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Bailey K Freund - One of the best experts on this subject based on the ideXlab platform.
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histology of geographic atrophy secondary to age related macular degeneration a multilayer approach
Retina-the Journal of Retinal and Vitreous Diseases, 2018Co-Authors: Miaoling Li, Jeffrey D Messinger, Rosa Dolzmarco, Daniela Ferrara, Carrie Huisingh, Bailey K Freund, Christine A CurcioAbstract:PURPOSE: To systematically characterize histologic features of multiple chorioretinal layers in eyes with geographic atrophy, or complete retinal pigment epithelium (RPE) and outer retinal atrophy, secondary to age-related macular degeneration, including Henle fiber layer and outer nuclear layer; and to compare these changes to those in the underlying RPE-Bruch Membrane-choriocapillaris complex and associated extracellular deposits. METHODS: Geographic atrophy was delimited by the external limiting Membrane (ELM) descent towards Bruch Membrane. In 13 eyes, histologic phenotypes and/or thicknesses of Henle fiber layer, outer nuclear layer, underlying supporting tissues, and extracellular deposits at four defined locations on the non-atrophic and atrophic sides of the ELM descent were assessed and compared across other tissue layers, with generalized estimating equations and logit models. RESULTS: On the non-atrophic side of the ELM descent, distinct Henle fiber layer and outer nuclear layer became dyslaminated, cone photoreceptor inner segment myoids shortened, photoreceptor nuclei and mitochondria translocated inward, and RPE was dysmorphic. On the atrophic side of the ELM descent, all measures of photoreceptor health declined to zero. Henle fiber layer/outer nuclear layer thickness halved, and only Muller cells remained, in the absence of photoreceptors. Sub-RPE deposits remained, Bruch Membrane thinned, and choriocapillaris density decreased. CONCLUSION: The ELM descent sharply delimits an area of marked gliosis and near-total photoreceptor depletion clinically defined as Geographic atrophy (or outer retinal atrophy), indicating severe and potentially irreversible tissue damage. Degeneration of supporting tissues across this boundary is gradual, consistent with steady age-related change and suggesting that RPE and Muller cells subsequently respond to a threshold of stress. Novel clinical trial endpoints should be sought at age-related macular degeneration stages before intense gliosis and thick deposits impede therapeutic intervention.
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correlation of type 1 neovascularization associated with acquired vitelliform lesion in the setting of age related macular degeneration
American Journal of Ophthalmology, 2015Co-Authors: Christine A Curcio, Jeffrey D Messinger, Bailey K Freund, Chandrakumar Balaratnasingam, Lawrence A YannuzziAbstract:Purpose To correlate postmortem histology with previously recorded multimodal imaging from a patient with type 1 neovascularization (NV) associated with an acquired vitelliform lesion in the setting of age-related macular degeneration (AMD). Design Case study. Methods Multimodal imaging that was obtained antemortem was matched with ex vivo and high-resolution histologic images of the preserved donor macula. Anatomic correlates for multimodal imaging findings were then defined. Results Spectral-domain optical coherence tomography (OCT) revealed a split in the retinal pigment epithelium–Bruch Membrane band. Type 1 NV in this case was composed of 6 layered components: (1) retinal pigment epithelium, (2) basal laminar deposits, (3) fibrovascular Membrane, (4) fibrocellular scar, (5) hemorrhage, and (6) Bruch Membrane. The anatomic correlates for the hyporeflective band on spectral-domain OCT included a thick basal laminar deposit. Not all structures could be readily separated on the basis of their reflectivity patterns. Conclusions This is an important clinicopathologic correlation of NV secondary to AMD in the spectral-domain OCT era. Our findings of 6 layers include and extend the anatomic framework encapsulated by the double-layer and triple-layer signs. The resolution of current devices does not always permit distinction of the different layers of NV tissue. Thick basal laminar deposits may appear hyporeflective on spectral-domain OCT and may be confused with fluid from a neovascular process. It will be important to perform a larger clinicopathologic series to aid our anatomic interpretation of spectral-domain OCT images.
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mechanism of retinal pigment epithelium tear formation following intravitreal anti vascular endothelial growth factor therapy revealed by spectral domain optical coherence tomography
American Journal of Ophthalmology, 2013Co-Authors: Aaron Nagiel, Bailey K Freund, Richard F. Spaide, Inger Christine Munch, Michael Larsen, David SarrafAbstract:Purpose To demonstrate the mechanism by which retinal pigment epithelium (RPE) tears occur in eyes with neovascular age-related macular degeneration (AMD) treated with intravitreal anti–vascular endothelial growth factor (VEGF) agents using spectral-domain optical coherence tomography (OCT). Design Retrospective observational case series. Methods OCT images of 8 eyes that developed RPE tears following the administration of intravitreal anti-VEGF agents for neovascular AMD were evaluated. Pretear and posttear images were compared in order to elucidate the mechanism by which RPE tears occur in this setting. Results In all eyes, pretear images revealed a vascularized pigment epithelial detachment (PED) containing hyperreflective material consistent with choroidal neovascularization (CNV). This CNV was adherent to the undersurface of the RPE and created contractile folds in the RPE contour. In 6 eyes, contractile neovascular tissue spanned the PED, causing outward bowing of the Bruch Membrane and a peaked appearance to the overlying RPE monolayer. RPE tears occurred after the first anti-VEGF injection in 6 of 8 eyes. The posttear OCT images showed a discontinuity in the RPE with the CNV adherent to the retracted RPE. In all eyes, the RPE ruptured along a segment of bare RPE not in contact with the CNV or Bruch Membrane. Conclusions Eyes with vascularized PEDs secondary to AMD may show specific OCT findings that increase the risk for RPE tear following intravitreal anti-VEGF injection. Rapid involution and contraction of neovascular tissue adherent to the undersurface of the RPE may impart a substantial contractile force that tears this already-strained tissue layer.
