Persistence, spatial distribution and implications for progression detection of blind parts of the visual field in glaucoma: A clinical cohort study

Background: Visual field testing is an essential part of glaucoma care. It is hampered by variability related to the disease itself, response errors and fatigue. In glaucoma, blind parts of the visual field contribute to the diagnosis but - once established - not to progression detection; they only increase testing time. The aims of this study were to describe the persistence and spatial distribution of blind test locations in standard automated perimetry in glaucoma and to explore how the omission of presumed blind test locations would affect progression detection. Methodology/Principal Findings: Data from 221 eyes of 221 patients from a cohort study with the Humphrey Field Analyzer with 30-2 grid were used. Patients were stratified according to baseline mean deviation (MD) in six strata of 5 dB width each. For one, two, three and four consecutive 0.1 for all strata). Omitting test locations with three consecutive <0 dB sensitivities at baseline did not affect the performance of the MD-based Nonparametric Progression Analysis progression detection algorithm. Conclusions/Significance: Test locations that have been shown to be reproducibly blind tend to display a reasonable blindness persistence and do no longer contribute to progression detection. There is no clinically useful universal MD cut-off value beyond which testing can be limited to 10 degree eccentricity

Influence of optic disc-fovea distance on macular thickness measurements with OCT in healthy myopic eyes

Assessment of macular thickness is important in the evaluation of various eye diseases. This study aimed to determine the influence of the optic disc-fovea distance (DFD) on macular thickness in myopic eyes. We determined the DFD and the macular thickness in 138 eyes from 138 healthy myopic subjects using the Cirrus HD-OCT. Correlation analysis and multiple linear regression were performed to determine the influence of DFD, axial length, disc area, and β-PPA on macular thickness. To further remove the confounding effect of ocular magnification on the DFD and OCT scan area, a subgroup analysis was performed in eyes with a limited axial length range (24-25 mm). DFD was significantly correlated with both regional (central, inner, and outer ETDRS subfields) and overall average macular thickness at a Bonferroni corrected P value of 0.004 (r ranging from-0.27 to-0.47), except for the temporal outer (r =-0.15, P = 0.089) and inferior outer (r =-0.22, P = 0.011) macular thickness. In the multivariable analysis, DFD was significantly associated with the average inner and outer macular thickness, the central subfield thickness, and the overall macular thickness (all P < 0.001), independent of ocular magnification and other covariates. Our findings indicate that eyes with a greater DFD have a lower macular thickness

In silico analysis of the molecular machinery underlying aqueous humor production: Potential implications for glaucoma

Background: The ciliary body epithelia (CBE) of the eye produce the aqueous humor (AH). The equilibrium between the AH production by the CBE and the outflow through the trabecular meshwork ultimately determines the intraocular pressure (IOP). An increased IOP is a major risk factor for primary open angle glaucoma (POAG). This study aims to elucidate the molecular machinery of the most important function of the CBE: the AH production and composition, and aims to find possible new molecular clues for POAG and AH production-lowering drugs.Methods: We performed a gene expression analysis of the non-pigmented (NPE) and pigmented epithelia (PE) of the human CBE of post mortem eyes. We used 44 k Agilent microarrays against a common reference design. Functional annotations were performed with the Ingenuity knowledge database.Results: We built a molecular model of AH production by combining previously published physiological data with our current genomic expression data. Next, we investigated molecular CBE transport features which might influence AH composition. These features included caveolin- and clathrin vesicle-mediated transport of large biomolecules, as well as a range of substrate specific transporters. The presence of these transporters implies that, for example, immunoglobins, thyroid hormone, prostaglandins, cholesterol and vitamins can be secreted by the CBE along with the AH. In silico, we predicted some of the molecular apical interactions between the NPE and PE, the side where the two folded epithelia face each other. Finally, we found high expression of seven POAG disease genes in the plasma membrane of extracellular space of the CBE, namely APOE, CAV1, COL8A2, EDNRA, FBN1, RFTN1 and TLR4 and we found possible new targets for AH lowering drugs in the AH.Conclusions: The CBE expresses many transporters, which account for AH production and/or composition. Some of these entries have also been associated with POAG. We hypothesize that the CBE may play a more prominent role than currently thought in the pathogenesis of POAG, for example by changing the composition of AH

