Mast cells in human choroid and their role in age-related macular degeneration (AMD).

The role of mast cells in physiologic and pathological processes extends far beyond the allergy processes: they are involved in wound healing, chronic inflammation, and tumor growth. This short article emphasizes the role played by mast cells in age-related macular degeneration (AMD). Mast cells can induce angiogenesis and are present around Bruch's membrane during the early and late stages of choroidal neovascularization in AMD. Proteolytic enzymes released by mast cells lead to thinning of the choroid in AMD as well as degradation of vascular basement membranes and Bruch's membrane, which in turn could result in retinal pigment epithelial death and choriocapillaris degeneration in geographical atrophy and exudative AMD.

Histological Findings in the Eyes of Abcc6 Knockout Rat Model of Pseudoxanthoma Elasticum.

Purpose: To describe the ocular findings of murine pseudoxanthoma elasticum (PXE) models with ATP-binding cassette subfamily C member 6 (Abcc6) gene knockout. Methods: This experiment was conducted in four Abcc6-/- rats and compared with six wild-type Abcc6+/+ control rats. The animals underwent necropsy at 6 months of age. Histological examination of the eyes was performed. Results: Histological examination of eight eyes from four Abcc6-/- rats revealed multiple nodular foci of calcification in the uvea, sclera, and conjunctiva, focally in perivascular distribution, as well as linear and nodular calcification of Bruch's membrane. Calcific foci were not associated with inflammation in the knockout rats. There was no evidence of calcification in control eyes. Discussion: The Abcc6-/- rat model shows that PXE can affect multiple ocular tissues beyond the calcification in Bruch's membrane noted in human eyes. Nodular calcific foci probably correspond to comet lesions seen in patients with PXE. The presence of ectopic calcium without inflammation distinguishes it from inflammatory calcium deposition in atherosclerosis. Further studies are needed to determine why PXE does not cause inflammatory infiltration. Translational Relevance: The Abcc6-/- murine model may be suitable for studying ocular PXE pathophysiology and ectopic calcification and developing effective therapies.

Effects of Deep Optic Nerve Head Structures on Bruch's Membrane Opening- Minimum Rim Width and Peripapillary Retinal Nerve Fiber Layer.

PURPOSE: To explore the effects of deep optic nerve head (ONH) structures on Bruch's membrane opening (BMO)-minimum rim width (MRW) and peripapillary retinal nerve fiber layer thickness (pRNFLT) in healthy eyes. DESIGN: Prospective cross-sectional study. METHODS: Two hundred five healthy eyes of 141 subjects (mean ± standard deviation of age and axial length (AXL): 46.9 ± 10.0 years and 24.79 ± 1.15 mm) were enrolled. Best fit multivariable linear mixed models identified factors associated with BMO-MRW and pRNFLT. Explanatory variables included age, gender, AXL, BMO and anterior scleral canal opening (ASCO) area and ovality, magnitude of BMO and ASCO shift, peripapillary choroidal thickness, lamina cribrosa (LC) parameters, prelaminar thickness, and peripapillary scleral (PPS) angle. RESULTS: Thinner BMO-MRW was associated with older age, smaller ASCO/BMO offset magnitude, larger BMO area, thinner prelaminar thickness, deeper LC, and thinner pRNFLT (P = .011, <.001, .004, <.001, <.001, <.001 respectively). Thinner pRNFLT was associated with shorter AXL, smaller ASCO area, a more posteriorly bowed PPS, shallower LC and thinner BMO-MRW. (P = .030, .002, .035, .012, <.001 respectively) CONCLUSIONS: BMO-MRW and pRNFLT were influenced by several deep ONH structures such as BMO and ASCO position shift, BMO or ASCO area, prelaminar thickness, PPS bowing and LC depth in addition to patient characteristics such as age and AXL. The degree and/or direction of associations varied between deep ONH structures and BMO-MRW or pRNFLT. Despite both BMO-MRW and pRNFLT being surrogate parameters for RGC loss, a complex relationship with ONH deep-layer morphology was indicated.

