Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Impact of Drusen Burden on Incidence of Subclinical CNV With OCTA

Atsuro Uchida, MD, PhD; Sunil K. Srivastava, MD; Deepa Manjunath, MD; Rishi P. Singh, MD; Aleksandra V. Rachitskaya, MD; Peter K. Kaiser, MD; Jamie L. Reese, BSN; Justis P. Ehlers, MD

Abstract

BACKGROUND AND OBJECTIVE:

To evaluate the impact of drusen burden on the detection of subclinical choroidal neovascularization (CNV) on optical coherence tomography angiography (OCTA) in nonexudative age-related macular degeneration (AMD).

PATIENTS AND METHODS:

A subanalysis of the AVATAR study, subjects diagnosed with nonexudative AMD without subfoveal atrophy were included. Subclinical CNV was assessed using OCTA software, and drusen burden was graded utilizing the advanced retinal pigment epithelium (RPE) analysis.

RESULTS:

Among eligible 58 eyes, 26 eyes (45%) had high drusen burden. Of the three eyes (5%) that demonstrated subclinical CNV, only one eye had high drusen burden, and all three eyes had neovascular AMD in the fellow eye. Extrafoveal RPE atrophy (odds ratio [OR] = 20.0; 95% confidence interval [CI], 1.53–261) and older age (OR = 1.27; 95% CI, 1.01–1.59) were predictive factors for subclinical CNV.

CONCLUSION:

Extrafoveal RPE atrophy, older age, and fellow-eye CNV were significant risk factors for underlying subclinical CNV in nonexudative AMD.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:22–30.]

Abstract

BACKGROUND AND OBJECTIVE:

To evaluate the impact of drusen burden on the detection of subclinical choroidal neovascularization (CNV) on optical coherence tomography angiography (OCTA) in nonexudative age-related macular degeneration (AMD).

PATIENTS AND METHODS:

A subanalysis of the AVATAR study, subjects diagnosed with nonexudative AMD without subfoveal atrophy were included. Subclinical CNV was assessed using OCTA software, and drusen burden was graded utilizing the advanced retinal pigment epithelium (RPE) analysis.

RESULTS:

Among eligible 58 eyes, 26 eyes (45%) had high drusen burden. Of the three eyes (5%) that demonstrated subclinical CNV, only one eye had high drusen burden, and all three eyes had neovascular AMD in the fellow eye. Extrafoveal RPE atrophy (odds ratio [OR] = 20.0; 95% confidence interval [CI], 1.53–261) and older age (OR = 1.27; 95% CI, 1.01–1.59) were predictive factors for subclinical CNV.

CONCLUSION:

Extrafoveal RPE atrophy, older age, and fellow-eye CNV were significant risk factors for underlying subclinical CNV in nonexudative AMD.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:22–30.]

Introduction

Age-related macular degeneration (AMD) is one of the leading causes of vision loss in adults aged 50 and older worldwide.1 Early and intermediate AMD are characterized by the presence of drusen often accompanied by pigmentary changes of the retinal pigment epithelium (RPE) in the macula, whereas advanced AMD is characterized by the development of choroidal neovascularization (CNV) or geographic atrophy (GA).2 In neovascular AMD, incompetent neovascular vessels invade the retina and leak fluid and exudates, leading to photoreceptor damage that causes rapid and profound vision loss.3 Early identification and treatment of active CNV exudation can help prevent poor visual outcomes.4

A number of high-risk disease features associated with progression to advanced AMD have been previously identified, including large macular drusen,5–11 greater drusen area,9,12 greater drusen volume,9,10 reticular pseudodrusen,5,7 RPE pigmentary abnormalities,5–7,11,12 and CNV in the fellow eye.5,6,8,13 Randomized trials have confirmed and suggested the importance of total drusen area and size as predictors of the development of neovascular AMD.6,11,14 Although high drusen burden appears to be a risk factor for the future development of exudative disease, the incidence of subclinical CNV in eyes with apparent “dry” disease and a high drusen burden is unknown.

Optical coherence tomography angiography (OCTA) is an emerging noninvasive imaging modality that allows for the direct visualization of blood flow within the chorioretinal vasculature.15 It is capable of visualizing CNV in a variety of diseases, including AMD.16–18 In particular, it has been shown to detect subclinical CNV membranes that do not present with signs of exudation on spectral-domain optical coherence tomography (SD-OCT) or clinical exam.19–22 In this study, we utilized OCTA to screen for subclinical CNV membranes in patients with nonexudative AMD and evaluated the overall association of drusen burden on the presence subclinical CNV.

Patients and Methods

The Observational Assessment of Visualizing and Analyzing Vessels with Optical Coherence Tomography Angiography in Retinal Diseases (AVATAR) is a prospective, observational study of OCTA in eyes undergoing routine SD-OCT for the macular disease at the Cole Eye Institute, Cleveland, Ohio. The study was approved by the Cleveland Clinic Institutional Review Board. The study complied with HIPAA guidelines and adhered to the tenets of the Declaration of Helsinki. All patients gave informed consent for study enrollment.

