Interaction between genetics and the adherence to the Mediterranean diet: the risk for age-related macular degeneration. Coimbra Eye Study Report 8.

BACKGROUND: Age-related macular degeneration (AMD) is a multifactorial degenerative disease of the macula. Different factors, environmental, genetic and lifestyle, contribute to its onset and progression. However, how they interconnect to promote the disease, or its progression, is still unclear. With this work, we aim to assess the interaction of the genetic risk for AMD and the adherence to the Mediterranean diet in the Coimbra Eye Study. METHODS: Enrolled subjects (n = 612) underwent ophthalmological exams and answered a food questionnaire. Adherence to the Mediterranean diet was assessed with mediSCORE. An overall value was calculated for each participant, ranging from 0 to 9, using the sum of 9 food groups, and a cut off value of ≥ 6 was considered high adherence. Rotterdam Classification was used for grading. Participants' genotyping was performed in collaboration with The European Eye Epidemiology Consortium. The genetic risk score (GRS) was calculated for each participant considering the number of alleles at each variant and their effect size. Interaction was assessed with additive and multiplicative models, adjusted for age, sex, physical exercise, and smoking. RESULTS: The AMD risk was reduced by 60% in subjects with high adherence to the Mediterranean diet compared to subjects with low adherence to the Mediterranean diet. Combined effects of having low adherence to the Mediterranean diet and high GRS led to almost a 5-fold increase in the risk for AMD, compared to low GRS and high adherence to the Mediterranean diet. The multiplicative scale suggested a multiplicative interaction, although not statistically significant [odds ratio (OR) = 1.111, 95% CI 0.346-3.569, P = 0.859]. The additive model showed a causal positive effect of the interaction of GRS and adherence to the Mediterranean diet: relative excess risk due to interaction (RERI) = 150.9%, (95% CI: - 0.414 to 3.432, P = 0.062), attributable proportion due to interaction (AP) = 0.326 (95% CI: - 0.074 to 0.726, P = 0.055) and synergy index (SI) = 1.713 (95% CI: 0.098-3.329, P = 0.019). High GRS people benefited from adhering to the Mediterranean diet with a 60% risk reduction. For low-GRS subjects, a risk reduction was also seen, but not significantly. CONCLUSIONS: Genetics and Mediterranean diet interact to protect against AMD, proving there is an interplay between genetics and environmental factors. TRIAL REGISTRATION: The AMD Incidence (NCT02748824) and Lifestyle and Food Habits Questionnaire in the Portuguese Population Aged 55 or More (NCT01715870) studies are registered at www. CLINICALTRIALS: gov . Five-year Incidence of Age-related Macular Degeneration in the Central Region of Portugal (AMD IncidencePT); NCT02748824: date of registration: 22/04/16. Lifestyle and Food Habits Questionnaire in the Portuguese Population Aged 55 or More; NCT01715870: date of registration: 29/10/12.

Common and rare genetic risk variants in age-related macular degeneration and genetic risk score in the Coimbra eye study.

PURPOSE: To determine the contribution of common and rare genetic variants in age-related macular degeneration (AMD) in a Portuguese population from the Coimbra Eye Study (CES), and the genetic risk score (GRS). METHODS: Participants underwent ophthalmologic examination and imaging. A centralized reading centre performed AMD staging. Genetic sequencing was carried out with the EYE-RISK assay. Sixty-nine single nucleotide polymorphisms (SNPs) were genotyped and tested for association with AMD. Case-control and progression-to-AMD analyses were performed using logistic regression to assess allelic odds ratio (OR) at a 95% confidence interval (CI) for each variant. GRS was calculated for cases/controls and progressors/non-progressors. Cumulative impact of rare variants was compared between cases/controls using logistic regression. RESULTS: In case-control analysis (237 cases/640 controls) variants associated with risk of disease were: ARMS2 rs10490924, ARMS2_HTRA1 rs3750846, CFH rs35292876, SLC16A8 rs8135665, TGFBR1 rs1626340. Major risk variants ARMS2/HTRA1 rs3750846, CFH rs570618 and C3 rs2230199 had unexpected lower allele frequency (AF), and the highest risk-conferring variant was a rare variant, CFH rs35292876 (OR, 2.668; p-value = 0.021). In progression-to-AMD analysis (137 progressors/630 non-progressors), variants associated with risk of progression were ARMS2 rs10490924, ARMS2_HTRA1 rs3750846, CFH rs35292876. GRS of cases/controls was 1.124 ± 1.187 and 0.645 ± 1.124 (p-value < 0.001), and of progressors/non-progressors was 1.190 ± 1.178 and 0.669 ± 1.141 (p-value < 0.001). Higher proportion of pathogenic rare CFH variants was observed in cases (OR, 9.661; p-value < 0.001). CONCLUSIONS: Both common and rare variants were associated with AMD, but a CFH rare variant conferred the highest risk of disease while three major risk variants had a lower-than-expected AF in our population originary from a geographic region with lower prevalence of AMD. GRS was still significantly higher in AMD patients. Damaging CFH rare variants were cumulatively more common in AMD cases.

