Associations of presenting visual acuity with morphological changes on OCT in neovascular age-related macular degeneration: PRECISE Study Report 2.

PURPOSE: To study associations of optical coherence tomography (OCT) features with presenting visual acuity (VA) in treatment naive neovascular age-related macular degeneration (nAMD). METHODS: Patients with nAMD initiated on aflibercept therapy were recruited from December 2019 to August 2021. Demographic and OCT (Spectralis, Heidelberg Engineering) features associated with good VA (VA ≥ 68 ETDRS letters, Snellen ≥ 6/12) and poor VA (VA < 54 letters, Snellen < 6/18) were analysed using Generalised Estimating Equations to account for inter-eye correlation. RESULTS: Of 2274 eyes of 2128 patients enrolled, 2039 eyes of 1901 patients with complete data were analysed. Mean age was 79.4 (SD 7.8) years, female:male 3:2 and mean VA 58.0 (SD 14.5) letters. On multivariable analysis VA < 54 letters was associated with increased central subfield thickness (CST) (OR 1.40 per 100 µm; P < 0.001), foveal intraretinal fluid (OR 2.14; P < 0.001), polypoidal vasculopathy (PCV) relative to Type 1 macular neovascularisation (MNV) (OR 1.66; P = 0.049), presence of foveal subretinal hyperreflective material (SHRM) (OR 1.73; P = 0.002), foveal fibrosis (OR 3.85; P < 0.001), foveal atrophy (OR 5.54; P < 0.001), loss of integrity of the foveal ellipsoid zone (EZ) or external limiting membrane (ELM) relative to their preservation (OR 3.83; P < 0.001) and absence of subretinal drusenoid deposits (SDD) (presence vs absence; OR 0.75; P = 0.04). These features were associated with reduced odds of VA ≥ 68 letters except MNV subtypes and SDD. CONCLUSION: Presence of baseline fovea-involving atrophy, fibrosis, intraretinal fluid, SHRM, PCV EZ/ELM loss and increased CST determine poor presenting VA. This highlights the need for early detection and treatment prior to structural changes that worsen baseline VA.

Treatment of cystoid macular oedema secondary to pentosan polysulfate maculopathy using anti-VEGF and intravitreal steroid injections.

BACKGROUND: Pentosan polysulfate-related maculopathy is a recently described clinical entity, related to dose and long term use of this medication, and may progress despite drug cessation. Cystoid macular oedema (CMO) has been reported in some cases, but there are few reports of treatment outcomes in the literature. AIMS: We present the case of a 55 year old female, with CMO secondary to pentosan polysulfate maculopathy, that was responsive to treatment with both intravitreal anti-VEGF and steroid injections, stabilising vision over a four year follow up period. CONCLUSIONS: This is the first report, to our knowledge, of CMO related to pentosan polysulfate maculopathy responding to intravitreal steroid injections, broadening the therapeutic options for preserving vision in these patients.

Pachychoroid spectrum disease.

Recent improvements in ophthalmic imaging have led to the identification of a thickened choroid or pachychoroid to be associated with a number of retinal diseases. The number of conditions linked to this phenotype has continued to widen with specific endophenotypes found within the pachychoroid spectrum. The spectrum includes choroidal features such as focal or diffuse choroidal thickening and thinning of the overlying inner choroid, and choroidal hyperpermeability as demonstrated by indocyanine green angiography. In addition, these diseases are associated with overlying retinal pigmentary changes and retinal pigment epithelial dysfunction and may also be associated with choroidal neovascularization. This article provides a comprehensive review of the literature looking at diseases currently described within the pachychoroid spectrum including central serous chorioretinopathy, pachychoroid pigment epitheliopathy, pachychoroid neovasculopathy, polypoidal choroidal vasculopathy/aneurysmal type 1 neovascularization, peripapillary pachychoroid disease and focal choroidal excavation. We particularly focus on clinical imaging, genetics and pathological findings in these conditions with the aim of updating evidence suggesting a common aetiology between diseases within the pachychoroid spectrum.

