Glaucoma

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Gauthier AC, Wiggs JL. Childhood glaucoma genes and phenotypes: Focus on FOXC1 mutations causing anterior segment dysgenesis and hearing loss. Exp Eye Res 2020;190:107893.Abstract
Childhood glaucoma is an important cause of blindness world-wide. Eleven genes are currently known to cause inherited forms of glaucoma with onset before age 20. While all the early-onset glaucoma genes cause severe disease, considerable phenotypic variability is observed among mutations carriers. In particular, FOXC1 genetic variants are associated with a broad range of phenotypes including multiple forms of glaucoma and also systemic abnormalities, especially hearing loss. FOXC1 is a member of the forkhead family of transcription factors and is involved in neural crest development necessary for formation of anterior eye structures and also pharyngeal arches that form the middle ear bones. In this study we review the clinical phenotypes reported for known FOXC1 mutations and show that mutations in patients with reported ocular anterior segment abnormalities and hearing loss primarily disrupt the critically important forkhead domain. These results suggest that optimal care for patients affected with anterior segment dysgenesis should include screening for FOXC1 mutations and also testing for hearing loss.
Gazzard G, Jayaram H, Roldan AM, Friedman DS. When gold standards change: time to move on from Goldmann tonometry?. Br J Ophthalmol 2021;105(1):1-2.
Geoffrion D, Robert M-C, Chodosh J, Di Polo A, Harissi-Dagher M. Perspectives for preclinical mouse models of glaucoma after Boston keratoprosthesis type 1. Exp Eye Res 2021;208:108615.Abstract
Animal models of the Boston keratoprosthesis type 1 (KPro) are needed to study glaucoma damage after KPro implantation to control for confounding comorbidities common in human KPro recipients. The purpose of this study was to determine the feasibility of establishing a reproducible mouse model of glaucoma after KPro surgery, specifically that of a miniaturized mouse model of KPro (mKPro). In the present study, a total of 20 corneas of donor C57BL/6 mice (n = 10) were implanted in one eye of each recipient BALB/C mouse (n = 20), assembled as part of the mKPro, either with or without intraoperative lensectomy. Main feasibility outcomes consisted in incidence rates of loss of tone, capsule nicking, and lens extrusion, as well as acquisition of posterior segment optical coherence tomography (OCT) images. With lensectomy (n = 10), loss of ocular tone and retinal detachment occurred in 100% of mice. Without lensectomy (n = 10), capsule nicking and opening, as well as lens extrusion, occurred in 80% of mice. Causes of these complications included the large proportion of intraocular volume occupied by the lens, the shallow anterior chamber, and thus the lack of available intraocular volume to implant the KPro if the lens remains present. Successful mouse KPro surgery may require a great deal of practice to be useful as a reproducible model. Animal KPro models ought to be pursued further by research teams in future studies.
Gharahkhani P, Burdon KP, Cooke Bailey JN, Hewitt AW, Law MH, Pasquale LR, Kang JH, Haines JL, Souzeau E, Zhou T, Siggs OM, Landers J, Awadalla M, Sharma S, Mills RA, Ridge B, Lynn D, Casson R, Graham SL, Goldberg I, White A, Healey PR, Grigg J, Lawlor M, Mitchell P, Ruddle J, Coote M, Walland M, Best S, Vincent A, Gale J, RadfordSmith G, Whiteman DC, Montgomery GW, Martin NG, Mackey DA, Wiggs JL, Macgregor S, Craig JE, Craig JE. Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma. Sci Rep 2018;8(1):3124.Abstract
Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - "response to fluid shear stress" and "abnormal retina morphology" - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.
Gharahkhani P, Burdon KP, Fogarty R, Sharma S, Hewitt AW, Martin S, Law MH, Cremin K, Bailey JCN, Loomis SJ, Pasquale LR, Haines JL, Hauser MA, Viswanathan AC, McGuffin P, Topouzis F, Foster PJ, Graham SL, Casson RJ, Chehade M, White AJ, Zhou T, Souzeau E, Landers J, Fitzgerald JT, Klebe S, Ruddle JB, Goldberg I, Healey PR, Healey PR, Healey PR, Mills RA, Wang JJ, Montgomery GW, Martin NG, Radford-Smith G, Whiteman DC, Brown MA, Wiggs JL, Mackey DA, Mitchell P, Macgregor S, Craig JE. Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma. Nat Genet 2014;46(10):1120-5.Abstract

Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10(-19)), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10(-10)) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10(-10)). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.

