Retinitis pigmentosa-associated cystoid macular oedema: pathogenesis and avenues of intervention.

Hereditary retinal diseases are now the leading cause of blindness certification in the working age population (age 16-64 years) in England and Wales, of which retinitis pigmentosa (RP) is the most common disorder. RP may be complicated by cystoid macular oedema (CMO), causing a reduction of central vision. The underlying pathogenesis of RP-associated CMO (RP-CMO) remains uncertain, however, several mechanisms have been proposed, including: (1) breakdown of the blood-retinal barrier, (2) failure (or dysfunction) of the pumping mechanism in the retinal pigment epithelial, (3) Müller cell oedema and dysfunction, (4) antiretinal antibodies and (5) vitreous traction. There are limited data on efficacy of treatments for RP-CMO. Treatments attempted to date include oral and topical carbonic anhydrase inhibitors, oral, topical, intravitreal and periocular steroids, topical non-steroidal anti-inflammatory medications, photocoagulation, vitrectomy with internal limiting membrane peel, oral lutein and intravitreal antivascular endothelial growth factor injections. This review summarises the evidence supporting these treatment modalities. Successful management of RP-CMO should aim to improve both quality and quantity of vision in the short term and may also slow central vision loss over time.

The UK Neovascular AMD Database Report 3: inter-centre variation in visual acuity outcomes and establishing real-world measures of care.

PurposeInternational variations in visual acuity (VA) outcomes of eyes treated for neovascular age-related macular degeneration (nAMD) are well-documented, but intra-country inter-centre regional variations are not known. These data are important for national quality outcome indicators. We aimed to determine intra-country and inter-centre regional variations in outcomes for treatment of nAMD.Patients and methodsProspective multicentre national database study of 13 UK centres that treated patients according to a set protocol (three loading doses, followed by Pro-Re-Nata retreatment). A total of 5811 treatment naive eyes of 5205 patients received a total of 36 206 ranibizumab injections over 12 months.ResultsMean starting VA between centres varied from 48.9 to 59.9 ETDRS letters. Mean inter-centre VA change from baseline to 12 months varied from +6.9 letters to -0.6 letters (mean of +2.5 letters). The proportion of eyes achieving VA of 70 letters or more varied between 21.9 and 48.7% at 12 months. Median number of injections (visits) at each centre varied from 5 to 8 (9 to 12), with an overall median of 6 (11). Age, starting VA, number of injections, and visits, but not gender were significantly associated with variation in these VA outcomes (P<0.01). Significant variation between centres persisted even after adjusting for these factors.ConclusionThere are modest differences in VA outcomes between centres in the UK. These differences are influenced, but not completely explained, by factors such as patient age, starting VA, number of injections, and visits. These data provide an indication of the VA outcomes that are achievable in real-world settings.

Hypertension is associated with narrower retinal arteriolar calibre in persons with and without coronary artery disease.

The aims of this study were to investigate independent associations between hypertension and retinal vessel calibre in a high cardiovascular risk cohort and to determine whether these associations also exist in patients without coronary artery disease (CAD). The Australian Heart Eye Study is an observational study that surveyed 1680 participants presenting to a tertiary referral hospital for the evaluation of potential CAD by coronary angiography. Hypertension was defined as systolic >140 mm Hg, diastolic >90 mm Hg or treated (use of antihypertensive medications). Retinal arteriolar and venular calibres were measured from retinal photographs. CAD was quantified using severity (Gensini) and extent scores. Subanalyses were performed for people with and without CAD and for men and women. A total of 1114 participants had complete data on hypertension, coronary vessel evaluation and retinal vessel measurements and were included in cross-sectional analyses. Among persons with CAD, those with hypertension (compared with without) had narrower retinal arteriolar calibre (mean arteriolar calibre difference 2.1 µm, P=0.02), adjusting for age, sex, ethnicity, body mass index, smoking status and fellow vessel calibre. This association was also present among persons without CAD (mean difference 5.0 µm, P=0.04). Stratification by sex indicated that women with hypertension had marginally narrower retinal arterioles compared with normotensive women (multivariable-adjusted P=0.04). No significant association between hypertension and retinal arteriolar calibre was observed in men (P=0.13). No significant differences in retinal venular calibre were observed (P>0.05). In conclusion, in both subjects with and without CAD, hypertension was independently associated with narrower retinal arterioles.

