Extensive macular atrophy with pseudodrusen-like appearance: comprehensive review of the literature.

PURPOSE: This review focuses on extensive macular atrophy with pseudodrusen-like appearance (EMAP), a recently described maculopathy presenting with pseudodrusen-like lesions and chorioretinal atrophy more pronounced in the vertical axis. METHODS: Narrative review of the literature published until May 2024. RESULTS: The early onset age of EMAP (50-55 years) and its distinctive natural history, which includes night blindness followed by severe vision loss, differentiate it from atrophic age-related macular degeneration (AMD). A clear pathogenesis has not been determined, but risk factors include female gender and complement system abnormalities (altered levels of C3 and CH50). Moreover, lifelong exposure to pesticides has been suggested as risk factor for direct neuronal degeneration involving rods and cones. In the early phase of the disease, reticular pseudodrusen-like lesions appear in the superior perifovea and tend to coalescence horizontally into a flat, continuous, reflective material localized between the retinal pigmented epithelium and Bruch's membrane. Over time, EMAP causes profound RPE and outer retinal atrophy in the macular area, with a recent classification reporting a 3-stages evolution pattern. Blue autofluorescence showed rapidly evolving atrophy with either hyperautofluorescent or isoautofluorescent borders. Significant similarities between the diffuse-trickling phenotype of geographic atrophy and EMAP have been reported. Macular neovascularization is a possible complication. CONCLUSION: EMAP is specific form of early-onset atrophic macular degeneration with rapid evolution and no treatment. Further studies are needed to assess the best management.

Topographic analysis of local OCT biomarkers which predict progression to atrophy in age-related macular degeneration.

PURPOSE: To define optical coherence tomography (OCT) biomarkers that precede the development of complete retinal pigment epithelium and outer retinal atrophy (cRORA) at that location in eyes with age-related macular degeneration (AMD). METHODS: In this retrospective case-control study, patients with dry AMD who had evidence of cRORA and OCT data available for 4 years (48 ± 4 months) prior to the first visit with evidence of cRORA were included. The visit 4 years prior to the development of cRORA was defined as the baseline visit, and the region on the OCT B-scans of future cRORA development was termed the case region. A region in the same eye at the same distance from the foveal center as the case region that did not progress to cRORA was selected as the control region. OCT B-scans at the baseline visit through both the case and control regions were evaluated for the presence of soft and cuticular drusen, drusen with hyporeflective cores (hcD), drusenoid pigment epithelial detachments (PED), subretinal drusenoid deposits (SDD), thick and thin double-layer signs (DLS), intraretinal hyperreflective foci (IHRF), and acquired vitelliform lesions (AVL). RESULTS: A total of 57 eyes of 41 patients with dry AMD and evidence of cRORA were included. Mean time from the baseline visit to the first visit with cRORA was 44.7 ± 6.5 months. The presence of soft drusen, drusenoid PED, AVL, thin DLS, and IHRF at the baseline visit was all associated with a significantly increased risk of cRORA at that location. Multivariable logistic regression revealed that IHRF (OR, 8.559; p < 0.001), drusenoid PED (OR, 7.148; p = 0.001), and a thin DLS (OR, 3.483; p = 0.021) were independent predictors of development of cRORA at that location. CONCLUSIONS: IHRF, drusenoid PED, and thin DLS are all local risk factors for the development of cRORA at that same location. These findings would support the inclusion of these features within a more granular staging system defining specific steps in the progression from early AMD to atrophy.

Drusen in the macula and parapapillary region.

