Publications by Year: 2013

2013
Zhang X, Igo RP, Fondran J, Mootha VV, Oliva M, Hammersmith K, Sugar A, Lass JH, Iyengar SK. Association of smoking and other risk factors with Fuchs' endothelial corneal dystrophy severity and corneal thickness. Invest Ophthalmol Vis Sci. 2013;54 (8) :5829-35.Abstract
PURPOSE: We investigated effects of smoking and other risk factors on the development of advanced Fuchs' endothelial corneal dystrophy (FECD) and on central corneal thickness (CCT). METHODS: Eyes from Caucasian probands, affected and unaffected family members, and unrelated controls matched for age from the FECD Genetics Multi-Center Study (n = 2044 subjects) were examined. Univariate and multivariate models, adjusted for family correlations, were used to determine the effect of smoking, sex, diabetes, and age on FECD case/control status and CCT. RESULTS: In a multivariate model, sex and smoking were associated significantly with advanced FECD (grades 4-6) development (P = 0.016 and P = 0.047, respectively). Female sex increased odds by 34%. Smoking increased odds by 30%. In a multivariate model, diabetes was associated with an increase of 9.1 μm in average CCT (P = 0.021). Female sex was associated significantly with a decrease in average CCT by 6.9 μm (P = 0.015). Smoking had no significant effect on CCT in any model. As shown previously, advanced FECD was associated with large increases in CCT (31.4-94.2 μm). CONCLUSIONS: Smoking was associated with an increased risk of advanced FECD and self-reported diabetes was associated with increased CCT. Further study of the impact of smoking and diabetes on FECD development and changes in corneal thickness is warranted.
Hamill CE, Schmedt T, Jurkunas U. Fuchs endothelial cornea dystrophy: a review of the genetics behind disease development. Semin Ophthalmol. 2013;28 (5-6) :281-6.Abstract
Fuchs dystrophy represents the most common form of endothelial dystrophy and is a significant cause of visual impairment. The cause of Fuchs dystrophy is a complicated combination of both genetic and environmental factors. Understanding the underlying causes of the disease can potentially lead to new medical treatments preventing loss of vision.
Verhoeven VJM, Hysi PG, Wojciechowski R, Fan Q, Guggenheim JA, Höhn R, Macgregor S, Hewitt AW, Nag A, Cheng C-Y, et al. Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia. Nat Genet. 2013;45 (3) :314-8.Abstract
Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.
Cheng C-Y, Schache M, Ikram KM, Young TL, Guggenheim JA, Vitart V, Macgregor S, Verhoeven VJM, Barathi VA, Liao J, et al. Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error. Am J Hum Genet. 2013;93 (2) :264-77.Abstract
Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.
Amparo F, Sadrai Z, Jin Y, Alfonso-Bartolozzi B, Wang H, Shikari H, Ciolino JB, Chodosh J, Jurkunas U, Schaumberg DA, et al. Safety and efficacy of the multitargeted receptor kinase inhibitor pazopanib in the treatment of corneal neovascularization. Invest Ophthalmol Vis Sci. 2013;54 (1) :537-44.Abstract
PURPOSE: To evaluate the safety and efficacy of topical pazopanib in the treatment of corneal neovascularization (CNV). METHODS: Twenty eyes of 20 patients with stable CNV were enrolled in a prospective, open label, noncomparative study and treated with topical pazopanib 0.5% for 3 weeks, and followed for 12 weeks. The primary endpoint was to determine the tolerability and safety of topical pazopanib in the treatment of CNV defined by the occurrence of ocular and systemic adverse events during the study. The secondary endpoint was to evaluate the effect of topical pazopanib on the reduction of (1) neovascular area (NA), defined as the area of the corneal vessels themselves, (2) invasion area (IA), defined as the fraction of the total cornea into which the vessels extend, (3) vessel length (VL), defined as the mean measurement of the extent of vessels from end to end, and (4) vessel caliber (VC), defined as the mean diameter of the corneal vessels. RESULTS: There were no severe adverse events following the use of topical pazopanib. Compared with the baseline visit, NA and VL showed a statistically significant decrease at week 3 (P = 0.02 and 0.01, respectively); and NA, IA, and VL statistically significantly decreased at week 12 (P = 0.03, 0.04, and <0.01, respectively). Visual acuity maintained without changes after the 12 week follow-up. CONCLUSIONS: This preliminary study suggests that topical treatment with pazopanib 0.5% is safe, well tolerated, and may have a role as an alternative for the treatment of CNV (ClinicalTrials.gov number, NCT01257750).