Phenotypic Expression of CFH Rare Variants in Age-Related Macular Degeneration Patients in the Coimbra Eye Study.

Purpose: To determine the association between rare genetic variants in complement factor H (CFH) and phenotypic features in age-related macular degeneration (AMD) patients from the Coimbra Eye Study (CES). Methods: AMD patients from the Incidence CES (NCT02748824) underwent ophthalmologic examination and color fundus photography, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence, and near-infrared imaging. Multimodal phenotypic characterization was carried out in a centralized reading center. The coding and splice-site regions of the CFH gene were sequenced through single-molecule molecular inversion probe-based next-generation sequencing in association with the EYE-RISK consortium. Variants with minor allele frequency <0.05 resulting in splice-site or protein change were selected. Differences in phenotypic features between carriers and noncarriers were analyzed using generalized estimated equations logistic regression models, considering intereye correlations. Results: We included 39 eyes of 23 patients carrying rare CFH variants and 284 eyes of 188 noncarriers. Carrier status was associated with having higher drusen burden in the macula in the inner Early Treatment Diabetic Retinopathy Study circle (odds ratio [OR], 5.44 [95% confidence interval {CI}, 1.61-18.37]; P = 0.006), outer circle (OR, 4.37 [95% CI, 1.07-17.77]; P = 0.04), and full grid (OR, 4.82 [95% CI, 1.13-20.52]; P = 0.033). In SD-OCT, a lower total macular volume and lower inner retinal layers' volume (OR, 0.449 [95% CI, 0.226-0.894]; P = 0.023; OR, 0.496 [95% CI, 0.252-0.979]; P = 0.043) and pigment epithelial detachments (PEDs) (OR, 5.24 [95% CI, 1.08-25.44]; P = 0.04) were associated with carrying a rare CFH variant. Carriers with subretinal drusenoid deposits (SDD) had the rare variant P258L in all cases except one. Conclusions: We identified in our cohort phenotypic differences between carriers and noncarriers of rare variants in the CFH gene. Carriers had more severe disease, namely superior drusen burden, PEDs, and thinner retinas. The rare variant P258L may be associated with SDD. Carriers are probably at increased risk of progression.

Retinal layer thicknesses and neurodegeneration in early age-related macular degeneration: insights from the Coimbra Eye Study.

PURPOSE: This study aims to analyze the retinal layers and choroidal thickness in a large set of eyes with early age-related macular degeneration (AMD), in order to detect differences by stage suggestive of early neurodegeneration, and to explore biomarkers of different phenotypes. METHODS: This study is a population-based, cross-sectional study. Patients from the incidence AMD study (NCT02748824) with early AMD (Rotterdam 2a, 2b, 3) were included. All performed spectral-domain optical coherence tomography (SD-OCT) (Spectralis, Heidelberg Engineering, Germany) and automatic segmentation of all retinal layers was obtained with built-in software. Manual correction was performed whenever necessary. The mean thicknesses (ETDRS grid) and volume of each layer were recorded. Subfoveal choroidal thickness was manually measured. Estimates for each layer thickness were calculated with linear mixed models and tested for pairwise differences between stages. Associations between layer thickness and microstructural findings were assessed by multivariate regression analysis. RESULTS: The final cohort comprised 346 eyes (233 patients): 82.66% (n = 286) in stage 2a, 5.49% (n = 19) in stage 2b, and 11.85% (n = 41) in stage 3. A global tendency for lower/inferior thickness of the neuroretinal layers was found comparing stage 3 to 2a: retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL) were inferior in the inner/outer ETDRS circles and the outer nuclear layer (ONL) and photoreceptors' segments layer in the central circle (p ≤ 0.002). The retinal pigment epithelium-Bruch's membrane (RPE/BrM) layer was thicker in stage 3 (p ≤ 0.001). Subretinal drusenoid deposits (SDD) were associated with thinner neuroretinal layers and choroid (p < 0.05). CONCLUSIONS: Our results showed in a large population-based dataset that several inner and outer neuroretinal layers were thinner with a higher stage in early AMD. These findings support the existence of early and progressive neurodegeneration. Neuronal retinal layer thicknesses might thus be used as quantitative biomarkers of disease progression in AMD. The presence of SDD is possibly associated to more prominent and faster neurodegeneration.

