Glaucoma

Huang X, Saki F, Wang M, Elze T, Boland MV, Pasquale LR, Johnson CA, Yousefi S. An Objective and Easy-to-Use Glaucoma Functional Severity Staging System Based on Artificial Intelligence. J Glaucoma 2022;Abstract
OBJECTIVE: To develop an objective and easy-to-use glaucoma staging system based on visual fields (VFs). SUBJECTS AND PARTICIPANTS: A total of 13,231 VFs from 8077 subjects were used to develop models and 8024 VFs from 4445 subjects were used to validate models. METHODS: We developed an unsupervised machine learning model to identify clusters with similar VF values. We annotated the clusters based on their respective mean deviation (MD). We computed optimal MD thresholds that discriminate clusters with highest accuracy based on Bayes minimum error principle. We evaluated the accuracy of the staging system and validated findings based on an independent validation dataset. RESULTS: The unsupervised k-means algorithm discovered four clusters with 6784, 4034, 1541, and 872 VFs and average MDs of 0.0▒dB (±1.4: Standard Deviation), -4.8▒dB (±1.9), -12.2▒dB (±2.9), and -23.0▒dB (±3.8), respectively. The supervised Bayes minimum error classifier identified optimal MD thresholds of -2.2▒dB, -8.0▒dB, and -17.3▒dB for discriminating normal eyes and eyes at the early, moderate, and advanced stages of glaucoma. The accuracy of the glaucoma staging system was 94%, based on identified MD thresholds with respect to the initial k-means clusters. CONCLUSIONS: We discovered that four severity levels based on MD thresholds of -2.2▒dB, -8.0▒dB, and -17.3▒dB, provides the optimal number of severity stages based on unsupervised and supervised machine learning. This glaucoma staging system is unbiased, objective, easy-to-use, and consistent, which makes it highly suitable for use in glaucoma research and for day-to-day clinical practice.
Sekimitsu S, Elze T, Zebardast N. Impact of the Affordable Care Act on Glaucoma Severity at First Presentation. Ophthalmic Epidemiol 2022;:1-4.Abstract
PURPOSE: To test whether the increase in insurance coverage in Massachusetts due to the Affordable Care Act (ACA) is associated with a decrease in glaucoma severity in patients presenting for the first time at a tertiary health system. METHODS: Clinical and billing data of first-time glaucoma patients from a tertiary health system in Massachusetts from 2006 to 2021 was used. Pre-ACA is defined as before 2014 and post-ACA is defined as after 2014. Visual field mean deviation was used to define glaucoma severity: greater than -6 dB, less than -6 dB and greater than -12 dB, and less than -12 dB was classified as "mild," "moderate," and "severe" respectively. Ordinal logistic regression models adjusted for age, race, gender, and insurance type were used to determine the odds of presenting with more severe glaucoma. RESULTS: 2,394 pre-ACA and 3,651 post-ACA first-time glaucoma patients were identified. There was no significant difference in the likelihood of more severe glaucoma at first presentation post-ACA compared to pre-ACA (OR=0.96; 95% CI 0.86-1.08; p=0.49) among the entire population. In stratified analyses, patients who utilized Medicaid for insurance had 52% decreased odds for presenting with more severe glaucoma at first presentation post-ACA compared to pre-ACA (OR=0.48; 95% CI 0.33-0.69; p<0.001). This remained significant after adjustment for age, race, and gender (adjusted OR=0.44; 95% CI 0.29-0.65; p<0.001). CONCLUSION: At a Massachusetts-based tertiary healthcare center, individuals on Medicaid were more likely to have more severe glaucoma at first presentation before the implementation of the ACA, compared to after.
