Natural History and Risk Factors for Glaucoma Progression in Chinese Patients With Normal-Tension Glaucoma.

Purpose: To characterize the natural history of normal-tension glaucoma (NTG) in Chinese patients. Methods: The prospective observational cohort study included patients with untreated NTG with a minimum follow-up of 2 years. Functional progression was defined by visual field (VF) deterioration, while structural progression was characterized by thinning of the retinal nerve fiber layer (RNFL) or ganglion cell inner plexiform layer (GCIPL). Results: Among 84 participants (mean age, 60.5 years; mean deviation, -5.01 decibels [dB]) with newly diagnosed NTG followed for an average of 69.7 months, 63.1% progressed during the observation period. Specifically, 29.8% progressed by VF, and 48.8% progressed by either RNFL or GCIPL. In Cox proportional hazards analysis, disc hemorrhage (hazard ratio [HR], 2.82; 95% confidence interval [CI], 1.48-5.35), female gender (HR, 1.98; 95% CI, 1.08-3.62), and mean IOP during the follow-up period (HR, 1.14 per mm Hg; 95% CI, 1.00-1.31) were significant predictors of glaucomatous progression. Additionally, longer axial length (AL; HR, 0.57 per millimeter; 95% CI, 0.35-0.94) was protective against VF progression faster than -0.50 dB/y, and higher minimum diastolic blood pressure (DBP; HR, 0.96 per mm Hg; 95% CI, 0.92-1.00) was protective against structural progression. Conclusions: Nearly two-thirds of untreated Chinese patients with NTG progressed over an average follow-up of 70 months by VF, RNFL, or GCIPL. Disc hemorrhage, female gender, higher mean IOP, shorter AL, and lower minimum DBP were significant predictors for disease progression.

Progressive peripapillary capillary vessel density loss and long-term visual field progression in Normal tension glaucoma.

PURPOSE: To explore the association between progressive peripapillary capillary vessel density (pcVD) reduction and the progression of visual field (VF) impairment in individuals with normal tension glaucoma (NTG). DESIGN: Prospective cohort study. METHODS: The study enrolled 110 participants with one eye each, totalling 110 NTG eyes. VF defects were evaluated using standard automated perimetry mean deviation (MD), while pcVD measurements were obtained using optical coherence tomography angiography throughout the follow-up period. Estimates of VF progression were determined by event-based and trend-based analyses. Fast VF progression was defined as an MD slope steeper than -0.5 dB/year, while the slow progression or stable VF was defined as an MD slope better or equal to -0.25 dB/year. Linear mixed-effects models were employed to analyse the rates of change in pcVD reduction and VF MD decline over time. Additionally, univariable and multivariable linear models were used to examine the relationship between pcVD changes and VF loss rates in NTG. RESULTS: Slow VF progression or stable VF was observed in 45% of subjects, while 25% had moderate progression and 30% showed fast progression. Patients with VF progression exhibited faster rate of pcVD reduction in peripapillary global region (-0.73 ± 0.40%/year vs. -0.56 ± 0.35%/year, p = 0.022). Moreover, this rate positively correlated with VF MD decline in NTG (estimate 0.278, 95% CI 0.122-0.433, p = 0.001). CONCLUSION: In individuals with NTG, faster VF progression was linked to a quicker reduction in pcVD, suggesting a positive correlation between pcVD decline and VF deterioration.

Risk of Normal Tension Glaucoma Progression From Automated Baseline Retinal-Vessel Caliber Analysis: A Prospective Cohort Study.

PURPOSE: To determine the relationship between baseline retinal-vessel calibers computed by a deep-learning system and the risk of normal tension glaucoma (NTG) progression. DESIGN: Prospective cohort study. METHODS: Three hundred and ninety eyes from 197 patients with NTG were followed up for at least 24 months. Retinal-vessel calibers (central retinal arteriolar equivalent [CRAE] and central retinal venular equivalent [CRVE]) were computed from fundus photographs at baseline using a previously validated deep-learning system. Retinal nerve fiber layer (RNFL) thickness and visual field (VF) were evaluated semiannually. The Cox proportional-hazards model was used to evaluate the relationship of baseline retinal-vessel calibers to the risk of glaucoma progression. RESULTS: Over a mean follow-up period of 34.36 ± 5.88 months, 69 NTG eyes (17.69%) developed progressive RNFL thinning and 22 eyes (5.64%) developed VF deterioration. In the multivariable Cox regression analysis adjusting for age, gender, intraocular pressure, mean ocular perfusion pressure, systolic blood pressure, axial length, standard automated perimetry mean deviation, and RNFL thickness, narrower baseline CRAE (hazard ratio per SD decrease [95% confidence interval], 1.36 [1.01-1.82]) and CRVE (1.35 [1.01-1.80]) were associated with progressive RNFL thinning and narrower baseline CRAE (1.98 [1.17-3.35]) was associated with VF deterioration. CONCLUSION: In this study, each SD decrease in the baseline CRAE or CRVE was associated with a more than 30% increase in the risk of progressive RNFL thinning and a more than 90% increase in the risk of VF deterioration during the follow-up period. Baseline attenuation of retinal vasculature in NTG eyes was associated with subsequent glaucoma progression. High-throughput deep-learning-based retinal vasculature analysis demonstrated its clinical utility for NTG risk assessment.

