Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye.

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness. Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. Design, Setting, and Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome. Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. Main Outcomes and Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses. Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. Conclusions and Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.

Risk Factors for Visual Field Deterioration in the United Kingdom Glaucoma Treatment Study.

PURPOSE: The United Kingdom Glaucoma Treatment Study (UKGTS) investigated the visual field (VF)-preserving effect of medical treatment in open-angle glaucoma (OAG). The objective of this analysis was to identify risk factors associated with VF deterioration. DESIGN: Randomized, double-masked, placebo-controlled multicenter trial. PARTICIPANTS: Five hundred sixteen participants with previously untreated OAG were recruited prospectively in 10 United Kingdom centers. METHODS: Eligibility criteria were modeled on those for the Early Manifest Glaucoma Trial. Study participants were randomized to either latanoprost 0.005% or placebo eye drops. The observation period was 2 years and involved, among other procedures, VF testing and intraocular pressure (IOP) measurement at 11 scheduled visits, with clustering of tests at baseline, 18 months, and 24 months. Guided progression analysis pattern deviation maps were used to determine VF deterioration. Cox regression was used to compute the hazard ratios (HRs) and respective 95% confidence intervals (CIs) while accounting for the correlation within sites. Model selection was guided by backward stepwise selection conducted on the model containing all variables that were significant at the 0.2 level in the univariate analysis. Follow-up variables that showed collinearity with baseline values were not retained in the final model. MAIN OUTCOME MEASURE: Time to VF deterioration. RESULTS: Treatment with latanoprost reduced the HR, for VF deterioration by 58% (HR, 0.42; 95% CI, 0.27-0.67; P = 0.001). Factors associated with deterioration were bilateral disease (HR, 1.59 for yes vs. no; 95% CI, 1.02-2.50; P = 0.041), higher baseline IOP (HR, 1.07 per mmHg; 95% CI, 1.02-1.12; P = 0.008), and disc hemorrhage at visit 1 (HR, 2.08; 95% CI, 1.07-4.04; P = 0.030). Smoking (current or previous) was associated with a reduced HR, for VF deterioration (HR, 0.59; 95% CI, 0.37-0.93; P = 0.023). No other evaluated factors were found to be statistically significant in the multivariable analysis. CONCLUSIONS: In the UKGTS, treatment with latanoprost halved VF deterioration risk. Bilateral disease, higher IOP, and disc hemorrhage were confirmed as risk factors for deterioration; smoking history seemed to be protective against VF deterioration.

The Decreasing Prevalence of Nonrefractive Visual Impairment in Older Europeans: A Meta-analysis of Published and Unpublished Data.

TOPIC: To estimate the prevalence of nonrefractive visual impairment and blindness in European persons 55 years of age and older. CLINICAL RELEVANCE: Few visual impairment and blindness prevalence estimates are available for the European population. In addition, many of the data collected in European population-based studies currently are unpublished and have not been included in previous estimates. METHODS: Fourteen European population-based studies participating in the European Eye Epidemiology Consortium (n = 70 723) were included. Each study provided nonrefractive visual impairment and blindness prevalence estimates stratified by age (10-year strata) and gender. Nonrefractive visual impairment and blindness were defined as best-corrected visual acuity worse than 20/60 and 20/400 in the better eye, respectively. Using random effects meta-analysis, prevalence rates were estimated according to age, gender, geographical area, and period (1991-2006 and 2007-2012). Because no data were available for Central and Eastern Europe, population projections for numbers of affected people were estimated using Eurostat population estimates for European high-income countries in 2000 and 2010. RESULTS: The age-standardized prevalence of nonrefractive visual impairment in people 55 years of age or older decreased from 2.22% (95% confidence interval [CI], 1.34-3.10) from 1991 through 2006 to 0.92% (95% CI, 0.42-1.42) from 2007 through 2012. It strongly increased with age in both periods (up to 15.69% and 4.39% in participants 85 years of age or older from 1991 through 2006 and from 2007 through 2012, respectively). Age-standardized prevalence of visual impairment tended to be higher in women than men from 1991 through 2006 (2.67% vs. 1.88%), but not from 2007 through 2012 (0.87% vs. 0.88%). No differences were observed between northern, western, and southern regions of Europe. The projected numbers of affected older inhabitants in European high-income countries decreased from 2.5 million affected individuals in 2000 to 1.2 million in 2010. Of those, 584 000 were blind in 2000, in comparison with 170 000 who were blind in 2010. CONCLUSIONS: Despite the increase in the European older population, our study indicated that the number of visually impaired people has decreased in European high-income countries in the last 20 years. This may be the result of major improvements in eye care and prevention, the decreasing prevalence of eye diseases, or both.