Elastin Layer in Bruch's Membrane as a Target for Immunization or Tolerization to Modulate Pathology in the Mouse Model of Smoke-Induced Ocular Injury.

Age-related macular degeneration (AMD) is associated with an overactive complement system and an increase in circulating antibodies. Our search for potential neoantigens that can trigger complement activation in disease has led us to investigate elastin. A loss of the elastin layer (EL) of Bruch's membrane (BrM) has been reported in aging and AMD together with an increase of serum elastin-derived peptides and α-elastin antibodies. In the mouse model of cigarette smoke exposure (CSE), damage in BrM, loss of the EL, and vision loss are dependent on complement activation. We have examined the hypothesis that CSE generates immunogenic elastin neoepitopes that trigger an increase in α-elastin IgG and IgM antibodies, which can then bind to the neoepitopes in the target cells or membranes, triggering complement activation. Specifically, we showed that immunization with elastin peptide oxidatively modified by cigarette smoke (ox-elastin) exacerbated ocular pathology and vision loss in CSE mice. In contrast, mice receiving peptide immunotherapy (PIT) with ox-elastin did not lose vision over the smoking period and exhibited a more preserved BrM. Immunization and PIT correlated with humoral immunity and complement activation and IgG/IgM deposition in the RPE/BrM/choroid. Finally, PIT modulated immune markers IFNγ and IL-4. The data further support the hypothesis that complement activation, triggered by immune complex formation in target tissues, plays a role in ocular damage in the CSE model. As PIT with ox-elastin peptides reduces damage, we discuss the possibility that AMD progression might be preventable.

Longitudinal Changes of Bruch's Membrane Opening, Anterior Scleral Canal Opening, and Border Tissue in Experimental Juvenile High Myopia.

Purpose: To investigate the relative positional changes between the Bruch's membrane opening (BMO) and the anterior scleral canal opening (ASCO), and border tissue configuration changes during experimental high myopia development in juvenile tree shrews. Methods: Juvenile tree shrews were assigned randomly to two groups: binocular normal vision (n = 9) and monocular -10 D lens treatment starting at 24 days of visual experience to induce high myopia in one eye while the other eye served as control (n = 12). Refractive and biometric measurements were obtained daily, and 48 radial optical coherence tomography B-scans through the center of the optic nerve head were obtained weekly for 6 weeks. ASCO and BMO were segmented manually after nonlinear distortion correction. Results: Lens-treated eyes developed high degree of axial myopia (-9.76 ± 1.19 D), significantly different (P < 0.001) from normal (0.34 ± 0.97 D) and control eyes (0.39 ± 0.88 D). ASCO-BMO centroid offset gradually increased and became significantly larger in the experimental high myopia group compared with normal and control eyes (P < 0.0001) with an inferonasal directional preference. The border tissue showed a significantly higher tendency of change from internally to externally oblique configuration in the experimental high myopic eyes in four sectors: nasal, inferonasal, inferior, and inferotemporal (P < 0.005). Conclusions: During experimental high myopia development, progressive relative deformations of ASCO and BMO occur simultaneously with changes in border tissue configuration from internally to externally oblique in sectors that are close to the posterior pole (nasal in tree shrews). These asymmetric changes may contribute to pathologic optic nerve head remodeling and an increased risk of glaucoma later in life.

Inner limiting membrane bridges within Bruch's membrane defects in pathological myopia.