Atherosclerosis, C-reactive protein, and risk for open-angle glaucoma: The Rotterdam Study

PURPOSE. To test the hypotheses that atherosclerosis and elevated serum C-reactive protein (CRP) levels are risk factors for open-angle glaucoma (OAG). METHODS. In a prospective, population-based cohort study, all participants 55 years and older and at risk for incident OAG underwent, at baseline (1990-1993) and at follow-up (1997-1999), the same ophthalmic examination, including visual field testing and optic disc photography. Baseline atherosclerosis was assessed by means of echography of the carotid arteries, abdominal x-ray examination, and ankle-arm index; baseline serum CRP levels were used in the analyses. The diagnosis of OAG was based on an algorithm using optic disc measures and visual field loss. Odds ratios of OAG were computed with logistic regression analyses. Risk factors were categorized in tenues and according to standard deviation. RESULTS. After a mean follow-up of 6.5 years, incident OAG was diagnosed in 87 of 3842 (2.3%) participants at risk for OAG. Carotid artery plaques, carotid intima-media thickness, aortic calcifications, ankle-arm index, and CRP levels were not significant risk factors for OAG. The odds ratio, given for the highest and lowest tertiles, for carotid plaques was 1.43 (95% confidence interval [CI], 0.68-2.99), for carotid intima-media thickness 0.86 (95% CI, 0.47-1.57), for aortic calcifications 1.02 (95% CI, 0.60-1.75), for ankle-arm index 0.69 (95% CI, 0.38-1.25), and for CRP 1.19 (95% CI, 0.68-2.07). CONCLUSIONS. In this prospective, population-based study, neither atherosclerosis nor serum CRP level was an important risk factor for OAG.

Incidence of glaucomatous visual field loss after two decades of follow-up: the Rotterdam Study

To determine the incidence of glaucomatous visual field loss (GVFL) two decades after the start of the Rotterdam Study, and to compare known risk factors for open-angle glaucoma (OAG) between different clinical manifestations of OAG. Of 6806 participants aged 55 years and older from the population-based Rotterdam Study, 3939 underwent visual field testing at baseline and at least one follow-up round. The ophthalmic examinations included optic disc assessment and measurements of intraocular pressure (IOP), refractive error, diastolic blood pressure (DBP), and height and weight. The incidence rate of GVFL was calculated. Associations with the risk factors age, gender, baseline IOP, family history, myopia, DBP, and body-mass index [BMI] were assessed using Cox regression, with different clinical manifestations of OAG as outcome measure (glaucomatous optic neuropathy (GON), GVFL, GVFL and GON, GVFL without GON, and GON without GVFL). Median follow-up was 11.1 (IQR 6.8–17.2; range 5.0–20.3) years. The incidence rate of GVFL was 2.9 (95% confidence interval 2.4–3.4) per 1000 person years (140 cas

Gene expression and functional annotation of the human and mouse choroid plexus epithelium

Background: The choroid plexus epithelium (CPE) is a lobed neuro-epithelial structure that forms the outer blood-brain barrier. The CPE protrudes into the brain ventricles and produces the cerebrospinal fluid (CSF), which is crucial for brain homeostasis. Malfunction of the CPE is possibly implicated in disorders like Alzheimer disease, hydrocephalus or glaucoma. To study human genetic diseases and potential new therapies, mouse models are widely used. This requires a detailed knowledge of similarities and differences in gene expression and functional annotation between the species. The aim of this study is to analyze and compare gene expression and functional annotation of healthy human and mouse CPE. Methods: We performed 44k Agilent microarray hybridizations with RNA derived from laser dissected healthy human and mouse CPE cells. We functionally annotated and compared the gene expression data of human and mouse CPE using the knowledge database Ingenuity. We searched for common and species specific gene expression patterns and function between human and mouse CPE. We also made a comparison with previously published CPE human and mouse gene expression data. Results: Overall, the human and mouse CPE transcriptomes are very similar. Their major functionalities included epithelial junctions, transport, energy production, neuro-endocrine signaling, as well as immunological, neurological and hematological functions and disorders. The mouse CPE presented two additional functions not found in the human CPE: carbohydrate metabolism and a more extensive list of (neural) developmental functions. We found three genes specifically expressed in the mouse CPE compared to human CPE, being ACE, PON1 and TRIM3 and no human specifically expressed CPE genes compared to mouse CPE. Conclusion: Human and mouse CPE transcriptomes are very similar, and display many common functionalities. Nonetheless, we also identified a few genes and pathways which suggest that the CPE between mouse and man differ with respect to transport and metabolic functions

