Brian W. Fleck

National study of microphthalmia, anophthalmia, and coloboma (MAC) in Scotland: investigation of genetic aetiology

We report an epidemiological and genetic study attempting complete ascertainment of subjects with microphthalmia, anophthalmia, and coloboma (MAC) born in Scotland during a 16 year period beginning on 1 January 1981. A total of 198 cases were confirmed giving a minimum live birth prevalence of 19 per 100 000. One hundred and twenty-two MAC cases (61.6%) from 115 different families were clinically examined and detailed pregnancy, medical, and family histories obtained. A simple, rational, and apparently robust classification of the eye phenotype was developed based on the presence or absence of a defect in closure of the optic (choroidal) fissure. A total of 85/122 (69.7%) of cases had optic fissure closure defects (OFCD), 12/122 (9.8%) had non-OFCD, and 25/122 (20.5%) had defects that were unclassifiable owing to the severity of the corneal or anterior chamber abnormality. Segregation analysis assuming single and multiple incomplete ascertainment, respectively, returned a sib recurrence risk of 6% and 10% in the whole group and 8.1% and 13.3% in the OFCD subgroup. Significant recurrence risks were found in both unilateral and bilateral disease. In four families, one parent had an OFCD, two of which were new diagnoses in asymptomatic subjects. All recurrences in first degree relatives occurred in the OFCD group with a single first cousin recurrence seen in the non-OFCD group. A total of 84/122 of the MAC cases were screened for mutations in the coding regions of PAX6, CHX10, and SIX3. No pathogenic mutations were identified in the OFCD cases. A single PAX6 homeodomain missense mutation was identified in a subject with partial aniridia that had been initially misclassified as coloboma.

Transcutaneous oxygen levels in retinopathy of prematurity

Retinopathy of prematurity (ROP) is a potentially blinding disease of preterm infants. 21 days of computer-recorded transcutaneous oxygen (TcPO2) data were compared in 31 infants with stage 3 or greater ROP and 38 infants with no ROP or stage 1 or 2. In a multiple logistic regression adjusted for significant perinatal factors (birthweight, gestation, and intraventricular haemorrhage), babies with stage 3 or higher ROP showed an increased variability of TcPO2 in week 1 (p < 0.01) and 2 (p = 0.012) but not week 3. Variability of TcPO2 in the first 2 weeks of life is a significant predictor of severe ROP.

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

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

The epidemiology of rhegmatogenous retinal detachment: geographical variation and clinical associations.

Aims/Background Rhegmatogenous retinal detachment (RRD) is a potentially blinding condition. Obtaining an accurate estimate of RRD incidence in the population is essential in understanding the healthcare burden related to this disorder. Methods A systematic review of all population-based epidemiology studies of RRD published between January 1970 and January 2009 from Medline database searches was performed. Results RRD incidence demonstrates significant geographical variation and its incidence has been reported to be between 6.3 and 17.9 per 100 000 population. For studies with a sample size >300 the median annual incidence per 100 000 population was 10.5 (IQR 8.1–13.2) and the mean proportion of bilateral RRD was 7.26%. Overall, the mean prevalence of lattice degeneration was 45.7±20.3% and myopia was 47.28±12.59%. Conclusions Estimates of RRD incidence have varied threefold, but inclusion criteria and other design features have differed across studies making direct comparisons difficult. The overall incidence of RRD is not yet well established: more incidence studies of adequate methodology are needed to explore temporal changes in incidence. RRD incidence varies with ethnicity and is strongly associated with increasing age, myopia and certain vitreo-retinal degenerations. Due to changes in cataract surgery trends, the proportion of pseudophakic RRD presenting to specialised centres appears to be increasing.

Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10−8 for rs6445055), two on chromosome 9 (P = 2.80 × 10−11 for rs2472493 near ABCA1 and P = 6.39 × 10−11 for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10−11 for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.

Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10−8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10−11) and 8q12 (minimum p value 1.82×10−11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. “Replication-level” association was also seen between hyperopia and 12 of Kiefer et al.s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

The epidemiology and socioeconomic associations of retinal detachment in Scotland: a two-year prospective population-based study.

PURPOSE Rhegmatogenous retinal detachment (RRD) is a common ophthalmic emergency. Population-based data on primary RRD incidence has been variable, with large differences reported. This study is the first large-scale prospective examination of the incidence of primary RRD in the United Kingdom. METHODS The authors established a two-year prospective, population-based observational study recruiting all cases of primary RRD in Scotland. The annual incidence was calculated and analyzed in relation to age, sex, refractive error, and lens status. A national, population-based tool, the Scottish Index of Multiple Deprivation (SIMD), was used to examine the socioeconomic distribution of all incident cases. RESULTS A total of 1244 cases were identified during the study period from a population of 5,168,500 yielding an annual incidence of 12.05 per 100,000 population (95% confidence interval, 11.35-12.70). The age-specific incidence increased to a peak in both sexes in the 60- to 69-year age group. RRD was significantly more frequent in males than in females (14.70 vs. 8.75 per 100,000; P < 0.001). Of the cases without previous intraocular surgery, 53.2% were myopic, with a spherical equivalent refractive error > -1 D, 23.4% had undergone cataract surgery, and 10.4% had sustained traumatic injury. A strong association was found between RRD incidence and affluence, with a significant rising trend across quintiles of deprivation. CONCLUSIONS The estimated annual incidence of primary RRD in Scotland is 12.05 per 100,000. Based on this estimate, there are approximately 7300 new cases annually in the United Kingdom. RRD incidence increases with age, is more common in men and right eyes, and is strongly associated with affluence.

