Glaucoma

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Springelkamp H, Höhn R, Mishra A, Hysi PG, Khor C-C, Loomis SJ, Bailey JCN, Gibson J, Thorleifsson G, Janssen SF, Luo X, Ramdas WD, Vithana E, Nongpiur ME, Montgomery GW, Xu L, Mountain JE, Gharahkhani P, Lu Y, Amin N, Karssen LC, Sim K-S, van Leeuwen EM, Iglesias AI, Verhoeven VJM, Hauser MA, Loon S-C, Despriet DDG, Nag A, Venturini C, Sanfilippo PG, Schillert A, Kang JH, Landers J, Jonasson F, Cree AJ, van Koolwijk LME, Rivadeneira F, Souzeau E, Jonsson V, Menon G, Menon G, Weinreb RN, de Jong PTVM, Oostra BA, Uitterlinden AG, Hofman A, Ennis S, Thorsteinsdottir U, Burdon KP, Burdon KP, Burdon KP, Spector TD, Mirshahi A, Saw S-M, Vingerling JR, Teo Y-Y, Haines JL, Wolfs RCW, Lemij HG, Tai E-S, Jansonius NM, Jonas JB, Cheng C-Y, Aung T, Viswanathan AC, Klaver CCW, Craig JE, Macgregor S, Mackey DA, Lotery AJ, Stefansson K, Bergen AAB, Young TL, Wiggs JL, Pfeiffer N, Wong T-Y, Pasquale LR, Hewitt AW, van Duijn CM, Hammond CJ, Hammond CJ, Hammond CJ, Hammond CJ. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process. Nat Commun 2014;5:4883.Abstract

Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.

Springelkamp H, Iglesias AI, Mishra A, Höhn R, Wojciechowski R, Khawaja AP, Nag A, Wang YX, Wang JJ, Cuellar-Partida G, Gibson J, Cooke Bailey JN, Vithana EN, Gharahkhani P, Boutin T, Ramdas WD, Zeller T, Luben RN, Yonova-Doing E, Viswanathan AC, Yazar S, Cree AJ, Haines JL, Koh JY, Souzeau E, Wilson JF, Amin N, Müller C, Venturini C, Kearns LS, Kang JH, Kang JH, Tham YC, Zhou T, van Leeuwen EM, Nickels S, Sanfilippo P, Liao J, van der Linde H, Zhao W, van Koolwijk LME, Zheng L, Rivadeneira F, Baskaran M, van der Lee SJ, Perera S, de Jong PTVM, Oostra BA, Uitterlinden AG, Fan Q, Hofman A, Tai E-S, Vingerling JR, Sim X, Wolfs RCW, Teo YY, Lemij HG, Khor CC, Willemsen R, Lackner KJ, Aung T, Jansonius NM, Montgomery G, Wild PS, Young TL, Burdon KP, Hysi PG, Pasquale LR, Wong TY, Klaver CCW, Hewitt AW, Jonas JB, Mitchell P, Lotery AJ, Foster PJ, Vitart V, Pfeiffer N, Craig JE, Mackey DA, Hammond CJ, Wiggs JL, Cheng C-Y, van Duijn CM, Macgregor S. New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics. Hum Mol Genet 2017;Abstract

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increase risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

Stacy R, Huttner K, Watts J, Peace J, Wirta D, Walters T, Sall K, Seaman J, Ni X, Prasanna G, Mogi M, Adams C, Yan J-H, Wald M, He Y, Newton R, Kolega R, Grosskreutz C. A Randomized, Controlled Phase I/II Study to Evaluate the Safety and Efficacy of MGV354 for Ocular Hypertension or Glaucoma. Am J Ophthalmol 2018;192:113-123.Abstract
PURPOSE: To assess the clinical safety, tolerability, and efficacy of topically administered MGV354, a soluble guanylate cyclase (sGC) activator, in patients with ocular hypertension (OH) or glaucoma. DESIGN: Double-masked, randomized, and vehicle-controlled study. METHODS: Parts 1 and 2 evaluated safety and tolerability to identify the maximum tolerated dose (MTD) of once-daily MGV354 in 32 healthy volunteers (Part 1) and 16 patients with OH or glaucoma (Part 2) at a single clinical site. Part 3 was a multisite trial that evaluated intraocular pressure (IOP)-lowering efficacy of the MTD administered nightly for 1 week in 50 patients with minimum IOP of 24 mm Hg at 8 AM, with a main outcome measure of mean diurnal IOP at day 8 compared to baseline (ClinicalTrials.govNCT02743780). RESULTS: There was no difference in favor of MGV354 for IOP lowering; change from baseline to day 8 in mean diurnal IOP was -0.6 mm Hg for MGV354-treated patients and -1.1 mm Hg for vehicle-treated patients in Part 3, with a confidence interval of -0.7 to 1.7. The most common adverse events reported after MGV354 administration were conjunctival and ocular hyperemia. CONCLUSIONS: Overall, MGV354 0.1% demonstrated no statistically significant effect compared to vehicle in lowering IOP based on the study's main outcome measure. MGV354 produced ocular hyperemia consistent with its pharmacology.
