Stewart Lake

Assessment of polygenic effects links primary open-angle glaucoma and age-related macular degeneration.

Primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD) are leading causes of irreversible blindness. Several loci have been mapped using genome-wide association studies. Until very recently, there was no recognized overlap in the genetic contribution to AMD and POAG. At genome-wide significance level, only ABCA1 harbors associations to both diseases. Here, we investigated the genetic architecture of POAG and AMD using genome-wide array data. We estimated the heritability for POAG (h2g = 0.42 ± 0.09) and AMD (h2g = 0.71 ± 0.08). Removing known loci for POAG and AMD decreased the h2g estimates to 0.36 and 0.24, respectively. There was evidence for a positive genetic correlation between POAG and AMD (rg = 0.47 ± 0.25) which remained after removing known loci (rg = 0.64 ± 0.31). We also found that the genetic correlation between sexes for POAG was likely to be less than 1 (rg = 0.33 ± 0.24), suggesting that differences of prevalence among genders may be partly due to heritable factors.

Common Sequence Variation in the VEGFA Gene Predicts Risk of Diabetic Retinopathy

PURPOSE Vascular endothelial growth factor (VEGF) is a multifunctional cytokine that plays a role in angiogenesis and microvascular permeability. This study was conducted to determine whether common sequence variation in the VEGFA gene plays a role in the development of diabetic retinopathy (DR). METHOD Five hundred fifty-four subjects with diabetes mellitus (DM) including 190 type 1 DM (T1DM) and 364 type 2 DM (T2DM) were recruited. The study group consisted of 235 participants without DR, 158 with nonproliferative DR (NPDR), 132 with proliferative DR (PDR), and 93 with clinically significant macular edema (CSME). Blinding DR was defined as severe NPDR, PDR, or CSME. Fifteen VEGFA tag single-nucleotide polymorphisms (SNPs) were genotyped in all subjects and tested for association with blinding DR. RESULTS Multiple tag SNPs in the VEGFA gene were associated with blinding DR. After controlling for sex, HbA1c, and duration of disease, in T1DM, the AA genotype of rs699946 (P = 0.007, odds ratio [OR], 4.1; 95% confidence interval [CI], 1.5-11.4) and the GG genotype of rs833068 (P = 0.017, OR, 3.1; 95% CI, 1.3-7.2) were most significantly associated. In T2DM, the C allele of rs3025021 (P = 0.002; OR, 3.8; 95% CI, 1.5-10.0) and the G allele of rs10434 (P = 0.002; OR, 2.6; 95% CI, 1.3-5.3) were most significantly associated with blinding DR. Haplotype analyses suggested an important role for the haplotype TCCGCG in blinding DR (P = 0.0004). CONCLUSIONS Sequence variation in the VEGFA gene is associated with risk of developing blinding DR in T1DM and T2DM. Identifying specific genetic markers will allow for refined screening algorithms and earlier intervention in patients at highest risk.

Aldose Reductase Gene Polymorphisms and Diabetic Retinopathy Susceptibility

OBJECTIVE Aldose reductase (ALR) is involved in diabetic microvascular damage via the polyol pathway. A recent meta-analysis found genetic variation in the ALR gene (AKR1B1) to be significantly associated with diabetic retinopathy (DR). We investigated the genetic association of AKR1B1 with DR. RESEARCH DESIGN AND METHODS The study enrolled 909 individuals with diabetes. Participants were genotyped for an AKR1B1 (CA)n microsatellite and 14 tag single nucleotide polymorphisms, and ophthalmological assessment was performed. RESULTS A total of 514 individuals were found to have DR. rs9640883 was significantly associated with DR (P = 0.0005). However, AKR1B1 variation was not independently associated with DR development after adjusting for relevant clinical parameters. rs9640883 was associated with duration of diabetes (P = 0.002). CONCLUSION Many previous reports have failed to account for known risk factors for DR. The commonly reported association of AKR1B1 with DR may be due to an association of the gene with younger age at onset of diabetes.

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

Aims/hypothesisDiabetic 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.MethodsRetinopathy 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.ResultsThe 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/interpretationGenetic 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.

Use of intravitreal rituximab for treatment of vitreoretinal lymphoma

Aim Vitreoretinal lymphoma is a diffuse large B cell non-Hodgkin lymphoma. Targeting malignant cells with rituximab is being used increasingly as local chemotherapy, but information on this treatment is scant. We aimed to describe current therapeutic approaches, as well as responses to and complications of, intravitreal rituximab in patients with vitreoretinal lymphoma. Methods Clinical data were collected in a standardised manner retrospectively on patients with vitreoretinal lymphoma treated with intravitreal rituximab. Results 48 eyes (34 patients) with vitreoretinal lymphoma were treated with a median of 3.5 intravitreal injections of rituximab (1 mg/0.1 mL) for new diagnosis (68.8%), progressive disease (29.9%) and maintenance therapy (2.1%). Intravitreal rituximab±methotrexate was the sole treatment in 19 eyes (39.6%). 31 eyes (64.6%) eyes achieved complete remission, after a median of 3 injections; 7 of these eyes developed recurrent disease. 11 eyes (22.9%) achieved partial remission. Although rituximab may have contributed to complications reported in 12 eyes (25.0%), a 2-line loss of Snellen visual acuity occurred in only 2 of those eyes (4.2%). Conclusions Approaches in rituximab-based intravitreal chemotherapy vary widely, but our findings suggest that this treatment may be safe and effective in inducing remission in a majority of eyes with vitreoretinal lymphoma.

