Advanced age-related macular degeneration and risk factors in eyes with pachydrusen.

The risk of progression to advanced age-related macular degeneration (AMD) varies depending on the type of drusen. This retrospective longitudinal study included 248 eyes of 156 patients with pachydrusen without advanced AMD at baseline. Macular neovascularization (MNV) and geographic atrophy (GA) were evaluated. Risk factors for progression to advanced AMD were determined using multivariate Cox regression analysis. The mean age at baseline was 65.4 ± 9.1 years, and the mean follow-up duration was 6.40 ± 3.58 years. The mean total number of pachydrusen and macular pachydrusen were 4.10 ± 2.85 and 2.27 ± 1.81 per eye, respectively. Pachydrusen was accompanied by other types of drusen in 4.8% (12 eyes) of eyes at baseline. During follow-up, MNVs occurred in 2.8% (seven eyes), including polypoidal choroidal vasculopathy (PCV six eyes); however, no GA occurred. Regarding risk factors for progression to neovascular AMD, age (p = 0.023) and macular pigmentary changes (p = 0.014) were significantly associated with MNV development. The cumulative incidence of MNV was significantly higher in the group with macular pigmentary changes (17.39% vs. 0.57% at 10 years; p = 0.0005). The number of macular pachydrusen and the presence of MNV in the fellow eye did not show a statistically significant relationship with MNV development. Age and macular pigmentary changes are risk factors for MNV development in the eyes with pachydrusen. Eyes with pachydrusen appear to have a risk profile for advanced AMD that is different from that of AMD eyes with drusen or drusenoid deposits other than pachydrusen.

Calpain-specific breakdown fragment in human drusen.

PURPOSE: With aging and age-related macular dystrophy (AMD), proteolytic fragments are deposited in extracellular drusen located between the RPE and Bruch's membrane. Localized hypoxia may be a risk factor for AMD. Our hypothesis is that following hypoxia, activation of proteolytic enzymes called calpains may cause proteolysis/degeneration of retinal cells and RPE. No direct evidence has yet demonstrated activation of calpains in AMD. The purpose of the present study was to identify calpain-cleaved proteins in drusen. METHODS: Seventy-six (76) drusen were analyzed in human eye sections from six normal and twelve AMD human donor eyes. The sections were subjected to immunofluorescence for the calpain-specific 150 kDa breakdown product from α-spectrin, SBDP150 - a marker for calpain activation, and for recoverin - a marker for photoreceptor cells. RESULTS: Among 29 nodular drusen, 80% from normal eyes and 90% from AMD eyes stained positive for SBDP150. Among 47 soft drusen, mostly from AMD eyes, 72% stained positive for SBDP150. Thus, the majority of both soft and nodular drusen from AMD donors contained SBDP150. CONCLUSIONS: SBDP150 was detected for the first time in soft and nodular drusen from human donors. Our results suggest that calpain-induced proteolysis participates in the degeneration of photoreceptors and/or RPE cells during aging and AMD. Calpain inhibitors may ameliorate AMD progression.

INFLAMMATORY CELL ACTIVITY IN TREATED NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Histologic Case Study.

BACKGROUND: Imaging indicators of macular neovascularization risk can help determine patient eligibility for new treatments for geographic atrophy secondary to age-related macular degeneration. Because type 1 macular neovascularization includes inflammation, we assessed by histology the distribution of cells with inflammatory potential in two fellow eyes with age-related macular degeneration. METHODS: Two eyes of a White woman in her 90's with type 3 macular neovascularization treated with antivascular endothelial growth factor were prepared for high-resolution histology. Eye-tracked spectral domain optical coherence tomography applied to the preserved donor eyes linked in vivo imaging to histology. Cells were enumerated in the intraretinal, subretinal, and subretinal retinal pigment epithelium (RPE)-basal lamina compartments on 199 glass slides. Cells with numerous organelles were considered to RPE-derived; cells with sparse RPE organelles were considered non-RPE phagocytes. RESULTS: Both eyes had soft drusen and abundant subretinal drusenoid deposit. In the retina and subretinal space, RPE-derived cells, including hyperreflective foci, were common (n = 125 and 73, respectively). Non-RPE phagocytes were infrequent (n = 5 in both). Over drusen, RPE morphology transitioned smoothly from the age-normal layer toward the top, suggesting transdifferentiation. The sub-RPE-basal lamina space had RPE-derived cells (n = 87) and non-RPE phagocytes (n = 49), including macrophages and giant cells. CONCLUSION: Numerous sub-RPE-basal lamina cells of several types are consistent with the documented presence of proinflammatory lipids in drusen and aged Bruch's membrane. The relatively compartmentalized abundance of infiltrating cells suggests that drusen contents are more inflammatory than subretinal drusenoid deposit, perhaps reflecting their environments. Ectopic RPE occurs frequently. Some manifest as hyperreflective foci. More cells may be visible as optical coherence tomography technologies evolve.

