Myra B. McGuinness

Reticular Pseudodrusen and Their Association with Age-Related Macular Degeneration: The Melbourne Collaborative Cohort Study.

PURPOSE To determine the prevalence of reticular pseudodrusen (RPD) and its association with age-related macular degeneration (AMD) and AMD risk factors in a large sample. DESIGN Community-based cohort study in Melbourne, Victoria, Australia. PARTICIPANTS A total of 21,130 participants 48 to 86 years of age available for ophthalmic assessment at follow-up from 2003 through 2007. METHODS Lifestyle, diet, and anthropometric measurements were obtained at baseline and follow-up. At follow-up, digital macular color photographs were graded for early, intermediate, and late AMD as well as the presence of RPD. Data were analyzed using multinomial logistic regression controlling for age, gender, smoking, country of birth, and diet. MAIN OUTCOME MEASURES Detection of RPD based on color fundus photographs. RESULTS Prevalence of RPD was 0.41% (87 of 21,130 participants), with 51% having bilateral RPD. Patients with RPD were older compared with patients with large drusen (>125 μm; 76±4 vs. 68±9 years; P < 0.001). Increasing age, female gender, being a current smoker, as well as focal pigmentary abnormalities and large drusen (>125 μm) were associated with a higher prevalence of RPD. Presence of geographic atrophy (GA) was associated with the highest odds of having RPD (odds ratio [OR], 153; 95% confidence interval [CI], 53-442), followed by choroidal neovascularization (CNV; OR, 90; 95% CI, 26-310), intermediate AMD (OR, 33; 95% CI, 14-77), and early AMD (OR, 12; 95% CI, 5-31) compared with those with no AMD. The ARMS2 single nucleotide polymorphism (SNP) rs10490924, HTRA1 SNPs rs11200638 and rs3793917, and CFH SNPs rs393955, rs1061170, and rs2274700 were associated with increased prevalence of RPD (all P < 0.05). CONCLUSIONS Reticular pseudodrusen are highly concurrent with AMD and have similar associations with known AMD risk factors such as age, gender, smoking, and genetic risk factors. Reticular pseudodrusen are associated more strongly with GA than with CNV. Although RPD are not specific to AMD, they are likely to be a strong risk factor for progression to late-stage AMD, similar to focal pigmentary abnormalities and large drusen.

Quantitative Fundus Autofluorescence in Early and Intermediate Age-Related Macular Degeneration

IMPORTANCE Increased lipofuscin accumulation is assumed to be an important factor in the pathogenesis of age-related macular degeneration (AMD), although direct evidence for this hypothesis is missing. OBJECTIVE To quantitatively investigate lipofuscin-associated fundus autofluorescence (AF) in patients with early and intermediate AMD. DESIGN, SETTING, AND PARTICIPANTS A prospective, single-center, case-control study was conducted from August 1, 2014, to October 31, 2015, at a university referral center. Participants included 40 patients aged 65 years or younger and 108 individuals without eye disease serving as controls. All participants underwent quantitative fundus AF (qAF) imaging with a modified scanning laser ophthalmoscope equipped with an internal fluorescent reference. Mean qAF values of an 8-segment circular ring centered on the fovea (qAF8) were measured and compared between patients and controls. For subgroup analysis, drusen were categorized as soft drusen, cuticular drusen, and/or reticular pseudodrusen (RPD). MAIN OUTCOMES AND MEASURES The qAF8 levels. RESULTS In the 40 patients with AMD, mean (SD) age was 54.8 (5.6) years, and 32 (80%) were women. None of the investigated patients had qAF8 values above the 95% prediction interval (PI) of the 108 controls. In the soft drusen (28 [70%]) and cuticular drusen (8 [20%]) groups, qAF8 levels within the 95% PI were noted in 22 patients (79%; 95% CI, 60% to 90%) and 7 patients (88%; 95% CI, 51% to 99%) respectively. The qAF8 values in the RPD group (4 [10%]) were below the 95% PI in 3 patients (75%; 95% CI, 29% to 97%). Compared with the controls, statistical analysis revealed lower qAF8 values in the overall AMD cohort after adjusting for age (difference, -19.9% [95% CI, -25.6% to -12.7%], P < .001) as well as in all subgroups (soft drusen, -17.1% [95% CI, -24.1% to -9.5%], P < .001; cuticular drusen, -19.6% [95% CI, -30.3% to -7.2%], P = .003; and RPD, -34.5% [95% CI, -47.1% to -21.3%]; P < .001). CONCLUSIONS AND RELEVANCE The qAF8 measurements in this sample showed no increased lipofuscin-related fundus AF in patients with early and intermediate AMD. Lower qAF levels in certain subgroups may point to subnormal lipofuscin levels in the retinal pigment epithelium or, alternatively, limitations to detection of true retinal pigment epithelial lipofuscin content. The results of this study might expand the understanding of the pathogenesis of AMD and may have an effect on upcoming treatment trials that aim to modify lipofuscin accumulation.