Normal-tension glaucoma: Current concepts and approaches-A review.

Normal tension glaucoma (NTG) has remained a challenging disease. We review, from an epidemiological perspective, why we should redefine normality, act earlier at lower pre-treatment intraocular pressure (IOP) level, and the role of ocular perfusion pressures, noting that perfusion is affected by defective vascular bed autoregulation and endothelial dysfunction. The correlation of silent cerebral infarcts (SCI) and NTG may indicate that NTG belongs to a wider spectrum of small vessel diseases (SVD), with its main pathology being also on vascular endothelium. Epidemiological studies also suggested that vascular geometry, such as fractal dimension, may affect perfusion efficiency, occurrence of SCI, SVD and glaucoma. Artificial intelligence with deep learning, may help predicting NTG progression from vascular geometry. Finally, we review latest evidence on the role of minimally-invasive glaucoma surgery, lasers, and newer drugs. We conclude that IOP is not the only modifiable risk factors as, many vascular risk factors are readily modifiable.

Global assessment of arteriolar, venular and capillary changes in normal tension glaucoma.

Microcirculatory insufficiency has been hypothesized in glaucoma pathogenesis. There is a scarcity of data to comprehensively examine the changes in retinal microvasculature and its role in normal tension glaucoma (NTG). We conducted a cross-sectional case-control study and included 168 eyes from 100 NTG patients and 68 healthy subjects. Quantitative retinal arteriolar and venular metrics were measured from retinal photographs using a computer-assisted program. Radial peripapillary capillary network was imaged with OCT-A and quantitative capillary metrics (circumpapillary vessel density (cpVD) and circumpapillary fractal dimension (cpFD)) were measured with a customized MATLAB program. We found that NTG was associated with decreased arteriolar and venular tortuosity, arteriolar branching angle, cpVD and cpFD. Decreased venular caliber, arteriolar and venular branching angles, cpVD and cpFD were associated with thinner average RNFL thickness. Decreased arteriolar and venular branching angles, cpVD and cpFD were also associated with worse standard automated perimetry measurements (mean deviation and visual field index). Compared with retinal arteriolar and venular metrics, regression models based on OCT-A capillary metrics consistently showed stronger associations with NTG and structural and functional measurements in NTG. We concluded that NTG eyes showed generalized microvascular attenuations, in which OCT-A capillary metrics attenuations were more prominent and strongly associated with NTG.

Factors correlating with failure to control intraocular pressure in primary angle-closure glaucoma eyes with coexisting cataract treated by phacoemulsification or combined phacotrabeculectomy.

PURPOSE: To identify clinical factors correlating with failure to control intraocular pressure (IOP) in primary angle-closure glaucoma (PACG) eyes with cataract after phacoemulsification or phacotrabeculectomy. DESIGN: Retrospective analysis of two prospective randomized controlled clinical trials. METHODS: Primary angle-closure glaucoma eyes with cataract received phacoemulsification or phacotrabeculectomy. Failure was defined as having IOP of 21mm Hg or greater, or requiring glaucoma drugs to maintain an IOP of less than 21 mm Hg, or having had additional IOP-lowering surgery. Factors correlating with failure at 24 months after surgery were identified using logistic regression model. RESULTS: One hundred twenty-three PACG eyes with cataract and receiving phacoemulsification (n = 62) and phacotrabeculectomy (n = 61) were analyzed. With univariate analysis, factors associated with failure included a higher preoperative IOP, a higher preoperative requirement for glaucoma drugs, absence of plateau iris configuration, and phacoemulsification alone. With multivariate analysis, factors associated with failure included a higher preoperative IOP [odds ratio (OR), 1.732 per increase in IOP of 5 mm Hg], a higher preoperative requirement for glaucoma drugs (OR, 1.913), and performance of phacoemulsification alone (OR, 10.24). CONCLUSIONS: In PACG eyes with cataract, higher preoperative IOP and increased requirement for glaucoma drugs correlate with failure to control IOP after phacoemulsification or phacotrabeculectomy. Phacotrabeculectomy is more likely than phacoemulsification to achieve IOP control.