Hyperreflective foci distribution in eyes with dry age-related macular degeneration with subretinal drusenoid deposits.

PURPOSE: To investigate the distribution of hyperreflective foci (HRF) in eyes with dry age-related macular degeneration (AMD). METHODS: We retrospectively reviewed optical coherence tomography (OCT) images of 58 dry AMD eyes presenting HRF. The distribution of HRF according to the early treatment diabetic retinopathy study area was analyzed according to the presence of subretinal drusenoid deposits (SDDs). RESULTS: We classified 32 eyes and 26 eyes into the dry AMD with SDD group (SDD group) and dry AMD without SDD group (non-SDD group), respectively. The non-SDD group had higher prevalence and density of HRF at the fovea (65.4% and 1.71 ± 1.48) than the SDD group (37.5% and 0.48 ± 0.63, P = 0.035 and P < 0.001, respectively). However, the prevalence and density of HRF in the outer circle area of the SDD group (81.3% and 0.11 ± 0.09) were greater than those of the non-SDD group (53.8% and 0.05 ± 0.06, p = 0.025 and p = 0.004, respectively). The SDD group showed higher prevalence and mean densities of HRF in the superior and temporal area than in the non-SDD group (all, p < 0.05). CONCLUSION: HRF distributions in dry AMD varied according to the presence of SDDs. This might support that the degenerative features may be different between dry AMD eyes with and without SDDs.

PATTERN AND CHARACTERISTICS OF DRUSEN SUBTYPES IN CHINESE AND INDIAN POPULATIONS IN SINGAPORE.

PURPOSE: To report the pattern and characteristics of drusen subtypes in Asian populations and the association with choroidal thickness. METHODS: This is the cross-sectional analysis of the population-based cohort study. Two thousand three hundred and fifty-three eyes of 1,336 Chinese and Indian participants aged older than 50 years, eyes with best-corrected visual acuity better than 20/60, and without other retinal diseases were recruited. Pachydrusen, reticular pseudodrusen, soft and hard drusen were graded on both color fundus photographs, and optical coherence tomography imaging with automated segmentation yielding and measurements of choroidal thickness. RESULTS: Nine hundred and fifty-five Chinese and 381 Indians were included in the final analysis. The pattern of pachydrusen, soft drusen, hard drusen, and reticular pseudodrusen was 14.0%, 3.7%, 12.5%, and 0.2%, respectively. Mean choroidal thickness was the thickest in eyes with pachydrusen (298.3 µm; 95% confidence interval: 290.5-306.1), then eyes with hard (298.1 µm; 95% confidence interval: 290.6-305.5) and soft drusen (293.7 µm; 95% confidence interval: 281.9-305.4) and thinnest in eyes without drusen (284.6 µm; 95% confidence interval: 280.5-288.7). Systemic associations of the various drusen subtypes also differed. CONCLUSION: Patterns, characterization and choroidal thickness of drusen subtypes, and their associations provide insights into the Asian phenotypic spectrum of age-related macular degeneration and the underlying pathogenesis.

Early onset drusen and RPE dysfunction in a patient with NLRP3-AID.

Retinal pigment epithelium (RPE) dysfunction, manifested as drusen formation and RPE mottling, is a characteristic lesion of aging. The mechanism of RPE dysfunction remains unknown. Previous animal studies have proven that the activation of NLRP3 inflammasome in RPE leads to apoptosis and pyroptosis, which may play a very important role in the development of age-related macular degeneration (AMD). However, there is a lack of clinical evidence to support the above hypothesis. Herein, we report a 38-year-old Chinese Han woman who had NLRP3-associated autoinflammatory disease (NLRP3-AID) with widely scattered drusen at the posterior pole in both eyes. NLRP3-AID is a rare disease caused by mutations of the NLRP3 gene, leading to NLRP3 inflammasome activation. This report of early-onset drusen provides clinical evidence that the NLRP3 inflammasome might contribute to the occurrence of RPE dysfunction and is a potential cause of age-related macular degeneration (AMD).