Non-exudative macular neovascularization in pseudoxanthoma elasticum.

PURPOSE: To characterize morphological changes in the retina and to report the frequency and natural history of non-exudative macular neovascularization (MNV) in a cohort of pseudoxanthoma elasticum (PXE). METHODS: A single-center, retrospective study was complemented by a cross-sectional examination. Consecutive patients with a definitive genetic and/or clinical diagnosis of PXE, visiting our department between January 2019 and December 2019, and with a minimum follow-up of 6 months were recruited. Baseline data were retrieved from each patient file. Additionally, a cross-sectional examination comprising color fundus photography, spectral-domain optical coherence tomography (SD-OCT), OCT-Angiography (OCT-A), and fundus autofluorescence was performed. The presence of typical PXE-related findings, as well as related complications, was multimodally evaluated. The prevalence and natural history of non-exudative MNV were assessed. All images were graded by two independent graders. RESULTS: Forty-eight eyes from 24 patients (mean age 59.11 ± 18.14) with a median follow-up of 53.00 months were included. Angioid streaks and peau d'orange were observed in 46/48 and 42/48 eyes, while MNV was present in 75.00% of the cohort. The prevalence of non-exudative MNV was 33.33% (6/18). In the 2 eyes that developed exudation, time to conversion was 9.50 ± 4.95 months. No significant difference in visual acuity was found between eyes with non-exudative MNV and those with no signs of MNV. CONCLUSION: We have shown that non-exudative MNV is a frequent finding in PXE but the majority of eyes did not develop exudation during follow-up. Our results are a clear evidence of the utility of OCT-A in the management of PXE.

Age-Related Macular Degeneration Staging by Color Fundus Photography vs. Multimodal Imaging-Epidemiological Implications (The Coimbra Eye Study-Report 6).

Epidemiology of age-related macular degeneration (AMD) is based on staging systems relying on color fundus photography (CFP). We aim to compare AMD staging using CFP to multimodal imaging with optical coherence tomography (OCT), infra-red (IR), and fundus autofluorescence (FAF), in a large cohort from the Epidemiologic AMD Coimbra Eye Study. All imaging exams from the participants of this population-based study were classified by a central reading center. CFP images were graded according to the International Classification and Grading System for AMD and staged with Rotterdam classification. Afterward, CFP images were reviewed with OCT, IR, and FAF and stage update was performed if necessary. Early and late AMD prevalence was compared in a total of 1616 included subjects. In CFP-based grading, the prevalence was 14.11% for early AMD (n = 228) and 1.05% (n = 17) for late AMD, nine cases (0.56%) had neovascular AMD (nAMD) and eight (0.50%) geographic atrophy (GA). Using multimodal grading, the prevalence increased to 14.60% for early AMD (n = 236) and 1.61% (n = 26) for late AMD, with 14 cases (0.87%) of nAMD and 12 (0.74%) of GA. AMD staging was more accurate with the multimodal approach and this was especially relevant for late AMD. We propose that multimodal imaging should be adopted in the future to better estimate and compare epidemiological data in different populations.

Incidence of Age-Related Macular Degeneration in the Central Region of Portugal: The Coimbra Eye Study - Report 5.

