Bruch's Membrane Research Articles

Changes in choroidal thickness and lamina cribrosa position in subjects with overdipper pattern of arterial pressure.

The purpose is to analyze the changes produced in subjects with an overdipper pattern of ambulatory blood pressure monitoring with the aim of understanding the pathophysiology of normal tension glaucoma. A cross sectional study was performed in patients exhibiting overdipper and non-overdipper blood pressure patterns, respectively. Different optic parameters were assessed including the analysis of ganglion cell layer (GCL), peripapillary retinal nerve fiber layer (pRNFL) and Bruch's membrane opening-minimum rim width (BMO-MRW), as well as changes produced in choroidal thickness (CT) and lamina cribrosa (LC) position at two different periods of the day (early morning and evening). A total of 80 eyes (42 overdipper and 38 non-overdipper) were analyzed. A shortening of the distance at the beginning and end of the LC was objectified in the overdipper subjects (p < 0.003) as well as a statistically significant shift of the LC between morning and evening measurements in the overdipper subjects (p < 0.023). In addition, a significant thickening was found in 13 measurements of the horizontal and vertical plane CT (p < 0.029) of the overdipper subjects and a thickening of the CT in both groups in the morning. No significant differences in pRNFL, BMO-MRW and GCL measures were objectified. Morning assessment in overdipper subjects showed a deeper LC and a LC shift in comparison to evening values. In addition, an increase in CT was found in these subjects. Altogether, these findings could illustrate an etiopathogenic mechanism of the damage produced in normal tension glaucoma associated to the overdipper pattern.

Subfoveal Choroidal Thickness in Patients with Histiocytosis and Multimodal Imaging Features of Choroidal Infiltrates.

To evaluate choroidal findings in patients with histiocytosis including subfoveal choroidal thickness (SFCT), and multimodal imaging in eyes with choroidal infiltrates visible by ophthalmoscopy; and to determine if abnormalities change with histiocytosis-directed (kinase inhibitor) therapy. 91 patients with histiocytosis and 41 age- and gender-matched controls. Retrospective comparative study at single tertiary cancer referral center. Clinical exam, fundus photography and OCT were used to assess choroidal findings. Clinically evident choroidal infiltrates by ophthalmoscopy were recorded and choroidal vascular architecture was qualitatively examined. SFCT and was measured using enhanced depth imaging spectral domain optical coherence tomography (EDI SD-OCT) from the outer portion of Bruch's membrane to the choroidal scleral interface. SFCT compared to matched controls; secondary outcome was change in SFCT on histiocytosis-directed (kinase inhibitor) therapy. Multimodal imaging of choroidal infiltrates visible by ophthalmoscopy. One hundred and eighty two eyes of 91 patients (46 males, 45 females) with histiocytiosis (Erdheim-Chester 35, Rosai-Dorfman 21, Xanthogranuloma 7, Mixed histiocytosis 11, Langerhans cell histiocytosis 15 and other 2) were examined. In histiocytosis patients, the mean SFCT was 336.2 +/- 94.9 μm compared with 250.3 +/- 60.7μm in the control group (p<0.0001). 69% of histiocystosis patients had SFCT > 275μm compared to 27% in controls (p< 0.0001). Subtype of histiocytosis, sites of bone or central nervous disease, posterior segment/other sites of ophthalmic disease, or mutational profile did not correlate with SFCT. In a subgroup analysis of 35 patients naïve to prior treatment, with > 6 mos follow-up, the proportion of SFCT > 275 μm significantly decreased (p-value = 0.0016) on histiocytosis-directed (kinase inhibitor) therapy. 19.8% of patients had clinically evident choroidal infiltration: majority were yellow creamy, geographic, located posteriorly and hyperautofluorescent; with enlarged Haller's vein bordering the infiltrate, choriocapillaris compression and loss of choroidal architecture by OCT. In this cohort, 19.8% of histiocytosis patients had clinically evident infiltration of their choroid. Furthermore, the majority of patients with histiocytosis had increased subfoveal choroidal thickness compared with age- and gender-matched controls. The thickened choroid decreases on histiocytosis-directed (kinase inhibitor) therapy and may be a marker of response to systemic treatment.

Retinal G-protein-coupled receptor deletion exacerbates AMD-like changes via the PINK1-parkin pathway under oxidative stress.