Multimodal imaging of a vascularized idiopathic epiretinal membrane.

PURPOSE: To report a case of vascularized idiopathic epiretinal membrane including the multimodal imaging. METHODS: Findings on clinical examination, color fundus photography, spectral-domain optical coherence tomography, optical coherence tomography angiography, and fluorescein angiography. RESULTS: Sixty-three-year-old woman with a previous rhegmatogenous retinal detachment (RRD) who presented with an asymptomatic idiopathic neovascular complex below an epiretinal membrane. It was assessed with fluorescein angiography, OCT and OCT-A. The vascularized ERM was already present previously to the retinal detachment. CONCLUSION: Our case report describes an example of idiopathic epiretinal membrane complicated by neovascularization; we hypothesized hypertension could be one of the factors in this case, as it may lead to decreased retinal perfusion and upregulation in vascular endothelial growth factor (VEGF). Multimodal imaging can help in detecting neovascularized ERM.

Individualizing Therapy for Neovascular Age-Related Macular Degeneration with Aflibercept (VITAL): A Two-Year Prospective, Interventional Single-Centre Trial.

AIMS: To report the mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) and reading performance (reading acuity and maximum reading speed (MRS) using the MNREAD test) between baseline and 24 months in treatment-naïve patients with neovascular age-related macular degeneration (nAMD) treated with intravitreal aflibercept injections. METHODS: A prospective, open-label, interventional non-randomised case series with 24 months' duration. Patients were recruited to the study from medical retina clinics at Moorfields Eye Hospital. Intravitreal injections of 2.0 mg aflibercept in the study eye were administered using a fixed dosing regimen during the first year and a treat-and-extend treatment regimen during the second year of treatment. RESULTS: Fifty patients were enrolled with a mean age (SD) of 78.7 (7.6) years; a mean BCVA of 62.8 ETDRS letters; mean reading acuity of 0.52 logMAR; mean maximum reading speed (MRS) of 141.3 words per minute and a central macular thickness of 322.6 µm at baseline. The mean improvement in BCVA was 6.4 letters for the 44 patients (88%) for whom data was available at 2 years. The mean improvement in reading acuity was 0.13 logMAR with an improvement in MRS of 2.9 words per minute. The mean reduction in CRT from baseline was 104.8 µm. CONCLUSIONS: Aflibercept treatment of nAMD using fixed dosing in year 1 and treat and extend in year 2 leads to improvements in reading ability, visual acuity and retinal morphology which were maintained to 2 years of treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02441816, the VITAL study.

Ten-year outcomes of antivascular endothelial growth factor therapy in neovascular age-related macular degeneration.

PURPOSE: Single center, noninterventional cohort study to assess 10-year visual and anatomical outcomes following initiation of treatment with antivascular endothelial growth factor (anti-VEGF) agents in neovascular age-related macular degeneration (AMD) patients. Neovascular AMD patients initiated on intravitreal anti-VEGF injections in 2008-2009 and continued to be followed up for at least 10 years were included in this study. METHODS: The Moorfields OpenEyes database was searched for all patients who were initiated on anti-VEGF therapy for neovascular AMD in 2008-2009 and the visual acuity (VA) in Early Diabetic Retinopathy Study (ETDRS) letters and injection records were analyzed for those who have had at least 10-year follow-up. The spectral-domain optical coherence tomography (SD-OCT) scans, color fundus photos, and fundus fluorescein angiography (FA) were graded by two retinal physicians. The outcomes were also compared between those with good and poor VA outcomes based on pre-defined criteria. The primary end point was change in VA at 10 years; secondary outcomes included percentage with VA of 20/40 or better, 20/70 or better, VA gains and losses, anatomic outcomes and number of injections. RESULTS: After a mean of 10.04 years after initiation of anti-VEGF therapy, the mean decline in VA from baseline was -2.1 ETDRS letters (SD 19.9, p = 0.65). One hundred eyes (67.1%) achieved a VA threshold of 20/70 or better, 33.5% achieved a VA of 20/40 or better, and 76.5% eyes maintained VA defined as a loss of less than 15 letters. Fourteen percent of study eyes had VA of 20/200 or worse and 23.5% declined by 15 letters or more. 87.5% of eyes were switched from ranibizumab to aflibercept during the course of 10 years and the eyes received a mean of 52.2 (SD 18.1) injections over 10 years. From this cohort, 87 (58.3%) eyes are having on-going treatment. On OCT, 34.9% had persistent fluid at the last visit, 6.7% patients showed new onset atrophy compared to baseline, and 43.7% had increased area of macular atrophy. The mean area of atrophy at the final visit was 4.15 mm2. Comparison between the good and worse visual outcome groups showed lower baseline VA, fovea-involving atrophy and final area of atrophy had a statistically significant negative effect on the final visual outcome (p < 0.05). CONCLUSIONS: Regular monitoring and anti-VEGF treatment over 10 years reduce the risk of visual loss of 15 letters or more in patients with neovascular AMD. The most common cause of substantial visual decline was macular atrophy.

