Associations with intraocular pressure across Europe: The European Eye Epidemiology (E3) Consortium.

Raised intraocular pressure (IOP) is the most important risk factor for developing glaucoma, the second commonest cause of blindness globally. Understanding associations with IOP and variations in IOP between countries may teach us about mechanisms underlying glaucoma. We examined cross-sectional associations with IOP in 43,500 European adults from 12 cohort studies belonging to the European Eye Epidemiology (E3) consortium. Each study conducted multivariable linear regression with IOP as the outcome variable and results were pooled using random effects meta-analysis. The association of standardized study IOP with latitude was tested using meta-regression. Higher IOP was observed in men (0.18 mmHg; 95 % CI 0.06, 0.31; P = 0.004) and with higher body mass index (0.21 mmHg per 5 kg/m2; 95 % CI 0.14, 0.28; P < 0.001), shorter height (-0.17 mmHg per 10 cm; 95 % CI -0.25, -0.08; P < 0.001), higher systolic blood pressure (0.17 mmHg per 10 mmHg; 95 % CI 0.12, 0.22; P < 0.001) and more myopic refraction (0.06 mmHg per Dioptre; 95 % CI 0.03, 0.09; P < 0.001). An inverted U-shaped trend was observed between age and IOP, with IOP increasing up to the age of 60 and decreasing in participants older than 70 years. We found no significant association between standardized IOP and study location latitude (P = 0.76). Novel findings of our study include the association of lower IOP in taller people and an inverted-U shaped association of IOP with age. We found no evidence of significant variation in IOP across Europe. Despite the limited range of latitude amongst included studies, this finding is in favour of collaborative pooling of data from studies examining environmental and genetic determinants of IOP in Europeans.

Ethnicity-Based Differences in the Association of LOXL1 Polymorphisms with Pseudoexfoliation/Pseudoexfoliative Glaucoma: A Meta-Analysis.

Pseudoexfoliation (PEX) is an age-related disorder of the extracellular matrix; it is strongly associated with glaucoma, the leading cause of irreversible blindness worldwide. We conducted an ethnic-based meta-analysis of the association of LOXL1 polymorphisms with PEX/pseudoexfoliative glaucoma (PEXG). Association studies were retrieved systematically from PubMed, EMBASE, and Web of Knowledge. Allelic and genotype frequencies of rs3825942, rs1048661, and rs2165241 were compared between PEX/PEXG and controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using a random effects model. Overall, 39 independent cohorts were included. Rs3825942 (G) was an at risk allele for PEX/PEXG in Caucasians, Japanese, Koreans, Chinese, South Asians, and Middle Easterners, but protective in Black South Africans (OR = 0.10, 95%CI:0.06-0.16). Rs1048661 (G) was an at risk allele for PEX/PEXG in Caucasians, South Asians, Middle Easterners and Black South Africans, but was protective in Japanese (OR = 0.03, 95%CI:0.02-0.06) and Koreans (OR = 0.10, 95%CI:0.05-0.22). These associations we-re confirmed for the genotypic recessive models. Rs2165241 (C) was a protective allele for PEX/PEXG in Caucasians, but was an at risk allele in Japanese (OR = 7.49, 95%CI:3.22-17.41) and Koreans (OR = 6.63, 95%CI:2.60-16.90). This was confirmed for the genotypic dominant model. Other genetic and/or environmental factors may modify the effect of LOXL1 polymorphisms in certain ethnic groups.

Survival of Visual Function in Patients with Advanced Glaucoma after Standard Guarded Trabeculectomy with MMC.