The intake of high dietary fat has been correlated with the progression of age-related macular degeneration (AMD), affecting the function of the retinal pigment epithelium through oxidative stress. A high-fat diet (HFD) can lead to lipid metabolism disorders, excessive production of circulating free fatty acids, and systemic inflammation by aggravating the degree of oxidative stress. Deletion of the retinal G-protein-coupled receptor (RGR-d) has been identified in drusen. In this study, we investigated how the RGR-d exacerbates AMD-like changes under oxidative stress, both invivo and invitro. Fundus atrophy became evident, at 12 months old, particularly in the RGR-d + HFD group, and fluorescence angiography revealed narrower retinal vessels and a reduced perfusion area in the peripheral retina. Although rod electroretinography revealed decreasing trends in the a- and b-wave amplitudes in the RGR-d + HFD group at 12 months, the changes were not statistically significant. Mice in the RGR-d + HFD group showed a significantly thinner and more fragile retinal morphology than those in the WT + HFD group, with disordered and discontinuous pigment distribution in the RGR-d + HFD mice. Transmission electron microscopy revealed a thickened Bruch's membrane along the choriocapillaris endothelial cell wall in the RGR-d + HFD mice, and the outer nuclear layer structure appeared disorganized, with reduced nuclear density. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated significantly lower levels of 25(OH)-vitamin D3 metabolites in the RGR-d + HFD group. Under oxidative stress, RGR-d localized to the mitochondria and reduced the levels of the PINK1-parkin pathway. RGR-d mice fed an HFD were used as a new animal model of dry AMD. Under high-fat-induced oxidative stress, RGR-d accumulated in the mitochondria, disrupting normal mitophagy and causing cellular damage, thus exacerbating AMD-like changes both invivo and invitro.

Validation of Inter-Reader Agreement/Consistency for Quantification of Ellipsoid Zone Integrity and Sub-RPE Compartmental Features Across Retinal Diseases.

An unmet need exists when clinically assessing retinal and layer-based features of retinal diseases. Therefore, quantification of retinal-layer-thicknesses/fluid volumes using deep-learning-augmented platforms to reproduce human-obtained clinical measurements is needed. In this analysis, 210 spectral-domain optical coherence tomography (SD-OCT) scans (30 without pathology, 60 dry age-related macular degeneration [AMD], 60 wet AMD, and 60 diabetic macular edema [total 23,625 B-scans]) were included. A fully automated segmentation platform segmented four retinal layers for compartmental assessment (internal limiting membrane, ellipsoid zone [EZ], retinal pigment epithelium [RPE], and Bruch's membrane). Two certified OCT readers independently completed manual segmentation and B-scan level validation of automated segmentation, with segmentation correction when needed (semi-automated). Certified reader metrics were compared to gold standard metrics using intraclass correlation coefficients (ICCs) to assess overall agreement. Across different diseases, several metrics generated from automated segmentations approached or matched human readers performance. Absolute ICCs for retinal mean thickness measurements showed excellent agreement (range 0.980-0.999) across four cohorts. EZ-RPE thickness values and sub-RPE compartment ICCs demonstrated excellent agreement (ranges of 0.953-0.987 and 0.944-0.997, respectively) for full dataset, dry-AMD, and wet-AMD cohorts. Analyses demonstrated high reliability and consistency of segmentation of outer retinal compartmental features using a completely human/manual approach or a semi-automated approach to segmentation. These results support the critical role that measuring features, such as photoreceptor preservation through EZ integrity, in future clinical trials may optimize clinical care.

Analysis of Henle's fiber layer and outer retinal layers in cone dystrophy.

To evaluate Henle's Fiber Layer (HFL) thickness and volume parameters in patients with cone photoreceptor atrophy with directional optical coherence tomography (D-OCT). Macular 20°×20° standard and D-OCT images were acquired from patients diagnosed with hereditary cone dystrophy with evident foveal ellipsoid zone defect in OCT, and age-matched healthy controls. Thickness and volume parameters of HFL, outer nuclear layer (ONL) and retinal layers between ellipsoid zone and Bruch membrane complex (EZ-BM) were calculated from manual segmentation through D-OCT images and comparative analysis is performed. Twelve eyes of 6 patients were compared to 12 eyes of 6 age-matched healthy controls (mean age: 29.5±16.6 and 26.6±3.9 years respectively; P=0.162). Patients had lower total HFL volume (0.45±0.03 and 0.85±0.15 mm3; P<0.001) and mean HFL thickness (16.1±1.1 and 30.1±5.3 µm; P<0.001) than healthy controls. Central subfield, parafoveal and perifoveal ETDRS zone HFL parameters in patients were significantly lower than healthy controls. A centrifugal correlation was found between central ONL and the corresponding parafoveal HFL (Spearman's rho: 0.785; P<0.001). HFL assessment might be a useful OCT biomarker in patients with cone photoreceptor atrophy. HFL thinning is observed in foveal, parafoveal and perifoveal areas of patients with cone photoreceptor atrophy, while volume reduction in ONL and EZ-BM components were limited to central and parafoveal zones.