Stein JD, Talwar N, Kang JH, Okereke OI, Wiggs JL, Pasquale LR. Bupropion Use and Risk of Open-Angle Glaucoma among Enrollees in a Large U.S. Managed Care Network. PLoS One 2015;10(4):e0123682.Abstract

OBJECTIVE: Tumor Necrosis Factor (TNF) mediates retinal ganglion cell death in glaucoma. Anti-TNF drugs are neuroprotective in an animal model of glaucoma. It is unclear whether medications with anti-TNF properties such as bupropion have an impact on the risk of developing open-angle glaucoma (OAG) in humans. The purpose of this study is to determine whether bupropion use alters the risk of developing OAG. METHODS: Claims data for beneficiaries age ≥35 years with no pre-existing OAG enrolled in a large nationwide U.S. managed care network continuously for ≥4 years between 2001-2011 was analyzed to identify patients who had been newly-diagnosed with OAG. The amount of bupropion use as captured from outpatient pharmacy claims over a four-year period was also quantified for each beneficiary. Multivariable Cox regression modeling assessed the impact of bupropion and other antidepressant medications on the risk of developing OAG with adjustment for sociodemographic characteristics of the enrollees along with medical and ocular comorbidities. RESULTS: Of 638,481 eligible enrollees, 15,292 (2.4%) developed OAG. After adjustment for confounding factors including use of other antidepressant medication classes, each additional month of bupropion use was associated with a 0.6% reduced risk of OAG (HR = 0.994, (95% CI: 0.989-0.998), p = 0.007). Compared to nonusers, those with 24-48 months of bupropion use had a 21% reduced hazard (HR=0.79, (CI: 0.65-0.94), p = 0.0099) of OAG. This association did not differ among persons taking bupropion for depression or for other reasons (p-interaction = 0.82). There was no significant association between use of tricyclic antidepressants (HR = 1.000, (CI: 0.997-1.004), p = 0.95) or selective serotonin reuptake inhibitors (HR = 0.999, (CI: 0.997-1.001), p = 0.39) and development of OAG. CONCLUSION: These findings suggest bupropion use may be beneficial in reducing the risk of OAG. If prospective studies confirm the findings of this analysis, this may identify a novel therapeutic target for OAG.

Struebing FL, King R, Li Y, Cooke Bailey JN, Wiggs JL, Geisert EE. Genomic loci modulating retinal ganglion cell death following elevated IOP in the mouse. Exp Eye Res 2018;169:61-67.Abstract
The present study was designed to identify genomic loci modulating the susceptibility of retinal ganglion cells (RGC) to elevated intraocular pressure (IOP) in the BXD recombinant inbred mouse strain set. IOP was elevated by injecting magnetic microspheres into the anterior chamber and blocking the trabecular meshwork using a handheld magnet to impede drainage. The IOP was then measured over the next 21 days. Only animals with IOP greater than 25 mmHg for two consecutive days or an IOP above 30 mmHg on a single day after microsphere-injection were used in this study. On day 21, mice were sacrificed and the optic nerve was processed for histology. Axons were counted for both the injected and the control eye in 49 BXD strains, totaling 181 normal counts and 191 counts associated with elevated IOP. The axon loss for each strain was calculated and the data were entered into genenetwork.org. The average number of normal axons in the optic nerve across all strains was 54,788 ± 16% (SD), which dropped to 49,545 ± 20% in animals with artificially elevated IOP. Interval mapping demonstrated a relatively similar genome-wide map for both conditions with a suggestive Quantitative Trait Locus (QTL) on proximal Chromosome 3. When the relative axon loss was used to generate a genome-wide interval map, we identified one significant QTL (p < 0.05) on Chromosome 18 between 53.6 and 57 Mb. Within this region, the best candidate gene for modulating axon loss was Aldh7a1. Immunohistochemistry demonstrated ALDH7A1 expression in mouse RGCs. ALDH7A1 variants were not significantly associated with glaucoma in the NEIGHBORHOOD GWAS dataset, but this enzyme was identified as part of the butanoate pathway previously associated with glaucoma risk. Our results suggest that genomic background influences susceptibility to RGC degeneration and death in an inducible glaucoma model.
