Faculty Bibliography

PURPOSE/OBJECTIVE:To describe two recurrent phenotypes of retinal pigment epithelium (RPE) defects, sealed and unsealed, which may occur in various diseases. METHODS:Medical records and multimodal imaging of 17 patients (70.3 ± 9.3 years) with RPE defects, including RPE apertures, RPE detachment (RPED) devoid of RPE, and serous maculopathy with the absence of RPE (SMARPE), were retrospectively analyzed. Proposed pathogenic mechanisms are presented, revising current terminology. RESULTS:Eyes with RPE apertures (12/17, 70.6%) and SMARPE (1/17, 5.9%) presented RPE defects connecting the subretinal and sub-RPE spaces with subretinal fluid (SRF) and intact outer retina. These features are consistent with patent RPE defects, termed 'unsealed'. RPED devoid of RPE defects developed in ¾ eyes (75%) over a serous PED without collapse. The lesions occurred beneath a degenerated outer retina that adheres to the RPE defect without SRF, supporting the term 'sealed'. CONCLUSIONS:RPE defects beneath a disrupted photoreceptor layer may become "sealed" by reactive Müller cell gliosis, preventing the occurrence of SRF. RPE defects with intact photoreceptors remain "unsealed", resulting in SRF accumulation. We propose "sealed" and "unsealed" as disease agnostic terms, which can be used for cases previously described as "RPE aperture," "SMARPE," and "RPED devoid of RPE".

OBJECTIVE:To characterize the long-term clinical and multimodal imaging (MMI) features of extensive macular atrophy with pseudodrusen (EMAP) in a U.S. DESIGN/METHODS:Multicentre retrospective case series. PARTICIPANTS/METHODS:Patients diagnosed with EMAP between 2015 and 2025. METHODS:Clinical records and MMI-including colour fundus photography, fundus autofluorescence, OCT, and OCT angiography-were reviewed at baseline and last follow-up. RESULTS:Fifteen patients (30 eyes) were included, with longitudinal MMI analysis available in 11 patients (22 eyes). Median age at referral was 72 years (range, 40-76 years), and median baseline visual acuity was 0.3 logMAR (20/40). All eyes demonstrated diffuse pseudodrusen-like deposits and retinal pigment epithelium-Bruch membrane separation consistent with basal laminar deposits. Four eyes (13.3%) showed no macular atrophy at baseline, suggesting an early disease stage (stage 0). Peripheral retinal degeneration was identified in approximately 50% of eyes, and macular neovascularization developed in 25%, including 2 eyes (6.7%) with type 3 macular neovascularization. Median visual acuity declined to 0.54 logMAR (20/70) at final follow-up (P < 0.001), and 27% met criteria for U.S. legal blindness. Disease progression was observed in 59% after a median follow-up of 47.5 months (range, 4-114 months). CONCLUSIONS:EMAP may represent a high-risk variant of age-related macular degeneration characterized by rapid progression to geographic atrophy. Critical diagnostic features include pseudodrusen-like deposits and basal laminar deposits, whereas a vertical pattern of atrophy represents the typical outcome. Atrophy may be absent in early disease stages. Genetic validation and consideration for inclusion in future atrophic AMD interventional trials are warranted.

PURPOSE/OBJECTIVE:Optical coherence tomography angiography (OCTA) has enabled detailed in vivo imaging of macular neovascularization (MNV) in neovascular age-related macular degeneration (nAMD), leading to a proliferation of morphological descriptive terms. This scoping review aimed to systematically map the existing literature on OCTA-based MNV morphology and evaluate its correlation with disease activity. METHODS:A systematic literature search covering publications through 2025 was performed. After screening 2,445 titles and obtaining 60 full texts, 43 studies were included. Data on morphological terminology, study design, and correlation with disease activity were extracted and synthesized. RESULTS:The included studies, encompassing a total of 2,712 eyes, identified a vast and heterogeneous lexicon of qualitative descriptors, including terms such as "medusa," "sea-fan," and "glomerulus", characterized by significant terminological overlap and inconsistent definitions across studies. Inconsistent, low-certainty associations between specific OCTA morphologies and MNV activity were identified across studies, with findings limited by significant methodological heterogeneity. The evidence for these patterns as reliable biomarkers of disease activity is weak and often contradictory, and several studies were found to use OCTA features to define activity, creating circular arguments that undermine their conclusions. CONCLUSION/CONCLUSIONS:The current terminology for OCTA morphology in nAMD is fragmented and inconsistently applied. The link between these patterns and disease activity is poorly established, severely limiting their clinical utility. These findings highlight a need for a standardized, consensus-based framework for describing and interpreting OCTA findings in nAMD.

