Prevalence and determinants of subretinal drusenoid deposits in patients' first-degree relatives.

PURPOSE: Subretinal drusenoid deposits (SDDs) are distinct extracellular alteration anterior to the retinal pigment epithelium (RPE). Given their commonly uniform phenotype, a hereditary predisposition seems likely. Hence, we aim to investigate prevalence and determinants in patients' first-degree relatives. METHODS: We recruited SDD outpatients at their visits to our clinic and invited their relatives. We performed a full ophthalmic examination including spectral domain-optical coherence tomography (SD-OCT) and graded presence, disease stage of SDD as well as percentage of infrared (IR) en face area affected by SDD. Moreover, we performed genetic sequencing and calculated a polygenic risk score (PRS) for AMD. We conducted multivariable regression models to assess potential determinants of SDD and associations of SDD with PRS. RESULTS: We included 195 participants, 123 patients (mean age 81.4 ± 7.2 years) and 72 relatives (mean age 52.2 ± 14.2 years), of which 7 presented SDD, resulting in a prevalence of 9.7%. We found older age to be associated with SDD presence and area in the total cohort and a borderline association of higher body mass index (BMI) with SDD presence in the relatives. Individuals with SDD tended to have a higher PRS, which, however, was not statistically significant in the multivariable regression. CONCLUSION: Our study indicates a potential hereditary aspect of SDD and confirms the strong association with age. Based on our results, relatives of SDD patients ought to be closely monitored for retinal alterations, particularly at an older age. Further longitudinal studies with larger sample size and older relatives are needed to confirm or refute our findings.

Geographic Atrophy-associated Intraretinal Neovascularization (GAIN): A novel clinical entity.

KEY MESSAGES     : WHAT IS KNOWN : Geographic atrophy could be associated with MNV or other vascular alterations. Intraretinal fluid could be present in GA also without neovascularization. WHAT IS NEW : GAIN is a novel clinical entity characterized by GA and an intraretinal neovascular network. GAIN could be exudative or non-exudative.

Optical coherence tomography biomarkers in early and intermediate age-related macular degeneration: A clinical guide.

Advanced forms of age-related macular degeneration (AMD), characterised by atrophic and neovascular changes, are a leading cause of vision loss in the elderly population worldwide. Prior to the development of advanced AMD, a myriad of risk factors from the early and intermediate stages of AMD have been published in the scientific literature over the last years. The ability to precisely recognise structural and anatomical changes in the ageing macula, altogether with the understanding of the individual risk implications of each one of them is key for an accurate and personalised diagnostic assessment. The present review aims to summarise updated evidence of the relative risk conferred by diverse macular signs, commonly seen on optical coherence tomography, in terms of progression to geographic atrophy or macular neovascularization. This information may also serve as a basis for tailored follow-up monitoring visits.

In vivo cone-photoreceptor density comparison between eyes with subretinal drusenoid deposits and healthy eyes using high magnification imaging.

PURPOSE: To compare photoreceptor density automated quantification in eyes with subretinal drusenoid deposits (SDD) and healthy controls using Heidelberg Spectralis High Magnification Module (HMM) imaging. METHODS: Twelve eyes of 6 patients with intermediate AMD, presenting with SDD were included, as well as twelve eyes of healthy controls. Individual dot SDD within the central 30° retina were examined with infrared confocal laser ophthalmoscopy, HMM, and spectral-domain optical coherence tomography (SD-OCT). Photoreceptor density analysis was performed on the best-quality image using the ImageJ Foci Picker plugin, after the removal of SDD from the HMM image. Correlations were made between the HMM quantified photoreceptor density, SD-OCT characteristics, stage, and number of SDD. RESULTS: Mean age was 75.17 ± 2.51 years in the SDD group (3 males, 3 females) versus 73.17 ± 3.15 years in the healthy control group (p = 0.2). Defects in the overlying ellipsoid zone were present on SD-OCT in 8/12 (66.66%) eyes. The mean ± standard deviation foci detected (i.e., cone photoreceptors) was 7123.75 ± 3683.32 foci/mm2 in the SDD group versus 13,253 ± 3331.00 foci/mm2 in the healthy control group (p = 0.0003). The number of SDD was associated with a reduction in foci density, p = 0.0055, r = - 0.7622. CONCLUSION: The decreased cone density in eyes with SDD may correlate with a decrease in retinal function in intermediate AMD eyes independent of neovascular complications or outer retinal pigment epithelial atrophy.