Differentiating drusen and drusenoid deposits subtypes on multimodal imaging and risk of advanced age-related macular degeneration.

Drusen are extracellular material considered a precursor lesion to advanced age-related macular degeneration (AMD), located either on the retinal pigment epithelium (RPE) or the sub-RPE; they contain various proteins associated with inflammation and lipids. Previous studies suggest that the lifecycle of drusen varies depending on drusen type and size. In general, conventional drusen grow and aggregate/coalesce in the first stage, and in the second stage, they regress with or without showing RPE atrophy. The risk of advanced AMD also varies depending on the drusen and drusenoid deposit types' along with their size and RPE abnormalities. In eyes with macular neovascularization (MNV), specific drusen/drusenoid deposits are closely associated with the MNV subtype. Recently, pachychoroid-associated drusen (pachydrusen) were proposed and clinical findings regarding this entity have been accumulating, as more attention is focused on drusen as well as pachychoroid diseases. With the advance in imaging modalities, various modalities can show specific characteristics depending on drusen types. To assess the risk of advanced AMD, it is essential for physicians to have accurate clinical knowledge about each druse/drusenoid lesion and correctly evaluate its imaging characteristics using multimodal imaging. This review summarizes the latest clinical knowledge about each druse/drusenoid lesions and documents their imaging characteristics on multimodal imaging, allowing clinicians to better manage patients and stratify the risk of developing advanced AMD. The most representative cases are illustrated, which can be helpful in the differential diagnosis of drusen and drusenoid deposits.

BILATERAL MACULAR CHOROIDAL ABNORMALITIES WITH DRUSENOID DEPOSITS IN PATIENTS WITH UNILATERAL PERIPHERAL EXUDATIVE HEMORRHAGIC CHORIORETINOPATHY.

PURPOSE: To investigate bilateral macular features on optical coherence tomography in patients with unilateral peripheral exudative hemorrhagic chorioretinopathy (PEHCR). METHODS: In this cross-sectional study, optical coherence tomography features of affected eyes (PEHCR group, n = 30) and unaffected contralateral eyes (contralateral group, n = 30) were investigated. Age-matched and sex-matched patients with polypoidal choroidal vasculopathy (PCV group, n = 51) and healthy controls (normal group, n = 50) were included to compare choroidal thickness, measured at six points apart from the fovea, with the PEHCR group. RESULTS: Subretinal drusenoid deposits were the most common feature in the PEHCR (20%) and contralateral (23%) groups, followed by soft drusen. Although the macular choroid was comparably thin in both the PEHCR and contralateral groups, pachyvessels were also observed. The choroids of the PEHCR group were significantly thinner than those of the normal group at the subfovea and 1-mm temporal to the fovea and considerably thinner than those of the polypoidal choroidal vasculopathy group from 3-mm nasal to 3-mm temporal to the fovea. CONCLUSION: In patients with unilateral PEHCR, bilateral choroidal thinning and drusenoid deposit accumulation were noted in the macula. The pathophysiology of PEHCR may be a rare peripheral complication of age-related macular degeneration with pathologic choroid.

Increased retinal drusen in IgA glomerulonephritis are further evidence for complement activation in disease pathogenesis.

Drusen are retinal deposits comprising cell debris, immune material and complement that are characteristic of macular degeneration but also found in glomerulonephritis. This was a pilot cross-sectional study to determine how often drusen occurred in IgA glomerulonephritis and their clinical significance. Study participants underwent non-mydriatic retinal photography, and their deidentified retinal images were examined for drusen by two trained graders, who compared central drusen counts, counts ≥ 10 and drusen size with those of matched controls. The cohort comprised 122 individuals with IgA glomerulonephritis including 89 males (73%), 49 individuals (40%) of East Asian or Southern European ancestry, with an overall median age of 54 years (34-64), and median disease duration of 9 years (4-17). Thirty-nine (33%) had an eGFR < 60 ml/min/1.73 m2 and 72 had previously reached kidney failure (61%). Overall mean drusen counts were higher in IgA glomerulonephritis (9 ± 27) than controls (2 ± 7, p < 0.001). Central counts ≥ 10 were also more common (OR = 3.31 (1.42-7.73, p = 0.006), and were associated with longer disease duration (p = 0.03) but not kidney failure (p = 0.31). Larger drusen were associated with more mesangial IgA staining (p = 0.004). Increased drusen counts were also present in IgA glomerulonephritis secondary to Crohn's disease but not with Henoch-Schonlein purpura. The finding of retinal drusen in IgA glomerulonephritis is consistent with complement activation and represents a model for better understanding glomerular immune deposition and a supporting argument for treatment with anti-complement therapies.