Sun D, Moore S, Jakobs TC. Optic nerve astrocyte reactivity protects function in experimental glaucoma and other nerve injuries. J Exp Med 2017;214(5):1411-1430.Abstract
Reactive remodeling of optic nerve head astrocytes is consistently observed in glaucoma and other optic nerve injuries. However, it is unknown whether this reactivity is beneficial or harmful for visual function. In this study, we used the Cre recombinase (Cre)-loxP system under regulation of the mouse glial fibrillary acidic protein promoter to knock out the transcription factor signal transducer and activator of transcription 3 (STAT3) from astrocytes and test the effect this has on reactive remodeling, ganglion cell survival, and visual function after experimental glaucoma and nerve crush. After injury, STAT3 knockout mice displayed attenuated astrocyte hypertrophy and reactive remodeling; astrocytes largely maintained their honeycomb organization and glial tubes. These changes were associated with increased loss of ganglion cells and visual function over a 30-day period. Thus, reactive astrocytes play a protective role, preserving visual function. STAT3 signaling is an important mediator of various aspects of the reactive phenotype within optic nerve astrocytes.
Susanna FN, Melchior B, Paula JS, Boland MV, Myers JS, Wellik SR, Elze T, Pasquale LR, Shen LQ, Ritch R, Susanna R, Hood DC, Liebmann JM, De Moraes CG. Variability and Power to Detect Progression of Different Visual Field Patterns. Ophthalmol Glaucoma 2021;Abstract
PURPOSE: To compare the variability and ability to detect visual field progression of 24-2, central 12 locations of the 24-2 and 10-2 visual field (VF) tests in eyes with abnormal VFs. DESIGN: Retrospective, multisite cohort. PARTICIPANTS: A total of 52,806 24-2 and 11,966 10-2 VF tests from 7,307 eyes from the Glaucoma Research Network database were analyzed. Only eyes with ≥ 5 visits and ≥ 2 years of follow-up were included. METHODS: Linear regression models were used to calculate the rates of MD (Mean Deviation) change (slopes) while their residuals were used to assess variability across the entire MD range. Computer simulations (n=10,000) based upon real MD residuals of our sample were performed to estimate power to detect significant progression (P < 5%) at various rates of MD change. MAIN OUTCOME MEASURES: Time required to detect progression. RESULTS: For all 3 patterns, the MD variability was highest within the -5 to -20 dB range and consistently lower with the 10-2 compared to 24-2 or Central 24-2. Overall, time to detect confirmed significant progression at 80% power was the lowest with 10-2 VF, with a decrease of 14.6% to 18.5% when compared to 24-2 and a decrease of 22.9% to 26.5% when compared to Central 24-2. CONCLUSION: Time to detect central VF progression was reduced with 10-2 MD compared with 24-2 and C24-2 MD in glaucoma eyes in this large dataset, in part because 10-2 tests had lower variability. These findings contribute to current evidence of the potential value of 10-2 testing in the clinical management of glaucoma patients and in clinical trial design.
