Glaucoma

PURPOSE: Prior research in animal models has shown that macrophages and microglia play an important role in pathogenesis of glaucoma, but the phenotype and distribution of macrophages in human glaucomatous tissue have not been sufficiently characterized. METHODS: We analyzed H&E, CD68-, and CD163-immunostained slides from 25 formaldehyde-fixed, paraffin-embedded autopsy eyes: 12 control eyes and 13 eyes with glaucoma. The diagnosis of glaucoma was made based on a history of glaucoma as reported in the medical record and histological changes characteristic of glaucoma. Glaucoma cases and controls were matched in terms of age, sex, and race. RESULTS: Qualitative analysis of the conventional outflow pathway and the optic nerve revealed that all eyes contained CD163+ cells but a negligible number of CD68+ cells. CD163+ macrophages infiltrated the trabecular meshwork and surrounded Schlemm's canal of normal eyes and eyes with glaucoma, but the pattern was variable and qualitatively similar between groups. In optic nerves of control eyes, CD163+ macrophages were present at low levels and restricted to septa between axon bundles. In glaucomatous optic nerves, the number of CD163+ cells was increased both qualitatively and quantitatively (glaucoma 5.1 ± 0.6 CD163+ cells/mm, control 2.5 ± 0.3 CD163+ cells/mm, p < 0.001), with CD163+ cells infiltrating axon bundles in cases of both mild and severe diseases. CONCLUSIONS: The increase in CD163+ cell number in eyes with mild and severe glaucoma is the first demonstration of macrophage infiltration in glaucomatous human optic nerves. This finding supports a role for macrophages in glaucoma pathogenesis and progression.

Deep learning (DL) is a subset of artificial intelligence (AI), which uses multilayer neural networks modelled after the mammalian visual cortex capable of synthesizing images in ways that will transform the field of glaucoma. Autonomous DL algorithms are capable of maximizing information embedded in digital fundus photographs and ocular coherence tomographs to outperform ophthalmologists in disease detection. Other unsupervised algorithms such as principal component analysis (axis learning) and archetypal analysis (corner learning) facilitate visual field interpretation and show great promise to detect functional glaucoma progression and differentiate it from non-glaucomatous changes when compared with conventional software packages. Forecasting tools such as the Kalman filter may revolutionize glaucoma management by accounting for a host of factors to set target intraocular pressure goals that preserve vision. Activation maps generated from DL algorithms that process glaucoma data have the potential to efficiently direct our attention to critical data elements embedded in high throughput data and enhance our understanding of the glaucomatous process. It is hoped that AI will realize more accurate assessment of the copious data encountered in glaucoma management, improving our understanding of the disease, preserving vision, and serving to enhance the deep bonds that patients develop with their treating physicians.

BACKGROUND: The optic nerve is an important tissue in glaucoma and the unmyelinated nerve head region remains an important site of many early neurodegenerative changes. In both humans and mice, astrocytes constitute the major glial cell type in the region, and in glaucoma they become reactive, influencing the optic nerve head (ONH) microenvironment and disease outcome. Despite recognizing their importance in the progression of the disease, the reactive response of optic nerve head astrocytes remains poorly understood. METHODS: To determine the global reactive response of ONH astrocytes in glaucoma we studied their transcriptional response to an elevation in IOP induced by the microbead occlusion model. To specifically isolate astrocyte mRNA in vivo from complex tissues, we used the ribotag method to genetically tag ribosomes in astrocytes, restricting analysis to astrocytes and enabling purification of astrocyte-associated mRNA throughout the entire cell, including the fine processes, for bulk RNA-sequencing. We also assessed the response of astrocytes in the more distal myelinated optic nerve proper (ONP) as glaucomatous changes manifest differently between the two regions. RESULTS: Astrocytes of the optic nerve exhibited a region-specific and temporally distinct response. Surprisingly, ONH astrocytes showed very few early transcriptional changes and ONP astrocytes demonstrated substantially larger changes over the course of the experimental period. Energy metabolism, particularly oxidative phosphorylation and mitochondrial protein translation emerged as highly upregulated processes in both ONH and ONP astrocytes, with the former showing additional upregulation in antioxidative capacity and proteolysis. Interestingly, optic nerve astrocytes demonstrated a limited neuroinflammatory response, even when challenged with a more severe elevation in IOP. Lastly, there were a greater number of downregulated processes in both astrocyte populations compared to upregulated processes. CONCLUSION: Our findings demonstrate an essential role for energy metabolism in the response of optic nerve astrocytes to elevated IOP, and contrary to expectations, neuroinflammation had a limited overall role. The transcriptional response profile is supportive of the notion that optic nerve astrocytes have a beneficial role in glaucoma. These previously uncharacterized transcriptional response of optic nerve astrocytes to injury reveal their functional diversity and a greater heterogeneity than previously appreciated.