Gharahkhani P, Jorgenson E, Hysi P, Khawaja AP, Pendergrass S, Han X, Ong JS, Hewitt AW, Segrè AV, Rouhana JM, Hamel AR, Igo RP, Choquet H, Qassim A, Josyula NS, Cooke Bailey JN, Bonnemaijer PWM, Iglesias A, Siggs OM, Young TL, Vitart V, Thiadens AAHJ, Karjalainen J, Uebe S, Melles RB, Nair SK, Luben R, Simcoe M, Amersinghe N, Cree AJ, Hohn R, Poplawski A, Chen LJ, Rong S-S, Aung T, Vithana EN, Vithana EN, Vithana EN, Vithana EN, Vithana EN, and Consortium UKBEV, and Consortium UKBEV, and Consortium UKBEV, Tamiya G, Shiga Y, Yamamoto M, Nakazawa T, Currant H, Birney E, Wang X, Auton A, Lupton MK, Martin NG, Ashaye A, Olawoye O, Williams SE, Akafo S, Ramsay M, Hashimoto K, Kamatani Y, Akiyama M, Momozawa Y, Foster PJ, Khaw PT, Morgan JE, Strouthidis NG, Kraft P, Kang JH, Pang CP, Pasutto F, Mitchell P, Lotery AJ, Palotie A, van Duijn C, Haines JL, Hammond C, Pasquale LR, Klaver CCW, Hauser M, Khor CC, Mackey DA, Kubo M, Cheng C-Y, Craig JE, Macgregor S, Wiggs JL. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries. Nat Commun 2021;12(1):1258.Abstract
Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.
Guhan S, Peng S-L, Janbatian H, Saadeh S, Greenstein S, Al Bahrani F, Fadlallah A, Yeh T-C, Melki SA. Surgical adhesives in ophthalmology: history and current trends. Br J Ophthalmol 2018;Abstract
Tissue adhesives are gaining popularity in ophthalmology, as they could potentially reduce the complications associated with current surgical methods. An ideal tissue adhesive should have superior tensile strength, be non-toxic and anti-inflammatory, improve efficiency and be cost-effective. Both synthetic and biological glues are available. The primary synthetic glues include cyanoacrylate and the recently introduced polyethylene glycol (PEG) derivatives, while most biological glues are composed of fibrin. Cyanoacrylate has a high tensile strength, but rapidly polymerises upon contact with any fluid and has been associated with histotoxicity. Fibrin induces less toxic and inflammatory reactions, and its polymerisation time can be controlled. Tensile strength studies have shown that fibrin is not as strong as cyanoacrylate. While more research is needed, PEG variants currently appear to have the most promise. These glues are non-toxic, strong and time-effective. Through MEDLINE and internet searches, this paper presents a systematic review of the current applications of surgical adhesives to corneal, glaucoma, retinal, cataract and strabismus surgeries. Our review suggests that surgical adhesives have promise to reduce problems in current ophthalmic surgical procedures.
