Anand Rajendran

Proinflammatory cytokines and angiogenic and anti-angiogenic factors in vitreous of patients with proliferative diabetic retinopathy and eales' disease

Purpose: To investigate the mechanism of angiogenesis in proliferative diabetic retinopathy (PDR) and Eales’ disease (ED) on the basis of the levels of proinflammatory cytokines, angiogenic growth factor, and antiangiogenic factor in the vitreous humor. Methods: Twenty-five patients with PDR, 10 patients with ED, and 25 with macular hole (MH) as control subjects were studied. The concentration of the proinflammatory cytokines interleukin-6 (IL-6), IL-8, IL-1&bgr;; chemokine-monocyte chemoattractant protein-1 (MCP-1); angiogenic factor-vascular endothelial growth factor (VEGF); and antiangiogenic factor-pigment epithelium derived factor (PEDF) in the vitreous fluid obtained from the eyes during vitrectomy were measured by sandwich enzyme linked immunosorbent assay (ELISA). Results: IL-6, IL-8, MCP-1, and VEGF levels in the vitreous were significantly higher in PDR (P < 0.0001) and ED (P < 0.0001) than in MH patients. Conversely, the vitreous level of PEDF was significantly reduced in PDR (P < 0.0001) but not in ED. A significant correlation was observed between VEGF and IL-6 in ED patients. Conclusion: The authors demonstrate the importance of VEGF in retinal neovascularization of ED which is an idiopathic inflammatory venous occlusion. Further study is required to understand the interrelationship between VEGF and inflammatory cytokines in PDR and ED.

Association analysis of nine candidate gene polymorphisms in Indian patients with type 2 diabetic retinopathy

BackgroundDiabetic retinopathy (DR) is classically defined as a microvasculopathy that primarily affects the small blood vessels of the inner retina as a complication of diabetes mellitus (DM).It is a multifactorial disease with a strong genetic component. The aim of this study is to investigate the association of a set of nine candidate genes with the development of diabetic retinopathy in a South Indian cohort who have type 2 diabetes mellitus (T2DM).MethodsSeven candidate genes (RAGE, PEDF, AKR1B1, EPO, HTRA1, ICAM and HFE) were chosen based on reported association with DR in the literature. Two more, CFH and ARMS2, were chosen based on their roles in biological pathways previously implicated in DR. Fourteen single nucleotide polymorphisms (SNPs) and one dinucleotide repeat polymorphism, previously reported to show association with DR or other related diseases, were genotyped in 345 DR and 356 diabetic patients without retinopathy (DNR). The genes which showed positive association in this screening set were tested further in additional sets of 100 DR and 90 DNR additional patients from the Aravind Eye Hospital. Those which showed association in the secondary screen were subjected to a combined analysis with the 100 DR and 100 DNR subjects previously recruited and genotyped through the Sankara Nethralaya Hospital, India. Genotypes were evaluated using a combination of direct sequencing, TaqMan SNP genotyping, RFLP analysis, and SNaPshot PCR assays. Chi-square and Fisher exact tests were used to analyze the genotype and allele frequencies.ResultsAmong the nine loci (15 polymorphisms) screened, SNP rs2070600 (G82S) in the RAGE gene, showed significant association with DR (allelic P = 0.016, dominant model P = 0.012), compared to DNR. SNP rs2070600 further showed significant association with DR in the confirmation cohort (P = 0.035, dominant model P = 0.032). Combining the two cohorts gave an allelic P < 0.003 and dominant P = 0.0013). Combined analysis with the Sankara Nethralaya cohort gave an allelic P = 0.0003 and dominant P = 0.00011 with an OR = 0.49 (0.34 - 0.70) for the minor allele. In HTRA1, rs11200638 (G>A), showed marginal significance with DR (P = 0.055) while rs10490924 in LOC387715 gave a P = 0.07. No statistical significance was observed for SNPs in the other 7 genes studied.ConclusionsThis study confirms significant association of one polymorphism only (rs2070600 in RAGE) with DR in an Indian population which had T2DM.

