Estimation of angle parameters by ASOCT and biometric parameters by optical biometer in eyes with occludable angles and open angles.

PURPOSE: To compare anterior chamber angle (ACA) parameters measured by Anterior Segment Optical Coherence Tomography (ASOCT) and biometric parameters measured by Swept-Source (SS) OCT-based biometry among patients with suspected occludable angles and open angles. METHODS: An analytical, cross-sectional study was performed on subjects attending our ophthalmology outpatient department with suspected occludable angles (van Herick grades 0, 1, and 2) in group 1, and with open angles (van Herick grades 3 and 4) in group 2. Each subject underwent a complete ophthalmic examination to exclude any intraocular pathology like cataract. We recruited 128 eyes of 64 subjects, 34 in group 1 and 30 in group 2. Each eye was henceforth subjected to ASOCT (Spectralis, Heidelberg Engineering, Heidelberg) and SS-OCT-based optical biometry (IOL Master 700, Carl Zeiss Meditec AG). Anatomical parameters were recorded and compared between the two groups. RESULTS: The main outcome measures of the study included nine ASOCT parameters (central corneal thickness [CCT], lens vault, AOD750, ACA, TISA750 [nasal and temporal], and ACW) and five optical biometric parameters (CCT, ACD, WTW, LT, and axial length). We found a significant difference (p < 0.05) among all the anatomical parameters between the two groups, except CCT which was not significantly different (p = 0.297). CONCLUSIONS: ASOCT and SSOCT biometry overcome the challenges of gonioscopy and allow screening for angle closure disease in otherwise normal subjects. ASOCT may serve as an alternative to gonioscopy as it clearly separates occludable angles from open angles in a non-invasive and objective manner.

Direct observation and measurement of circumlental space and its relation to anterior chamber angle characteristics in iridotomized phakic eyes with primary angle closure disease.

Primary angle closure disease (PACD) is a major cause of blindness worldwide. It has a high prevalence in East Asia, especially in China, which leads to a higher incidence of blindness than open-angle glaucoma. The aim of this study was to directly observe the circumlental space (CLS) in laser peripheral iridotomized eyes with PACD and to determine whether this structure plays a role in the pathogenesis of PACD. Fifty eyes of 50 patients with PACD, who had received laser peripheral iridotomy performed with neodymium:yttrium-aluminum-garnet were recruited from glaucoma clinics from March 2021 to May 2022, including 17 primary angle closure suspect (PACS), 16 primary angle closure (PAC) and 17 primary angle closure glaucoma (PACG). They were classified into two groups based on whether the ciliary process and the crystalline lens equator were in contact using slit-lamp photograph: the attached group and the unattached group. The demographic, clinical characteristics and anterior segment parameters measured from ultrasound biomicroscopy were compared between the attached group and the unattached group. Thirty-three eyes were assigned to the attached group and 17 eyes belonged to the unattached group. In the unattached group, the mean CLS was 0.10 ± 0.07 mm. No significant differences were identified between the different diagnosis groups in age, sex, best-corrected visual acuity, intraocular pressure, white-to-white, axial length, central corneal thickness, anterior chamber depth, flat keratometry, steep keratometry or iridotomy diameter (p > 0.05). The unattached group had shorter trabecular-ciliary process distance (p = 0.021) and larger ciliary process area (p = 0.001) compared with the attached group. Small CLS and its potential effect (partial ciliary block) might be considered as one of the mechanisms of PACD.

Phacoemulsification combined with goniosynechialysis versus phacoemulsification alone for patients with primary angle­closure disease: A meta-analysis.