The purpose of the study was to examine peculiarities of the inner limiting membrane (ILM) in axially elongated eyes. The histomorphometric study included human globes enucleated due to reasons such as painful secondary angle-closure glaucoma or malignant uveal melanomas. Using light microscopy, we searched for regions with ILM-specific features in association with a marked axial elongation. Out of 279 eyes (279 patients) (mean age: 61.8 ± 13.9 years; axial length: 25.5 ± 3.1 mm (range: 20.0-37.0 mm)), two eyes (axial length: 30 mm and 34 mm, respectively) showed one region and two regions, respectively, characterized by ILM presence and absence of all other retinal layers, retinal pigment epithelium, Bruch´s membrane (BM) and choroid. The length of these regions, called ILM-bridges, was 1.06 mm, 0.73 mm, and 0.62 mm, respectively. All ILM-bridges were spatially associated with a larger, underlying BM defect and with localized scleral thinning without a staphylomatous scleral configuration. The distance between the ILM-bridges and the optic disc ranged between 1.92 mm and 4.21 mm. In univariable analysis, ILM-bridge number increased with longer axial length (beta: 0.19; P = 0.002) and higher BM defect prevalence (beta: 0.21; P = 0.001), while in multivariable analysis, the ILM-bridges number remained to be significantly correlated only with a higher prevalence of BM defect (beta: 0.15; P = 0.048). ILM-bridges occur in eyes with pathologic myopia in spatial association with underlying, larger BM defects. They may be due to an axial elongation-associated local stretching and rupture of all other retinal layers, caused by the BM defect-related enlargement of the retinal undersurface. Future studies may explore whether these histologic observations support the notion of the ILM having a relatively high biomechanical strength against myopic stretching-associated forces.

Microbiota mitochondria disorders as hubs for early age-related macular degeneration.

Age-related macular degeneration (AMD) is a progressive neurodegenerative disease affecting the central area (macula lutea) of the retina. Research on the pathogenic mechanism of AMD showed complex cellular contribution governed by such risk factors as aging, genetic predisposition, diet, and lifestyle. Recent studies suggested that microbiota is a transducer and a modifier of risk factors for neurodegenerative diseases, and mitochondria may be one of the intracellular targets of microbial signaling molecules. This review explores studies supporting a new concept on the contribution of microbiota-mitochondria disorders to AMD. We discuss metabolic, vascular, immune, and neuronal mechanism in AMD as well as key alterations of photoreceptor cells, retinal pigment epithelium (RPE), Bruch's membrane, choriocapillaris endothelial, immune, and neuronal cells. Special attention was paid to alterations of mitochondria contact sites (MCSs), an organelle network of mitochondria, endoplasmic reticulum, lipid droplets (LDs), and peroxisomes being documented based on our own electron microscopic findings from surgically removed human eyes. Morphometry of Bruch's membrane lipids and proteoglycans has also been performed in early AMD and aged controls. Microbial metabolites (short-chain fatty acids, polyphenols, and secondary bile acids) and microbial compounds (lipopolysaccharide, peptidoglycan, and bacterial DNA)-now called postbiotics-in addition to local effects on resident microbiota and mucous membrane, regulate systemic metabolic, vascular, immune, and neuronal mechanisms in normal conditions and in various common diseases. We also discuss their antioxidant, anti-inflammatory, and metabolic effects as well as experimental and clinical observations on regulating the main processes of photoreceptor renewal, mitophagy, and autophagy in early AMD. These findings support an emerging concept that microbiota-mitochondria disorders may be a crucial pathogenic mechanism of early AMD; and similarly, to other age-related neurodegenerative diseases, new treatment approaches should be targeted at these disorders.

Elastin turnover in ocular diseases: A special focus on age-related macular degeneration.

The extracellular matrix (ECM) and its turnover play a crucial role in the pathogenesis of several inflammatory diseases, including age-related macular degeneration (AMD). Elastin, a critical protein component of the ECM, not only provides structural and mechanical support to tissues, but also mediates several intracellular and extracellular molecular signaling pathways. Abnormal turnover of elastin has pathological implications. In the eye elastin is a major structural component of Bruch's membrane (BrM), a critical ECM structure separating the retinal pigment epithelium (RPE) from the choriocapillaris. Reduced integrity of macular BrM elastin, increased serum levels of elastin-derived peptides (EDPs), and elevated elastin antibodies have been reported in AMD. Existing reports suggest that elastases, the elastin-degrading enzymes secreted by RPE, infiltrating macrophages or neutrophils could be involved in BrM elastin degradation, thus contributing to AMD pathogenesis. EDPs derived from elastin degradation can increase inflammatory and angiogenic responses in tissues, and the elastin antibodies are shown to play roles in immune cell activity and complement activation. This review summarizes our current understanding on the elastases/elastin fragments-mediated mechanisms of AMD pathogenesis.

