Glaucoma

Glaucoma Publications

King R, Struebing FL, Li Y, Wang J, Koch AA, Cooke Bailey JN, Gharahkhani P, Gharahkhani P, Gharahkhani P, Macgregor S, Allingham RR, Hauser MA, Wiggs JL, Geisert EE. Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma. PLoS Genet 2018;14(1):e1007145.Abstract
Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG. The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60-100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to QTLs modulating this phenotype using the bioinformatics tools on GeneNetwork (www.genenetwork.org). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human POAG genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10-6 for SNP rs76319873. POU6F2 is found in retinal ganglion cells and in corneal limbal stem cells. To test the effect of POU6F2 on CCT we examined the corneas of a Pou6f2-null mice and the corneas were thinner than those of wild-type littermates. In addition, these POU6F2 RGCs die early in the DBA/2J model of glaucoma than most RGCs. Using a mouse genetic reference panel, we identified a transcription factor, Pou6f2, that modulates CCT in the mouse. POU6F2 is also found in a subset of retinal ganglion cells and these RGCs are sensitive to injury.
Yin Y, Benowitz LI. In Vitro and In Vivo Methods for Studying Retinal Ganglion Cell Survival and Optic Nerve Regeneration. Methods Mol Biol 2018;1695:187-205.Abstract
Glaucoma is marked by a progressive degeneration of the optic nerve and delayed loss of retinal ganglion cells (RGCs), the projection neurons of the eye. Because RGCs are not replaced and because surviving RGCs cannot regenerate their axons, the visual loss in glaucoma is largely irreversible. Here, we describe methods to evaluate treatments that may be beneficial for treating glaucoma using in vitro cell culture models (immunopanning to isolate neonatal RGCs, dissociated mature retinal neurons, retinal explants) and in vivo models that test potential treatments or investigate underlying molecular mechanisms in an intact system. Potentially, use of these models can help investigators continue to improve treatments to preserve RGCs and restore visual function in patients with glaucoma.
Chou JC, Cousins CC, Miller JB, Song BJ, Shen LQ, Kass MA, Wiggs JL, Pasquale LR. Fundus Densitometry Findings Suggest Optic Disc Hemorrhages in Primary Open-Angle Glaucoma Have an Arterial Origin. Am J Ophthalmol 2018;Abstract
PURPOSE: To analyze optic disc hemorrhages (DH) associated with primary open-angle glaucoma by quantifying their geometric profile and comparing their densitometry with hemorrhages from retinal vein occlusions (RVO) and retinal macroaneurysms (MA), which have venous and arterial sources of bleeding, respectively. DESIGN: Retrospective cross-sectional study METHODS: Setting: Massachusetts Eye & Ear POPULATION: Fundus images of DH (n=40), MA (n=14), and RVO (n=25) were identified. Patient clinical backgrounds and demographics were obtained. MAIN OUTCOME: Grayscale pixel intensity units of hemorrhages and adjacent arteriole and venule over the same background tissue were measured. Densitometry differentials (arteriole or venule minus hemorrhage [ΔA and ΔV, respectively]) were calculated. The ratios of length (radial) to midpoint width for DH were calculated. T-tests compared mean ΔA and ΔV between groups. Multiple linear regression assessed the relation of retinal hemorrhage diagnosis to ΔA and ΔV and of DH shape to ΔA and ΔV. RESULTS: Mean (±standard deviation) ΔA and ΔV for DH (6.9±7.1 and -4.7±8.0 pixel intensity units, respectively) and MA (5.3±5.9 and -6.0±4.6, respectively) were comparable (P≥0.43). Mean ΔA (14.6±7.7) and ΔV (6.4±6.3) for RVO were significantly higher compared to DH and MA (P<0.0001) and remained significant in multivariable analyses. A unit increase in DH length-to-width ratio was associated with 1.2 (0.5) and 1.3 (0.5) pixel intensity unit (standard error) decrease in ΔA and ΔV, respectively (P≤0.014). CONCLUSIONS: DH have densitometry profiles comparable to MA and different from RVO, suggesting that DH in glaucoma have an arterial origin.
