BACKGROUND: Advanced age-related macular degeneration (AMD) is a major cause of vision loss. Therefore, there is interest in precursor lesions that may predict or prevent the onset of advanced AMD. One such lesion is a shallow separation of the retinal pigment epithelium (RPE) and Bruch\'s membrane (BM), which is described by various terms, including double-layer sign (DLS).
METHODS: In this article, we aim to examine and clarify the different terms referring to shallow separation of the RPE and BM. We also review current evidence on the outcomes associated with DLS: firstly, whether DLS is predictive of exudative neovascular AMD; and secondly, whether DLS has potential protective properties against geographic atrophy.
RESULTS: The range of terms used to describe a shallow separation of the RPE and BM reflects that DLS can present with different characteristics. While vascularised DLS appears to protect against atrophy but can progress to exudation, non-vascularised DLS is associated with an increased risk of atrophy. Optical coherence tomography (OCT) angiography (OCTA) is the principal method for identifying and differentiating various forms of DLS. If OCTA is unavailable or not practically possible, simplified classification of DLS as thick or thin, using OCT, enables the likelihood of vascularisation to be approximated. Research is ongoing to automate DLS detection by applying deep-learning algorithms to OCT scans.
CONCLUSIONS: The term DLS remains applicable for describing shallow separation of the RPE and BM. Detection and classification of this feature provides valuable information regarding the risk of progression to advanced AMD. However, the appearance of DLS and its value in predicting AMD progression can vary between patients. With further research, individualised risks can be confirmed to inform appropriate treatment.
Age-related macular degeneration (AMD) is an eye disease that may develop in older people, usually those aged over 60 years. Early in the disease, people often do not show any symptoms, but as the disease progresses, vision loss may occur. The advanced forms of AMD are called neovascular AMD (also called “wet” AMD) and advanced dry AMD (called geographic atrophy; GA). It is important to identify features and signs on eye scans that can help to predict if someone with AMD will develop an advanced form of the disease because this will help doctors plan the most appropriate treatment. One such feature on eye scans is the double-layer sign (DLS). In this article, we summarise the different names used for DLS, and assess if having a DLS increases the likelihood of someone with early AMD developing wet AMD or GA. We conclude that how DLS looks varies between people, which leads to DLS being called by various names. Someone with early AMD and a DLS containing blood vessels may be more likely to develop wet AMD; whereas someone with early AMD and a DLS without blood vessels may be more likely to develop GA. Taking photos of the eye using optical coherence tomography angiography imaging is the main method of identifying DLS and confirming whether it contains blood vessels.

Physiologically relevant in vitro models of the human outer retina are required to better elucidate the complex interplay of retinal tissue layers and investigate their role in retinal degenerative disorders. Materials currently used to mimic the function of Bruch\'s membrane fail to replicate a range of important structural, mechanical, and biochemical properties. Here, we detail the fabrication of a surface-functionalized, fibrous collagen I membrane. We demonstrate its ability to better replicate a range of important material properties akin to the function of human Bruch\'s membrane when compared with a commonly utilized synthetic polyethylene terephthalate alternative. We further reveal the ability of this membrane to support the culture of the ARPE-19 cell line, as well as human pluripotent stem cell-derived RPE-like cells and human umbilical vein endothelial cells. This material could provide greater physiological relevance to the native Bruch\'s membrane than current synthetic materials and further improve the outcomes of in vitro outer retinal models.