Patients were imaged with the Avanti RTVue XR HD (Optovue, Fremont, CA) and the Cirrus HD-OCT system (Zeiss, Oberkochen, Germany) systems. The Avanti system was equipped with split-spectrum amplitude decorrelation (SSADA) software with bulk motion-correction technology and operated at a rate of 70,000 A-scans per second. Scan sizes obtained included 3 mm × 3 mm, 6 mm × 6 mm, and/or 8 mm × 8 mm scans centered at the fovea. OCT angiograms were automatically segmented into the superficial retina, deep retina, outer retina, and choriocapillaris layers.

Image Analysis

All images were reviewed by a masked expert reviewer. Study eyes with early and intermediate AMD and no evidence of CNV on clinical exam or multimodal imaging were included in the present analysis. Eyes with advanced nonexudative AMD with foveal-involving GA were excluded from the study. Eyes were assessed for total drusen area, total drusen volume, the presence of intermediate (soft) drusen (63 μm to 124 μm), large (soft) drusen (≥ 125 μm), confluent drusen (defined as soft drusen with diameter ≥ 500 μm), RPE pigmentary abnormalities including hyperpigmentation/hypopigmentation, extrafoveal RPE atrophy (≥ 175 μm in diameter), and a diagnosis of neovascular AMD in the fellow eye. Drusen area and volume measurements were derived from the Advanced RPE Analysis tool in the Cirrus HD-OCT software and included RPE elevations within a 5-mm diameter circle.

Study eyes were divided into three categories of drusen burden based on total drusen area. High drusen burden was defined by a total drusen area 1 mm2 or greater. Intermediate drusen burden was defined by a total drusen area of 0.5 mm2 or greater but less than 1 mm2. Low drusen burden was defined as total drusen area less than 0.5 mm2.

Segmented OCTA scans were assessed for the presence or absence of CNV within the outer retinal or choriocapillaris slabs. This was defined as any de-correlation signal in the outer retina or abnormal de-correlation signal in the choriocapillaris that was consistent with known morphologies of CNV. Manual review of the three-dimensional OCTA cube was then used to confirm the presence of CNV within sub-RPE drusenoid deposits or in the outer retina.

Statistical Analysis

Data analyses were performed using R software version 3.2.3 (Software Foundation's GNU project, https://www.r-project.org). Results are presented as a mean ± standard deviation. Univariate analysis and logistic regression analysis were performed to correlate high-risk disease features for advanced AMD with the detection of subclinical CNV by OCTA. Fisher's exact test was used for two categorical variables, and two-sample t-test was performed for continuous variables. Predictor variables included age, the grade of drusen burden, the area and volume of RPE elevation, the presence of soft drusen (eg, intermediate, large, confluent), RPE pigmentary abnormalities, extrafoveal RPE atrophy, and neovascular AMD in the fellow eye. Regression findings were reported as odds ratios (OR) with 95% confidence intervals (CI). The statistical significance level was set at P value less than .05.

Results

Clinical Characteristics

Overall, 58 eyes of 43 patients (34 female eyes; mean age: 74.4 ± 7.9 years, range: 58–92 years) that enrolled in the AVATAR study with early and intermediate AMD were included in the present analysis. Eleven (19%) eyes had early AMD whereas 41 (71%) eyes had intermediate AMD. Six (10%) eyes had advanced AMD with extrafoveal atrophy. The mean drusen area and volume within a 5-mm diameter circle was 1.11 ± 1.22 mm2 (median = 0.70; range = 0 to 5.10 mm2), and 0.056 ± 0.079 mm3 (median = 0.02; range: 0 to 0.43 mm3), respectively. Clinical characteristics and the prevalence of high-risk disease characteristics are given in Table 1. Among 58 study eyes, 26 eyes (45%) had a high drusen burden, 11 eyes (19%) had intermediate drusen burden, and 21 eyes (36%) had low drusen burden. A representative example of each group is given in Figure 1.

Clinical Characteristics and Prevalence of High-Risk Features for Disease Progression in Eyes With Early and Intermediate AMD

Table 1:

Clinical Characteristics and Prevalence of High-Risk Features for Disease Progression in Eyes With Early and Intermediate AMD

Drusen burden in early and intermediate age-related macular degeneration. Cross-sectional retinal pigment epithelium elevation maps and spectral-domain optical coherence tomography horizontal scans demonstrating a high (top), intermediate (middle), and low (bottom) drusen burden.

Figure 1.

Drusen burden in early and intermediate age-related macular degeneration. Cross-sectional retinal pigment epithelium elevation maps and spectral-domain optical coherence tomography horizontal scans demonstrating a high (top), intermediate (middle), and low (bottom) drusen burden.