Swaminathan SS, Oh D-J, Kang MH, Ren R, Jin R, Gong H, Rhee DJ. Secreted protein acidic and rich in cysteine (SPARC)-null mice exhibit more uniform outflow. Invest Ophthalmol Vis Sci 2013;54(3):2035-47.Abstract
PURPOSE: Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein known to regulate extracellular matrix (ECM) in many tissues and is highly expressed in trabecular meshwork (TM). SPARC-null mice have a 15% to 20% decrease in intraocular pressure (IOP) compared to wild-type (WT) mice. We hypothesized that mouse aqueous outflow is segmental, and that transgenic deletion of SPARC causes a more uniform pattern that correlates with IOP and TM morphology. METHODS: Eyes of C57BL6-SV129 WT and SPARC-null mice were injected with fluorescent microbeads, which were also passively exposed to freshly enucleated eyes. Confocal and electron microscopy were performed. Percentage effective filtration length (PEFL) was calculated as PEFL = FL/TL × 100%, where TL = total length and FL = filtration length. IOP was measured by rebound tonometry. RESULTS: Passive microbead affinity for WT and SPARC-null ECM did not differ. Segmental flow was observed in the mouse eye. SPARC-null mice had a 23% decrease in IOP. PEFL increased in SPARC-null (70.61 ± 11.36%) versus WT mice (54.68 ± 9.95%, P < 0.005; n = 11 pairs), and PEFL and IOP were negatively correlated (R(2) = 0.72, n = 10 pairs). Morphologically, TM of high-tracer regions had increased separation between beams compared to low-tracer regions. Collagen fibril diameter decreased in SPARC-null (28.272 nm) versus WT tissue (34.961 nm, P < 0.0005; n = 3 pairs). CONCLUSIONS: Aqueous outflow in mice is segmental. SPARC-null mice demonstrated a more uniform outflow pattern and decreased collagen fibril diameter. Areas of high flow had less compact juxtacanalicular connective tissue ECM, and IOP was inversely correlated with PEFL. Our data show a correlation between morphology, aqueous outflow, and IOP, indicating a modulatory role of SPARC in IOP regulation.
Swaminathan SS, Oh D-J, Kang MH, Shepard AR, Pang I-H, Rhee DJ. TGF-β2-mediated ocular hypertension is attenuated in SPARC-null mice. Invest Ophthalmol Vis Sci 2014;55(7):4084-97.Abstract
PURPOSE: Transforming growth factor-β2 (TGF-β2) has been implicated in the pathogenesis of primary open-angle glaucoma through extracellular matrix (ECM) alteration among various mechanisms. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that regulates ECM within the trabecular meshwork (TM), and is highly upregulated by TGF-β2. We hypothesized that, in vivo, SPARC is a critical regulatory node in TGF-β2-mediated ocular hypertension. METHODS: Empty (Ad.empty) or TGF-β2-containing adenovirus (Ad.TGF-β2) was injected intravitreally into C57BL6-SV129 WT and SPARC-null mice. An initial study was performed to identify a stable period for IOP measurement under isoflurane. The IOP was measured before injection and every other day for two weeks using rebound tonometry. Additional mice were euthanized at peak IOP for immunohistochemistry. RESULTS: The IOP was stable under isoflurane during minutes 5 to 8. The IOP was significantly elevated in Ad.TGF-β2-injected (n = 8) versus Ad.empty-injected WT (n = 8) mice and contralateral uninjected eyes during days 4 to 11 (P < 0.03). The IOPs were not significantly elevated in Ad.TGF-β2-injected versus Ad.empty-injected SPARC-null mice. However, on day 8, the IOP of Ad.TGF-β2-injected SPARC-null eyes was elevated compared to that of contralateral uninjected eyes (P = 0.0385). Immunohistochemistry demonstrated that TGF-β2 stimulated increases in collagen IV, fibronectin, plasminogen activator inhibitor-1 (PAI-1), connective tissue growth factor (CTGF), and SPARC in WT mice, but only PAI-1 and CTGF in SPARC-null mice (P < 0.05). CONCLUSIONS: SPARC is essential to the regulation of TGF-β2-mediated ocular hypertension. Deletion of SPARC significantly attenuates the effects of TGF-β2 by restricting collagen IV and fibronectin expression. These data provide further evidence that SPARC may have an important role in IOP regulation and possibly glaucoma pathogenesis.
Swaminathan SS, Oh D-J, Kang MH, Rhee DJ. Aqueous outflow: segmental and distal flow. J Cataract Refract Surg 2014;40(8):1263-72.Abstract
UNLABELLED: The elevated intraocular pressure (IOP) of primary open-angle glaucoma is caused by impaired outflow of aqueous humor through the trabecular meshwork. Within the juxtacanalicular region, alterations of both extracellular matrix homeostasis and the cellular tone of trabecular meshwork endothelial and the inner wall of Schlemm canal cells affect outflow. Newer pharmacologic agents that target trabecular meshwork and Schlemm canal cell cytoskeleton lower IOP. Aqueous drainage occurs nonhomogenously with greater flow going through certain portions of the TM and less going through other portions-a concept known as segmental flow, which is theoretically the result of outflow being dependent on the presence of discrete pores within Schlemm canal. The limited long-term success of trabecular meshwork bypass surgeries implicates the potential impact of resistance in Schlemm canal itself and collector channels. Additionally, others have observed that outflow occurs preferentially near collector channels. These distal structures may be more important to aqueous outflow than previously believed. FINANCIAL DISCLOSURE: Dr. Rhee is a consultant to Aerie Pharmaceuticals, Alcon Laboratories, Inc., Allegan, Inc., Aquesys, Inc., Glaukos Corp., Ivantis, Inc., Johnson & Johnson, Merck Sharp & Dohme Corp. and Santen, Inc., and has received research funding from Alcon Laboratories, Inc., Merck Sharp & Dohme Corp., and Ivantis, Inc. No other author has a financial or proprietary interest in any material or method mentioned.