Critical Impact of Working Distance on OCT Imaging: Correction of Optical Distortion and Its Effects on Measuring Retinal Curvature.

To assess the impact of working distance (WD) on optical distortion in optical coherence tomography (OCT) imaging and to evaluate the effectiveness of optical distortion correction in achieving consistent retinal Bruch's membrane (BM) layer curvature, regardless of variations in WD. Ten subjects underwent OCT imaging with four serial macular volume scans, each employing distinct WD settings adjusted by balancing the sample and reference arm of the OCT interferometer (eye length settings changed). Either of two types of 30° standard objectives (SOs) was used. A ray tracing model was used to correct optical distortion, and BM layer curvature (represented as the second derivative of the curve) was measured. Linear mixed effects (LME) modeling was used to analyze factors associated with BM layer curvature, both before and after distortion correction. WD exhibited significant associations with axial length (β = -1.35, P < 0.001), SO type (P < 0.001), and eye length settings (P < 0.001). After optical distortion correction, the mean ± SD BM layer curvature significantly increased from 16.80 ± 10.08µm-1 to 49.31 ± 7.50µm-1 (P < 0.001). The LME model showed a significant positive association between BM layer curvature and WD (β = 1.94, P < 0.001). After distortion correction, the percentage change in BM layer curvature due to a 1-mm WD alteration decreased from 9.75% to 0.25%. Correcting optical distortion in OCT imaging significantly mitigates the influence of WD on BM layer curvature, enabling a more accurate analysis of posterior eye morphology, especially when variations in WD are unavoidable.

Acute effects of swimming goggle wearing on intraocular pressure, anterior chamber biometrics, and optic nerve head morphology

Swimming goggles (SG) are widely used in water sports, and this study aimed to evaluate the acute effects of wearing SG on intraocular pressure (IOP), anterior chamber biometrics, axial length (AL), and optic nerve head (ONH) morphology. Twenty-eight healthy young adults participated in this cross-sectional study, with assessed parameters including IOP, central corneal thickness (CCT), anterior chamber depth (ACD), anterior chamber angle (ACA), AL, and optical coherence tomography (OCT) imaging of the ONH, specifically Bruch membrane opening (BMO), Bruch membrane opening-minimum rim width (BMO-MRW), lamina cribrosa depth (LCD), and prelaminar tissue (PLT). Measurements were taken at four time points: before wearing SG, at the 1st and 10th minutes of wearing, and immediately after removal. The results showed a significant increase in IOP at the 1st and 10th minutes of SG wear compared to pre-wear and post-removal values. Additionally, decreases in CCT, ACD, and ACA, along with an increase in AL, were observed while wearing SG. However, these changes reverted to baseline after the goggles were removed. No significant alterations were detected in ONH parameters during the study. The findings suggest that wearing SG induces an acute rise in IOP and changes in anterior segment parameters, likely due to oculopression, but does not appear to affect ONH morphology in the short term. Further studies are needed to investigate any potential long-term effects.

Abetalipoproteinemia with angioid streaks, choroidal neovascularization, atrophy, and extracellular deposits revealed by multimodal retinal imaging

ABSTRACT Purpose Abetalipoproteinemia (ABL, MIM 200,100) is a rare autosomal recessive disorder caused by nonfunctional microsomal triglyceride transfer protein leading to absence of apolipoprotein B-containing lipoproteins in plasma and a retinitis pigmentosa-like fundus. The MTTP gene is expressed in retinal pigment epithelium (RPE) and ganglion cells of the human retina. Understanding ABL pathophysiology would benefit from new cellular-level clinical imaging of affected retinas. Methods We report multimodal retinal imaging in two patients with ABL. Case 1 (67-year-old woman) exhibited a bilateral decline of vision due to choroidal neovascularization (CNV) associated with angioid streaks and calcified Bruch membrane. Optical coherence tomography were consistent with basal laminar deposits and subretinal drusenoid deposits (SDD). Results Case 2 (46-year-old woman) exhibited unusual hyperpigmentation at the right fovea with count-fingers vision and a relatively unremarkable left fundus with 20/30 vision. The left eye exhibited the presence of nodular drusen and SDD and the absence of macular xanthophyll pigments. Conclusion We propose that mutated MTTP within the retina may contribute to ABL retinopathy in addition to systemic deficiencies of fat-soluble vitamins. This concept is supported by a new mouse model with RPE-specific MTTP deficiency and a retinal degeneration phenotype. The observed range of human pathology, including angioid streaks, underscores the need for continued monitoring in adulthood, especially for CNV, a treatable condition.