PURPOSE: To examine histological characteristics and differences between drusen beneath the retinal pigment epithelium (small hard drusen) located in the macula and located in the parapapillary region. METHODS: We histomorphometrically examined human eyes enucleated due to uveal melanomas or secondary angle-closure glaucoma. RESULTS: The study included 106 eyes (age, 62.6 ± 15.2 years) with macular drusen (n = 7 globes) or parapapillary drusen (n = 29 eyes) and 70 eyes without drusen. In all drusen, periodic-acid-Schiff-positive material was located between the RPE basal membrane and the inner collagenous layer of Bruch's membrane (BM). Macular drusen as compared with parapapillary drusen had lower height (15.2 ± 10.1 µm versus 34.3 ± 19.8 µm; P = 0.003), while both groups did not differ significantly in basal drusen width (74.0 ± 36.3 µm versus 108.7 ± 101.0 µm; P = 0.95). Eyes with macular drusen and eyes without drusen did not differ significantly in BM thickness (2.74 ± 0.44 µm versus 2.55 ± 0.88 µm; P = 0.57) or in RPE cell density (35.4 ± 10.4 cells/480 µm versus 32.8 ± 7.5 cells/480 µm; P = 0.53), neither in the drusen region nor in the drusen vicinity, while BM thickness (4.60 ± 1.490 µm; P < 0.001) and RPE cell density (56.9 ± 26.8 cells/480 µm; P = 0.005) were higher at the parapapillary drusen. Eyes with macular drusen, eyes with parapapillary drusen, and eyes without drusen did not differ significantly in choriocapillaris density (all P > 0.10) and thickness (all P > 0.35). Limitations of the study, among others, were a small number and size of drusen examined, diseases leading to enucleation, lack of serial sections, limited resolution of light microscopy, and enucleation-related and histological preparation-associated artefacts. CONCLUSIONS: The findings of this study, also taking into account its methodological limitations, suggest that macular drusen and parapapillary drusen shared the morphological feature of periodic-acid-Schiff-positive material between the RPE basal membrane and BM and that they did not vary significantly in choriocapillaris thickness and density. RPE cell density and BM thickness were higher in parapapillary drusen than in macular drusen.

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.

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.

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.

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.

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.

Topography of choriocapillaris flow deficit predicts development of neovascularization or atrophy in age-related macular degeneration.

PURPOSE: To evaluate the relationship between choriocapillaris (CC), flow deficits (FD), and structural optical coherence tomography (OCT) biomarkers, and the progression of intermediate age-related macular degeneration (iAMD) to complete retinal pigment epithelial and outer retinal atrophy (cRORA) or macular neovascularization (MNV). METHODS: Consecutive patients with iAMD were sequentially reviewed to define three equal sized groups: progressed to MNV, progressed to cRORA, or remained stable over 12 months of follow-up. Odds ratios for progression to cRORA and MNV were estimated by logistic regression for intraretinal hyperreflective foci (IHRF), hyporeflective drusen cores (hDC), subretinal drusenoid deposits (SDDs), high central drusen volume, fellow eye with late AMD, and peripheral and central CC FD. RESULTS: Thirty iAMD eyes from 30 patients were enrolled into each group. The CC FD was greater in the peripheral sectors of the macula of eyes which progressed to cRORA compared to the other two groups (P < 0.0001). The central CC FD was also significantly impaired in eyes that progressed to cRORA or MNV compared to eyes that did not progress (P = 0.001 and P = 0.02, respectively). CC FD in the peripheral macula was significantly and independently associated with the development of cRORA, while CC FD in the center was significantly and independently associated with the development of MNV. CONCLUSIONS: While the CC is diffusely impaired throughout the macula in iAMD eyes that progress to cRORA, it is relatively spared in the more peripheral macula among eyes which progress to MNV. These differential findings may have implications for the pathophysiology of the different late-stage manifestations of AMD.

Drusen ooze: Predictor for progression of dry age-related macular degeneration.

BACKGROUND: To evaluate natural history of drusen ooze and its role as a predictor for progression of dry age-related macular degeneration (AMD) longitudinally. METHODS: Multi-centric retrospective observational case series of 72 eyes (72 patients) with dry AMD with a minimum follow-up of 4 years. Drusen types were identified on volume scans on optical coherence tomography (OCT) and were characterized for occurrence of drusen ooze at baseline until last visit. Drusen ooze was defined as hyperreflective dots overlying a collapsing drusen or pseudodrusen, or hyperreflective RPE above drusen or isoreflective dots at the level of outer nuclear layer. The consequent incidence of incomplete retinal pigment epithelium and outer retinal atrophy (iRORA), complete retinal pigment epithelium and outer retinal atrophy (cRORA), and neovascular AMD (nAMD) were evaluated statistically. RESULTS: In total, 72 eyes with a mean follow-up of 68.89 (± 25.57 months) were studied. At presentation, 11 eyes (15.3%) had a single drusen type, whereas 61 eyes (84.7%) had mixed drusen. Reticular pseudodrusen were most common (84.7%) followed by soft drusen (66.6%). Drusen ooze was seen in 47 eyes (65.2%) at presentation. The presence of drusen ooze at baseline (p < 0.01) and baseline best corrected visual acuity (BCVA) (p = 0.04) significantly correlated with development of iRORA and cRORA. In total, 14 eyes progressed from iRORA to cRORA over a mean follow up of 29.14 (± 24.33) months. Odds of progression to iRORA or cRORA were 20.3 times greater for eyes with drusen ooze at baseline (95% C.I., 4.4-94.2). CONCLUSIONS: In dry AMD, drusen ooze is a useful sign for predicting progression to iRORA and cRORA over time.

