Strategies for improving early detection and diagnosis of neovascular age-related macular degeneration

Treatment of the neovascular form of age-related macular degeneration (AMD) has been revolutionized by the introduction of such agents as ranibizumab, bevacizumab, and aflibercept. As a result, the incidence of legal blindness occurring secondary to AMD has fallen dramatically in recent years in many countries. While these agents have undoubtedly been successful in reducing visual impairment and blindness, patients with neovascular AMD typically lose some vision over time, and often lose the ability to read, drive, or perform other important activities of daily living. Efforts are therefore under way to develop strategies that allow for earlier detection and treatment of this disease. In this review, we begin by providing an overview of the rationale for, and the benefits of, early detection and treatment of neovascular AMD. To achieve this, we begin by providing an overview of the pathophysiology and natural history of choroidal neovascularization, before reviewing the evidence from both clinical trials and "real-world" outcome studies. We continue by highlighting an area that is often overlooked: the importance of patient education and awareness for early AMD detection. We conclude the review by reviewing an array of both established and emerging technologies for early detection of choroidal neovascularization, ranging from Amsler chart testing, to hyperacuity testing, to advanced imaging techniques, such as optical coherence tomography

Frequency and Distribution of Refractive Error in Adult Life: Methodology and Findings of the UK Biobank Study

PURPOSE: To report the methodology and findings of a large scale investigation of burden and distribution of refractive error, from a contemporary and ethnically diverse study of health and disease in adults, in the UK.METHODS:U K Biobank, a unique contemporary resource for the study of health and disease, recruited more than half a million people aged 40-69 years. A subsample of 107,452 subjects undertook an enhanced ophthalmic examination which provided autorefraction data (a measure of refractive error). Refractive error status was categorised using the mean spherical equivalent refraction measure. Information on socio-demographic factors (age, gender, ethnicity, educational qualifications and accommodation tenure) was reported at the time of recruitment by questionnaire and face-to-face interview.RESULTS: Fifty four percent of participants aged 40-69 years had refractive error. Specifically 27% had myopia (4% high myopia), which was more common amongst younger people, those of higher socio-economic status, higher educational attainment, or of White or Chinese ethnicity. The frequency of hypermetropia increased with age (7% at 40-44 years increasing to 46% at 65-69 years), was higher in women and its severity was associated with ethnicity (moderate or high hypermetropia at least 30% less likely in non-White ethnic groups compared to White).CONCLUSIONS: Refractive error is a significant public health issue for the UK and this study provides contemporary data on adults for planning services, health economic modelling and monitoring of secular trends. Further investigation of risk factors is necessary to inform strategies for prevention. There is scope to do this through the planned longitudinal extension of the UK Biobank study

Automated quantification of retinal vessel morphometry in the UK Biobank Cohort

The following topics are dealt with: feature extraction; learning (artificial intelligence); image classification; image segmentation; computer vision; object detection; feedforward neural nets; image colour analysis; image representation; medical image processing

Suitability of UK biobank retinal images for automatic analysis of morphometric properties of the vasculature

To assess the suitability of retinal images held in the UK Biobank--the largest retinal data repository in a prospective population-based cohort--for computer assisted vascular morphometry, generating measures that are commonly investigated as candidate biomarkers of systemic disease.Non-mydriatic fundus images from both eyes of 2,690 participants--people with a self-reported history of myocardial infarction (n=1,345) and a matched control group (n=1,345)--were analysed using VAMPIRE software. These images were drawn from those of 68,554 UK Biobank participants who underwent retinal imaging at recruitment. Four operators were trained in the use of the software to measure retinal vascular tortuosity and bifurcation geometry.Total operator time was approximately 360 hours (4 minutes per image). 2,252 (84%) of participants had at least one image of sufficient quality for the software to process, i.e. there was sufficient detection of retinal vessels in the image by the software to attempt the measurement of the target parameters. 1,604 (60%) of participants had an image of at least one eye that was adequately analysed by the software, i.e. the measurement protocol was successfully completed. Increasing age was associated with a reduced proportion of images that could be processed (p=0.0004) and analysed (p<0.0001). Cases exhibited more acute arteriolar branching angles (p=0.02) as well as lower arteriolar and venular tortuosity (p<0.0001).A proportion of the retinal images in UK Biobank are of insufficient quality for automated analysis. However, the large size of the UK Biobank means that tens of thousands of images are available and suitable for computational analysis. Parametric information measured from the retinas of participants with suspected cardiovascular disease was significantly different to that measured from a matched control group

Fixed bimonthly aflibercept in naïve and switched neovascular age related macular degeneration patients: 1 year outcomes