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.

Update on pseudoexfoliation syndrome pathogenesis and associations with intraocular pressure, glaucoma and systemic diseases.

PURPOSE OF REVIEW: Pseudoexfoliation (PEX) syndrome is a common age-related disorder affecting intraocular and extraocular tissues. This review focuses on recent publications related with the pathogenesis and associations of PEX syndrome with intraocular pressure (IOP), glaucoma and systemic diseases. RECENT FINDINGS: In PEX tissues, expression of lysyl oxidase-like 1 (LOXL1) was found to be markedly dysregulated. This may adversely affect elastin metabolism and lead to elastotic alteration in tissues such as lamina cribrosa. There is increasing evidence that cellular stress conditions and low-grade chronic inflammatory processes are involved in the pathogenesis of PEX. Although there is an increased risk for glaucoma development in patients with PEX and ocular hypertension as compared with non-PEX patients with ocular hypertension, LOXL1 single nucleotide polymorphisms were not associated with intraocular pressure (IOP) differences. Lack of association of PEX with all-cause mortality or dementia has been reported recently. The association with vascular diseases is not consistent among different studies. SUMMARY: Despite the high prevalence of the LOXL1 variants in the general population, a much lower proportion of the population develops PEX, suggesting that in addition to LOXL1, other genetic, epigenetic and environmental factors may contribute to the development of PEX. Also, LOXL1 cannot help to identify those with PEX at increased risk for glaucoma development. Increased risk for glaucoma development in PEX patients who present with increased IOP may be related to other factors beyond IOP, contributing to increased vulnerability of the optic nerve to glaucoma development in the presence of PEX.

Outcomes of newly referred patients with suspected angle closure: do we need to redefine the clinical pathways?

BACKGROUND/OBJECTIVES: To investigate outcomes of referrals for suspected angle closure and explore whether anterior segment optical coherence tomography (AS-OCT) can be used to tighten triaging criteria in a glaucoma virtual clinic. SUBJECTS/METHODS: Retrospectively collected data. The first audit (04/2018-03/2019) identified referrals for suspected angle closure without other glaucoma-related findings (primary angle closure suspect (PACS) referrals). All patients underwent gonioscopy. The second audit (04-08/2019) identified patients with suspected angle closure in a virtual clinic. Management outcomes were assessed, using gonioscopy as reference standard. The outcomes of the second audit were re-audited after changing the triaging criterion from angle width <10° to iridotrabecular contact (ITC) in ≥1 quadrants on AS-OCT. RESULTS: Out of 1754 glaucoma referrals (first audit), 24.6% (431/1754) were PACS referrals. Of these, only 10.7% (42/393) had an occludable angle on gonioscopy, with 97.6% (41/42) being PACS. Of these, 78% (32/41) underwent laser peripheral iridotomy. Out of 137 referrals in the virtual clinic (second audit), 66.4% (91/137) were triaged to the face-to-face clinic. Of these, 31.9% (29/91) were discharged. AS-OCT had positive and negative predictive value of 74.3% (95% confidence intervals (CI) 57.8-86.0) and 82.1% (95% CI 70.0-90.2%), respectively, in detecting ITC in ≥1 quadrants. In the re-audit 45.9% (45/98) of those with suspected angle closure were triaged for gonioscopy, with 24.4% (11/45) of them being discharged. CONCLUSION: PACS referrals represent a substantial burden to hospital-based services and their accuracy is low. ITC in ≥1 quadrants on AS-OCT can be useful in triaging those who need further evaluation with gonioscopy.