Stuart KV, Madjedi K, Luben RN, Chua SYL, Warwick AN, Chia M, Pasquale LR, Wiggs JL, Kang JH, Hysi PG, Tran JH, Foster PJ, Khawaja AP, for Collaboration MRFG. Alcohol, Intraocular Pressure, and Open-Angle Glaucoma: A Systematic Review and Meta-analysis. Ophthalmology 2022;129(6):637-652.Abstract
TOPIC: This systematic review and meta-analysis summarizes the existing evidence for the association of alcohol use with intraocular pressure (IOP) and open-angle glaucoma (OAG). CLINICAL RELEVANCE: Understanding and quantifying these associations may aid clinical guidelines or treatment strategies and shed light on disease pathogenesis. The role of alcohol, a modifiable factor, in determining IOP and OAG risk also may be of interest from an individual or public health perspective. METHODS: The study protocol was preregistered in the Open Science Framework Registries (https://osf.io/z7yeg). Eligible articles (as of May 14, 2021) from 3 databases (PubMed, Embase, Scopus) were independently screened and quality assessed by 2 reviewers. All case-control, cross-sectional, and cohort studies reporting a quantitative effect estimate and 95% confidence interval (CI) for the association between alcohol use and either IOP or OAG were included. The evidence for the associations with both IOP and OAG was qualitatively summarized. Effect estimates for the association with OAG were pooled using random effects meta-analysis. Studies not meeting formal inclusion criteria for systematic review, but with pertinent results, were also appraised and discussed. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. RESULTS: Thirty-four studies were included in the systematic review. Evidence from 10 studies reporting an association with IOP suggests that habitual alcohol use is associated with higher IOP and prevalence of ocular hypertension (IOP > 21 mmHg), although absolute effect sizes were small. Eleven of 26 studies, comprising 173 058 participants, that tested for an association with OAG met inclusion criteria for meta-analysis. Pooled effect estimates indicated a positive association between any use of alcohol and OAG (1.18; 95% confidence interval [CI], 1.02-1.36; P = 0.03; I2 = 40.5%), with similar estimates for both prevalent and incident OAG. The overall GRADE certainty of evidence was very low. CONCLUSIONS: Although this meta-analysis suggests a harmful association between alcohol use and OAG, our results should be interpreted cautiously given the weakness and heterogeneity of the underlying evidence base, the small absolute effect size, and the borderline statistical significance. Nonetheless, these findings may be clinically relevant, and future research should focus on improving the quality of evidence.
Madjedi KM, Stuart KV, Chua SYL, Foster PJ, Strouthidis NG, Luben RN, Warwick AN, Kang JH, Wiggs JL, Pasquale LR, Khawaja AP. The association of female reproductive factors with glaucoma and related traits: A systematic review. Ophthalmol Glaucoma 2022;Abstract
TOPIC: This systematic review summarizes the existing evidence for the association between female reproductive factors (age at menarche, parity, oral contraceptive (OC) use, age at menopause, and postmenopausal hormone (PMH) use) and intraocular pressure (IOP) or open-angle glaucoma (OAG). CLINICAL RELEVANCE: Understanding the association between female reproductive factors and glaucoma may shed light on disease pathogenesis and aid clinical prediction and personalized treatment strategies. Importantly, some factors are modifiable which may lead to new therapies. METHODS: Two reviewers independently extracted articles in Medline, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials databases to identify relevant studies. Eligibility criteria included studies with human subjects over 18 years of age; a measured exposure of at least one of the following: age at menarche, parity, OC use, age at menopause, PMH use; a measured outcome of either IOP or OAG; a cohort, case-control, cross-sectional or randomized-controlled trial design; and a reported measure of association including hazard, risk or odds ratio or mean difference with associated confidence intervals. RESULTS: We included a total of 27 studies. Substantial differences in study design, exposure and treatment levels, treatment duration and variable reporting precluded meaningful quantitative synthesis of the identified studies. Overall, relatively consistent associations between PMH use and lower IOP were identified. With respect to OAG, estrogen-only PMH use may be associated with lower OAG risk and this association may be modified by race. No significant associations were found with combined estrogen + progesterone PMH use. No strong associations between parity, or age at menarche and glaucoma were found, but a younger age at menopause was associated with increased glaucoma risk, and adverse associations were identified with longer duration of OC use, though no overall association with OC use was found. CONCLUSION: The association between PMH use and lower IOP/OAG risk is a potentially clinically relevant and modifiable risk factor and should be investigated further, although this needs to be interpreted in the context of a high risk of bias across included studies. There is a need for future research examining associations with IOP specifically, and how the relationship between genetic factors and OAG risk may be influenced by female reproductive factors.