Cardiovascular Adverse Effects of Phenylephrine Eyedrops A Systematic Review and Meta-analysis

IMPORTANCE Topical phenylephrine hydrochloride is routinely administered with few safety precautions, but evidence regarding its systemic safety to date is controversial. As even short-term variations in 24-hour blood pressure (BP) and heart rate (HR) can adversely affect cardiovascular health, better evidence on phenylephrines effects on HR and BP is required. OBJECTIVE To perform a meta-analysis of available evidence regarding cardiovascular adverse effects of topical phenylephrine. DATA SOURCES PubMed, MEDLINE, and the Cochrane Database of Systematic Reviews and Clinical Trials were searched for relevant literature from January 1, 1970, to January 1, 2014, using a combination of the following search terms: topical, ocular, ophthalmic, phenylephrine, tropicamide, cardiovascular effect, side effect, blood pressure, heart rate, mydriatic, and eye drops. A total of 70 articles related to the topic were identified and all full texts were retrieved. STUDY SELECTION Randomized clinical trials reporting change in BP and HR for adults were included in this review. All studies reporting results for neonates or infants, not reporting standard deviations, or not specifying the time of measurement or the concentration of phenylephrine used were excluded. DATA EXTRACTION AND SYNTHESIS Data from randomized clinical trials that reported BP and/or HR as well as the time following administration of topical phenylephrine at which measurements were obtained by concentration of phenylephrine as a mean change and its standard deviation were extracted. Data were synthesized by concentration of phenylephrine and time of measurement following topical application using random-effects models with inverse variance weighting to account for heterogeneity across studies. MAIN OUTCOMES AND MEASURES Difference in BP and HR after topical administration of phenylephrine. RESULTS Eight RCTs with a total of 916 participants were included. Data were available for phenylephrine, 2.5%, at 20 to 30 minutes and 60 minutes or longer after administration, and neither BP nor HR changed at either time. Following application of phenylephrine, 10%, BP increased at 5 and 10 minutes (mean difference for both, +15 mm Hg; 95% CI, 11.94-18.54; P < .001) but decreased at 20 to 30 minutes and 60 minutes or longer with no changes detected against baseline. A mean increase in HR by 4.48 beats/min (95% CI, 1.09-7.88; P = .01) was present at 20 to 30 minutes following application of phenylephrine, 10%, and HR decreased by 60 minutes or longer with no changes detected compared with baseline. CONCLUSIONS AND RELEVANCE Phenylephrine, 2.5%, leads to no clinically relevant change in BP or HR, and the changes in BP and HR seen with phenylephrine, 10%, are short lived. Thus, phenylephrine, 2.5%, is safe to use in clinical routine.