Reticular Pseudodrusen: The Third Macular Risk Feature for Progression to Late Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report 30.

PURPOSE: To analyze reticular pseudodrusen (RPD) as an independent risk factor for progression to late age-related macular degeneration (AMD), alongside traditional macular risk factors (soft drusen and pigmentary abnormalities) considered simultaneously. DESIGN: Post hoc analysis of 2 clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2. PARTICIPANTS: Eyes with no late AMD at baseline in AREDS (6959 eyes, 3780 participants) and AREDS2 (3355 eyes, 2056 participants). METHODS: Color fundus photographs (CFPs) from annual visits were graded for soft drusen, pigmentary abnormalities, and late AMD. Presence of RPD was from grading of fundus autofluorescence images (AREDS2) and deep learning grading of CFPs (AREDS). Proportional hazards regression analyses were performed, considering AREDS AMD severity scales (modified simplified severity scale [person] and 9-step scale [eye]) and RPD presence simultaneously. MAIN OUTCOME MEASURES: Progression to late AMD, geographic atrophy (GA), and neovascular AMD. RESULTS: In AREDS, for late AMD analyses by person, in a model considering the simplified severity scale simultaneously, RPD presence was associated with a higher risk of progression: hazard ratio (HR), 2.15 (95% confidence interval [CI], 1.75-2.64). However, the risk associated with RPD presence differed at different severity scale levels: HR, 3.23 (95% CI, 1.60-6.51), HR, 3.81 (95% CI, 2.38-6.10), HR, 2.28 (95% CI, 1.59-3.27), and HR, 1.64 (95% CI, 1.20-2.24), at levels 0-1, 2, 3, and 4, respectively. Considering the 9-step scale (by eye), RPD presence was associated with higher risk: HR, 2.54 (95% CI, 2.07-3.13). The HRs were 5.11 (95% CI, 3.93-6.66) at levels 1-6 and 1.78 (95% CI, 1.43-2.22) at levels 7 and 8. In AREDS2, by person, RPD presence was not associated with higher risk: HR, 1.18 (95% CI, 0.90-1.56); by eye, it was HR, 1.57 (95% CI, 1.31-1.89). In both cohorts, RPD presence carried a higher risk for GA than neovascular AMD. CONCLUSIONS: Reticular pseudodrusen represent an important risk factor for progression to late AMD, particularly GA. However, the added risk varies markedly by severity level, with highly increased risk at lower/moderate levels and less increased risk at higher levels. Reticular pseudodrusen status should be included in updated AMD classification systems, risk calculators, and clinical trials.

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.

Age-Related Macular Degeneration: Epidemiology and Clinical Aspects.

Age-related macular degeneration (AMD) is a degenerative disease of the human retina affecting individuals over the age of 55 years. This heterogeneous condition arises from a complex interplay between age, genetics, and environmental factors including smoking and diet. It is the leading cause of blindness in industrialized countries. Worldwide, the number of people with AMD is predicted to increase from 196 million in 2020 to 288 million by 2040. By this time, Asia is predicted to have the largest number of people with the disease. Distinct patterns of AMD prevalence and phenotype are seen between geographical areas that are not explained fully by disparities in population structures. AMD is classified into early, intermediate, and late stages. The early and intermediate stages, when visual symptoms are typically absent or mild, are characterized by macular deposits (drusen) and pigmentary abnormalities. Through risk prediction calculators, grading these features helps predict the risk of progression to late AMD. Late AMD is divided into neovascular and atrophic forms, though these can coexist. The defining lesions are macular neovascularization and geographic atrophy, respectively. At this stage, visual symptoms are often severe and irreversible, and can comprise profoundly decreased central vision in both eyes. For these reasons, the condition has major implications for individuals and society, as affected individuals may experience substantially decreased quality of life and independence. Recent advances in retinal imaging have led to the recognition of an expanded set of AMD phenotypes, including reticular pseudodrusen, nonexudative macular neovascularization, and subtypes of atrophy. These developments may lead to refinements in current classification systems.

Subtype-differentiated impacts of subretinal drusenoid deposits on photoreceptors revealed by adaptive optics scanning laser ophthalmoscopy.