Subclinical CNV Detection and Risk Factors

Three eyes (5%) had subclinical CNV on OCTA as identified on automated OCTA report based on expert review and confirmed with manual OCTA volume review. The mean age was higher in eyes with subclinical CNV identified on OCTA compared with eyes without subclinical CNV (84.7 ± 7.5 years vs. 73.9 ± 7.6 years; P = .045). Manual OCTA volume review allowed better visualization of the CNV; each of these was located below the RPE within apparent drusenoid deposits (Figure 2). The remainder of eyes did not display evidence of CNV on OCTA (Figure 3). Of the three eyes with subclinical CNV on OCTA, only one eye had high drusen burden (drusen area = 4.4 mm2; volume = 0.21 mm3). Of the remaining two eyes, one eye had the intermediate drusen burden (drusen area = 0.5 mm2; volume = 0.01 mm3) with extrafoveal RPE atrophy, and the other eye had low drusen burden (no calculable drusen area), also with extrafoveal RPE atrophy. Overall, extrafoveal RPE atrophy was observed in two (67%) eyes with subclinical CNV identified on OCTA and in five (9%) of eyes without CNV, respectively (P = .036). All study eyes with subclinical CNV on OCTA had neovascular AMD in the fellow eye which was statistically significant (P = .0499); two fellow eyes were undergoing observation whereas one fellow eye had begun receiving anti-vascular endothelial growth factor (VEGF) therapy on the same visit. Results of the univariate logistic regression analysis are given in Table 2. The patient older age (OR = 1.27; CI, 1.01–1.59; P = .042) and the presence of extrafoveal RPE atrophy (OR = 20.0; CI, 1.53–261; P = .022) were found to have a significant predictive value for the presence of subclinical CNV on OCTA.

Subclinical choroidal neovascularization (CNV) detected by optical coherence tomography angiography (OCTA) in patients with early and intermediate age-related macular degeneration (AMD). All OCTA images were manually reviewed with a lower segmentation border at Bruch's membrane. (Left column) Case example categorized as a low drusen burden (no calculable drusen area or volume) with extrafoveal RPE atrophy, measured by a 5-mm diameter circle retinal pigment epithelium (RPE) elevation map (top). OCTA reveals neovascular lesion in the outer retina (middle) that corresponds to a sub-RPE deposit at the margin of an RPE atrophy on the horizontal cross-sectional optical coherence tomography (OCT) (bottom). (Middle column) Case example categorized as an intermediate drusen burden (drusen area = 0.5 mm2, volume = 0.01 mm3) with a well-demarcated area of RPE elevation on the map (top). OCTA reveals a subclinical CNV lesion (middle) that corresponds to an area of vascularized sub-RPE material mimicking the appearance of drusen on horizontal cross-sectional OCT (bottom). An extrafoveal RPE atrophy is also noted. (Right column) Case example categorized as a high drusen burden (drusen area = 4.4 mm2, volume = 0.21 mm3), as evidenced by RPE elevation map (top). OCTA scan reveals a complex neovascular lesion (middle) corresponding to vascularized RPE elevation on horizontal cross-sectional OCT (bottom).

Figure 2.

Subclinical choroidal neovascularization (CNV) detected by optical coherence tomography angiography (OCTA) in patients with early and intermediate age-related macular degeneration (AMD). All OCTA images were manually reviewed with a lower segmentation border at Bruch's membrane. (Left column) Case example categorized as a low drusen burden (no calculable drusen area or volume) with extrafoveal RPE atrophy, measured by a 5-mm diameter circle retinal pigment epithelium (RPE) elevation map (top). OCTA reveals neovascular lesion in the outer retina (middle) that corresponds to a sub-RPE deposit at the margin of an RPE atrophy on the horizontal cross-sectional optical coherence tomography (OCT) (bottom). (Middle column) Case example categorized as an intermediate drusen burden (drusen area = 0.5 mm2, volume = 0.01 mm3) with a well-demarcated area of RPE elevation on the map (top). OCTA reveals a subclinical CNV lesion (middle) that corresponds to an area of vascularized sub-RPE material mimicking the appearance of drusen on horizontal cross-sectional OCT (bottom). An extrafoveal RPE atrophy is also noted. (Right column) Case example categorized as a high drusen burden (drusen area = 4.4 mm2, volume = 0.21 mm3), as evidenced by RPE elevation map (top). OCTA scan reveals a complex neovascular lesion (middle) corresponding to vascularized RPE elevation on horizontal cross-sectional OCT (bottom).

Optical coherence tomography angiography (OCTA) in eyes with early and intermediate age-related macular degeneration (AMD) revealing no subclinical choroidal neovascularization. (Top left) Retinal pigment epithelium (RPE) elevation map and horizontal cross-sectional optical coherence tomography (OCT) demonstrate a low drusen burden (no calculable drusen area or volume). Segmented OCTA scan of the outer retina (top middle) and choriocapillaris (top right) with no evidence of neovascularization. Multiple projection artifacts from the superficial retina are visible in the choriocapillaris slab (asterisks). (Bottom left) Case example categorized as a high drusen burden (drusen area = 1.1 mm2; volume = 0.05 mm3), as evidenced by RPE elevation map. Confluent drusen can be seen on horizontal cross-sectional OCT. OCTA scans of the outer retina (bottom middle) and choriocapillaris (bottom right) are devoid of neovascularization. Projection artifacts are visible in the choriocapillaris slab (asterisks).

Figure 3.