This meta-analysis aims to systematically compare the efficacy between phacoemulsification (PE) combined with goniosynechialysis (GSL) and PE alone for primary angle-closure disease (PACD) patients. All the data were searched from the PubMed, EMBASE and the Cochrane Library. The Cochrane Handbook was used to evaluate the quality of the included studies. Additionally, this meta-analysis was performed by using the Revman 5.4 software. Nine randomized controlled trials (RCTs) were included in this study. Compared with PE alone group, PE+GSL could result significant reduction in the IOP (MD, 1.81; p = 0.002). In the instrumental subgroup, also more reduction of IOP was shown in the PE+GSL group (MD, 2.11; p = 0.02). In the viscogonioplasty (VGP) subgroup, there was not no statistical difference between PE alone group and PE+GSL group (MD, 1.53; p = 0.11). Also, more reduction of peripheral anterior synechiae (PAS) was shown in the PE+GSL group (MD,59.15; p<0.00001). For the change in angle open distance (AOD)500, AOD 750, trabecular-iris space (TISA)500, number of glaucoma medications and best corrected visual acuity (BCVA), there was no difference between two groups (p = 0.25, 0.35, 0.17, 0.56, 0.08). For TISA 750, more improvement was shown in the PE+GSL group (p<0.00001). Instrumental separation had better effect on lowering IOP when it combined with PE. Both instrumental separation and VGP could reduce postoperative PAS. The operation of GSL has no obvious effect on postoperative vision.

Comparison of the Choroid in Primary Open Angle and Angle Closure Glaucoma Using Optical Coherence Tomography.

PRCIS: The current study highlights distinct choroidal alterations in primary open angle (POAG) and primary angle closure (PACG) glaucomas, underscoring the potential of the Choroidal Vascularity Index (CVI) as a valuable indicator for understanding glaucoma pathogenesis. PURPOSE: To evaluate choroidal structural changes in patients with POAG and PACG and healthy controls utilizing the CVI and subfoveal choroidal thickness by enhanced depth imaging optical coherence tomography. METHODS: This study was cross-sectional. A total of 171 eyes of 171 subjects, comprising 69 eyes with untreated POAG, 58 eyes with untreated PACG, and 44 healthy eyes, were enrolled in this study. Subfoveal choroidal thickness, luminal area (LA), stromal area (SA), and total choroidal area were measured on enhanced depth imaging-optical coherence tomography scans. The CVI parameter is calculated as the proportion of LA to the total choroidal area. RESULTS: This study included 69 patients with POAG with a mean age of 51.4 ± 13.3 years, 58 patients with PACG with a mean age of 57.0 ± 7.3 years, and 44 healthy subjects with a mean age of 51.11 ± 10.7 years. The CVI in the POAG and PACG groups was significantly lower than that in the control group ( P = 0.001 and P = 0.005, respectively); however, not significantly different between the two glaucoma groups ( P = 1.000). POAG eyes had significantly lower LA than PACG and controls ( P = 0.014 and P = 0.049, respectively), whereas PACG eyes had significantly greater SA than controls ( P = 0.041). CONCLUSIONS: The CVI of POAG and PACG eyes was significantly lower than that of normal eyes. A reduced LA was observed mainly in eyes with POAG, and an increased SA was observed mainly in eyes with PACG. The role of the choroid may differ between POAG and PACG eyes.

Evaluation of microvascular changes in the retina and choriocapillaris in primary glaucoma and neuromyelitis optica spectrum disorder with optical coherence tomography angiography.

BACKGROUND: To assess quantitatively the microvascular changes in the retina and choroid of healthy eyes, eyes of subjects with primary angle-closure glaucoma (PACG), primary open-angle glaucoma (POAG) and neuromyelitis optica spectrum disorder (NMOSD) using optical coherence tomography angiography (OCTA). METHODS: A series of healthy individuals and subjects with PACG, POAG and NMOSD were recruited in this cross-sectional study. OCTA was performed to capture the optic nerve head and macula images and the vessel density (VD) and retinal nerve fiber layer (RNFL) thickness were quantified. The choriocapillary flow density (CFD) was calculated as the percentage of flow area to the whole selected area. RESULTS: A total of 68 PACG subjects, 25 POAG subjects, 51 NMOSD subjects and 37 healthy controls were enrolled. Significant decreases in peripapillary VD and RNFL thickness were observed in PACG (p < 0.001) and POAG (p < 0.001) eyes and also in NMOSD subjects with an optic neuritis history (p < 0.001) compared with healthy controls. Unaffected eyes in PACG and POAG subjects had lower baseline peripapillary VD than healthy controls (p = 0.002 and p = 0.011, respectively). PACG eyes showed a lower baseline CFD than POAG (p = 0.0027) and the CFD in early and advanced PACG eyes showed a significantly much more decrease than POAG (p = 0.002 and p < 0.001, respectively). CONCLUSIONS: The peripapillary vessel density and RNFL thickness was reduced in glaucomatous and NMOSD eyes compared with healthy controls. PACG eyes showed a lower CFD than POAG and the distinct peripapillary and choriocapillaris microvasculature changes may be correlated to different PACG and POAG pathogenesis.