Clinical correlation of optic nerve head analysis performed by SD-OCT in children with pseudopapilledema and papilledema

PurposeTo investigate some diagnostic indicators in optic nerve head (ONH) analysis of children with ‘Pseudopapilledema’ and ‘Papilledema’ by Spectral Domain Optical Coherence Tomography (SD-OCT). MethodsMedical records of 52 children with optic disc swelling, who were followed up by the departments of pediatric neurology and ophthalmology between May 2018 and May 2019 were reviewed retrospectively. Cases were classified as group 1 (Papilledema secondary to Idiopathic Intracranial Hypertension) including 54 eyes of 27 cases, group 2 (Pseudopapilledema secondary to bilateral optic disc drusen) including 50 eyes of 25 cases and control group. Three-dimensional imaging of ONH, peripapillary retinal nerve fiber layer (RNLF) thickness, Bruch's membrane opening height in the nasal respectively temporal quadrant (BMHN, BMH-T) levels were measured by SD-OCT and B-mode ocular ultrasonography data of all cases were evaluated. ResultsWhen RNFL levels were compared between groups, nasal RNFL levels were found to be significantly higher in group 1 cases compared to group 2 (p < 0.001). In 3D imaging of the ONH among group 1 patients, the mean height of the apex in disc swelling was significantly higher than that of group 2 (p = 0,024). The apex in disc swelling was mostly observed to be localized at the middle and had a diffuse swelling pattern in group 1; whereas, in group 2, the it was localized mostly at the nasal quadrant. This variation was statistically significant (p < 0.001). When, Bruch's membrane opening height in the nasal respectively temporal quadrant (BMHN, BMH-T) levels were compared, the measurements obtained were found to be significantly higher in group 1 (p = 0,050 and p = 0,003 respectively). ConclusionNasal RNFL values of SD-OCT, Bruch's membrane opening height in the nasal respectively temporal quadrant (BMHN, BMH-T) levels, the location of the apex in disc swelling obtained by 3D analysis of the ONH are found to be potential diagnostic parameters when combined with clinical findings. It is important that the nasal quadrant elevation, where the highest peak in 3D imaging was measured, was higher in the papilledema group. The elevation of the optic disc peak in 3D imaging can be used as a parameter to help clinicians distinguish between optic disc drusen (ODD) and papilledema.

Retinal Pigment Epithelium Curvature Can Predict Late Age-Related Macular Degeneration.

Outer retinal band integrity strongly predicts late age-related macular degeneration (AMD). However, it is often assessed subjectively as "continuity" using inconsistent definitions. Alternatively, "curvature" of the outer retinal bands is a quantitative metric that strongly correlates with AMD biomarkers and can screen for intermediate AMD. We evaluated the prognostic ability of retinal pigment epithelium (RPE) and ellipsoid zone (EZ) curvature for late AMD against outer retinal band continuity, pigmentary abnormalities, reticular pseudodrusen, and drusen volume. Consecutive patients with intermediate AMD who progressed to late AMD (n = 17) or remained stable (n = 42) were recruited. RPE and EZ curvature were quantified as a ratio of their lengths over Bruch's membrane using the sinuosity method of assessing river curvature, where a ratio of ∼1 indicates no outer retinal pathology. RPE, EZ, and Bruch's membrane were manually segmented and their lengths automatically extracted. The primary outcomes were outer retinal sinuosity and the odds ratio of predicting late AMD. Mean follow-up time for progressors and nonprogressors was 4.4 and 3.6 years. RPE sinuosity was strongly associated with pigmentary abnormalities (P = 0.001) and drusen volume (P = 0.004) but not reticular pseudodrusen (P = 0.28). RPE sinuosity >1.03 was the strongest predictor of late AMD developing within 5 years (15 [2.9-75]) and across the study period (25 [2.3-282]). Drusen volume >0.03 mm3 was the strongest predictor of progression within 2 years (33 [2.5-426]), and RPD could not independently predict progression within any time frame. RPE curvature is a promising, quantitative outer retinal biomarker that can prognosticate late AMD and potentially enhance prognostic models.