PURPOSE: To examine the structure of photoreceptors surrounding two subtypes of subretinal drusenoid deposits (SDD), namely, dot and ribbon SDD, using multimodal imaging including adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral-domain optical coherence tomography (SD-OCT). METHODS: Twenty-six eyes of 13 patients with age-related macular degeneration (AMD) and SDD and 16 eyes of 8 subjects in normal chorioretinal health were studied. SDD presence, stage, and subtype were determined using color fundus photographs, infrared reflectance, autofluorescence imaging, and SD-OCT. SDD and surrounding photoreceptors were imaged using AOSLO. The structure of cone photoreceptors and SDD was examined at the baseline and at 2-year follow-up studies in 6 patients. RESULTS: Dot SDD were identified in 18 eyes of 9 patients and coexisting dot and ribbon SDD were observed in 8 eyes of 4 patients. While a characteristic photoreceptor mosaic was clearly revealed by AOSLO in the area unaffected by lesions in those eyes with dot-only SDD, in unaffected areas adjacent to retinal regions with predominantly ribbon SDD, photoreceptors could no longer be visualized. CONCLUSION: The invisibility of the photoreceptor mosaic in unaffected areas adjacent to retinal regions with predominantly ribbon SDD suggests degeneration in the outer segment and the interdigitation zone, which impairs the waveguiding ability of the photoreceptors. Our study implies possible differentiation of disease outcome and functional impact in different types of SDD.

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.

Natural course of adult-onset vitelliform lesions in eyes with and without comorbid subretinal drusenoid deposits.

PURPOSE: Adult vitelliform lesions (AVL) are associated with age related macular degeneration (AMD) and subretinal drusenoid deposits (SRDD). We evaluated the natural course of AVL, assessing the influence of SRDD on disease progression, visual function and incidence of macular atrophy (MA) and choroidal neovascular membranes (CNVM). METHODS: A retrospective cohort study was conducted between January 2011 and March 2016. Demographic, clinical and imaging data from 26 consecutive AVL patients were analysed following case note review. Optical coherence tomography images were graded for SRDD and patients divided into those with/without SRDD. Outcomes included presenting/changes in best corrected visual acuity (BCVA) and incidence of MA/CNVM. RESULTS: Mean age was 78.6 ± 7.6 years. Mean follow-up was 51.5 ± 25.6 months. Twelve patients (46.2%) had SRDD at presentation with 3 more (11.5%) developing them. Subjects with SRDD were older (mean 81.7 ± 6.1 years vs 74.3 ± 7.6 years, p = 0.010). Mean presenting BCVA was worse in SRDD eyes (0.39 ± 0.31 logMAR vs 0.19 ± 0.18 logMAR, p = 0.017). Eight of 15 patients with SRDD (53.3%) developed incident MA or CNVM; higher than those with no SRDD (1/11, 9.1%; p = 0.036). Two patients (7.7%) developed full thickness macular holes. CONCLUSIONS: Patients with AVL and SRDD likely represent an advanced pathological stage or phenotype with worse visual outcome and higher risk of MA/CNVM. Possible overlap with AMD exists. Follow-up, counselling and provisions for early detection/treatment of complications should be made. Better classification including improved understanding of phenotypic and genetic variations with reference to comorbid diseases including AMD is required. Presence of SRDD in AVL offers a dichotomous classification, indicating risk of future MA/CNVM formation.

Novel clinical findings in autosomal recessive NR2E3-related retinal dystrophy.

PURPOSE: To evaluate the clinical phenotype of autosomal recessive NR2E3-related retinal dystrophy. METHODS: We retrospectively studied 11 patients carrying out at least 2 NR2E3 mutations; they had undergone comprehensive ophthalmological examination, fundus photography, optical coherence tomography, electrophysiological testing, and visual field at the Regional Reference Center for Hereditary Retinal Degenerations of the Eye Clinic in Florence. RESULTS: Five females and six males with a diagnosis of NR2E3-related retinal dystrophy were included in the study. All patients complained of nyctalopia. Visual acuity ranged from 0.00 logMAR to hand motion. Two patients presented bull's eye maculopathy, and one of these was characterized by a triple hyper-autofluorescent ring at the fundus autofluorescence examination. Three patients showed small yellowish dots and spots at the mid-periphery. One patient was characterized by widespread subretinal drusenoid deposits (SDD) at the posterior pole. Four patients showed vitreous abnormalities. Optical coherence tomography (OCT) examinations detected variable degrees of abnormal retinal lamination and schitic changes. Seven patients were compound heterozygous and four were homozygous for mutations in NR2E3. CONCLUSIONS: Our study confirmed high variable phenotype in autosomal recessive NR2E3-related retinal dystrophy. Bull's eye maculopathy, subretinal drusenoid deposits, and foveal hypoplasia represent novel clinical findings in NR2E3-related retinal dystrophy. Macular involvement was detectable in all the patients, and the abnormal foveal avascular zone (FAZ) supports the role of NR2E3 in retinal development.