MicroRNA-Related Genetic Variants Are Associated With Diabetic Retinopathy in Type 1 Diabetes Mellitus.

Purpose: Few studies have explored the association of genetic variants in microRNA genes and binding sites with diabetic retinopathy (DR) in type 1 diabetes. We conducted a genome-wide scan for single nucleotide polymorphisms (SNPs) in these genes by using data from a genome-wide association study (GWAS). Methods: All known SNPs were imputed from our GWAS data (n = 325) of DR cases and diabetic controls (no DR). Relevant SNPS were extracted using miRNASNP and PolymiRTS (version 2) databases. χ2 tests and logistic regression (adjusting for age, sex, duration of diabetes, HbA1c, and hypertension) were used to test the association between the imputed SNPs and DR phenotypes (any DR, nonproliferative DR [NPDR], proliferative DR [PDR], diabetic macular edema [DME], and sight-threatening DR defined as PDR, severe NPDR, or clinically significant macula edema [CSME]) compared with diabetic controls. Top-ranking SNPs were genotyped in a larger cohort (N = 560) to confirm their association with DR. Results: Three SNPs (rs10061133, rs1049835, rs9501255) were selected and genotyped in the final cohort. Rs10061133 in MIR449b was protective of sight-threatening DR (odds ratio [OR] = 0.32, P = 3.68 × 10-4) and PDR (OR = 0.30, P = 8.12 × 10-4), and the associations became more significant as the cohort increased in size. Conclusions: Rs10061133 in MIR449b is significantly associated with a decreased risk of PDR and sight-threatening DR in Caucasian patients with type 1 diabetes. This can guide future studies on genetic risk profiling and on developing microRNA-related therapies for sight-threatening DR.

Mitochondrial haplogroups are not associated with diabetic retinopathy in a large Australian and British Caucasian sample.

Mitochondrial haplogroups H1, H2 and UK have previously been reported to be associated with proliferative diabetic retinopathy (PDR) in Caucasian patients with diabetes. We aimed to replicate this finding with a larger sample and expand the analysis to include different severities of DR, and diabetic macular edema (DME). Caucasian participants (n = 2935) with either type 1 or type 2 diabetes from the Australian Registry of Advanced Diabetic Retinopathy were enrolled in this study. Twenty-two mitochondrial single nucleotide polymorphisms were genotyped by MassArray and haplogroups reconstructed using Haplogrep. Chi square tests and logistic regressions were used to test associations between haplogroup and DR phenotypes including any DR, non-proliferative DR (NPDR), proliferative DR (PDR) and DME. After stratifying the samples in type 1 and type 2 diabetes groups, and adjusting for sex, age, diabetes duration, concurrent HbA1c and hypertension, neither haplogroups H1, H2, UK, K or JT were associated with any DR, NPDR, PDR or DME.