Influence of vitrectomy on the progression of dry age-related macular degeneration.

PURPOSE: To demonstrate whether pars plana vitrectomy (PPV) changes the progression of dry age-related macular degeneration (AMD) by assessing longitudinal changes in drusen volume over follow-up. METHODS: Dry AMD patients who had undergone unilateral PPV for symptomatic vitreomacular disorders were evaluated for the progression of disease by spectral domain-optical coherence tomography (SD-OCT) features including drusen volume, development of geographic atrophy, or choroidal neovascularization during follow-up. Drusen volume was manually calculated using an image processing software (ImageJ, NIH) on raster SD-OCT scans. Mean change in drusen volume of surgery eyes was compared with values of the fellow eyes of the same subjects (control group). RESULTS: Among 183 eyes with both vitreoretinal disorder and dry AMD, 48 eyes of 24 patients met the inclusion criteria and were included. The mean drusen volume change during a mean of 25.49 ± 23.35 months of follow-up (range: 6.00-86.87 months) was 4.236.899 ± 20.488.913 µm3 in the study eye and 7.796.357 ± 34.798.519 µm3 in the fellow eye (p = 0.297). Best-corrected visual acuity (BCVA) significantly increased from 0.40 ± 0.18 logMAR (≈ 20/50 Snellen equivalent) to 0.32 ± 0.31 (≈ 20/41 Snellen equivalent) after surgery (p = 0.012) in the study group while BCVA remained stable in the control group (0.19 ± 0.34 logMAR [≈ 20/30 Snellen equivalent] at baseline and 0.20 ± 0.31 logMAR [≈ 20/31 Snellen equivalent], p = 0.432). Choroidal neovascularization developed in 1 vitrectomized eye (4.54%) and in 1 eye (4.54%) from the control group during follow-up. CONCLUSION: Vitrectomy did not seem to worsen dry AMD progression; even more visual acuity may improve despite a slight increase in drusen volume following surgery.

GANGLION CELL-INNER PLEXIFORM LAYER THICKNESS IN EYES WITH NONEXUDATIVE AGE-RELATED MACULAR DEGENERATION OF DIFFERENT DRUSEN SUBTYPES.

PURPOSE: We sought to investigate the ganglion cell-inner plexiform layer (GCIPL) thickness in eyes with nonexudative age-related macular degeneration. METHODS: We classified eyes into four categories-pachydrusen, soft drusen, subretinal drusenoid deposit (SDD), and soft drusen with SDD-and compared the baseline mean macular GCIPL thickness according to the Early Treatment Diabetic Retinopathy Study grid and its change between groups. RESULTS: We classified 53, 29, 36, and 34 eyes into the four categories, respectively. The mean GCIPL thickness values in the 3-mm area were 82.61 ± 9.54 µm for the pachydrusen group, 79.11 ± 10.26 µm for the soft drusen group, 77.72 ± 6.04 µm for the SDD group, and 71.63 ± 8.69 µm for the soft drusen with SDD group (P < 0.001). The soft drusen with the SDD group showed a greater change in GCIPL thickness (-2.50 ± 0.29 µm/year) in the 3-mm area as compared with the pachydrusen group (-0.18 ± 0.35 µm/year), soft drusen group (-0.55 ± 0.36 µm/year), and SDD group (-0.55 ± 0.37) (all P < 0.001). CONCLUSION: The GCIPL thickness varied according to the type of nonexudative age-related macular degeneration. The thinner baseline GCIPL and its greater change in eyes with soft drusen with SDD may suggest that these eyes are experiencing more prominent neuroretinal degeneration in the central 3-mm area than those in the other groups.