Directional ABCA1-mediated cholesterol efflux and apoB-lipoprotein secretion in the retinal pigment epithelium.

Cholesterol-containing soft drusen and subretinal drusenoid deposits (SDDs) occur at the basolateral and apical side of the retinal pigment epithelium (RPE), respectively, in the chorioretina and are independent risk factors for late age-related macular degeneration (AMD). Cholesterol in these deposits could originate from the RPE as nascent HDL or apoB-lipoprotein. We characterized cholesterol efflux and apoB-lipoprotein secretion in RPE cells. Human RPE cells, ARPE-19, formed nascent HDL that was similar in physicochemical properties to nascent HDL formed by other cell types. In highly polarized primary human fetal RPE (phfRPE) monolayers grown in low-lipid conditions, cholesterol efflux to HDL was moderately directional to the apical side and much stronger than ABCA1-mediated efflux to apoA-I at both sides; ABCA1-mediated efflux was weak and equivalent between the two sides. Feeding phfRPE monolayers with oxidized or acetylated LDL increased intracellular levels of free and esterified cholesterol and substantially raised ABCA1-mediated cholesterol efflux at the apical side. phfRPE monolayers secreted apoB-lipoprotein preferentially to the apical side in low-lipid and oxidized LDL-feeding conditions. These findings together with evidence from human genetics and AMD pathology suggest that RPE-generated HDL may contribute lipid to SDDs.

Retinal dystrophy and subretinal drusenoid deposits in female choroideremia carriers.

PURPOSE: To describe clinical and molecular characteristics in a group of Italian female choroideremia (CHM) carriers and report fundus patterns. METHODS: We retrospectively studied 11 female carriers belonging to six CHM families examined at the Regional Reference Center for Hereditary Retinal Degenerations at the Eye Clinic in Florence. We took into consideration patients with a comprehensive ophthalmological examination, fundus photography, optical coherence tomography (OCT), full field electro-retinography (ERG), and visual field (VF). All patients were screened for mutations of the CHM gene. RESULTS: Fundus examination revealed retinal abnormalities in all female carriers (11/11) in the study; in particular four fundus patterns were identified: pattern A (RPE dystrophy involving only the peripheral retina), pattern B (RPE dystrophy involving the peripheral retina and the posterior pole with small hypo-pigmented RPE areas), pattern C (RPE dystrophy involving the peripheral retina and the posterior pole with small yellowish well-defined dots), and pattern D (RPE dystrophy involving the peripheral retina and the posterior pole with large hypo-pigmented RPE areas and well-defined yellowish dots). Pattern D was characterized by widespread macular subretinal drusenoid deposits (SDD). Half of the observed mutations were novel mutations. A genotype-phenotype correlation was not identified. CONCLUSIONS: Retinal dystrophy and SDD were detected in our female CHM carriers, and fundus patterns have been described in this study. The recognition of specific fundoscopic patterns may permit a correct diagnosis, an appropriate molecular investigation and genetic counseling.

Exploring choriocapillaris under reticular pseudodrusen using OCT-Angiography.