Phenotypic consequences of a nanophthalmos-associated TMEM98 variant in human and mouse.

Nanophthalmos is characterised by shorter posterior and anterior segments of the eye, with a predisposition towards high hyperopia and primary angle-closure glaucoma. Variants in TMEM98 have been associated with autosomal dominant nanophthalmos in multiple kindreds, but definitive evidence for causation has been limited. Here we used CRISPR/Cas9 mutagenesis to recreate the human nanophthalmos-associated TMEM98 p.(Ala193Pro) variant in mice. The p.(Ala193Pro) variant was associated with ocular phenotypes in both mice and humans, with dominant inheritance in humans and recessive inheritance in mice. Unlike their human counterparts, p.(Ala193Pro) homozygous mutant mice had normal axial length, normal intraocular pressure, and structurally normal scleral collagen. However, in both homozygous mice and heterozygous humans, the p.(Ala193Pro) variant was associated with discrete white spots throughout the retinal fundus, with corresponding retinal folds on histology. This direct comparison of a TMEM98 variant in mouse and human suggests that certain nanophthalmos-associated phenotypes are not only a consequence of a smaller eye, but that TMEM98 may itself play a primary role in retinal and scleral structure and integrity.

Myopic Versus Glaucomatous Parapapillary Beta Zone in Myopic Eyes Versus Eyes With Secondary Angle-Closure Glaucoma.

Purpose: To search for histologic differences in the beta zone between myopic eyes versus eyes with secondary angle-closure glaucoma. Methods: The histomorphometric study consisted of human eyes enucleated due to uveal melanomas or secondary angle-closure glaucoma. Results: The study included 100 eyes (age: 62.1 ± 15.1 years; axial length: 25.6 ± 3.1 mm; range: 20.0-35.0 mm). In non-highly myopic glaucomatous eyes compared with non-highly myopic nonglaucomatous eyes, the parapapillary alpha zone was longer (223 ± 168 µm vs. 125 ± 128 µm; P = 0.03), beta zone prevalence (15/20 vs. 6/41; P < 0.001) and length (277 ± 245 µm vs. 44 ± 150 µm; P = 0.001) were higher, and RPE cell density in the alpha zone and alpha zone border was lower (all P < 0.05). In highly myopic nonglaucomatous eyes compared with non-highly myopic glaucomatous eyes, parapapillary RPE drusen prevalence (2/19 vs. 10/10; P = 0.01) and alpha zone prevalence (2/19 vs. 16/20; P < 0.001) and length (23 ± 68 µm vs. 223 ± 168 µm; P < 0.001) were lower. In non-highly myopic glaucomatous eyes, Bruch's membrane (BM) thickness decreased (P < 0.001) from the beta zone (6.0 ± 3.1 µm) to the alpha zone (5.1 ± 4.3 µm) and peripheral to it (3.0 ± 0.9 µm). In highly myopic nonglaucomatous eyes, BM thickness did not differ (P > 0.10) between all three regions. In the total study population, RPE cell density in the alpha zone (24.5 ± 9.3 cells/240 µm) was higher than at the alpha zone border (19.2 ± 4.8 cells/240 µm; P < 0.001) or peripheral to it (19.0 ± 3.6 cells/240 µm; P < 0.001). Conclusions: The glaucomatous beta zone in eyes with chronic angle-closure glaucoma (with the alpha zone, parapapillary RPE drusen, thickened BM, and higher RPE cell count in the adjacent alpha zone) differs histologically from the myopic beta zone (characterized by the absence of the alpha zone and parapapillary RPE drusen, unremarkable BM thickness, and unremarkable parapapillary RPE). The differences suggest different etiologies of the glaucomatous versus myopic beta zone.