PURPOSE/UNASSIGNED:In geographic atrophy (GA) of AMD, comparing photoreceptor disintegrity and RPE loss in optical coherence tomography (OCT) and microscopy may elucidate atrophy expansion and suggest imaging biomarkers. METHODS/UNASSIGNED:One eye of a 93-year-old woman with bilateral drusen-driven GA of AMD was analyzed. RPE loss and reduced photoreceptor segment integrity (rPSi) was quantified automatically in clinical OCT volumes over a five-year period ending six years pre-mortem. In transmission electron micrographs of the outer junctional zone (OJZ) and a comparison area, tissue component volumes were measured. RESULTS/UNASSIGNED:By OCT, rPSi area exceeded RPE loss at baseline. Yearly RPE loss (2.432 mm2) exceeded rPSi (1.770 mm2) as these areas converged. By microscopy, the mean distance between the external limiting membrane (ELM) and RPE basal lamina in the OJZ was 50% of the comparison. Volumes of interphotoreceptor space, outer segments, inner segment myoids, inner segment ellipsoids, and in-layer RPE were 16%, 17%, 25%, 50%, and 104%, respectively, of the comparison. Cone inner segments exhibited fragmented and translocating mitochondria over drusen and at the ELM descent. In some OCT scans, the descent appeared especially hyperreflective. CONCLUSIONS/UNASSIGNED:In this first clinicopathologic correlation of an AMD eye with a known GA growth rate, the area of rPSi (a composite representing photoreceptor shortening, disorganization, altered waveguiding, and true cell death) exceeds the area of RPE loss. The OJZ exhibits dysmorphic but continuous RPE. Photoreceptors degenerate from the outer segments inward. Mitochondrial fission and translocation at the ELM descent may be visible clinically.

PURPOSE/UNASSIGNED:Müller cell morphology and markers were investigated using histology and immunohistochemistry in an eye with clinically documented multifocal geographic atrophy (GA) and correlated with clinical images. METHODS/UNASSIGNED:The donor was followed clinically for 5 years, 6 years before death. The superior posterior pole retina of the right eye was dissected and immunolabeled with antibodies against glial fibrillary acidic protein (GFAP; activated Müller cells and astrocytes) and glutamine synthetase (GS; Müller cells) and Ulex europaeus Agglutinin-1 lectin (blood vessels) before embedding for JB-4 cross section analysis. The inferior macula was cryopreserved. Cryosections were immunolabeled with Müller cell homeostatic and activation markers. Transmission electron microscopy (TEM) of the left eye was used to study ultrastructure changes. RESULTS/UNASSIGNED:Gross examination demonstrated mottled retinal pigment epithelium (RPE) over presumably calcified drusen. In the macular area, Müller cell processes surrounding both drusen and outer retinal pigmented lesions created a large subretinal membrane. Cryosection analysis demonstrated persistence of aquaporin 4 and GS in Müller cells with both proteins prominently expressed in the subretinal membrane. Increased MC S100B and GFAP expression were also observed in the atrophic area as well as the outer junctional zone. Cryosection labeling and TEM confirmed Müller cell encasing calcified drusen and RPE debris as well as invading basal laminar deposits. CONCLUSIONS/UNASSIGNED:This multifocal GA case demonstrates how MC activation and structural changes surrounding individual drusen could coalesce, contributing to photoreceptor loss. Müller cells penetrating basal laminar deposits and encasing calcified drusen suggests attempting clearing and/or protecting the retina from harmful contents.