Aim: To determine real life clinical outcomes in poorly responsive and treatment-naïve neovascular age related macular degeneration (nvAMD) patients using bi-monthly fixed dosing aflibercept regimen.Methods: This was a retrospective study of 165 eyes with nvAMD started on aflibercept at Southampton Eye Unit between June 2013 and June 2014. Patients were either switched from pro re nata (PRN) ranibizumab/bevacizumab due to poor response (107 eyes), or treatment-naïve (58 eyes). Patients received 3 initial monthly intravitreal aflibercept injections followed by 2-monthly fixed doses. Clinic visits were scheduled at months 0, 4, 10 and 12. Mean change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline were assessed using the Wilcoxon signed-rank test. The proportion of patients maintaining BCVA (&lt;15 letters loss) at 12 months was also evaluated.Results: Mean BCVA change at month 12 was +3.29 and +4.67 letters in the switched and naïve aflibercept groups respectively (p&lt;0.01). BCVA was maintained in 95.3% of switched and 96.6% of naïve patients. CRT at month 12 showed a decrease of -6.16µm in the switched group and -35.36µm decrease in the naïve group (p&lt;0.01). Patients previously treated with ranibizumab/bevacizumab had on average received 7.4 ranibizumab/bevacizumab injections over 12.6 months, attending 10 clinic visits. The fixed dosing aflibercept regimen required an average of 7.13 injections (naïve group), 7.5 injections (switched group) and 4 clinic visits per year.Conclusion: Fixed bimonthly aflibercept is effective in both treatment-naïve and poorly responsive nvAMD patients. Adopting a fixed dosing regimen can reduce patient burden without compromising on outcomes

Fine-scale linkage disequilibrium mapping of age-related macular degeneration in the complement factor H gene region

Aim: To present results from a nested association study of the complement factor H (CFH) gene region using a novel methodology that uses a high-resolution genetic linkage disequilibrium map to estimate a point location for a causal mutation. Method: Age-related macular degeneration (AMD) case–control data from a genomewide single-nucleotide polymorphism (SNP) panel were used to identify the target interval to be genotyped at higher density in a second independent panel. The pattern of linkage disequilibrium (LD) and segmental duplications across this region are described in detail. Result: Data were consistent with other studies in that strong association between the Y402H variant and AMD is observed. However, composite likelihood analysis, which combines association data from all SNPs in the region, and uses genetic locations on a high-resolution LD map, gave a point location for a causal variant between exons 1 and 2 of the CFH gene. Conclusion: The findings are consistent with evidence that, in addition to the widely described Y402H variant, there is at least one and, most probably, several other mutations in the CFH gene which determine disease manifestation in AMD. A genetic model in which multiple mutations contribute to a varying degree to disease aetiology has been previously well described in ophthalmic genetics, and is typified by the COL2A1 and ABCA4 genes

Shorter axial length and increased astigmatic refractive error are associated with socio-economic deprivation in an adult UK cohort

Purpose: to evaluate whether socio-economic deprivation is associated with ocular axial length and refractive error in a British cohort.Methods: the study population consisted of 7,652 individuals who provided data to the prospective cataract database at Portsmouth Eye unit, UK over a 4 year period (January 2004 to June 2008). Indices of multiple deprivation (IMD) scores measuring both social and economic domains for each patient’s locality were calculated. The association of these measures of deprivation with axial length and refractive error (astigmatic and spherical) were evaluated using regression analyses after adjusting for age and sex.Results: socio-economically deprived areas (higher IMD scores) were inversely associated with axial lengths and astigmatic refraction. After controlling for age and sex, an inverse linear association was observed between axial length and IMD scores (-0.24mm in highest quintile compared to lowest; 95% confidence intervals: -0.33 to -0.15) and between astigmatic refraction and IMD scores (-0.12 dioptres in highest quintile compared to lowest; 95% confidence intervals: -0.21 to -0.03). There was no association between spherical refraction and IMD scores.Conclusions: axial length and astigmatic refraction were inversely associated with socio-economic deprivation in this population. Identification of the environmental exposures involved may identify reversible risk factors for impaired vision<br/