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characteristic spectral domain optical coherence tomography findings of multifocal choroiditis
Retina-the Journal of Retinal and Vitreous Diseases, 2011Co-Authors: Sushma K Vance, Samira Khan, James M Klancnik, Bailey K FreundAbstract:Purpose To compare the spectral-domain optical coherence tomography (SD-OCT) findings of the acute lesions of multifocal choroiditis (MFC) with those of new-onset myopic choroidal neovascularization (CNV). Methods Observational case series. A retrospective review comparing the SD-OCT findings of the acute lesions of MFC with those of early myopic CNV. Spectral-domain optical coherence tomography findings in two female patients and one male patient presenting with acute inflammatory lesions of MFC were compared with those of new-onset CNV in three patients with myopic macular degeneration. Each patient underwent a comprehensive eye examination, fundus photography, and fluorescein angiography on the initial visit. The patients underwent SD-OCT scanning at baseline and at follow-up visits using image registration and eye tracking. Results Spectral-domain optical coherence tomography imaging of the acute lesions of MFC showed drusenlike material between the retinal pigment epithelium and the Bruch Membrane, presumed vitreous cells, and localized choroidal hyperreflectivity below the subretinal pigment epithelial material. These SD-OCT findings were not usually present in the eyes with myopic CNV. The subretinal pigment epithelial material corresponded to acute lesions found on color photographs and fluorescein angiography. The subretinal pigment epithelial material and choroidal hyperreflectivity appeared to improve after treatment with antiinflammatory or anti-vascular endothelial growth factor therapy. In contrast, SD-OCT in the patients with myopic CNV showed a very thin choroid, a posterior staphyloma, and a Type 2 (subretinal) neovascular pattern. Conclusion The acute lesions of MFC can be difficult to distinguish from myopic CNV based on clinical examination and fluorescein angiography. However, the inflammatory lesions of MFC can demonstrate characteristic SD-OCT findings not seen with myopic CNV. These SD-OCT findings may help to differentiate these two entities that typically require different treatments.
Christine A Curcio - One of the best experts on this subject based on the ideXlab platform.
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histology of geographic atrophy secondary to age related macular degeneration a multilayer approach
Retina-the Journal of Retinal and Vitreous Diseases, 2018Co-Authors: Miaoling Li, Jeffrey D Messinger, Rosa Dolzmarco, Daniela Ferrara, Carrie Huisingh, Bailey K Freund, Christine A CurcioAbstract:PURPOSE: To systematically characterize histologic features of multiple chorioretinal layers in eyes with geographic atrophy, or complete retinal pigment epithelium (RPE) and outer retinal atrophy, secondary to age-related macular degeneration, including Henle fiber layer and outer nuclear layer; and to compare these changes to those in the underlying RPE-Bruch Membrane-choriocapillaris complex and associated extracellular deposits. METHODS: Geographic atrophy was delimited by the external limiting Membrane (ELM) descent towards Bruch Membrane. In 13 eyes, histologic phenotypes and/or thicknesses of Henle fiber layer, outer nuclear layer, underlying supporting tissues, and extracellular deposits at four defined locations on the non-atrophic and atrophic sides of the ELM descent were assessed and compared across other tissue layers, with generalized estimating equations and logit models. RESULTS: On the non-atrophic side of the ELM descent, distinct Henle fiber layer and outer nuclear layer became dyslaminated, cone photoreceptor inner segment myoids shortened, photoreceptor nuclei and mitochondria translocated inward, and RPE was dysmorphic. On the atrophic side of the ELM descent, all measures of photoreceptor health declined to zero. Henle fiber layer/outer nuclear layer thickness halved, and only Muller cells remained, in the absence of photoreceptors. Sub-RPE deposits remained, Bruch Membrane thinned, and choriocapillaris density decreased. CONCLUSION: The ELM descent sharply delimits an area of marked gliosis and near-total photoreceptor depletion clinically defined as Geographic atrophy (or outer retinal atrophy), indicating severe and potentially irreversible tissue damage. Degeneration of supporting tissues across this boundary is gradual, consistent with steady age-related change and suggesting that RPE and Muller cells subsequently respond to a threshold of stress. Novel clinical trial endpoints should be sought at age-related macular degeneration stages before intense gliosis and thick deposits impede therapeutic intervention.