Lin S-C, Pasquale LR, Singh K, Lin SC. The Association between Body Mass Index and Open-angle Glaucoma in a South Korean Population-based Sample. J Glaucoma 2018;Abstract
PURPOSE: To investigate the association between body mass index (BMI) and open-angle glaucoma (OAG) in a sample of the South Korean population. MATERIALS AND METHODS: The sample consisted of a cross-sectional, population-based sample of 10,978 participants, 40 years of age and older, enrolled in the 2008-2011 Korean National Health and Nutrition Examination Survey (KNHANES). All participants had measured intraocular pressure <22▒mm Hg and open anterior chamber angles. OAG was defined using disc and visual field criteria established by the International Society for Geographical and Epidemiological Ophthalmology. Multivariable analyses were performed to determine the association between BMI and OAG. These analyses were also performed in a sex- and age-stratified fashion. RESULTS: After adjusting for potential confounding variables, lower BMI (<19▒kg/m) was associated with greater risk of OAG compared with normal BMI (19-24.9▒kg/m) (Odds Ratio [OR]=2.28 [95% confidence interval] [CI]: 1.22-4.26). In sex-stratified analyses, low BMI remained adversely related to glaucoma in women (OR=3.45 [95% CI: 1.42-8.38]) but not in men (OR=1.72 [95% CI: 0.71-4.20]). In age-stratified analyses, lower BMI was adversely related to glaucoma among subjects 40-49 year-old (OR=5.16 [95% CI: 1.86-14.36]) but differences in glaucoma prevalence were not statistically significant between those with low versus normal BMI in other age strata. CONCLUSIONS: Lower BMI was associated with increased odds of OAG in a sample of the South Korean population. Multivariate analysis revealed the association to be statistically significant in women and those in the youngest age stratum.
Feinstein M, Moussa K, Han Y. Ab Interno Tube Occlusion for Postoperative Hypotony in a Patient with an Ahmed Glaucoma Drainage Device. J Glaucoma 2018;Abstract
PURPOSE: To report a case of Ahmed glaucoma valve-induced hypotony that was successfully managed with postoperative intraluminal stenting of the aqueous shunt tube. PATIENT AND METHODS: We describe a 68-year-old male with advanced uveitic glaucoma with an intraocular pressure (IOP) of 25▒mm Hg in the left eye. The patient initially responded well to an Ahmed glaucoma valve implant, but at 10 weeks post-implantation, the patient underwent cataract surgery and developed persistent hypotony, choroidal folds, and decreased vision. RESULTS: Prior to partial occlusion of the aqueous shunt tube, the patient had an IOP of 3▒mm Hg and a best corrected visual acuity (BCVA) of 20/60. Following intraluminal stenting of the aqueous shunt tube with 4-0 polypropylene suture (Prolene; Ethican), IOP rose to 7-10▒mm Hg, BCVA improved to 20/30, and the choroidal folds resolved; IOP and BCVA remained stable through one-year of follow up and no additional surgical or pharmacological interventions were required. CONCLUSION: Aqueous shunt-induced hypotony can be successfully managed with intraluminal stenting and should be considered before tubal ligation or shunt removal.
Bains U, Hoguet A. Aqueous Drainage Device Erosion: A Review of Rates, Risks, Prevention, and Repair. Semin Ophthalmol 2017;:1-10.Abstract
Aqueous drainage device tube erosions require prompt intervention to prevent endophthalmitis. As the use of drainage devices in glaucoma surgery continues to increase, recognizing and managing tube erosions is a pertinent issue. This review provides a comprehensive overview of tube erosions, including the rates of erosion with various types of patch grafts, the risk factors associated with erosion, and approaches to repair in order to counsel and treat our patients to prevent endophthalmitis.
Haleem MS, Han L, van Hemert J, Li B, Fleming A, Pasquale LR, Song BJ. A Novel Adaptive Deformable Model for Automated Optic Disc and Cup Segmentation to Aid Glaucoma Diagnosis. J Med Syst 2017;42(1):20.Abstract
This paper proposes a novel Adaptive Region-based Edge Smoothing Model (ARESM) for automatic boundary detection of optic disc and cup to aid automatic glaucoma diagnosis. The novelty of our approach consists of two aspects: 1) automatic detection of initial optimum object boundary based on a Region Classification Model (RCM) in a pixel-level multidimensional feature space; 2) an Adaptive Edge Smoothing Update model (AESU) of contour points (e.g. misclassified or irregular points) based on iterative force field calculations with contours obtained from the RCM by minimising energy function (an approach that does not require predefined geometric templates to guide auto-segmentation). Such an approach provides robustness in capturing a range of variations and shapes. We have conducted a comprehensive comparison between our approach and the state-of-the-art existing deformable models and validated it with publicly available datasets. The experimental evaluation shows that the proposed approach significantly outperforms existing methods. The generality of the proposed approach will enable segmentation and detection of other object boundaries and provide added value in the field of medical image processing and analysis.
