Theofanis Pappas

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.

A 45-year-old man presented with clinical manifestations of foveomacular retinitis, including visual symptoms and foveal lesions characteristic of solar retinopathy, but repeated questions failed to elicit a history of sun gazing. Cross-sectional retinal images produced by optical coherence tomography revealed localized loss of retinal pigment epithelium cells in both eyes. A different pattern of reflectivity at the level of the photoreceptor layer was observed between the right and left eye, reflecting asymmetry in tissue damage. This case is described to provide additional evidence that solar retinopathy and foveomacular retinitis are the same entity and may also have common optical coherence tomography findings.

To assess the overdiagnosis of open-angle glaucoma (OAG) and to investigate associated factors. 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. 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 ...

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10(-14)) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10(-8)). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the patholo...

To estimate the age- and gender-specific prevalence of age-related macular degeneration (AMD) in a population-based sample of subjects 60 years of age or older in Thessaloniki, Greece. Cross-sectional population-based study. A total of 2554 subjects randomly identified from municipality registers in Thessaloniki underwent a complete ophthalmologic examination. Of the 3617 eligible subjects, 2554 (71%) participants completed a clinical examination. The prevalence was 2.5% for AMD, 1.4% for neovascular (NV) AMD, and 1.3% for geographic atrophy (GA). Bilateral AMD was present in 40% of AMD cases. The prevalence of AMD, NV, GA, and bilateral AMD increased with increasing age (P< .0001). No gender-specific statistically significant differences were noted. Of all participants with AMD, 67% were unaware of the diagnosis. The prevalence of AMD in Greece is comparable to that in other Caucasian populations. A dramatic increase in prevalence in people older than 80 years of age was observed.

To compare Heidelberg Retina Tomograph (HRT) optic disc parameters and structure-function correlation between primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma (PEXG). Prospective, observation case series. 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. 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. 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.

To report on the prevalence of pseudoexfoliation (PEX) and its association with ophthalmic characteristics and systemic diseases in a well-defined population. The Thessaloniki Eye study is a cross-sectional population-based study of chronic eye diseases in Thessaloniki, Greece. Participants with PEX were identified by clinical examination and were compared with those without PEX with regards to ophthalmic characteristics and systemic diseases, after adjusting for age and sex. PEX was found in 11.9% of the 2261 clinic-visit participants. Participants with PEX, compared with those without, had higher intraocular pressure, larger vertical cup-to-disc ratio, and higher percentage with vertical cup-to-disc ratio asymmetry and optic disc damage. The proportion with glaucoma among pseudoexfoliative participants (15.2%) was higher than that for glaucoma among nonpseudoexfoliative participants (4.7%). After excluding glaucoma participants, the only difference was the 0.6 mm Hg higher intraocular pressure in participants with PEX. Compared with nonpseudoexfoliative eyes, the presence of PEX on iris only or on both iris and lens was associated with higher intraocular pressure, whereas the presence of PEX on lens only was not. PEX was not associated with any systemic disease. The prevalence of PEX in Greece is relatively high compared with other white populations. PEX was associated with higher intraocular pressure and higher percentage with optic disc damage, secondary to the higher proportion with glaucoma among pseudoexfoliative participants than among nonpseudoexfoliative participants. In nonglaucoma participants, eyes with PEX had only slightly higher intraocular pressure, but this was not observed in eyes with PEX on lens only.

To investigate the association of antihypertensive medications with optic disc structure by blood pressure (BP) level, in nonglaucoma subjects. Cross-sectional, population-based study. A subset of Thessaloniki Eye Study participants was included in this study. Subjects were interviewed for medical history and underwent extensive ophthalmic examination, BP measurement, and optic disc imaging with the Heidelberg retinal tomograph. Subjects treated for hypertension were grouped in the following groups: (1) angiotensin-converting enzyme inhibitors and/or angiotensin-receptor blockers; (2) beta blockers and/or calcium-channel blockers; (3) diuretics alone or combined with others; and (4) other combinations. Cup size and cup-to-disc (C/D) ratio in the above groups were compared with the untreated group, using regression models. Analyses were rerun for subjects with systolic BP (SBP)<140 mm Hg, SBP≥140 mm Hg, diastolic BP (DBP)<90 mm Hg, and DBP≥90 mm Hg. Among 232 subjects, 131 were receiving antihypertensive medications. In subjects with DBP<90 mm Hg, all medications groups were associated with larger cup size and higher C/D ratio compared with the untreated group. Results were similar in subjects with SBP<140 mm Hg, with the exception of the beta blockers and/or calcium-channel blockers group. None of the medications groups were associated with the Heidelberg retinal tomograph parameters in those with DBP≥90 mm Hg or SBP≥140 mm Hg. All classes of antihypertensive medications were associated with larger cup size and higher C/D ratio in subjects with either DBP<90 mm Hg or SBP<140 mm Hg. These results suggest that there is no specific medication-related effect on optic disc structure, and the associations found are mediated through the hypotensive effect of antihypertensive medications.

