Peter N. Dimitrov

Prevalence of amblyopia and associated refractive errors in an adult population in Victoria, Australia

The study aimed to describe the prevalence of amblyopia and associated refractive errors among an adult Australian population. The Visual Impairment Project (VIP) is a population-based study of age-related eye disease in the state of Victoria, Australia. Data were collected through standardised interviews and orthoptic and ophthalmic dilated examinations. Amblyopia was defined as best-corrected visual acuity of 6/9 or worse in the absence of any pathological cause. The participants were 3,265 urban residents and 1,456 rural residents of the VIP ranging in age from 40-92 years (mean = 59 years; 53% female). The prevalence of unilateral amblyopia was 3.06% (95% C.I. 2.59, 3.53). Amblyopia was not found to be statistically different by age group (p=0.096), gender (p=0.675), or place of birth (p=0.14). Anisometropia was statistically more common (p<0.001) in amblyopic cases (51.1%) compared to the normal population (9.7%), and 54% of amblyopic eyes had visual acuity of worse than 6/12. Amblyopia is a significant cause of unilateral reduced visual acuity in a population aged 40 years and older. Anisometropia was more prevalent and the degree of anisometropia was greater in the amblyopic group compared with the normal population. Oblique astigmatism was more prevalent in the amblyopic group compared with the normal population.

First-in-Human Trial of a Novel Suprachoroidal Retinal Prosthesis

Retinal visual prostheses (“bionic eyes”) have the potential to restore vision to blind or profoundly vision-impaired patients. The medical bionic technology used to design, manufacture and implant such prostheses is still in its relative infancy, with various technologies and surgical approaches being evaluated. We hypothesised that a suprachoroidal implant location (between the sclera and choroid of the eye) would provide significant surgical and safety benefits for patients, allowing them to maintain preoperative residual vision as well as gaining prosthetic vision input from the device. This report details the first-in-human Phase 1 trial to investigate the use of retinal implants in the suprachoroidal space in three human subjects with end-stage retinitis pigmentosa. The success of the suprachoroidal surgical approach and its associated safety benefits, coupled with twelve-month post-operative efficacy data, holds promise for the field of vision restoration. Trial Registration Clinicaltrials.gov NCT01603576

Gene–environment interaction in progression of AMD: the CFH gene, smoking and exposure to chronic infection

A number of risk factors including the complement factor H (CFH) gene, smoking and Chlamydia pneumoniae have been associated with age-related macular degeneration (AMD). However, the mechanisms underlying how these risk factors might be involved in disease progression and disease aetiology is poorly understood. A cohort series of 233 individuals followed for AMD progression over a mean period of 7 years underwent a full eye examination, blood was taken for DNA and antibody titre and individuals completed a standard medical and general questionnaire. Y402H variants of the CFH gene were assessed with disease progression as well as examination of interaction between Y402H variants and smoking and Y402H variants and the pathogen C. pneumoniae. The CC risk genotype of Y402H was significantly associated with increased AMD progression [odds ratio (OR) 2.43, 95% confidence interval (95% CI) 1.07-5.49] as was smoking (OR 2.28, 95% CI 1.26-4.12). However, the risk of progression was greatly increased to almost 12-fold (OR 11.8, 95% CI 2.1-65.8) when, in addition to having the C risk allele, subjects also presented with the upper tertile of antibodies to the bacterial pathogen C. pneumoniae compared with those with the T allele of Y402H and the lowest antibody tertile. This demonstrates for the first time the existence of a gene environment-interaction between pathogenic load of C. pneumoniae and the CFH gene in the aetiology of AMD.

