Glaucoma

Cousins CC, Pan BX, Chou JC, Shen LQ, Gordon MO, Kass MA, Ritch R, Pasquale LR. Densitometric Profiles of Optic Disc Hemorrhages in the Ocular Hypertension Treatment Study. Am J Ophthalmol 2020;217:10-19.Abstract
PURPOSE: The origin of blood in glaucoma-related disc hemorrhages (DH) remains unknown. A prior clinic-based study of primary open-angle glaucoma (POAG)-related DH showed that they had grayscale pixel intensities more similar to blood from retinal macroaneurysms and adjacent retinal arterioles than to blood from retinal vein occlusions or adjacent retinal venules, suggesting an arterial source. Here we assessed the densitometric profile of DH from fundus photographs in the Ocular Hypertension Treatment Study (OHTS). DESIGN: Retrospective cross-sectional study of prospectively collected images. METHODS: Stereo disc photographs of 161 DH events from 83 OHTS participants (mean age [standard deviation (SD)]: 65.6 [9.2] years; 46.6% female; 13.0% black race) were imported into ImageJ to measure densitometry differences (adjacent arterioles minus DH [ΔA] or venules minus DH [ΔV]). Their size as percentage of disc area, ratio of length to midpoint width, and location relative to the disc margin were also analyzed. We performed t tests to compare ΔA and ΔV, analysis of variance to compare ΔA and ΔV across DH recurrent events, and multivariable linear regression to identify determinants of ΔA and ΔV. RESULTS: Mean (SD) ΔA and ΔV were -2.2 (8.7) and -11.4 (9.7) pixel intensity units, respectively (P < .001). ΔA and ΔV each did not differ significantly across recurrence of DH (P ≥ .92) or between DH events with and without POAG (P ≥ .26). CONCLUSIONS: OHTS DH had densitometric measurements more similar in magnitude to adjacent arterioles than venules, supporting an arterial origin for DH. Vascular dysregulation may contribute to disc hemorrhage formation in ocular hypertension.
Kang JH, VoPham T, Laden F, Rosner BA, Wirostko B, Ritch R, Wiggs JL, Qureshi A, Nan H, Pasquale LR. Cohort Study of Non-melanoma Skin Cancer and the Risk of Exfoliation Glaucoma. J Glaucoma 2020;Abstract
PRECIS: In a cohort study of 120,307 participants with 25+ years of follow-up, a history of non-melanoma skin cancer was associated with a 40% higher exfoliation glaucoma risk. PURPOSE: To evaluate the relationship between non-melanoma skin cancer (a marker of ultraviolet radiation exposure) and exfoliation glaucoma (XFG). METHODS: We performed a cohort study of US women (n=79,102; 1980-2014) and men (n=41,205; 1986-2014), aged 40+ years and at risk for glaucoma who reported eye exams. From 1984 (women)/1988 (men), we asked about basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) history separately; in prior years, we asked about any non-melanoma skin cancer history in a single question. SCC was confirmed with histopathology reports while BCC and any early (<1984/<1988) non-melanoma skin cancer history was self-reported. Incident XFG cases (362 women and 83 men) were confirmed with medical records. Using pooled data, we estimated multivariable-adjusted relative risks (MVRR; 95% confidence intervals [CIs]) with Cox proportional hazards models that were stratified by age (in months), 2-year time period at risk and average lifetime residential latitude. RESULTS: In multivariable-adjusted analyses, we observed a 40% higher XFG risk with any non-melanoma skin cancer history (MVRR=1.40; 95% CI=1.08,1.82); the association was observed even with 4 and 8 year lags in non-melanoma skin cancer history. Also, the non-melanoma skin cancer association was stronger in younger (<65▒y; MVRR=2.56; 95% CI=1.62,4.05) versus older participants (≥65▒y; MVRR=1.25; 95% CI=0.94,1.66; p for interaction=0.01) and those living in northern latitudes (≥42° north; MVRR=1.92; 95% CI=1.28,2.88) versus more southern latitudes (<42° north; MVRR=1.19; 95% CI=0.86,1.66; p for interaction=0.04). CONCLUSIONS: Non-melanoma skin cancer was associated with higher XFG risk, particularly among younger participants and those living in Northern US.
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.