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visualizing retinal pigment epithelium phenotypes in the transition to geographic atrophy in age related macular degeneration
Retina-the Journal of Retinal and Vitreous Diseases, 2016Co-Authors: Emma C Zanzottera, Jeffrey D Messinger, Carrie Huisingh, Richard F. Spaide, Christine A CurcioAbstract:PURPOSE: To inform the interpretation of clinical optical coherence tomography and fundus autofluorescence imaging in geographic atrophy (GA) of age-related macular degeneration by determining the distribution of retinal pigment epithelium (RPE) phenotypes in the transition from health to atrophy in donor eyes. METHODS: In RPE-Bruch Membrane flat mounts of two GA eyes, the terminations of organized RPE cytoskeleton and autofluorescent material were compared. In high-resolution histological sections of 13 GA eyes, RPE phenotypes were assessed at ±500 and ±100 μm from the descent of the external limiting Membrane (ELM) toward Bruch Membrane. The ELM descent was defined as curved, reflected, or oblique in shape. Thicknesses of RPE, basal laminar deposit (BLamD), and RPE plus BLamD were measured. RESULTS: A border of atrophy that can be precisely delimited is the ELM descent, as opposed to the termination of the RPE layer itself, because of dissociated RPE in the atrophic area. Approaching the ELM descent, the percentage of abnormal RPE morphologies increases, the percentage of age-normal cells decreases, overall RPE thickens, and BLamD does not thin. The combination of RPE plus BLamD is 19.7% thicker at -100 μm from the ELM descent than that at -500 μm (23.1 ± 10.7 μm vs. 19.3 ± 8.2 μm; P = 0.05). CONCLUSION: The distribution of RPE phenotypes at the GA transition supports the idea that these morphologies represent defined stages of a degeneration sequence. The idea that RPE dysmorphia including rounding and stacking helps explain variable autofluorescence patterns in GA is supported. The ELM descent and RPE plus BLamD thickness profile may have utility as spectral domain optical coherence tomography metrics in clinical trials.
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correlation of type 1 neovascularization associated with acquired vitelliform lesion in the setting of age related macular degeneration
American Journal of Ophthalmology, 2015Co-Authors: Christine A Curcio, Jeffrey D Messinger, Bailey K Freund, Chandrakumar Balaratnasingam, Lawrence A YannuzziAbstract:Purpose To correlate postmortem histology with previously recorded multimodal imaging from a patient with type 1 neovascularization (NV) associated with an acquired vitelliform lesion in the setting of age-related macular degeneration (AMD). Design Case study. Methods Multimodal imaging that was obtained antemortem was matched with ex vivo and high-resolution histologic images of the preserved donor macula. Anatomic correlates for multimodal imaging findings were then defined. Results Spectral-domain optical coherence tomography (OCT) revealed a split in the retinal pigment epithelium–Bruch Membrane band. Type 1 NV in this case was composed of 6 layered components: (1) retinal pigment epithelium, (2) basal laminar deposits, (3) fibrovascular Membrane, (4) fibrocellular scar, (5) hemorrhage, and (6) Bruch Membrane. The anatomic correlates for the hyporeflective band on spectral-domain OCT included a thick basal laminar deposit. Not all structures could be readily separated on the basis of their reflectivity patterns. Conclusions This is an important clinicopathologic correlation of NV secondary to AMD in the spectral-domain OCT era. Our findings of 6 layers include and extend the anatomic framework encapsulated by the double-layer and triple-layer signs. The resolution of current devices does not always permit distinction of the different layers of NV tissue. Thick basal laminar deposits may appear hyporeflective on spectral-domain OCT and may be confused with fluid from a neovascular process. It will be important to perform a larger clinicopathologic series to aid our anatomic interpretation of spectral-domain OCT images.
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the oil spill in ageing Bruch Membrane
British Journal of Ophthalmology, 2011Co-Authors: Christine A Curcio, Mark Johnson, M Rudolf, Jiahn Dar HuangAbstract:Ageing is the largest risk factor for age-related macular degeneration (AMD), and soft drusen and basal linear deposits are lipid-rich extracellular lesions specific to AMD. Oil red O binding neutral lipid represents a major age-related deposition in the Bruch Membrane (BrM) and the first identified druse component. Decades after these seminal observations, a natural history of neutral lipid deposition has been articulated and a biochemical model proposed. Results obtained with multiple biochemical, histochemical, and ultrastructural methods, and supported indirectly by epidemiology, suggest that the RPE secretes apolipoprotein B (apoB)-lipoprotein particles of unusual composition into BrM, where they accumulate with age eventually forming a lipid wall, a precursor of basal linear deposit. The authors propose that constituents of these lesions interact with reactive oxygen species to form pro-inflammatory peroxidised lipids that elicit neovascularisation. Here, the authors summarise key evidence supporting both accumulation of BrM lipoproteins leading to lesion formation and lipoprotein production by the RPE. The authors update their model with genetic associations between AMD and genes historically associated with plasma HDL metabolism, and suggest future directions for research and therapeutic strategies based on an oil-spill analogy.