Anatomical effects of clear lens extraction by phacoemulsification versus trabeculectomy on anterior chamber drainage angle in primary angle-closure glaucoma (PACG) patients.

PURPOSE: To document the anatomical effects of clear lens extraction by phacoemulsification versus trabeculectomy on anterior chamber angle in patients with primary angle-closure glaucoma (PACG). METHODS: Gonioscopy and ultrasound biomicroscopy (UBM) were performed pre-operatively, and at 1 year after clear lens extraction or trabeculectomy in PACG eyes. RESULTS: Fifty PACG eyes of 50 patients were included. Twenty-six eyes had clear lens extraction by phacoemulsification, while 24 eyes underwent trabeculectomy. The mean extent of synechial angle closure was significantly reduced from 272.3° ± 57.3° to 253.3° ± 70.5° (p = 0.007) by phacoemulsification, but it was only reduced from 285.0° ± 64.6° to 283.1° ± 55.5° (p = 0.32) by trabeculectomy. The mean angle-opening distance at 500 microns from sclera spur (AOD500) measured by UBM was significantly increased from 220.3 ± 93.8 microns to 388.9 ± 134.1 microns (p < 0.001) by clear lens extraction, but decreased from 220.9 ± 79.8 microns to 214.5 ± 70.2 microns (p = 0.11) by trabeculectomy. The mean anterior chamber depth (ACD) measured by UBM was significantly increased from 1,983.8 ± 176.8 microns to 3335.0 ± 174.2 microns (p < 0.001) by clear lens extraction, but decreased from 2,000.2 ± 214.5 microns to 1975.8 ± 218.2 microns (p = 0.001) by trabeculectomy. CONCLUSION: Compared to trabeculectomy, clear lens extraction resulted in a significant reduction in synechial angle closure, and an increase in anterior chamber angle width and anterior chamber depth in PACG eyes without cataract.

Management of bleb complications after trabeculectomy.

Trabeculectomy remains a mainstay surgery for glaucoma. The necessity to raise a bleb and use of chemoadjuvants may result in bleb-related complications, such as bleb-fibrosis, bleb-leaks, bleb-related infections, overfiltration, or hypotony. This review highlights some of the latest developments in preventing and managing these complications, including anti-vascular endothelial growth factors, monoclonal antibodies for moderate reduction of fibrosis, newer surgical strategies for bleb leaks, an update from a randomized clinical trial highlighting the incidence and management of bleb-related infections, and various treatment strategies for an overfiltering bleb. In addition, other surgical interventions with less or no bleb-related complications will be discussed, including non-penetrating glaucoma surgeries, glaucoma drainage devices, or phacoemulsification.

Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus.

Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10(-8)). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4-1.88, P = 2.7 × 10(-10), and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29-1.68, P = 4.9 × 10(-9)). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10(-4); tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.

Phacoemulsification versus trabeculectomy in medically uncontrolled chronic angle-closure glaucoma without cataract.

OBJECTIVE: To compare phacoemulsification versus trabeculectomy with adjunctive mitomycin C in medically uncontrolled chronic angle-closure glaucoma (CACG) without cataract. DESIGN: Prospective, randomized clinical trial. PARTICIPANTS: Fifty medically uncontrolled CACG eyes without cataract of 50 patients. INTERVENTION: Patients were randomized into undergoing either phacoemulsification or trabeculectomy with adjunctive mitomycin C. After surgery, patients were followed up every 3 months for 2 years. MAIN OUTCOME MEASURES: Intraocular pressure (IOP) and requirement for glaucoma drugs. RESULTS: Twenty-six CACG eyes were randomized to receive phacoemulsification, and 24 eyes underwent trabeculectomy with mitomycin C. Phacoemulsification and trabeculectomy resulted in significant and comparable IOP reduction at 24 months after surgery (reduction of 8.4 mmHg or 34% for phacoemulsification vs. 8.9 mmHg or 36% for trabeculectomy; P=0.76). Over first 24 months, trabeculectomy-treated eyes required on average 1.1 fewer drugs than phacoemulsification-treated eyes (P<0.001). However, trabeculectomy was associated with significantly more surgical complications than phacoemulsification (46% vs. 4%; P=0.001). Eight (33%) of 24 trabeculectomy eyes demonstrated cataract during follow-up. CONCLUSIONS: Both phacoemulsification and trabeculectomy are effective in reducing IOP in medically uncontrolled CACG eyes without cataract. Trabeculectomy is more effective than phacoemulsification in reducing dependence on glaucoma drugs, but is associated with more complications. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Evaluation of NTF4 as a causative gene for primary open-angle glaucoma.