Clinicopathological study of the polypoidal lesions of polypoidal choroidal vasculopathy.

PURPOSE: To investigate the pathogenic features of the polypoidal lesions from the specimens of polypoidal choroidal vasculopathy extracted from human subjects. METHODS: Seven specimens of polypoidal lesions extracted from five eyes of six patients (mean age, 60.16 ± 10.41 years) of polypoidal choroidal vasculopathy were examined. The polypoidal lesions were obtained by surgical excision. Thereafter, a histopathological analysis of the specimens was performed. RESULTS: The polypoidal lesions were oval nodules located underneath the retinal pigment epithelium. A pathological study of the lesions revealed that Bruch's membrane schisis was observed in all specimens and they were all located in the Bruch's membrane. The Bruch's membrane schisis and serosanguineous materials constituted the main structure of the lesions in five of the seven specimens, with small vessels being observed in two specimens. One specimen was composed of two polypoidal lesions of different characteristics, and one specimen had a neovessel membrane complex with several polypoidal lesions. Inflammatory cells and blood vessels were observed in the polypoidal lesion of the specimen with neovessel membrane complex. CONCLUSION: Polypoidal lesions of polypoidal choroidal vasculopathy are abnormalities of the Bruch's membrane. The lesions are characterized by the Bruch's membrane schisis, which is filled with serosanguineous materials. The lesions are progressive and may contain inflammatory cells and blood vessels.

ARE THERE TWO FORMS OF MULTIPLE EVANESCENT WHITE DOT SYNDROME?

PURPOSE: To analyze the nature of multiple evanescent white dot syndrome (MEWDS) and differentiate an idiopathic or primary form of MEWDS from a secondary form that is seen in association with other clinical conditions affecting the posterior segment of the eye. METHODS: Clinical and multimodal imaging findings including color fundus photography, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, spectral-domain optical coherence tomography, and optical coherence tomography angiography of patients with secondary MEWDS are presented. RESULTS: Twenty consecutive patients with secondary MEWDS were evaluated. Fifteen patients were female. Most were young adults aged between 20 to 40 years with myopia (less than -6 diopters). Pathologic conditions associated with the secondary MEWDS reaction were high myopia (greater than -6 diopters) in two eyes, previous vitreoretinal surgery for rhegmatogenous retinal detachment in 2 eyes, and manifestations of multifocal choroiditis in 18 eyes. In all eyes, the MEWDS lesions followed a course of progression and resolution independent from the underlying condition. CONCLUSION: Secondary MEWDS seems to be an epiphenomenon ("EpiMEWDS") that may be seen in association with clinical manifestations disruptive to the choriocapillaris-Bruch membrane-retinal pigment epithelium complex.

Offset of openings in optic nerve head canal at level of Bruch's membrane, anterior sclera, and lamina cribrosa.

We compared the central retinal vascular trunk (CRVT) position, as a surrogate of lamina cribrosa (LC) offset, with the anterior scleral opening (ASCO) offset from the Bruch's membrane opening (BMO). Based on the BMO-centered radial scans, the BMO and ASCO margins were demarcated, and each center was determined as the center of the best-fitted ellipse for each margin. The ASCO/BMO offset was defined as the offset between each center. Angular deviations and the extent of ASCO and CRVT offsets from the BMO center were compared directly. Incomplete demarcation of ASCO was found in 20%, which was associated with a larger BMO area and a larger ASCO offset from the BMO. The angular deviation of ASCO offset was associated with that of CRVT offset and that of the longest externally oblique border. The ASCO offset was smaller than the CRVT offset, and, unlike the CRVT offset, it was rarely deviated to the inferior side. The complete ASCO margin might not be demarcatable when determined on BMO-centered radial scans in the presence of an offset. Also, the ASCO, which reflects only the superficial scleral layer, might not reflect the LC position, because the LC might be shifted further from the ASCO.

Interactions between hydroxyapatite and cholesterol associated with calcification in age-related macular degeneration.