Factors associated with severe corneal endothelial damage following acute primary angle closure in Chinese subjects.

PURPOSE: To investigate the corneal endothelial damage caused by acute primary angle closure (APAC) and related risk factors for severe corneal endothelial cell damage in Chinese subjects. METHODS: In this multicentre retrospective study, 160 Chinese patients (171 eyes) diagnosed with APAC were recruited. Endothelial cell density (ECD) and morphological changes short after APAC were studied. Univariate regression and multivariate regression were used to identify risk factors associated with the extent of ECD reduction, including age, gender, education level, patients' location, systemic diseases, APAC duration (hours), highest recorded intraocular pressure (IOP), and presenting IOP. Factors associated with the probability of severe corneal damage (ECD lower than 1000/mm2) were analysed based on a linear function. RESULTS: After one APAC episode, 12.28% eyes had ECD lower than 1000/mm2, 30.41% had ECD between 1000 and 2000/mm2, and 57.31% had ECD more than 2000/mm2. Attack duration was the only factor associated with severe endothelial damage (p < 0.0001). If the attack were to be subsided within 15.0 h, possibility of ECD lower than 1000/mm2 could be controlled under 1%. CONCLUSION: Shortly after the abortion of APAC, 12.28% patients experienced severe endothelial cell damage with ECD less than 1000/mm2. The only factor associated with severe ECD decrease was attack duration. Immediate and effective treatment is pivotal for preserving corneal endothelial function in APAC patients.

The inflammatory cytokine profiles and ocular biometric characteristics of primary angle-closure glaucoma.

OBJECTIVE: To investigate the pathogenesis of primary angle-closure disease (PACG) by measuring the anatomical structures of the anterior and posterior segments of the eye and inflammatory markers in the peripheral blood. METHODS: This case-control study enrolled patients diagnosed with acute PACG (APACG) and chronic PACG (CPACG). It also enrolled control subjects without PACG. The anterior and posterior anatomical features were measured in all study participants. The levels of interleukin (IL)-6, tumour necrosis factor-α and the neutrophil-to-lymphocyte ratio (NLR) in the peripheral blood were measured. RESULTS: This study analysed a total of 99 eyes: 34 eyes from 34 patients with APACG, 28 eyes from 28 patients with CPACG and 37 eyes from 37 control patients with senile cataract. The axis length, corneal diameter, anterior chamber depth and anterior chamber volume were significantly smaller in the APACG and CPACG groups compared with the controls. The level of IL-6 in the peripheral blood of patients with PACG was significantly lower than that of the controls. The NLR in the peripheral blood of patients with PACG was significantly greater than that of the controls. CONCLUSIONS: Changes in the ocular anatomy and some inflammatory markers might be involved in the pathogenesis of PACG.

[Phacoemulsification combined with goniosynechialysis under a gonioscope in the treatment of angle-closure glaucoma: the effect of reopening the synechial anterior chamber angle].

A total of 170 consecutive patients (181 eyes) who were diagnosed with primary angle-closure glaucoma (PACG) and underwent phacoemulsification and intraocular lens implantation (PEI) combined with goniosynechialysis (GSL) with an instrument under a gonioscope in the Eye Hospital, Wenzhou Medical University from January 1, 2017 to December 31, 2019 were observed. Anterior chamber angle synechiae of 0 (0, 2) clock hour were released after PEI, while after combined goniosynechialysis, synechiae of 6 (3, 8) clock hours were further released. No matter in chronic PACG and acute PACG with cornea edema, the extent of anterior chamber angle synechiae was different before surgery and after PEI, and so was it in post-PEI and PEI-GSL prospectively (all P<0.01). Phacoemulsification alone can reopen the synechial anterior chamber angle in both chronic PACG and acute PACG in part, but not sufficiently. Combined goniosynechialysis under a gonioscope with an instrument is essential and effective.