Chintalapudi SR, Maria D, Di Wang X, Bailey JCN, Bailey JCN, Bailey JCN, Hysi PG, Wiggs JL, Williams RW, Jablonski MM. Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility. Nat Commun 2017;8(1):1755.Abstract
Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype. Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found. Importantly, these results demonstrate that our systems genetics approach represents an efficient method to identify genetic variation that can guide the selection of therapeutic targets.
Learned D, Eliott D. Management of Delayed Suprachoroidal Hemorrhage after Glaucoma Surgery. Semin Ophthalmol 2017;:1-5.Abstract
PURPOSE: To review the most current treatment recommendations and outcomes for delayed suprachoroidal hemorrhages. METHODS: Article review of management and outcomes of suprachoroidal hemorrhages, with emphasis on delayed suprachoroidal hemorrhages in the setting of glaucoma surgery. CONCLUSION: Time of drainage of suprachoroidal hemorrhages remains controversial. Earlier drainage should be considered with high intraocular pressure, expulsion of intraocular content, or retinal detachment. In clinically stable eyes with suprachoroidal hemorrhage, recommendations range from observation to immediate drainage. Clot lysis occurs at roughly 14 days.
Thomson BR, Souma T, Tompson SW, Onay T, Kizhatil K, Siggs OM, Feng L, Whisenhunt KN, Yanovitch TL, Kalaydjieva L, Azmanov DN, Finzi S, Tanna CE, Hewitt AW, Mackey DA, Bradfield YS, Souzeau E, Javadiyan S, Wiggs JL, Pasutto F, Liu X, John SWM, Craig JE, Jin J, Young TL, Quaggin SE. Angiopoietin-1 is required for Schlemm's canal development in mice and humans. J Clin Invest 2017;Abstract
Primary congenital glaucoma (PCG) is a leading cause of blindness in children worldwide and is caused by developmental defects in 2 aqueous humor outflow structures, Schlemm's canal (SC) and the trabecular meshwork. We previously identified loss-of-function mutations in the angiopoietin (ANGPT) receptor TEK in families with PCG and showed that ANGPT/TEK signaling is essential for SC development. Here, we describe roles for the major ANGPT ligands in the development of the aqueous outflow pathway. We determined that ANGPT1 is essential for SC development, and that Angpt1-knockout mice form a severely hypomorphic canal with elevated intraocular pressure. By contrast, ANGPT2 was dispensable, although mice deficient in both Angpt1 and Angpt2 completely lacked SC, indicating that ANGPT2 compensates for the loss of ANGPT1. In addition, we identified 3 human subjects with rare ANGPT1 variants within an international cohort of 284 PCG patients. Loss of function in 2 of the 3 patient alleles was observed by functional analysis of ANGPT1 variants in a combined in silico, in vitro, and in vivo approach, supporting a causative role for ANGPT1 in disease. By linking ANGPT1 with PCG, these results highlight the importance of ANGPT/TEK signaling in glaucoma pathogenesis and identify a candidate target for therapeutic development.
Aschard H, Kang JH, Iglesias AI, Hysi P, Cooke Bailey JN, Khawaja AP, Allingham RR, Ashley-Koch A, Lee RK, Moroi SE, Brilliant MH, Wollstein G, Schuman JS, Fingert JH, Budenz DL, Realini T, Gaasterland T, Scott WK, Singh K, Sit AJ, Igo RP, Song YE, Hark L, Ritch R, Rhee DJ, Gulati V, Haven S, Vollrath D, Zack DJ, Medeiros F, Weinreb RN, Cheng C-Y, Chasman DI, Christen WG, Pericak-Vance MA, Liu Y, Kraft P, Richards JE, Rosner BA, Hauser MA, Hauser MA, Klaver CCW, van Duijn CM, Haines J, Wiggs JL, Pasquale LR. Genetic correlations between intraocular pressure, blood pressure and primary open-angle glaucoma: a multi-cohort analysis. Eur J Hum Genet 2017;25(11):1261-1267.Abstract
Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14-1.21), P=1.8 × 10-27) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 × 10-5); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG.