Surgical intervention in patients with severe glaucoma remains controversial, especially in unilateral cases with a minimally affected fellow eye. Many question the benefit of trabeculectomy in such cases due to high complication rates and prolonged recovery. In this retrospective, non-comparative, interventional case series we aimed to determine the effect of trabeculectomy or combined phaco-trabeculectomy on the visual function of advanced glaucoma patients. Consecutive cases with perimetric mean deviation loss worse than -20 dB were included. Survival of visual function according to five predetermined visual acuity and perimetric criteria was set as the primary outcome. Qualified surgical success utilizing two different sets of criteria commonly used in the literature constituted secondary outcomes. Forty eyes with average baseline visual field mean deviation -26.3 ± 4.1 dB were identified. The average pre-operative intraocular pressure was 26.5 ± 11.4 mmHg and decreased to 11.4 ± 4.0 mmHg (p < 0.001) after an average follow-up of 23.3 ± 15.5 months. Visual function was preserved at two years in 77% or 66% of eyes respectively according to two different sets of visual acuity and perimetric criteria. Qualified surgical success was 89%, 72% at 1 and 3 years respectively. Trabeculectomy and/or phaco-trabeculectomy is associated with meaningful visual outcomes in patients with uncontrolled advanced glaucoma.

Twelve-Year Incidence of Open-angle Glaucoma: The Thessaloniki Eye Study.

OBJECTIVE: The objective of this study was to determine the 12-year incidence of open-angle glaucoma (OAG), with further classification into primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma (PEXG), in an elderly White population. DESIGN: A longitudinal, population-based study in urban Northern Greece. PARTICIPANT: Surviving cohort of the 2554 Thessaloniki Eye Study subjects 60 years and above who had the baseline examination. METHODS: The surviving cohort was re-examined 12 years after baseline, using the same methodology and the same standard operating procedures as in the baseline examination. The definitions of glaucoma and pseudoexfoliation were consistent throughout the study. The 12-year incidences of OAG, POAG, and PEXG with corresponding 95% confidence intervals (CIs) were calculated for the whole study population, consisting of clinic-visit and home-visit participants. The population at risk was defined as those who did not meet the study criteria for the diagnosis of glaucoma in either eye at baseline. MAIN OUTCOME MEASURES: Twelve-year incidence of OAG, with further classification into POAG and PEXG. RESULTS: Of 1468 eligible subjects in the surviving cohort, 1092 were examined (participation rate 74%). Mean age at baseline was 68.9±4.6 years. Mean follow-up time was 11.6±1.6 years. The 12-year incidence of OAG was 4.4% (95% CI: 3.3-5.8); 0.37% per year. In the overall population the incidence of POAG and PEXG was 2.1% (95% CI: 1.3-3.2) and 2.3% (95% CI: 1.5-3.4), respectively. The corresponding incidence proportions were 2.9 (95% CI: 1.8-4.3) in those without PEX and 8.9 (95% CI: 5.8-12.9) in those with PEX at baseline and/or incidence. The latter was strongly associated with higher odds for incident glaucoma (odds ratio=3.34, 95% CI: 1.83-6.08, P<0.001). Of all incident OAG cases, 11.1% (95% CI: 4.4-24) had baseline intraocular pressure >21 mm Hg. CONCLUSIONS: The incidence of OAG was similar or higher compared with other White populations. The incidence of glaucoma in those with PEX was higher compared with the incidence of glaucoma in those without PEX.

Tolerable rates of visual field progression in a population-based sample of patients with glaucoma.

AIMS: To provide population-based data on the maximum tolerable rate of progression to avoid visual impairment (maxTRoP_VI) and blindness (maxTRoP_BL) from open-angle glaucoma (OAG). METHODS: Participants with OAG in the Thessaloniki Eye Study (cross-sectional, population-based study in a European population) were included in the analysis. Visual impairment was defined as mean deviation (MD) equal to or worse than -12dB and blindness as MD equal to or worse than -24dB. Additional thresholds for visual impairment were tested. For each participant maxTRoP_VI was defined as the rate of progression which would not lead to visual impairment during expected lifetime. MaxTRoP_BL was defined accordingly. Both parameters were calculated for each OAG subject using age, sex, MD and life expectancy data. The eye with the better MD per subject was included in the analysis. RESULTS: Among 135 subjects with OAG, 123 had reliable visual fields and were included in the analysis. The mean age was 73±6 years and the median MD was -3.65±5.28dB. Among those, 69.1% would have a maxTRoP_VI slower than -1dB/year and 18.7% would have a maxTRoP_VI between -1 and -2dB/year. Also, 72.4% would have a maxTRoP_BL slower than -2dB/year. For all tested thresholds for visual impairment, approximately 86% of the OAG study participants would not be able to tolerate a rate of progression equal to or faster than -2dB/year. CONCLUSIONS: The majority of patients with glaucoma in our study would have a maximum tolerable rate of progression slower than -1dB/year in their better eye. Patient-tailored strategies to monitor the visual field are important, but raise the issue of feasibility with regard to the number of visual field tests needed.