Retinal drusen counts are increased in inflammatory bowel disease, and with longer disease duration, more complications and associated IgA glomerulonephritis.

Retinal drusen are deposits of inflammatory proteins that are found in macular degeneration and glomerulonephritis and result, in part, from complement activation. This was a cross-sectional observational study of individuals with inflammatory bowel disease (IBD) recruited from a Gastroenterology clinic who underwent non-mydriatic retinal photography. Deidentified images were examined for drusen, and drusen counts and size were compared with matched controls, and examined for clinical associations. The cohort with IBD comprised 19 individuals with ulcerative colitis, 41 with Crohn's disease and three with indeterminate colitis, including 34 males (54%) and an overall median age of 48 (IQR 23) years. Their median IBD duration was 7 (IQR 10) years, median CRP level was 7 (IQR 14) mg/L, and 28 (44%) had complications (fistula, stricture, bowel resection etc.), while 28 with Crohn's disease (68%) had colonic involvement. Drusen counts were higher in IBD than controls (12 ± 34, 3 ± 8 respectively, p = 0.04). Counts ≥ 10 were also more common (14, 22%, and 4, 6%, p = 0.02, OR 4.21, 95%CI 1.30 to 13.63), and associated with longer disease duration (p = 0.01, OR 1.06, 95%CI 1.00 to 1.13), an increased likelihood of complications (p = 0.003, OR 6.90, 95%CI 1.69 to 28.15) and higher CRP levels at recruitment (p = 0.008, OR1.02, 95%CI 1.00 to 1.05). Increased retinal drusen were found in all four individuals with Crohn's disease and IgA glomerulonephritis. IBD and drusen may share pathogenetic mechanisms and underlying risk factors such as complement activation.

Heritability and Risk Factors of Incident Small and Large Drusen in the Copenhagen Twin Cohort Eye Study: A 20-Year Follow-Up.

INTRODUCTION: The transition from a normal fundus to one with early drusen (≥20 small hard drusen) to age-related macular degeneration (AMD) in the form of drusen ≥63 µm in diameter is of interest, because small hard drusen may be precursors of large drusen. Study of AMD precursor lesions may provide valuable insight into factors that initiate AMD. Here, the progression of drusen was studied over an interval of 20 years in a population-based twin cohort. METHODS: Single-center, 20-year follow-up of 138 twins include biometry, fundus optical coherence tomography, and fundus photography. Macular characteristics were hierarchically classified as (per eye) (1) <20 small hard drusen, (2) ≥20 small hard drusen, (3) drusen ≥63 µm, or (4) ≥20 small hard drusen combined with drusen ≥63 µm. Additive and dominant genetic effects as well as shared and nonshared environmental effects were analyzed in a bivariate biprobit model with a classic liability-threshold approach and polygenic modeling with random effects. RESULTS: Median participant age was 59 (range 41-66) years. Of 25 (18%) cases of incident macular drusen, 7 had ≥20 small hard drusen, and 18 had drusen ≥63 µm at follow-up, whereas no participant had developed both traits simultaneously. Smoking was associated with incident ≥20 small hard drusen (p = 0.04) and incident drusen ≥63 µm (p = 0.003). Having ≥20 small hard drusen at baseline was associated with incident drusen ≥63 µm at follow-up (p = 0.02). Development of drusen ≥63 µm was attributable to 49% genetic effects and 51% environmental effects. CONCLUSION: The risk of progressing from 0 to 19 small hard macular drusen per eye to having ≥20 small hard drusen or drusen ≥63 µm at follow-up was associated with smoking and genetic predisposition. Having ≥20 small hard drusen in the absence of drusen ≥63 µm at baseline was associated with incident drusen ≥63 µm when examined 20 years later. The study confirms that small hard macular drusen is a forewarning of AMD and that progression to AMD may be hindered by avoidance of smoking.