SIGNIFICANCE: The α2-adrenergic receptor agonist brimonidine has been reported to induce conjunctival blanching in cataract, strabismus, laser refractive, and filtration procedures. Clinicians are often faced with red eyes with no apparent underlying pathology. Low-dose brimonidine reduced ocular redness in such subjects with efficacy maintained over 1 month and negligible rebound redness. PURPOSE: The aim of this study was to evaluate the safety and efficacy of brimonidine tartrate ophthalmic solution 0.025% for the treatment of ocular redness. METHODS: In this single-center, double-masked, phase 3 clinical trial, adult subjects with baseline redness of more than 1 unit in both eyes (0- to 4-unit scale) were randomized 2:1 to brimonidine 0.025% or vehicle. A single dose was administered in-office (day 1); thereafter subjects instilled treatment four times a day for 4 weeks, with clinic visits on days 15, 29, and 36 (7 days post-treatment). Efficacy end points included investigator-evaluated redness 5 to 240 minutes post-instillation on day 1 (primary); investigator-evaluated change from baseline 1, 360, and 480 minutes post-instillation on day 1, and 1 and 5 minutes post-instillation on days 15 and 29; total clearance of redness, and subject-assessed redness. Safety/tolerability measures included adverse events, rebound redness, and drop comfort. RESULTS: Sixty subjects were randomized (n = 40 brimonidine, n = 20 vehicle). Investigator-assessed redness was lower with brimonidine versus vehicle over the 5- to 240-minute post-instillation period (mean [SE], 0.62 [0.076] vs. 1.49 [0.108]; P < .0001) and at each time point within that period (P < .0001). At 1, 360, and 480 minutes post-instillation, respectively, the mean differences (95% confidence interval) between treatments were -0.73 (-1.05 to -0.41), -0.57 (-0.84 to -0.29), and -0.39 (-0.67 to -0.10), respectively. No tachyphylaxis was evident with brimonidine on days 15 and 29, and minimal rebound redness was observed following discontinuation. Adverse events were infrequent, and brimonidine was rated as very comfortable. CONCLUSIONS: Brimonidine 0.025% appeared safe and effective for reduction of ocular redness, with an 8-hour duration of action, no evidence of tachyphylaxis, and negligible rebound redness.