PURPOSE: To evaluate if choriocapillaris (CC) vessel density and CC decorrelation signal index are compromised in eyes with reticular pseudodrusen (RPD) using optical coherence tomography angiography (OCT-A). METHODS: Decorrelation values in OCT-A CC images of 20 RPD patients were measured in the outer superior and the outer inferior sector of the EDTRS grid and compared to age-matched healthy controls. CC vessel density and CC decorrelation signal index were measured within a 30 µm and a 10 µm OCT-A CC slab. CC data were correlated to number of RPD lesions, predominantly present RPD stage, predominantly present RPD type, retinal area affected by RPD and choroidal thickness (CT). RESULTS: CC vessel density and CC decorrelation signal index decreased in correlation to advancing age in healthy subjects particularly in subjects older than 60 years (CC vessel density: 30 µm: p=0.0019; 10 µm: p=0.0014; CC decorrelation signal index: 30 µm: p=0.0005; 10 µm: p=0.0003). In the RPD group, CC vessel density (outer superior sector, 10 µm: 98.299) and CC decorrelation signal index (89.07) were significantly reduced compared to controls (99.203, p=0.0002; 98.09, p=0.0010). The number of RPD lesions was correlated to a reduced CC vessel density (30 µm: p=0.0355) but not to changes in CC decorrelation signal index. No correlations were found between CC parameters and either RPD stage, RPD type, size of RPD affected area or CT. CONCLUSIONS: OCT-A reveals a distinct reduction in CC vessel density and CC decorrelation signal index in eyes affected by RPD, which emphasizes the relevance of the CC layer in RPD pathogenesis.

Characteristics of Vitamin A Deficiency Retinopathy at a Tertiary Referral Center in the United States.

PURPOSE: To explore the risk factors and fundus imaging features of vitamin A deficiency retinopathy (VADR) in an academic tertiary referral center in Atlanta, GA, United States, and to propose guidance regarding diagnostic workup and management of affected patients. DESIGN: Single-center retrospective case series. SUBJECTS: Nine patients seen between 2015 and 2021 at the Emory Eye Center diagnosed with VADR. METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: Baseline serum retinol level, Snellen visual acuity, multimodal fundus imaging findings, and electroretinography findings. RESULTS: Nine patients, 4 (44.4%) female, with a median (range) age of 68 (50-75) years were identified. The most common underlying etiologies for vitamin A deficiency included history of gastrointestinal surgery (55.6%), liver disease (44.4%), and nutritional depletion due to low-quality diet (44.4%). Only 1 (11.1%) patient had a history of bariatric surgery. Four (44.4%) patients were on some form of vitamin A supplementation before the diagnosis of VADR. Median (range) serum retinol level was 0.06 (< 0.06-0.19) mg/L. All patients had macular subretinal hyperreflective deposits resembling subretinal drusenoid deposits, although in some cases, these were scant and sparsely distributed. Six eyes of 3 patients with longstanding deficiency had defects in the external limiting membrane (ELM). Three of these eyes additionally had macular areas of complete retinal pigment epithelium and outer retinal atrophy (cRORA). Full-field electroretinography demonstrated severe rod dysfunction and mild to moderate cone system dysfunction. Many findings of VADR were reversible with vitamin A repletion. However, all eyes with ELM defects or cRORA had persistence or continued growth of these lesions. CONCLUSION: Vitamin A deficiency retinopathy is uncommon in the developed world. However, given that early intervention can lead to dramatic visual improvement and avoid potentially permanent retinal damage, retina specialists should be familiar with its clinical presentation. The presence of nyctalopia and subretinal hyperreflective deposits in a patient with a history of gastrointestinal surgery, liver disease, and/or poor diet can be suggestive of this diagnosis, even in the presence of ongoing vitamin A supplementation. Vitamin A supplementation can vary in route and dosage and can be tailored to the individual with serial testing of serum retinol. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Pachy-Reticular Pseudodrusen.

PURPOSE: To characterize the features of a peculiar association between reticular pseudodrusen (RPD) and pachychoroid (pachy-RPD) and to compare them with eyes affected by RPD and normal/leptochoroid. DESIGN: Observational, retrospective, case-control study. PARTICIPANTS: Among a cohort of patients with intermediate age-related macular degeneration (AMD), we selected eyes with RPD and pachychoroid (i.e., choroidal thickness of >50 µm). A control group of RPD eyes but without pachychoroid (i.e., a choroidal thickness of <250 µm) was included. METHODS: Number and stages of RPD were evaluated in each ETDRS subfield. Furthermore, choroidal perfusion was investigated using the choroidal vascularity index (CVI), and choriocapillaris perfusion density (PD) on structural OCT and OCT angiography. MAIN OUTCOME MEASURES: Description of the multimodal imaging features of pachy-RPD and differences with RPD associated with normal/leptochoroid. RESULTS: Among 111 RPD eyes, 37 were included in the pachy-RPD group and 74 in the control group. Patients with pachy-RPD were significantly younger than patients with RPD and normal/leptochoroid (mean age, 75 ± 16 and 82 ± 7 years, respectively; P = 0.002). Total RPD number was comparable between the 2 groups (P = 0.220). However, pachy-RPD eyes showed a significantly higher number of stage 1 RPD in comparison to the controls (P < 0.001), and a lower number of stage 3 (P < 0.001) and stage 4 RPD (P = 0.052). The CVI and choriocapillaris PD were greater in pachy-RPD than in the control group (P < 0.001 and P= 0.010, respectively). CONCLUSIONS: Pachy-RPD are characterized by a different distribution of RPD stages (i.e., more early stages and fewer advanced stages) in comparison to RPD with normal/leptochoroid. Furthermore, pachy-RPD eyes showed greater perfusion indices of the choroid. These features suggest that the presence of pachychoroid could be a protective factor in the RPD evolution to the advanced AMD forms. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