Retinal microvascular signs are associated with chronic kidney disease in persons with and without diabetes.

BACKGROUND/AIMS: In persons with diabetes, retinal microvascular abnormalities are associated with chronic kidney disease (CKD). However, it is not clear if the same relationship applies in persons without diabetes. METHODS: We examined 2,971 participants from a population-based study (240 with, 2,731 without diabetes). Retinal photographs were masked graded for retinal microvascular signs, and CKD was defined as estimated glomerular filtration rate (eGFR(MDRD)) <60 ml/min/1.73 m(2). RESULTS: Retinal microvascular signs were more frequent in persons with CKD. After adjusting for age, gender, systolic blood pressure and fasting plasma glucose, CKD was associated with both presence of retinopathy (odds ratio, OR, 1.2, 95% confidence interval, CI 1.0-1.5) and venular dilation (OR 1.2, 95% CI 1.0-1.5). These associations were similar in persons with and without diabetes. There was a significant trend for increasing magnitude of associations of retinopathy with increasing severity levels of CKD (p for trend 0.03). CONCLUSIONS: Retinal microvascular signs, namely retinopathy lesions and venular dilation, are associated with CKD both in persons with, and without diabetes. This supports the concept that retinal microvascular signs are indicators of generalized microvascular disease even in the absence of diabetes, and reinforces the link between retinal and renal microcirculations.

Relationship between glycated haemoglobin and microvascular complications: is there a natural cut-off point for the diagnosis of diabetes?

AIMS/HYPOTHESIS: This study was designed to determine whether the relationship of glycated haemoglobin to diabetic microvascular complications shows any natural thresholds that could be useful in diagnosing diabetes. METHODS: We examined a population-based sample of 3,190 Malay adults aged 40-80 years in Singapore. The microvascular outcomes of interest were: (1) any retinopathy, defined from fundus photographs; (2) mild retinopathy, defined as in (1); (3) moderate retinopathy, defined as in (1); (4) chronic kidney disease, defined from estimated glomerular filtration rate; (5) micro- or macroalbuminuria, defined from urinary albumin to creatinine ratio; and (6) peripheral neuropathy, defined from neurothesiometer or monofilament sensory testing. RESULTS: Increasing HbA(1c) was associated with all microvascular complications. The optimal cut-off points for detecting mild and moderate retinopathy were 6.6% (87.0% sensitivity, 77.1% specificity and area under the receiver operating characteristics [ROC] curve 0.899) and 7.0% (82.9% sensitivity, 82.3% specificity and area under ROC curve 0.904). The prevalences of mild and moderate retinopathy were <1% below the optimal cut-off points. For other complications, the association with HbA(1c) was linear without evidence of a distinct threshold. Although ROC analysis for these other complications also suggested optimal cut-off points between 6.6% and 7.0%, the sensitivity at these cut-off points was considerably lower than for mild and moderate retinopathy, ranging from 31.8% to 66.5%. CONCLUSIONS/INTERPRETATION: Higher levels of HbA(1c) were associated with microvascular complications. Our data support use of an HbA(1c) cut-off point of between 6.6 and 7.0% in diagnosing diabetes. Cut-off points in this range were best for the identification of individuals with mild and moderate retinopathy. Any retinopathy, chronic kidney disease, albuminuria and peripheral neuropathy are less well detected at these cut-off points.

Retinopathy predicts coronary heart disease mortality.