Singh RB, Ichhpujani P, Thakur S, Jindal S. Promising therapeutic drug delivery systems for glaucoma: a comprehensive review. Ther Adv Ophthalmol 2020;12:2515841420905740.Abstract
The delivery of ophthalmic drugs is challenging despite easy accessibility via the ocular surface. Topical instillation of eye drops is a relatively easy and most commonly used as a conduit for drug delivery for treating a myriad of ocular morbidities, particularly involving the anterior segment, and has an additional benefit of avoiding the first-pass metabolism while passing through the systemic circulation. The primary challenges of drug administration through traditional methods include-inadequate patient education for proper drug instillation technique, compliance, adherence, and persistence. Various dynamic (choroidal and conjunctival blood flow, lymphatic clearance, and tear dilution) and static (namely, different layers of cornea, sclera, and retina including blood aqueous and blood-retinal barriers) ocular barriers limit drug delivery to the target ocular tissues. The maintenance of the therapeutic drug levels on the ocular surface for a prolonged duration is an added challenge, thus preventing persistent delivery for longer durations. These factors result in inadequate management, leading to poor prognosis in vision loss in as many as 27% of the patients diagnosed with glaucoma. We have reviewed the research and advancements in the development of novel and well-tolerated drug delivery systems with the common goal of overcoming the factors limiting adequate drug delivery to the target tissues in glaucomatous patients with traditional techniques. In the recent past, multiple research groups have successfully designed noninvasive, sustained drug delivery systems, promoting the efficacy as well as the feasibility of delivering topical drugs to the anterior segment.
Lu SY, Rong SS, Wu Z, Huang C, Matsushita K, Ng TK, Leung CKS, Kawashima R, Usui S, Tam POS, Tsujikawa M, Young AL, Zhang M, Wiggs JL, Nishida K, Tham CC, Pang CP, Chen LJ. Association of the CAV1-CAV2 locus with normal-tension glaucoma in Chinese and Japanese. Clin Exp Ophthalmol 2020;48(5):658-665.Abstract
BACKGROUND: The CAV1-CAV2 locus has been associated with primary open-angle glaucoma (POAG) and intraocular pressure. However, its association with normal-tension glaucoma (NTG) was inconclusive. Therefore, we evaluated this association in Chinese and Japanese. METHODS: Two single-nucleotide polymorphisms (SNPs, rs4236601 and rs1052990) from previous genome-wide association studies of POAG were genotyped in a total of 2220 study subjects: a Hong Kong Chinese cohort of 537 NTG patients and 490 controls, a Shantou Chinese cohort of 102 NTG and 731 controls and an Osaka Japanese cohort of 153 NTG and 207 controls. Subgroup analysis by gender was conducted. Outcomes from different cohorts were combined using meta-analysis. RESULTS: SNP rs4236601 was significantly associated with NTG in the two Chinese cohorts (P = .0019, OR = 4.55, I = 0). In contrast, rs4236601 was monomorphic in the Osaka cohort. The association of rs1052990 was insignificant in a meta-analysis combining Chinese and Japanese cohorts (P = .81, OR = 1.05; I = 64%), and the OR tended towards opposite directions between Chinese (OR = 1.26) and Japanese (OR = 0.69). Gender-specific effects of the SNPs were not statistically significant in the logistic regression or Breslow-day tests of ORs (P > .05), although rs4236601 was significant in males (P = .0068; OR = 10.30) but not in females (P = .14; OR = 2.65) in the meta-analysis of Chinese subjects. CONCLUSIONS: In this study, we confirmed the association of rs4236601 at the CAV1-CAV2 locus with NTG in Chinese. SNP rs4236601 is monomorphic, and rs1052990 tends towards a different direction in the Japanese cohort. Further studies are warranted to verify the ethnic difference and gender-specific effects of this locus.
Razeghinejad R, Lin MM, Lee D, Katz JL, Myers JS. Pathophysiology and management of glaucoma and ocular hypertension related to trauma. Surv Ophthalmol 2020;65(5):530-547.Abstract
Ocular trauma is a significant cause of blindness worldwide, particularly if associated with glaucoma. Direct damage from blunt or penetrating trauma, bleeding, inflammation, lens-related problems, orbital and brain vascular pathologies related to trauma, and chemical injuries may increase intraocular pressure and lead to traumatic glaucoma. Treatment may be as simple as eliminating the underlying cause in some conditions or management can be challenging, depending on the mechanism of damage. If proper management is not undertaken, visual outcomes can be poor. We discuss a broad spectrum of trauma-related mechanisms of intraocular pressure elevation, as well as their management.
Jacobi A, van Zyl T. [Recent Research Efforts to Achieve Neuroprotection, Progression and Treatment of Glaucoma]. Klin Monbl Augenheilkd 2020;237(2):133-139.Abstract
Glaucoma is a neurodegenerative disease that leads to irreversible blindness over time. Its defining feature is the loss of retinal ganglion cells (RGCs) in the eye and their axons in the optic nerve. Increased intraocular pressure (IOP) is a major risk factor for the development of glaucoma, but is neither necessary nor sufficient for the disease and its progression; this motivates research and development of new strategies for the detection and treatment of glaucoma that focus on neuroprotection - protection of RGCs from dying. In addition, for diagnosis and treatment by reducing IOP, new approaches have been developed in recent years. This article reviews current theories of pathophysiological mechanisms underlying glaucoma and recent research - with a focus on neuroprotection and current preclinical and clinical studies to improve the diagnosis and treatment of glaucoma.