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Taibbi G, Kim JD, Bakir BH, Shenoy SR, Pearce WA, Taroyan G, Birdsong OC, Loucks EK, Vizzeri G. Correlation and Agreement Between Cirrus HD-OCT "RNFL Thickness Map" and Scan Circle Retinal Nerve Fiber Layer Thickness Measurements. J Glaucoma 2016;25(2):208-16.Abstract

PURPOSE: To evaluate the correlation and agreement between optical coherence tomography (Cirrus HD-OCT) retinal nerve fiber layer (RNFL) thickness map and scan circle RNFL thickness measurements. METHODS: ImageJ and custom Perl scripts were used to derive RNFL thickness measurements from RNFL thickness maps of optic disc scans of healthy and glaucomatous eyes. Average, quadrant, and clock-hour RNFL thickness of the map, and RNFL thickness of the areas inside/outside the scan circle were obtained. Correlation and agreement between RNFL thickness map and scan circle RNFL thickness measurements were evaluated using R and Bland-Altman plots, respectively. RESULTS: A total of 104 scans from 26 healthy eyes and 120 scans from 30 glaucomatous eyes were analyzed. RNFL thickness map and scan circle measurements were highly reproducible (eg, in healthy eyes, average RNFL thickness coefficients of variation were 2.14% and 2.52% for RNFL thickness map and scan circle, respectively) and highly correlated (0.55≤R≤0.98). In general, the scan circle provided greater RNFL thickness than the RNFL thickness map in corresponding sectors and the differences tended to increase as RNFL thickness increased. The width of the 95% limits of agreement ranged between 5.28 and 36.80 μm in healthy eyes, and between 11.69 and 42.89 μm in glaucomatous eyes. CONCLUSIONS: Despite good correlation between RNFL thickness map and scan circle measurements, agreement was generally poor, suggesting that RNFL thickness assessment over the entire scan area may provide additional clinically relevant information to the conventional scan circle analysis. In the absence of available measurements from the entire peripapillary region, the RNFL thickness maps can be used to investigate localized RNFL thinning in areas not intercepted by the scan circle.

Takusagawa HL, Hoguet A, Junk AK, Nouri-Mahdavi K, Radhakrishnan S, Chen TC. Swept-Source OCT for Evaluating the Lamina Cribrosa: A Report by the American Academy of Ophthalmology. Ophthalmology 2019;126(9):1315-1323.Abstract
PURPOSE: To review the published literature on the use of swept-source (SS) OCT for evaluating the lamina cribrosa in glaucoma. METHODS: A PubMed and Cochrane Library literature search initially conducted on March 3, 2017, and updated on June 26, 2018, yielded a total of 64 articles. Articles that were reviews or that were not published in English were excluded, and 29 were found to fit the inclusion criteria. The panel methodologist then assigned a level of evidence rating to each study. Fifteen studies were rated level III, 14 studies were rated level II, and no studies were rated level I. RESULTS: Different aspects of the lamina cribrosa were studied using SS-OCT, including the anterior lamina cribrosa curvature, anterior lamina cribrosa depth, anterior lamina cribrosa insertions, laminar thickness, focal lamina cribrosa defects (FLCDs), and lamina cribrosa microarchitecture. In general, imaging of the anterior lamina can be achieved reliably, although shadowing from blood vessels at the neuroretinal rim remains an issue. Imaging of the posterior lamina can be achieved with varying levels of success. In glaucoma, there is posterior migration of the anterior lamina cribrosa insertions as well as increased thinning and posterior curvature of the lamina cribrosa. Focal lamina cribrosa defects appear more commonly in glaucoma, and this may hint at the pathogenesis of axonal damage. In addition, there may be remodeling of the microarchitecture of the lamina, resulting in more variable laminar pores. There are limited studies comparing SS-OCT with spectral-domain (SD) OCT with regard to imaging of the lamina, but the difference in image quality between enhanced depth imaging (EDI) with SD-OCT and SS-OCT seems minimal. CONCLUSIONS: Imaging of the lamina cribrosa using SS-OCT has demonstrated that the lamina cribrosa is likely biomechanically active and that significant changes occur in glaucoma. The diagnostic utility of SS-OCT for lamina cribrosa imaging is promising, but standardized nomenclature, automated measurements, and longitudinal studies with larger and more diverse sample sizes are needed.