Optical coherence tomography angiography (OCTA) in eyes with early and intermediate age-related macular degeneration (AMD) revealing no subclinical choroidal neovascularization. (Top left) Retinal pigment epithelium (RPE) elevation map and horizontal cross-sectional optical coherence tomography (OCT) demonstrate a low drusen burden (no calculable drusen area or volume). Segmented OCTA scan of the outer retina (top middle) and choriocapillaris (top right) with no evidence of neovascularization. Multiple projection artifacts from the superficial retina are visible in the choriocapillaris slab (asterisks). (Bottom left) Case example categorized as a high drusen burden (drusen area = 1.1 mm2; volume = 0.05 mm3), as evidenced by RPE elevation map. Confluent drusen can be seen on horizontal cross-sectional OCT. OCTA scans of the outer retina (bottom middle) and choriocapillaris (bottom right) are devoid of neovascularization. Projection artifacts are visible in the choriocapillaris slab (asterisks).

Logistic Regression of High-Risk Non-Exudative AMD Characteristics Predicting the Presence of Subclinical CNV on OCTA

Table 2:

Logistic Regression of High-Risk Non-Exudative AMD Characteristics Predicting the Presence of Subclinical CNV on OCTA

Discussion

Subclinical or quiescent CNV (ie, nonexudative neovascular AMD) has been previously described as neovascular lesions visible on indocyanine green angiography as a hyperfluorescent vascular network in early to mid-phases that do not present with signs of leakage on structural OCT.24 Querques et al. demonstrated that quiescent CNV detected by traditional angiographic techniques most often presented on structural OCT as moderately reflective material below an irregularly elevated RPE with no associated fluid.24 Recently, OCTA has been used to detect subclinical CNV lesions in patients with intermediate AMD in one eye and neovascular AMD in the fellow eye.20,21 Our results corroborate the findings of previous reports regarding the ability of OCTA to detect subclinical CNV in patients with high-risk nonexudative AMD. In addition, all three eyes with CNV on OCTA presented with type 1 CNV (sub-RPE), which is consistent with previous descriptions of quiescent CNV in AMD.20,21,24 The natural history of quiescent CNV remains unclear, with some evidence to suggest that they tend to remain stable or slowly enlarge over time without exudative retinal changes, leading to reduced retinal sensitivity.20,22,24 There is still considerable uncertainty and ongoing debate as to whether these quiescent CNV need proactive treatment since anti-VEGF therapy may exacerbate progression of RPE atrophy if present.20,21,25 Further investigations are required to better characterize the natural history and clinical management of subclinical CNV in nonexudative AMD.

In this study, OCT-based high drusen burden was hypothesized to place eyes at a higher risk of developing subclinical CNV on OCTA since drusen load has been reported as a significant predisposing factor for progression to advanced AMD.6, 8–12,14 Soft drusen consist of extracellular protein and lipid deposits which accumulate below RPE, leading to degenerative changes in the overlying retina.2 In a retrospective analysis on 83 patients, an increased drusen load as defined by automated drusen area and volume measurements was associated with an increased risk of developing both RPE atrophy and neovascular AMD.9 SD-OCT based automated algorithms for drusen quantification has also indicated drusen volume as a predictor of AMD disease progression.10 However, in this study there was not a significant association between drusen burden and the identification of subclinical CNV; in fact, only one of the three eyes with CNV had a high drusen burden. There are several potential explanations for this finding. First, the event rate of OCTA detection of subclinical CNV in this analysis was low, and the sample size was small, which may have affected statistical analysis results. Second, since drusen can have poorly demarcated boundaries, automated measurements of RPE elevation area and volume are susceptible to segmentation error where drusenoid pigment epithelial detachment (PED) or RPE atrophy exist, and this may have led to an underestimation of drusen burden. Lastly, individual soft drusen or drusenoid PED have been described to increase or decrease in size over time and may dynamically regress, occasionally leaving only an irregular mottling of the RPE.26–29 It is possible that changeable drusen burden may not directly or solely represent the activity of the disease. Drusen-specific features such as reflectivity or irregularity in shape may also impart progression risk and the existence of subclinical CNV,24,30 although this was not evaluated in this study.

Regression analysis revealed that the presence of extrafoveal RPE atrophy was a significant predictor of subclinical CNV on OCTA. The findings in this report suggest that the presence of extrafoveal RPE atrophy represents the greater severity of the AMD compared with drusen burden alone and may increase risk of subclinical CNV.31 In this study, the two eyes with subclinical CNV on OCTA categorized as low or intermediate drusen burden had extrafoveal RPE atrophy. Given the dynamic nature of drusen, the low or intermediate drusen burden in these eyes may be more consistent with atrophic conversion of the disease. The coexistence of RPE atrophy and subclinical CNV is not uncommon, it has been suggested that both advanced pathologies are initiated by common pathways with similar genetic background.32 Histological studies have demonstrated that eyes with GA may contain small subclinical CNV.33,34 Moreover, in a recent study using OCTA, among two (6%) eyes found to have subclinical CNV in eyes with drusen and pigmentary changes, one eye presented RPE atrophy, also consistent with our findings.20 Several researchers have hypothesized that some CNV may not always be detrimental and might play a protective role as compensatory vessels in the prevention of RPE atrophy.3,35

