vitelliform dystrophy with Optical Coherence Tomography Angiography, Photodiagnosis and Photodynamic Therapy (2020), doi: https://doi.org/10.1016/j.pdpdt.2020.101702
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Study of vessel density in adult-onset foveomacular vitelliform dystrophy with Optical Coherence Tomography Angiography.
Gilda Cennamo MD1, Daniela Montorio MD2, Federica Mirra MD2, Chiara Comune MD2, Anna D’Alessandro MD2, Fausto Tranfa MD2.
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Eye Clinic, Public Health Department, University of Naples Federico II, Naples, Italy.
2
Department of Neurosciences, Reproductive Sciences and Dentistry, University of Naples Federico
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II, Naples, Italy.
Corresponding author: Gilda Cennamo MD, Department of Public Health, University Federico II,
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Naples, Italy, University of Naples Federico II, Via S. Pansini 5, 80133 Naples, Italy. Phone:
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00390817143731. Fax: 00390817462383. Email: [email protected]
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Highlights
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OCTA showed retinal and CC vascular features in different AOVFD stages. Foveal VD in CC significantly increased from vitelliform to vitelliruptive
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stages.
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No significant difference in retinal VD among patients in different AOVFD stages.
OCTA provides to better understand the vascular role in physiopathology of AOVFD.
Abstract 1
Background: To evaluate retinal and choriocapillaris (CC) vessel density in macular region in patients affected by adult-onset foveomacular vitelliform dystrophy (AOFVD) using optical coherence tomography angiography (OCTA) Methods: A total forty-four right eyes of 44 AOFVD patients (20 females, 24 males, mean age 69.17 ± 11.57 years) divided in 3 stages (vitelliform, pseudohypopyon and vitelliruptive) and 60 normal right eyes of 60 controls (20 females, 40 males, mean age 66.04 ± 6.40 years) were included in this prospective study. We evaluated the vessel density of superficial capillary plexus (SCP), deep capillary plexus (DCP) and CC in different macular areas (whole image, parafovea and fovea).
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We also analyzed the subfoveal choroidal thickness (SFCT) with Enhanced Depth Image (EDI)OCT.
Results: The vessel density of SCP and of DCP did not differ between patients and controls in all
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macular sectors. The vessel density of CC was lower in patients compared to controls but the
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difference turned out to be statistically significant only in foveal region (p<0.001). We found that the foveal vessel density of the CC was lower in vitelliform stage and significantly increased in
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vitelliruptive stage (p=0.031). At EDI-OCT, the SFCT revealed a statistically significant increase in patients compared to controls (p=0.002) whereas it was similar in the different stages of this
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dystrophy (p=0.276).
Conclusions: In vitelliform stage of AOFVD, OCTA and EDI-OCT can be useful to avoid mistakes
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of evaluation, due to the masking effect artifact. OCTA provides us a better understanding of the
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vascular role in the physiopathology of the macular diseases.
Keywords: Adult-onset foveomacular vitelliform dystrophy, optical coherence tomography angiography, vessel density, choroidal thickness.
Introduction
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Adult-onset foveomacular vitelliform dystrophy (AOFVD) is a relatively uncommon macular disease, first described by Gass in 1974 [1]. It typically occurs between the fourth and sixth decade of life showing bilateral, heterogeneous, yellowish, subfoveal material within the macular area due to altered cellular turnover mechanisms between retinal pigment epithelium (RPE) and photoreceptor cell layer [1,2]. The diagnosis of AOFVD is based on the typical clinical features of the macula displayed by different techniques such as fluorescein angiography (FA), indocyanine green angiography (ICGA), spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) [3,4].
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Previous studies have evaluated the choroidal thickness mainly in subfoveal region in AOVFD
patients using SD-OCT with enhanced depth image (EDI) technique that provides more accurate assessments of the choroidal morphology [5]. In order to better understand the pathophysiology of
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this disease, retinal and choriocapillaris (CC) vascular networks must be carefully analyzed. The
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oxidative damage, due to accumulation of the vitelliform material, could involve these vascular plexa [6-9]. The introduction of optical coherence tomography angiography (OCTA), a novel and
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non-invasive diagnostic technique, has allowed a detailed and objective quantitative analysis of the retinal and CC vessel density [10,11].
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The purpose of this study was to analyze the macular vessel density in the superficial capillary
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plexus (SCP), deep capillary plexus (DCP) and in CC in patients affected by AOVFD using OCTA.