Tan NYQ, Friedman DS, Stalmans I, Ahmed IIK, Sng CCA. Glaucoma screening: where are we and where do we need to go?. Curr Opin Ophthalmol 2020;31(2):91-100.Abstract
PURPOSE OF REVIEW: Current recommendations for glaucoma screening are decidedly neutral. No studies have yet documented improved long-term outcomes for individuals who undergo glaucoma screening versus those who do not. Given the long duration that would be required to detect a benefit, future studies that may answer this question definitively are unlikely. Nevertheless, advances in artificial intelligence and telemedicine will lead to more effective screening at lower cost. With these new technologies, additional research is needed to determine the costs and benefits of screening for glaucoma. RECENT FINDINGS: Using optic disc photographs and/or optical coherence tomography, deep learning systems appear capable of diagnosing glaucoma more accurately than human graders. Eliminating the need for expert graders along with better technologies for remote imaging of the ocular fundus will allow for less expensive screening, which could enable screening of individuals with otherwise limited healthcare access. In India and China, where most glaucoma remains undiagnosed, glaucoma screening was recently found to be cost-effective. SUMMARY: Recent advances in artificial intelligence and telemedicine have the potential to increase the accuracy, reduce the costs, and extend the reach of screening. Further research into implementing these technologies in glaucoma screening is required.
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.
Tiedemann D, Mouhammad ZA, Utheim TP, Dartt DA, Heegaard S, Petrovski G, Kolko M. Conjunctival Goblet Cells, the Overlooked Cells in Glaucoma Treatment. J Glaucoma 2019;28(4):325-333.Abstract
Glaucoma is the leading cause of irreversible blindness worldwide. Although no definitive cure exists, lowering of the intraocular pressure decreases the rate of progression in the majority of patients with glaucoma. Antiglaucomatous treatment modalities consist predominantly of chronic use of eye drops. It has become increasingly evident that long-term exposure to eye drops has a significant impact on the ocular surface, and thereby on patient compliance and quality of life. Maintenance of the ocular surface is highly dependent on a stable tear film. Conjunctival goblet cells (GCs) of the ocular surface play an important role in providing the innermost mucin layer of the tear film and are essential for maintaining the ocular surface homeostasis. Recent studies have reported severe side effects of antiglaucomatous drops on GCs. In particular, a preservative containing antiglaucomatous drops have been shown to affect the viability and functions of the GCs. Furthermore, GC density has been suggested as a potential predictor of surgical outcome after filtration surgery. The present review provides an overview of the current literature on the impact of antiglaucomatous eye drops on GCs as well as the impact on the ocular surface. Moreover, the existing evidence of a possible association between GC density and glaucoma filtration surgery outcome is summarized. We conclude that prostaglandin analogs spare the conjunctival GCs more compared with other antiglaucomatous drops and that GCs may be a good predictor of surgical outcome after filtration surgery. Overall, given the multiple functions of GCs in the ocular surface homeostasis, dedicated strategies should be adopted to preserve this cell population during the course of glaucoma.
Truong TN, Li H, Hong Y-K, Chen L. Novel characterization and live imaging of Schlemm's canal expressing Prox-1. PLoS One 2014;9(5):e98245.Abstract
Schlemm's canal is an important structure of the conventional aqueous humor outflow pathway and is critically involved in regulating the intraocular pressure. In this study, we report a novel finding that prospero homeobox protein 1 (Prox-1), the master control gene for lymphatic development, is expressed in Schlemm's canal. Moreover, we provide a novel in vivo method of visualizing Schlemm's canal using a transgenic mouse model of Prox-1-green fluorescent protein (GFP). The anatomical location of Prox-1⁺ Schlemm's canal was further confirmed by in vivo gonioscopic examination and ex vivo immunohistochemical analysis. Additionally, we show that the Schlemm's canal is distinguishable from typical lymphatic vessels by lack of lymphatic vessel endothelial hyaluronan receptor (LYVE-1) expression and absence of apparent sprouting reaction when inflammatory lymphangiogenesis occurred in the cornea. Taken together, our findings offer new insights into Schlemm's canal and provide a new experimental model for live imaging of this critical structure to help further our understanding of the aqueous humor outflow. This may lead to new avenues toward the development of novel therapeutic intervention for relevant diseases, most notably glaucoma.