Guo C, Wu N, Niu X, Wu Y, Chen DF, Guo W. Comparison of T Helper Cell Patterns in Primary Open-Angle Glaucoma and Normal-Pressure Glaucoma. Med Sci Monit 2018;24:1988-1996.Abstract
BACKGROUND HSP60-related immunological activities are found in normal-pressure glaucoma (NPG) patients, in whom an elevated intraocular pressure (IOP) found in primary open-angle glaucoma (POAG) is not observed. HSP60 was found in POAG and NPG patients, while anti-HSP60 level was mainly found to be higher in NPG patients. The purpose of this study was to compare the percentages of Th cells and levels of related cytokines, attempting to provide evidence to explain this discrepancy. MATERIAL AND METHODS Blood samples from POAG, NPG, and normal control (NC) groups were collected and peripheral blood monocytes were isolated and cultured with or without the stimulation of HSP60. Flow cytometry and enzyme-linked immunosorbent assay were used to assess the percentages of Th1, Th2, Th17, and Treg cells, as well as HSP60 antibody levels and related cytokine levels, before and after culture. RESULTS Significantly higher titers of anti-HSP60 were observed only in NPG patients. Comparable Th1 and Th2 cell frequencies, IL-4 level, and IFN-γ level were found in POAG and NPG patients, while higher Treg cell frequency was only found in POAG patients. After culturing with HSP60, increased Th2 frequencies and decreased Th1 frequencies were observed in the POAG, NPG, and NC groups, while increased Treg frequency was only identified in the POAG and NC groups. CONCLUSIONS Different Th cell patterns were observed among POAG, NPG, and NC groups. Lack of induction of Treg cells and imbalance of the pro-inflammatory and anti-inflammatory response patterns of Th cells exist in some NPG patients.
Guo Z-Z, Chang K, Wei X. Intraocular pressure fluctuation and the risk of glaucomatous damage deterioration: a Meta-analysis. Int J Ophthalmol 2019;12(1):123-128.Abstract
AIM: To systematically review whether the increased fluctuation of intraocular pressure (IOP) is a risk factor for open angle glaucoma (OAG) progression. METHODS: Scientific studies relevant to IOP fluctuation and glaucoma progression were retrieved from MEDLINE, EMBASE and CENTRAL databases, and were listed as references in this paper. The hazard ratio (HR) was calculated by using fixed or random-effects models according to the heterogeneity of included studies. RESULTS: Individual data for 2211 eyes of 2637 OAG patients in fourteen prospective studies were included in this Meta-analysis. All studies were longitudinal clinical studies with follow-up period ranging from 3 to 8.5y. The combined HR was 1.23 (95%CI 1.04-1.46, =0.02) for the association between IOP fluctuation and glaucoma onset or progression with the evidence of heterogeneity (<0.1). Subgroup analyses with different types of IOP fluctuation were also evaluated. Results indicated that the summary HR was 0.98 (95%CI 0.78-1.24) in short-term IOP fluctuation group, which showed no statistical significance with heterogeneity, whereas, the combined HR was 1.43 (95%CI 1.13-1.82, =0.003) in long-term IOP fluctuation group without homogeneity. Sensitivity analysis further showed that the pooled HR was 1.10 (95%CI 1.03-1.18, =0.004) for long-term IOP fluctuation and visual function progression with homogeneity among studies (=0.3). CONCLUSION: Long-term IOP fluctuation can be a risk factor for glaucoma progression based on the presented evidence. Thus, controlling the swing of IOP is crucial for glaucoma or glaucoma suspecting patients.
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Haddadin RI, Oh D-J, Kang MH, Villarreal G, Kang J-heon, Jin R, Gong H, Rhee DJ. Thrombospondin-1 (TSP1)-null and TSP2-null mice exhibit lower intraocular pressures. Invest Ophthalmol Vis Sci 2012;53(10):6708-17.Abstract
PURPOSE: Thrombospondin-1 (TSP1) and TSP2 are matricellular proteins that have been shown to regulate cytoskeleton, cell adhesion, and extracellular matrix remodeling. Both TSP1 and TSP2 are found in the trabecular meshwork (TM). In cadaver eyes with primary open-angle glaucoma (POAG), TSP1 is increased in one third of patients. We hypothesized that TSP1 and TSP2 participate in the regulation of intraocular pressure (IOP). Methods. IOPs of TSP1-null, TSP2-null mice, and their corresponding wild-type (WT) mice were measured using a commercial rebound tonometer. Fluorophotometric measurements assessed aqueous turnover. Central corneal thickness (CCT) was measured by optical coherence tomography. Iridocorneal angles were examined using light microscopy (LM), immunofluorescence (IF), and transmission electron microscopy (TEM). RESULTS: Average IOPs of TSP1-null and TSP2-null mice were 10% and 7% less than that of the corresponding WT mice, respectively. CCTs were 6.5% less in TSP1-null mice (P < 0.05) and 1.1% less in TSP2-null mice (P > 0.05). Fluorophotometric measurements suggest that aqueous turnover rates in TSP1-null and TSP2-null mice are greater than those of WT mice. LM of the TSP1-null and TSP2-null iridocorneal angles reveals morphology, which is indistinguishable from that of their corresponding WTs. IF revealed possible concurrent underexpression of TSP2 in TSP1-null mice and of TSP1 in TSP2-null mice. TEM revealed larger collagen fibril diameters in TSP1-null and TSP2-null mice compared with WTs. CONCLUSIONS: TSP1-null and TSP2-null mice have lower IOPs than their WT counterparts. The rate of aqueous turnover suggests that the mechanism is enhanced outflow facility. An alteration in the extracellular matrix may contribute to this finding.