PURPOSE: The neurotrophin-4 (NTF4) gene has been recently implicated in primary open-angle glaucoma (POAG). In this study, we investigated the implication of NTF4 in POAG among three Chinese cohorts. METHODS: The coding regions and exon-intron boundaries of NTF4 was sequenced in 950 unrelated Chinese subjects, including a Hong Kong cohort of 390 patients and 230 controls, a Shantou cohort of 130 patients, and a Beijing cohort of 200 patients. Constructs carrying the detected variants were generated using site-directed mutagenesis and transfected into HeLa cells, followed by solubility and migration analyses. RESULTS: Three variants were identified. p.Pro151Pro was detected in three POAG patients and one control subject. Two novel missense variants, p.Gly157Ala and p.Ala182Val, were identified each in one POAG patient from the Hong Kong cohort, but not in controls. Functional assays showed that the p.Gly157Ala mutant protein was less soluble in Triton X-100, and that migration of HeLa cells transfected with either mutant construct was less than cells transfected with the wildtype. CONCLUSIONS: The NTF4 variants p.Gly157Ala and p.Ala182Val have been shown to be functional mutations, occurring in 2 of a total of 720 Chinese POAG patients. NTF4 is functionally related to POAG pathogenesis but its mutation frequency is low. Therefore, NTF4 does not have a major contribution in the molecular genetics of POAG.

SNP rs1533428 at 2p16.3 as a marker for late-onset primary open-angle glaucoma.

PURPOSE: To investigate the associations between gene variants in cholesterol 24S-hydroxylase (CYP46A1), LIM homeobox transcription factor 1-beta (LMX1B), plexin domain containing 2 (PLXDC2), toll-like receptor 4 (TLR4), transmembrane and tetratricopeptide repeat containing 2 (TMTC2), zona pellucida glycoprotein 4 (ZP4), chromosome 2p16.3, and primary open-angle glaucoma (POAG). METHODS: We studied 462 POAG patients and 577 controls from three cohorts (Hong Kong, Shantou, and Beijing, China). Twelve single-nucleotide polymorphisms (SNPs) were genotyped in the Hong Kong cohort using TaqMan genotyping assay. Significant associations were validated in the Shantou and Beijing cohorts. RESULTS: Association of POAG with TLR4 rs7037117, in a recessive model, was identified in the Hong Kong and Shantou cohorts (both southern Chinese, p(rec)=0.0019) but not the Beijing cohort (northern Chinese). rs1533428 at chromosome 2p16.3 showed a consistent trend of age-specific association in all three cohorts. Genotypes TT + CT conferred a 2.16 fold of significantly increased risk to late-onset POAG (p(dom)=0.00025), but no significant risk to POAG of younger ages of onset in the combined cohort. A joint effect was found between rs7037117 and rs1533428, with carriers of both higher-risk genotypes having a 4.53 fold of increased disease risk (p=0.00028). CONCLUSIONS: Our study reveals discrepant association patterns of 12 candidate SNPs in 7 genes/loci with POAG in Chinese, provides positive replications for POAG markers rs1533428 at 2p16.3 and TLR4 rs7037117, and suggests that rs1533428 is a putative risk variant for late-onset POAG. The identification of an age-specific association between rs1533428 and late-onset POAG highlights a new genotype-phenotype association in POAG. Further studies are warranted to confirm the age-specific association.

Pressure-cornea-vascular index (PCVI) for predicting disease progression in normal tension glaucoma.