Materials and Methods
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In this prospective study, we enrolled a total of 44 right eyes of 44 patients (20 females, 24 males, mean age 69.17 ± 11.57 years) affected by adult-onset foveomacular vitelliform dystrophy (AOVFD) divided in 3 different stages (18 eyes were in vitelliform, 16 eyes in pseudohypopyon and 10 eyes in vitelliruptive) who consecutively presented to the Eye Clinic of the University of Naples “Federico II”.
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The criteria for diagnosis of AOVFD were: 1) age older than 40 years; 2) presence of macular yellowish deposits on fundus examination; 3) hyper-autofluorescence spots in fundus autofluorescence images; 4) fluorescein angiography exhibiting late staining, without leakage; 5) indocyanine green angiography without any sign of choroidal neovascularization. In this study, the patients with AOVFD presented different stages: vitelliform (the presence of hyper-reflective material located between the photoreceptor layer and the retinal pigment epithelium); pseudohypopyon (a partial resorption of the vitelliform material occurred); vitelliruptive (a progressive resorption of the fluid). Eyes with the atrophic/fibrotic stage of the
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disease were not included in this study.
Each patient underwent evaluation of best corrected visual acuity (BCVA) according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) [12], slit-lamp biomicroscopy, intraocular
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pressure measurement, fundus examination with a +90 D lens, FA, ICGA, SD-OCT and OCTA.
Engineering, Heidelberg, Germany).
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The SFCT was measured using Spectralis Heidelberg with EDI mode (Spectralis, Heidelberg
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Sixty healthy subjects (20 females, 40 males) for a total of 60 right eyes with a normal ophthalmic examination, no history of intraocular surgery or retinal pathologic features were included in the
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control group and were underwent SD-OCT and OCTA. Exclusion criteria included history of choroidal neovascularization, central serous
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chorioretinopathy, geographical atrophy, subretinal fibrosis, retinal vascular diseases, vitreoretinal disease, myopia greater than 6 diopters, history of ocular surgery and significant lens opacities.
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The study was approved by the Institutional Review Board of the University of Naples “Federico II” and all investigations adhered to the tenets of the Declaration of Helsinki. Written informed consents were obtained from the patients enrolled in the study.
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EDI-OCT measurement The SFCT was measured using the Spectralis OCT device in EDI mode (Spectralis, Heidelberg Engineering, Heidelberg, Germany). The choroidal thickness was evaluated in the subfoveal region as a manual linear measurement between the outer border of Bruch’s membrane and the most posterior identifiable aspect of the choroidal-scleral interface, which is seen as a hyper-reflective layer in the posterior margin of the
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choroid in EDI mode [9].
Optical Coherence Tomography Angiography
We obtained OCTA images with the Optovue Angiovue System (software ReVue version
2017.1.0.151, Optovue Inc., Fremont, CA, USA) which is based on split-spectrum amplitude de-
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correlation algorithm (SSADA). The instrument has an A-scan rate of 70,000 scans per seconds
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with a tissue axial resolution of 5 µm and a 15-µm beam width. Each B-scan contained 304 Ascans. Two consecutive B-scans were captured at a fixed position before proceeding to the next
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sampling location. Blood flowing through vessels causes a change in reflectance over time and results in localized areas of flow de-correlation between frames. The spectrum of the light source
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was split into multiple component parts to decrease the noise present in the image; each part was used to perform the de-correlation step and the results of all the split spectra were averaged. In any
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given region of tissue, the projection image can be viewed to obtain an image of the contained blood flow [13].
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Cross-sectional registered reflectance intensity images and flow images were summarized and viewed as an en face maximum flow projection from the inner limiting layer to the retinal epithelial pigment. Macular capillary network was visualized in scans centered on the fovea by performing a 6 mm × 6 mm scan over the macular region. Vessel density was defined as the percentage area occupied by the large vessels and microvasculature in the analyzed region [14]. The OCT software, according to the ETDRS classification of diabetic retinopathy, applies to all angiograms a grid 5
centered on fovea, which divides macular region in foveal and parafoveal area. For each eye analyzed, the software automatically calculates vessel density in whole scan area and in all sections of applied grid in different vascular networks of the retina (SCP, DCP) and in CC, as previously described [15,16]. Poor-quality images with a signal strength index less than 40 or registered image sets with residual motion artefacts were excluded from the analysis.
Statistical Analysis
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Statistical analysis was performed with the Statistical Package for Social Sciences (Version 20.0 for Windows; SPSS Inc, Chicago, Ill, USA). The Chi-squared test was used to determine differences in term of sex. The Mann–Whitney U test was used to evaluate differences in vessel density of each
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capillary plexus and in SFCT between controls and patients. Kruskal-Wallis test was used to
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compare retinal, choriocapillaris vessel density and SFCT among the patients divided according to
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disease stages. A p value of < 0.05 was considered statistically significant.