Unilateral pigmentary retinopathy: a retrospective case series.

PURPOSE: To review the clinical characteristics and address the aetiology in a group of patients presenting with unilateral retinal pigmentary changes, best described as unilateral pigmentary retinopathy (UPR). METHODS: The cohort of 42 patients was identified retrospectively from the Moorfields Eye Hospital electrophysiology database. All had undergone full-field [electroretinography (ERG)] and pattern electroretinography (PERG), with 13 additionally having multifocal ERG (mfERG). The clinical findings, fundus photographs and fundus autofluorescence (AF) images were reviewed. RESULTS: All index eyes showed ERG evidence of generalized photoreceptor dysfunction with most showing a similar degree of rod and cone involvement. However, although the fellow eyes all had a normal fundus examination, there were bilateral but asymmetrical ERG abnormalities in eight patients and a further four patients had PERG evidence of macular dysfunction in the fellow eye. A relevant medical history or the diagnosis of an ophthalmologic entity that might be related to the unilateral fundus changes was ascertained in 15 cases (~36%) including acute zonal occult outer retinopathy, trauma, systemic malignancy or autoimmune disease, retinal vasculitis, presumed pregnancy-related choroidal ischaemia and meningitis. Two patients had a family history of retinitis pigmentosa (RP; 4.8%). CONCLUSION: The underlying aetiology in most cases of UPR cannot accurately be identified, but an heritable cause is unlikely. Aspects of the history clearly suggest an acquired disorder in some patients. Twenty-five patients (60%) with nongenetic UPR did not adhere to the pattern of rod greater than cone dysfunction that occurs in RP (rod-cone dystrophy), and the pattern of rod > cone dysfunction seen in true RP is thus not a feature of most patients with UPR.

Genome-wide association studies for diabetic macular edema and proliferative diabetic retinopathy.

BACKGROUND: Diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) are sight-threatening complications of diabetes mellitus and leading causes of adult-onset blindness worldwide. Genetic risk factors for diabetic retinopathy (DR) have been described previously, but have been difficult to replicate between studies, which have often used composite phenotypes and been conducted in different populations. This study aims to identify genetic risk factors for DME and PDR as separate complications in Australians of European descent with type 2 diabetes. METHODS: Caucasian Australians with type 2 diabetes were evaluated in a genome-wide association study (GWAS) to compare 270 DME cases and 176 PDR cases with 435 non-retinopathy controls. All participants were genotyped by SNP array and after data cleaning, cases were compared to controls using logistic regression adjusting for relevant covariates. RESULTS: The top ranked SNP for DME was rs1990145 (p = 4.10 × 10- 6, OR = 2.02 95%CI [1.50, 2.72]) on chromosome 2. The top-ranked SNP for PDR was rs918519 (p = 3.87 × 10- 6, OR = 0.35 95%CI [0.22, 0.54]) on chromosome 5. A trend towards association was also detected at two SNPs reported in the only other reported GWAS of DR in Caucasians; rs12267418 near MALRD1 (p = 0.008) in the DME cohort and rs16999051 in the diabetes gene PCSK2 (p = 0.007) in the PDR cohort. CONCLUSION: This study has identified loci of interest for DME and PDR, two common ocular complications of diabetes. These findings require replication in other Caucasian cohorts with type 2 diabetes and larger cohorts will be required to identify genetic loci with statistical confidence. There is considerable overlap in the patient cohorts with each retinopathy subtype, complicating the search for genes that contribute to PDR and DME biology.

Central Serous Chorioretinopathy Associated with Desmopressin Nasal Spray: Causality or Unfortunate Association.

PURPOSE: To describe the possible association between central serous chorioretinopathy (CSCR) and desmopressin use. METHODS: The case histories of 2 middle-aged men with CSCR using desmopressin nasal spray were studied. RESULTS: The diagnosis of CSCR was made on the basis of clinical features and ancillary testing (fluorescein angiography and optical coherence tomography). Both patients were using desmopressin nasal spray for polyuria when they developed the first ocular symptoms. Both of them also had an independent risk factor for developing CSCR. CONCLUSION: We suggest that desmopressin-induced hypercortisolism might implicate the development of CSCR in some patients. A larger study on patients using desmopressin nasal spray would be beneficial to confirm the possible association between this form of therapy and the development of CSCR.