PURPOSE: To describe the 6.5-year incidence and progression of age-related macular degeneration (AMD) in a coastal town of central Portugal. METHODS: Population-based cohort study. Participants underwent standardized interviews and ophthalmological examination. Color fundus photographs were graded according to the International Classification and Grading System for AMD and ARM. The crude and age-standardized incidence of early and late AMD was calculated, and progression was analyzed. RESULTS: The 6.5-year cumulative incidence of early AMD was 10.7%, and of late AMD it was 0.8%. The incidence of early AMD was 7.2, 13.1 and 17.7% for participants aged 55-64, 65-74 and 75-84 years (p < 0.001). The late AMD incidence was 0.3, 0.9 and 2.8% for the corresponding age groups (p = 0.003). The age-standardized incidence was 10.8% (95% CI, 10.74-10.80%) for early and 1.0% (95% CI, 1.00-1.02%) for late AMD. The incidence of both neovascular AMD and geographic atrophy was 0.4%. Progression occurred in 17.2% of patients. CONCLUSION: The early AMD incidence in a coastal town of central Portugal was found to be similar to that of major epidemiological studies of European-descent populations; however, the incidence of late AMD was lower, and further analysis on risk factors will be conducted.

The Decreasing Prevalence of Nonrefractive Visual Impairment in Older Europeans: A Meta-analysis of Published and Unpublished Data.

TOPIC: To estimate the prevalence of nonrefractive visual impairment and blindness in European persons 55 years of age and older. CLINICAL RELEVANCE: Few visual impairment and blindness prevalence estimates are available for the European population. In addition, many of the data collected in European population-based studies currently are unpublished and have not been included in previous estimates. METHODS: Fourteen European population-based studies participating in the European Eye Epidemiology Consortium (n = 70 723) were included. Each study provided nonrefractive visual impairment and blindness prevalence estimates stratified by age (10-year strata) and gender. Nonrefractive visual impairment and blindness were defined as best-corrected visual acuity worse than 20/60 and 20/400 in the better eye, respectively. Using random effects meta-analysis, prevalence rates were estimated according to age, gender, geographical area, and period (1991-2006 and 2007-2012). Because no data were available for Central and Eastern Europe, population projections for numbers of affected people were estimated using Eurostat population estimates for European high-income countries in 2000 and 2010. RESULTS: The age-standardized prevalence of nonrefractive visual impairment in people 55 years of age or older decreased from 2.22% (95% confidence interval [CI], 1.34-3.10) from 1991 through 2006 to 0.92% (95% CI, 0.42-1.42) from 2007 through 2012. It strongly increased with age in both periods (up to 15.69% and 4.39% in participants 85 years of age or older from 1991 through 2006 and from 2007 through 2012, respectively). Age-standardized prevalence of visual impairment tended to be higher in women than men from 1991 through 2006 (2.67% vs. 1.88%), but not from 2007 through 2012 (0.87% vs. 0.88%). No differences were observed between northern, western, and southern regions of Europe. The projected numbers of affected older inhabitants in European high-income countries decreased from 2.5 million affected individuals in 2000 to 1.2 million in 2010. Of those, 584 000 were blind in 2000, in comparison with 170 000 who were blind in 2010. CONCLUSIONS: Despite the increase in the European older population, our study indicated that the number of visually impaired people has decreased in European high-income countries in the last 20 years. This may be the result of major improvements in eye care and prevention, the decreasing prevalence of eye diseases, or both.

Changes in reticular pseudodrusen area in eyes that progressed from early to late age-related macular degeneration.

OBJECTIVE: This retrospective cohort study utilized 3 imaging modalities to analyze quantitatively reticular pseudodrusen (RPD) area changes in eyes that progressed from early to late age-related macular degeneration (AMD). METHODS: Subjects with AMD, unilateral choroidal neovascularization (CNV), and early AMD with RPD in the fellow eye (the study eye) were included. The study eyes underwent indocyanine green angiography (ICGA), near-infrared reflectance (NIR-R), and short-wavelength autofluorescence (AF) imaging of the macula at baseline and at follow-up. Study eyes were analyzed for RPD and for the development of late AMD-CNV and/or geographic atrophy (GA). RPD area was measured at baseline and at follow-up as a percentage of the 30-degree field. RESULTS: During the study period (mean follow-up time 23.5 ± 5.0 months), 12/31 study eyes developed CNV and 4/31 developed GA. In the eyes that developed CNV, there was a statistically significant decrease in mean RPD area over the follow-up period as seen on AF (P < 0.01) and NIR-R (P = 0.01), and the decrease in mean RPD area approached statistical significance on ICGA (P = 0.08). CONCLUSION: Using 3 en face imaging techniques, we demonstrate that RPD undergo dynamic spatiotemporal changes in eyes that progress from early AMD to CNV, namely a decrease in the area of lesions detected.

Multimodal Evaluation of the Fellow Eye of Patients with Retinal Angiomatous Proliferation.