European Glaucoma Society research priorities for glaucoma care.

BACKGROUND/AIMS: The goal of health research is to improve patients care and outcomes. Thus, it is essential that research addresses questions that are important to patients and clinicians. The aim of this study was to develop a list of priorities for glaucoma research involving stakeholders from different countries in Europe. METHODS: We used a three-phase method, including a two-round electronic Delphi survey and a workshop. The clinician and patient electronic surveys were conducted in parallel and independently. For phase I, the survey was distributed to patients from 27 European countries in 6 different languages, and to European Glaucoma Society members, ophthalmologists with expertise in glaucoma care, asking to name up to five research priorities. During phase II, participants were asked to rank the questions identified in phase I using a Likert scale. Phase III was a 1 day workshop with patients and clinicians. The purpose was to make decisions about the 10 most important research priorities using the top 20 priorities identified by patients and clinicians. RESULTS: In phase I, 308 patients and 150 clinicians were involved. In phase II, the highest-ranking priority for both patients and clinicians was 'treatments to restore vision'. In phase III, eight patients and four clinicians were involved. The top three priorities were 'treatments to stop sight loss', 'treatments to restore vision' and 'improved detection of worsening glaucoma'. CONCLUSION: We have developed a list of priorities for glaucoma research involving clinicians and patients from different European countries that will help guide research efforts and investment.

Association Between Dietary Salt Intake and Open Angle Glaucoma in the Thessaloniki Eye Study.

PRCIS: In the Thessaloniki Eye Study (TES) incidence phase population, frequent dietary salt intake was potentially associated with increased risk of open angle glaucoma in antihypertensive users. PURPOSE: The aim was to examine the association between dietary salt intake and glaucoma by antihypertensive use in the TES population. MATERIALS AND METHODS: The study population included TES incidence phase participants. Dietary salt intake frequency was assessed by self-report. Outcomes included prevalence of any open angle glaucoma (OAG), primary open angle glaucoma (POAG), and pseudoexfoliation (PEX). Covariates included demographics, cardiovascular disease, migraines, diabetes, steroid use, smoking, history of cataract surgery, central corneal thickness, intraocular pressure, blood pressure, and antihypertensive use. Logistic regression was used to examine associations between frequency of salt intake and glaucoma, controlling for covariates and stratified by antihypertensive use. RESULTS: The study included 1076 participants 80.5±4.4 years old, of whom 518 were female. There were 89/1076 (8.3%) participants with any OAG, 46/789 (5.8%) with POAG, and 287/1030 (27.9%) with PEX. In participants with antihypertensive use, frequent versus never salt intake was associated with increased risk of any OAG [adjusted odds ratio (aOR)=2.65, 95% confidence interval (CI)=1.12, 6.28; n=784] and POAG (aOR=3.59, 95% CI=1.16, 11.11; n=578) overall, and additionally in participants with diastolic blood pressure <90 mm Hg (aOR=2.42, 95% CI=1.00, 5.84; n=735) for OAG. There were no statistically significant adjusted associations between salt intake and PEX, or in participants without antihypertensive use. CONCLUSIONS: In TES participants assessed for OAG in the prevalence and incidence phases, frequent salt intake may be associated with increased OAG in those who take antihypertensive medication. Further investigation is needed of salt intake and glaucoma in hypertensive individuals.

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.

Factors associated with non-active retinal capillary density as measured with Confocal Scanning Laser Doppler Flowmetry in an elderly population: the Thessaloniki Eye Study (TES).