A single-nucleotide polymorphism in the MicroRNA-146a gene is associated with diabetic nephropathy and sight-threatening diabetic retinopathy in Caucasian patients.

AIMS: This study aimed to investigate whether the single-nucleotide polymorphism (SNP) rs2910164 residing within microRNA-146a (miR-146a) is associated with diabetic microvascular complications diabetic nephropathy (DN), proliferative diabetic retinopathy (PDR) or diabetic macular oedema (DME) in either Caucasian patients with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus. METHODS: Caucasian patients with T1DM (n = 733) or T2DM (n = 2215) were recruited from ophthalmology, renal and endocrine clinics in Australia and the UK. Patients with T2DM were required to have diabetes mellitus (DM) for at least 5 years and be on treatment with oral hypoglycaemic drugs or insulin. In total, 890 participants had DN (168 with T1DM and 722 with T2DM), 731 had PDR (251 with T1DM and 480 with T2DM) and 1026 had DME (170 with T1DM and 856 with T2DM). Participants were genotyped for SNP rs2910164 in miR-146a. Analyses investigating association were adjusted for relevant clinical covariates including age, sex, DM duration, HbA1c and hypertension. RESULTS: A significant association was found between the C allele of rs2910164 and DN in the T1DM group (OR 1.93; CI 1.23-3.03; P = 0.004), but no association found in the T2DM group (OR 1.05; CI 0.83-1.32; P = 0.691). In the subset of T2DM patients, the C allele was specifically associated with DME (OR 1.25; CI 1.03-1.53; P = 0.025). No association with DME was found in the T1DM group (OR 0.87; CI 0.54-1.42); P = 0.583), or with PDR for either type of DM. CONCLUSIONS: Rs2910164 is significantly associated with microvascular complications DN in patients with T1DM and DME in patients with T2DM.

Promoter polymorphism at the tumour necrosis factor/lymphotoxin-alpha locus is associated with type of diabetes but not with susceptibility to sight-threatening diabetic retinopathy.

AIM: To investigate, in a large cohort of 2494 individuals with diabetes mellitus, whether functional single nucleotide polymorphisms in the promoter region of tumour necrosis factor (TNF) and lymphotoxin-alpha (LTA) genes are associated with type of diabetes or presence of diabetic retinopathy. METHODS: A total of 334 type 1 diabetes and 999 type 2 diabetes participants with sight-threatening diabetic retinopathy, and 260 type 1 diabetes and 901 type 2 diabetes participants with no diabetic retinopathy or minimal non-proliferative diabetic retinopathy, were genotyped for two single nucleotide polymorphisms (rs1800629 and rs361525). RESULTS: The A allele of rs1800629 was associated with type 1 diabetes (p < 0.001; odds ratio = 0.62). After adjustment for age, sex, diabetes duration, HbA1c, hypertension and nephropathy, no significant association was found between rs1800629 or rs361525 and sight-threatening diabetic retinopathy. CONCLUSION: An association between the A allele of rs1800629 and type of diabetes was found. No association was found between two promoter variants of TNF and LTA, and diabetic retinopathy in a large cohort of Caucasian patients with type 1 diabetes and type 2 diabetes.