Eyes with RPE atrophy present a practical challenge in OCTA interpretation. Deep choroidal vessels visible through areas of RPE and choriocapillaris atrophy mimic the appearance of discrete CNV lesions in the automatically segmented choriocapillaris slab. In this report, two of the three eyes with subclinical CNV on OCTA had extrafoveal RPE atrophy; in one of these eyes (Figure 2, middle column), the CNV appeared to originate from the margin of the area of RPE atrophy, making it difficult to distinguish on the static segmented angiograms. Manual review of the OCTA cube with careful outer retinal segmentation at Bruch's membrane was required to distinguish vascularized drusen from “window defect” in eyes with RPE atrophy.

In the present study, all three eyes with subclinical CNV on OCTA had neovascular AMD in the fellow eye, which was statistically significant. The presence of advanced AMD in the fellow eye is a well-established and strong risk factor for the development of advanced AMD in the contralateral eye.5,6,8,13 A report from AREDS revealed that category 4 participants who had either central GA or neovascular AMD in one eye, had 14.8% to 35.4% chance of developing advanced AMD in the fellow eye at 5-year follow-up.6 Since the diagnosis of CNV was made primarily based on stereoscopic color photographs or exudative changes on fluorescein angiography in previous studies, our finding might suggest that the incidence of developing any types of CNV (ie, including nonexudative subclinical CNV) in the second eye is even higher. Close monitoring on OCTA may be recommended in eyes with unilateral advanced AMD as bilateral CNV involvement has devastating effects on the visual capabilities.

Several potential limitations of our study should be mentioned. The study included a limited sample size; only three eyes had subclinical CNV, which potentially compromises the validity of the conclusion, and multivariate logistic regression analysis was not performed to avoid overfitting. Additionally, the decorrelation signal is not proportional to the flow velocity, and very slow blood flow cannot be detected with the current device. Inactive, subclinical CNV with an undetectable blood flow velocity might have been overlooked. Further improvements in the OCTA technology may overcome this limitation.

In conclusion, OCTA may allow for the early identification of subclinical CNV in eyes with early and intermediate AMD involving high-risk features for disease progression, particularly in the presence of extrafoveal RPE atrophy and neovascular AMD in the fellow eye. Although a careful manual review of the OCTA cube would likely be required, identification of subclinical CNV is of paramount importance since it allows for closer surveillance and early treatment when the eye progress to an active form of exudative AMD. Further investigation is required to clarify the association between drusen burden and the development of neovascularization in AMD. Future studies should include drusen burden assessment in the absence of concurrent atrophy to better define the risk of drusen burden with the development of subclinical CNV.