Normative Profile of Retinal Nerve Fiber Layer Thickness and Lamina Cribrosa-Related Parameters in a Healthy Non-Glaucoma Cynomolgus Monkey Colony.

The purpose of this study was to investigate the normal range of ophthalmic parameters and the correlations between systematic and ocular parameters and retinal nerve fiber layer (RNFL) thickness among a healthy non-glaucoma cynomolgus monkey colony. All included monkeys were given detailed ophthalmic examinations, including anterior and posterior segments. Furthermore, univariate and multivariate linear regression models were conducted to estimate the relationship between systemic and ophthalmic parameters and global RNFL thickness. A total of 349 non-glaucoma monkeys (18.69 ± 2.88 years old) were collected. The global RNFL thickness was 94.61 ± 10.13 µm, and sex-specific differences existed in all sectors. The decreasing trend of RNFL is as follows: inferotemporal, superotemporal, inferonasal, superonasal, temporal, and nasal. For lamina cribrosa (LC)-related parameters, cup depth (P < 0.01), LC thickness (P = 0.014), and Bruch's membrane opening (BMO) - minimum rim width 2 (P = 0.002) were greater in the male group. However, LC depth (P = 0.02), anterior laminar insertion depth-1 (P = 0.009), and mean anterior laminar insertion depth (P = 0.029) of female monkeys were greater than those of male monkeys. In multivariate linear regression, only older age was significantly related to reduced global RNFL thickness (P < 0.001). Our findings suggest the differences in RNFL thickness distribution and sex between non-glaucoma cynomolgus monkeys and humans. Therefore, the impact of this difference on outcomes should be fully considered in laboratory animal studies. Our findings are also significant in terms of developing a normative optical coherence tomography (OCT) database in nonhuman primates (NHPs). We found that the differences in RNFL thickness distribution and sex between non-glaucoma cynomolgus monkey colonies and humans should be thoroughly taken into account in laboratory animal studies.

Temporal Changes in the Retinal Pigment Epithelium-Bruch's Membrane Complex Thickness After Autologous Retinal Transplantation in Myopic Eyes.

To investigate the association between the thickness of the retinal pigment epithelium (RPE)-Bruch's membrane (BM) complex and the development of retinal autograft edema as a postoperative complication following autologous retinal transplantation (ART). This retrospective study examined data from 28 eyes of 28 patients (14 males, 14 females; mean age, 61.5 ± 19.8 years) who underwent ART and were followed for 1 year. The RPE-BM complex thickness was measured 2000 µm from the fovea using Image J software. Additionally, the graft blood flow was also evaluated by optical coherence tomography angiography and fluorescein angiography. Macular hole (MH) diameters ranged from 711.2 ± 251.9 µm to 1299.9 ± 333.0 µm, with MH closure achieved in all patients. RPE-BM complex thickness decreased by 4.17 µm at 6 months and 4.34 µm at 1 year, showing significant differences from preoperative measurements (29.88 ± 4.99 µm; 6 months: 95% confidence interval [CI], 1.62-6.71, P = 0.0018; 1 year: 95% CI, 2.03-6.65 µm, P = 0.00044). The decrease was significantly greater in the edema-positive group (95% CI, -8.33 to -0.82, P = 0.020). Furthermore, the rates of ellipsoid zone (EZ) recovery, alignment of neurosensory layers (ANL), and graft reperfusion were lower in the edema-positive group (EZ, P = 0.017; ANL, P = 0.0098; reperfusion, P = 0.039). After ART, RPE-BM complex thickness decreases, particularly in cases with postoperative edema, suggesting a potential relationship between RPE function and postoperative outcomes, highlighting the importance of monitoring RPE-BM complex thickness after surgery.