An Essential Role of the Cysteine-rich Domain of FZD4 in Norrin/Wnt Signaling and Familial Exudative Vitreoretinopathy

The Wnt pathway plays important yet diverse roles in health and disease. Mutations in the Wnt receptor FZD4 gene have been confirmed to cause familial exudative vitreoretinopathy (FEVR). FEVR is characterized by incomplete vascularization of the peripheral retina, which can lead to vitreous bleeding, tractional retinal detachment, and blindness. We screened for mutations in the FZD4 gene in five families with FEVR and identified five mutations (C45Y, Y58C, W226X, C204R, and W496X), including three novel mutations (C45Y, Y58C, and W226X). In the retina, Norrin serves as a ligand and binds to FZD4 to activate the Wnt signaling pathway in normal angiogenesis and vascularization. The cysteine-rich domain (CRD) of FZD4 has been shown to play a critical role in Norrin-FZD4 binding. We investigated the effect of mutations in the FZD4 CRD in Norrin binding and signaling in vitro and in vivo. Wild-type and mutant FZD4 proteins were assayed for Norrin binding and Norrin-dependent activation of the canonical Wnt pathway by cell-surface and overlay binding assays and luciferase reporter assays. In HEK293 transfection studies, C45Y, Y58C, and C204R mutants did not bind to Norrin and failed to transduce FZD4-mediated Wnt/β-catenin signaling. In vivo studies using Xenopus embryos showed that these FZD4 mutations disrupt Norrin/β-catenin signaling as evidenced by decreased Siamois and Xnr3 expression. This study identified a new class of FZD4 gene mutations in human disease and demonstrates a critical role of the CRD in Norrin binding and activation of the β-catenin pathway.

Recent developments in retinal lasers and delivery systems

Photocoagulation is the standard of care for several ocular disorders and in particular retinal conditions. Technology has offered us newer lasing mediums, wavelengths and delivery systems. Pattern scan laser in proliferative diabetic retinopathy and diabetic macular edema allows laser treatment that is less time consuming and less painful. Now, it is possible to deliver a subthreshold micropulse laser that is above the threshold of biochemical effect but below the threshold of a visible, destructive lesion thereby preventing collateral damage. The advent of solid-state diode yellow laser allows us to treat closer to the fovea, is more effective for vascular structures and offers a more uniform effect in patients with light or irregular fundus pigmentation. Newer retinal photocoagulation options along with their advantages is discussed in this review.

Management of rhegmatogenous retinal detachment with coexisting macular hole: a comparison of vitrectomy with and without internal limiting membrane peeling.

Purpose: To compare the outcomes of vitrectomy with or without internal limiting membrane peeling for rhegmatogenous retinal detachment and coexisting macular hole. Methods: Thirty-one consecutive patients (31 eyes) with macula-off retinal detachment, peripheral breaks and a coexisting macular hole were prospectively enrolled over a 3-year period. All patients underwent vitrectomy with encirclage and gas or silicone oil tamponade. The 17 patients who underwent internal limiting membrane peeling for macular hole constituted Group A and the remaining 14 patients constituted Group B. The main outcome measures were change in best-corrected visual acuity, retinal reattachment, macular hole closure, and type of macular hole closure. Results: The two groups were comparable in preoperative demographics and clinical parameters. The retinal reattachment rate was 100% in both the groups. Macular hole closed in 14 of 17 eyes (82.4%) in Group A and 13 of 14 eyes (92.9%) in Group B (P = 0.607). A flat-open configuration of macular hole closure was observed in 8 of 14 eyes (57%) in Group A and 3 of 13 eyes (27.5%) in Group B (P = 0.188). Mean logarithm of the minimum angle of resolution best-corrected visual acuity improved to 1.0 ± 0.3 (20/200; range, 0.8–1.7) in Group A and 0.6 ± 0.2 (20/80; range, 0.3–1.1) in Group B (P < 0.0001). Ten patients achieved best-corrected visual acuity of ≥20/80 in Group B and none in Group A (P < 0.0001). Conclusion: The anatomical and visual outcomes of vitrectomy without internal limiting membrane peeling in macular hole in retinal detachment were similar to or better than the outcomes obtained with internal limiting membrane peeling.