References

  1. Friedman DS, O'Colmain BJ, Muñoz B, et al. Eye Diseases Prevalence Research Group. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122(4):564–572. https://doi.org/10.1001/archopht.1941.00870100042005 PMID: doi:10.1001/archopht.122.4.564 [CrossRef]15078675
  2. Coleman HR, Chan CC, Ferris FL III, Chew EY. Age-related macular degeneration. Lancet. 2008;372(9652):1835–1845. https://doi.org/10.1016/S0140-6736(08)61759-6 PMID: doi:10.1016/S0140-6736(08)61759-6 [CrossRef]19027484
  3. Grossniklaus HE, Green WR. Choroidal neovascularization. Am J Ophthalmol. 2004;137(3):496–503. https://doi.org/10.1016/j.ajo.2003.09.042 PMID: doi:10.1016/j.ajo.2003.09.042 [CrossRef]15013874
  4. Ying GS, Maguire MG, Daniel E, et al. Association of Baseline Characteristics and Early Vision Response with 2-Year Vision Outcomes in the Comparison of AMD Treatments Trials (CATT). Ophthalmology. 2015;122(12):2523–2531.e1. https://doi.org/10.1016/j.ophtha.2015.08.015 PMID: doi:10.1016/j.ophtha.2015.08.015 [CrossRef]26383996
  5. Wang JJ, Foran S, Smith W, Mitchell P. Risk of age-related macular degeneration in eyes with macular drusen or hyperpigmentation: the Blue Mountains Eye Study cohort. Arch Ophthalmol. 2003;121(5):658–663. https://doi.org/10.1001/archopht.121.5.658 PMID: doi:10.1001/archopht.121.5.658 [CrossRef]12742843
  6. Ferris FL, Davis MD, Clemons TE, et al. Age-Related Eye Disease Study (AREDS) Research Group. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol. 2005;123(11):1570–1574. https://doi.org/10.1001/archopht.123.11.1570 PMID: doi:10.1001/archopht.123.11.1570 [CrossRef]16286620
  7. Joachim N, Mitchell P, Kifley A, Rochtchina E, Hong T, Wang JJ. Incidence and progression of geographic atrophy: observations from a population-based cohort. Ophthalmology. 2013;120(10):2042–2050. https://doi.org/10.1016/j.ophtha.2013.03.029 PMID: doi:10.1016/j.ophtha.2013.03.029 [CrossRef]23706948
  8. Seddon JM, Reynolds R, Yu Y, Daly MJ, Rosner B. Risk models for progression to advanced age-related macular degeneration using demographic, environmental, genetic, and ocular factors. Ophthalmology. 2011;118(11):2203–2211. https://doi.org/10.1016/j.ophtha.2011.04.029 PMID: doi:10.1016/j.ophtha.2011.04.029 [CrossRef]21959373
  9. Nathoo NA, Or C, Young M, et al. Optical coherence tomography-based measurement of drusen load predicts development of advanced age-related macular degeneration. Am J Ophthalmol. 2014;158:757–761.e1. https://doi.org/10.1016/j.ajo.2014.06.021 PMID: doi:10.1016/j.ajo.2014.06.021 [CrossRef]24983793
  10. Abdelfattah NS, Zhang H, Boyer DS, et al. Drusen Volume as a Predictor of Disease Progression in Patients With Late Age-Related Macular Degeneration in the Fellow Eye. Invest Ophthalmol Vis Sci. 2016;57(4):1839–1846. https://doi.org/10.1167/iovs.15-18572 PMID: doi:10.1167/iovs.15-18572 [CrossRef]27082298
  11. Bressler SB, Maguire MG, Bressler NM, Fine SLThe Macular Photocoagulation Study Group. Relationship of drusen and abnormalities of the retinal pigment epithelium to the prognosis of neovascular macular degeneration. Arch Ophthalmol. 1990;108(10):1442–1447. https://doi.org/10.1001/archopht.1990.01070120090035 PMID: doi:10.1001/archopht.1990.01070120090035 [CrossRef]1699513
  12. Complications of Age-related Macular Degeneration Prevention Trial (CAPT) Research Group. Risk factors for choroidal neovascularization and geographic atrophy in the complications of age-related degeneration prevention trial. Ophthalmology. 2008;115(9):1474–1479,1479.e1–6. https://doi.org/10.1016/j.ophtha.2008.03.008 PMID: doi:10.1016/j.ophtha.2008.03.008 [CrossRef]
  13. Macular Photocoagulation Study Group. Five-year follow-up of fellow eyes of patients with age-related macular degeneration and unilateral extrafoveal choroidal neovascularization. Arch Ophthalmol. 1993;111(9):1189–1199. https://doi.org/10.1001/archopht.1993.01090090041018 PMID: doi:10.1001/archopht.1993.01090090041018 [CrossRef]7689826
  14. Davis MD, Gangnon RE, Lee LY, et al. Age-Related Eye Disease Study Group. The Age-Related Eye Disease Study severity scale for age-related macular degeneration: AREDS Report No. 17. Arch Ophthalmol. 2005;123(11):1484–1498. https://doi.org/10.1001/archopht.123.11.1484 PMID: doi:10.1001/archopht.123.11.1484 [CrossRef]16286610
  15. Jia Y, Tan O, Tokayer J, et al. Split-spectrum amplitude-decorrelation angiography with optical coherence tomography. Opt Express. 2012;20(4):4710–4725. https://doi.org/10.1364/OE.20.004710 PMID: doi:10.1364/OE.20.004710 [CrossRef]22418228
  16. Jia Y, Bailey ST, Wilson DJ, et al. Quantitative optical coherence tomography angiography of choroidal neovascularization in age-related macular degeneration. Ophthalmology. 2014;121(7):1435–1444. https://doi.org/10.1016/j.ophtha.2014.01.034 PMID: doi:10.1016/j.ophtha.2014.01.034 [CrossRef]24679442
  17. de Carlo TE, Bonini Filho MA, Chin AT, et al. Spectral-domain optical coherence tomography angiography of choroidal neovascularization. Ophthalmology. 2015;122(6):1228–1238. https://doi.org/10.1016/j.ophtha.2015.01.029 PMID: doi:10.1016/j.ophtha.2015.01.029 [CrossRef]25795476
  18. Kuehlewein L, Dansingani KK, de Carlo TE, et al. Optical Coherence Tomography Angiography of Type 3 Neovascularization Secondary to Age-Related Macular Degeneration. Retina. 2015;35(11):2229–2235. https://doi.org/10.1097/IAE.0000000000000835 PMID: doi:10.1097/IAE.0000000000000835 [CrossRef]26502007