Wang Z, Wiggs JL, Aung T, Khawaja AP, Khor CC. The genetic basis for adult onset glaucoma: Recent advances and future directions. Prog Retin Eye Res 2022;90:101066.Abstract
Glaucoma, a diverse group of eye disorders that results in the degeneration of retinal ganglion cells, is the world's leading cause of irreversible blindness. Apart from age and ancestry, the major risk factor for glaucoma is increased intraocular pressure (IOP). In primary open-angle glaucoma (POAG), the anterior chamber angle is open but there is resistance to aqueous outflow. In primary angle-closure glaucoma (PACG), crowding of the anterior chamber angle due to anatomical alterations impede aqueous drainage through the angle. In exfoliation syndrome and exfoliation glaucoma, deposition of white flaky material throughout the anterior chamber directly interfere with aqueous outflow. Observational studies have established that there is a strong hereditable component for glaucoma onset and progression. Indeed, a succession of genome wide association studies (GWAS) that were centered upon single nucleotide polymorphisms (SNP) have yielded more than a hundred genetic markers associated with glaucoma risk. However, a shortcoming of GWAS studies is the difficulty in identifying the actual effector genes responsible for disease pathogenesis. Building on the foundation laid by GWAS studies, research groups have recently begun to perform whole exome-sequencing to evaluate the contribution of protein-changing, coding sequence genetic variants to glaucoma risk. The adoption of this technology in both large population-based studies as well as family studies are revealing the presence of novel, protein-changing genetic variants that could enrich our understanding of the pathogenesis of glaucoma. This review will cover recent advances in the genetics of primary open-angle glaucoma, primary angle-closure glaucoma and exfoliation glaucoma, which collectively make up the vast majority of all glaucoma cases in the world today. We will discuss how recent advances in research methodology have uncovered new risk genes, and how follow up biological investigations could be undertaken in order to define how the risk encoded by a genetic sequence variant comes into play in patients. We will also hypothesise how data arising from characterising these genetic variants could be utilized to predict glaucoma risk and the manner in which new therapeutic strategies might be informed.
Friedman DS, Chang DS, Jiang Y, Huang S, Kim JA, Munoz B, Aung T, He M, Foster PJ. Acute Angle Closure Attacks Are Uncommon in Primary Angle-Closure Suspects: The Zhongshan Angle Closure Prevention Trial. Ophthalmol Glaucoma 2022;Abstract
PURPOSE: Angle-closure glaucoma is a major cause of blindness worldwide that carries an excess risk of severe, bilateral visual impairment. A common concern among clinicians is precipitating acute angle closure (AAC) attacks by mydriasis. We evaluated the risk of AAC after pharmacologic dilation in Chinese individuals classified as bilateral primary angle-closure suspects (PACS). DESIGN: Randomized interventional controlled trial. PARTICIPANTS: A total of 889 bilateral PACS aged between 50 and 70 years were identified through community screening in Guangzhou, China and enrolled in the study. METHODS: In the Zhongshan Angle Closure Prevention (ZAP) Trial, bilateral PACS were treated by laser peripheral iridotomy (LPI) in one randomly selected eye, with the fellow eye serving as an untreated control. Over 72 months of follow-up, participants had their pupils pharmacologically dilated six times with 5% phenylephrine and 0.5% tropicamide. MAIN OUTCOME MEASURES: Incidence and risk of post-mydriasis AAC in LPI-treated and untreated control PACS eyes. RESULTS: One bilateral AAC attack occurred after mydriasis at the two-week post-LPI visit. No other AAC events occurred in LPI-treated eyes. In untreated eyes, four additional attacks occurred: two after dilation (one at 54- and one at 72-months follow-up) and two spontaneously. The risk of post-mydriasis AAC in untreated eyes was one attack in 1,587 dilations. The risk of spontaneous AAC in untreated eyes was 0.44 per 1000 eye-years (95% CI: 0.11-1.77 per 1000 eye-years). CONCLUSIONS: The risk of an incident AAC attack in PACS eyes was extremely low, even in a higher-risk group with repeated pharmacologic pupillary dilation over six years of follow-up. Prophylactic LPI reduced this small but real risk.