INTRODUCTION: We conducted a multimodal, cross-sectional evaluation. METHODS: Eyes were divided into 4 study groups: controls, early/intermediate age-related macular degeneration (AMD), fellow eyes of retinal angiomatous proliferation (RAP), and RAP eyes. Patients were evaluated with spectral-domain optical coherence tomography (OCT), enhanced depth imaging-OCT, and OCT angiography (OCTA). OCTA images were processed to generate maps of the vessel density and perfusion density of the superficial and deep retinal layers (SRL and DRL) and the choriocapillaris level (CL). The thickness of the outer nuclear layer and choroid was manually assessed. RESULTS: We included 135 eyes of 100 patients (51 controls, 30 AMD, 42 RAP, and 12 fellow eyes). The fellow eyes showed a significantly lower vascular perfusion of the SRL, DRL, and CL (p < 0.02) than the early/intermediate AMD and control eyes did. Similarly, RAP eyes presented a lower vascular perfusion of the DRL and CL (p < 0.05). Besides, structural analyses of the fellow eyes and RAP eyes revealed a significantly higher prevalence of macular pigmentary changes, atrophy of the retinal pigment epithelium, hyperreflective "clumps" above flat drusen, amongst others, than early/intermediate AMD and control eyes (p < 0.05). CONCLUSION: We present the first report on the OCTA analysis of the fellow eye of patients with RAP. The reduced perfusion density and vessel density observed contributes, in association with clearly defined structural changes, to a wider characterization of RAP as a distinctive phenotype.

Anterior Chamber Epithelial Cyst After Uneventful Deep Anterior Lamellar Keratoplasty.

PURPOSE: To report the case of an anterior chamber epithelial cyst after uncomplicated deep anterior lamellar keratoplasty (DALK) treated with a tissue-sparing surgical technique. METHODS: A 35-year-old female patient underwent DALK in her OS because of stage IV keratoconus. The surgery was uneventful, and 3 months postoperatively, best-corrected visual acuity (BCVA) was 20/25. By the sixth postoperative month, a cystic iris lesion was noticed. The lesion grew progressively larger, and BCVA dropped to 20/63 in OS. Cyst excision was performed. RESULTS: No complications possibly related to the surgery were observed. Two years later, BCVA was 20/25 in OS, and there were no signs of cyst recurrence. Histopathological examination of the lesion showed an epithelial implantation cyst. CONCLUSIONS: An anterior chamber epithelial cyst is a sight-threatening condition that may occur after DALK. In selected cases, a conservative surgical approach is an effective treatment option, conveying excellent functional and anatomical outcomes.

Efficacy and safety of postvitrectomy intravitreal triamcinolone therapy for diabetic macular edema.

PURPOSE: After vitrectomy, diffusion and clearance rates of numerous drugs are increased, leading to a shorter intravitreal half-life. This raises doubts about the efficacy of intravitreal therapies, as retina specialists generally believe that a shorter half-life compromises the drugs' therapeutic effect. We conducted a study to evaluate the functional and anatomical effect of intravitreal triamcinolone acetonide therapy (IVTA) in previously vitrectomized eyes with diabetic macular edema (DME). METHODS: In this retrospective, multicenter case series study including vitrectomized patients with DME who underwent IVTA injections, central macular thickness (CMT) measured with spectral-domain optical coherence tomography and best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study letters were evaluated after each procedure. All relevant medical data were collected, including previous ophthalmologic treatments and comorbidities. RESULTS: Twenty vitrectomized eyes of 20 patients, mean age 58.1 years (range 40-72 years), were enrolled in the study. All patients presented DME and received at least one IVTA injection. Mean time between pars plana vitrectomy and IVTA was 12.9 ± 8.7 months. Mean pretreatment and posttreatment CMT was 438.8 ± 90.8 µm and 301.2 ± 76.2 µm, respectively, a difference that reached statistical significance (p<0.001). Mean gain in BCVA letter score was 7.83 ± 14.9 letters after treatment (p = 0.039). Mean intraocular pressure was significantly increased after IVTA (17.2 ± 1.9 mm Hg at baseline vs 21.2 ± 4.59 mm Hg after IVTA, p = 0.002). CONCLUSIONS: A positive anatomical and functional effect was observed in our cohort. Our results suggest that, despite prior vitrectomy, triamcinolone remains a valid therapeutic approach for eyes with persistent DME. Further prospective randomized studies with larger patient samples are needed to validate this conclusion.