PRCIS: In this prospective interventional case series that included 474 patients, there were no significant differences in visual field (VF) parameters between fields from patients tested one-at-a-time and simultaneously, except for fixation losses. PURPOSE: To test for differences in reliability and performance parameters of patients taking VF tests while using a remote patient monitoring system to supervise 1 or 2 test sessions simultaneously. METHODS: In a prospective interventional case series, 861 eyes of 474 consecutive patients undergoing automated perimetry during a 6-month period were monitored during the test using an audio/video-enabled remote monitoring system. Two patients were simultaneously tested (simultaneous test) by a single technician if they were ready for testing at the same time. Patients were otherwise tested individually (single test). Performance and reliability parameters including false negatives, false positives, fixation losses, mean deviation, pattern standard deviation, VF index, and test duration were compared between patients undergoing simultaneous tests and single tests. Patients undergoing remotely monitored testing, for whom a prior VF could be found, had performance and reliability parameters compared with those prior tests. VFs were analyzed separately for 2 test strategies: SITA Standard 24-2 and SITA Faster 24-2C. RESULTS: No significant parameter differences were observed among SITA Standard 24-2 VFs between single and simultaneous tests, except for fixation losses (single: 16.8±19.7%, simultaneous: 22.5±25.0%, P=0.01). Similarly, there were no significant differences observed among SITA Faster 24-2C tests. Paired analyses comparing remotely monitored VFs with prior traditionally monitored VFs showed no significant differences for any parameters, except for fewer fixation losses with remote monitoring (traditional: 23.6±27.5%, remote 17.7±20.8%, P=0.003). CONCLUSIONS: Remote patient monitoring of VF testing enabled technicians to supervise testing of 2 patients simultaneously with preserved performance and reliability.

PURPOSE: To examine IOP measurement disagreement between technicians and physicians and the impact of an educational intervention on the short and long-term disagreement in IOP measurement using Goldmann applanation tonometry. DESIGN: Prospective study designed to enhance measurement reliability. SETTING: A glaucoma clinic at a university hospital. StudyPopulation: 6 technicians and 2 physicians. INTERVENTION: An educational intervention was implemented for the technicians to improve IOP measurement agreement with physicians. MainOutcomeMeasures: Frequency of IOP measurement disagreement between physicians and technicians, defined as a difference in IOP of >2 or >3 mm Hg and assessed at baseline and immediately and 6 months postintervention. RESULTS: IOP was evaluated for a total of 529 eyes (physician measured mean IOP = 16.4 mm Hg [SD = 5.9]), 30 per technician-physician pair for each data collection period: baseline, immediately postintervention and 6 months postintervention. At baseline, physicians disagreed 17% and 7% of the time when measuring IOP using >2 and >3 mm Hg to define disagreement, respectively, whereas the average disagreement between technicians and physicians was 25% and 13%. Disagreement was greater at IOPs greater than 20 mm Hg. No significant changes were noted in the frequency of disagreement between technicians and physicians immediately or 6 months postintervention. CONCLUSIONS: Two physicians measuring the same patient in the same room disagreed by >2 mm Hg in 17% of patients' eyes, and this amount of disagreement was even higher when comparing physicians to certified technicians. An educational intervention did not improve agreement in IOP measurements between technicians and physicians. This highlights an important limitation of Goldmann tonometry.

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.

IMPORTANCE: Retinal ganglion cells are known to express estrogen receptors and prior studies have suggested an association between postmenopausal hormone (PMH) use and decreased intraocular pressure, suggesting that PMH use may decrease the risk for primary open-angle glaucoma (POAG). OBJECTIVE: To determine whether the use of 3 different classes of PMH affects the risk for POAG. DESIGN, SETTING, AND PARTICIPANTS: Retrospective longitudinal cohort analysis of claims data from women 50 years or older enrolled in a US managed-care plan for at least 4 years in which enrollees had at least 2 visits to an eye care provider during the period 2001 through 2009. EXPOSURE: Postmenopausal hormone medications containing estrogen only, estrogen + progesterone, and estrogen + androgen, as captured from outpatient pharmacy claims over a 4-year period. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) for developing incident POAG. RESULTS: Of 152,163 eligible enrollees, 2925 (1.9%) developed POAG. After adjustment for confounding factors, each additional month of use of PMH containing estrogen only was associated with a 0.4% reduced risk for POAG (HR, 0.996 [95% CI, 0.993-0.999]; P = .02). The risk for POAG did not differ with each additional month of use of estrogen + progesterone (HR, 0.994 [95% CI, 0.987-1.001]; P = .08) or estrogen + androgen (HR, 0.999 [95% CI, 0.988-1.011]; P = .89). CONCLUSIONS AND RELEVANCE: Use of PMH preparations containing estrogen may help reduce the risk for POAG. If prospective studies confirm the findings of this analysis, novel treatments for this sight-threatening condition may follow.