Hydroxyapatite deposition and calcification occurs over cholesterol-containing lipid droplets between Bruch's membrane and sub-retinal pigment epithelium (sub - RPE) in the eyes of patients affected by age-related macular degeneration (AMD) as spherules, nodules, and Bruch's membrane plaques. In the present study, an attempt has been made to prepare a composite containing hydroxyapatite and cholesterol to elucidate interactions involved in the formation of such organic-inorganic interphase. To understand the mechanism of hydroxyapatite deposition on cholesterol, we have applied various biophysical techniques such as dynamic light scattering (DLS) measurements, transmission electron microscopy (TEM) imaging, Fourier transform infrared (FTIR) spectroscopy and solid-state nuclear magnetic resonance (ssNMR) spectroscopy on the prepared composite. Our results give molecular level insight into the mechanism of biocalcification in the disease system.

Pattern dystrophy-like changes and coquille d'oeuf atrophy in elderly patients affected by pseudoxanthoma elasticum.

PURPOSE: To evaluate the retinal features of elderly patients affected by pseudoxanthoma elasticum (PXE). MATERIALS AND METHODS: This is a retrospective case series of 62 eyes of 31 elderly PXE patients (age > 50 years). Clinical data, ultra-widefield fundus imaging (color, red-free (RF), infra-red imaging (IR), fundus autofluorescence (FAF)), and OCT examinations were collected. Diagnosis was confirmed by genetic testing or skin biopsy. RESULTS: Thirty-one patients (10 males and 21 females (mean age 61.3 years, range 50-74 years)) were included in our study. Visual acuity ranged from 20/20 Snellen equivalent to 20/200. The mean follow-up was 66.4 ± 20.7 months (range 10-88). Pattern dystrophy-like changes (PD) (52 eyes of 26 patients, 83.8%) and atrophy resembling the "diffuse trickling" pattern described in geographic atrophy were present in the majority of patients. Twenty-three eyes of 12 patients (67.6%) had peripapillary atrophy, 9 eyes of 5 patients (26.4%) macular atrophy, 6 eyes of 3 patients (17.6%) displayed posterior pole atrophy and in 6 eyes of 3 patients (17.6%), atrophy could be detected beyond the vascular arcades (mid-peripheral atrophy). End-stage atrophy covered the entire area indicated as "coquille d'oeuf" (eggshell). Choroidal neovascularization occurred in 49 eyes of 26 patients (94.2%) with PD and in 6 eyes of 3 patients (60%) without PD. Genetic examinations were available for 29 patients (29/31, 93.5%). CONCLUSIONS: The elderly PXE patients were characterized by pattern dystrophy-like changes with more or less extensive atrophy, progressive over time, which in some cases affected the whole area of the coquille d'oeuf during the course of the disease.

Optical Coherence Tomography Optic Nerve Head Morphology in Myopia I: Implications of Anterior Scleral Canal Opening Versus Bruch Membrane Opening Offset.

PURPOSE: To measure the magnitude and direction of anterior scleral canal opening (ASCO) offset relative to the Bruch membrane opening (BMO) (ASCO/BMO offset) to characterize neural canal obliqueness and minimum cross-sectional area (NCMCA) in 69 highly myopic and 138 healthy, age-matched, control eyes. DESIGN: Cross-sectional study. METHODS: Using optical coherence tomography (OCT) scans of the optic nerve head (ONH), BMO and ASCO were manually segmented and their centroids and size and shape were calculated. ASCO/BMO offset magnitude and direction were measured after projecting the ASCO/BMO centroid vector onto the BMO plane. Neural canal axis obliqueness was defined as the angle between the ASCO/BMO centroid vector and the vector perpendicular to the BMO plane. NCMCA was defined by projecting BMO and ASCO points onto a plane perpendicular to the neural canal axis and measuring their overlapping area. RESULTS: ASCO/BMO offset magnitude was greater (highly myopic eyes 264.3 ± 131.1 µm; healthy control subjects 89.0 ± 55.8 µm, P < .001, t test) and ASCO centroid was most frequently nasal relative to BMO centroid (94.2% of eyes) in the highly myopic eyes. BMO and ASCO areas were significantly larger (P < .001, t test), NCMCA was significantly smaller (P < .001), and all 3 were significantly more elliptical (P ≤ .001) in myopic eyes. Neural canal obliqueness was greater in myopic (65.17° ± 14.03°) compared with control eyes (40.91° ± 16.22°; P < .001, t test). CONCLUSIONS: Our data suggest that increased temporal displacement of BMO relative to the ASCO, increased BMO and ASCO area, decreased NCMCA, and increased neural canal obliqueness are characteristic components of ONH morphology in highly myopic eyes.