Overdiagnosis of open-angle glaucoma in the general population: the Thessaloniki Eye Study.

PURPOSE: To assess the overdiagnosis of open-angle glaucoma (OAG) and to investigate associated factors. METHODS: This was a cross-sectional, population-based study of an urban Caucasian population in northern Greece. Randomly selected subjects ≥60 years (n = 2554) participated in the Thessaloniki Eye Study. The definition of OAG required the presence of structural and functional damage, irrespective of intraocular pressure (IOP). Non-OAG subjects were classified as overdiagnosed with OAG if they had reported at least one of the following (self-reported glaucoma): (i) prior diagnosis of glaucoma, (ii) prior laser for glaucoma, (iii) prior glaucoma surgery. Factors associated with the overdiagnosis of OAG were investigated using a logistic regression model. RESULTS: Of 57 (2.2%) subjects with self-reported glaucoma, 34 (60%) were overdiagnosed with OAG, corresponding to a prevalence of 1.3% (34/2554). In a logistic regression model among non-OAG subjects, worse visual acuity (VA) (20/200 or worse versus 20/25 or better; odds ratio (OR) = 4.30, 95% Confidence Intervals (CI), 1.13-16.35), family history of glaucoma (OR = 8.69, 95% CI, 2.83-26.67) and history of cataract surgery (OR = 11.50, 95% CI, 3.85-34.36) were statistically significantly associated with the overdiagnosis of OAG. Age, sex, higher IOP, higher vertical cup-to-disc ratio and pseudoexfoliation were not statistically significant. CONCLUSION: The overdiagnosis of OAG was substantial in this elderly, Caucasian population. The overdiagnosis of glaucoma has not been previously addressed in population-based studies and needs to be further explored.

Structure-Function Correlation Using Confocal Laser Ophthalmoscope in Primary Open-Angle Glaucoma and Pseudoexfoliative Glaucoma.

PURPOSE: To compare Heidelberg Retina Tomograph (HRT) optic disc parameters and structure-function correlation between primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma (PEXG). DESIGN: Prospective, observation case series. PATIENTS AND METHODS: A total of 54 POAG and 33 PEXG cases, consecutively recruited from a University Glaucoma Service, underwent a comprehensive ophthalmic examination, including HRT optic disc imaging. Glaucoma definition required the presence of both structural and functional damage. One eye per subject was included in the analysis. T test, Mann-Whitney U test, and analysis of covariance were used to compare HRT parameters between POAG and PEXG, adjusting for age, mean deviation (MD) in the visual field, intraocular pressure, and disc area. The correlation between HRT and MD was assessed in each group. RESULTS: Cup area (P=0.048), height variation contour (P=0.016), and cup/disc area ratio (P=0.023) were higher in POAG, whereas the mean retinal nerve fiber layer thickness (P=0.048), retinal nerve fiber layer cross-section area (P=0.044), and rim area (P=0.048) were lower in POAG, compared with PEXG. The correlation of HRT parameters with MD was significant only in the POAG group. CONCLUSIONS: At a similar level of functional damage, POAG subjects presented with more pronounced structural damage than PEXG subjects. The correlation between HRT and visual field parameters was more evident in POAG, compared with PEXG.