Comparison between OCT B-scan and En Face Imaging for the Diagnosis of Early Macular Atrophy in Age-Related Macular Degeneration

The gradings of complete retinal pigment epithelium and outer retinal atrophy (cRORA) and incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) on spectral domain optical coherence tomography (SD-OCT) B-scans were compared with the grading of persistent choroidal hypertransmission defects (hyperTDs) on swept-source OCT angiography (SS-OCTA) en face images. Comparative diagnostic analysis of prospective study data METHODS: Patients with late nonexudative AMD underwent same day 6 × 6 mm macular scans using both SD-OCT (Spectralis® Heidelberg, 512 × 97, ART:9) and SS-OCTA (PLEX® Elite 9000, Carl Zeiss Meditec, 500 × 500 angio pattern) instruments. SS-OCTA and SD-OCT en face images were generated from a sub-retinal pigment epithelium slab positioned 64-400 μm below Bruch's membrane. SD-OCT B-scan gradings, which included an inspection of neighboring B-scans for the diagnosis of cRORA and iRORA, were performed at the Moran Eye Center, while gradings of en face images to identify persistent choroidal hyperTDs were performed at the Bascom Palmer Eye Institute and Tel Aviv Medical Center. There was a high degree of agreement (99.6%) between the gradings of cRORA lesions and persistent hyperTDs. However, 27.4% of iRORA lesions were found to be contained within persistent hyperTDs. This discrepancy was due to the finding that 27.5% of iRORA lesions were diagnosed as having a greatest linear horizontal dimension of < 250 µm on B-scans, but on en face images, these B-scan defined iRORA lesions were found to have a greatest linear dimensions in the non-horizontal dimension that were ≥ 250 µm. This report demonstrates the benefits of using en face OCT imaging to identify cRORA lesions and highlights the need to acquire dense raster B-scans with the grading neighboring B-scans when identifying iRORA lesions to assess the full extent of the iRORA lesions in the non-horizontal dimension. Even though neighboring B-scans were inspected, 27.5% of iRORA lesions were actually part of larger cRORA lesions when graded using an en face strategy.

A distributed integral control mechanism for regulation of cholesterol concentration in the human retina.

Tight homeostatic control of cholesterol concentration within the complex tissue microenvironment of the retina is the hallmark of a healthy eye. By contrast, dysregulation of biochemical mechanisms governing retinal cholesterol homeostasis likely contributes to the aetiology and progression of age-related macular degeneration (AMD). While the signalling mechanisms maintaining cellular cholesterol homeostasis are well-studied, a systems-level description of molecular interactions regulating cholesterol balance within the human retina remains elusive. Here, we provide a comprehensive overview of all currently-known molecular-level interactions involved in cholesterol regulation across the major compartments of the human retina, encompassing the retinal pigment epithelium (RPE), photoreceptor cell layer, Müller cell layer and Bruch's membrane. We develop a comprehensive chemical reaction network (CRN) of these interactions, involving 71 molecular species, partitioned into 10 independent subnetworks. These subnetworks collectively ensure robust homeostasis of 14 forms of cholesterol across distinct retinal cellular compartments. We provide mathematical evidence that three independent antithetic integral feedback controllers tightly regulate ER cholesterol in retinal cells, with additional independent mechanisms extending this regulation to other forms of cholesterol throughout the retina. Our novel mathematical model of retinal cholesterol regulation provides a framework for understanding the mechanisms of cholesterol dysregulation in diseased eyes and for exploring potential therapeutic strategies.

Prevalence and associations of dome-shaped maculas. The Beijing Eye Study.

To explore the prevalence and associated factors of a dome-shaped macula (DSM) in a general population. Out of the population-based Beijing Eye Study cohort (n = 3468 participants), the investigation included all eyes with an axial length of ≥25 mm, and a randomized sample of eyes with an axial length of <25 mm. Using optical coherence tomographic (OCT) images, we examined presence and height of DSMs, defined as an inward convexity of the foveal retinal pigment epithelium (RPE)/Bruch's membrane (BM) line, detectable in at least two OCT scans perpendicularly orientated to each other. The study cohort consisted of 366 eyes (314 individuals) with a mean age of 63.7 ± 9.7 years and a mean axial length of 24.8 ± 2.1 mm (median: 25.1 mm; range: 18.96-30.88 mm). Prevalence of DSMs (found in 6/366 eyes; 1.9%; 95%CI: 1.0, 3.0) increased from 0/125 (0%) in non-myopic eyes to 1/152 (0.7%; 95%CI: 0.0, 2.0) in moderately myopic eyes, and to 6/83 (7.2%; 95%CI: 1.7, 12.7) in the highly myopic group. In multivariable analysis, higher DSM prevalence corelated with longer axial length (OR: 2.05; 95%CI: 1.36, 3.08; p < 0.001) and higher stage of myopic macular degeneration (OR: 1.08; 95%CI: 1.01, 1.16; p = 0.03). The mean maximal DSM height was 139 ± 107 μm (median: 100 μm; range: 25-350 μm). It was associated with higher stage of myopic macular degeneration (beta: 0.24; p < 0.001) and higher prevalence of macular BM defects (beta: 0.17; p < 0.001). None of the DSMs showed a serous retinal detachment or relative choroidal thickening. Higher DSM prevalence correlated non-linearly with longer axial length, with DSM height increasing with the presence of a BM defect. DSMs may be associated with an axial elongation-related BM overproduction in the fundus midperiphery in all meridians.