Haleem MS, Han L, van Hemert J, Fleming A, Pasquale LR, Silva PS, Song BJ, Aiello LP. Regional Image Features Model for Automatic Classification between Normal and Glaucoma in Fundus and Scanning Laser Ophthalmoscopy (SLO) Images. J Med Syst 2016;40(6):132.Abstract

Glaucoma is one of the leading causes of blindness worldwide. There is no cure for glaucoma but detection at its earliest stage and subsequent treatment can aid patients to prevent blindness. Currently, optic disc and retinal imaging facilitates glaucoma detection but this method requires manual post-imaging modifications that are time-consuming and subjective to image assessment by human observers. Therefore, it is necessary to automate this process. In this work, we have first proposed a novel computer aided approach for automatic glaucoma detection based on Regional Image Features Model (RIFM) which can automatically perform classification between normal and glaucoma images on the basis of regional information. Different from all the existing methods, our approach can extract both geometric (e.g. morphometric properties) and non-geometric based properties (e.g. pixel appearance/intensity values, texture) from images and significantly increase the classification performance. Our proposed approach consists of three new major contributions including automatic localisation of optic disc, automatic segmentation of disc, and classification between normal and glaucoma based on geometric and non-geometric properties of different regions of an image. We have compared our method with existing approaches and tested it on both fundus and Scanning laser ophthalmoscopy (SLO) images. The experimental results show that our proposed approach outperforms the state-of-the-art approaches using either geometric or non-geometric properties. The overall glaucoma classification accuracy for fundus images is 94.4 % and accuracy of detection of suspicion of glaucoma in SLO images is 93.9 %.

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.
Han X, Liu Y, Kam WR, Sullivan DA. Effect of brimonidine, an α2 adrenergic agonist, on human meibomian gland epithelial cells. Exp Eye Res 2018;170:20-28.Abstract
We recently discovered that the anti-glaucoma pharmaceuticals timolol, a β adrenergic antagonist, and pilocarpine, a cholinergic compound, negatively influence the morphology, proliferative capacity and survival of human meibomian gland epithelial cells (HMGECs). We hypothesize that another class of anti-glaucoma drugs, the α2 adrenergic agonists, also acts directly on HMGECs to affect their structure and function. We tested this hypothesis. Immortalized (i) HMGECs were cultured with brimonidine, as well as clonidine (α2 agonist), phenylephrine (α1 agonist), RX821002 (inverse α2 agonist) and MK912 (neutral α2 agonist) for up to 7 days. Cells were counted with a hemocytometer, and evaluated for morphology, signaling pathway activity, protein biomarker expression, and the accumulation of neutral lipids, phospholipids and lysosomes. Our findings demonstrate that brimondine treatment induces a dose-dependent decrease in Akt signaling and proliferation of iHMGECs. In contrast, brimonidine also promotes a dose-dependent differentiation of iHMGECs, including an increase in neutral lipid, phospholipid and lysosome levels. These effects were paralleled by an inhibition of p38 signaling, and duplicated by cellular exposure to clonidine, but not phenylephrine. Brimonidine also enhanced the cellular content of sterol regulatory binding protein-1, a master regulator of lipid synthesis. Of particular interest, the putative α2 antagonists, RX821002 and MK912, did not interfere with brimonidine action, but rather stimulated IHMGEC differentiation. Our results support our hypothesis and demonstrate that α2 adrenergic agonists act directly on iHMGECs. However, these compounds do not elicit an overall negative effect. Rather, the α2 agonists promote the differentiation of iHMGECs.