Secretory proteostasis of the retinal pigmented epithelium: Impairment links to age-related macular degeneration.

Secretory proteostasis integrates protein synthesis, processing, folding and trafficking pathways that are essential for efficient cellular secretion. For the retinal pigment epithelium (RPE), secretory proteostasis is of vital importance for the maintenance of the structural and functional integrity of apical (photoreceptors) and basal (Bruch's membrane/choroidal blood supply) sides of the environment it resides in. This integrity is achieved through functions governed by RPE secreted proteins, which include extracellular matrix modelling/remodelling, angiogenesis and immune response modulation. Impaired RPE secretory proteostasis affects not only the extracellular environment, but leads to intracellular protein aggregation and ER-stress with subsequent cell death. Ample recent evidence implicates dysregulated proteostasis as a key factor in the development of age-related macular degeneration (AMD), the leading cause of blindness in the developed world, and research aiming to characterise the roles of various proteins implicated in AMD-associated dysregulated proteostasis unveiled unexpected facets of the mechanisms involved in degenerative pathogenesis. This review analyses cellular processes unveiled by the study of the top 200 transcripts most abundantly expressed by the RPE/choroid in the light of the specialised secretory nature of the RPE. Functional roles of these proteins and the mechanisms of their impaired secretion, due to age and genetic-related causes, are analysed in relation to AMD development. Understanding the importance of RPE secretory proteostasis in relation to maintaining retinal health and how it becomes impaired in disease is of paramount importance for the development and assessment of future therapeutic advancements involving gene and cell therapies.

Dynamics of structural reversal in Bruch's membrane opening-based morphometrics after glaucoma drainage device surgery.

PURPOSE: Structural reversal of disc cupping is a known phenomenon after trabeculectomy. The aim of this retrospective, longitudinal, cross-sectional analysis was to evaluate the postoperative dynamics of Bruch's membrane opening-based morphometrics of the optic nerve head following glaucoma drainage device surgery. METHODS: Forty-three eyes, treated by glaucoma drainage device surgery, were included in the study. Individual changes in the spectral domain optic coherence tomography (SD-OCT) parameters Bruch's membrane opening minimum rim width (BMO-MRW), Bruch's membrane opening minimum rim area (BMO-MRA) and peripapillary retinal nerve fiber layer (RNFL) thickness as well as mean defect in 30-2 perimetry were analyzed. Changes were correlated to postoperative intraocular pressure levels over time. Available follow-up visits were aggregated and grouped into a short-term follow-up (20 to 180 days after surgery), a midterm follow-up (181 to 360 days after surgery) and a long-term follow-up (more than 360 days after surgery). RESULTS: In short-term follow-up, BMO-MRW and BMO-MRA increased significantly (p <= 0.034). This increase correlated negatively with the intraocular pressure at the time of the follow-up (Pearson's rho = - 0.49; p = 0.039). From 6 months after surgery on, there was no statistically significant change in BMO-MRW and BMO-MRA (p >= 0.207). RNFL thickness and mean defect of 30-2 perimetry showed no significant changes after GDD implantation (p >= 0.189). CONCLUSIONS: Lowering of intraocular pressure by glaucoma drainage device surgery leads to an increase of Bruch's membrane opening based parameters in the first 6 months after surgery. These changes have to be taken into account when evaluating patients' longitudinal follow-up after glaucoma drainage device implantation.