Results
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Forty-four patients (20 females, 24 males, mean age 69.17 ± 11.57 years) for a total of 44 right eyes were included in this study. The control group was constituted by 60 healthy subjects (20 females,
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40 males, mean age 66.04 ± 6.40 years). There were no significative differences for age (p=0.094) and sex (p=0.907) between patients and controls. Regarding disease stages, 18 eyes presented the
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vitelliform stage (figure 1), 16 eyes the pseudohypopyon stage (figure 2) and 10 eyes the vitelliruptive stage (figure 3). The demographic and clinical characteristics of the controls and patients were reported in table 1.
Regarding the vessel density of the SCP we did not find statistically significant differences between controls and AOFVD patients in whole image (47.28 ± 4.08% vs 46.97 ± 4.32%; p=0.856), 6
parafoveal area (49.32 ± 6.16% vs 47.06 ± 5.88%; p=0.274) and foveal area (18.99 ± 6.63 vs 22.17 ± 10.70; p=0.158). Similar findings for the vessel density of DCP when compared between the two groups in whole image (48.84 ± 7.04% vs 49.42 ± 6.17%; p=0.861), parafoveal area (53.30 ± 5.67% vs 51.83 ± 6.18%; p=0.523) and foveal area (36.19 ± 6.87% vs 34.47 ± 12.47%; p=0.465). The vessel density of the choriocapillaris resulted reduced in patients compared to controls in whole image (69.19 ± 5.06% vs 70.87 ± 3.5% p=0.239) and parafoveal area (66.72 ± 7.36% vs 69.09 ± 4.27% p=0.106) but the difference turned out to be statistically significant only in foveal area (50.15 ± 15.55% vs 69.58 ± 4.82%; p<0.001).
to controls (328.25 ± 60.86 vs 295.78 ± 29.93; p=0.002) (table 2).
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With EDI-OCT evaluation, SFCT revealed a statistically significant increase in patients compared
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Analyzing the patients according to disease staging, we found that the retinal vessel density and
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SFCT were similar among the different groups (p=0.276) while the foveal vessel density in CC
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significantly increased from vitelliform to vitelliruptive stage (p=0.031) (table 3).
Discussion
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In this prospective study, we performed a quantitative analysis of retinal, choriocapillaris vessel density and SFCT in patients with AOFVD compared with controls. We also analyzed the vascular features of the capillary plexa in the different stages of this disease.
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Previous studies have performed only a morphological analysis on retinal and choriocapillaris
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microvascular networks, other studies have not evaluated the patients according to disease stage [17-20].
We found, using OCTA and EDI-OCT, a different behavior of retinal and choroid vasculature. Regarding the retinal vascular network, we found that vessel density did not differ significantly between patients and controls in all macular sectors of SCP and DCP. In accordance with our results, the study, conducted by Toto et al, showed that superficial and deep vessel density were not statistically different in AOFVD group compared to controls except for the 7
parafoveal deep vessel density that appeared increased due to a possible inflammatory response aimed to reabsorb vitelliform material [17]. In agreement with previous studies [18-20], we found a reduction in choriocapillaris vessel density in different macular sectors comparing patients to controls but this difference was statistically significant only in foveal region that represents the main site of vitelliform material accumulation [20]. Regarding the different disease stages, we observed a reduced choriocapillaris vessel density in vitelliform stage and a progressive, statistically significant increase in vitelliruptive stage. These findings could be researched in the changes of the vascular network secondary to the
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vitelliform material accumulation in the outer retina. It is possible that the deposition of waste
materials in outer retina causes oxidative damages between RPE and the underlying CC resulting in hypoxia with consequent reduced perfusion density.
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On the other hand, the size of areas of reduced vessel density in CC at OCTA images corresponded
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with the size of vitelliform material detected on structural OCT B scans in vitelliform and pseudohypopyon stages, as shown in figures 1 and 2. Instead, in the vitelliruptive stage,
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characterized by reabsorption of this material followed by fluid accumulation, we did not observe this artifact.
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We hypothesized that our findings at OCTA may be related to shadowing effect of subfoveal vitelliform lesion rather than a true absence of flow.
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As previously shown in other studies, using EDI-OCT, we noted that the SFCT turned out to be thicker in AOVFD patients compared with controls, [8,22-24,25].