VITREOMACULAR TRACTION AFFECTS ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT OUTCOMES FOR EXUDATIVE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To evaluate the effect of vitreomacular traction (VMT) on visual acuity outcomes and central retinal thickness (CRT) measurements after intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy for treatment of exudative age-related macular degeneration (AMD). METHODS: In this retrospective series, the authors evaluate the clinical records and optical coherence tomography of 34 eyes of 32 patients, with VMT confirmed on optical coherence tomography at baseline, to assess the effects of VMT on anti-VEGF therapy for newly diagnosed exudative wet AMD. Best-corrected visual acuity at baseline, 1, 3, 6, 9, and 12 months and CRT at baseline, 3, 6, and 12 months were assessed. Comparison was made with a control group of 29 eyes of 28 patients with wet AMD and no VMT on optical coherence tomography and with key variable-dosing studies for anti-VEGF in exudative AMD (CATT, HARBOR, PrONTO, SUSTAIN, and Gupta et al). RESULTS: Best-corrected visual acuity results showed a visual acuity improvement that peaked at 3 months with 2.47 letters, well below other variable-dosing studies for anti-VEGF therapy in exudative AMD. This was then followed by a steady decline with mean best-corrected visual acuity at 12 months ending below the baseline level (-1.00 letters) compared with a gain of 9.39 letters in the control group at 12 months. Comparison of the mean CRT in the VMT group between baseline and 12 months showed no significant difference (P = 0.67), whereas the PrONTO study and control groups showed a highly significant difference at 12 months compared with baseline (P < 0.001). Mean CRT values at 6 months and 12 months were essentially at baseline levels (0.26 µm, -0.62 µm, respectively). CONCLUSION: Vitreomacular traction at baseline, existing concurrently with newly diagnosed exudative AMD treated with intravitreal anti-VEGF therapy on a variable-dosing regime, was associated with poorer visual outcomes and a decreased response to reduction in CRT, compared with a control group of wet AMD without VMT and compared with major variable-dosing studies for intravitreal anti-VEGF in exudative AMD.

Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene.

AIMS/HYPOTHESIS: Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study. METHODS: Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (n = 336) with diabetic controls with no retinopathy (n = 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene GRB2 by immunohistochemistry and quantitative western blot. RESULTS: The top ranked variant was rs3805931 with p = 2.66 × 10(-7), but no association was found in the replication cohort. Only rs9896052 (p = 6.55 × 10(-5)) was associated with sight-threatening diabetic retinopathy in both the type 2 (p = 0.035) and the type 1 (p = 0.041) replication cohorts, as well as in the Indian cohort (p = 0.016). The study-wide meta-analysis reached genome-wide significance (p = 4.15 × 10(-8)). The GRB2 gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina. CONCLUSIONS/INTERPRETATION: Genetic variation near GRB2 on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular GRB2 is upregulated during retinal stress and neovascularisation.

Common Sequence Variation in the VEGFC Gene Is Associated with Diabetic Retinopathy and Diabetic Macular Edema.

PURPOSE: To investigate associations between single nucleotide polymorphisms (SNPs) in the VEGFC gene and the development of diabetic retinopathy (DR) in white patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). DESIGN: Cross-sectional, case control study. PARTICIPANTS: White patients with T1DM or T2DM (n = 2899) were recruited from ophthalmology and endocrine clinics in Australia and the United Kingdom. Patients with T2DM were required to have diabetes mellitus (DM) for at least 5 years and be receiving oral hypoglycemic treatment or insulin. METHODS: Participants were categorized according to their worst-ever DR grading, as having "no DR" (no history of nonproliferative DR [NPDR], proliferative DR [PDR], or diabetic macular edema [DME]) or "any DR" (further subclassified as NPDR or PDR, without or with DME). Clinical characteristics, glycemic control (hemoglobin A1c [HbA1c]), and presence of diabetic complications were determined at recruitment. Genotyping was performed for 13 VEGFC tag SNPs. MAIN OUTCOME MEASURES: Odds ratios (ORs) were determined for associations with DR of VEGFC tag SNPs, individually and within haplotypes. Logistic regression was used to adjust for clinical covariates, including DM type, age, sex, DM duration, hypertension, nephropathy, HbA1c, and smoking. RESULTS: Participants with DM but "no DR" (n = 980) were compared with 1919 participants with DM and "any DR." Three VEGFC SNPs were associated with DR after logistic regression: rs17697419 (P = 0.001; OR, 0.67; confidence interval [CI], 0.52-0.85), rs17697515 (P = 0.001; OR, 0.62; CI, 0.47-0.81), and rs2333526 (P = 0.005; OR, 0.69; CI, 0.54-0.90). rs17697515 Was also specifically associated with DME in those with T2DM (P = 0.004; OR, 0.53; CI, 0.35-0.82). Haplotype analysis revealed 2 significantly associated haplotypes, both protective against DR development. CONCLUSIONS: Significant associations were found between VEGFC tag SNPs (individually and within haplotypes) and the presence of any DR or DME in white participants with T1DM and T2DM.