Measuring Rod and Cone Dynamics in Age-Related Maculopathy

PURPOSE A cathode-ray-tube (CRT) monitor-based technique was used to isolate clinically significant components of dark adaptation. The utility of the technique in identifying adaptation abnormalities in eyes with age-related maculopathy (ARM) is described. METHODS A CRT dark adaptometer was developed to assess cone and rod recovery after photopigment bleach. The following measures were obtained: cone recovery rate (R(c); in decades per minute) and absolute threshold (Tf(c); log candelas per square meter), rod recovery rate (R(r); decades per minute), and rod-cone transition (rod-cone break [RCB], in minutes). These components were isolated by appropriately selecting stimulus size, stimulus location, pigment bleach, and test duration and by coupling the CRT with judiciously selected neutral-density (ND) filters. The protocol was developed by using 5 young observers and was tested on 27 subjects with ARM in the study eye and 22 age-matched control subjects. RESULTS The parameters necessary for effective isolation of cone and early phase rod dark adaptation were a 2.6 ND filter (for a standard CRT monitor, 0.08-80 cd . m(-2) luminance output); a 4 degrees foveated, 200-ms, achromatic spot; approximately 30% pigment bleaching; and a 30-minute test duration. These settings returned obvious rod and cone recovery curves in control and ARM eyes that were compatible with conventional test methods and identified 93% of participants with ARM as having delayed dynamics in at least one of the parameters. Cone recovery dynamics were significantly slower in the ARM group when compared with age-matched control subjects (R(c), 0.99 +/- 0.35 vs. 2.63 +/- 0.61 decades . min(-1), P < 0.0001). Three of the 27 eyes with ARM did not achieve RCB during the allowed duration (30 minutes). The remaining eyes with ARM (n = 24) exhibited a significant delay in rod recovery (R(r)(,) ARM, 0.16 +/- 0.03 vs. controls, 0.22 +/- 0.02 decades . min(-1), P < 0.0001) and the average time to RCB (+/-SD) in the ARM group was significantly longer than in the control subjects (19.12 +/- 5.17 minutes vs. 10.40 +/- 2.49 minutes, P < 0.0001). CONCLUSIONS The CRT dark-adaptation technique described in this article is an effective test for identifying abnormalities in cone and rod recovery. Slowed cone and rod recovery and a delayed RCB were evident in the eyes with ARM. The test method is potentially useful for clinical intervention trials in which ARM progression is monitored.

Visual function tests as potential biomarkers in age-related macular degeneration.

PURPOSE To evaluate the potential of psychophysical assessments of retinal function to provide diagnostic biomarkers of early age-related macular degeneration (AMD). METHODS Unilateral visual function was assessed in 221 participants (72.86 ± 9.94 years; 67% women) with early AMD (visual acuity better than 20/60) and 109 controls (73.07 ± 10.32 years; 65% women). Psychophysical assessment included steady state thresholds (4- and 14-Hz flicker and red and blue color) and dynamic tests (photostress recovery [PSR] and dark adaptation [DA]). All test parameters were compared in terms of their diagnostic capacity (sensitivity and specificity), reproducibility, and clinical applicability (test duration and participants perception of test difficulty). AMD status was determined by digital photography, according to the International Classification and Grading System. RESULTS All functional measurements were significantly worse, on average, in the AMD group than in the control group (P < 0.001). Static and dynamic parameters showed weak correlations (range, 0.003-0.225). Rod recovery in DA and cone recovery in PSR had the best diagnostic capacity (area under curve [AUC], receiver operating characteristic [ROC] analysis, 0.93 ± 0.016 and 0.85 ± 0.021, respectively). Considering diagnostic capacity together with test reproducibility and clinical applicability, the 14-Hz flicker gave the best outcome, followed by PSR. Combination of these two tests detected 71% of abnormal early AMD cases. CONCLUSIONS All the visual function tests had good diagnostic capacity. Combination of the 14-Hz flicker thresholds and dynamics of the PSR test provided optimal quantitative assessment of retinal function in early AMD, suggesting that this set is a potentially useful clinical tool for following progression of early AMD and assessing the efficacy of interventions.