Bim Expression Influences Choroidal Endothelial Cell Characteristics and Their Response to Therapeutic Intervention.

In the aging population, choroidal vessels grow through the Bruch's membrane, resulting in a loss of central vision due to choroidal neovascularization (CNV). During active neovascularization, CNV is associated with inappropriate levels of apoptosis in multiple cell types, including choroidal endothelial cells (ChECs). Bim is a pro-apoptotic member of the Bcl-2 family. It is essential for cell apoptosis due to exposure to drugs such as dexamethasone or decreased pro-survival factors, including vascular endothelial growth factor (VEGF). To better elucidate the cell autonomous contribution of Bim expression in the integrity and neovascularization of the choroidal vasculature, we isolated ChECs from wild-type and Bim-deficient (Bim-/-) mice. ChECs lacking Bim expression demonstrated increased expression of VEGF, osteopontin, and the inflammatory cytokines Rantes/Ccl5 and IL6. Bim-/- ChECs were more proliferative and demonstrated an increased capacity to undergo capillary morphogenesis. Anti-VEGF had a diminished capacity to disrupt capillary morphogenesis in Bim-/- ChECs. In vivo, utilizing the mouse laser photocoagulation model, anti-VEGF treatment mitigated CNV in wild-type but not Bim-/- mice. We also tested other modalities that are thought to not require the intrinsic death pathway for their function and showed that propranolol, anti-CTGF, and the TSP1-mimetic peptide ABT898 mitigated CNV in mice lacking Bim expression to varying degrees. Thus, in ChECs, Bim expression could impact the effectiveness of treatment modalities that require the intrinsic death pathway to mitigate CNV.

Differential Expression of Mitogen-Activated Protein Kinase Signaling Pathways in the Human Choroid-Retinal Pigment Epithelial Complex Indicates Regional Predisposition to Disease.

The retina is composed of neuronal layers that include several types of interneurons and photoreceptor cells, and separate underlying retinal pigment epithelium (RPE), Bruch's membrane, and choroid. Different regions of the human retina include the fovea, macula, and periphery, which have unique physiological functions and anatomical features. These regions are also unique in their protein expression, and corresponding cellular and molecular responses to physiological and pathophysiological stimuli. Skeie and Mahajan analyzed regional protein expression in the human choroid-RPE complex. Mitogen-Activated Protein Kinase (MAPK) signaling pathways have been implicated in responses to stimuli such as oxidative stress and inflammation, which are critical factors in retina diseases including age-related macular degeneration. We, therefore, analyzed the Skeie and Mahajan, 2014, dataset for regional differences in the expression of MAPK-related proteins and discussed the potential implications in retinal diseases presenting with regional signs and symptoms. Regional protein expression data from the Skeie and Mahajan, 2014, study were analyzed for members of signaling networks involving MAPK and MAPK-related proteins, categorized by specific MAPK cascades, such as p38, ERK1/2, and JNK1/2, both upstream or downstream of the respective MAPK and MAPK-related proteins. We were able to identify 207 MAPK and MAPK-related proteins, 187 of which belonging to specific MAPK cascades. A total of 31 of these had been identified in the retina with two proteins, DLG2 and FLG downstream, and the other 29 upstream, of MAPK proteins. Our findings provide evidence for potential molecular substrates of retina region-specific disease manifestation and potential new targets for therapeutics development.