Tsikata E, Lee R, Shieh E, Simavli H, Que CJ, Guo R, Khoueir Z, de Boer J, Chen TC. Comprehensive Three-Dimensional Analysis of the Neuroretinal Rim in Glaucoma Using High-Density Spectral-Domain Optical Coherence Tomography Volume Scans. Invest Ophthalmol Vis Sci 2016;57(13):5498-5508.Abstract

Purpose: To describe spectral-domain optical coherence tomography (OCT) methods for quantifying neuroretinal rim tissue in glaucoma and to compare these methods to the traditional retinal nerve fiber layer thickness diagnostic parameter. Methods: Neuroretinal rim parameters derived from three-dimensional (3D) volume scans were compared with the two-dimensional (2D) Spectralis retinal nerve fiber layer (RNFL) thickness scans for diagnostic capability. This study analyzed one eye per patient of 104 glaucoma patients and 58 healthy subjects. The shortest distances between the cup surface and the OCT-based disc margin were automatically calculated to determine the thickness and area of the minimum distance band (MDB) neuroretinal rim parameter. Traditional 150-μm reference surface-based rim parameters (volume, area, and thickness) were also calculated. The diagnostic capabilities of these five parameters were compared with RNFL thickness using the area under the receiver operating characteristic (AUROC) curves. Results: The MDB thickness had significantly higher diagnostic capability than the RNFL thickness in the nasal (0.913 vs. 0.818, P = 0.004) and temporal (0.922 vs. 0.858, P = 0.026) quadrants and the inferonasal (0.950 vs. 0.897, P = 0.011) and superonasal (0.933 vs. 0.868, P = 0.012) sectors. The MDB area and the three neuroretinal rim parameters based on the 150-μm reference surface had diagnostic capabilities similar to RNFL thickness. Conclusions: The 3D MDB thickness had a high diagnostic capability for glaucoma and may be of significant clinical utility. It had higher diagnostic capability than the RNFL thickness in the nasal and temporal quadrants and the inferonasal and superonasal sectors.

Turalba AV, Shah AS, Andreoli MT, Andreoli CM, Rhee DJ. Predictors and outcomes of ocular hypertension after open-globe injury. J Glaucoma 2014;23(1):5-10.Abstract
PURPOSE: Evaluate predictors and outcomes of ocular hypertension after open-globe injury. PATIENTS AND METHODS: This is a retrospective, case-control study reviewing records of consecutive patients with open-globe injuries treated at Massachusetts Eye and Ear Infirmary between February 1999 and January 2007. Of 658 patients treated, 382 had at least 2 months of follow-up and sufficient data to be included. Main outcome measures are visual acuity, intraocular pressure (IOP), and type of glaucoma intervention employed. RESULTS: Sixty-five (17%) patients developed ocular hypertension defined as IOP≥22 mm Hg at >1 visit or requiring treatment. Increased age (P<0.001), hyphema (0.025), lens injury (P<0.0001), and zone II injury (P=0.0254) are risk factors for developing ocular hypertension after open-globe injury. Forty-eight (74%) patients with ocular hypertension were treated medically, 8 (12%) underwent filtering or glaucoma drainage device surgery, 5 (8%) had IOP normalization with observation, while 4 (6%) required anterior chamber washout with no other glaucoma surgery. Patients with ocular hypertension had an average maximum IOP=33.4 mm Hg at a median follow-up of 21 days, with most patients maintaining normal IOP at all follow-up time points. Visual acuity improved over time with median acuity of hand motions preoperatively, and 20/60 at 12 and 36 months. CONCLUSIONS: Ocular hypertension is a significant complication after open-globe injury that sometimes requires surgical intervention. Predictive factors can alert physicians to monitor for elevated IOP in the first month after trauma. Most patients with traumatic ocular hypertension had improved visual acuity and IOP normalization over time.