Comparison of microvascular parameters and diagnostic ability of optical coherence tomography angiography between eyes with primary angle closure glaucoma and primary open angle glaucoma.

BACKGROUND: To investigate and compare the peripapillary and macular microvascular parameters between eyes with primary angle closure glaucoma (PACG) and primary open-angle glaucoma (POAG) using optical coherence tomography angiography (OCTA). METHODS: Seventy-nine eyes of 43 patients with primary angle closure glaucoma (PACG), 78 eyes of 43 patients with primary open-angle glaucoma (POAG), 64 eyes of 35 patients with primary angle closure (PAC), and 73 eyes of 40 control subjects underwent imaging with OCTA. Perfusion density (PD) and vessel density (VD) for the macular area, and PD and flux index (FI) for the peripapillary area were calculated automatically. The area under receiver operator characteristic curves (AUC) were constructed to distinguish PACG and POAG eyes from healthy control eyes. RESULTS: The peripapillary FI in all quadrants and PD and VD of the macular outer circle in superior and inferior quadrants were significantly lower in PACG and POAG eyes than in control eyes. The peripapillary FI in the inferior quadrant was significantly lower in the POAG group than in the PACG group (0.348 ± 0.06 vs. 0.369 ± 0.06, p = 0.04). The remaining OCTA parameters in the peripapillary and macular area did not show a significant difference between the POAG and PACG groups. Eyes with PAC presented significantly lower PD and VD than healthy control eyes at the superior and inferior quadrant of the macular outer circle, while retinal nerve fiber layer and ganglion cell inner complex thickness were not significantly different from than control eyes. The best diagnostic parameter was peripapillary FI in both PACG (AUC: 0.922) and POAG (AUC: 0.938) eyes. CONCLUSIONS: We found significantly lower peripapillary FI in the inferior quadrant in POAG eyes compared to the PACG eyes, which may indicate the different underlying pathogenesis between POAG and PACG. The PAC eyes had lower macular PD and VD than normal eyes. This suggests that retinal vascular impairment may develop earlier than structural damage in PAC eyes.

Predicting demographic characteristics from anterior segment OCT images with deep learning: A study protocol.

INTRODUCTION: Anterior segment optical coherence tomography (AS-OCT) is a non-contact, rapid, and high-resolution in vivo modality for imaging of the eyeball's anterior segment structures. Because progressive anterior segment deformation is a hallmark of certain eye diseases such as angle-closure glaucoma, identification of AS-OCT structural changes over time is fundamental to their diagnosis and monitoring. Detection of pathologic damage, however, relies on the ability to differentiate it from normal, age-related structural changes. METHODS AND ANALYSIS: This proposed large-scale, retrospective cross-sectional study will determine whether demographic characteristics including age can be predicted from deep learning analysis of AS-OCT images; it will also assess the importance of specific anterior segment areas of the eyeball to the prediction. We plan to extract, from SUPREME®, a clinical data warehouse (CDW) of Seoul National University Hospital (SNUH; Seoul, South Korea), a list of patients (at least 2,000) who underwent AS-OCT imaging between 2008 and 2020. AS-OCT images as well as demographic characteristics including age, gender, height, weight and body mass index (BMI) will be collected from electronic medical records (EMRs). The dataset of horizontal AS-OCT images will be split into training (80%), validation (10%), and test (10%) datasets, and a Vision Transformer (ViT) model will be built to predict demographics. Gradient-weighted Class Activation Mapping (Grad-CAM) will be used to visualize the regions of AS-OCT images that contributed to the model's decisions. The accuracy, sensitivity, specificity, and area under the receiver operating characteristic (ROC) curve (AUC) will be applied to evaluate the model performance. CONCLUSION: This paper presents a study protocol for prediction of demographic characteristics from AS-OCT images of the eyeball using a deep learning model. The results of this study will aid clinicians in understanding and identifying age-related structural changes and other demographics-based structural differences. TRIAL REGISTRATION: Registration ID with open science framework: 10.17605/OSF.IO/FQ46X.

Explore the molecular mechanism of angle-closure glaucoma in elderly patients induced telomere shortening of retinal ganglion cells through oxidative stress.