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A spayed, 8-year-old female Poodle, weighing 5.7 kg, was presented with the chief complaint of vision impairment. Vision assessment, including pupillary light reflexes, menace response, dazzle reflex, and maze navigation in photopic and scotopic circumstances, revealed a negative response in both eyes except for positive direct pupillary light reflex in the right eye and positive consensual pupillary light reflex from the right eye to the left eye. Systemic evaluation, including neurologic status, blood profile, and thoracic radiographs, did not reveal any abnormalities. Complete ophthalmic examinations, ocular ultrasonography, and electroretinography did not identify a cause of blindness. Upon funduscopy, the left eye exhibited an increased optic disk diameter, blurred optic disk borders, and loss of the physiologic pit, as well as an increase in vascular tortuosity. In the right eye, there were multifocal depigmented areas in the non-tapetal fundus and several pigmented spots surrounded by a region of dull tapetal reflection in the tapetal fundus. The optical coherence tomography revealed severe anterior deformation of the optic nerve head and Bruch\'s membrane in the peripapillary region of the left eye. Magnetic resonance imaging revealed an irregular, broad-based suprasellar mass, with features suggestive of intracranial hypertension, including dorsal displacement of third ventricles, a rightward shift of the falx cerebri, trans-tentorial herniation, perilesional edema, flattening/protrusion of the posterior sclera, and lager optic nerve sheath diameter in left side than right side. This is the first comprehensive report that describes unilateral papilledema in a dog with a brain tumor, using advanced ophthalmic and neuro-imaging modalities.

Background/Objectives: To assess the frequency, extent, localization and potential progression of optic disc drusen (ODD) and the correlation with the angioid streak (AS) length and retinal atrophy in patients with pseudoxanthoma elasticum (PXE). Methods: This retrospective study included patient data from a dedicated PXE clinic at the Department of Ophthalmology, University of Bonn, Germany (observation period from February 2008 to July 2023). Two readers evaluated the presence, localization, and the extent of the ODD on fundus autofluorescence (FAF) imaging at baseline and the follow-up assessments. Additionally, we measured the length of the longest AS visible at baseline and follow-up and the area of atrophy at baseline, both on FAF. Results: A total of 150 eyes of 75 PXE patients (median age at baseline 51.8 years, IRQ 46.3; 57.5 years, 49 female) underwent retrospective analysis. At baseline, 23 of 75 patients exhibited ODD in a minimum of one eye, resulting in an ODD prevalence of 30.7% in our cohort of PXE patients. Among these, 14 patients showed monocular and 9 binocular ODD that were localized predominantly nasally (46.9%). During the observational period (mean 97.5 ± 44.7 months), only one patient developed de novo ODD in one eye and one other patient showed a progression in the size of the existing ODD. The group of patients with ODD had significantly longer ASs (median 7020 µm, IQR 4604; 9183, vs. AS length without ODD: median 4404 µm, IQR 3512; 5965, p < 0.001). No association with the size of the atrophy was found at baseline (p = 0.27). Conclusions: This study demonstrates a prevalence of ODD of 30.7%. ODD presence is associated with longer ASs (an indicator of the severity and extent of ocular Bruch\'s membrane calcification), suggesting that ODD formation is tightly related to ectopic calcification-possibly secondary to calcification of the lamina cribrosa. Prospective studies investigating the impact of ODD (in conjunction with intraocular pressure) on visual function in PXE warrant consideration.