Past physical activity and age-related macular degeneration: the Melbourne Collaborative Cohort Study

Background/aims To assess the association between past physical activity and early, intermediate and late age-related macular degeneration (AMD) in a community-based cohort study in Melbourne, Australia. Methods Diet and lifestyle information was recorded at baseline (1990–1994) and total recreational activity was derived from walking, vigorous and non-vigorous exercise. At follow-up (2003–2007), digital macular photographs were graded for early, intermediate and late AMD. Data were analysed using multinomial logistic regression controlling for age, sex, smoking, region of descent, diet and alcohol. Effect modification by sex was investigated. Results Out of 20 816 participants, early, intermediate and late AMD were detected at follow-up in 4244 (21%), 2661 (13%) and 122 (0.6%) participants, respectively. No association was detected between past total recreational physical activity and early, intermediate or late AMD. Frequent (≥3 times/week) and less frequent (1–2 times/week) vigorous exercise were associated with lower odds of intermediate and late AMD in univariable models. After controlling for confounders, there was evidence of effect modification by sex and frequent vigorous exercise was associated with a 22% decrease in the odds of intermediate AMD (95% CI 4% to 36%) in women, but no association was found for men. Conclusions Past frequent vigorous exercise may be inversely related to the presence of intermediate AMD in women. Further studies are needed to confirm whether physical activity and exercise have a protective effect for AMD.

Monoallelic ABCA4 Mutations Appear Insufficient to Cause Retinopathy: A Quantitative Autofluorescence Study

PURPOSE To investigate the effect of ABCA4 mutation status on lipofuscin-related quantitative autofluorescence (qAF) in humans and on bisretinoid accumulation in mice. METHODS Genotyped parents (n = 26; age 37-64 years) of patients with biallelic ABCA4-related retinopathy underwent in-depth retinal phenotyping including qAF imaging as a surrogate measure for RPE lipofuscin accumulation. In addition, bisretinoids as the main components of autofluorescent lipofuscin at the ocular fundus were quantified in Abca4-/-, Abca4+/-, and wild-type mice. RESULTS Index patients showed a retinal phenotype characteristic for ABCA4-related retinopathy, including increased qAF levels. In contrast, qAF measures in carriers of only one ABCA4 mutation were not different from age-matched controls in this sample, and there was no difference between truncating and missense mutations. Also, none of these carriers presented an abnormal phenotype on conventional imaging. One parent with ABCA4-related retinopathy and increased qAF carried an additional ABCA4 mutation, explaining the phenotype under a recessive disease model (pseudodominance). Biochemical analysis in the mouse model revealed direct downstream products (A2PE-H2, at-RALdimer-PE) of the ABCA4 substrate N-Ret-PE to be similar in wild-type and Abca4+/- mice. Both bisretinoids were 12- to 18-fold increased in Abca4-/- mice. Levels of A2E and A2PE in Abca4+/- mice were in between those measured in wild-type and Abca4-/- mice. CONCLUSIONS This study indicates that carriers of monoallelic ABCA4 mutations are phenotypically normal. However, biochemical analysis in the Abca4-deficient mouse model suggests detectable effects of one mutation in ABCA4 on the molecular level. The findings may have implications for therapeutic approaches such as gene replacement therapy.

Age-Related Macular Degeneration and Mortality: A Systematic Review and Meta-Analysis

ABSTRACT Purpose: Age-related macular degeneration (AMD) is the leading cause of severe, irreversible vision loss in older adults. Evidence for an association between AMD and mortality remains inconclusive despite evidence for an association with cardiovascular and inflammatory diseases. We aim to compare all-cause, cardiovascular and cancer mortality between those with early or late AMD and control study participants. Methods: A protocol was registered at PROSPERO (CRD42015020622). A systematic search of Medline (Ovid), PubMed, and Embase (Ovid) was conducted on 6 June 2015. Reference lists from identified studies and four clinical trial registries were searched for additional studies. Participants were required to be over the age of 40 years, and AMD status must have been objectively assessed. The Risk Of Bias In Non-Randomized Studies – of Interventions (ROBINS-I) tool was used to assess the risk of bias. Random-effects meta-analyses were performed. Results: A total of 12 reports from 10 studies were included in the meta-analysis. Late AMD was associated with elevated rates of all-cause (nine studies, hazard ratio (HR) 1.20, 95% confidence interval, CI, 1.02–1.41) and cardiovascular mortality (six studies, HR 1.46, 95% CI 1.13–1.98), but early AMD was not (all-cause mortality, 10 studies, HR 1.06, 95% CI 0.98–1.14; cardiovascular mortality, five studies, HR 1.12, 95% CI 0.96–1.31). There was no evidence of an association between early or late AMD and cancer mortality (early AMD, three studies, HR 1.17, 95% CI 0.78–1.75; late AMD, three studies, HR 1.01, 95% CI 0.77–1.33). Conclusion: Late AMD is associated with increased rates of all-cause and cardiovascular mortality, suggesting shared pathways between late AMD and systemic disease.