Histology of myopic posterior scleral staphylomas.

PURPOSE: Since histomorphometric descriptions of posterior scleral staphylomas, although forming a major part of myopic maculopathy, have been scarce so far, we histomorphometrically examined scleral staphylomas in enucleated human eyes. METHODS: Using light microscopy, we histomorphometrically examined sagittal histological sections of human globes enucleated due to malignant choroidal melanomas or secondary angle-closure glaucoma. RESULTS: Out of 246 globes included into the study, posterior scleral staphylomas were detected in 10 eyes (mean length: 31.4 ± 3.0 mm; range: 28.0-37.0 mm). In the staphylomatous region in the study group as compared with the corresponding region of a control group adjusted for age and axial length, scleral thickness was significantly lower (109 ± 25 µm versus 319 ± 161 µm; p = 0.001). The study group in the staphylomatous region as compared to the highly myopic control group in the corresponding region did not differ significantly in retinal pigment epithelium (RPE) cell density (19.6 ± 4.9 cells/300 µm versus 21.1 ± 5.7 cells/300 µm; p = 0.84) and RPE height (8.2 ± 2.8 µm versus 6.1 ± 2.5 µm; p = 0.13), Bruch's membrane (BM) thickness (3.5 ± 1.3 µm versus 4.2 ± 2.3 µm; p = 0.40) and choriocapillaris thickness (5.3 ± 2.8 µm versus 4.4 ± 2.8 µm; p = 0.49) and density (164 ± 99 µm versus 226 ± 38 µm; p = 0.13). All staphylomatous regions showed a localized BM defect. CONCLUSIONS: Marked scleral thinning and spatially correlated BM defects histologically characterized myopic scleral staphylomas, while thickness and density of the choriocapillaris and RPE and BM thickness did not differ significantly between staphylomatous versus non-staphylomatous eyes in the respective regions. These findings support the notion that a locally reduced scleral resistance against a backward pushing BM led to a local scleral outpouching. The outpouching-associated increase in curvature length may stretch BM with the sequel of a localized BM rupture.

Retinal Pigment Epithelium Cell Density and Bruch's Membrane Thickness in Secondary versus Primary High Myopia and Emmetropia.

To assess differences between secondary high myopia (SHM) due to congenital glaucoma and primary high myopia (PHM) and non-highly myopic eyes (NHM) in the relationships between axial length and Bruch's membrane (BM) thickness and retinal pigment epithelium (RPE) density. The histomorphometric study included human globes enucleated for reasons such as malignant uveal melanoma, end-stage painful secondary angle-closure glaucoma and congenital glaucoma. BM thickness and RPE cell density were measured upon light microscopy. The investigation included 122 eyes (mean axial length: 26.7 ± 3.7 mm; range: 20.0-37.0 mm): 7 eyes with SHM (axial length: 33.7 ± 2.1 mm; range: 31.0-37.0 mm), 56 eyes with PHM (mean axial length: 29.1 ± 2.4 mm; range: 26.0-36.0 mm) and 59 eyes in the NHM-group (axial length: 23.5 ± 1.3 mm; range: 20.0-25.5 mm). In the SHM group, longer axial length was associated with lower RPE cell density at the posterior pole (standardized regression coefficient beta: 0.92; non- standardized regression coefficient B: -2.76; 95% confidence interval (CI): -4.41, -1.10;P = 0.01), at the midpoint posterior pole/equator (beta: -0.87; B: -3.60; 95% CI: -6.48, -0.73;P = 0.03), and at the equator (beta: -0.88; B: -0.95; 95% CI: -1.68, -0.23; P = 0.02), but not at the ora serrata (P = 0.88). In the PHM-group and NHM group, RPE cell density at the posterior pole (P = 0.08) and ora serrata (P = 0.88) was statistically independent of axial length, while at the midpoint posterior pole/equator (P = 0.01) and equator (P < 0.001), RPE cell density decreased with longer axis. BM thickness in the SHM group decreased with longer axial length at the posterior pole (beta: -0.93;B: -0.29; 95% CI: -0.39, -0.14; P = 0.003), midpoint posterior pole/equator (beta: -0.79; B: -0.22; 95% CI: -0.42, -0.02; P = 0.035) and equator (beta: -0.84; B: -0.21; 95% CI: -0.37, -0.06; P = 0.017), while in the PHM-group and NHM-group, BM thickness at any ocular region was not statistically significantly correlated with axial length (all P > 0.05). In the SHM-group, but not in the PHM-group or NHM-group (P = 0.98), lower BM thickness was associated with lower RPE cell density (beta: 0.93; B: 0.09; 95% CI: 0.04, 0.14; P = 0.007), while in the eyes without congenital glaucoma the relationship was not statistically significant. In SHM in contrast to PHM, BM thickness and RPE cell density decrease in a parallel manner with longer axial length. The findings fit with the notion of BM being a primary driver in the process of axial elongation in PHM as compared to SHM.