Hanyuda A, Rosner BA, Wiggs JL, Willett WC, Tsubota K, Pasquale LR, Kang JH. Low-carbohydrate-diet scores and the risk of primary open-angle glaucoma: data from three US cohorts. Eye (Lond) 2020;34(8):1465-1475.Abstract
BACKGROUND/OBJECTIVES: To assess the long-term association between low-carbohydrate dietary patterns and incident primary open-angle glaucoma (POAG), and POAG subtypes defined by highest untreated intraocular pressure (IOP) and by pattern of visual field (VF) loss at diagnosis. SUBJECTS/METHODS: We followed 185,638 participants of three large US prospective cohorts biennially (1976-2016, 1986-2016 and 1991-2017). Deciles of three low-carbohydrate-diet scores were calculated to represent adherence to diets lower in carbohydrate and higher in protein and fat from any source, animal sources or plant sources. We confirmed POAG cases (n = 2112) by medical record review and used Cox proportional hazards models to estimate multivariable-adjusted relative risks (MVRRs) and 95% confidence intervals (CIs). RESULTS: There was no association between the three types of low-carbohydrate-diet scores and POAG: the MVRR for POAG in the highest vs. lowest deciles was 1.13 (95% CI, 0.91-1.39; P = 0.40) for the overall score; 1.10 (95% CI, 0.89-1.35; P = 0.38) for the animal score and 0.96 (95% CI, 0.79-1.18; P = 0.88) for the vegetable score. No differential associations by IOP level was found (P ≥ 0.06). However, the vegetable score showed a suggestive inverse association with early paracentral VF loss (highest vs. lowest decile MVRR = 0.78 [95% CI, 0.55-1.10]; P = 0.12) but not with peripheral VF loss only (MVRR = 1.09 [95% CI, 0.83-1.44]; P = 0.14; P = 0.03). CONCLUSIONS: Low-carbohydrate diets were not associated with risk of POAG. Our data suggested that higher consumption of fat and protein from vegetable sources substituting for carbohydrates was associated with lower risk of the POAG subtype with initial paracentral VF loss.
Hark LA, Katz JL, Myers JS, Waisbourd M, Johnson D, Pizzi LT, Leiby BE, Fudemberg SJ, Mantravadi AV, Henderer JD, Zhan T, Molineaux J, Doyle V, Divers M, Burns C, Murchison AP, Reber S, Resende A, Bui TDV, Lee J, Crews JE, Saaddine JB, Lee PP, Pasquale LR, Haller JA. Philadelphia Telemedicine Glaucoma Detection and Follow-up Study: Methods and Screening Results. Am J Ophthalmol 2017;181:114-124.Abstract
PURPOSE: To describe methodology and screening results from the Philadelphia Telemedicine Glaucoma Detection and Follow-up Study. DESIGN: Screening program results for a prospective randomized clinical trial. METHODS: Individuals were recruited who were African-American, Hispanic/Latino, or Asian over age 40 years; white individuals over age 65 years; and any ethnicity over age 40 years with a family history of glaucoma or diabetes. Primary care offices and Federally Qualified Health Centers were used for telemedicine (Visit 1). Two posterior fundus photographs and 1 anterior segment photograph were captured per eye in each participant, using a nonmydriatic, autofocus, hand-held fundus camera (Volk Optical, Mentor, Ohio, USA). Medical and ocular history, family history of glaucoma, visual acuity, and intraocular pressure measurements using the ICare rebound tonometer (ICare, Helsinki, Finland) were obtained. Images were read remotely by a trained retina reader and a glaucoma specialist. RESULTS: From April 1, 2015, to February 6, 2017, 906 individuals consented and attended Visit 1. Of these, 553 participants were female (61.0%) and 550 were African-American (60.7%), with a mean age of 58.7 years. A total of 532 (58.7%) participants had diabetes, and 616 (68%) had a history of hypertension. During Visit 1, 356 (39.3%) participants were graded with a normal image. Using image data from the worse eye, 333 (36.8%) were abnormal and 155 (17.1%) were unreadable. A total of 258 (28.5%) had a suspicious nerve, 62 (6.8%) had ocular hypertension, 102 (11.3%) had diabetic retinopathy, and 68 (7.5%) had other retinal abnormalities. CONCLUSION: An integrated telemedicine screening intervention in primary care offices and Federally Qualified Health Centers detected high rate of suspicious optic nerves, ocular hypertension, and retinal pathology.