PURPOSE: To identify factors associated with retinal capillary density as measured with Confocal Scanning Laser Doppler Flowmetry (Heidelberg retina flowmeter (HRF)) in the Thessaloniki Eye Study (TES). METHODS: Participants of the TES (age ≥60 years, cross-sectional population-based study) were assessed for active capillary density in the superior and inferior peripapillary retina using the HRF. Pixel-by-pixel analysis was performed to quantify the percentage of zero flow pixels (ZFPs; surrogate for % retinal area with non-active capillaries). Multivariable regression analyses were performed to assess the association of non-active vascular density with ophthalmic and systemic variables. Glaucoma, late age-related macular degeneration and diabetic retinopathy subjects were excluded. RESULTS: 1189 subjects were included in the analysis. Older age (per year) was associated with higher percentage of ZFP in both the superior (slope estimate (SE)=0.0020) and the inferior (SE=0.0019) peripapillary retina (p<0.0001). History of migraine was associated with lower percentage of ZFP (SE=-0.0166) compared with no history of migraine in the superior peripapillary retina only (p<0.05). Higher intraocular pressure ((IOP) per mm Hg) and height (per cm) were associated with higher percentage of ZFP in the inferior peripapillary retina only (SE=0.0012, p<0.05 and SE=0.0005, p<0.05, respectively). The group consuming vegetables one to three times per week compared with the group consuming vegetables at least once a day had higher percentage of ZFP only in the inferior peripapillary retina (SE=0.0080, p<0.05). CONCLUSION: At a population level, our study revealed associations of older age, higher IOP and taller height with lower active retinal capillary density and of migraine with higher capillary density. Looking further into these associations may provide insight into disease mechanisms.

Twelve-Year Incidence and Baseline Risk Factors for Pseudoexfoliation: The Thessaloniki Eye Study (An American Ophthalmological Society Thesis).

PURPOSE: To determine the 12-year incidence of pseudoexfoliation (PEX), baseline risk factors for incident PEX and risk factors for incident pseudoexfoliative glaucoma (PEXG) among those with PEX in an elderly white population. METHODS: Longitudinal, population-based study in Thessaloniki, the major urban center in Northern Greece. The baseline cohort included 2554 participants ≥60 years old. The surviving cohort was re-examined 12 years later using the same methodology. PEX was defined as typical fibrillar material at the pupil margin and/or on the lens capsule. Glaucoma was defined as both structural and functional damage, irrespective of intraocular pressure (IOP). RESULTS: Of 1468 eligible subjects in the surviving cohort, 1092 (74%) participated in the follow-up study. The mean age ± standard deviation (SD) at baseline was 68.9 ± 4.6 years. The mean follow-up time was 11.6 ± 1.6 years. The 12-year incidence of PEX was 19.6% (95% confidence interval (CI), 17.1-22.2), with women more likely to be affected than men (Fisher's exact test, P = .0197). Higher axial length was associated with lower odds of incident PEX (odds ratio [OR], 0.72 per mm; 95% CI, 0.57-0.92). PEX at baseline was not associated with an increased likelihood of major vascular disease (P = .9038). Higher baseline IOP (OR, 1.26 per mm Hg; 95% CI, 1.07-1.48) and history of heart attack at baseline (OR, 13.49; 95% CI, 2.85-63.87) were associated with a greater likelihood of developing PEXG among those with PEX. A history of alcohol consumption at baseline was protective of individuals developing PEXG if they had PEX at baseline. CONCLUSION: This is one of the very few longitudinal population-based studies that has specifically assessed the incidence of PEX. The association with axial length was previously found only in a cross-sectional study. The associations with heart attack and alcohol consumption are new findings. In individuals with baseline PEX, higher IOP at baseline, history of heart attack at baseline, and no alcohol consumption were associated with a greater likelihood of developing glaucomatous damage approximately 12 years later. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Factors Associated With Retinal Vessel Diameters in an Elderly Population: the Thessaloniki Eye Study.