BACKGROUND: Retinopathy lesions are fairly common findings in clinic settings and may predict risk of coronary heart disease (CHD). OBJECTIVE: To examine whether retinopathy independently predicts a risk of CHD-related mortality in people with and without diabetes. METHODS: In an Australian population-based cohort of people with (n = 199) and without (n = 2768) diabetes (Blue Mountains Eye Study, total n = 2967), the presence and severity of retinopathy was assessed from retinal photographs. 12-Year cumulative CHD deaths were ascertained from Australian National Death Index records. RESULTS: Over 12 years, 353 participants (11.9%) had incident CHD-related deaths. Retinopathy was present in 57/199 (28.6%) participants with, and in 268/2768 (9.7%) without, diabetes. The presence of retinopathy increased the CHD mortality rate per person-year by an amount (0.005) equivalent to the presence of diabetes itself (12-year CHD mortality rate per person-year of 0.010 in people with neither diabetes nor retinopathy, 0.015 in those with diabetes alone, 0.016 in those with retinopathy alone). After adjusting for cardiovascular risk factors, retinopathy remained an independent predictor of CHD death both in people with diabetes (hazard ratio (HR) = 2.21, 95% CI 1.20 to 4.05) and in those without diabetes (HR = 1.33, 95% CI 1.02 to 1.83). Moderate retinopathy was associated with adjusted HR = 6.68 (95% CI 2.24 to 20.0) in people with diabetes and adjusted HR = 2.29 (95% CI 1.10 to 4.76) in people without diabetes. CONCLUSIONS: A finding of retinopathy in people with or without diabetes may signal increased CHD risk. The increased CHD mortality associated with retinopathy in people without diabetes was equivalent to the presence of diabetes itself.

Age-related macular degeneration and mortality from cardiovascular disease or stroke.

BACKGROUND/AIMS: Age-related macular degeneration (AMD) and vascular disease share similar risk factors. Recent data suggest AMD may independently predict stroke or coronary heart disease. We prospectively assessed the relationship between AMD and risk of stroke- or cardiovascular-related death in an Australian population. METHODS: Of 3654 baseline participants (1992-4) aged 49+ years, 2335 were re-examined after 5 years and 1952 after 10 years. Retinal photographs were graded using the Wisconsin System. History and physical examination provided data on possible risk factors. Deaths and cause of death were confirmed by data linkage with the Australian National Death Index. Risk ratios (RR) were estimated in Cox models. RESULTS: Among persons aged <75 years at baseline, early AMD predicted a doubling of cardiovascular mortality (RR, 2.32; 95% confidence interval (CI), 1.03 to 5.19), over the next decade, after controlling for traditional cardiovascular risk factors. Late AMD predicted fivefold higher cardiovascular mortality (RR, 5.57; 95% CI, 1.35 to 22.99) and 10-fold higher stroke mortality (RR, 10.21; 95% CI, 2.39 to 43.60) after adjusting for age and sex only. These associations were not present when persons older than 75 were included. CONCLUSION: AMD predicted stroke and cardiovascular events over the long term in persons aged 49-75 years. This may have potential implications for new intravitreal anti-VEGF AMD therapies.

Birth weight is not related to risk of diabetic retinopathy in type 2 diabetes: the Atherosclerosis Risk in Communities Study.

PURPOSE: Low birth weight has been suggested as a risk factor for diabetes. Whether it is related to diabetic retinopathy is unclear and is examined in this study. MATERIALS AND METHODS: We examined 609 adults with type 2 diabetes from the population-based Atherosclerosis Risk in Communities Study. Retinal photographs were graded for diabetic retinopathy. Birth weight was assessed by self-report. RESULTS: Retinopathy was present in 116 (19%) participants (113 non-proliferative and 3 proliferative). After adjusting for age, sex, race, education level, body mass index, fasting glucose, duration of diabetes, glycosylated hemoglobin A1c, family history of diabetes, serum total cholesterol, and blood pressure, there was no evidence of either a linear or non-linear relationship between birthweight and diabetic retinopathy. CONCLUSIONS: Birth weight was not associated with diabetic retinopathy.