To report on the prevalence of pseudoexfoliation (PEX) and its association with ophthalmic characteristics and systemic diseases in a well-defined population. The Thessaloniki Eye study is a cross-sectional population-based study of chronic eye diseases in Thessaloniki, Greece. Participants with PEX were identified by clinical examination and were compared with those without PEX with regards to ophthalmic characteristics and systemic diseases, after adjusting for age and sex. PEX was found in 11.9% of the 2261 clinic-visit participants. Participants with PEX, compared with those without, had higher intraocular pressure, larger vertical cup-to-disc ratio, and higher percentage with vertical cup-to-disc ratio asymmetry and optic disc damage. The proportion with glaucoma among pseudoexfoliative participants (15.2%) was higher than that for glaucoma among nonpseudoexfoliative participants (4.7%). After excluding glaucoma participants, the only difference was the 0.6 mm Hg higher intraocular pressure in participants with PEX. Compared with nonpseudoexfoliative eyes, the presence of PEX on iris only or on both iris and lens was associated with higher intraocular pressure, whereas the presence of PEX on lens only was not. PEX was not associated with any systemic disease. The prevalence of PEX in Greece is relatively high compared with other white populations. PEX was associated with higher intraocular pressure and higher percentage with optic disc damage, secondary to the higher proportion with glaucoma among pseudoexfoliative participants than among nonpseudoexfoliative participants. In nonglaucoma participants, eyes with PEX had only slightly higher intraocular pressure, but this was not observed in eyes with PEX on lens only.

A 45-year-old man presented with clinical manifestations of foveomacular retinitis, including visual symptoms and foveal lesions characteristic of solar retinopathy, but repeated questions failed to elicit a history of sun gazing. Cross-sectional retinal images produced ...

To explore the association of two single nucleotide polymorphisms (SNPs) in the CX3CR1 gene with grades of age-related macular degeneration (AMD) in a population-based setting. The Thessaloniki Eye study is a cross-sectional population-based epidemiologic study of chronic eye diseases in Thessaloniki, Greece. A total of 371 subjects were included and classified according to their AMD status. Subjects with AMD Grades 0-1 (n = 188) were compared to those with AMD Grades 2-3 (n = 138), to those with AMD Grade 4 (geographic atrophy) (n = 20) and to those with AMD Grade 5 (neovascular AMD) (n = 25) with regard to the presence of CX3CR1 polymorphisms (V249I and T280M). Polychotomous logistic regression analysis adjusted for age, gender, and smoking was conducted and the log-additive allelic model was preferred. Participants with AMD Grade 4 were approximately three times more likely to carry the VI249 and nine times more likely to carry the II249 alleles, compared to those with AMD Grades 0-1, whereas those with AMD Grades 2-3 or Grade 5 did not differ. The T280M polymorphism was not associated with either AMD Grades 2-3 or AMD Grades 4 or 5. In this Greek population, after adjusting for known risk factors, increased risk of geographic atrophy (GA) AMD among the carriers of the V249I polymorphism in the CX3CR1 gene was found. Our study failed to reveal any association with the T280M polymorphism reported in previous studies. Additional studies in different ethnic populations using standardized methodology are needed in order to confirm this association.