Survival Bias When Assessing Risk Factors for Age-Related Macular Degeneration: A Tutorial with Application to the Exposure of Smoking

ABSTRACT Purpose: We illustrate the effect of survival bias when investigating risk factors for eye disease in elderly populations for whom death is a competing risk. Our investigation focuses on the relationship between smoking and late age-related macular degeneration (AMD) in an observational study impacted by censoring due to death. Methods: Statistical methodology to calculate the survivor average causal effect (SACE) as a sensitivity analysis is described, including example statistical computing code for Stata and R. To demonstrate this method, we examine the causal effect of smoking history at baseline (1990–1994) on the presence of late AMD at the third study wave (2003–2007) using data from the Melbourne Collaborative Cohort Study. Results: Of the 40,506 participants eligible for inclusion, 38,092 (94%) survived until the start of the third study wave, 20,752 (51%) were graded for AMD (60% female, aged 47–85 years, mean 65 ± 8.7 years). Late AMD was detected in 122 participants. Logistic regression showed strong evidence of an increased risk of late AMD for current smokers compared to non-smokers (adjusted naïve odds ratio 2.99, 95% confidence interval, CI, 1.74–5.13). Among participants expected to be alive at the start of follow-up regardless of their smoking status, the estimated SACE odds ratio comparing current smokers to non-smokers was at least 3.42 (95% CI 1.57–5.15). Conclusions: Survival bias can attenuate associations between harmful exposures and diseases of aging. Estimation of the SACE using a sensitivity analysis approach should be considered when conducting epidemiological research within elderly populations.

Relationship between reticular pseudodrusen and choroidal thickness in intermediate age-related macular degeneration: Reticular pseudodrusen choroidal thickness

Reticular pseudodrusen (RPD) is strongly associated with late age‐related macular degeneration (AMD) but their aetiology remains unknown. RPD have been associated with reduced choroidal thickness (ChT) but most studies are limited by small sample size and varying severity of AMD.

Diabetic retinopathy screening in incident diabetes mellitus type 2 in Germany between 2004 and 2013 - A prospective cohort study based on health claims data

OBJECTIVE To assess factors associated with diabetic retinopathy (DR) screening uptake following a diagnosis of type 2 diabetes mellitus (type 2 diabetes) in Germany. MATERIALS AND METHODS A nationally representative prospective sample of individual-level health claims data for 250,000 members from Germanys largest public insurance provider in 2004-2013 was assessed. In the sample, 26,560 persons with incident type 2 diabetes were identified. Factors associated with subsequent DR screening were assessed using descriptive statistics, Kaplan-Meier estimator, and Cox regression analysis. RESULTS On average 27.6 visits to an ophthalmologist per 100 person-years in persons with incident type 2 diabetes occurred. Half of all incident cases (Kaplan-Meier estimator) had not seen an ophthalmologist after more than two years (2.25 years) following their diabetes diagnosis. In the multivariate analysis, an older age (from hazard ratio HR(70-74) = 0.93 [95%-CI: 0.89-0.97] to HR(90+) = 0.50 [95%-CI: 0.42-0.60] compared to persons aged 50-69 years) and a higher disability level (i.e. HR(disability level 3) = 0.30 [95%-CI: 0.25-0.36]) were associated with a lower likelihood, while female sex (HR = 1.12 [95%-CI: 1.08-1.15]), six or more comorbidities (HR = 1.26 [95%-CI: 1.15-1.37]), moderate (HR = 1.51 [95%-CI: 1.46-1.56]) or severe type 2 diabetes (HR = 1.53 [95%-CI: 1.45-1.61]) as well as being enrolled in a type 2 diabetes disease management program (HR = 1.78 [95%-CI: 1.69-1.87]) were associated with a higher likelihood of DR screening. CONCLUSIONS A high proportion of newly diagnosed persons with type 2 diabetes did not follow current German recommendations for DR screening, impeding timely detection and management of potential complications. This was more apparent among persons who were men, older or had a disability. The uptake of screening was considerably greater among those enrolled in a diseases management program. These factors need to be considered when planning DR screening services and/or referrals.