PURPOSE: To compare the effectiveness and safety of phacoemulsification combined with endoscopic cyclophotocoagulation (phaco/ECP), phacoemulsification combined with MicroPulse transscleral cyclophotocoagulation (phaco/MP-TSCPC), and phacoemulsification alone (phaco) in the treatment of coexisting cataract and glaucoma. METHODS: Retrospective cohort study of consecutive cases at Massachusetts Eye & Ear. The main outcome measures were the cumulative probabilities of failure between the phaco/ECP group, phaco/MP-TSCPC group, and the phaco alone group with failure defined as reaching NLP vision at any point postoperatively, undergoing additional glaucoma surgery, or the inability to maintain ≥ 20% IOP reduction from baseline with IOP between 5-18 mmHg while maintaining ≤ baseline medications. Additional outcome measures included changes in average IOP, number of glaucoma medications, and complication rates. RESULTS: Sixty-four eyes from 64 patients (25 phaco/ECP, 20 phaco/MPTSCPC, 19 phaco alone) were included in this study. The groups did not differ in age (mean 71.04 ± 6.7 years) or length of follow-up time. Baseline IOPs were significantly different between groups (15.78 ± 4.7 mmHg phaco/ECP, 18.37 ± 4.6 mmHg phaco/MP-TSCPC, 14.30 ± 4.2 mmHg phaco alone, p = 0.02). Primary open-angle glaucoma was the most common type of glaucoma in the phaco alone (42%) and phaco/ECP (48%) groups while mixed-mechanism glaucoma was the most common type in the phaco/MP-TSCPC group (40%). Surgical failure was less likely in eyes in the phaco/MP-TSCPC (3.40 times, p = 0.005) and phaco/ECP (1.40 times, p = 0.044) groups compared to phaco alone based on the Kaplan-Meier survival criteria. These differences maintained statistical significance when differences in preoperative IOP were taken into account using the Cox PH model (p = 0.011 and p = 0.004, respectively). Additionally, surgical failure was 1.98 times less likely following phaco/MP-TSCPC compared to phaco/ECP (p = 0.038). This difference only approached significance once differences in preoperative IOP were accounted for (p = 0.052). There was no significant difference in IOP reduction at 1 year between groups. Mean IOP reductions at 1 year were 3.07 ± 5.3 mmHg from a baseline of 15.78 ± 4.7 in the phaco/ECP group, 6.0 ± 4.3 mmHg from a baseline of 18.37 ± 4.6 in the phaco/MP-TSCPC group and 1.0 ± 1.6 from a baseline of 14.30 ± 4.2 mmHg in the phaco alone group. There were no differences in complication rates among the three groups. CONCLUSIONS: Both Phaco/MP-TSCPC and phaco/ECP appear to provide superior efficacy for IOP control when compared to phaco alone. All three procedures had similar safety profiles.