PurposeSingle nucleotide polymorphisms (SNPs) within the lysyl oxidase like-1 gene (LOXL1; rs1048661 and rs3825942) were found to confer risk to pseudoexfoliation glaucoma (XFG) through the pseudoexfoliation syndrome (XFS) in Nordic, Caucasian, and two Asiatic populations (Indian and Japanese). The prevalence (0.2%–0.7%) of XFS in the Chinese is considerably lower compared to Nordic populations. The aim of this study was to determine the association of LOXL1 in Chinese subjects with XFS/XFG.MethodsChinese subjects with clinically diagnosed XFS/XFG and normal controls were recruited. Genomic DNA was extracted, and the two LOXL1 SNPs (rs1048661 and rs3825942) were genotyped by bidirectional sequencing. Allele and genotype frequencies were compared between cases and unrelated controls using PLINK. Linkage disequilibrium (LD) calculations and haplotype association analysis were done using the Haploview package and WHAP package, respectively.ResultsSixty-two Chinese patients (17 XFG and 45 XFS) and 171 Chinese controls were studied. The G allele of LOXL1 SNP rs3825942 was moderately associated (OR=10.97, p=0.0018) with pseudoxfoliation in the Chinese. The frequency of the G allele of rs1048661 was not significantly different in cases compared to controls (p=0.142) in the allelic association test. However, the genotype test showed marginal association for rs1048661 (p=0.030). Only three haplotypes were observed (T-G, G-G, and G-A) with G-G as a risk haplotype (p=0.0034) and G-A as a protective haplotype (p=0.00039). T-G, which was a risk haplotype in the Japanese, was not associated with XFG in the Chinese (p=0.124).ConclusionsPolymorphisms in LOXL1 confer risk to XFS/XFG in the Chinese. The lower incidence of XFS compared to other populations suggests additional genetic or environmental factors to have a major influence on the phenotypic expression of XFS in the Chinese. The G allele of rs3825942 has been shown to be associated with XFS/XFG in all populations studied to date.

The surgical patients had a mean diurnal IOP of 12.1±2.2 versus 13.5±2.0 mmHg for the matched medically treated patients (P = 0.0001). The average maximum IOP for the surgical group was 13.4±2.3 and 16.3±3.2 mm Hg for the medical group (P<0.0001). The 24-hour range of ...

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). Cross-sectional, population-based study. 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. 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. 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.

To study the association of blood pressure (BP) status on the optic disk structure as measured with the Heidelberg Retina Tomograph (HRT) in people without glaucoma. Cross-sectional population-based setting study. Consecutive participants in the Thessaloniki Eye Study were included in this study. HRT images of the optic disk and BP measurements were taken. Hypertension was defined as a systolic BP (SBP) > or =140 mm Hg, diastolic BP (DBP) >/=90 mm Hg, or both. Subjects were classified in three groups by SBP and DBP. The Kruskal-Wallis test was used to compare the three groups with respect to the HRT parameters. Regression models adjusted for age, gender, height, disk size, intraocular pressure, cardiovascular disease, diabetes, and duration of antihypertensive treatment were used for each HRT parameter to compare values among the different groups. The P value was considered significant at <.05. A total of 232 subjects were included in the analysis. Rim area was significantly different among groups when DBP was considered as the criterion to classify subjects (P = .005). In regression models, cup area, and cup-to-disk (c/d) ratio were increased in subjects with normal DBP that was the result of treatment, as compared with both the high DBP and untreated normal DBP groups. In patients without glaucoma, the DBP <90 mm Hg that results from antihypertensive treatment is associated with increased cupping and decreased rim area of the optic disk. This information should be considered in research aiming to define the role of the BP status as an independent factor initiating optic disk changes and/or as a contributing factor to glaucoma damage.

To explore the association of two single nucleotide polymorphisms (SNPs) in the CX3CR1 gene with grades of age-related macular degeneration (AMD) in a population-based setting. The Thessaloniki Eye study is a cross-sectional population-based epidemiologic study of chronic eye diseases in Thessaloniki, Greece. A total of 371 subjects were included and classified according to their AMD status. Subjects with AMD Grades 0-1 (n = 188) were compared to those with AMD Grades 2-3 (n = 138), to those with AMD Grade 4 (geographic atrophy) (n = 20) and to those with AMD Grade 5 (neovascular AMD) (n = 25) with regard to the presence of CX3CR1 polymorphisms (V249I and T280M). Polychotomous logistic regression analysis adjusted for age, gender, and smoking was conducted and the log-additive allelic model was preferred. Participants with AMD Grade 4 were approximately three times more likely to carry the VI249 and nine times more likely to carry the II249 alleles, compared to those with AMD Grades 0-1, whereas those with AMD Grades 2-3 or Grade 5 did not differ. The T280M polymorphism was not associated with either AMD Grades 2-3 or AMD Grades 4 or 5. In this Greek population, after adjusting for known risk factors, increased risk of geographic atrophy (GA) AMD among the carriers of the V249I polymorphism in the CX3CR1 gene was found. Our study failed to reveal any association with the T280M polymorphism reported in previous studies. Additional studies in different ethnic populations using standardized methodology are needed in order to confirm this association.

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. 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. 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. 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.