Senile glaucoma is a common ophthalmological disease in the elderly. It is a disease of visual papillary perfusion caused by elevated intraocular pressure, complicated by visual dysfunction. Glaucoma can cause serious damage to the normal vision of the elderly. Therefore, exploring the related molecular mechanisms of glaucoma is of great significance to the diagnosis and treatment of glaucoma. This is an exploratory study. Establish a mouse model and conduct experimental groupings. After one week of adaptive feeding, the mice were intraperitoneally injected with an anesthetic mixture: ketamine + xylazine. Then the mice were sacrificed by neck dissection, and the eyeball tissues were immediately dissected. HE staining was used to analyze the histopathological characteristics of the retina of each group of mice. MitoSOX fluorescent probe was used to analyze the content of ROS in retinal tissue. The ELISA analysis was used to detect the activation of ß-galactosidase for the aging characteristics of retinal ganglion cells in retinal tissues. Immunohistochemistry experiments were used to analyze the expression of telomerase TERT in retinal tissues. Western blot analysis was used to determine the expression of proteins POT1, TERF1, TERF2, and TINF2 in retinal tissues. The HE staining experiment showed that the damage of retinal tissue decreased from group Glaucoma to group Old, group Old to group Young. The experimental results of MitoSOX fluorescent probe show that ROS content is positively correlated with the degree of tissue damage. ELISA analysis results showed that the expression trend of ß-galactosidase was the same as the ROS content. The protein expression levels related to telomere protection (TRET, POT1, TREF1, TREF2 and TINF2) all increased from group Glaucoma to group Old, group Old to group Young. The increase in ROS content, the decrease in telomere protection-related protein expression (telomere shortening) induced by ROS, and the increase of the expression of ß-galactosidase, are all potential molecular mechanisms for the occurrence of angle-closure glaucoma in elderly patients.

Pigmented paravenous retinochoroidal atrophy with acute angle-closure glaucoma and posterior subcapsular cataract: a case report.

BACKGROUND: Pigmented paravenous retinochoroidal atrophy (PPRCA) is a rare fundus disease characterized by the presence of osteoblast-like pigment, atrophy of retinal pigment epithelium (RPE), and choroid deposition along the large retinal veins. CASE PRESENTATION: A 55-year-old Chinese female presented with right eye distention and bilateral vision loss. Osteocyte-like pigmentation and retinal choroidal atrophy distributed along the large retinal veins were seen in the fundus of bilateral eyes. The atrophy in the left eye was more severe compared to the right eye. The patient also presented with bilateral acute angle-closure glaucoma (AACG) and posterior subcapsular cataract (PSC) accompanied with anterior segmental manifestations, similar to the complications of retinitis pigmentosa (RP). The patient underwent ultrasound biomicroscopy (UBM), Humphrey field analyser (HFA), optical coherence tomography (OCT), fundus autofluorescence (FAF), fluorescein fundus angiography (FFA), electroretinogram (ERG), and electrooculography (EOG), all of which confirmed the aforementioned diagnose. CONCLUSION: PPRCA is a rare disease of unknown etiology. The patient in this case presented with complications similar to those of RP, and the two conditions may share a genetic basis. Further studies are needed to confirm this relationship.

Occurrence of Oxidative Stress and Premature Senescence in the Anterior Segment of Acute Primary Angle-Closure Eyes.