Natural History of the Relative Ellipsoid Zone Reflectivity in Age-Related Macular Degeneration.

PURPOSE: Relative ellipsoid zone reflectivity (rEZR) has been reported to be reduced in intermediate age-related macular degeneration (iAMD). However, longitudinal changes in rEZR remain unknown. This study investigated the natural history of rEZR in iAMD and its association with risk factors for disease progression, including the presence or extent of drusen volume, reticular pseudodrusen (RPD), and pigmentary abnormalities (PAs). DESIGN: Longitudinal observational study. PARTICIPANTS: Subjects with bilateral large drusen. METHODS: Spectral-domain (SD) OCT images of both eyes from each participant were obtained every 6 months for 3 years. Using an automated rEZR determination approach, the average rEZR of the central 20° macula was determined for each SD-OCT volume scan. Linear mixed models were used to determine the rate of change in rEZR with age (using the cross-sectional data at baseline) and over time (longitudinal data) and the interactions between the rate of rEZR changes with AMD risk factors at baseline. MAIN OUTCOME MEASURES: Relative ellipsoid zone reflectivity and its rate of change with age and over time. RESULTS: A total of 280 eyes from 140 individuals with bilateral large drusen were included in this study. Cross-sectional data showed that rEZR reduced with increasing age (-8.4 arbitrary units [AUs] per decade; 95% confidence interval [CI], -11.5 to -5.2; P < 0.001). Longitudinal data showed that, on average, rEZR declined at a rate of -2.1 AU per year (95% CI, -2.6 to -1.6 AU per year; P < 0.001). Larger RPD area (P = 0.042) at baseline was associated with a faster rate of rEZR decline over time, whereas the presence of PAs and the drusen volume at baseline showed no significant association with rEZR decline over time (P = 0.068 and P = 0.529, respectively). CONCLUSIONS: The rEZR significantly reduces over 3 years in subjects with iAMD, and both the presence and increasing extent of coexistent RPD at baseline are associated with a faster rate of decline. These findings warrant further studies to understand the value of rEZR as a biomarker of AMD progression.

Incidence and risk of advanced age-related macular degeneration in eyes with drusenoid pigment epithelial detachment.

To investigate the incidence and risk of advanced age-related macular degeneration (AMD), including geographic atrophy (GA) and macular neovascularization (MNV), in eyes with drusenoid pigment epithelial detachment (PED). Eighty-five eyes with drusenoid PED from 85 patients (77.2 ± 7.0 years, male/female: 44/41) were included in this study. Patients were followed up every 1-3 months via spectral-domain optical coherence tomography (SD-OCT) and color fundus photography. If exudation was observed on SD-OCT, fluorescein and indocyanine green angiography were performed to confirm the MNV subtype accordingly. The maximum follow-up period was 60 months. During the study period, GA developed in 8 eyes while MNV also developed in 8 eyes. The Kaplan-Meier estimator revealed that the cumulative incidence for 60 months was 17.9% and 12.2% for GA and MNV, respectively. In eyes developing MNV, retinal angiomatous proliferation was the most common. Cox regression analysis revealed that baseline PED width was the only factor associated with advanced AMD. (p = 0.0026, Cox regression analysis). The 5-year cumulative incidence of advanced AMD, including GA and MNV, was approximately 30% in eyes with drusenoid PED among the Japanese elderly. A larger baseline PED width was the only risk factor for advanced AMD.

Subretinal Drusenoid Deposit Formation: Insights From Turing Patterns.

PURPOSE: The purpose of this study was to demonstrate that the organized formation of subretinal drusenoid deposits (SDDs) may be a Turing pattern. METHODS: A Java-based computational model of an inferred reaction-diffusion system using paired partial differential equations was used to create topographic images. Reaction kinetics were varied to illustrate a spectrum of pattern development, which were then compared to dot-like, reticular, and confluent SDD patterns observed clinically. RESULTS: A reaction-diffusion system using two agents, one an "activator" that increases its own production, and the other an "inhibitor" that decreases the activator's production, can create patterns that match the spectrum of topographic appearance of organized SDD. By varying a single parameter, the strength of the activator, the full spectrum of clinically observed SDD patterns can be generated. A new pattern, confluence with holes, is predicted and identified in one case example. CONCLUSIONS: The formation of clinically significant SDD and its different patterns can be explained using Turing patterns obtained by simulating a two-component reaction-diffusion system. TRANSLATIONAL RELEVANCE: This model may be able to guide future risk stratification for patients with SDD, and provide mechanistic insights into the cause of the disease.