Association of LOXL1 polymorphisms with pseudoexfoliation, glaucoma, intraocular pressure, and systemic diseases in a Greek population. The Thessaloniki eye study.

PURPOSE: To investigate the association of the two single-nucleotide polymorphisms (SNPs) in the lysyl oxidase-like 1 (LOXL1) gene with pseudoexfoliation syndrome (PEX), pseudoexfoliative glaucoma (PEXG), and primary open-angle glaucoma (POAG) in a Greek population-based setting, from the Thessaloniki Eye study. METHODS: A total of 233 subjects with successful DNA extraction, PCR amplification, and genotyping were included in the genetic analysis of G153D and R141L SNPs of LOXL1 gene and classified into four groups: controls (n = 93); subjects with PEX (n = 40); POAG (n = 66); and PEXG (n = 34). Multinomial logistic regression was used to test their association with LOXL1 SNPs with adjustment for covariates. The association of LOXL1 with IOP (in untreated subjects) and with systemic diseases was explored. RESULTS: Both LOXL1 SNPs were present in high frequencies in controls and cases. The G153D was strongly associated with both PEX (odds ratio [OR] = 23.2, P = 0.003 for allele G) and PEXG (OR = 24.75, P = 0.003 for allele G) and was not associated with POAG (P = 0.451). In contrast, the R141L was not associated with PEX (P = 0.81), PEXG (P = 0.063), or POAG (P = 0.113). No association of the G153D with either intraocular pressure (IOP) or systemic diseases was found. CONCLUSIONS: In the Thessaloniki Eye Study, the G153D SNP of LOXL1 gene was strongly associated with both PEX and PEXG, whereas the R141L was not associated. No association of the LOXL1 with IOP or with systemic diseases was found. These findings further support the hypothesis that the LOXL1 gene contributes to onset of PEXG through PEX. Gene variants of LOXL1 do not help to identify those with PEX at increased risk for glaucoma development.

Association of open-angle glaucoma with perfusion pressure status in the Thessaloniki Eye Study.

PURPOSE: To investigate the association of open-angle glaucoma (OAG), primary open-angle glaucoma (POAG), and pseudoexfoliative glaucoma (PEXG) with ocular perfusion pressure status (ocular perfusion pressure with or without antihypertensive treatment). DESIGN: Cross-sectional, population-based study. METHODS: A total of 2554 randomly selected, ≥ 60-year old subjects participated in the Thessaloniki Eye Study. Only clinic-visit participants (n = 2261), who had uniformly collected data, were included in the analyses. A logistic regression model was run for OAG in all clinic-visit participants; covariates included age, sex, diastolic ocular perfusion pressure, antihypertensive treatment, intraocular pressure (IOP), IOP-lowering treatment, pseudoexfoliation, and vascular factors identified as risk factors for glaucoma in a previous analysis. Similar logistic regression models were run separately for POAG and PEXG. In addition, logistic regression models were run for OAG, POAG, and PEXG in subjects with and without antihypertensive treatment. Also, logistic regression models were run to assess the role of systolic ocular perfusion pressure in OAG, POAG, and PEXG. RESULTS: Among clinic-visits, 1212 subjects (53.7%) were using antihypertensive treatment. An association of borderline significance was found between low diastolic ocular perfusion pressure and POAG (OR = 0.84 per 10 mm Hg, 95% CI = 0.70-1.01, P = .059). The effect of antihypertensive treatment on POAG was not statistically significant (OR = 1.20, 95% CI = 0.75-1.91, P = .45). In subgroup analyses, diastolic ocular perfusion pressure was significantly associated with POAG in subjects using antihypertensive treatment (OR = 0.78 per 10 mm Hg, 95% CI = 0.62-0.97, P = .028). No association was found between diastolic ocular perfusion pressure and PEXG, regardless of the use of antihypertensive treatment. No associations were found between systolic ocular perfusion pressure and OAG, POAG, or PEXG, regardless of the use of antihypertensive treatment. CONCLUSIONS: Low diastolic ocular perfusion pressure may be associated with increased risk for POAG. This association was confirmed in subjects treated for systemic hypertension in subgroup analysis. This may support the hypothesis that the concept of ocular perfusion pressure status may be more relevant to glaucoma pathogenesis than ocular perfusion pressure alone.