Atypical manifestations of diabetic retinopathy.

Purpose of review As the prevalence of diabetes mellitus increases globally, recognition of the atypical manifestations of diabetic retinopathy will become increasingly important. Recent findings In addition to the inherent variability in the spectrum of diabetic retinopathy, coexisting systemic or ocular conditions can dramatically alter the retinal manifestations of diabetes mellitus in any given patient. Summary We review here the clinical features and treatment implications associated with the atypical manifestations of diabetic retinopathy.

Chronic retinal pigment epithelial detachments with unusual clinical, angiographic, and tomographic presentations.

The authors report two cases of central serous chorioretinopathy of long duration where retinal pigment epithelial detachment presented with unusual clinical features and led to misdiagnosis of a cystic mass lesion in one patient. Fluorescein angiography showed atypical fluorescence patterns, which did not help to diagnose or explain the clinical appearance. Optical coherence tomography confirmed the diagnosis and explained the anatomic basis of the anomalous clinical and angiographic presentation by highlighting the atrophic changes in the retinal pigment epithelial lining of the pigment epithelial detachment in both cases.

Localized Serous Retinal Detachment of Macula as a Marker of Malignant Hypertension.

The association between serous retinal detachment of macula (SRD) in hypertensive retinopathy (HTR) and malignant hypertension has been reported. This cross-sectional study included 14 consecutive patients on treatment for hypertension, who were referred for ophthalmic evaluation and were found to have macular SRD, documented by optical coherence tomography. All underwent systemic evaluation for hypertensive status and to rule out other associated/similar diseases such as diabetes, coagulopathies, lupus etc. The mean age of the patients was 44.35 +/- 15.5 years; the mean best-corrected visual acuity was 6/12. All had grade 3-4 HTR; 10 patients had bilaterally symmetrical retinopathy (grade 3 or 4); 4 had asymmetric fundus changes. Systemically, every patient was found to have malignant hypertension. The mean systolic and diastolic pressures were 208.57 +/- 32.78 and 117.86 +/- 14.2 mm Hg, respectively. SRD predicted malignant hypertension more consistently than papilledema (P = .0132). The presence of macular SRD in a hypertensive patient may serve as an indicator of malignant hypertension.

Early closure of macular hole secondary to rhegmatogenous retinal detachment with internal limiting membrane peeling.

The authors report rapid closure of macular holes secondary to rhegmatogenous retinal detachment with internal limiting membrane peeling. Four patients with macular hole and macula-off rhegmatogenous retinal detachment underwent belt buckling, vitrectomy, and silicone oil tamponade. The internal limiting membrane was removed using trypan blue dye. Preoperative visual acuity ranged from hand motions to 4/60. Optical coherence tomography was performed preoperatively and postoperatively on day 1 and at each visit. One day postoperatively, the retina was attached and macular holes were closed. Follow-up ranged from 6 to 12 months (mean: 9.5 months). Visual acuity improved significantly in all patients.

Masqueraders of central serous chorioretinopathy

Central serous chorioretinopathy (CSCR) is one of the most common chorioretinal pathologies affecting middle-aged men worldwide. Although it has a self-limited course, a significant number of patients suffer from chronic and recurrent episodes. This often leaves the patient with various degrees of visual impairment. The situation is further aggravated by the fact that it is one of the most common conditions to be misdiagnosed. Because of overlapping features with other diseases or the atypical presentation of the disease itself, CSCR is a great mimicker and is one of the commonest causes of referral. We describe some of the conditions which can masquerade as CSCR.