TOPOGRAPHIC ASSESSMENT OF CHORIOCAPILLARIS FLOW DEFICITS IN THE INTERMEDIATE AGE-RELATED MACULAR DEGENERATION EYES WITH HYPOREFLECTIVE CORES INSIDE DRUSEN.

PURPOSE: To evaluate the choriocapillaris (CC) flow deficit (FD) in eyes with hyporeflective cores (HCs) inside drusen in eyes with intermediate age-related macular degeneration. METHODS: Intermediate age-related macular degeneration subjects underwent optical coherence tomography and optical coherence tomography angiography using a Cirrus HD-optical coherence tomography (Carl Zeiss Meditec, Dublin, CA). All B-scans were inspected for the presence of drusen with an HC that was defined as dark, condense materials inside drusen. Drusen regions delineated in the manufactures advanced retinal pigment epithelium elevation map were superimposed to the compensated CC optical coherence tomography angiography images. Quantitative analysis of CC FD% was performed under drusen with and without HCs, 150-µm-wide ring region around drusen with and without HCs, drusen-free region, and whole macula. RESULTS: Fifty eyes were included in this cross-sectional study. Twenty eyes had drusen with HCs. Thirty eyes without HCs were matched for age and sex. The CC FD% of whole macula was significantly greater in eyes with an HC than those without it (46.3% vs. 42.9%; P = 0.001). In eyes with HCs, regional CC FD% was the greater under drusen (59.8%) and in a 150-µm-wide ring surrounding drusen with HCs (53.0%) than corresponding regions for drusen without HCs (52.5% and 47.3%, respectively) (P < 0.005 in all, Bonferroni correction). The CC FD% in macular regions remote from drusen was 43.2%. CONCLUSION: Intermediate age-related macular degeneration eyes with HCs demonstrated more impaired CC flow, compared with those without this featured. The CC was also more severely impaired directly below these drusen with HCs. These findings highlight that the appearance of HCs may be an indicator of a more advanced disease phenotype.

DRUSEN SUBTYPES AND CHOROIDAL CHARACTERISTICS IN ASIAN EYES WITH TYPICAL NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate the prevalence of pachydrusen, soft drusen, and subretinal drusenoid deposits in eyes with different neovascular age-related macular degeneration (nAMD) subtypes, determine the relationship between each drusen type and the choroidal thickness, and analyze the distinct features of each nAMD subtype according to the drusen type. METHODS: Medical records involving 454 eyes from 454 patients with nAMD were retrospectively reviewed. The prevalence of each drusen type and the choroidal thickness and choroidal characteristics were evaluated according to the nAMD subtype. RESULTS: Pachydrusen were prevalent in the typical nAMD (40.4%) and polypoidal choroidal vasculopathy (47.8%) groups and were not detected in the retinal angiomatous proliferation group. No significant drusen were detected in 24.3% of typical nAMD, 43.3% of polypoidal choroidal vasculopathy, and 0% of retinal angiomatous proliferation groups. Regardless of the nAMD subtype, pachydrusen, soft drusen, and subretinal drusenoid deposits were associated with a thick, moderately thick, and thin choroid, respectively. For eyes with typical nAMD, the prevalence of choroidal vascular hyperpermeability and extrafoveal neovascularization was significantly higher in the pachydrusen group than in the other groups. By contrast, the prevalence of Type 2 neovascularization was significantly lower in the pachydrusen group than in the subretinal drusenoid deposit group (P < 0.001 for all). CONCLUSION: The prevalence of various drusen differed according to the nAMD subtypes, and each drusen type was strongly associated with the choroidal thickness. Typical nAMD showed distinct features according to the accompanying drusen type.

SUBRETINAL DRUSENOID DEPOSIT IN AGE-RELATED MACULAR DEGENERATION: Histologic Insights Into Initiation, Progression to Atrophy, and Imaging.