Liu Y, Baniasadi N, Ratanawongphaibul K, Chen TC. Effect of partial posterior vitreous detachment on spectral-domain optical coherence tomography retinal nerve fibre layer thickness measurements. Br J Ophthalmol 2020;104(11):1524-1527.Abstract
BACKGROUND/AIMS: To assess the effect of partial posterior vitreous detachment (pPVD) on spectral-domain optical coherence tomography (OCT) peripapillary retinal nerve fibre layer thickness (RNFL) measurements. METHODS: Spectral-domain OCT RNFL thickness measurements were obtained from 684 consecutive patients who were seen in the Massachusetts Eye and Ear Glaucoma Service. Of these patients, we compared RNFL thickness measurements between 101 eyes of 101 glaucoma suspects who met inclusion criteria (55 eyes with and 46 eyes without pPVD). RESULTS: Among all 684 patients, 253 (37%) had pPVD in at least one eye. Among a subset of 101 eyes of 101 glaucoma suspects, average RNFL thickness was greater in eyes with compared to eyes without pPVD (p=0.02). Measurements were significantly greater in the inferior (p=0.004) and superior quadrants (p=0.008), but not in the nasal (p=0.10) and temporal quadrants (p=0.25). The difference in average RNFL thickness remained significant (p=0.05) even when corrected for expected age-related decline in RNFL thickness. CONCLUSION: Over a third of patients were found on peripapillary spectral-domain OCT to have a pPVD, which was associated with greater RNFL thickness measurements. Judicious clinical interpretation of this finding on spectral-domain OCT RNFL thickness scans should be factored into the assessment of glaucoma suspects.
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.
Craig JE, Han X, Qassim A, Hassall M, Cooke Bailey JN, Kinzy TG, Khawaja AP, An J, Marshall H, Gharahkhani P, Igo RP, Graham SL, Healey PR, Ong J-S, Zhou T, Siggs O, Law MH, Souzeau E, Ridge B, Hysi PG, Burdon KP, Mills RA, Landers J, Ruddle JB, Agar A, Galanopoulos A, White AJR, Willoughby CE, Andrew NH, Best S, Vincent AL, Goldberg I, Radford-Smith G, Martin NG, Montgomery GW, Vitart V, Hoehn R, Wojciechowski R, Jonas JB, Aung T, Pasquale LR, Cree AJ, Sivaprasad S, Vallabh NA, Vallabh NA, and Consortium UKBEV, Viswanathan AC, Pasutto F, Haines JL, Klaver CCW, van Duijn CM, Casson RJ, Foster PJ, Khaw PT, Hammond CJ, Mackey DA, Mitchell P, Lotery AJ, Wiggs JL, Hewitt AW, Macgregor S. Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression. Nat Genet 2020;52(2):160-166.Abstract
Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.
Wang M, Tichelaar J, Pasquale LR, Shen LQ, Boland MV, Wellik SR, De Moraes CG, Myers JS, Ramulu P, Kwon MY, Saeedi OJ, Wang H, Baniasadi N, Li D, Bex PJ, Elze T. Characterization of Central Visual Field Loss in End-stage Glaucoma by Unsupervised Artificial Intelligence. JAMA Ophthalmol 2020;Abstract
Importance: Although the central visual field (VF) in end-stage glaucoma may substantially vary among patients, structure-function studies and quality-of-life assessments are impeded by the lack of appropriate characterization of end-stage VF loss. Objective: To provide a quantitative characterization and classification of central VF loss in end-stage glaucoma. Design, Setting, and Participants: This retrospective cohort study collected data from 5 US glaucoma services from June 1, 1999, through October 1, 2014. A total of 2912 reliable 10-2 VFs of 1103 eyes from 1010 patients measured after end-stage 24-2 VFs with a mean deviation (MD) of -22 dB or less were included in the analysis. Data were analyzed from March 28, 2018, through May 23, 2019. Main Outcomes and Measures: Central VF patterns were determined by an artificial intelligence algorithm termed archetypal analysis. Longitudinal analyses were performed to investigate whether the development of central VF defect mostly affects specific vulnerability zones. Results: Among the 1103 patients with the most recent VFs, mean (SD) age was 70.4 (14.3) years; mean (SD) 10-2 MD, -21.5 (5.6) dB. Fourteen central VF patterns were determined, including the most common temporal sparing patterns (304 [27.5%]), followed by mostly nasal loss (280 [25.4%]), hemifield loss (169 [15.3%]), central island (120 [10.9%]), total loss (91 [8.3%]), nearly intact field (56 [5.1%]), inferonasal quadrant sparing (42 [3.8%]), and nearly total loss (41 [3.7%]). Location-specific median total deviation analyses partitioned the central VF into a more vulnerable superonasal zone and a less vulnerable inferotemporal zone. At 1-year and 2-year follow-up, new defects mostly occurred in the more vulnerable zone. Initial encroachments on an intact central VF at follow-up were more likely to be from nasal loss (11 [18.4%]; P < .001). One of the nasal loss patterns had a substantial chance at 2-year follow-up (8 [11.0%]; P = .004) to shift to total loss, whereas others did not. Conclusions and Relevance: In this study, central VF loss in end-stage glaucoma was found to exhibit characteristic patterns that might be associated with different subtypes. Initial central VF loss is likely to be nasal loss, and 1 specific type of nasal loss is likely to develop into total loss.