Purpose: To identify the factors associated with retinal vessel diameters in the population of the Thessaloniki Eye Study. Methods: Cross-sectional population-based study (age ≥ 60 years). Subjects with glaucoma, late age-related macular degeneration, and diabetic retinopathy were excluded from the analyses. Retinal vessel diameters were measured using the IVAN software, and measurements were summarized to central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and arteriole to venule ratio (AVR). Results: The analysis included 1614 subjects. The hypertensive group showed lower values of CRAE (P = 0.033) and AVR (P = 0.0351) compared to the normal blood pressure (BP) group. On the contrary, the group having normal BP under antihypertensive treatment did not have different values compared to the normal BP group. Diastolic BP (per mm Hg) was negatively associated with CRAE (P < 0.0001) and AVR (P < 0.0001), while systolic BP (per mm Hg) was positively associated with CRAE (P = 0.001) and AVR (P = 0.0096). Other factors significantly associated included age, sex, alcohol, smoking, cardiovascular disease history, ophthalmic medication, weight, and IOP; differences were observed in a stratified analysis based on BP medication use. Conclusions: Our study confirms previous reports about the association of age and BP with vessel diameters. The negative correlation between BP and CRAE seems to be guided by the effect of diastolic BP as higher systolic BP is independently associated with higher values of CRAE. The association of BP status with retinal vessel diameters is determined by diastolic BP status in our population. Multiple other factors are also independently associated with retinal vessel diameters.

Factors associated with undiagnosed open-angle glaucoma: the Thessaloniki Eye Study.

PURPOSE: To identify factors associated with undiagnosed open-angle glaucoma (OAG), primary open-angle glaucoma (POAG), and pseudoexfoliative glaucoma (PEXG) in an elderly population in Thessaloniki, Greece. DESIGN: Cross-sectional population-based study. METHODS: Randomly selected subjects > or =60 years (n = 2,554) participated in the study. Subjects were classified as having POAG or PEXG according to specific criteria and using a two-scale definition of glaucoma. Undiagnosed glaucoma was defined as absence of either prior diagnosis of glaucoma or ocular hypertension or prior medical treatment for glaucoma or prior glaucoma surgery. Logistic regression analyses were performed with age, gender, family history of glaucoma, history of cataract surgery, visual acuity, vertical cup-to-disk (C/D) ratio, intraocular pressure, Advanced Glaucoma Intervention Study visual field score, time since last eye doctor visit, and type of OAG as covariates. RESULTS: The prevalence of undiagnosed glaucoma was 57.1% (56/98) for POAG, significantly higher than the prevalence of 34.9% (15/43) for PEXG (P = .017). POAG patients presented three to four times increased risk to be undiagnosed compared with PEXG patients (P = .02 and P = .04, respectively). Patients with OAG who had not visited an ophthalmologist during the last year had six times an increased risk to be undiagnosed (P = .003). In POAG, smaller vertical C/D ratio was statistically significantly associated with an increased risk to be undiagnosed (P = .008). CONCLUSIONS: Lack of regular visits to an ophthalmologist was a major factor for undiagnosed OAG. POAG was more likely to be undiagnosed than PEXG. Since C/D ratio was associated with undiagnosed POAG, standardized protocols involving thorough evaluation of the optic disk are recommended for ophthalmologists.

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.

Prospective study of glaucoma referrals across Europe: are we using resources wisely?