Differences in clinical presentation of primary open-angle glaucoma between African and European populations

Purpose: Primary open-angle glaucoma (POAG) has been reported to occur more frequently in Africans, and to follow a more severe course compared to Europeans. We aimed to describe characteristics of POAG presentation and treatment across three ethnic groups from Africa and one from Europe. Methods: We ascertained 151 POAG patients from South African Coloured (SAC) and 94 South African Black (SAB) ethnicity from a university hospital in South Africa. In Tanzania, 310 patients were recruited from a university hospital and a referral hospital. In the Netherlands, 241 patients of European ancestry were included. All patients were over 35 years old and had undergone an extensive ophthalmic examination. Patients were diagnosed according to the ISGEO criteria. A biogeographic ancestry analysis was performed to estimate the proportion of genetic African ancestry (GAA). Results: The biogeographic ancestry analysis showed that the median proportion of GAA was 97.6% in Tanzanian, 100% in SAB, 34.2% in SAC and 1.5% in Dutch participants. Clinical characteristics at presentation for Tanzanians, SAB, SAC and Dutch participants, respectively: mean age: 63, 57, 66, 70 years (p < 0.001); visual acuity in the worse eye: 1.78, 1.78, 0.3, 0.3 LogMAR (p < 0.001); maximum intraocular pressure of both eyes: 36, 34, 29, 29 mmHg (panova < 0.001); maximum vertical cup to disc ratio (VCDR) of both eyes: 0.90, 0.90, 0.84, 0.83 (p < 0.001); mean central corneal thickness: 506, 487, 511, 528 μm (p < 0.001). Fourteen percent of Tanzanian patients presented with blindness (<3/60 Snellen) in the better eye in contrast to only 1% in the Dutch. Conclusion: In this multi-ethnic comparative study, Sub-Saharan Africans present at a younger age with lower visual acuity, higher IOP, larger VCDR, than SAC and Dutch participants. This indicates the more progressive and destructive course in Sub-Saharan Africans

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

Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future

Purpose Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. Design Meta-analysis of prevalence data. Participants A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. Methods AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). Main Outcome Measures Prevalence of early and late AMD, BCVA, and number of AMD cases. Results Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%–5.0%) in those aged 55–59 years to 17.6% (95%

Glaucoma screening during regular optician visits: The feasibility and specificity of screening in real life

Purpose: To determine the feasibility and specificity of glaucoma screening during regular optician visits. Methods: In four optician shops, glaucoma screening was offered to 400 consecutive visitors aged 45 years or above. If the visitor agreed to participate, an intraocular pressure measurement and - in those with a pressure below 25 mmHg - a frequency-doubling perimeter (FDT) C20-1 visual field screening test were performed. Those with an elevated pressure or at least one reproducibly abnormal test location on FDT were referred to our hospital. Results: Three-hundred and fifty-two of 400 consecutive visitors (88%) were screened. Fifteen of the unscreened visitors were not screened because they were already regularly checked by an ophthalmologist related to glaucoma. Forty-two of 352 screened participants (12%) were referred. Of these 42 referrals, seven were diagnosed with glaucoma, 10 were diagnosed with ocular hypertension (OHT), 12 did not have any eye disease, seven had an eye disease other than glaucoma or OHT that was diagnosed previously and six were newly diagnosed with an eye disease other than glaucoma or OHT. The specificity of the screening protocol was 91% (95% confidence interval 88-94%). Conclusions: Glaucoma screening at the optician shop was feasible, but the specificity of the screening protocol was rather low. With more stringent cut-off points (30 mmHg; at least two reproducibly abnormal test locations), the specificity could be improved to 96% (94-98%), apparently without a significant loss of sensitivity. This suggests that screening during regular optician visits might be a viable approach