BACKGROUND: It has been shown that the pressure-to-cornea index (PCI), which estimates the relative effects of intraocular pressure (IOP) and central corneal thickness (CCT), may differentiate between glaucoma and non-glaucoma states. The authors investigated the utility of the pressure-cornea-vascular index (PCVI) in predicting field-progression in patients with normal tension glaucoma (NTG). METHODS: PCVI was constructed from PCI (maximum IOP/CCT(3)) extended with risk factors identified as associated with field-progression in a prospective NTG cohort. Receiver operator characteristics and area under the curve (AUC) of a range of constructs were calculated to arrive at an optimal PCVI. RESULTS: 415 eyes from 415 NTG subjects (184 field-progressed and 231 field-stable) with 3 years of follow-up were analysed. The construct PCVI=(maximum pretreatment office IOP × age at presentation × vertical cup-to-disc ratio at presentation × (1.5 if presence of systemic hypertension; 2.5 if presence of disc haemorrhage; 3.5 if presence of both; 1.0 if none))/(CCT(3)×100) (CCT in mm) gave the highest AUC at 0.71 (95% CI 0.66 to 0.76, p<0.001). The mean PCVI were 113.1±76.8 and 69.7±39.7 for progressed and stable NTG groups, respectively (p<0.001). CONCLUSION: PCVI may be useful for predicting progression in NTG with a satisfactory AUC comparable to established scoring systems in neurovascular medicine. Validation of PCVI in other NTG cohorts, preferably of different ethnicity, is necessary. Trial registration number NCT00321386.

Phacoemulsification vs phacotrabeculectomy in chronic angle-closure glaucoma with cataract: complications [corrected].

OBJECTIVE: To compare the complications of phacoemulsification alone vs combined phacotrabeculectomy in chronic angle-closure glaucoma (CACG) with coexisting cataract. METHODS: Patients with CACG with coexisting cataract recruited into 2 randomized controlled trials comparing phacoemulsification alone vs combined phacotrabeculectomy were pooled for analysis. The first trial recruited patients with medically controlled intraocular pressure, while the second trial recruited patients with medically uncontrolled intraocular pressure. The 2 trials had otherwise identical study designs. All patients were reviewed every 3 months for 2 years after surgery. The main outcome measure was the surgical complications of phacoemulsification alone vs combined phacotrabeculectomy in CACG eyes with cataract. RESULTS: One hundred twenty-three CACG eyes with cataract from 123 patients were included. Sixty-two CACG eyes were randomized to receive phacoemulsification alone, and 61 eyes had combined phacotrabeculectomy. In the phacoemulsification group, 5 of the 62 CACG eyes (8.1%) had a total of 5 surgical complications. In the combined phacotrabeculectomy group, 16 of the 61 CACG eyes (26.2%) had a total of 19 surgical complications. The difference in the proportion of eyes with 1 or more surgical complications between the 2 treatment groups was statistically significant (P = .007, Pearson chi(2) test). There was no statistically significant difference in final visual acuity or glaucomatous progression during the 24-month follow-up. CONCLUSIONS: Combined phacotrabeculectomy resulted in significantly more surgical complications than phacoemulsification alone in CACG eyes with coexisting cataract. There was no difference in visual acuity or disease progression between the 2 treatment groups.

Simvastatin and disease stabilization in normal tension glaucoma: a cohort study.

PURPOSE: To investigate whether simvastatin use is associated with visual field (VF) stabilization in patients with normal tension glaucoma (NTG). DESIGN: Prospective cohort study (ClinicalTrials.gov Identifier: NCT00321386). PARTICIPANTS: A total of 256 eyes from 256 Chinese subjects with NTG. METHODS: Patients were followed up at 4-month intervals for 36 months for VF progression per Anderson's criteria. Clinical parameters were checked for association with progression in multivariate analysis. MAIN OUTCOME MEASURES: The primary outcome was the association between simvastatin use and VF progression. RESULTS: Thirty-one patients (12.1%) were taking simvastatin (statin+), and 225 patients (87.9%) were not taking simvastatin (statin-). Baseline age, gender, untreated intraocular pressure, VF indices, vertical cup-to-disc ratio, and central corneal thickness (CCT) were comparable between the 2 groups. There were significantly more patients with a history of hypercholesterolemia, systemic hypertension, and ischemic heart disease in the statin+ group. A total of 121 patients (47.3%) showed evidence of VF progression (mean rate of mean deviation loss was -0.30 decibel per year) during the 36 months of follow-up. Simvastatin use was among 8 of 121 patients (6.6%) who progressed compared with 23 of 135 patients (17.0%) who did not progress (P = 0.011). Logistic regression revealed that history of disc hemorrhage (relative risk [RR] 3.26; 95% confidence interval [CI], 1.21-8.76; P = 0.019), history of cerebrovascular accidents (RR 2.28; 95% CI, 1.03-5.06; P = 0.043), and baseline age (per 10 years older; RR 1.38; 95% CI, 1.08-1.76; P = 0.009) were significant risk factors for VF progression, whereas simvastatin use conferred a protective effect (RR 0.36; 95% CI, 0.14-0.91; P = 0.030). CONCLUSIONS: Simvastatin use may be associated with VF stabilization in patients with NTG. A larger scale randomized controlled trial and cost-effectiveness analyses seem warranted.