Importance: Elevated intraocular pressure is a major risk factor for glaucoma, a leading cause of irreversible blindness worldwide. Environmental air pollution has been suggested as a potential contributor to elevated intraocular pressure; however, no studies have demonstrated such an association to date. Objective: To investigate the association of long-term ambient black carbon exposure with intraocular pressure in community-dwelling older adults. Design, Setting, and Participants: This population-based analysis, conducted from October 18, 2017, through March 22, 2018, used data from the all-male, New England-based Normative Aging Study of the US Department of Veterans Affairs. The analysis included 419 older men with a total of 911 follow-up study visits between January 1, 2000, and December 30, 2011. Intraocular pressure was measured by Goldmann applanation tonometry during the study visits. Validated spatiotemporal models were used to generate 1-year black carbon exposure levels at the addresses of the participants. Main Outcomes and Measures: An independently developed genetic score approach was used to calculate allelic risk scores for 3 pathways associated with black carbon toxicity: endothelial function, oxidative stress, and metal processing. The associations among black carbon exposure, allelic risk scores, and intraocular pressure were explored using linear mixed-effects models. Results: All 419 participants were men with a mean (SD) age of 75.3 (6.9) years. The mean (SD) 1-year black carbon exposure was 0.51 (0.18) μg/m3, and the mean (SD) intraocular pressure for the left eye was 14.1 (2.8) mm Hg and for the right eye was 14.1 (3.0) mm Hg. Of the 911 visits, 520 (57.1%) had a high endothelial function allelic risk score, 644 (70.7%) had a high metal-processing allelic risk score, and 623 (68.4%) had a high oxidative stress allelic risk score. In fully adjusted linear mixed-effects models, the association of black carbon with intraocular pressure was greater in individuals with a high oxidative stress allelic score (β = 0.36; 95% CI, 0.003-0.73) compared with individuals with a low score (β = -0.35; 95% CI, -0.86 to 0.15). Conclusions and Relevance: Ambient black carbon exposure may be a risk factor for increased intraocular pressure in individuals susceptible to other biological oxidative stressors. If additional studies confirm these results, monitoring ambient black carbon exposure and physiological oxidative stress may prevent the development and progression of intraocular pressure-related disease.

PURPOSE: Intraocular pressure (IOP) regulation is largely unknown. SPARC-null mice demonstrate a lower IOP resulting from increased outflow. SPARC is a matricellular protein often associated with fibrosis. We hypothesized that SPARC overexpression would alter IOP by affecting extracellular matrix (ECM) synthesis and/or turnover in the trabecular meshwork (TM). METHODS: An adenoviral vector containing human SPARC was used to increase SPARC expression in human TM endothelial cells and perfused human anterior segments using multiplicities of infection (MOIs) 25 or 50. Total RNA from TM was used for quantitative PCR, while protein from cell lysates and conditioned media were used for immunoblot analyses and zymography. After completion of perfusion, the anterior segments were fixed, sectioned, and examined by light and confocal microscopy. RESULTS: SPARC overexpression increased the IOP of perfused human anterior segments. Fibronectin and collagens IV and I protein levels were elevated in both TM cell cultures and within the juxtacanalicular (JCT) region of perfused anterior segments. Collagen VI and laminin protein levels were increased in TM cell cultures but not in perfused anterior segments. The protein levels of pro-MMP-9 decreased while the kinetic inhibitors of metalloproteinases, TIMP-1 and PAI-1 protein levels, increased at MOI 25. At MOI 50, the protein levels of pro-MMP-1, -3, and -9 also decreased while PAI-1 and TIMP-1 and -3 increased. Only MMP-9 activity was decreased on zymography. mRNA levels of the collagens, fibronectin, and laminin were not affected by SPARC overexpression. CONCLUSIONS: SPARC overexpression increases IOP in perfused cadaveric human anterior segments resulting from a qualitative change the JCT ECM. Selective decrease of MMP-9 activity is likely part of the mechanism. SPARC is a regulatory node for IOP.

Glaucoma is a leading cause of irreversible blindness. Intraocular pressure (IOP) is the only modifiable risk factor for glaucoma, yet there is little known about the molecular events that regulate IOP. Genetic and genomic studies have helped identify genes that influence IOP and could lead to the identification of biological pathways that serve as targets for novel pressure-modifying therapies. Genetic linkage studies resulted in the identification of several genes that cause Mendelian (autosomal dominant or autosomal recessive) forms of high-pressure glaucoma, including MYOC. PITX2, FOXC1, and CYP1B1. Classical twin studies suggest that IOP is a heritable trait. More recently, genome-wide association studies (GWAS) have shown that common genetic variants in the GAS7 and TMCO1 genomic regions are associated with elevated IOP. TMCO1 has also been associated with primary open-angle glaucoma in patients with advanced disease. A further study identifying additional genes contributing to IOP will be necessary to fully define the underlying genetic architecture of IOP.