Hark LA, Myers JS, Rahmatnejad K, Wang Q, Zhan T, Hegarty SE, Leiby BE, Udyaver S, Waisbourd M, Leite S, Henderer JD, Pasquale LR, Lee PP, Haller JA, Katz JL. Philadelphia Telemedicine Glaucoma Detection and Follow-up Study: Analysis of Unreadable Fundus Images. J Glaucoma 2018;27(11):999-1008.Abstract
PURPOSE: The purpose of this study was to ascertain determinants of unreadable fundus images for participants enrolled in the Philadelphia Telemedicine Glaucoma Detection and Follow-up Study. METHODS: Individuals were screened for glaucoma at 7 primary care practices and 4 Federally Qualified Health Centers using telemedicine. Screening (visit 1) included fundus photography, assessing family history of glaucoma, and intraocular pressure (IOP) measurements. Participants with an unreadable image in at least one eye were deemed unreadable and invited to return for a confirmatory eye examination (visit 2). RESULTS: A total of 906 participants completed the visit 1 eye screening and 17.1% (n=155/906) were "unreadable." In the multivariable logistic regression analysis, older age, male sex, smoking, and worse visual acuity were significantly associated with an unreadable fundus image finding at the eye screening (P<0.05). Of the 89 participants who were invited for the confirmatory eye examination solely for unreadable images and attended visit 2, 58 (65.2%) were diagnosed with at least one ocular pathology. The most frequent diagnoses were cataracts (n=71; 15 visually significant, 56 nonvisually significant), glaucoma suspects (n=27), and anatomical narrow angle (n=10). CONCLUSIONS: Understanding the causes of unreadable fundus images will foster improvements in telemedicine techniques to optimize the predictive accuracy, efficiency, and cost in ophthalmology. A high proportion of participants with unreadable images (65.2%) in our study were diagnosed with some ocular pathology, indicating that the finding of an unreadable fundus image warrants a referral for a comprehensive follow-up eye examination.
Hoguet A, Parrish RK. Unexpected Hypotony After Glaucoma Drainage Implant Surgery Associated With Anti-Vascular Endothelial Growth Factor Treatment. JAMA Ophthalmol 2014;
Hoguet A, Chen PP, Junk AK, Mruthyunjaya P, Nouri-Mahdavi K, Radhakrishnan S, Takusagawa HL, Chen TC. The Effect of Anti-Vascular Endothelial Growth Factor Agents on Intraocular Pressure and Glaucoma: A Report by the American Academy of Ophthalmology. Ophthalmology 2019;126(4):611-622.Abstract
PURPOSE: To assess the effect of intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents on immediate and long-term intraocular pressure (IOP) elevation and glaucoma. METHODS: Literature searches of the PubMed and Cochrane databases, last conducted in April 2018, yielded 253 unique citations. Of these, 41 met the inclusion criteria and were rated according to the strength of evidence. Two articles were rated level I, 17 were rated level II, and 15 were rated level III; an additional 7 were excluded because of poor study design and lack of relevance to the topic under evaluation. RESULTS: The studies that reported on short-term IOP elevation (i.e., between 0 and 60 minutes) showed that an immediate increase in IOP is seen in all patients when measured between 0 and 30 minutes of intravitreal injection and that the IOP elevation decreases over time. The data on long-term IOP elevation were mixed; 7 studies reported that between 4% and 15% of patients developed sustained elevation of IOP at 9 to 24 months after injection, whereas 6 studies found no long-term change in IOP from 1 to 36 months after injection. Pretreatment with glaucoma medications, anterior chamber tap, vitreous reflux, longer intervals between injections, and longer axial lengths were associated with lower IOP elevations after injection. Data were mixed on the relationship between IOP increase and the type of intravitreal injection, number of intravitreal injections, preexisting glaucoma, and globe decompression before injection. There were no data on the onset or progression of glaucoma in the studies reviewed in this assessment. CONCLUSIONS: Intravitreal injection of anti-VEGF agents results in an immediate and transient increase in IOP. A long-term increase in IOP also may be seen, and further studies are needed to determine at-risk populations. Although there is some suggestion in the literature, there is currently insufficient data to determine the impact of intravitreal anti-VEGF injections on glaucoma progression. Although pretreatment with glaucoma medications, performing anterior chamber paracentesis, or increasing the interval between injections may reduce the impact of transient IOP elevation, the clinical significance and associated risks of these interventions are unknown.