BACKGROUND: To investigate the outcomes of glaucoma referrals across different European countries. METHODS: 250 patients newly referred to tertiary referral glaucoma specialist practices in the UK, Hungary, Slovenia, Italy and Greece were prospectively enrolled (50 consecutive patients per centre). Referral accuracy and predictive value of referral criteria for an intervention or further monitoring (positive predictive value) were analysed. RESULTS: Same-day discharges occurred in 43% (95% CI 39% to 75%) (12/28) of optometrist-initiated referrals (UK only), 37% (95% CI 30% to 45%) (59/158) of ophthalmologist-initiated referrals (all centres) and 54% (95% CI 40% to 68%) (26/48) of self-referrals (Hungary, Italy and Greece). The percentages from all referral sources were 46% (95% CI 32% to 60%) in the UK, 56% (95% CI 44% to 70%) in Hungary, 30% (95% CI 17% to 43%) in Slovenia, 22% (95% CI 11% to 34%) in Italy and 60% (95% CI 46% to 74%) in Greece (p<0.001). Overall, the referring criterion was confirmed in 54% (95% CI 45% to 63%) (64/119) for intraocular pressure (IOP) >21 mm Hg, 56% (95% CI 43% to 69%) (33/59) for a suspicious optic disc and 61% (95% CI 45% to 77%) (22/36) for a suspicious visual field, with large between-country differences (p<0.05 for all comparisons). Of all referrals, 32% (95% CI 26% to 37%) were initiated on the basis of IOP >21 mm Hg only. By combining the IOP criterion with any other referring criterion, the positive predictive value increased from 56% (95% CI 45% to 67%) to at least 89% (95% CI 68% to 100%). In the UK, a hypothetical IOP threshold of >26 mm Hg, as a requirement for IOP-only referrals, would reduce IOP-only referrals by 44%, while not missing any definite glaucoma cases. CONCLUSION: The accuracy of referrals was poor in the UK and the other countries. Requiring a combination of criteria and raising the IOP threshold for IOP-only referrals are needed to cut waste in clinical care.

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.

MicroRNA-related polymorphisms in pseudoexfoliation syndrome, pseudoexfoliative glaucoma, and primary open-angle glaucoma.

BACKGROUND: Pseudoexfoliation syndrome (PEX) and glaucoma (pseudoexfoliative glaucoma; PEXG, primary open-angle glaucoma; POAG) have mainly been studied for their associations with genes' polymorphisms. The purpose of this exploratory study was to investigate the role of polymorphisms in genes encoding for micro RNAs (miRNAs) and in genes related to miRNA biogenesis. MATERIAL AND METHODS: In the present genetic association study, ninety-two polymorphisms were investigated for their contribution to PEX (n = 203), PEXG (n = 38), and POAG (n = 40) pathogenesis compared to a control group (n = 188). The next generation sequencing (NGS) genotypic analysis revealed data for additional 28 variants. RESULTS: A protective association was found between PEX and polymorphism 11382316 (mir-3161) [odds ratio (OR) = 0.64, 95% confidence interval (CI): 0.47-0.86, p = 0.003], rs2155248 (mir-1304) [OR = 0.66, 95%CI: 0.47-0.94, p = 0.019], and rs28635903 (mir-1268a) [OR = 0.30, 95%CI: 0.10-0.94, p = 0.029]. Polymorphism rs113297757 (mir-3196) was associated with an increased risk of POAG [OR = 7.75, 95%CI: 2.13-28.76, p = 3 × 10-4]. Polymorphism rs1057035 (DICER) and rs55671916 (XPO5) in the 3'-UTR of genes related to miRNA biogenesis was associated with decreased risk of PEX [OR = 0.65, 95%CI: 0.46-0.92, p = 0.014] and increased risk of PEXG [OR = 2.84, 95%CI: 1.02-7.94, p = 0.038], respectively. The aforementioned associations according to the allelic model were further supported by the genotypic models of statistical analyses. CONCLUSIONS: This is the first study to report distinct associations of PEX, PEXG, and POAG in the same population with variants of genes involved in miRNA biogenesis and with miRNA genes' polymorphisms. Further studies in larger groups of patients of various origins are needed to confirm the reported preliminary results.

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.