PRCIS: Over a third of electronically prescribed glaucoma medications were not picked up within 1 month of patient request. Feedback-driven protocols may help minimize treatment interruptions attributed to electronic prescribing. PURPOSE: Glaucoma treatment relies on long-term medication compliance and many socioeconomic factors impact the ability of patients to receive their medications. This study aims to quantify treatment interruptions attributable to electronically prescribed medications and propose interventions to minimize this barrier. METHODS: This is a cross-sectional study of the electronic prescribing patterns at a tertiary care hospital serving a socioeconomically diverse patient population. Glaucoma medication refill requests received over a 6-week interval were reviewed and patient pharmacies were contacted 1 month after the request date to determine whether the medication was received by the patient. Patients who did not pick up the prescriptions were contacted and consented to participate in a survey to identify the barriers to acquiring the medications. RESULTS: Refill requests of 198 glaucoma medications met the inclusion criteria and the most common classes were prostaglandin analogs (44%) and alpha-2-agonists (21%). Medications were not obtained within 1 month in 71 (35.9%) cases. Prior authorization requirement was significantly associated with patients not obtaining their medication (odds ratio, 0.07; 95% confidence interval, 0.03-0.45). Patient reported challenges to successful receipt electronically prescribed medications included insurance coverage (32.2%) and pharmacy availability (22.6%). CONCLUSIONS: Approximately a third of electronically prescribed glaucoma medications were not received by patients within a month of refill request due to the need for prior authorization, insurance coverage, and pharmacy availability. A mechanism to alert providers and to address these barriers to medication access may minimize treatment interruption and disease progression.

BACKGROUND: Acute primary angle closure (APAC) is a potentially blinding condition. It is one of the few ophthalmic emergencies and carries high rates of visual morbidity in the absence of timely intervention. Laser peripheral iridotomy (LPI) has been the standard of care thus far. However, LPI does not eliminate the long-term risk of chronic angle closure glaucoma and other associated sequelae. There has been increasing interest in lens extraction as the primary treatment for the spectrum of primary angle closure disease, and it is as yet unclear whether these results can be extrapolated to APAC, and whether lens extraction provides better long-term outcomes. We therefore sought to evaluate the effectiveness of lens extraction in APAC to help inform the decision-making process.  OBJECTIVES: To assess the effect of lens extraction compared to LPI in the treatment of APAC. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2022, Issue 1), Ovid MEDLINE, Ovid MEDLINE E-pub Ahead of Print, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily (January 1946 to 10 January 2022), Embase (January 1947 to 10 January 2022), PubMed (1946 to 10 January 2022), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to 10 January 2022), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search. We last searched the electronic databases on 10 January 2022. SELECTION CRITERIA: We included randomized controlled clinical trials comparing lens extraction against LPI in adult participants ( ≥ 35 years) with APAC in one or both eyes. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and assessed the certainty of the body of evidence for prespecified outcomes using the GRADE approach. MAIN RESULTS: We included two studies conducted in Hong Kong and Singapore, comprising 99 eyes (99 participants) of predominantly Chinese origin. The two studies compared LPI with phacoemulsification performed by experienced surgeons. We assessed that both studies were at high risk of bias. There were no studies evaluating other types of lens extraction procedures.  Phacoemulsification may result in an increased proportion of participants with intraocular pressure (IOP) control compared with LPI at 18 to 24 months (risk ratio (RR) 1.66, 95% confidence interval (CI) 1.28 to 2.15; 2 studies, n = 97; low certainty evidence) and may reduce the need for further IOP-lowering surgery within 24 months (RR 0.07, 96% CI 0.01 to 0.51; 2 studies, n = 99; very low certainty evidence). Phacoemulsification may result in a lower mean IOP at 12 months compared to LPI (mean difference (MD) -3.20, 95% CI -4.79 to -1.61; 1 study, n = 62; low certainty evidence) and a slightly lower mean number of IOP-lowering medications at 18 months (MD -0.87, 95% CI -1.28 to -0.46; 1 study, n = 60; low certainty evidence), but this may not be clinically significant. Phacoemulsification may have little to no effect on the proportion of participants with one or more recurrent APAC episodes in the same eye (RR 0.32, 95% CI 0.01 to 7.30; 1 study, n = 37; very low certainty evidence). Phacoemulsification may result in a wider iridocorneal angle assessed by Shaffer grading at six months (MD 1.15, 95% CI 0.83 to 1.47; 1 study, n = 62; very low certainty evidence). Phacoemulsification may have little to no effect on logMAR best-corrected visual acuity (BCVA) at six months (MD -0.09, 95% CI -0.20 to 0.02; 2 studies, n = 94; very low certainty evidence). There was no evidence of a difference in the extent of peripheral anterior synechiae (PAS) (clock hours) between intervention arms at 6 months (MD -1.86, 95% CI -7.03 to 3.32; 2 studies, n = 94; very low certainty evidence), although the phacoemulsification group may have less PAS (degrees) at 12 months (MD -94.20, 95% CI -140.37 to -48.03; 1 study, n = 62) and 18 months (MD -127.30, 95% CI -168.91 to -85.69; 1 study, n = 60).  In one study, there were 26 adverse events in the phacoemulsification group: intraoperative corneal edema (n = 12), posterior capsular rupture (n = 1), intraoperative bleeding from iris root (n = 1), postoperative fibrinous anterior chamber reaction (n = 7), and visually significant posterior capsular opacification (n = 5), and no cases of suprachoroidal hemorrhage or endophthalmitis. There were four adverse events in the LPI group: closed iridotomy (n = 1) and small iridotomies that required supplementary laser (n = 3). In the other study, there was one adverse event in the phacoemulsification group (IOP > 30 mmHg on day 1 postoperatively (n = 1)), and no intraoperative complications. There were five adverse events in the LPI group: transient hemorrhage (n = 1), corneal burn (n = 1), and repeated LPI because of non-patency (n = 3).  Neither study reported health- or vision-related quality of life measures. AUTHORS' CONCLUSIONS: Low certainty evidence suggests that early lens extraction may produce more favorable outcomes compared to initial LPI in terms of IOP control. Evidence for other outcomes is less clear. Future high-quality and longer-term studies evaluating the effects of either intervention on the development of glaucomatous damage and visual field changes as well as health-related quality of life measures would be helpful.