MULTIMODAL ASSESSMENTS OF DRUSENOID PIGMENT EPITHELIAL DETACHMENTS IN THE AGE-RELATED EYE DISEASE STUDY 2 ANCILLARY SPECTRAL-DOMAIN OPTICAL COHERENCE TOMOGRAPHY STUDY COHORT.

PURPOSE: To identify features correlating with drusenoid pigment epithelial detachment (DPED) progression in the Age-Related Eye Disease Study 2 Ancillary spectral-domain optical coherence tomography study cohort. METHODS: In this retrospective analysis of a prospective longitudinal study, eyes with intermediate age-related macular degeneration and DPEDs were followed longitudinally with annual multimodal imaging. RESULTS: Thirty-one eyes of 25 participants (mean age 72.6 years) in the Age-Related Eye Disease Study 2 Ancillary spectral-domain OCT substudy (A2A study) had DPED identified in color fundus images. Spectral-domain optical coherence tomography inspection confirmed a subretinal pigment epithelium drusenoid elevation of ≥433 µm diameter in 25 eyes (80.6%). Twenty-four of these eyes were followed longitudinally (median 4.0 years), during which 7 eyes (29.2%) underwent DPED collapse (with 3/7 further progressing to geographic atrophy), 6 (25.0%) developing neovascular age-related macular degeneration, and 11 (45.8%) maintaining DPED persistence without late age-related macular degeneration. On Kaplan-Meier analysis, mean time to DPED collapse was 3.9 years. Both DPED collapse and progression to neovascular age-related macular degeneration were preceded by the presence of hyperreflective foci over the DPED. CONCLUSION: The natural history of DPED comprises collapse (sometimes followed by the development of atrophy), vascularization followed by exudation, or DPED persistence. Spectral-domain optical coherence tomography can confirm retinal pigment epithelial elevation caused by drusenoid accumulation and facilitate the identification of high-risk features that correlate with progression.

Hyporeflective Cores within Drusen: Association with Progression of Age-Related Macular Degeneration and Impact on Visual Sensitivity.

PURPOSE: To examine the association between hyporeflective cores within drusen (HCD) and disease progression in age-related macular degeneration (AMD) and with visual function. DESIGN: Longitudinal observational study. PARTICIPANTS: Two hundred and eighty eyes from 140 participants with bilateral large drusen, without late AMD. METHODS: Multimodal imaging and microperimetry were performed at baseline and subsequently every 6 months for up to 3 years. Baseline OCT scans were graded for the presence of HCD and used to calculate drusen volume. The total area of the drusenoid lesions containing hyporeflective cores (HCD extent) on color fundus photographs (CFPs) was calculated. CFPs were also graded for the presence of pigmentary abnormalities. The association between HCD extent with progression to late AMD (including OCT signs of atrophy) and visual sensitivity measured using microperimetry at baseline and its rate of change over time was evaluated with and without adjustment for confounders of drusen volume, pigmentary abnormalities, and age. MAIN OUTCOME MEASURES: Time to develop late AMD and visual sensitivity. RESULTS: Twenty (7%) eyes from 12 (9%) individuals were found to have HCD at baseline, which was associated with a nonsignificantly increased rate of progression to late AMD (unadjusted P = 0.050). HCD extent was significantly associated with an increased rate of progression to late AMD (unadjusted P = 0.034) and lower visual sensitivity at baseline (unadjusted P < 0.001). However, these associations were no longer significant (P ≥ 0.264 for both) after adjusting for known risk factors for AMD progression. HCD extent was also not associated with a faster rate of visual sensitivity decline before the development of late AMD, with or without adjustment (P ≥ 0.674 for both). Increasing age and larger drusen volume were associated with HCD extent (P ≤ 0.041). CONCLUSIONS: In a cohort with bilateral large drusen, HCD presence and extent were not independently associated with an increased rate of progression to late AMD over 3 years, nor with lower visual sensitivity or an increased rate of visual sensitivity decline before the development of late AMD, after adjusting for known risk factors for disease progression.