Purpose: To explore whether oxidative stress and premature senescence occur in the anterior segment of acute primary angle-closure (APAC) eyes after increased intraocular pressure. Methods: The eye samples of 21 APAC patients, 22 age-related cataract patients, and 10 healthy donors were included. Aqueous humor (AqH), iris, and anterior lens capsule samples were collected. The levels of oxidative stress markers and senescence-associated secretory phenotype (SASP)-related cytokines in AqH were estimated using relevant reagent kits and multiplex bead immunoassay technique. The intensity of relevant markers in anterior segment tissues was examined by immunofluorescence- and senescence-associated ß-galactosidase (SA-ß-gal) staining. Results: Oxidative stress marker levels elevated significantly in the AqH of APAC eyes. Reactive oxygen species (ROS) and 8-hydroxydeoxyguanosine levels were positively correlated with preoperative peak intraocular pressure and age, whereas reduced glutathione/oxidized glutathione (GSH/GSSH) ratio was negatively correlated with both parameters. The levels of several SASP-related cytokines were markedly increased. ROS and malondialdehyde levels were positively correlated with the levels of some SASP-related cytokines, whereas superoxide dismutase level and GSH/GSSH ratio showed an opposite trend. The number of cells positive for oxidative mitochondrial DNA damage and apoptosis-related markers increased in the iris and anterior lens capsule of the APAC group. Senescence-associated markers (p16, p21, and p53) and SA-ß-gal activity were increased in the iris of the APAC group. Conclusions: Oxidative stress and premature senescence occurred in the anterior segment of APAC patients, suggesting that they may be involved in the development of pathological changes in the anterior segment of APAC eyes.

Biallelic variants in CPAMD8 are associated with primary open-angle glaucoma and primary angle-closure glaucoma.

BACKGROUND/AIMS: This study aims to assess the contribution of biallelic CPAMD8 variants in patients with different forms of glaucoma, especially primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG), based on a systematic analysis of exome sequencing (ES). METHODS: Potentially pathogenic CPAMD8 variants were selected from the ES data of 5307 subjects with various eye conditions through multiple bioinformatics analyses. Of the 5307 subjects, 1221 probands had different forms of primary glaucoma. The genotype-phenotype correlation was assessed by a systematic review of biallelic CPAMD8 variants that including our data and data from the literature. The expression profile of CPAMD8 in human tissues was determined at the mRNA and protein levels. RESULTS: Biallelic CPAMD8 variants, including one frameshift and six missense variants, were exclusively present and significantly enriched in patients with glaucoma (one with juvenile open-angle glaucoma (JOAG), two with POAG and two with PACG) compared with none of the 4086 probands with other eye conditions in this cohort (p=4.1E-07). The effect of variants in these patients is relatively mild compared with that reported in patients with anterior segment dysgenesis or primary congenital glaucoma. CPAMD8 mRNA was highly expressed in the optic nerve, ciliary body, retina and iris, whereas the CPAMD8 protein was mainly detected in the nonpigmented epithelium of the iris and ciliary process, determined by immunohistochemistry. CONCLUSIONS: The data from this study not only provide further evidence to support the association of biallelic CPAMD8 variants with JOAG but also suggest that biallelic CPAMD8 variants might be associated with POAG and PACG.

Development and validation of methods to visualize conventional aqueous outflow pathways in canine primary angle closure glaucoma.

PURPOSE: Angle closure glaucoma (PACG) is highly prevalent in dogs and is often refractory to medical therapy. We hypothesized that pathology affecting the post-trabecular conventional aqueous outflow pathway contributes to persistent intraocular pressure (IOP) elevation in dogs with PACG. The goal of this study was to determine the potential for aqueous angiography (AA) and optical coherence tomography (OCT) to identify abnormalities in post-trabecular aqueous outflow pathways in canine PACG. METHODS: AA and anterior segment OCT (Spectralis HRA + OCT) were performed ex vivo in 19 enucleated canine eyes (10 normal eyes and 9 irreversibly blind eyes from canine patients enucleated for management of refractory PACG). Eyes were cannulated and maintained at physiologic IOP (10-20 mmHg) prior to intracameral infusion of fluorescent tracer. OCT scleral line scans were acquired in regions of high and low perilimbal AA signal. Eyes were then perfusion fixed and cryosections prepared from 10/10 normal and 7/9 PACG eyes and immunolabeled for a vascular endothelial marker. RESULTS: Normal canine eyes showed segmental, circumferential limbal AA signal, whereas PACG eyes showed minimal or no AA signal. AA signal correlated with scleral lumens on OCT in normal dogs, but lumens were generally absent or flattened in PACG eyes. Collapsed vascular profiles were identified in tissue sections from PACG eyes, including those in which no lumens were identified on AA and OCT. CONCLUSIONS: In canine eyes with PACG, distal aqueous outflow channels are not identifiable by AA, despite normalization of their IOP, and intra-scleral vascular profiles are collapsed on OCT and histopathology.