BACKGROUND: Primary angle-closure glaucoma (PACG) is characterized by a rise in intraocular pressure (IOP) secondary to aqueous outflow obstruction, with relative pupillary block being the most common underlying mechanism. There is increasing evidence that lens extraction may relieve pupillary block and thereby improve IOP control. As such, comparing the effectiveness of lens extraction against other commonly used treatment modalities can help inform the decision-making process. OBJECTIVES: To assess the effectiveness of lens extraction compared with other interventions in the treatment of chronic PACG in people without previous acute angle-closure attacks. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, one other database, and two trials registers (December 2019). We also screened the reference lists of included studies and the Science Citation Index database. We had no date or language restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing lens extraction with other treatment modalities for chronic PACG. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. MAIN RESULTS: We identified eight RCTs with 914 eyes. We obtained data for participants meeting our inclusion criteria for these studies (PACG only, no previous acute angle-closure attacks), resulting in 513 eyes included in this review. The participants were recruited from a diverse range of countries. We were unable to conduct meta-analyses due to different follow-up periods and insufficient data. One study compared phacoemulsification with laser peripheral iridotomy (LPI) as standard care. Participants in the phacoemulsification group were less likely to experience progression of visual field loss (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.13 to 0.91; 216 eyes; moderate certainty evidence), and required fewer IOP-lowering medications (mean difference [MD] -0.70, 95% CI -0.89 to -0.51; 263 eyes; moderate certainty evidence) compared with standard care at 12 months. Moderate certainty evidence also suggested that phacoemulsification improved gonioscopic findings at 12 months or later (MD -84.93, 95% CI -131.25 to -38.61; 106 eyes). There was little to no difference in health-related quality of life measures (MD 0.04, 95% CI -0.16 to 0.24; 254 eyes; moderate certainty evidence), and visual acuity (VA) (MD 2.03 ETDRS letter, 95% CI -0.77 to 4.84; 242 eyes) at 12 months, and no observable difference in mean IOP (MD -0.03mmHg, 95% CI -2.34 to 2.32; 257 eyes; moderate certainty evidence) compared to standard care. Irreversible loss of vision was observed in one participant in the phacoemulsification group, and three participants in standard care at 36 months (moderate-certainty evidence). One study (91 eyes) compared phacoemulsification with phaco-viscogonioplasty (phaco-VGP). Low-certainty evidence suggested that fewer IOP-lowering medications were needed at 12 months with phacoemulsification (MD -0.30, 95% CI -0.55 to -0.05). Low-certainty evidence also suggested that phacoemulsification may have improved gonioscopic findings at 12 months or later compared to phaco-VGP (angle grading MD -0.60, 95% CI -0.91 to -0.29; TISA500 MD -0.03, 95% CI -0.06 to -0.01; TISA750 MD -0.03, 95% CI -0.06 to -0.01; 91 eyes). Phacoemulsification may result in little to no difference in best corrected VA at 12 months (MD -0.01 log MAR units, 95% CI -0.10 to 0.08; low certainty evidence), and the evidence is very uncertain about its effect on IOP at 12 months (MD 0.50 mmHg, 95% CI -2.64 to 3.64; very low certainty evidence). Postoperative fibrin reaction was observed in two participants in the phacoemulsification group and four in the phaco-VGP group. Three participants in the phaco-VGP group experienced hyphema. No data were available for progression of visual field loss and quality of life measurements at 12 months. Two studies compared phacoemulsification with phaco-goniosynechialysis (phaco-GSL). Low-certainty evidence suggested that there may be little to no difference in mean IOP at 12 months (MD -0.12 mmHg, 95% CI -4.72 to 4.48; 1 study, 32 eyes) between the interventions. Phacoemulsification did not reduce the number of IOP-lowering medications compared to phaco-GSL at 12 months (MD -0.38, 95% CI -1.23 to 0.47; 1 study, 32 eyes; moderate certainty evidence). Three eyes in the phaco-GSL group developed hyphemas. No data were available at 12 months for progression of visual field loss, gonioscopic findings, visual acuity, and quality of life measures. Three studies compared phacoemulsification with combined phaco-trabeculectomy, but the data were only available for one study (63 eyes). In this study, low-certainty evidence suggested that there was little to no difference between groups in mean change in IOP from baseline (MD -0.60 mmHg, 95% CI -1.99 to 0.79), number of IOP-lowering medications at 12 months (MD 0.00, 95% CI -0.42 to 0.42), and VA measured by the Snellen chart (MD -0.03, 95% CI -0.18 to 0.12). Participants in the phacoemulsification group had fewer complications (risk ratio [RR] 0.59, 95% CI 0.34 to 1.04), and the phaco-trabeculectomy group required more IOP-lowering procedures (RR 5.81, 95% CI 1.41 to 23.88), but the evidence was very uncertain. No data were available for other outcomes. AUTHORS' CONCLUSIONS: Moderate certainty evidence showed that lens extraction has an advantage over LPI in treating chronic PACG with clear crystalline lenses over three years of follow-up; ultimately, the decision for intervention should be part of a shared decision-making process between the clinician and the patient. For people with chronic PACG and visually significant cataracts, low certainty evidence suggested that combining phacoemulsification with either viscogonioplasty or goniosynechialysis does not confer any additional benefit over phacoemulsification alone. There was insufficient evidence to draw any meaningful conclusions regarding phacoemulsification versus trabeculectomy. Low certainty evidence suggested that combining phacoemulsification with trabeculectomy does not confer any additional benefit over phacoemulsification alone, and may cause more complications instead. These conclusions only apply to short- to medium-term outcomes; studies with longer follow-up periods can help assess whether these effects persist in the long term.