Migraine and coronary heart disease mortality: a prospective cohort study.

A recent population-based prospective study reported that in women, migraine with aura (MA), but not migraine without aura (MoA), was associated with increased risk of coronary heart disease events (CHD). We sought to confirm this association in an Australian population-based cohort of older men and women (n = 2331, aged 49-97 years). We defined MA and MoA from face-to-face interview using International Headache Society criteria. Over a mean 6-year follow-up, 30 women (2.8%) and 30 men (4.4%) without any prior CHD history died from CHD-related causes. In women, a history of MA was associated with a non-significant twofold higher risk of CHD death (age-adjusted relative risk 2.2, 95% confidence interval 0.8, 5.8, P = 0.11), which remained similar after adjustment for cardiovascular risk factors. There were no CHD deaths in men with a history of migraine. Our findings support reports that in women, MA, but not MoA, may be associated with increased risk of CHD.

Retinal vascular calibre and the risk of coronary heart disease-related death.

OBJECTIVE: To examine whether retinal vascular calibre independently predicts risk of coronary heart disease (CHD) -related death. METHODS: In a population-based cohort study of 3654 Australians aged > or = 49 years, retinal arteriolar and venular calibres were measured from baseline retinal photographs and the arteriole to venule ratio (AVR) was calculated. CHD-related death was confirmed from the Australian National Death Index. RESULTS: Over nine years, 78 women (4.1%) and 114 men (7.8%) had incident CHD-related deaths. In people aged 49-75 years, wider venules were associated with CHD death, with relative risk (RR) 1.8 (95% confidence interval (CI) 1.1 to 2.7) and RR 2.0 (95% CI 1.1 to 3.6) per standard deviation (SD) increase in venular calibre for men and women, respectively, after adjustment for traditional risk factors. Additionally, in women aged 49-75 years, smaller AVR and narrower arterioles were associated with CHD death (RR 1.5, 95% CI 1.1 to 2.2, and RR 1.9, 95% CI 1.0 to 3.5 per SD decrease in AVR and arteriolar calibre, respectively, after adjustment). These associations were not observed in people aged > 75 years. CONCLUSIONS: These findings suggest that microvascular disease processes may have a role in CHD development in middle-aged people, particularly in women. Retinal photography may be useful in cardiovascular risk prediction.

Cytotrophoblast stem cell lines derived from human embryonic stem cells and their capacity to mimic invasive implantation events.

BACKGROUND: An effective embryonic-maternal interaction is crucial for successful human pregnancy. Failure of this process is a major cause of infertility and can lead to placental dysfunction resulting in recurrent miscarriage, fetal retardation and pre-eclampsia. Research is severely constrained by ethical and practical considerations; therefore, we aimed to generate cytotrophoblast stem (CTBS) cell lines from human embryonic stem cells (HESCs). METHOD: Beta-HCG was used as a marker of viable trophoblast cells. In defined culture, embryoid bodies were generated from HESCs and selected for trophoblast enrichment by rounds of cellular aggregation and disaggregation. Distinct CTBS cell lines were isolated and characterized. Spheroid cytotrophoblast bodies were generated and their interaction with luteal-phase endometrial stroma was analysed by real-time image analysis. RESULTS: Three CTBS cell lines were derived, which were maintained in the absence of residual HESCs, fibroblast feeder cells or extracellular matrix. CTBS cells displayed typical cytotrophoblast and syncytiotrophoblast characteristics and exhibited further differentiation to invasive endovascular cell phenotype. One cell line was generated with constitutive expression of enhanced green fluorescent protein (eGFP). Spheroid trophoblast bodies mimicked closely the early invasive stages of implantation when incubated with human endometrial stromal preparations in vitro. CONCLUSION: These human CTBS cell lines are a significant new model for investigating human placentation and may have considerable potential in cell therapy applications.