Sequential Morphological Changes in the CNV Net after Intravitreal Anti-VEGF Evaluated with OCT Angiography.

PURPOSE: To assess and describe sequential morphological changes in the choroidal neovascularization (CNV) net using optical coherence tomography angiography (OCTA) in patients undergoing treatment with intravitreal antivascular endothelial growth factor (VEGF). METHODS: Prospective cohort study. OCTA was performed sequentially: before (t0), 1 h (t1), 1 week (t2) and 1 month after the injection (t3), using Avanti RTVue XR equipped with the AngioVue® software (Optovue, Calif., USA). All images were classified by two independent graders. RESULTS: Ten eyes of 10 patients, with a mean age of 72.4 ± 10.5 years, were included. CNV morphology was described as tree-like in 5 eyes, glomerular in 1 and fragmented in 4. A fibrovascular capsule surrounding the CNV net was found in 4 eyes and a feeder trunk was noticed in 6. No changes were observed at t1. Loss of peripheral capillaries, vessel fragmentation and decreased vessel density were evident in 8 eyes at t2. The CNV capillary density and the peripheral anastomosis increased in all of these at t3. Two eyes remained unchanged through the whole length of follow-up. CONCLUSIONS: Significant changes in the CNV net can be observable in OCTA at least 1 week after intravitreal anti-VEGF. The safety of frequent examinations may provide a method of gauging treatment effects.

Treatment of Retinal Vein Occlusion with Ranibizumab in Clinical Practice: Longer-Term Results and Predictive Factors of Functional Outcome.

PURPOSE: To evaluate long-term results and predictors of efficacy in patients with macular edema due to retinal vein occlusion (RVO) treated with intravitreal ranibizumab in a clinical practice setting. METHODS: The clinical records of patients with a minimum follow-up of 3 years were retrospectively analyzed. Sixteen eyes with branch RVO (BRVO) and 16 with central RVO (CRVO) were included. All patients performed cross-sectional evaluation with best-corrected visual acuity (BCVA), spectral domain optical coherence tomography and fluorescein angiography. The foveal avascular zone (FAZ) was assessed and microstructural morphology of the retina was characterized. RESULTS: Follow- up was 42.9 ± 9.0 and 44.8 ± 8.0 months in the CRVO and BRVO groups, respectively. Patients with CRVO received on average 6.9 injections, with a final VA gain of 8.3 ± 15.0 letters (p = 0.05). BRVO eyes had on average 5.9 injections, with a final VA gain of 1.6 ± 21.0 letters (p > 0.05). The FAZ area remained stable in both groups (p > 0.05). Baseline BCVA and disruption of the retinal pigment epithelium (RPE) were predictors of final BCVA (p = 0.001 and 0.011, respectively). CONCLUSION: Although functional outcomes were inferior to those reported in clinical trials, ranibizumab was satisfactory in the long-term treatment of macular edema secondary to RVO and was not associated with increased macular ischemia. Final BCVA depends on baseline BCVA and RPE integrity.

Ocular Risk Factors for Exudative AMD: A Novel Semiautomated Grading System.

Purpose. To evaluate the contribution of the ocular risk factors in the conversion of the fellow eye of patients with unilateral exudative AMD, using a novel semiautomated grading system. Materials and Methods. Single-center, retrospective study including 89 consecutive patients with unilateral exudative AMD and ≥3 years of followup. Baseline color fundus photographs were graded using an innovative grading software, RetmarkerAMD (Critical Health SA). Results. The follow-up period was 60.9 ± 31.3 months. The occurrence of CNV was confirmed in 42 eyes (47.2%). The cumulative incidence of CNV was 23.6% at 2 years, 33.7% at 3 years, 39.3% at 5 years, and 47.2% at 10 years, with a mean annual incidence of 12.0% (95% CI = 0.088-0.162). The absolute number of drusen in the central 1000 and 3000 µ m (P < 0.05) and the absolute number of drusen ≥125 µm in the central 3000 and 6000 µm (P < 0.05) proved to be significant risk factors for CNV. Conclusion. The use of quantitative variables in the determination of the OR of developing CNV allowed the establishment of significant risk factors for neovascularization. The long follow-up period and the innovative methodology reinforce the value of our results. This trial is registered with ClinicalTrials.gov NCT00801541.