Faculty Bibliography
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Müller Cell Changes and Subretinal Membrane Formation in an Eye With Multifocal Geographic Atrophy [Case Report]
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.
PMCID:13086172
PMID: 41960965
ISSN: 1552-5783
CID: 6025812
Histologic Photoreceptor and Retinal Pigment Epithelium Degeneration in an Eye With Clinically Documented Geographic Atrophy of AMD [Case Report]
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.
PMCID:13069352
PMID: 41944541
ISSN: 1552-5783
CID: 6025232
Choroidal Vascular Findings in a Case of Multifocal Geographic Atrophy: A Clinicopathologic Correlation [Case Report]
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.
PMCID:12988676
PMID: 41805150
ISSN: 1552-5783
CID: 6015442
Functional Deficits Associated with Dark Without Pressure
PURPOSE/OBJECTIVE:To describe a patient with progressive visual symptoms and reduced retinal sensitivity corresponding to dark without pressure (DWP). METHODS:Retrospective chart review of a single patient. Comprehensive ophthalmic examinations and multimodal imaging techniques, including optical coherence tomography (OCT), OCT-angiography, and microperimetry, were analyzed. RESULTS:A 23-year-old male presented with progressive peripheral areas of blurred vision superiorly in his right eye and temporally in his left eye. These disturbances corresponded with dark areas of retina inferiorly in his right eye and nasally in his left eye having characteristic features of DWP on multimodal imaging. Although Humphrey visual field (HVF) 24-2 testing was normal, microperimetry showed decreased retinal sensitivity in areas of DWP relative to adjacent areas without DWP. CONCLUSION/CONCLUSIONS:Prior descriptions of DWP have described it as a benign retinal finding showing no functional deficits. We demonstrate that DWP can be associated with progressive visual complaints showing decreased retinal sensitivity on microperimetry and undetected with HVF 24-2 testing.
PMID: 39903922
ISSN: 1937-1578
CID: 5783882
Expanded Spectrum of Chrysanthemum and Miliary Multifocal Choroiditis with Panuveitis: Novel Imaging and Pathophysiological Insights
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.
PMID: 41619898
ISSN: 1879-1891
CID: 6003892
Angular Sign of Henle Fiber Layer Hyperreflectivity (ASHH) in Contusion Maculopathy: A Multimodal Imaging Analysis
PURPOSE/OBJECTIVE:To describe the multimodal imaging findings of the angular sign of Henle fiber layer (HFL) hyperreflectivity (ASHH) at baseline and follow-up in patients with contusion maculopathy. METHODS:Eleven eyes of ten patients were captured with multimodal imaging after non-penetrating ocular blunt trauma from a soccer ball, fist, or airsoft pellet. Baseline clinical and imaging characteristics and follow-up outcomes are presented. RESULTS:Hyper-reflective lesions extending along the HFL from the ellipsoid zone (EZ) to the outer plexiform layer consistent with ASHH were identified with optical coherence tomography (OCT). Mean presenting visual acuity (VA) was logMAR 0.59 ± 0.64 (Snellen VA 20/77, range 20/25 to counting fingers) and follow-up visual acuity was logMAR 0.43 ± 0.35 (Snellen VA 20/53, range 20/20 to 20/200). Additional OCT findings included external limiting membrane attenuation and retinal pigment epithelium (RPE) disruption. On follow-up, resolution of ASHH was accompanied by outer nuclear layer thinning with varying degrees of EZ attenuation and RPE loss. A macular hole was detected in one patient on follow-up. CONCLUSION/CONCLUSIONS:ASHH is a distinctive acute OCT feature of contusion maculopathy secondary to blunt injury, causing disruption of the photoreceptors and presumably anterograde alterations in the HFL. Associated RPE alterations may ensue, either acutely or delayed, and are a biomarker of persistent structural abnormalities and variable visual outcomes.
PMID: 40857723
ISSN: 1539-2864
CID: 5910082
De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa
Small nuclear RNAs (snRNAs) combine with specific proteins to generate small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. U4 snRNA forms a duplex with U6 and, together with U5, contributes to the tri-snRNP spliceosomal complex. Variants in RNU4-2, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in RNU4-2 and in four RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode U6, recur in individuals with nonsyndromic retinitis pigmentosa (RP), a genetic disorder causing progressive blindness. These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF31), and seem to affect snRNP biogenesis. Based on our cohort, deleterious variants in RNU4-2 and RNU6 paralogs may explain up to ~1.4% of otherwise undiagnosed RP cases. This study highlights the contribution of noncoding RNA genes to Mendelian disease and reveals pleiotropy in RNU4-2, where distinct variants underlie neurodevelopmental disorder and retinal degeneration.