  19. Nehemy MB, Brocchi DN, Veloso CE. Optical Coherence Tomography Angiography Imaging of Quiescent Choroidal Neovascularization in Age-Related Macular Degeneration. Ophthalmic Surg Lasers Imaging Retina. 2015;46(10):1056–1057. https://doi.org/10.3928/23258160-20151027-13 PMID: doi:10.3928/23258160-20151027-13 [CrossRef]26599251
  20. Palejwala NV, Jia Y, Gao SS, et al. Detection of Nonexudative Choroidal Neovascularization in Age-Related Macular Degeneration with Optical Coherence Tomography Angiography. Retina. 2015;35(11):2204–2211. https://doi.org/10.1097/IAE.0000000000000867 PMID: doi:10.1097/IAE.0000000000000867 [CrossRef]26469533
  21. Roisman L, Zhang Q, Wang RK, et al. Optical Coherence Tomography Angiography of Asymptomatic Neovascularization in Intermediate Age-Related Macular Degeneration. Ophthalmology. 2016;123(6):1309–1319. https://doi.org/10.1016/j.ophtha.2016.01.044 PMID: doi:10.1016/j.ophtha.2016.01.044 [CrossRef]26876696
  22. Lane M, Ferrara D, Louzada RN, Fujimoto JG, Seddon JM. Diagnosis and Follow-Up of Nonexudative Choroidal Neovascularization With Multiple Optical Coherence Tomography Angiography Devices: A Case Report. Ophthalmic Surg Lasers Imaging Retina. 2016;47(8):778–781. https://doi.org/10.3928/23258160-20160808-13 PMID: doi:10.3928/23258160-20160808-13 [CrossRef]27548457
  23. Age-Related Eye Disease Study Research Group. The Age-Related Eye Disease Study system for classifying age-related macular degeneration from stereoscopic color fundus photographs: the Age-Related Eye Disease Study Report Number 6. Am J Ophthalmol. 2001;132(5):668–681. https://doi.org/10.1016/S0002-9394(01)01218-1 PMID: doi:10.1016/S0002-9394(01)01218-1 [CrossRef]11704028
  24. Querques G, Srour M, Massamba N, et al. Functional characterization and multimodal imaging of treatment-naive “quiescent” choroidal neovascularization. Invest Ophthalmol Vis Sci. 2013;54(10):6886–6892. https://doi.org/10.1167/iovs.13-11665 PMID: doi:10.1167/iovs.13-11665 [CrossRef]24084095
  25. Capuano V, Miere A, Querques L, et al. Treatment-Naïve Quiescent Choroidal Neovascularization in Geographic Atrophy Secondary to Nonexudative Age-Related Macular Degeneration. Am J Ophthalmol. 2017;182:45–55. https://doi.org/10.1016/j.ajo.2017.07.009 PMID: doi:10.1016/j.ajo.2017.07.009 [CrossRef]28734811
  26. Thiele S, Pfau M, Larsen PP, Fleckenstein M, Holz FG, Schmitz-Valckenberg S. Multimodal Imaging Patterns for Development of Central Atrophy Secondary to Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci. 2018;59(4):AMD1–AMD11. https://doi.org/10.1167/iovs.17-23315 PMID: doi:10.1167/iovs.17-23315 [CrossRef]29558532
  27. Gass JD. Drusen and disciform macular detachment and degeneration. Arch Ophthalmol. 1973;90(3):206–217. https://doi.org/10.1001/archopht.1973.01000050208006 PMID: doi:10.1001/archopht.1973.01000050208006 [CrossRef]4738143
  28. Klein R, Klein BE, Tomany SC, Meuer SM, Huang GH. Ten-year incidence and progression of age-related maculopathy: the Beaver Dam eye study. Ophthalmology. 2002;109(10):1767–1779. https://doi.org/10.1016/S0161-6420(02)01146-6 PMID: doi:10.1016/S0161-6420(02)01146-6 [CrossRef]12359593
  29. Yehoshua Z, Wang F, Rosenfeld PJ, Penha FM, Feuer WJ, Gregori G. Natural history of drusen morphology in age-related macular degeneration using spectral domain optical coherence tomography. Ophthalmology. 2011;118(12):2434–2441. https://doi.org/10.1016/j.ophtha.2011.05.008 PMID: doi:10.1016/j.ophtha.2011.05.008 [CrossRef]21724264
  30. Dansingani KK, Balaratnasingam C, Klufas MA, Sarraf D, Freund KB. Optical Coherence Tomography Angiography of Shallow Irregular Pigment Epithelial Detachments In Pachychoroid Spectrum Disease. Am J Ophthalmol. 2015;160(6):1243–1254.e2. https://doi.org/10.1016/j.ajo.2015.08.028 PMID: doi:10.1016/j.ajo.2015.08.028 [CrossRef]26319161
  31. Ferris FL III, Wilkinson CP, Bird A, et al. Beckman Initiative for Macular Research Classification Committee. Clinical classification of age-related macular degeneration. Ophthalmology. 2013;120(4):844–851. https://doi.org/10.1016/j.ophtha.2012.10.036 PMID: doi:10.1016/j.ophtha.2012.10.036 [CrossRef]23332590
  32. Holz FG, Strauss EC, Schmitz-Valckenberg S, van Lookeren Campagne M. Geographic atrophy: clinical features and potential therapeutic approaches. Ophthalmology. 2014;121(5):1079–1091. https://doi.org/10.1016/j.ophtha.2013.11.023 PMID: doi:10.1016/j.ophtha.2013.11.023 [CrossRef]24433969
  33. Green WR, Enger C. Age-related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology. 1993;100(10):1519–1535. https://doi.org/10.1016/S0161-6420(93)31466-1 PMID: doi:10.1016/S0161-6420(93)31466-1 [CrossRef]7692366
  34. Sarks SH. Ageing and degeneration in the macular region: a clinico-pathological study. Br J Ophthalmol. 1976;60(5):324–341. https://doi.org/10.1136/bjo.60.5.324 PMID: doi:10.1136/bjo.60.5.324 [CrossRef]952802
  35. Engelbert M, Zweifel SA, Freund KB. Long-term follow-up for type 1 (subretinal pigment epithelium) neovascularization using a modified “treat and extend” dosing regimen of intravitreal antivascular endothelial growth factor therapy. Retina. 2010;30(9):1368–1375. https://doi.org/10.1097/IAE.0b013e3181d50cbf PMID: doi:10.1097/IAE.0b013e3181d50cbf [CrossRef]20517175