Di Zazzo A, Roberti G, Mashaghi A, Abud TB, Pavese D, Bonini S. Use of Topical Cannabinomimetic Palmitoylethanolamide in Ocular Surface Disease Associated with Antiglaucoma Medications. J Ocul Pharmacol Ther 2017;33(9):670-677.Abstract
PURPOSE: Chronic use of topical hypotensive therapies in glaucoma patients leads to chronic inflammation of the ocular surface, which decreases the success rate of long-term glaucoma management. The aim of this study is to evaluate the effect of topical palmitoylethanolamide (PEA) (Defluxa©), a well-known anti-inflammatory and analgesic agent, in suppressing the ocular surface inflammation associated with the use of hypotensive eye drops. METHODS: In a pilot clinical trial, we enrolled 15 glaucomatous patients who received topical PEA (Defluxa) in addition to the current antiglaucoma drugs, while 15 glaucomatous patients did not receive any additional treatment. At 3 different time points (day 0, 15, and 30), signs of ocular surface involvement, adverse events, visual acuity, and intraocular pressure were assessed. RESULTS: Topical PEA (Defluxa) was effective in increasing the Schirmer test (P < 0.05) and the tear film breakup time (T-BUT) (P < 0.0001), and improving the conjunctival hyperemia (P < 0.0001) by day 30, compared to baseline. Compared to control, by day 15, the conjunctival hyperemia score was significantly decreased in the PEA (Defluxa) group (P < 0.01), while the T-BUT and the Schirmer Test achieved a significant improvement by day 30 (P < 0.05; P < 0.01). DISCUSSION: Our data suggests that topical PEA (Defluxa) is a safe, effective, and generally well-tolerated treatment to prevent or suppress ocular surface inflammation attributable to chronic glaucoma treatment.
Rahman SI, Turalba A. Anticoagulation in Glaucoma Surgery. Semin Ophthalmol 2017;:1-4.Abstract
Anticoagulation medications are used commonly, particularly in an elderly population. There are many systemic diseases and scenarios that require modulation of coagulation to prevent serious adverse outcomes. While there is some consensus about their use in cataract surgery, there is less certainty about their management with glaucoma surgery. Glaucoma surgery presents a unique challenge when considering anticoagulation. Currently, there is great diversity in surgeon practices regarding anticoagulation in glaucoma surgery. Based on available evidence, it is unclear whether it is beneficial to hold anticoagulation, with or without bridging therapy, leading up to a planned surgery. Considering the potential serious adverse outcomes related to holding anticoagulation therapy, altering these medications for glaucoma surgery should be done sparingly and in consultation with the primary prescriber of such medications.
Foulsham W, Tatham AJ. High Altitude-associated Changes in Intraocular Pressure Abrogated by Trabeculectomy. J Glaucoma 2017;26(10):957-960.Abstract
PURPOSE: To highlight the effect of ascent to high altitude on intraocular pressure (IOP) in a patient with primary open-angle glaucoma, who had previously undergone trabeculectomy in 1 eye. METHODS: Case report. RESULTS: A 66-year-old mountaineer with primary open-angle glaucoma and previous right trabeculectomy performed self-tonometry using a rebound tonometer (Icare HOME) before and during an expedition in the Himalaya. In the nonoperated eye, there was a statistically significant increase in IOP as the patient ascended to 5000 m over 8 days (R=0.790, P=0.001), consistent with recent literature. IOP increased by 1.73 mm Hg with each 1000 m increase in altitude. In the trabeculectomized eye there was no significant increase in IOP (R=0.219, P=0.172). CONCLUSIONS: Filtration surgery may be protective against IOP fluctuations associated with ascent to high altitude. Self-tonometry complements standard glaucoma care by providing opportunities for IOP monitoring outside office hours and in remote locations.

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