C-Reactive Protein Levels and Complement Factor H Polymorphism Interaction in Age-related Macular Degeneration and Its Progression

PURPOSE To determine the effect of elevated level of C-reactive protein (CRP) and its joint effect with the complement factor H (CFH) polymorphism on prevalent age-related macular degeneration (AMD) and its progression. DESIGN Two-arm case-control study: (a) Study on prevalent AMD cases and population-based controls; (b) longitudinal study on AMD progression, comparing those in whom AMD progressed with those with no progression. PARTICIPANTS (a) A cross-sectional sample of 544 participants, of whom 312 had features of early or late AMD and 232 were controls; (b) a sample of 254 early AMD cases, followed for 7 years. METHODS The study was conducted in Melbourne, Australia. Macular stereo photographs were graded for AMD according to the International Classification and Grading System. High-sensitivity CRP was measured in fresh serum, and genotyping was performed through the Australian Genome Research Facility. The association of CRP with outcomes was tested using multivariate logistic regression analysis adjusted for age, smoking, anti-inflammatory medications, and the CC genotype of the CFH gene. Risk factor interaction was explored using an additive model. MAIN OUTCOME MEASURES Prevalent early AMD, prevalent late AMD, progressed AMD, and measures of risk factor interaction. RESULTS Elevated CRP levels were associated with late AMD: odds ratio (OR), 3.12; 95% confidence interval (CI), 1.38-7.07. An association of elevated CRP with AMD progression was weaker: OR, 1.90 (95% CI, 0.88-4.10). A combination of elevated CRP and the CC (Y402H) genotype resulted in a super-additivity of the risks, with odds ratios of 19.3 (95% CI, 2.8-134) for late AMD, and 6.8 (95% CI, 1.2-38.8) for AMD progression, with the attributable proportion of risk owing to CRP-CFH interaction calculated at 26% for prevalent late AMD and 22% for AMD progression. CONCLUSIONS Synergistic influence of CRP levels and the at risk genotype of the CFH gene resulted in a super-additive risk for prevalent late AMD and AMD progression. Testing for the combination of these 2 risk factors to predict a high risk of AMD and its progression would allow for targeted trials of new intervention strategies.

Factors affecting perceptual thresholds in a suprachoroidal retinal prosthesis.

PURPOSE The suprachoroidal location for a retinal prosthesis provides advantages over other locations in terms of a simplified surgical procedure and a potentially more stable electrode-neural interface. The aim of this study was to assess the factors affecting perceptual thresholds, and to optimize stimulus parameters to achieve the lowest thresholds in patients implanted with a suprachoroidal retinal prosthesis. METHODS Three patients with profound vision loss from retinitis pigmentosa were implanted with a suprachoroidal array. Perceptual thresholds measured on individual electrodes were analyzed as a function of stimulus (return configuration, pulse polarity, pulse width, interphase gap, and rate), electrode (area and number of ganged electrodes), and clinical (retinal thickness and electrode-retina distance) parameters. RESULTS A total of 92.8% of 904 measurements made up to 680 days post implantation yielded thresholds (range, 44-436 nanocoulombs [nC]) below the safe charge limit. Thresholds were found to vary between individuals and to depend significantly on electrode-retina distance, negligibly on retinal thickness, and not on electrode area or the number of ganged electrodes. Lowest thresholds were achieved when using a monopolar return, anodic-first polarity, short pulse widths (100 μs) combined with long interphase gaps (500 μs), and high stimulation rates (≥400 pulses per second [pps]). CONCLUSIONS With suprachoroidal stimulation, anodic-first pulses with a monopolar return are most efficacious. To enable high rates, an appropriate combination of pulse width and interphase gap must be chosen to ensure low thresholds and electrode voltages. Electrode-retina distance needs to be monitored carefully owing to its influence on thresholds. These results inform implantable stimulator specifications for a suprachoroidal retinal prosthesis. (ClinicalTrials.gov number, NCT01603576.).

Incidence and progression of cataract in the Melbourne Visual Impairment Project.