PURPOSE: To clarify the role of subretinal drusenoid deposits (SDD; pseudodrusen) in the progression of age-related macular degeneration through high-resolution histology. METHODS: In 33 eyes of 32 donors (early age-related macular degeneration, n = 15; geographic atrophy, n = 9; neovascular age-related macular degeneration, n = 7; unremarkable, n = 2), and 2 eyes of 2 donors with in vivo multimodal imaging including optical coherence tomography, examples of SDD contacting photoreceptors were assessed. RESULTS: Subretinal drusenoid deposits were granular extracellular deposits at the apical retinal pigment epithelium (RPE); the smallest were 4-µm wide. Outer segment (OS) fragments and RPE organelles appeared in some larger deposits. A continuum of photoreceptor degeneration included OS disruption, intrusion into inner segments, and disturbance of neurosensory retina. In a transition to outer retinal atrophy, SDD appeared to shrink, OS disappeared, inner segment shortened, and the outer nuclear layer thinned and became gliotic. Stage 1 SDD on optical coherence tomography correlated with displaced OS. Confluent and disintegrating Stage 2 to 3 SDD on optical coherence tomography and dot pseudodrusen by color fundus photography correlated with confluent deposits and ectopic RPE. CONCLUSION: Subretinal drusenoid deposits may start at the RPE as granular, extracellular deposits. Photoreceptor OS, RPE organelles, and cell bodies may appear in some advanced deposits. A progression to atrophy associated with deposit diminution was confirmed. Findings support a biogenesis hypothesis of outer retinal lipid cycling.

MORPHOLOGIC FEATURES OF THE RETINAL PIGMENT EPITHELIUM AND ASSOCIATED CHORIORETINAL CHARACTERISTICS IN EYES WITH EARLY AGE-RELATED MACULAR DEGENERATION AND SUBRETINAL DRUSENOID DEPOSITS.

PURPOSE: To investigate the features of the retinal pigment epithelium (RPE) on optical coherence tomography in eyes with early age-related macular degeneration with subretinal drusenoid deposit. METHODS: We classified the eyes into three types: nonundulating RPE, undulating RPE, and wedge-shaped RPE. We compared the retinal vessel densities, retinal thickness, and choroidal thickness of a 3-mm-diameter zone. RESULTS: We classified 33, 27, and 20 as nonundulating RPE, undulating RPE, and wedge-shaped RPE eyes, respectively. The vascular densities of the superficial and deep capillary plexus showed differences; nonundulating RPE group (23.93 ± 2.26% and 23.54 ± 1.78%), undulating RPE group (22.29 ± 2.80% and 21.94 ± 2.42%), and wedge-shaped RPE group (21.93 ± 2.70% and 20.63 ± 2.42%, P = 0.010 and P < 0.001). The mean retinal thickness and choroidal thickness were also different, nonundulating RPE group (298.26 ± 13.81 µm and 180.08 ± 55.49 µm), undulating RPE group (285.29 ± 21.88 µm and 148.45 ± 55.08 µm), and wedge-shaped RPE group (274.86 ± 20.62 µm and 135.75 ± 39.77 µm) (P = 0.001 and P = 0.007). CONCLUSION: Altered features of the RPE on optical coherence tomography may indicate advancement in disease and be part of an overall degeneration process in these eyes.

CHOROIDAL THICKNESS AND VASCULARITY VARY WITH DISEASE SEVERITY AND SUBRETINAL DRUSENOID DEPOSIT PRESENCE IN NONADVANCED AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate how choroidal features vary with age-related macular degeneration (AMD) severity in early-intermediate disease. METHODS: One hundred fifty-one eyes of 151 participants >50 years with no to intermediate AMD were analyzed with enhanced depth imaging optical coherence tomography. Mean macular choroidal thickness (CT), choroidal vascular thickness (CV), and choroidal vascularity index (CVI) were determined, and statistical associations were calculated. RESULTS: Decreased CT and CV were associated with increased axial length (+30 and +14 µm/mm, respectively; P < 0.0001 each), whereas decreased CVI was associated with increased age (+0.1%/year; P = 0.004). Compared with eyes with no/early AMD (Group 0), eyes with large drusen without late AMD in the fellow eye (Group 1) showed increased CV and CVI (+22 µm, P = 0.03 and +2.2%, P = 0.02, respectively). However, eyes with large drusen and late AMD in the fellow eye (Group 2) resembled Group 0. Eyes with subretinal drusenoid deposits demonstrated lower mean CT/CV/CVI than Group 0 (-57 µm, P = 0.02; -31 µm, P = 0.02; -3.6%, P = 0.007). CONCLUSION: Early AMD progression seems associated with biphasic alterations in choroidal dimensions, increasing during early drusen formation but decreasing thereafter. Subretinal drusenoid deposits are independently associated with marked reductions in all choroidal parameters. Changes in choroidal vascular anatomy may drive or reflect the pathobiology of AMD progression.