PMID: 41513982
ISSN: 1546-1718
CID: 5981482
Clinical and Multimodal Imaging of Acute Outer Retinopathy Expanding the Spectrum of Acute Annular Outer Retinopathy
PURPOSE/OBJECTIVE:To describe the clinical features, multimodal imaging findings, natural history, and treatment outcomes of acute outer retinopathy (AOR), which represents an expanded spectrum of acute annular outer retinopathy (AAOR). DESIGN/METHODS:Retrospective, observational, longitudinal, multicenter case series. PARTICIPANTS/METHODS:Twenty-three patients (15 female, 8 male) with a mean age of 41.8 ± 18.6 years (range: 14-86 years) and a mean follow-up duration of 3.7 ± 1.5 years (range: 1-12 years). METHODS:Clinical characteristics, multimodal imaging findings, laboratory evaluations, genetic testing, natural history, therapeutic management, and outcomes were reviewed and analyzed. MAIN OUTCOMES MEASURES/METHODS:Specific multimodal imaging signatures of AOR were identified, including findings from ophthalmoscopy, fundus autofluorescence (FAF), fluorescein angiography (FA), indocyanine green angiography (ICGA), and optical coherence tomography (OCT). Humphrey visual field testing, full-field electroretinography (ERG), and multifocal ERG were analyzed. Baseline features and the natural course of the disease were delineated. RESULTS:Thirty-eight eyes from 23 patients were analyzed. Presenting symptoms included photopsia (87%), blurred vision (57%), and scotoma (57%). On ophthalmoscopy, AOR was acutely characterized by yellow-greyish outer retinal lesions corresponding to hyperautofluorescent changes on FAF and the angular sign of Henle fiber layer hyperreflectivity (ASHH) on OCT. FAF imaging revealed ring-like hyperautofluorescent lesions surrounding the optic disc in 18% of eyes. Additional lesion patterns on FAF included perivenular (53%), sectoral (16%), and spot-like distributions (13%). FA and ICGA findings were mostly unremarkable. Lesion progression primarily occurred within the initial weeks following presentation and stabilized in size beyond this period in the majority of eyes. Over time, affected areas progressed to outer retinal atrophy with pigmentary changes. Foveal sparing was observed in 68% of the eyes. None of the therapeutic interventions appeared effective in halting the progression to complete outer retinal atrophy or preventing lesion enlargement. CONCLUSIONS:AOR is characterized by early photoreceptor disruption, evidenced by ASHH on OCT, leading to rapid outer retinal atrophy and subsequent degeneration of the retinal pigment epithelium within the damaged zones. Although distinct patterns of lesion distribution were observed, their consistent features on multimodal imaging support their inclusion within a unified disease spectrum termed acute outer retinopathy.
PMID: 40436146
ISSN: 2468-6530
CID: 5854872
Re: Monés et al: Spontaneous soft drusen regression without atrophy and the drusen ooze (Ophthalmology Retina 2025;9:828-837) [Letter]
PMID: 40905894
ISSN: 2468-6530
CID: 5930892
Peripapillary Retinoschisis - The Expanded Spectrum and New Insights from Multimodal Imaging
PURPOSE/OBJECTIVE:To characterize and classify different forms of peripapillary retinoschisis (PPRS), and to clarify the nomenclature of this condition. METHODS:A retrospective, multicenter, multinational case series of PPRS was performed from August 2021 to September 2024. Cases were included if they demonstrated retinoschisis contiguous with and thought to be originating from the optic disc. Demographic and clinical data collected included age, gender, visual acuity, intraocular pressure, axial length, refraction and referring symptoms. Mandatory investigations included optical coherence tomography of the optic disc and macula with radial scans, colour fundus photography, and fundus autofluorescence. Select cases underwent fundus fluorescein and/or indocyanine green angiography. Retinoschisis was characterised by the meridian in relation to the optic disc, layer(s) of the retina affected and associated conditions. A literature review was performed to identify all causes of PPRS. RESULTS:A total of 47 eyes from 41 patients with PPRS were identified, comprising of 22 (54%) females and a mean age of 56 years (range 14-92 years). These were classified into nine aetiologies: Congenital Disc Abnormalities (CDA, n=16 eyes), peripapillary chorioretinal coloboma (n=1), peripapillary atrophy (n=3), glaucoma (n=7), Peripapillary Pachychoroid Syndrome (PPS, n=4), peripapillary choroidal neovascularization (PP-CNV, n=3), high/ pathological myopia (n=5), vitreopapillary traction (VPT, n=4) and idiopathic (n=4). CONCLUSION/CONCLUSIONS:The nine aetiologies of peripapillary retinoschisis can be classified into five groups: non-glaucomatous optic disc abnormalities (CDA, PP-coloboma, PP-atrophy), glaucomatous optic disc abnormalities, peripapillary choroidal diseases (PPS and PP-CNV), vitreous optic disc interface abnormalities and idiopathic. A new entity, "Focal Optic Disc Dome" (FODD) was identified. Understanding the full spectrum of PPRS can assist in correct diagnosis and management.
PMID: 41110675
ISSN: 1879-1891
CID: 5956482