The Predisposing Pathology and Clinical Characteristics in the Scottish Retinal Detachment Study

PURPOSE To describe the predisposing pathology and clinical features of all incident cases of rhegmatogenous retinal detachment (RRD) recruited in Scotland during a 2-year period. DESIGN Prospective surveillance study of incident cases of RRD. PARTICIPANTS All incident cases of RRD recruited as part of the Scottish Retinal Detachment Study. METHODS During a 2-year period, we coordinated a comprehensive system in which every case of primary RRD presenting to 1 of 6 vitreoretinal surgical sites in Scotland was examined and approached for study inclusion. MAIN OUTCOME MEASURES Rhegmatogenous retinal detachment incidence, predisposing features, and clinical characteristics. RESULTS A total of 1202 cases were recruited. Detailed clinical information was available on 1130 (94%) of cases. By causative break, the proportions of RRD were horseshoe tear (HST) associated with posterior vitreous detachment (PVD) in 86.2%, giant retinal tear (GRT) and PVD in 1.3%, non-PVD round hole (RH) in 4.9%, retinal dialysis in 5.9%, and retinoschisis RRD in 1.6%. One in 10 cases reported significant ocular trauma. One in 5 cases were pseudophakic. Round hole RRD more frequently presented with multiple retinal breaks compared with HST RRD (67.8% vs. 48.7%; P = 0.003). In PVD-associated RRD, 56.1% (95% confidence interval [CI], 53.8-58.3) of breaks were identified in the superotemporal retina. In non-PVD RRD, 54.6% (95% CI, 47.9-61.1) of breaks were inferotemporal, followed by superotemporal in 34.9% (95% CI, 28.7-41.5). Lattice degeneration was present in 18.7% of affected eyes and more common in RH RRD (35.7%) than in HST RRD (19.3%) (P = 0.003). Seven percent reported an affected first-degree relative, and these cases were significantly more myopic than nonfamilial cases. CONCLUSIONS More than 85% of RRD cases are associated with PVD and related tractional tears. Non-PVD RH RRD occurred in younger and more myopic individuals. The majority of cases are caused by more than 1 retinal break, and the macula is affected in more than 50% at presentation. Ocular trauma, previous cataract surgery, family history, and lattice degeneration are important predisposing features.

Wide-field digital retinal imaging versus binocular indirect ophthalmoscopy for retinopathy of prematurity screening: a two-observer prospective, randomised comparison

Aim: To compare the diagnostic accuracy of wide-field digital retinal imaging (WFDRI) with the current “gold standard” of binocular indirect ophthalmoscopy (BIO) for retinopathy of prematurity (ROP) screening examinations. Methods: A consecutive series of premature infants undergoing ROP screening at Edinburgh Royal Infirmary were eligible for recruitment into this prospective, randomised, comparative study. Infants were screened using both WFDRI (Retcam II with neonatal lens) and BIO by two paediatric ophthalmologists who were randomised to the examination technique. Both examiners documented their clinical findings and management plans in a masked fashion. WFDRI eye findings were compared with those of BIO. Results: A total of 81 infants were recruited, and information from 245 eye examinations was analysed. The sensitivity of WFDRI in detecting any stage of ROP, stage 3 ROP and “plus” disease was 60%, 57% and 80%, respectively, and specificity 91%, 98% and 98%, respectively. The proportional agreement between WFDRI and BIO was 0.96 for detecting stage 3 disease and 0.97 for detecting “plus” disease. There was very good agreement on management decisions (kappa 0.85). Conclusion: When used in a routine ROP screening setting, a randomised comparison of WFDRI and BIO, WFDRI showed relatively poor sensitivity in detecting mild forms of ROP in the retinal periphery. This resulted in difficulty in making decisions to discharge infants from the screening programme. Sensitivity was better for more severe forms of ROP, but at present WFDRI should be regarded as an adjunct to, rather than a replacement for, BIO in routine ROP screening.

Pathogenesis of rhegmatogenous retinal detachment: predisposing anatomy and cell biology

Background: The pathogenesis of rhegmatogenous retinal detachment is complex, and our knowledge of the exact mechanism of vitreoretinal attachment and detachment remains incomplete. Methods: We performed a Medline, Ovid, and EMBASE search using search words rhegmatogenous, retinal detachment, vitreous, and retinal adhesion. All appropriate articles were reviewed, and the evidence was compiled. Results: Cortical vitreous contains fibrillar collagens type II, V/XI, and IX. The inner limiting membrane of the retina contains collagens type I, IV, VI, and XVIII as well as numerous other glycoproteins and potential adhesion molecules. The distribution and age-related changes in the structure of these molecules play an important role in the formation of a retinal break, which may compromise and disrupt the normal mechanisms of neurosensory retinal adhesion. Conclusion: Rhegmatogenous retinal detachment development is intimately related to changes in the fibrillar structure of the aging vitreous culminating in posterior vitreous detachment with regions of persistent and tangential vitreoretinal traction predisposing to retinal tear formation. A complex interplay of factors such as weakening of vitreoretinal adhesion, posterior migration of the vitreous base, and molecular changes at the vitreoretinal interface are important in predisposing to focal areas of vitreoretinal traction precipitating rhegmatogenous retinal detachment. Once formed, the passage of liquefied vitreous through a retinal break may overwhelm normal neurosensory-retinal pigment epithelium adhesion perpetuating and extending detachment and causing visual loss. To understand the molecular events underlying rhegmatogenous retinal detachment so that new therapies can be developed, it is important to appreciate the structural organization of the vitreous, the biology underlying vitreous liquefaction and posterior vitreous detachment, and the mechanisms of vitreoretinal attachment and detachment.