Clinical Characteristics and Prevalence of High-Risk Features for Disease Progression in Eyes With Early and Intermediate AMD

All 58 EyesSubclinical CNV Identified on OCTA

Yes; Three EyesNo; 55 EyesP Value

Age, Years74.4 ± 7.984.7 ± 7.573.9 ± 7.6.045

Gender, Female34 (59%)2 (67%)32 (58%)NS

Drusen Area, mm21.11 ± 1.221.63 ± 2.411.09 ± 1.16.958

Drusen Volume, mm30.056 ± 0.0790.073 ± 0.1190.055 ± 0.078.777

Drusen Burden
  High (≥ 1 mm2)26 (45%)1 (33%)25 (45%)NS
  Intermediate (≥ 0.5 mm2, < 1 mm2)11 (19%)1 (33%)10 (18%).474
  Low (< 0.5 mm2)21 (36%)1 (33%)20 (36%)NS

Presence of Soft Drusen
  Intermediate drusen (63 μm to 124 μm)57 (98%)3 (100%)54 (98%)NS
  Large drusen (≥125 μm)46 (79%)2 (67%)44 (80%).508
  Confluent drusen (≥ 500 μm)20 (34%)2 (67%)18 (33%).271

RPE Pigmentary Abnormalities (Hyper-/Hypopigmentation)42 (72%)3 (100%)39 (71%).554

Extrafoveal RPE Atrophy7 (12%)2 (67%)5 (9%).036

Neovascular AMD in the Fellow Eye22 (58%)3 (100%)19 (35%).0499

  Undergoing anti-VEGF therapy12 (21%)1 (33%)11 (20%).508

Logistic Regression of High-Risk Non-Exudative AMD Characteristics Predicting the Presence of Subclinical CNV on OCTA

Odds Ratio (95% CI)P Value
Age, Years1.27 (1.01 – 1.59).042
Drusen Area, mm21.35 (0.612 – 2.99).456
Drusen Volume, mm311.7 (6.39 × 10-5 – 214 × 104).691
High Drusen Burden0.600 (0.513 – 7.01).684
Intermediate Drusen (63 μm to 124 μm)8.70 × 105 (0 – infinity).995
Large Drusen (≥ 125 μm)0.50 (4.15 × 10-2 – 6.03).585
Confluent Drusen (≥ 500 μm)4.11 (0.349 – 48.4).261
RPE Pigmentary Abnormalities2.42 × 107 (0 – infinity).995
Extrafoveal RPE Atrophy20.0 (1.53 – 261).022
Neovascular AMD in the Fellow Eye1.35 × 108 (0 – infinity).995
Authors

From The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic, Cleveland (AU, SKS, DM, JLR, JPE); and Cole Eye Institute, Cleveland Clinic, Cleveland (AU, SKS, RPS, AVR, PKK, JLR, JPE).

Presented at the ARVO Annual Meeting, May 7–11, 2017.

Supported by the Betty J. Powers Retina Research Fellowship (AU); an unrestricted travel grant from Alcon Novartis Hida Memorial Award 2015 funded by Alcon Japan Ltd. (AU); NIH/NEI K23-EY022947-01A1 (JPE); and Research to Prevent Blindness (Cole Eye Institutional Grant).

Dr. Srivastava has received grants from Allergan, has a patent through Bioptigen/Leica, and has received personal fees from Zeiss, Bausch + Lomb, and Santen outside the submitted work. Dr. Singh has received personal fees from Zeiss, Genentech, Regeneron, and Alcon outside the submitted work. Dr. Rachitskaya has received personal fees from Allergan outside the submitted work. Dr. Kaiser has received personal fees from Zeiss, Regeneron, Alcon, Novartis, Bayer, Neurotech, Bausch + Lomb, and Topcon outside the submitted work. Dr. Ehlers reports grants from the NIH during the conduct of the study, in addition to personal fees from Leica, Aerpio, and Allegro; grants and personal fees from Novartis, Alcon, Thrombogenics, Genentech; and grants from Regeneron outside the submitted work. The remaining authors report no relevant financial disclosures.

Dr. Singh did not participate in the editorial review of this manuscript.

Address correspondence to Justis P. Ehlers, MD, Norman C. and Donna L. Harbert Endowed Chair for Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, 9500 Euclid Ave/i32, Cleveland, OH 44195; email: ehlersj@ccf.org.

Received: March 24, 2019
Accepted: July 29, 2019

10.3928/23258160-20191211-03

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