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lipoprotein particles of intraocular origin in human Bruch Membrane an unusual lipid profile
Investigative Ophthalmology & Visual Science, 2009Co-Authors: Lan Wang, Jeffrey D Messinger, Martin Rudolf, Olga V Belyaeva, Byung Hong Chung, Natalia Y Kedishvili, Christine A CurcioAbstract:Age-related maculopathy (ARM) is the leading cause of new, untreatable vision loss in the elderly of industrialized nations. 1 Its main clinical and histopathologic lesions affect the retinal pigment epithelium (RPE; support cells for photoreceptors), Bruch Membrane (BrM; a thin intima-like extracellular matrix), and the choriocapillaris vessels, ultimately impacting vision by the photoreceptors.2 Early ARM is characterized by drusen (focal extracellular debris), basal linear deposit (BlinD; a diffusely distributed drusenoid material), and altered RPE morphology and pigmentation. This disease stage has limited treatment options, including antioxidant nutritional supplements, and, in its later stages, loss of eyesight is possible. Although some gene sequence variants increase ARM risk,3 the largest risk factor for early ARM remains advanced age. It is therefore important to understand how age-related changes in the affected tissues impel some individuals toward severe disease. Lipoproteins are naturally occurring nanoparticles composed of lipid and protein held together by noncovalent forces. Each particle is a microemulsion consisting of a surface of phospholipids (PLs), unesterified cholesterol (UC), and apolipoproteins and a core of neutral lipids, principally esterified cholesterol (EC) and triglyceride (TG). Lipoprotein classes differ in relative amount of lipids, protein/lipid ratio, and apolipoprotein species present, resulting in differences in size, density, and electrophoretic mobility. Lipoprotein classes containing apoB are chylomicrons (CM; from intestine), very-low-density lipoproteins (VLDL; from liver), and LDL (metabolite of VLDL). ApoB lipoproteins must be properly lipidated by their source cells in order for particle maturation and secretion to proceed. Core lipid composition reflects the availability of input FA and the substrate preferences of catalytic enzymes in upstream pathways.4 From late adolescence through senescence, BrM in normal human eyes markedly accumulates histochemically detectable EC associated with abundant 60- to 80-nm-diameter solid lipoprotein– like particles (LLP).5–8 Further, drusen contain EC, UC, and immunoreactivity for apos A-I, B, C-I, C-II, and E.9 This deposition is not necessarily attributable to the systemic aging phenomenon by which EC from LDL accumulates in connective tissues, including arterial intima and cornea.10 Rather, recent evidence implicates EC as part of an apoB lipoprotein constitutively produced within the eye by the RPE and secreted into BrM, where it participates in ARM progression. Native human RPE expresses apolipoprotein mRNA transcripts, the proteins of apos B-100 and E, and notably, microsomal triglyceride transfer protein (MTP), required for apoB secretion and the product of the abetalipoproteinemia gene.11,12 Isolated BrM-LLP segregate into the appropriate band of a density gradient but differ from plasma lipoproteins in cholesterol profile.13 Cultured RPE secretes apoE, primarily into a high-density fraction.14 Size and lipid composition are strongly related for apoB lipoproteins, in that particles >25 nm diameter (CM and VLDL) have TG-rich cores and smaller particles (including LDL) have EC-rich cores.15 BrM-LLP, as large as VLDL or small CM, are expected to be TG-rich. Indeed, an early assay of BrM/choroid indicated 1.77-fold more moles TG than EC.16 However, other studies in which polarizing microscopy in tissue sections6 and enzymatic assay in isolated particles13 were used indicate that EC predominates over TG by at least threefold. To facilitate insight into the biological function of BrM-LLP and improve understanding of the lipids available to form the characteristic ARM extracellular lesions, we used comprehensive profiling of neutral lipid, PL, and retinoid components of BrM-LLP isolated from human donor eyes, comparing these results to plasma apoB lipoproteins and the secreta of an RPE cell line.
Richard F. Spaide - One of the best experts on this subject based on the ideXlab platform.
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visualizing retinal pigment epithelium phenotypes in the transition to geographic atrophy in age related macular degeneration
Retina-the Journal of Retinal and Vitreous Diseases, 2016Co-Authors: Emma C Zanzottera, Jeffrey D Messinger, Carrie Huisingh, Richard F. Spaide, Christine A CurcioAbstract:PURPOSE: To inform the interpretation of clinical optical coherence tomography and fundus autofluorescence imaging in geographic atrophy (GA) of age-related macular degeneration by determining the distribution of retinal pigment epithelium (RPE) phenotypes in the transition from health to atrophy in donor eyes. METHODS: In RPE-Bruch Membrane flat mounts of two GA eyes, the terminations of organized RPE cytoskeleton and autofluorescent material were compared. In high-resolution histological sections of 13 GA eyes, RPE phenotypes were assessed at ±500 and ±100 μm from the descent of the external limiting Membrane (ELM) toward Bruch Membrane. The ELM descent was defined as curved, reflected, or oblique in shape. Thicknesses of RPE, basal laminar deposit (BLamD), and RPE plus BLamD were measured. RESULTS: A border of atrophy that can be precisely delimited is the ELM descent, as opposed to the termination of the RPE layer itself, because of dissociated RPE in the atrophic area. Approaching the ELM descent, the percentage of abnormal RPE morphologies increases, the percentage of age-normal cells decreases, overall RPE thickens, and BLamD does not thin. The combination of RPE plus BLamD is 19.7% thicker at -100 μm from the ELM descent than that at -500 μm (23.1 ± 10.7 μm vs. 19.3 ± 8.2 μm; P = 0.05). CONCLUSION: The distribution of RPE phenotypes at the GA transition supports the idea that these morphologies represent defined stages of a degeneration sequence. The idea that RPE dysmorphia including rounding and stacking helps explain variable autofluorescence patterns in GA is supported. The ELM descent and RPE plus BLamD thickness profile may have utility as spectral domain optical coherence tomography metrics in clinical trials.