[Use of artificial intelligence for recognition of biomarkers in intermediate age-related macular degeneration]. / Einsatz von künstlicher Intelligenz zur Erkennung von Biomarkern bei der intermediären altersabhängigen Makuladegeneration.

Advances in imaging and artificial intelligence (AI) have revolutionized the detection, quantification and monitoring for the clinical assessment of intermediate age-related macular degeneration (iAMD). The iAMD incorporates a broad spectrum of manifestations, which range from individual small drusen, hyperpigmentation, hypopigmentation up to early stages of geographical atrophy. Current high-resolution imaging technologies enable an accurate detection and description of anatomical features, such as drusen volumes, hyperreflexive foci and photoreceptor degeneration, which are risk factors that are decisive for prediction of the course of the disease; however, the manual annotation of these features in complex optical coherence tomography (OCT) scans is impractical for the routine clinical practice and research. In this context AI provides a solution by fully automatic segmentation and therefore delivers exact, reproducible and quantitative analyses of AMD-related biomarkers. Furthermore, the application of AI in iAMD facilitates the risk assessment and the development of structural endpoints for new forms of treatment. For example, the quantitative analysis of drusen volume and hyperreflective foci with AI algorithms has shown a correlation with the progression of the disease. These technological advances therefore improve not only the diagnostic precision but also support future targeted treatment strategies and contribute to the prioritized target of personalized medicine in the diagnostics and treatment of AMD.

Retro Mode Imaging for Detection and Quantification of Sub-RPE Drusen and Subretinal Drusenoid Deposits in Age-Related Macular Degeneration.

Background: Drusen and drusenoid deposits are a hallmark of age-related macular degeneration (AMD). Nowadays, a multimodal retinal imaging approach enables the detection of these deposits. However, quantitative data on subretinal drusenoid deposits (SDDs) are still missing. Here, we compare the capability of en-face drusen and SDD area detection in eyes with non-exudative AMD using conventional imaging modalities versus Retro mode imaging. We also quantitatively assess the topographic distribution of drusen and SDDs. Methods: In total, 120 eyes of 90 subjects (mean age ± standard deviation = 74.6 ± 8.6 years) were included. Coherent en-face drusen and SDD areas were measured via near-infrared reflectance, green (G-) and blue (B-) fundus autofluorescence (AF), and Retro mode imaging. Drusen phenotypes were classified by correlating en-face drusen areas using structural high-resolution spectral domain optical coherence tomography. The topographic distribution of drusen was analyzed according to a modified ETDRS (Early Treatment of Diabetic Retinopathy Study) grid. Intraclass correlation coefficient (ICC) analysis was applied to determine the inter-reader agreement in the SDD en-face area assessment. Results: The largest coherent en-face drusen area was found using Retro mode imaging with a mean area of 105.2 ± 45.9 mm2 (deviated left mode (DL)) and 105.4 ± 45.5 mm2 (deviated right mode (DR)). The smallest en-face drusen areas were determined by GAF (50.9 ± 42.6 mm2) and BAF imaging (49.1 ± 42.9 mm2) (p < 0.001). The inter-reader agreement for SDD en-face areas ranged from 0.93 (DR) to 0.70 (BAF). The topographic analysis revealed the highest number of SDDs in the superior peripheral retina, whereas sub-retinal pigment epithelium drusen were mostly found in the perifoveal retina. Retro mode imaging further enabled the detection of the earliest SDD stages. Conclusions: Retro mode imaging allows for a detailed detection of drusen phenotypes. While hundreds/thousands of SDDs can be present in one eye, the impact of SDD number or volume on AMD progression still needs to be evaluated. However, this new imaging modality can add important knowledge on drusen development and the pathophysiology of AMD.