Methods to Analyze Time-to-Event Data: The Cox Regression Analysis.

The Cox model is a regression technique for performing survival analyses in epidemiological and clinical research. This model estimates the hazard ratio (HR) of a given endpoint associated with a specific risk factor, which can be either a continuous variable like age and C-reactive protein level or a categorical variable like gender and diabetes mellitus. When the risk factor is a continuous variable, the Cox model provides the HR of the study endpoint associated with a predefined unit of increase in the independent variable (e.g., for every 1-year increase in age, 2 mg/L increase in C-reactive protein). A fundamental assumption underlying the application of the Cox model is proportional hazards; in other words, the effects of different variables on survival are constant over time and additive over a particular scale. The Cox regression model, when applied to etiological studies, also allows an adjustment for potential confounders; in an exposure-outcome pathway, a confounder is a variable which is associated with the exposure, is not an effect of the exposure, does not lie in the causal pathway between the exposure and the outcome, and represents a risk factor for the outcome.

Novel Discoveries of Anterior Segment Parameters in Fellow Eyes of Acute Primary Angle Closure and Chronic Primary Angle Closure Glaucoma.

Purpose: To investigate the biometric differences of anterior segment parameters between fellow eyes of acute primary angle closure (F-APAC) and chronic primary angle closure glaucoma (F-CPACG) to get information about differences between APAC and CPAC. Methods: Patients with F-APAC and F-CPACG without prior treatment were enrolled from glaucoma clinics. Parameters were measured on ultrasound biomicroscopy images, including pupil diameter, lens vault (LV), anterior chamber depth, anterior chamber width, iris area, iris thickness (IT 750 and 2000), angle-opening distance (AOD 500 and 750), trabecular-iris space area (TISA 500 and 750), trabecular iris angle (TIA 500 and 750), trabecular-ciliary angle, and ciliary process area. Multivariate logistic regression analysis was performed to determine the most important parameters associated with F-APAC compared with F-CPACG. Results: Fifty-five patients with APAC and 55 patients with CPACG were examined. The anterior chamber depth, IT 750, AOD 750, trabecular iris angle 750, and trabecular-ciliary angle were smaller, and LV and ciliary process area were greater in F-APAC as compared with F-CPACG (P ≤ 0.01). Multivariate logistic regression showed that thinner IT 750, smaller AOD 750, and larger LV were significantly associated with F-APAC (P < 0.01). IT 750 (area under the curve, 0.703) performed relatively better than AOD 750 (area under the curve, 0.696) in distinguishing F-APAC from F-CPACG, with the best cutoff of 0.404 mm and 0.126 mm, respectively. Conclusions: Compared with F-CPACG, F-APAC had thinner peripheral iris, narrower anterior chamber angle, shallower anterior chamber depth, greater LV, larger and anteriorly positioned ciliary body. IT 750, AOD 750, and LV played important roles in distinguishing eyes predisposed to APAC or CPAC.

Glaucoma Syndromes: Insights into Glaucoma Genetics and Pathogenesis from Monogenic Syndromic Disorders.

Monogenic syndromic disorders frequently feature ocular manifestations, one of which is glaucoma. In many cases, glaucoma in children may go undetected, especially in those that have other severe systemic conditions that affect other parts of the eye and the body. Similarly, glaucoma may be the first presenting sign of a systemic syndrome. Awareness of syndromes associated with glaucoma is thus critical both for medical geneticists and ophthalmologists. In this review, we highlight six categories of disorders that feature glaucoma and other ocular or systemic manifestations: anterior segment dysgenesis syndromes, aniridia, metabolic disorders, collagen/vascular disorders, immunogenetic disorders, and nanophthalmos. The genetics, ocular and systemic features, and current and future treatment strategies are discussed. Findings from rare diseases also uncover important genes and pathways that may be involved in more common forms of glaucoma, and potential novel therapeutic strategies to target these pathways.