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Macular Bruch Membrane Holes in Highly Myopic Patchy Chorioretinal Atrophy
American journal of ophthalmology, 2016Co-Authors: Kyoko Ohno-matsui, Jost B. Jonas, Richard F. SpaideAbstract:Purpose Patchy atrophy is a type of chorioretinal atrophy located outside of the fovea in eyes with myopic retinopathy. Bruch Membrane defects have previously been described to occur in highly myopic eyes in foveal chorioretinal atrophy associated with choroidal neovascularization (CNV). We examined whether Bruch Membrane defects can be found also in patchy atrophy. Design Retrospective observational case series. Methods The study included all patients who were consecutively examined for high axial myopia (axial length ≥26.5 mm) and patchy atrophy in the study period from September to November 2015. The patients underwent a comprehensive ophthalmologic examination including swept-source optical coherence tomography (OCT) of the macula. Main outcome measures were macular Bruch Membrane defects. Results Out of 22 eyes (17 patients) with patchy atrophy, 21 eyes (96%) showed macular Bruch Membrane defects, which were characterized by a lack of Bruch Membrane, retinal pigment epithelium (RPE), photoreceptors, and choriocapillaris. At the edges of the macular Bruch Membrane defects, the ends of the Bruch Membrane were folded and the RPE was upturned. The inner retina overlying the area of the Bruch Membrane defect was markedly thinned. Conclusions Macular Bruch Membrane defects belong to the hallmarks of a type of myopic chorioretinal atrophy not associated with CNV (ie, patchy atrophy). Considering that Bruch Membrane defects were also observed in myopic CNV-related foveal atrophy, macular Bruch Membrane defect might be a common finding in fundus lesions related to pathologic myopia.
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Macular Bruch Membrane Holes in Choroidal Neovascularization-Related Myopic Macular Atrophy by Swept-Source Optical Coherence Tomography.
American journal of ophthalmology, 2015Co-Authors: Kyoko Ohno-matsui, Jost B. Jonas, Richard F. SpaideAbstract:Purpose To determine frequency and associations of macular Bruch Membrane defects in the region of macular atrophy developing after the onset of myopic choroidal neovascularization (CNV). Design Retrospective observational case series. Methods The study included all patients who were consecutively examined for high myopia (axial length ≥26.5mm) and CNV-related macular atrophy in the study period from June to July 2015. The patients underwent a comprehensive ophthalmologic examination including swept-source optical coherence tomography (OCT) of the macula. Main outcome measures were macular Bruch Membrane defects. Results Out of 33 eyes (28 patients) with myopic CNV-related macular atrophy, 25 eyes (76%) showed macular Bruch Membrane defects, which were characterized by a lack of Bruch Membrane, retinal pigment epithelium, photoreceptors, and choriocapillaris. At the edges of the macular Bruch Membrane defects, the ends of the Bruch Membrane were upturned, and an inward protrusion of large choroidal vessels could be detected. In the center of macular Bruch Membrane defects, remnants of Bruch Membrane could be crumpled. In multivariate analysis, higher prevalence of secondary macular Bruch Membrane defects was significantly associated with a lower prevalence of intravitreal medical therapy ( P P P = .42). Conclusions Macular Bruch Membrane defects belong to the hallmarks of myopic CNV-related macular atrophy. Since macular Bruch Membrane defects lack photoreceptors and thus represent psychophysically an absolute scotoma, they are of profound importance for visual prognosis. As incidentally observed at study end, the prevalence of macular Bruch Membrane defects may be lower if a previous myopic CNV was treated by intravitreal medical therapy.