Analysis of the Association Between Physical Activity and Age-Related Macular Degeneration

Choroidal neovascularization resulting from age-related macular degeneration (AMD) is a major cause of blindness among the elderly residing in developed nations. Current interventions for neovascular AMD can be costly and cause patient distress and are not without the potential for adverse effects.1 Thus, the quest to identify modifiable risk factors for AMD is important, with the potential to assist in the prevention or delay of AMD progression. In this issue of JAMA Ophthalmology, Rim and coauthors2 report their unexpected finding of a 1.2-fold increase in the incidence of neovascular AMD (95% CI, 1.02-1.49) among participants who exercised vigorously, using data from a large cohort (211 960 participants) of the Korean National Health Screening Program. The authors are understandably cautious in their interpretation of the results because of the observational nature of the study and the problems associated with selfreported measures of activity. We believe that additional caution may be warranted owing to inclusion in the analysis being conditional on survival until 2009 when use of ranibizumab was recorded in the Korean National Health Information Database. Of the 315 901 participants who were eligible for inclusion and had no missing baseline data (collected in 2002-2003), 15 634 (4.9%) who had died before August 2009 were excluded from the analysis. Exclusion of these individuals (known as “left truncation” in statistical literature) may introduce bias when the exposure of interest—in this case physical activity (PA)—is related to survival and therefore inclusion in the study.3,4 Failing to account for left truncation may also result in underestimation of the SE, increasing the chance of falsely rejecting the null hypothesis.5 It can be assumed that differential rates of survival were observed between the 2 PA groups before the start of the period of AMD status ascertainment in 2009. Despite the use of propensity score matching to maximize exchangeability between the exposure groups, survival bias introduces an additional barrier to exchangeability that cannot be resolved through the use of covariate adjustment or matching techniques.6 Even in groups that are well matched on measured covariates, those who survive without vigorous exercise are likely to be more robust compared with those who survived following exercise, but may not have survived in its absence. If increased survival subsequent to PA led to differential entry into the period under observation (August 2009 to December 2013), the results of this study may represent an overestimate of any detrimental effect of PA on the incidence of neovascular AMD. In the primary analysis of this study, the lower confidence limit for the hazard ratio was 1.02, so any downward shift in the estimate may influence the statistical inferences drawn from the results. The vigorous vs no-vigorous PA groups were well matched on the 42 baseline characteristics. However, exchangeability was lost following subdivision of PA into no, moderatefrequency, and high-frequency groups. The results of these subanalyses would most likely be biased without additional adjustment for confounders, such as smoking, which was more prevalent among the active than the inactive participants in the unmatched baseline cohort and which may differ between those who are active 1 to 4 times per week and those who are active 5 or more times per week. A further concern of ours relates to the ascertainment of AMD status. Participants who were identified as having neovascular AMD were likely to be correctly classified because of the requirement of both an AMD diagnosis code and the use of ranibizumab following fundus fluorescein angiography. However, it is unclear whether additional cases could have been missed because of treatment being completed before 2009, the absence of treatment, or the use of other treatment modalities during the follow-up period. A disproportionate failure to identify cases between the PA groups presents another potential source of bias, one that would be particularly influential if the nonactive group had higher rates of diagnosis and treatment between 2003 and 2009. Earlier diagnoses among nonactive participants would be expected if prior beliefs regarding the beneficial effect of PA on the later stages of AMD were true.7 Despite these concerns, the proportion of baseline participants who died before the ascertainment of AMD status was relatively low (5%) and any subsequent selection bias is likely to be small in magnitude. The authors highlight several plausible biological mechanisms for their findings and the evidence from such a large cohort should not be ignored. Currently, conflicting evidence remains on the effect of PA on AMD; however, we believe that these findings from Rim and colleagues2 should be carefully considered when generating hypotheses for future research into the development of neovascular AMD.