Structural Features of Optic Nerve Head in Glaucoma with Single-hemispheric and Bi-hemispheric Visual Field Defects

Purpose: To compare the structural features of the optic nerve head (ONH) in moderate glaucoma patients with single-hemispheric and bi-hemispheric visual field (VF) defects.Methods: Patients with open-angle glaucoma (OAG) and a VF mean deviation between -6 and -12 dB were retrospectively enrolled. Based on VF defect patterns, eyes were classified into two groups: those with single-hemispheric VF defects and those with bi-hemispheric VF defects. Structural features analyzed included Bruch’s membrane opening area, lamina cribrosa (LC) thickness, temporal β-zone parapapillary atrophy with and without Bruch's membrane (βPPA&lt;sub&gt;+BM&lt;/sub&gt;, βPPA&lt;sub&gt;-BM&lt;/sub&gt;, respectively), and peripapillary retinal nerve fiber layer thickness using spectral-domain optical coherence tomography.Results: Out of 137 eyes from 124 patients, 80 eyes had single-hemispheric VF defects and 57 eyes had bi-hemispheric VF defects. The bi-hemispheric group exhibited longer axial length (&lt;i&gt;p&lt;/i&gt; = 0.038), thinner central corneal thickness (&lt;i&gt;p&lt;/i&gt; = 0.003), thinner LC (&lt;i&gt;p&lt;/i&gt; &lt; 0.001), and larger temporal βPPA&lt;sub&gt;+BM&lt;/sub&gt; (&lt;i&gt;p&lt;/i&gt; = 0.002) compared to the single-hemispheric group.Conclusions: Among Korean OAG patients with moderate VF defects, those with bi-hemispheric VF defects showed more structurally vulnerable optic discs characterized by longer axial lengths, thinner central corneal thickness, thinner LC, and larger β PPA+BM compared to those with single-hemispheric VF defects. These findings underline the importance of evaluating ONH structures in monitoring glaucoma progression particularly in patients with extensive VF damage.

Photoreceptor outer segment reflectivity with ultrahigh resolution visible light optical coherence tomography in systemic hydroxychloroquine use.

To evaluate outer retinal organization in normal subjects and those using hydroxychloroquine (HCQ) with ultrahigh resolution visible light optical coherence tomography (VIS-OCT). Forty eyes of 22 adult subjects were recruited from a tertiary care retina practice including controls (20 eyes, 12 subjects, mean age 40±22yrs, mean logMAR BCVA 0.19, 90% female) and subjects with a history of HCQ use (20 eyes, 10 subjects, mean age 62±17yrs, mean logMAR BCVA 0.03, 67% female). Each subject was imaged using a custom-built VIS-OCT device (axial resolution 1.3μm) and FDA-approved OCT devices. Using VIS-OCT, control subjects demonstrate 5 and 6 hyperreflective bands in the foveal and parafoveal regions, respectively, between the outer nuclear layer and Bruch's membrane. These bands demonstrate intensity profiles complementary to the known histopathologic distribution of rods and cones. In comparison to controls, subjects taking HCQ demonstrate blunting of all bands, particularly bands 2-4. In all cases of suspected or known toxicity, VIS-OCT demonstrated attenuation of band 3i and in no cases was there attenuation of other bands that was more severe than band 3i, suggesting that changes in the reflectivity of Band 3i may be the earliest identifiable sign of HCQ toxicity. VIS-OCT of the outer retina demonstrates a unique outer retinal banding pattern corresponding to photoreceptor density profiles. There is a notable attenuation of the photoreceptor outer segment reflectivity profile associated with early HCQ toxicity. This finding may be an early, and possibly reversible, sign of HCQ toxicity, primarily impacting the cones.

A New Ocular Phenotype Combining Juvenile Glaucoma and Doyne Honeycomb Retinal Dystrophy (Malattia Leventinese) due to a Novel EFEMP1 Pathogenic Variant.

Doyne honeycomb retinal dystrophy (DHRD), also termed malattia leventinese (MLVT), is a dominantly inherited ocular disease characterized by the progressive accumulation of macular and peripapillary drusenoid material beneath the retinal pigment epithelium in the Bruch membrane. In all affected individuals genetically characterized to date, DHRD/MLVT is caused by a single heterozygous p.Arg345Trp missense variant in the EGF-containing fibulin-like extracellular matrix protein 1, EFEMP1. Recently, pathogenic variants in the EFEMP1 gene have also been demonstrated in several families with juvenile or adult-onset hereditary isolated glaucoma. Here, we describe a family featuring a unique phenotype of juvenile glaucoma and DHRD/MLVT caused by a novel EFEMP1 variant. Our results expand both the ocular phenotype associated with EFEMP1 variants and the molecular spectrum causing DHRD by describing the first non-p.Arg345Trp EFEMP1 pathogenic allele.