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.
Silva RNE, Taniguchi EV, Cruzat A, Paschalis EI, Pasquale LR, Colby KA, Dohlman CH, Chodosh J, Shen LQ. Angle Anatomy and Glaucoma in Patients With Boston Keratoprosthesis. Cornea 2020;39(6):713-719.Abstract
PURPOSE: To quantitatively analyze the angle anatomy in eyes with a Boston type 1 keratoprosthesis (KPro) using anterior segment optical coherence tomography (AS-OCT) and to assess the diagnostic ability of AS-OCT in KPro-associated glaucoma. METHODS: AS-OCT (RTVue) images from KPro eyes with and without glaucoma were reviewed. The angle opening distance at 500 μm from the scleral spur (AOD500), trabecular-iris angle at 500 μm from the scleral spur (TIA500), and trabecular-iris surface area at 500 μm from the scleral spur (TISA500) were measured by 2 observers masked to the diagnosis. The measurements for each visible quadrant were compared between KPro eyes with and without glaucoma. RESULTS: Twenty-two eyes with glaucoma and 17 eyes without glaucoma from 39 patients with KPro were included. Of the 4 quadrants imaged, the temporal angle was the most visible (79.5%) and angle measurements of the temporal quadrant were the only ones that differentiated the 2 groups: the mean AOD500, TIA500, and TISA500 were significantly lower in KPro eyes with glaucoma than without glaucoma (388.2 ± 234.4 μm vs. 624.5 ± 310.5 μm, P = 0.02; 26.1 ± 14.0 degrees vs. 39.1 ± 17.1 degrees, P = 0.03; and 0.15 ± 0.09 mm vs. 0.23 ± 0.12 mm, P = 0.03; respectively). The highest area under the receiver operating characteristic curve for detecting glaucoma was 0.75 for temporal TIA500 (95% confidence interval 0.57-0.94, P = 0.02) with 50% specificity at 80% of sensitivity and a cutoff value of 37 degrees. CONCLUSIONS: The temporal angle was the most visible on AS-OCT in eyes with a KPro. Significant narrowing of the temporal angle detected on AS-OCT was associated with glaucoma in these eyes.
Choquet H, Wiggs JL, Khawaja AP. Clinical implications of recent advances in primary open-angle glaucoma genetics. Eye (Lond) 2020;34(1):29-39.Abstract
Over the last decade, genetic studies, including genome-wide association studies (GWAS), have accelerated the discovery of genes and genomic regions contributing to primary open-angle glaucoma (POAG), a leading cause of irreversible vision loss. Here, we review the findings of genetic studies of POAG published in English prior to September 2019. In total, 74 genomic regions have been associated at a genome-wide level of significance with POAG susceptibility. Recent POAG GWAS provide not only insight into global and ethnic-specific genetic risk factors for POAG susceptibility across populations of diverse ancestry, but also important functional insights underlying biological mechanisms of glaucoma pathogenesis. In this review, we also summarize the genetic overlap between POAG, glaucoma endophenotypes, such as intraocular pressure and vertical cup-disc ratio (VCDR), and other eye disorders. We also discuss approaches recently developed to increase power for POAG locus discovery and to predict POAG risk. Finally, we discuss the recent development of POAG gene-based therapies and future strategies to treat glaucoma effectively. Understanding the genetic architecture of POAG is essential for an earlier diagnosis of this common eye disorder, predictive testing of at-risk patients, and design of gene-based targeted medical therapies none of which are currently available.

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