Chang DS-T, Jiang Y, Kim JA, Huang S, Munoz B, Aung T, He M, Foster PJ, Friedman D. Cataract progression after Nd:YAG laser iridotomy in primary angle-closure suspect eyes. Br J Ophthalmol 2022;Abstract
BACKGROUND/AIMS: Prophylactic laser peripheral iridotomy (LPI) is performed in primary angle-closure suspect (PACS) eyes to prevent acute angle-closure attacks. However, accelerated cataractogenesis is a potential risk of the procedure that may result in decreased visual acuity. We aimed to assess the long-term impact of LPI on cataract formation in Chinese PACS. METHODS: In the Zhongshan Angle Closure Prevention Trial, eligible bilateral PACS participants received LPI in one randomly selected eye, while the fellow eye remained untreated. Cataract was graded using the Lens Opacity Classification System III, and progression was defined as an increase in grade by at least two units in any category or cataract surgery. RESULTS: In total, 889 participants were randomly assigned to LPI in one eye only (mean age 59±5 years, 83% female). At 72 months, treated eyes had slightly higher average nuclear grades (p<0.001). However, there were no differences between eyes for predefined cataract progression (cumulative probability at 72 months: 21.2% in LPI vs 19.4% in control, p=0.401) or cataract surgery (1% for both). While LPI-treated eyes had a 10% higher risk of progression over 6 years (HR=1.10 (95% CI 0.88 to 1.36)), this was not statistically significant. Visual acuity at 72 months was similar in treated and untreated eyes (p=0.43). CONCLUSION: Although lenses were graded on average as slightly more opaque in laser-treated eyes, prophylactic neodymium:yttrium-aluminum-garnet LPI did not cause significant cataract progression. Our results suggest that LPI treatment of asymptomatic narrow angles does not increase the risk of developing clinically meaningful cataract worsening over time. TRIAL REGISTRATION NUMBER: ISRCTN45213099.
Halawa OA, Roldan AM, Meshkin RS, Zebardast N, Fenwick EK, Lamoureux EL, Friedman DS. Factors associated with glaucoma-specific quality of life in a US glaucoma clinic in a pilot implementation of an online computerised adaptive test (GlauCAT). Br J Ophthalmol 2022;Abstract
OBJECTIVES: Measure quality of life (QoL) outcomes using a novel computerised adaptive test in a clinical setting, and determine the social and demographic factors associated with specific QoL domains in patients with glaucoma. DESIGN: Cross-sectional study between July 2020 and April 2021. PARTICIPANTS: English-speaking adults presenting to glaucoma clinic. Patients with cognitive impairment on a six-item cognitive impairment screen or with intraocular surgery within 90 days prior to presentation were excluded. RESULTS: Of 206 patients surveyed, mean age was 64.8 years (SD 15.2), 122 (56.7%) were female and 159 (74.7%) were white. On multivariable regression, visual acuity was associated with greater activity limitation (β=-2.8 points, 95% CI -3.8 to -1.8, p<0.001) and worse mobility (β=-2.1 points, 95% CI -3.2 to -0.9, p<0.001), while poorer visual field (VF) mean deviation was associated with lower scores on the emotional well-being domain (β=-2.4 points, 95% CI -4.6 to -0.3, p=0.03). Glaucoma suspects and those with early VF defects had higher QoL scores than those with severe glaucoma in the following domains: activity limitation (88.5±14.6 vs 74.3±21.9, respectively, p<0.001), mobility (91.0±12.5 vs 80.0±25.3, respectively, p=0.005) and concerns domains (82.2±13.9 vs 72.5 5±18.9, respectively, p=0.01). CONCLUSIONS: In a busy glaucoma clinic where QoL was measured with online adaptive tests for glaucoma, we found that several demographic and clinical variables are associated with lower domain scores, suggesting that patients with predisposing demographic and clinical factors are at a higher risk of worse QoL.