PURPOSE/UNASSIGNED:We examined the choroid in both eyes from a donor with multifocal geographic atrophy (GA), enlarged choroidal vessels, and choroidal neovascularization (CNV) secondary to age-related macular degeneration, using histology and immunohistochemistry, and we correlated the findings with multimodal clinical imaging. METHODS/UNASSIGNED:A Caucasian woman with bilateral GA was followed clinically for 5 years, until 6 years prior to her death at age 93. To correlate clinical and histologic features, the right eyecup was photographed before dissecting the posterior pole. Choroidal blood vessels were labeled with Ulex europaeus agglutinin-1 (UEA-1) lectin following retinal pigment epithelium removal and imaged by confocal microscopy. Selected regions were embedded and sectioned for histologic staining. The left eye was used for ultrastructure analysis. RESULTS/UNASSIGNED:The posterior pole exhibited areas of atrophy surrounded by mottled retinal pigment epithelium overlying calcified drusen. Confocal imaging of the UEA-1 lectin-labeled choroidal flatmounts showed limited visualization of the submacular vasculature, consistent with masking by basal laminar and lipid-rich deposits seen in histologic sections. In well-labeled regions of the posterior pole, the choriocapillaris was attenuated and widely separated by markedly thickened, hyalinized intercapillary pillars. Venules and veins appeared dilated, and arteries exhibited arteriosclerotic changes. A choroidal neovascular complex was observed superior to the optic nerve head near the atrophic border; the adjacent choriocapillaris was attenuated. CONCLUSIONS/UNASSIGNED:In this single case of multifocal GA, choroidal thickening and large-caliber outer choroidal vessels coexisted with marked choriocapillaris degeneration and adjacent neovascularization. These observations suggest that structural choroidal enlargement does not preclude choriocapillaris failure and may be associated with ischemic and neovascular phenotypes.

PURPOSE/OBJECTIVE:To characterize the clinical and ultra-widefield (UWF) imaging of the chrysanthemum phenotype of multifocal choroiditis with panuveitis (MFCPU) and to describe a related variant, termed the miliary phenotype. DESIGN/METHODS:Multicenter, retrospective, observational case series. SUBJECTS/METHODS:Fifteen patients (20 eyes) with MFCPU exhibiting chrysanthemum lesions. METHODS:Comprehensive ophthalmic examination and multimodal imaging, including UWF color fundus photography, fundus autofluorescence, fluorescein angiography, indocyanine green angiography (ICGA), and optical coherence tomography (OCT), at baseline-first visit with both UWF-ICGA and OCT through active MFCPU lesions) and follow-up-were reviewed. Lesion morphology, topography, quadrant distribution, and choroidal vascular features such as vortex vein (VV) dilation, intervortex vein anastomoses (IVA) and choroidal vascular hyperpermeability (CVH) were analyzed. OCT was evaluated for subretinal hyperreflective material (SHRM), subfoveal choroidal thickness (SFCT), and secondary choroidal neovascularization (CNV). MAIN OUTCOME MEASURES/METHODS:Morphologic and topographic characterization of chrysanthemum and miliary lesions, prevalence of VV dilation, IVA, and CVH, complications, and visual outcomes. RESULTS:Baseline, mean age was 37.1±17.3 years; 80% were female and 73% myopic. Mean follow-up duration was 23.2±20.5 months. Disease was unilateral 67% and bilateral in 33% of patients. Lesions were predominantly peripheral, involving the mid- and far periphery in 60% of eyes and multiple quadrants in 65%. ICGA revealed VV dilation and CVH in 17/20 (85%) eyes and IVA in 15/20 (75%) eyes, colocalizing with chrysanthemum lesions. OCT showed focal (lesion-level) choroidal thickening, SHRM, and outer retinal atrophy; CNV developed in 10/20 (50%) eyes and persisted in 56% at follow-up, while subretinal fibrosis occurred in 25%. Mean SFCT decreased from 318.8±73.2 µm to 285.8±69.6 µm. Visual acuity remained stable with long-term follow-up (0.24 logMAR, 20/35). The miliary variant, identified in 4/20 (20%) eyes, presented as clusters of confluent white-yellow lesions spanning all quadrants. CONCLUSIONS:Chrysanthemum MFCPU predominantly affects the peripheral choroid and is associated with venocentric features including CVH, IVA, and VV dilation on UWF-ICGA, suggesting a potential pathogenetic role for focal choroidal congestion. The identification of a miliary variant broadens the morphologic spectrum of MFCPU. Recognition of these patterns is critical for accurate diagnosis, differentiation from other inflammatory chorioretinopathies, and prevention of CNV and fibrosis.