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peau d orange and angioid streaks manifestations of Bruch Membrane pathology
Retina-the Journal of Retinal and Vitreous Diseases, 2015Co-Authors: Richard F. SpaideAbstract:PURPOSE The aim of this study was to characterize peau d'orange and angioid streaks, characteristic findings in eyes of patients with pseudoxanthoma elasticum, by examining fundus photography and optical coherence tomography imaging. METHODS Color photographs were evaluated directly as were the component red and green channels. Optical coherence tomography images were evaluated for reflectivity pattern of the band corresponding to the retinal pigment epithelium-Bruch Membrane complex. RESULTS Eighteen eyes of 9 patients with a mean age of 48.7 years (range, 31-61 years) were examined; 7 of them were women. Color photographs showed areas of yellowish opacification that obscured visualization of the underlying choroid. At the outer edges of this confluent area, opacification were nonconfluent changes with similar appearance and these regions were typical peau d'orange. Angioid streaks occurred within and extended up to the outer border of the confluent opacification. Underlying choroidal details could be seen through the regions of peau d'orange and through the gaps in angioid streaks. The red channel image showed increased reflectivity from the confluent deposit and improved visualization of the choroidal vasculature, except where the confluent opacification was located. Optical coherence tomography imaging showed increased reflectivity from the outer border of the retinal pigment epithelium-Bruch Membrane complex. CONCLUSION The findings suggest that the confluent region is the relevant lesion, not the subconfluent zone known as peau d'orange. Imaging characteristics of the confluent area of opacity are consistent with diffuse infiltration with calcium, a chief histologic abnormality of pseudoxanthoma elasticum. The name coquille d'oeuf was suggested for the confluent area of opacity as a consequence.
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mechanism of retinal pigment epithelium tear formation following intravitreal anti vascular endothelial growth factor therapy revealed by spectral domain optical coherence tomography
American Journal of Ophthalmology, 2013Co-Authors: Aaron Nagiel, Bailey K Freund, Richard F. Spaide, Inger Christine Munch, Michael Larsen, David SarrafAbstract:Purpose To demonstrate the mechanism by which retinal pigment epithelium (RPE) tears occur in eyes with neovascular age-related macular degeneration (AMD) treated with intravitreal anti–vascular endothelial growth factor (VEGF) agents using spectral-domain optical coherence tomography (OCT). Design Retrospective observational case series. Methods OCT images of 8 eyes that developed RPE tears following the administration of intravitreal anti-VEGF agents for neovascular AMD were evaluated. Pretear and posttear images were compared in order to elucidate the mechanism by which RPE tears occur in this setting. Results In all eyes, pretear images revealed a vascularized pigment epithelial detachment (PED) containing hyperreflective material consistent with choroidal neovascularization (CNV). This CNV was adherent to the undersurface of the RPE and created contractile folds in the RPE contour. In 6 eyes, contractile neovascular tissue spanned the PED, causing outward bowing of the Bruch Membrane and a peaked appearance to the overlying RPE monolayer. RPE tears occurred after the first anti-VEGF injection in 6 of 8 eyes. The posttear OCT images showed a discontinuity in the RPE with the CNV adherent to the retracted RPE. In all eyes, the RPE ruptured along a segment of bare RPE not in contact with the CNV or Bruch Membrane. Conclusions Eyes with vascularized PEDs secondary to AMD may show specific OCT findings that increase the risk for RPE tear following intravitreal anti-VEGF injection. Rapid involution and contraction of neovascular tissue adherent to the undersurface of the RPE may impart a substantial contractile force that tears this already-strained tissue layer.
Peter Charbel Issa - One of the best experts on this subject based on the ideXlab platform.
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mesopic and scotopic light sensitivity and its microstructural correlates in pseudoxanthoma elasticum
JAMA Ophthalmology, 2020Co-Authors: Kristina Hess, Peter Charbel Issa, Martin Gliem, Johannes Birtel, Philipp L Muller, Leon Von Der Emde, Philipp Herrmann, Frank G HolzAbstract:Importance Correlates for Bruch Membrane alterations are needed for interventional trials targeting the Bruch Membrane in pseudoxanthoma elasticum (PXE). Objectives To quantify mesopic and scotopic light sensitivity and identify its microstructural correlates associated with a diseased Bruch Membrane in patients with PXE. Design, setting, and participants A prospective, single-center, cross-sectional case-control study was conducted at a tertiary referral center from January 31, 2018, to February 20, 2020. Twenty-two eyes of 22 patients with PXE and 40 eyes of 40 healthy individuals were included. Data analysis was completed March 15, 2020. Exposures Mesopic and dark-adapted 2-color fundus-controlled perimetry (microperimetry) and multimodal retinal imaging including spectral-domain optical coherence tomography (SD-OCT) and OCT angiography were performed. Perimetry thresholds were analyzed using mixed models, and structure-function correlation with SD-OCT data was performed using machine learning. Main outcomes and measures Observed dark-adapted cyan sensitivity loss as measure of rod photoreceptor dysfunction, as well as mean absolute error between predicted and observed retinal sensitivity to assess the accuracy of structure-function correlation. Results Of the 22 patients with PXE included in this study, 15 were women (68%); median age was 56.5 years (interquartile range, 50.4-61.2). These patients exhibited mesopic (estimate, 5.13 dB; 95% CI, 2.89-7.38 dB), dark-adapted cyan (estimate, 9.08 dB; 95% CI, 6.34-11.82 dB), and dark-adapted red (estimate, 7.05 dB; 95% CI, 4.83-9.27 dB) sensitivity losses. This sensitivity loss was also evident in 9 eyes with nonneovascular PXE (mesopic: estimate, 3.21 dB; 95% CI, 1.28-5.14 dB; dark-adapted cyan: 5.93 dB; 95% CI, 3.59-8.27 dB; and dark-adapted red testing: 4.84 dB; 95% CI, 2.88-6.80 dB), showing a distinct centrifugal pattern of sensitivity loss with preserved function toward the periphery. Retinal function could be predicted from microstructure with high accuracy (mean absolute errors, of 4.91 dB for mesopic, 5.44 dB for dark-adapted cyan, and 4.99 dB for dark-adapted red). The machine learning-based analysis highlighted an association of a thinned inner retina and putative separation of the pigment-epithelium-photoreceptor complex with sensitivity loss. Conclusions and relevance In this study, among 22 patients with PXE, those with and without choroidal neovascularization exhibited reductions of retinal sensitivity being most pronounced in dark-adapted cyan testing. This finding suggests that pathologic characteristics of this Bruch Membrane disease may be dominated by rod photoreceptor degeneration and/or dysfunction. A putative pigment-epithelium-photoreceptor separation may further impair rod function, while inner retinal abnormalities appear to be correlated with overall dysfunction.