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The increased choroidal thickness was thought to be associated to choroidal vasodilatation and to increased blood flow due. A compensatory vascular mechanism to the metabolic overload of the RPE and photoreceptor layer occurs in the attempt to remove the vitelliform material. In our study the SFCT was similar in different stages of the disease because patients presented vitelliform, pseudohypopyon and vitelliruptive stages and no eyes was in atrophic/fibrotic phase of disease.
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Our results could be useful in clinical practice. We believe that the vitelliform lesion could be considered an important artifact that influences the visualization of the vascular network and therefore the measurements of the vessel density in macular region. The present study has several limitations, especially the relatively small sample size of the groups, the impaired visualization of the CC due to masking effect at OCTA, the EDI-OCT software inability to measure automatically the choroidal thickness and the difficulty to identify its precise boundaries because of shadowing of the vitelliform material.
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In conclusion, our study, using OCT-A and EDI-OCT, provides detailed evaluation about the vascular features of the retina, CC and choroid in AOVFD patients divided according to disease stages. OCTA is a new technique that allows us a better understanding of the possible vascular role
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in physiopathology of macular diseases.
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Declarations of interest: none
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commercial, or not-for-profit sectors.
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Funding: This research did not receive any specific grant from funding agencies in the public,
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Optical coherence tomography angiography to assess vascular remodeling of the choriocapillaris after low-fluence photodynamic therapy for chronic central serous
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chorioretinopathy. Photodiagnosis and Photodynamic Therapy 27 (2019):162–166. 17. L. Toto, E. Borrelli, R. Mastropasqua, Adult-onset foveomacular vitelifform dystrophy
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19. M. Treder, JL. Lauermann, M. Alnawaiseh, P. Heiduschka, N. Eter, Quantitative changes in flow density in patients with adult-onset foveomacular vitelliform dystrophy: an OCT angiography study, Graefes Arch Clin Exp Ophthalmol. 256 (2018):23-28. 20. G. Querques, O. Zambrowski, F. Corvi, et al. Optical coherence tomography angiography in adult-onset foveomacular vitelliform dystrophy, Br J Ophthalmol, 100 (2016):1724-1730. 21. JJ. Arnold, JP. Sarks, MC. Killingsworth, EK. Kettle, SH. Sarks, Adult vitelliform macular degeneration: a clinicopathological study, Eye. 17 (2003):717-726. 22. M. Battaglia Parodi, R. Sacconi, P. Iacono, C. Del Turco, F. Bandello, Choroidal thickness
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24. Eriş E. Association between choroidal vascular density, age and sex: A prospective study. Photodiagnosis Photodyn Ther. 27 (2019):452-454.
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25. Eriş E, Aydin E, Özçift SG. The effect of the smoking on choroidal thickness, central macular vascular and optic disc perfusion. Photodiagnosis Photodyn Ther. 28 (2019):142-
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Figure Legends
Figure 1. Right eye of a patient with adult-onset foveomacular vitelliform dystrophy at the vitelliform stage. (a) Multicolor image shows a yellowish macular lesion. (b) Fundus
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autofluorescence shows a central area hyper/hypoautofluorescence. (c) Spectral-domain optical coherence tomography reveals subfoveal accumulation of hyperreflective material between retinal
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pigment epithelium and the ellipsoid zone of the photoreceptors. (d,e) In the early phase of
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fluorescein angiography the vitelliform lesion appears hypofluorescent while in the later phase becomes hyperfluorescent. (f,g) In the early of indocyanine green angiography the lesion appears
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hypocyanescent with hypercyanescent border in the late phase. (h,i) OCTA of the superficial capillary plexus and deep capillary plexus shows no significative changes in vessel density. (j)
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OCTA of the choriocapillaris shows a reduction of the vessel density below the corresponding
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vitelliform lesion in foveal region.
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Figure 2. Right eye of a patient with adult-onset foveomacular vitelliform dystrophy at the
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pseudohypopyon stage. (a) Multicolor image is characterized by the yellow material that accumulates centrally and inferiorly. (b) Fundus autofluorescence shows loss of autofluorescence, particularly in the upper part of the lesion. (c) Spectral-domain optical coherence tomography
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reveals a partial reabsorption of the material resulting in some hyporeflective areas with clumping of hyperreflective material on the posterior retinal surface located between the retinal pigment
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epithelium (RPE) and the ellipsoid zone of the photoreceptors. There is also a hyperreflective area corresponding to vitelliform material still visible. (d,f) In the early phase of fluorescein angiography
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and indocyanine green angiography the lesion shows a central hypofluorescence/hypocyanescent (e,g) with areas of hyperfluorescence/hypercyanescence in the late stages due to window defect and
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staining. (h,i) OCTA of the superficial capillary plexus and deep capillary plexus show no significative changes in vessel density. (j) OCTA of the choriocapillaris shows a reduction of the
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vessel density below the corresponding vitelliform lesion in foveal region.