Agreement among three examiners of colour Doppler imaging retrobulbar blood flow velocity measurements.

PURPOSE: To assess the agreement among three masked examiners on central retinal artery (CRA) and ophthalmic artery (OA) blood flow velocity measurements performed with colour Doppler imaging (CDI) in healthy volunteers. METHODS: The study included 30 eyes of 15 healthy volunteers. Prior to the study, all examiners underwent intensive CDI training by an expert to facilitate uniformity in performing measurements according to a specific protocol. Following the eligibility visit, three masked examiners performed CDI measurements assessing the CRA and OA in both eyes of all subjects. All CDI images were analysed by a masked grader. Intraclass correlation coefficients (ICC) were calculated for peak systolic velocity (PSV) and end diastolic velocity (EDV) in the CRA and OA among the examiners. p-values < 0.05 were considered statistically significant. RESULTS: The study included seven men and eight women (mean age 30.9 ± 4.5 years). In right eyes, ICCs for PSV and EDV in the CRA ranged from 0.917 to 0.961 and from 0.937 to 0.980, respectively. ICCs for PSV and EDV in the OA ranged from 0.802 to 0.926 and from 0.611 to 0.891, respectively. In left eyes, all ICCs for PSV and EDV were >0.9, both in the CRA and the OA. All p-values calculated for ICCs were statistically significant. CONCLUSION: Expert training and execution of a specific protocol for CDI of ocular blood flow velocity measurements provide highly reproducible results in healthy volunteers. This is important for long-term studies assessing ocular hemodynamics, where multiple examiners may be involved.

Risk factors for primary open-angle glaucoma and pseudoexfoliative glaucoma in the Thessaloniki eye study.

PURPOSE: To investigate risk factors for primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma (PEXG) in the Thessaloniki Eye Study. DESIGN: Cross-sectional, population-based study. METHODS: Randomly selected subjects 60 years of age and older (n=2554) participated in the Thessaloniki Eye Study. Glaucomatous damage and presence of pseudoexfoliation (PEX) were defined according to specific criteria. Open-angle glaucoma (OAG) subjects were compared with nonglaucoma subjects (controls), POAG subjects were compared with controls without PEX, and PEXG subjects were compared with controls with PEX for demographic, lifestyle, ophthalmic, and systemic factors. Factors with P < .2 in the univariate analysis were retained for multivariate analyses. RESULTS: In multivariate analysis restricted to persons who participated in clinic visits and who had at least 1 phakic eye (n=2078), intraocular pressure (odds ratio [OR], 1.21 per 1 mm Hg; P<.001), PEX (OR, 2.81; P<.001), history of coronary artery bypass or vascular surgery (OR, 1.95; P=.017), and moderate-to-high myopia (≥ -3 diopters; OR, 2.40; P=.009) were associated with higher odds for OAG. In analysis including all clinic visits (n=2261), age became significantly associated (OR, 1.05; P=.004). In multivariate analysis for POAG (n=1840), associations were found for age (OR, 1.04 per year; P=.048), IOP (OR, 1.19 per 1 mm Hg; P<.001), history of coronary artery bypass or vascular surgery (OR, 2.09; P=.01), and history of diabetes treated with insulin (OR, 3.05; P=.045). In multivariate analysis for PEXG (n=238), the latter was associated with increased IOP (OR, 1.25 per 1 mm Hg; P<.001). CONCLUSIONS: IOP was the only factor associated with both POAG and PEXG, whereas moderate-to-high myopia showed borderline significance in both. Vascular systemic diseases and their treatment were associated only with POAG. The implications of these differences for the pathogenesis between the 2 common types of OAG should be explored further.