Hoguet A, Grajewski A, Hodapp E, Chang TCP. A retrospective survey of childhood glaucoma prevalence according to Childhood Glaucoma Research Network classification. Indian J Ophthalmol 2016;64(2):118-23.Abstract

PURPOSE: To evaluate the Childhood Glaucoma Research Network (CGRN) classification system and describe the prevalence of each subtype according to this classification. MATERIALS AND METHODS: Retrospectively, the medical records of 205 consecutive childhood glaucoma and glaucoma suspect patients at an urban tertiary care center were reviewed. The initial diagnosis and new diagnosis according to CGRN classification were recorded. RESULTS: All patients fit one of the seven categories of the new classification. Seventy-one percent of diagnoses were changed upon reclassification. Twenty-three percent of patients had primary glaucoma (juvenile open-angle glaucoma and primary congenital glaucoma [PCG]); 36% had secondary glaucoma (glaucoma associated with nonacquired ocular anomalies; glaucoma associated with nonacquired systemic disease or syndrome; glaucoma associated with acquired condition; and glaucoma following cataract surgery); and 39% were glaucoma suspect. Of the patients diagnosed with glaucoma, PCG was the most common diagnosis, seen in 32% of patients. CONCLUSION: The CGRN classification provides a useful method of classifying childhood glaucoma.

Hysi PG, Cheng C-Y, Springelkamp H, Macgregor S, Bailey JCN, Wojciechowski R, Vitart V, Nag A, Hewitt AW, Höhn R, Venturini C, Mirshahi A, Ramdas WD, Thorleifsson G, Vithana E, Khor C-C, Stefansson AB, Liao J, Haines JL, Amin N, Wang YX, Wild PS, Ozel AB, Li JZ, Fleck BW, Zeller T, Staffieri SE, Teo Y-Y, Cuellar-Partida G, Luo X, Allingham RR, Richards JE, Senft A, Karssen LC, Zheng Y, Bellenguez C, Xu L, Iglesias AI, Wilson JF, Kang JH, van Leeuwen EM, Jonsson V, Thorsteinsdottir U, Despriet DDG, Ennis S, Moroi SE, Martin NG, Jansonius NM, Yazar S, Tai E-S, Amouyel P, Kirwan J, van Koolwijk LME, Hauser MA, Jonasson F, Leo P, Loomis SJ, Fogarty R, Rivadeneira F, Kearns L, Lackner KJ, de Jong PTVM, Simpson CL, Pennell CE, Oostra BA, Uitterlinden AG, Saw S-M, Lotery AJ, Bailey-Wilson JE, Hofman A, Vingerling JR, Maubaret C, Pfeiffer N, Wolfs RCW, Lemij HG, Young TL, Pasquale LR, Delcourt C, Spector TD, Klaver CCW, Small KS, Burdon KP, Stefansson K, Wong T-Y, Wong T-Y, Wong T-Y, Wong T-Y, Viswanathan A, Mackey DA, Craig JE, Wiggs JL, van Duijn CM, Hammond CJ, Aung T. Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma. Nat Genet 2014;46(10):1126-30.Abstract

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 × 10(-11) for rs2472493 near ABCA1 and P = 6.39 × 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.

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