Multimodal imaging of exudative maculopathy associated with hand-foot-mouth disease.

A 31-year-old man presented with acute unilateral visual loss secondary to hand-foot-mouth disease (HFMD). Ophthalmic examination demonstrated best corrected visual acuity (BCVA) of 6/24 and a macular neurosensory detachment. He was diagnosed with unilateral acute idiopathic maculopathy (UAIM), and multimodality imaging was performed. No treatment was warranted. At 3 months, BCVA was 6/5 and funduscopy revealed a juxtafoveal scar. Based on the evidence of the association between HFMD and UAIM, the authors refer to this condition as exudative maculopathy associated with HFMD. Multimodality imaging during acute and convalescent phases is useful to study this disorder and raises questions about choroidal and bilateral involvement. Ophthalmologists should be aware of this and query about systemic signs and symptoms.

Genetic study of diabetic retinopathy: recruitment methodology and analysis of baseline characteristics.

BACKGROUND: Diabetic retinopathy (DR) is a blinding disease of increasing prevalence that is caused by a complex interplay of genetic and environmental factors. Here we describe the patient recruitment methodology, case and control definitions, and clinical characteristics of a study sample to be used for genome-wide association analysis to detect genetic risk variants of DR. METHODS: One thousand six hundred sixty-nine participants with either type 1 (T1) or type 2 (T2) diabetes mellitus (DM) aged 18 to 95 years were recruited in Australian hospital clinics. Individuals with T2DM had disease duration of at least 5 years and were taking oral hypoglycaemic medication, and/or insulin therapy. Participants underwent ophthalmic examination. Medical history and biochemistry results were collected. Venous blood was obtained for genetic analysis. RESULTS: Six hundred eighty-three diabetic cases (178 T1DM and 505 T2DM participants) with sight-threatening DR, defined as severe non-proliferative DR, proliferative DR or diabetic macular oedema were included in this analysis. Eight hundred twelve individuals with DM but no DR or minimal non-proliferative DR were recruited as controls (191 with T1DM and 621 with T2DM). The presence of sight-threatening DR was significantly correlated with DM duration, hypertension, nephropathy, neuropathy, HbA1C and body mass index. Diabetic macular oedema was associated with T2DM (P < 0.001), whereas proliferative DR was associated with T1DM (P < 0.001). CONCLUSIONS: Adoption of a case-control study design involving extremes of the DR phenotype makes this a suitable cohort, for a well-powered genome-wide association study to detect genetic risk variants for DR.

Recessive mutations in SLC38A8 cause foveal hypoplasia and optic nerve misrouting without albinism.

Foveal hypoplasia and optic nerve misrouting are developmental defects of the visual pathway and only co-occur in connection with albinism; to date, they have only been associated with defects in the melanin-biosynthesis pathway. Here, we report that these defects can occur independently of albinism in people with recessive mutations in the putative glutamine transporter gene SLC38A8. Nine different mutations were identified in seven Asian and European families. Using morpholino-mediated ablation of Slc38a8 in medaka fish, we confirmed that pigmentation is unaffected by loss of SLC38A8. Furthermore, by undertaking an association study with SNPs at the SLC38A8 locus, we showed that common variants within this gene modestly affect foveal thickness in the general population. This study reveals a melanin-independent component underpinning the development of the visual pathway that requires a functional role for SLC38A8.