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impaired dark adaptation associated with a diseased Bruch Membrane in pseudoxanthoma elasticum
Retina-the Journal of Retinal and Vitreous Diseases, 2019Co-Authors: Kristina Hess, Frank G Holz, Martin Gliem, Johannes Birtel, Philipp L Muller, Doris Hendig, Colm Andrews, Ian J Murray, Peter Charbel IssaAbstract:PURPOSE To characterize dark adaptation in patients with pseudoxanthoma elasticum, a systemic disease leading to calcification of elastic tissue including the Bruch Membrane. METHODS In this prospective case-control study, dark adaptation thresholds were measured using a Goldmann-Weekers dark adaptometer. Additional assessments included best-corrected visual acuity testing, contrast sensitivity, low luminance deficit, and vision-related quality of life. RESULTS Dark adaptation thresholds were significantly higher, and adaptation periods were prolonged in patients with pseudoxanthoma elasticum (n = 35; 33 with 2 ABCC6 mutations) compared with controls (n = 35). The time to adapt 4 log units (20.6 ± 8.6 vs. 8.0 ± 1.3 minutes) and the mean dark adaptation threshold after 15 minutes (3.5 ± 1.1 vs. 1.8 ± 0.2 log units) were significantly different between patients and controls (both P < 0.001). Low luminance deficits (12.3 ± 6.4 vs. 6.1 ± 4.3 ETDRS letters), contrast sensitivity (1.4 ± 0.3 vs. 1.9 ± 0.1), and low luminance-related quality of life (LLQ score: 1,286 ± 355 vs. 2,167 ± 68) were also significantly worse in patients with pseudoxanthoma elasticum (all, P < 0.001). Two patients were treated with high-dose vitamin A which partially reversed impaired dark adaptation. CONCLUSION Patients with pseudoxanthoma elasticum often have impaired dark adaptation. Positive effects of vitamin A supplementation may indicate restricted retinal access of vitamin A through the Bruch Membrane as one possible underlying pathogenic factor.
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reticular pseudodrusen associated with a diseased Bruch Membrane in pseudoxanthoma elasticum
JAMA Ophthalmology, 2015Co-Authors: Martin Gliem, Frank G Holz, Doris Hendig, Robert P Finger, Peter Charbel IssaAbstract:Importance Reticular pseudodrusen (RPD) are frequently associated with age-related macular degeneration and considered to be an independent risk factor for disease progression, but the pathophysiologic mechanisms are only incompletely understood. Therefore, it may be helpful to identify the associations of RPD with other diseases that have defined pathophysiologic mechanisms. Objective To describe the phenotype, prevalence, and topographic distribution of RPD in patients with pseudoxanthoma elasticum (PXE) and their association with a diseased Bruch Membrane. Design, Setting, and Participants In this single-center, prospective, cross-sectional case series, 57 consecutive patients with PXE from a university referral center whose diagnosis has been confirmed by genetic testing and/or skin biopsy were studied from March 1, 2013, through February 28, 2014. Main Outcomes and Measures Phenotypic characteristics of RPD were evaluated with multiple imaging techniques. The RPD were defined as irregular networks of round to oval lesions that appear hyporeflective on near-infrared reflectance, hypoautofluorescent on fundus autofluorescence, and as subretinal deposits on spectral-domain optical coherence tomographic images. The presence of RPD was judged based on characteristic findings in at least 2 of the 3 imaging modalities. Results A total of 57 patients were examined, and 15 patients were excluded mainly because of large central atrophy or fibrosis. In the remaining 42 patients with PXE, RPD were detected in 22 patients (52%; 95% CI, 38%-67%). Prevalence of RPD was highest in the fifth decade at 67% (10/15; 95% CI, 42%-85%). The RPD were most frequently located within the superior quadrant and least frequently located within the central macula. The RPD were always located central to areas with peau d’orange and within an area of hypofluorescence on late-phase indocyanine green angiographic images. Conclusions and Relevance These data suggest that RPD have a high prevalence in eyes of patients with PXE. Although RPD in patients with PXE occur at a younger age, their distribution and phenotype appear to be similar to RPD associated with age-related macular degeneration. The association with diseased Bruch Membrane in PXE suggests a pathogenetic role of Bruch Membrane alterations for the development of RPD.