Incidental hypoglobus: primary amyloidosis of the superior rectus.

A 69-year-old man who presented with incidental hypoglobus was found to have an isolated superior rectus mass. Diagnosis of primary amyloidosis of superior rectus was made on incisional biopsy and negative systemic work-up. This is an unusual manifestation and site for amyloidosis and should be a differential of any extraocular muscle mass.

Five-year incidence and progression of vascular retinopathy in persons without diabetes: the Blue Mountains Eye Study.

PURPOSE: To assess the 5-year incidence of vascular retinopathy and its associations in an older nondiabetic population. METHODS: The Blue Mountains Eye Study examined 3654 residents aged 49+ years (82.4% response rate) during 1992-1994, and re-examined 2335 (75.1% of survivors) during 1997-1999. Retinopathy lesions (microaneurysms, haemorrhages, hard or soft exudates) were assessed from 6-field retinal photographs in persons without diabetes. Incident retinopathy was assessed in those at risk. Hypertensive status was defined following the WHO/International Society of Hypertension guidelines. RESULTS: Of the 2335 re-examined, 195 had retinopathy lesions at baseline and 1725 were at risk of retinopathy after excluding subjects with diabetes (n=261), retinal vein occlusion (n=52) or missing/un-gradable photographs (n=102). The cumulative 5-year incidence was 9.7% (95% confidence intervals (CI) 8.3-11.1%). Age was the only factor significantly associated with incident retinopathy (Pfor trend=0.012). Neither fasting blood glucose (age-sex-adjusted P=0.147) nor hypertension (adjusted Pfor trend=0.43) was associated with incident retinopathy. Of the 195 with retinopathy lesions at baseline, 3.5% developed diabetes, 13.3% progressed, and 72.3% regressed/disappeared over 5 years. Progression was positively associated with elevated blood pressure (BP) (adjusted odds ratio (OR) 1.3, 95% CI 1.1-1.6 per 10 mmHg systolic BP) and inversely associated with fasting glucose level (OR 0.36, CI 0.14-0.92 per mmol/l increase). Aspirin use was weakly associated with regression (OR 2.4, CI 1.0-6.0). CONCLUSIONS: Over 5 years, retinopathy developed in 10% of older people without diabetes, while 72% of baseline lesions regressed. Age was significantly associated with the development of these lesions.

Epidemiology of pterygium on a tropical island in the Riau Archipelago.

OBJECTIVES: To describe the epidemiology of pterygium among residents of an island in Indonesia and to examine the roles of age and gender as determinants of bilaterality and severity of the disease. METHODS: Voluntary eye screening on Pulau Jaloh, Riau Archipelago, Indonesia. Gender difference was tested using the chi2 test. The difference in age between subjects with and without disease was tested using unpaired Student's t-test. Odds ratio (relative risk) for gender was calculated using logistic regression model with adjustment for age. RESULTS: Of the 550 inhabitants, 477 (86.7%) responded to the eye screening. The overall prevalence rate of pterygium was 17.0%. Out of 211, 48 male (22.7%) and 33 out of 266 female subjects (12.4%) had the disorder, with the gender difference being statistically significant. Adjusted for age, the risk of disease was 3.1-fold higher among the males. In all, 71.6% of subjects with pterygium had bilateral disease. Subjects with pterygium were significantly older, their mean age being 42.9 years compared to 18.7 years among those without disease. The prevalence rates in male subjects increased from age 20 to reach a plateau of 63.6% at age 35 and remained stable thereafter. In the female subjects, the rates also increased with age, albeit at a slower rate, from age 20 to reach a plateau of 46.7% at age 55 and remained stable thereafter. CONCLUSIONS: There is a high prevalence rate of pterygium among the study subjects, with the rates increasing rapidly with age.