CUTICULAR DRUSEN: Risk of Geographic Atrophy and Macular Neovascularization.

PURPOSE: Cuticular drusen (CD) have been associated with manifestations of age-related macular degeneration such as atrophy and neovascularization in the macula. In this study, eyes with CD were followed and investigated for the estimated 5-year risk of progression to sequelae of age-related macular degeneration such as geographic atrophy (GA) and macular neovascularization (MNV). METHODS: A consecutive series of patients with CD were followed for the development of GA and MNV. Whenever possible, they were also studied retrospectively. The patients with CD were categorized into three phenotypic groups. Phenotype 1: eyes had concentrated, densely populated CD in the macular and paramacular area, Phenotype 2: eyes showed scattered CD in the posterior fundus, and Phenotype 3: involved eyes with CD mixed with large drusen (>200 µm). The 5-year incidence of progression was then estimated using a Kaplan-Meier estimator. RESULTS: A total of 63 eyes from 38 patients (35 women with a mean age at presentation of 58.9 ± 14.2 years) were studied and followed for a mean of 40 ± 18 months. Thirteen patients had single eyes with GA (84.5%; 11/13) or MNV (15.5%; 2/13) in one eye at presentation and were subsequently excluded. Geographic atrophy developed in 19.0% (12/63) of eyes and MNV in 4.8% (3/63) of eyes. The cumulative estimated 5-year risk of GA and MNV was 28.4% and 8.7%, respectively. The estimated 5-year incidence of MNV or GA was 12.6%, 50.0%, and 51.6% in Phenotype 1, Phenotype 2, and Phenotype 3, respectively (P = 0.0015, log-rank test). No difference in risk was found in the development of GA or MNV (P = 0.11) between the subgroup of patients presenting with GA or MNV in their fellow eye and those with both eyes included. CONCLUSION: When patients with CD are followed longitudinally, there was a significant risk of progression to GA or MNV for Phenotype 2 and Phenotype 3. Patients with CD are commonly first diagnosed in the fifth decade of life, and there is a female predominance. Clinicians should use multimodal imaging to detect and be aware of the risk of progression to manifestations of GA and MNV. These risks of GA and MNV suggest that patients with CD may be part of the overall spectrum of age-related macular degeneration.

Drusen characteristics of type 2 macular neovascularization in age-related macular degeneration.

BACKGROUND: Type 2 macular neovascularization (MNV) is supposed to be a rare condition in age-related macular degeneration (AMD). The main purpose of this study was to assess accompanying factors of type 2 MNV in AMD. METHODS: Retrospective data analysis of eyes previously diagnosed with neovascular AMD in a tertiary eye care center (Medical Retina Unit, Rudolf Foundation Hospital, Vienna, Austria) between June 2008 and December 2017. Drusen subtypes, fibrosis, atrophy and subfoveal choroidal thickness (SFCT) of both eyes in patients with type 2 MNV lesions were categorized based on multimodal imaging. RESULTS: Type 2 MNV was diagnosed in 27 (3.2%) of 835 eyes (749 patients). Drusen characteristics in type 2 MNV were observed as followed: drusen < 63 µm in 2 eyes (7.4%), drusen ≥63 µm in 10 eyes (37%), subretinal drusenoid deposits (SDD) in 8 eyes (29.6%), cuticular drusen in 2 eye (7.4%) and no drusen were evident in 10 eyes (37%). Drusen distribution in 23 fellow eyes was detected as followed: drusen < 63 µm in 2 eyes (8.7%), drusen ≥63 µm in 9 eyes (39.1%), SDD in 5 eyes (21.7%), cuticular drusen in 1 eye (4.3%) and no drusen were evident in 9 eyes (39.1%). Mean SFCT was 140 ± 49 µm in affected eyes and 152 ± 41 µm in the fellow eyes. Patients with drusen or SDD were significantly younger (mean 70.88 ± 6.85, p = 0.04) than patients without deposits (mean 77.40 ± 5.74). CONCLUSIONS: Type 2 MNV remains a rare entity in AMD. It was frequently seen in the absence of drusen, a hallmark of AMD. These findings contribute to the heterogeneity of phenotypes related to pure type 2 lesions.