OBJECTIVE: To describe the clinical outcome and late-stage findings of extensive macular atrophy with pseudodrusen-like appearance (EMAP).
METHODS: Retrospective cohort study.
METHODS: Seventy-eight patients (156 eyes) affected by EMAP.
METHODS: We collected data on best-corrected visual acuity, kinetic perimetry, OCT, short-wavelength autofluorescence, and near-infrared autofluorescence findings. Genetic testing for the TIMP3 and C1QTNF5 genes was performed via Sanger sequencing for 58 patients, with no pathogenic variants identified.
METHODS: The primary outcomes were best-corrected visual acuity at the last examination, visual field at the last examination, and incidence rates and time-to-event curves for blindness with the United States Social Security Administration and World Health Organization (WHO) criteria, foveal involvement, and atrophy enlargement beyond the 30° and 55° field of view. Imaging findings at the last examination were secondary outcomes.
RESULTS: At the most recent visit, mean age was 70.9 ± 5.2 years. Using United States criteria, 58.1% of the patients were blind, and 25.8% were blind according to WHO criteria. All eyes showed large central scotomas, which were associated with visual field constriction in 22.2% of eyes. We detected focal openings or large dehiscences of Bruch\'s membrane (BM) in 25.4% of eyes. Near-infrared autofluorescence showed increased visibility of the choroidal vessels beyond the atrophy in 87.2% of eyes. The incidence rates for blindness were 3.95 per 100 patient-years with United States criteria and 1.54 per 100 patient-years according to WHO criteria. The incidence rates were 22.8 per 100 eye-years for foveal involvement, 12.0 per 100 eye-years for atrophy enlargement beyond 30°, and 6.6 per 100 eye-years for atrophy enlargement beyond 55°. The estimates were not influenced by the age at onset.
CONCLUSIONS: We identified characteristic imaging findings, including BM ruptures, in elder patients with EMAP and calculated incidence rates for different functional and anatomic outcomes.
BACKGROUND: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Aim: Angioid streaks (ASs) are a rare retinal condition and compromise visual acuity when complicated with choroidal neovascularization (CNV). They represent crack-like dehiscences at the level of the Bruch\'s membrane. This objective narrative review aims to provide an overview of pathophysiology, current treatment modalities, and future perspectives on this condition. Materials and Methods: A literature search was performed using \"PubMed\", \"Web of Science\", \"Scopus\", \"ScienceDirect\", \"Google Scholar\", \"medRxiv\", and \"bioRxiv.\" Results: ASs may be idiopathic, but they are also associated with systemic conditions, such as pseudoxanthoma elasticum, hereditary hemoglobinopathies, or Paget\'s disease. Currently, the main treatment is the use of anti-vascular endothelial growth factors (anti-VEGF) to treat secondary CNV, which is the major complication observed in this condition. If CNV is detected and treated promptly, patients with ASs have a good chance of maintaining functional vision. Other treatment modalities have been tried but have shown limited benefit and, therefore, have not managed to be more widely accepted. Conclusion: In summary, although there is no definitive cure yet, the use of anti-VEGF treatment for secondary CNV has provided the opportunity to maintain functional vision in individuals with AS, provided that CNV is detected and treated early.

Apolipoprotein B (APOB) is a constituent of unique lipoprotein particles (LPPs) produced in the retinal pigment epithelium (RPE), which separates the neural retina from Bruch\'s membrane (BrM) and choroidal circulation. These LPPs accumulate with age in BrM and contribute to the development of age-related macular degeneration, a major blinding disease. The APOB100 transgenic expression in mice, which unlike humans lack the full-length APOB100, leads to lipid deposits in BrM. Herein, we further characterized APOB100 transgenic mice. We imaged mouse retina in vivo and assessed chorioretinal lipid distribution, retinal sterol levels, retinal cholesterol input, and serum content as well as tracked indocyanine green-bound LPPs in mouse plasma and retina after an intraperitoneal injection. Retinal function and differentially expressed proteins were also investigated. APOB100 transgenic mice had increased serum LDL content and an additional higher density HDL subpopulation; their retinal cholesterol levels (initially decreased) became normal with age. The LPP cycling between the RPE and choroidal circulation was increased. Yet, LPP trafficking from the RPE to the neural retina was limited, and total retinal cholesterol input did not change. There were lipid deposits in the RPE and BrM, and retinal function was impaired. Retinal proteomics provided mechanistic insights. Collectively, our data suggested that the serum LDL/HDL ratio may not affect retinal pathways of cholesterol input as serum LPP load is mainly handled by the RPE, which offloads LPP excess to the choroidal circulation rather than neural retina. Different HDL subpopulations should be considered in studies linking serum LPPs and age-related macular degeneration.