Immunization Against Oxidized Elastin Exacerbates Structural and Functional Damage in Mouse Model of Smoke-Induced Ocular Injury.

Purpose: Age-related macular degeneration (AMD) is the leading cause of blindness in Western populations. While an overactive complement system has been linked to pathogenesis, mechanisms contributing to its activation are largely unknown. In aged and AMD eyes, loss of the elastin layer (EL) of Bruch's membrane (BrM) has been reported. Elastin antibodies are elevated in patients with AMD, the pathogenic significance of which is unclear. Here we assess the role of elastin antibodies using a mouse model of smoke-induced ocular pathology (SIOP), which similarly demonstrates EL loss. Methods: C57BL/6J mice were immunized with elastin or elastin peptide oxidatively modified by cigarette smoke (ox-elastin). Mice were then exposed to cigarette smoke or air for 6 months. Visual function was assessed by optokinetic response, retinal morphology by spectral-domain optical coherence tomography and electron microscopy, and complement activation and antibody deposition by Western blot. Results: Ox-elastin IgG and IgM antibodies were elevated in ox-elastin immunized mice following 6 months of smoke, whereas elastin immunization had a smaller effect. Ox-elastin immunization exacerbated smoke-induced vision loss, with thicker BrM and more damaged retinal pigment epithelium (RPE) mitochondria compared with mice immunized with elastin or nonimmunized controls. These changes were correlated with increased levels of IgM, IgG2, IgG3, and complement activation products in RPE/choroid. Conclusions: These data demonstrate that SIOP mice generate elastin-specific antibodies and that immunization with ox-elastin exacerbates ocular pathology. Elastin antibodies represented complement fixing isotypes that, together with the increased presence of complement activation seen in immunized mice, suggest that elastin antibodies exert pathogenic effects through mediating complement activation.

FULL-THICKNESS MACULAR HOLE WITH MACULAR INTRACHOROIDAL CAVITATION IN A PATIENT WITH PATHOLOGIC MYOPIA.

PURPOSE: To describe a full-thickness macular hole (MH) opening to macular intrachoroidal cavitation in a patient with pathologic myopia. METHODS: Full ophthalmologic examination, fundus camera (Topcon TRC; Topcon Co, Tokyo, Japan), optical coherence tomography (RetinaScan Advanced RS-3000; NIDEK, Gamagori, Japan) imaging, and cataract surgery. RESULTS: A 61-year-old woman admitted with decreased vision in the left eye. Visual acuity was counting fingers from 30 cm. Anterior segment examination showed advanced cataract. Fundus examination revealed pathologic myopia. There was full-thickness MH opening to macular intrachoroidal cavitation in contact with the anterior surface of the sclera subfoveally. Except for the communicating part of MH and macular intrachoroidal cavitation, outer retina, ellipsoid zone, and retinal pigment epithelium were intact. Choroid was intact except for a small part at subfoveal area. The patient received an uncomplicated cataract surgery. Visual acuity improved to 5/10. Because she was satisfied, MH surgery was postponed to a later date. CONCLUSION: Full-thickness MH may occur within the area of macular intrachoroidal cavitation in pathologic myopia.