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choroidal changes associated with Bruch Membrane pathology in pseudoxanthoma elasticum
American Journal of Ophthalmology, 2014Co-Authors: Martin Gliem, Frank G Holz, Philipp L Muller, Doris Hendig, Rolf Fimmers, Christian K Brinkmann, Robert P Finger, Peter Charbel IssaAbstract:Purpose To investigate the impact of Bruch Membrane pathology on the choroid in pseudoxanthoma elasticum (PXE). Design Monocenter cross-sectional prospective case series. Methods The study included 61 eyes of 51 patients with PXE and 54 eyes of 54 normal subjects. The diagnosis of PXE was based on skin biopsy, genetic analysis or both. Eyes with PXE were subdivided into 3 groups: eyes without choroidal neovascularization (CNV) or chorioretinal atrophy (Group 1); eyes with active or fibrotic CNV (Group 2); and eyes with chorioretinal atrophy only (Group 3). Choroidal thickness was measured using enhanced-depth imaging optical coherence tomography (EDI-OCT). Results Compared to controls (331 μm ± 24; mean ± 95% CI), mean subfoveal choroidal thickness in eyes of patients with PXE was significantly reduced within all 3 groups (Group 1: 243 μm ± 29; Group 2: 184 μm ± 28; Group 3: 104 μm ± 28; P Conclusions The results indicate that changes of Bruch Membrane can be associated with choroidal alterations, which are most pronounced in the presence of advanced disease. A role of Bruch Membrane in choroidal homeostasis may reflect a possible contribution of Bruch Membrane alterations to CNV and geographic atrophy development in age-related macular degeneration.
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spectral domain optical coherence tomography in adult onset vitelliform macular dystrophy with cuticular drusen
Retina-the Journal of Retinal and Vitreous Diseases, 2010Co-Authors: Robert Finger, Peter Charbel Issa, Ulrich Kellner, Steffen Schmitzvalckenberg, Monika Fleckenstein, Hendrik P N Scholl, Frank G HolzAbstract:PURPOSE The purpose of this study was to investigate morphologic differences in a consecutive case series of patients suffering from adult-onset vitelliform macular dystrophy with cuticular drusen (CD) compared with another patient group with a vitelliform lesion only using high-resolution in vivo retinal imaging. METHODS Simultaneous spectral domain optical coherence tomography (870 nm, 40.000 A-scans per second) and confocal scanning laser ophthalmoscopy were performed in 6 patients (12 eyes) with adult-onset vitelliform macular dystrophy using a combined instrument (Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany). RESULTS Mean age was 69 years (59-82 years), and mean visual acuity was 20/80. The vitelliform lesion presented with an accumulation of yellow-gray material with increased fundus autofluorescence. Spectral domain optical coherence tomography imaging showed that the neurosensory detachment was filled with an amorphous homogenously reflective material located between the retinal pigment epithelium and neurosensory retina in the inferior part of the lesion with the superior part being optically empty. The retinal pigment epithelium basal Membrane/Bruch Membrane band on spectral domain optical coherence tomography showed multiple focal nodules, in analogy to histologic descriptions of CD. Longitudinal observations in a subgroup of patients showed that the vitelliform detachment collapsed with subsequent development of geographic atrophy in patients with CDs. CONCLUSION Cuticular drusen may be an indicator for a generalized retinal pigment epithelium dysfunction. High-resolution spectral domain optical coherence tomography allows to image morphologic differences in adult-onset vitelliform macular dystrophy with and without CDs, providing further evidence that adult-onset vitelliform macular dystrophy with CDs represents a separate disease entity.
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spectral domain optical coherence tomography derived characteristics of Bruch Membrane opening in a young adult australian population
American Journal of Ophthalmology, 2016Co-Authors: Paul G Sanfilippo, Emily Huynh, Seyhan Yazar, Alex W Hewitt, David A MackeyAbstract:Purpose To characterize and quantify Bruch Membrane opening (BMO)-based optic nerve head (ONH) parameters in a large, young and healthy, predominantly white population. Design Cross-sectional study and reliability analysis. Methods The ONH of 1344 predominantly white subjects were imaged with spectral-domain optical coherence tomography (SD-OCT). A customized script, coded in Matlab, was used to manually segment and measure multiple BMO-based parameters of the ONH. Measurements were compared to those obtained with confocal scanning laser ophthalmoscopy (Heidelberg Retina Tomograph; HRT). Regression analysis was performed to assess the relationship between BMO parameters and other ocular and demographic variables. Results Mean BMO disc and neuroretinal rim (NRR) areas ranged from 0.94 to 4.06 mm 2 (mean 1.77 ± 0.38 mm 2 ) and 0.94 to 3.99 mm 2 (mean 1.56 ± 0.31 mm 2 ), respectively. When compared to the equivalent HRT measurements, SD-OCT-derived measures differed significantly for all comparable ONH parameters ( P Conclusions We have quantified BMO-based parameters in a large cohort of young adults using SD-OCT. These data will be informative in constructing normative profiles for clinical and research purposes in glaucoma diagnosis and management.