Mitchell WG, Azuara-Blanco A, Foster PJ, Halawa O, Burr J, Ramsay CR, Cooper D, Cochran C, Norrie J, Friedman D, Chang D. Predictors of long-term intraocular pressure control after lens extraction in primary angle closure glaucoma: results from the EAGLE trial. Br J Ophthalmol 2022;Abstract
BACKGROUND/AIMS: To assess baseline ocular parameters in the prediction of long-term intraocular pressure (IOP) control after clear lens extraction (CLE) or laser peripheral iridotomy (LPI) in patients with primary angle closure (PAC) disease using data from the Effectiveness of Early Lens Extraction for the treatment of primary angle-closure glaucoma (EAGLE) tria. METHODS: This study is a secondary analysis of EAGLE data where we define the primary outcome of 'good responders' as those with IOP<21 mm Hg without requiring additional surgery and 'optimal responders' as those who in addition were medication free, at 36-month follow-up. Primary analysis was conducted using a multivariate logistic regression model to assess how randomised interventions and ocular parameters predict treatment response. RESULTS: A total of 369 patients (182 in CLE arm and 187 in LPI arm) completed the 36-month follow-up examination. After CLE, 90% met our predefined 'good response' criterion compared with 67% in the LPI arm, and 66% met 'optimal response' criterion compared with 18% in the LPI arm, with significantly longer drops/surgery-free survival time (p<0.05 for all). Patients randomised to CLE (OR=10.1 (6.1 to 16.8)), Chinese (OR=2.3 (1.3 to 3.9)), and those who had not previously used glaucoma drops (OR=2.8 (1.6 to 4.8)) were more likely to maintain long-term optimal IOP response over 36 months. CONCLUSION: Patients with primary angle closure glaucoma/PAC are 10 times more likely to maintain drop-free good IOP control with initial CLE surgery than LPI. Non-Chinese ethnicity, higher baseline IOP and using glaucoma drops prior to randomisation are predictors of worse long-term IOP response.
Hall NE, Chang EK, Samuel S, Gupta S, Klug E, Elze T, Lorch AC, Miller JW, Solá-Del Valle D. Risk factors for glaucoma drainage device revision or removal using the IRIS Registry. Am J Ophthalmol 2022;Abstract
PURPOSE: To elucidate risk factors for revision or removal of glaucoma drainage devices (GDD) in glaucoma patients in the United States. DESIGN: Retrospective cohort study. METHODS: IRIS® Registry (Intelligent Research in Sight) patients who underwent GDD insertion between 01/01/2013 and 12/31/2018 were included. Various demographic and clinical factors were collected. Kaplan-Meier (KM) survival plots, Cox proportional-hazard models utilizing Firth's Penalized Likelihood (CRFPL), and multivariate linear regression models were used. The main outcome measures were hazard ratios (HRs) and beta coefficient (β) estimates. RESULTS: 44,330 distinct patients underwent at least one GDD implantation, and 3,354 of these underwent subsequent GDD revision or removal surgery. With failure defined as GDD revision/removal, factors significantly associated with decreased failure included unknown race (HR=0.83; p=0.004) and unknown ethnicity (HR=0.68; p<0.001). Factors associated with increased risk of GDD revision/removal surgery included presence of chronic angle closure glaucoma (HR=1.32; p<0.001) and dry eye disease (HR=1.30; p=0.007). Additionally, factors associated with a decreased average time (in days) to GDD revision/removal included male sex (β=-25.96; p=0.044), unknown race (β=-55.28; p=0.013), and right-eye laterality (β=-38.67; p=0.026). Factors associated with an increased average time to GDD revision/removal included having a history of a past eye procedure (β=104.83; p<0.001) and being an active smoker (β=38.15; p=0.024). CONCLUSIONS: The size and scope of the IRIS Registry allows for detection of subtle associations between risk factors and GDD revision or removal surgery. Aforementioned demographic and clinical factors may all have an impact on GDD longevity and can inform the treatment options available for glaucoma patients.