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Figure 3. Right eye of a patient with adult-onset foveomacular vitelliform dystrophy at the vitelliruptive stage. (a) Multicolor image reveals partial reabsorption of the vitelliform material with typical scrambled-egg appearance and dispersion of the material. (b) Fundus autofluorescence
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shows a central area of hypoautofluorescence surrounded by an area of slight
hyperautofluorescence. (c) Spectral-domain optical coherence tomography reveals optically empty
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lesion between the retinal pigment epithelium (RPE) and the photoreceptor ellipsoid zone, with clumping of hyperreflective material on the posterior retinal surface and with some zones of
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hyperreflective mottling on the RPE layer corresponding to areas of focal hypertrophy. (d,e,f,g) In the early and late phases, the fluorescein angiography and indocyanine green angiography show
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central hypofluorescence with some areas of hyperfluorescence due to staining and window defects linked to RPE and chorioretinal atrophy. (h,i) Optical coherence tomography angiography (OCTA)
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of the superficial capillary plexus and deep capillary plexus shows no significative changes in
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vessel density. (j) OCTA of the choriocapillaris shows some areas of reduced vessel density below the previous vitelliform lesion in foveal region.
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Table 1. Demographic and clinical characteristics in controls and AOFVD patients. Controls
Patients
Eyes (n.)
60
44
Female/Male
20 / 40
20 / 24
Age (years; mean ± SD)
66.04 ± 6.40
69.17 ± 11.57
Vitelliform
-
18
Pseudohypopyon
-
16
Vitelliruptive
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AOVFD stage, (eyes n.)
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SD: Standard Deviation; AOVFD:Adult-Onset Foveomacular Vitelliform Dystrophy
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Table 2. Differences in OCT angiography vessel density and subfoveal choroidal thickness between controls and AOFVD patients. Controls
Patients
p value
Whole image
47.28 ± 4.08
46.97 ± 4.32
0.856
Parafovea
49.32 ± 6.16
47.06 ± 5.88
0.274
Fovea
18.99 ± 6.63
22.17 ± 10.70
0.158
Whole image
48.84 ± 7.04
49.42 ± 6.17
0.861
Parafovea
53.30 ± 5.67
51.83 ± 6.18
0.523
Fovea
36.19 ± 6.87
34.47 ± 12.47
0.465
70.87 ± 3.5
69.19 ± 5.06
0.239
69.09 ± 4.27
66.72 ± 7.36
0.106
69.58 ± 4.82
50.15 ± 15.55
<0.001
328.25 ± 60.86
0.002
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Deep Capillary Plexus (%)
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Superficial Capillary Plexus (%)
Choriocapillaris (%)
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Whole image Parafovea
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Fovea
Subfoveval Choroidal Thickness (µm)
295.78 ± 29.93
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Data expressed as mean ± SD The Mann-Whitney U test, p <0.05
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Table 3. Differences in OCT angiography vessel density and subfobveal choroidal thickness among patients divided according to AOFVD stages. Vitelliform
Pseudohypopyon
Vitellirupture
P value
Whole image
45.85 ± 4.41
48.35 ± 4.56
46.80 ± 3.41
0.256
Parafovea
46.23 ± 3.20
49.96 ± 5.78
43.92 ± 7.92
0.243
Fovea
20.10 ± 8.46
23.55 ± 11.62
23.69 ± 13.14
0.765
Whole image
47.11 ± 4.69
51.68 ± 6.94
49.96 ± 6.33
0.194
Parafovea
50.45 ± 3.78
53.98 ± 6.62
50.87 ± 8.32
0.329
Fovea
33.24 ± 14.41
34.01 ± 10.93
37.40 ± 11.77
0.521
Superficial Capillary Plexus
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(%)
Whole image
re 69.01 ± 4.72
68.78 ± 5.25
70.18 ± 5.73
0.891
64.22 ± 8.01
65.19 ± 7.36
69.27 ± 5.30
0.543
47.02 ± 16.28
53.35 ± 17.20
57.37 ± 14.11
0.031
328.83 ± 75.73
321.25 ± 67.46
318.40 ± 54.01
0.276
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Parafovea
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Choriocapillaris (%)
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Fovea
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Deep Capillary Plexus (%)
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Subfoveal Choroidal Thickness (µm)
Data expressed as mean ± SD Kruskal-Wallis test, p <0.05
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