Revisiting transconjunctival sutureless 25‐gauge vitrectomy: still worthwhile?

To present the outcomes of various retinal conditions treated with the sutureless 25‐gauge (25G) vitrectomy technique. Retrospective case review of 232 eyes of 228 patients who underwent 25G vitrectomy from January 2003 to August 2006. Follow‐up was a minimum of 3 months. Indications for surgery included idiopathic macular hole, rhegmatogenous retinal detachment, epiretinal membrane and proliferative diabetic retinopathy. Main outcome measures included final visual acuity, re‐operation rate and surgical complications such as endophthalmitis, hypotony and retinal (re)detachment. For all cases, the mean overall visual acuity (logMAR) improved from 0.9 preoperatively to 0.5 (P < 0.0001). The improvement in acuity was highest in the rhegmatogenous detachment and diabetic groups. Transient postoperative hypotony was observed in 15 cases (9.2%) on day 1 after surgery but all these cases resolved. In 7.3% of the cases (17 out of 232) additional surgery was performed due to retina (re)detachment but final anatomic success was achieved in all cases; the detachments occurred within the first 3 months. One patients developed endophthalmitis (0.4%) which coincided with subconjunctival antibiotics being discontinued in favour of topical treatment. The 25G system remains a safe and effective technique for a variety of retinal conditions; significant fast visual rehabilitation is an advantage.

Review of the prevalence of diabetic retinopathy in Indigenous Australians

The purpose of this review is to compare the prevalence of diabetic retinopathy (DR) between Indigenous and non‐Indigenous Australians with Diabetes Mellitus (DM). Australian DR prevalence data from 6 Indigenous studies (n = 2865) and 5 non‐Indigenous studies (n = 9801) conducted between 1985 and 2013 were included for analysis. Estimated prevalence of any DR among Indigenous Australians with DM was 23.4% compared with 28.9% for non‐Indigenous Australians (χ2 = 26.9, P < 0.001). In studies performed after 1990, a significantly higher rate of diabetic macular edema was found in Indigenous compared with non‐Indigenous Australians with DM (7.6% versus 4.9%, χ2 = 6.67, P = 0.01). Although there are limitations in comparing these studies, one explanation for the observed data could be a model in which Indigenous Australians are relatively resistant to early stage DR, but with a subset progressing to sight threatening DR due to individual genetic and environmental susceptibility factors coupled with poor glycemic control.

Retinal Vascular Abnormalities in Patients with Cerebral Amyloid Angiopathy

Objective: To describe the ophthalmology findings in patients with cerebral amyloid angiopathy (CAA). Methods: Data source and subjects: 7 consecutive patients admitted to a tertiary stroke unit with CAA-related hemorrhage, confirmed on magnetic resonance brain imaging gradient echo sequences by 2 independent neuroradiologists. Design: case series. Measurements and data analysis: fundus colored photographs and fundus fluorescein angiography. Results: All patients showed bilateral multiple dot and blot hemorrhages as well as multiple microaneurysms on fundus fluorescein angiography. Conclusion: Microaneurysms and dot and blot hemorrhages funduscopically mirror the histopathology of CAA. This case series is the first to describe retinal vessel changes in CAA and, if confirmed in larger population studies, has the potential to provide insights into the natural history of CAA.

Understanding the patient’s lived experience of neovascular age-related macular degeneration: a qualitative study

PurposeIn industrialised populations age-related macular degeneration (ARMD) is the leading cause of visual disability of the elderly. Successful new treatment with anti-endothelial growth factors for neovascular-classified ARMD has led to a divergence in treatment and experiences of people ARMD. This study aimed to understand the participant’s experience of neovascular ARMD, including ongoing treatment with anti-vascular endothelial growth factor.MethodsTwenty-five participants from one clinical site were qualitatively interviewed to elicit their experiences of treatment for neovascular ARMD.ResultsTwo major themes were identified. A life negotiated by neovascular ARMD captures the participants’ experience of living with the condition and treatment regime for neovascular ARMD. The second major theme: Uncertainty displayed their appraisal of life, treatment and their perceived future.ConclusionsAnxieties concerning the injections, new limitations to lifestyles, and an uncertain future all emerged from the data analysis. However, thankfulness for the treatment, the importance of familiar patterns in treatments and recovery and a guarded optimism also emerged. Knowledge of the experiences, anxieties and concerns of this patient population can be used to inform clinical practice and lead to patient-centred care.

Neuroretinitis following bull ant sting

Cat scratch disease causes the majority of cases of neuroretinitis. Neuroretinitis is characterised by clinical features of papillitis, macular oedema and macular star. We report a case study of infection with Bartonella henselae most likely transmitted by a bull ant sting. The patient presented with blurred vision and reduced visual acuity after being stung by an ant in her garden some 7 days earlier. Further testing revealed positive serology to B henselae and the patient improved with appropriate treatment.