PURPOSE To determine the 5-year incidence and progression of cataract and cataract surgery in the Melbourne Visual Impairment Project. DESIGN Prospective cohort study. methods: Demographic information including race, sex, age, and education level was collected at baseline. Cortical cataract was defined as 4/16 or greater opacity; progression was defined as a more than 2/16 increase. Nuclear cataract was defined as Wilmer standard grade 2 or higher; progression was defined as more than 0.5 increase. Posterior subcapsular (PSC) cataract was defined as opacity 1 mm(2) or greater; progression was defined as greater than 1 mm(2) increase. results: Of the 3040 participants eligible to attend follow-up examinations, 2594 (85% of those eligible) participated. The mean age of participants at follow-up was 62.5 years, and 55% were female. The percentage of patients who had at least one lens extracted over 5 years increased from 0.5% of those aged 40 to 49 years at baseline to 35.7% of those aged 80 years or more at baseline. The overall incidence of the three types of cataract was as follows: cortical 7.7% (95% confidence limits [CL] = 5.8-9.8), nuclear 16.4% (95% CL = 12.1-20.8), and PSC 7% (95% CL = 5.3-8.7). The overall progression of cataract was cortical 14.3% (95% CL = 10.2-18.3), nuclear 19.3% (95% CL = 15.9-22.7), and PSC 20% (95% CL = 8.7-31.1). The incidence and progression rates increased significantly by age, but the rates were not significantly different by sex. CONCLUSION These cataract incidence data confirm the public health importance of cataract in Australia. The data also support the need to plan both primary prevention program and adequate surgical services to meet the anticipated increase in demand with the aging population.

Nanosecond‐laser application in intermediate AMD: 12‐month results of fundus appearance and macular function

A novel, ultra‐low energy nanosecond laser (retinal rejuvenation therapy) has been developed with the aim to slow progression of early age‐related macular degeneration (AMD). The safety, changes in fundus characteristics and macular function in a cohort of participants with bilateral intermediate AMD are reported.

Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration

Background HMG Co-A reductase inhibitors are ubiquitous in our community yet their potential role in age-related macular degeneration (AMD) remains to be determined. Methodology/Principal Findings Objectives: To evaluate the effect of simvastatin on AMD progression and the effect modification by polymorphism in apolipoprotein E (ApoE) and complement factor H (CFH) genes. Design: A proof of concept double-masked randomized controlled study. Participants: 114 participants aged 53 to 91 years, with either bilateral intermediate AMD or unilateral non-advanced AMD (with advanced AMD in fellow eye), BCVA≥20/60 in at least one eye, and a normal lipid profile. Intervention: Simvastatin 40 mg/day or placebo, allocated 1∶1. Main outcome measures: Progression of AMD either to advanced AMD or in severity of non-advanced AMD. Results. The cumulative AMD progression rates were 70% in the placebo and 54% in the simvastatin group. Intent to treat multivariable logistic regression analysis, adjusted for age, sex, smoking and baseline AMD severity, showed a significant 2-fold decrease in the risk of progression in the simvastatin group: OR 0.43 (0.18–0.99), p = 0.047. Post-hoc analysis stratified by baseline AMD severity showed no benefit from treatment in those who had advanced AMD in the fellow eye before enrolment: OR 0.97 (0.27–3.52), p = 0.96, after adjusting for age, sex and smoking. However, there was a significant reduction in the risk of progression in the bilateral intermediate AMD group compared to placebo [adjusted OR 0.23 (0.07–0.75), p = 0.015]. The most prominent effect was observed amongst those who had the CC (Y402H) at risk genotype of the CFH gene [OR 0.08 (0.02–0.45), p = 0.004]. No evidence of harm from simvastatin intervention was detected. Conclusion/Significance Simvastatin may slow progression of non-advanced AMD, especially for those with the at risk CFH genotype CC (Y402H). Further exploration of the potential use of statins for AMD, with emphasis on genetic subgroups, is warranted. Trial Registration Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065