A mouse model to study Aβ-driven pathology in the ageing retina

Purpose : The Alzheimer’s-linked Amyloid beta (Aβ) peptide is reported to be deposited in aged retinas. Aβ has been implicated in key stages of Age-related Macular Degeneration (AMD), yet its role remains poorly understood. Here we employ a mouse model to study the in-vivo effects of Aβ to delineate its mechanisms of action and to understand how Aβ triggers/drives retinal pathology with age. Methods : Aβ was characterised by negative stain TEM and immunogold labelling. C57BL/6 mice were subretinally injected with 3µL of oligomeric Aβ1-42 (625nM, n=5) or vehicle control (n=3). At 8 days post-injection eyes were enucleated, OCT-embedded and cryosectioned at 16µM intervals for histological analysis. H&amp;E staining and confocal immunofluorescence analysed retinal morphology in response to Aβ exposure and reported Aβ localisation. Exclusion criteria included a 200µM radius from the injection site to omit areas of mechanical trauma. Morphometric analysis was performed blind using OlyVIA and ImageJ. Data is expressed as means ± SEM with a statistical significance of *P ≤ 0.05. Results : TEM and Dot Blot assay enabled us to identify a window in which Aβ is reported to be most toxic. Fundus images showed large areas of pathology in Aβ exposed mice (9582 ± 4831) compared to controls (48.33 ± 8.97) which were indistinguishable from non-injected littermates, p=0.12. Serial line scans of Aβ injected mice revealed a 2-fold increase in RPE hypopigmentation associated with photoreceptor outer segment (POS) loss, RPE disorganisation and RPE hypertrophy compared to controls. Similarly, confocal data showed POS and inner segment disorganisation compared to well-preserved retinal architecture in control retinas. Aβ was detected in multiple retinal locations including POS, the RPE/choroid interface and the outer and inner plexiform layers. Conclusions : Our findings demonstrate that subretinal Aβ injections faithfully recapitulate key features of early AMD including dysfunctional RPE and damaged photoreceptors. Critically, we found no obvious indication of apoptosis or disruption of the blood-retinal barrier indicating gradual cellular impairment over time. Previously published literature showing static images of Abeta in human post-mortem eyes tantalisingly correlates the presence of Aβ with high drusen-loads and AMD. Our model therefore represents a powerful tool to investigate the dynamic nature of Aβ-mediated pathology in living retinas

Impact of graft thickness on visual acuity after Descemet's stripping endothelial keratoplasty

ObjectiveTo evaluate the relationship, over time, between central graft thickness and visual acuity following Descemet’s stripping endothelial keratoplasty (DSEK). MethodsA retrospective analysis of 70 consecutive cases of DSEK. All donor lenticules were dissected manually. Serial postoperative measurements of central graft and total corneal thicknesses were made using anterior segment optical coherence tomography. Visual acuity, refraction and patient demographics were collected from case notes. The correlation between central graft thickness and visual acuity at serial time points was calculated.ResultsThe median age at surgery was 75 years (lower quartile (LQ) 66, upper quartile (UQ) 83, range 36e90 years). Nineteen eyes were excluded from statistical analysis, leaving 51 eyes of 46 patients remaining. Last follow-up occurred a median of 12 months postoperatively (LQ 6, UQ 23, range 4e38 months). The median preoperative visual acuity was 0.71 logarithm of the minimum angle of resolution (logMAR), improving to 0.34 logMAR postoperatively (p&lt;0.001, n¼43). Median graft thickness decreased from 209 mm at day 1 to 142 mm at last follow-up (p&lt;0.001). No statistically significant correlation was found between central total corneal thickness and visual acuity at any time point. Except for a single time point, no statistically significant correlation was found between central graft thickness and visual acuity.ConclusionThere is no clear association between central graft, or total corneal, thickness and visual acuity following DSEK

Association of HLA class I and class II polymorphisms with age-related macular degeneration

PURPOSE: To evaluate whether HLA genotypes are associated with age-related macular degeneration (AMD). METHODS: HLA class I-A, -B, and -Cw and class II DRB1 and DQB1 principal allele groups were genotyped in two stages: initially for principal allele groups in a cohort of 100 AMD cases and 92 control subjects, and then, in the next 100 cases and controls from the same cohort, for alleles or allele groups with P &lt; 0.1 on initial typing. Genotype frequencies were compared by 2 x 2 contingency tables. The strongest associations for individual HLA alleles were calculated with two-locus stratification analysis and logistic regression for all possible pair-wise HLA combinations. Bonferroni corrections were applied for multiple measurements (P(c)). Each HLA allele was subjected to logistic regression for known AMD covariates. HLA immunohistochemistry for class I antigens was performed on elderly donor eyes. RESULTS: Allele Cw*0701 (P = 0.004, P(c) = 0.036) correlated positively with AMD, whereas alleles B*4001 (P = 0.003, P(c) = 0.027) and DRB1*1301(P = 0.001, P(c) = 0.009) were negatively associated. These HLA associations were independent of any linkage disequilibrium. Immunohistochemistry demonstrated differential HLA class I expression in choriocapillary endothelial cells. CONCLUSIONS: Significant positive and negative associations exist between HLA alleles and AMD. HLA polymorphisms influence the development of AMD, possibly via modulating choroidal immune function