Tam EK, Elhusseiny AM, Shah AS, Mantagos IS, VanderVeen DK. Etiology and outcomes of childhood glaucoma at a tertiary referral center. J AAPOS 2022;Abstract
PURPOSE: To describe the etiology, clinical features, and outcomes for a large contemporary cohort of children presenting with glaucoma at a tertiary referral center. METHODS: The medical records of patients presenting to Boston Children's Hospital from January 2014 to July 2019 with a diagnosis of childhood glaucoma were retrospectively reviewed. Data regarding etiology, treatment, and visual and anatomic outcomes were collected; visual acuity outcomes were analyzed by laterality and diagnosis categories, using the Childhood Glaucoma Research Network (CGRN) classifications. RESULTS: A total of 373 eyes of 246 patients (51% males) diagnosed with glaucoma before 18 years of age were identified. Mean follow-up was 7.04 ± 5.61 years; 137 cases were bilateral. The mean age at diagnosis was 4.55 ± 5.20 years. The most common diagnoses were glaucoma following cataract surgery (GFCS, 36.5%) and primary congenital glaucoma (PCG, 29.0%). Overall, 164 eyes (44.0%) underwent at least one glaucoma surgery. Intraocular pressure (IOP) was ≤21 mm Hg with or without glaucoma medications in 300 eyes (80.4%) at the last follow-up visit. Poor final best-corrected visual acuity (≤20/200) was found in 110 eyes; patients with poor final visual acuity tended to have poor visual acuity at presentation. The most common reason for poor vision was amblyopia. Uncontrolled IOP was an uncommon cause for vision loss. CONCLUSIONS: Childhood glaucoma can be challenging to manage, but poor vision usually results from amblyopia or presence of other ocular abnormalities or syndromes rather than glaucomatous optic neuropathy.
Huang JJ, Geduldig JE, Jacobs EB, Tai TYT, Ahmad S, Chadha N, Buxton DF, Vinod K, Wirostko BM, Kang JH, Wiggs JL, Ritch R, Pasquale LR. Head and neck region dermatological UV-related cancers are associated with exfoliation syndrome in a clinic-based population. Ophthalmol Glaucoma 2022;Abstract
OBJECTIVE: We assessed the relation between UV-associated dermatological carcinomas (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)) and exfoliation syndrome with or without glaucoma (XFS/XFG). DESIGN: Case-control study. Subjects, participants, and controls:321 participants with XFS/XFG, primary open angle glaucoma (POAG), and control subjects (XFS/XFG = 98, POAG = 117, control = 106, ages 50-90) were recruited between 2019-2021. METHODS: Subjects were recruited for a cross-sectional survey assessing medical history, maximum known intraocular pressure, cup-to-disc ratio, Humphrey Visual Field 24-2 (HVF), propensity to tan or burn in early life, history of BCC and/or SCC and XFS/XFG diagnosis. We generated multivariable models adjusting for age, sex, medical history, eye color, hair color, and likeliness of tanning vs burning at a young age. MAIN OUTCOME MEASURES: History of diagnosed XFS/XFG. RESULTS: Any history of BCC/SCC in the head and neck region was associated with a 2-fold higher risk for having XFS/XFG versus having POAG or being a control subject (odds ratio (OR) = 2.01, 95% confidence interval (CI) = 1.04 - 3.89) in multivariable-adjusted analysis. Additionally, we observed a dose-response association where the chance of having XFS/XFG was higher by 67% per head and neck BCC/SCC occurrence (OR = 1.67, 95% CI = 1.09 - 2.56). When we excluded POAG participants, head and neck BCC/SCC was associated with 2.8-fold higher risk of XFS/XFG (OR = 2.80, 95% CI = 1.12 - 7.02) and each additional occurrence of head and neck BCC/SCC had a 2-fold higher risk for XFS/XFG (OR = 1.97, 95% CI = 1.09 - 3.58). The association between head and neck region BCC/SCC and POAG compared to control subjects was null (OR = 1.42, 95% CI = 0.58 - 3.48). When BCC/SCC located anywhere on the body was considered, there was a non-significant higher risk of XFS/XFG compared to having POAG or being a control subject (OR = 1.65, 95% CI = 0.88 - 3.09). CONCLUSIONS: Head and neck region BCC/SCCs are associated with a higher risk for having XFS/XFG. These findings support prior evidence that head and neck UV exposure may be a risk factor for XFS.

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