Hyperautofluorescent material inside areas of macular atrophy may reveal non-lipofuscin fluorophores in late stage AMD.

PURPOSE: To characterize fundus autofluorescence (FAF) in complete (cRORA) and incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) by fluorescence lifetime imaging ophthalmology (FLIO). METHODS: Overall, 98 macular atrophy (MA) lesions in 42 eyes of 37 age-related macular degeneration (AMD) patients (mean age: 80.9 ± 5.8 years), 25 of them classified as iRORA and 73 as cRORA by OCT, were investigated by FLIO in a short (SSC: 498-560 nm) and a long wavelength channel (LSC: 560-720 nm). Differences of FAF lifetimes and peak emission wavelength (PEW) between atrophic lesions and intact retinal pigment epithelium (RPE) in the outer ring of the ETDRS grid were considered. RESULTS: FAF lifetimes in MA were longer and PEW were significantly (p < 0.001) shorter than in intact RPE by 112 ± 78 ps (SSC), 91 ± 64 ps (LSC), 27 ± 18 nm (PEW) in iRORA and by 227 ± 112 ps (SSC), 167 ± 81 ps (LSC), and 54 ± 17 nm (PEW) in cRORA. 37% of iRORA and 24% of cRORA were hyperautofluorescent in SSC. Persistent sub-RPE-BL material in MA was newly found as a hyperautofluorescent entity with lifetimes considerably longer than that of drusen and RPE. CONCLUSIONS: Despite RPE and, thus, lipofuscin are greatly absent in MA, considerable FAF, preferably at short wavelengths, was found in those lesions. Drusen, persistent sub-RPE-BL material, basal laminar deposits, persistent activated RPE, and sclera were identified as putative sources of this fluorescence. FLIO can help to characterize respective fluorophores.

Acquired Vitelliform Lesions in Intermediate Age-Related Macular Degeneration: A Cross Sectional Study.

PURPOSE: This study aims to define the characteristics of acquired vitelliform lesions (AVLs) in patients with intermediate age-related macular degeneration (iAMD). DESIGN: Retrospective, observational, cross sectional study. SUBJECTS: This study included 217 eyes with AVLs associated with iAMD, and an equivalent number of control patients. METHODS: OCT scans were evaluated for qualitative and quantitative parameters at both the eye and lesion level. Eye-level parameters included the presence of: hyporeflective core drusen, intraretinal hyperreflective foci (IHRF), subretinal drusenoid deposits, macular pachyvessels, central retinal thickness, and central choroidal thickness. Lesion-level qualitative parameters included the presence of ellipsoid zone (EZ) and external limiting membrane disruption overlying the AVL, IHRF overlying the AVL, AVL overlying drusen, pachyvessels under the AVL, a solid core within AVL, and AVL location. Lesion-level quantitative characteristics included AVL height and width, AVL distance from the fovea, and sub-AVL choroidal thickness. MAIN OUTCOME MEASURES: The primary outcomes assessed included the frequency of IHRF, the presence of macular pachyvessels, central choroidal thickness, and the dimensions (both height and width) of AVLs. RESULTS: Comparing the AVL and control groups, the frequency of IHRF (AVL: 49.3% vs. control: 26.3%) and macular pachyvessels (37.3% vs. 6.9%) was significantly higher in the AVL case group, and the central choroidal thickness (256.8 ± 88 µm vs. 207.1± 45 µm) was thicker in the AVL group. Acquired vitelliform lesions located over drusen, with overlying IHRF, or situated subfoveally, and AVL lesions with EZ disruption were found to have a greater lesion height and width compared with AVL lesions lacking these characteristics (P value < 0.001 for all). Additionally, a significant negative correlation was observed between the distance from the fovea and AVL height (Spearman rho: -0.19, P = 0.002) and width (Spearman rho: -0.30, P = 0.001). CONCLUSIONS: This study represents the largest reported cohort of AVL lesions associated with iAMD. Novel findings include the higher frequency of pachyvessels in addition to the presence of a thicker choroid in these eyes, as well as the greater height and width of AVL closer to the foveal center. These findings may offer insights into pathophysiologic mechanisms underlying the development of AVL. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.