Turalba AV, Pasquale LR. Hypertensive phase and early complications after Ahmed glaucoma valve implantation with intraoperative subtenon triamcinolone acetonide. Clin Ophthalmol 2014;8:1311-6.Abstract
OBJECTIVE: To evaluate intraoperative subtenon triamcinolone acetonide (TA) as an adjunct to Ahmed glaucoma valve (AGV) implantation. DESIGN: Retrospective comparative case series. PARTICIPANTS: Forty-two consecutive cases of uncontrolled glaucoma undergoing AGV implantation: 19 eyes receiving intraoperative subtenon TA and 23 eyes that did not receive TA. METHODS: A retrospective chart review was performed on consecutive pseudophakic adult patients with uncontrolled glaucoma undergoing AGV with and without intraoperative subtenon TA injection by a single surgeon. Clinical data were collected from 42 eyes and analyzed for the first 6 months after surgery. MAIN OUTCOME MEASURES: Primary outcomes included intraocular pressure (IOP) and number of glaucoma medications prior to and after AGV implantation. The hypertensive phase (HP) was defined as an IOP measurement of greater than 21 mmHg (with or without medications) during the 6-month postoperative period that was not a result of tube obstruction, retraction, or malfunction. Postoperative complications and visual acuity were analyzed as secondary outcome measures. RESULTS: Five out of 19 (26%) TA cases and 12 out of 23 (52%) non-TA cases developed the HP (P=0.027). Mean IOP (14.2±4.6 in TA cases versus [vs] 14.7±5.0 mmHg in non-TA cases; P=0.78), and number of glaucoma medications needed (1.8±1.3 in TA cases vs 1.6±1.1 in the comparison group; P=0.65) were similar between both groups at 6 months. Although rates of serious complications did not differ between the groups (13% in the TA group vs 16% in the non-TA group), early tube erosion (n=1) and bacterial endophthalmitis (n=1) were noted with TA but not in the non-TA group. CONCLUSIONS: Subtenon TA injection during AGV implantation may decrease the occurrence of the HP but does not alter the ultimate IOP outcome and may pose increased risk of serious complications within the first 6 months of surgery.
Turalba A, Payal AR, Gonzalez-Gonzalez LA, Cakiner-Egilmez T, Chomsky AS, Vollman DE, Baze EF, Lawrence M, Daly MK. Cataract Surgery Outcomes in Glaucomatous Eyes: Results From the Veterans Affairs Ophthalmic Surgery Outcomes Data Project. Am J Ophthalmol 2015;160(4):693-701.e1.Abstract

PURPOSE: To compare visual acuity outcomes, vision-related quality of life, and complications related to cataract surgery in eyes with and without glaucoma. DESIGN: Retrospective cohort study. METHODS: Cataract surgery outcomes in cases with and without glaucoma from the Veterans Affairs Ophthalmic Surgical Outcomes Data Project were compared. RESULTS: We identified 608 glaucoma cases and 4306 controls undergoing planned cataract surgery alone. After adjusting for age, pseudoexfoliation, small pupil, prior ocular surgery, and anterior chamber depth, we found that glaucoma cases were more likely to have posterior capsular tear with vitrectomy (odds ratio [OR] 1.8, P = .03) and sulcus intraocular lens placement (OR 1.65, P = .03) during cataract surgery. Glaucoma cases were more likely to have postoperative inflammation (OR 1.73, P < .0001), prolonged elevated intraocular pressure (OR 2.96, P = .0003), and additional surgery within 30 days (OR 1.92, P = .03). Mean best-corrected visual acuity (BCVA) and Visual Function Questionnaire (VFQ) scores significantly improved after cataract surgery in both groups (P < .0001), but there were larger improvements in BCVA (P = .01) and VFQ composite scores (P < .0001) in the nonglaucoma vs the glaucoma group. A total of 3621 nonglaucoma cases (94.1%) had postoperative BCVA 20/40 or better, compared to 466 glaucoma cases (89.6%) (P = .0003). CONCLUSIONS: Eyes with glaucoma are at increased risk for complications and have more modest visual outcomes after cataract surgery compared to eyes without glaucoma. Despite this, glaucoma patients still experience significant improvement in vision-related outcomes after cataract extraction. Further study is needed to explore potential factors that influence cataract surgery outcomes in glaucomatous eyes.

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