UNASSIGNED: To investigate the histology of Bruch\'s membrane (BM) calcification in pseudoxanthoma elasticum (PXE) and correlate this to clinical retinal imaging.
UNASSIGNED: Experimental study with clinicopathological correlation.
UNASSIGNED: Six postmortem eyes from 4 PXE patients and 1 comparison eye from an anonymous donor without PXE. One of the eyes had a multimodal clinical image set for comparison.
UNASSIGNED: Calcification was labeled with OsteSense 680RD, a fluorescent dye specific for hydroxyapatite, and visualized with confocal microscopy. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy (SEM-EDX) and time-of-flight secondary ion mass spectrometry (TOF-SIMs) were used to analyze the elemental and ionic composition of different anatomical locations. Findings on cadaver tissues were compared with clinical imaging of 1 PXE patient.
UNASSIGNED: The characteristics and topographical distribution of hydroxyapatite in BM in eyes with PXE were compared with the clinical manifestations of the disease.
UNASSIGNED: Analyses of whole-mount and sectioned PXE eyes revealed an extensive, confluent OsteoSense labeling in the central and midperipheral BM, transitioning to a speckled labeling in the midperiphery. These areas corresponded to hyperreflective and isoreflective zones on clinical imaging. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy and TOF-SIMs analyses identified these calcifications as hydroxyapatite in BM of PXE eyes. The confluent fluorescent appearance originates from heavily calcified fibrous structures of both the collagen and the elastic layers of BM. Calcification was also detected in an aged comparison eye, but this was markedly different from PXE eyes and presented as small snowflake-like deposits in the posterior pole.
UNASSIGNED: Pseudoxanthoma elasticum eyes show extensive hydroxyapatite deposition in the inner and outer collagenous and elastic BM layers in the macula with a gradual change toward the midperiphery, which seems to correlate with the clinical phenotype. The snowflake-like calcification in BM of an aged comparison eye differed markedly from the extensive calcification in PXE.
UNASSIGNED: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

UNASSIGNED: To describe the natural history of Bruch\'s membrane (BM) calcification in patients with pseudoxanthoma elasticum (PXE).
UNASSIGNED: Retrospective cohort study.
UNASSIGNED: Both eyes of 120 PXE patients younger than 50 years, 78 of whom had follow-up imaging after more than 1 year.
UNASSIGNED: All patients underwent multimodal imaging, including color fundus photography, near-infrared reflectance (NIR) imaging, and late phase indocyanine green angiography (ICGA). We determined the distance from the optic disc to the central and temporal border of peau d\'orange on NIR, expressed in horizontal optic disc diameter (ODD). The length of the longest angioid streak was classified into 5 zones.
UNASSIGNED: Age-specific changes of peau d\'orange, angioid streaks, and ICGA hypofluorescence as surrogate markers for the extent of BM calcification.
UNASSIGNED: In cross-sectional analysis, longer angioid streaks were associated with increasing age (P < 0.001 for trend). The temporal border of peau d\'orange showed a weak association with increasing age (β = 0.02; 95% confidence interval [CI], 0.00-0.04), whereas the central border showed a strong association (β = 0.12; 95% CI, 0.09-0.15). Longitudinal analysis revealed a median shift of the central border to the periphery of 0.08 ODD per year (interquartile range [IQR], 0.00-0.17; P < 0.001). This shift was more pronounced in patients younger than 20 years (0.12 ODD per year [IQR, 0.08-0.28]) than in patients older than 40 years (0.07 ODD per year [IQR, -0.05 to 0.15]). The temporal border did not shift during follow-up (P = 0.69). New or growing angioid streaks were detected in 39 of 156 eyes (25%). The hypofluorescent area on ICGA was visible only in the fourth or fifth decade and correlated with longer angioid streaks.
UNASSIGNED: In PXE patients, the speckled BM calcification slowly confluences during life. The location of the temporal border of peau d\'orange remains rather constant, whereas the central border shifts to the periphery. This suggests the presence of a predetermined area for BM calcification. A larger ICGA hypofluorescent area correlates with older age and longer angioid streaks, which implies that it depends on the degree of BM calcification.