Amparo F, Dastjerdi MH, Okanobo A, Ferrari G, Smaga L, Hamrah P, Jurkunas U, Schaumberg DA, Dana R. Topical interleukin 1 receptor antagonist for treatment of dry eye disease: a randomized clinical trial. JAMA Ophthalmol. 2013;131 (6) :715-23.Abstract
IMPORTANCE: The immunopathogenic mechanisms of dry eye disease (DED), one of the most common ophthalmic conditions, is incompletely understood. Data from this prospective, double-masked, randomized trial demonstrate that targeting interleukin 1 (IL-1) by topical application of an IL-1 antagonist is efficacious in significantly reducing DED-related patient symptoms and corneal epitheliopathy. OBJECTIVE: To evaluate the safety and efficacy of treatment with the topical IL-1 receptor antagonist anakinra (Kineret; Amgen Inc) in patients having DED associated with meibomian gland dysfunction. DESIGN AND SETTING: Prospective phase 1/2, randomized, double-masked, vehicle-controlled clinical trial. PARTICIPANTS: Seventy-five patients with refractory DED. INTERVENTIONS: Participants were randomized to receive treatment with topical anakinra, 2.5% (n = 30), anakinra, 5% (n = 15), or vehicle (1% carboxymethylcellulose) (n = 30) 3 times daily for 12 weeks. MAIN OUTCOMES AND MEASURES: Primary outcomes were corneal fluorescein staining (CFS), complete bilateral CFS clearance, dry eye-related symptoms as measured by the Ocular Surface Disease Index, tear film breakup time, and meibomian gland secretion quality. RESULTS: Topical anakinra was well tolerated compared with vehicle, with no reports of serious adverse reactions attributable to the therapy. After 12 weeks of therapy, participants treated with anakinra, 2.5%, achieved a 46% reduction in their mean CFS score (P = .12 compared with vehicle and P < .001 compared with baseline); participants treated with anakinra, 5%, achieved a 17% reduction in their mean CFS score (P = .88 compared with vehicle and P = .33 compared with baseline); and patients treated with vehicle achieved a 19% reduction in their mean CFS score (P = .11). Complete bilateral CFS clearance was noted in 8 of 28 patients (29%) treated with anakinra, 2.5%, vs in 2 of 29 patients (7%) treated with vehicle (P = .03). By week 12, treatment with anakinra, 2.5%, and treatment with anakinra, 5%, led to significant reductions in symptoms of 30% and 35%, respectively (P = .02 and P = .01, respectively, compared with vehicle); treatment with vehicle led to a 5% reduction in symptoms. CONCLUSIONS AND RELEVANCE: Treatment with topical anakinra, 2.5%, for 12 weeks was safe and significantly reduced symptoms and corneal epitheliopathy in patients with DED. These data suggest that the use of an IL-1 antagonist may have a role as a novel therapeutic option for patients with DED. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00681109.
Schrems-Hoesl LM, Schrems WA, Cruzat A, Shahatit BM, Bayhan HA, Jurkunas UV, Hamrah P. Cellular and subbasal nerve alterations in early stage Fuchs' endothelial corneal dystrophy: an in vivo confocal microscopy study. Eye (Lond). 2013;27 (1) :42-9.Abstract
PURPOSE: To analyze the morphology and density of corneal epithelial cells, keratocytes, and subbasal nerves, in patients with early stage Fuchs' endothelial corneal dystrophy (FECD) by in vivo confocal microscopy (IVCM). METHODS: IVCM (Confoscan 4, Nidek, Inc.) of the central cornea was performed in 30 corneas of 30 patients with early stage FECD and 13 corneas of 13 normal controls. Images were analyzed for morphology and density of the superficial and basal epithelial cells, keratocyte density, endothelial cell density (ECD), as well as subbasal corneal nerve parameters. Central corneal thickness (CCT) was measured in all patients and normals by ultrasound pachymetry. RESULTS: The ECD was significantly lower (-45.5%, P<0.001) in FECD patients as compared with controls. Total number of nerves and main nerve trunks were significantly reduced (-46.3%, P<0.001; -39.7%, P<0.001) in patients with FECD. Posterior keratocyte density was significantly higher in FECD patients (P<0.001). Significant inverse correlations were found between CCT and total number of nerves (r=-0.69, P<0.001), CCT and main nerve trunks (-0.47, P=0.016), as well as CCT and total nerve length (r=-0.62, P=0.006). Significant correlation was found between ECD and total number of nerves (r=0.44, P=0.012) as well as between ECD and main nerve trunks (r=0.65, P<0.001). CONCLUSIONS: IVCM demonstrates alterations in corneal innervation in patients with early stage FECD, suggesting a potential role of corneal nerves in the pathogenesis of FECD. Additional studies are required to investigate whether subbasal nerve alterations are caused by nonspecific corneal edema, from FECD-induced decrease in ECD, or potentially leading to loss of endothelial cells.
Jašinskas V, Rudalevičius P, Miliauskas A, Milčius D, Jurkūnas UV. Keratoprosthesis surgery as an alternative to keratoplasty. Medicina (Kaunas). 2013;49 (6) :291-9.Abstract
Corneal transplant surgery after chemical or thermal burns has a very low success rate. Vision in these patients can be restored by using an artificial cornea (keratoprosthesis). In this report, we present 5 clinical cases of implanting a fresh corneal graft with Boston type 1 keratoprosthesis in patients with corneas inappropriate for standard corneal transplantation. The mean follow-up was 26.4 months (range, 12 to 36 months; SD, 13.1). The main measures of outcomes were visual acuity and keratoprosthesis stability. At least 1 year after the operation (5 eyes), vision acuity was >0.1 in 100% of the eyes and >0.4 in 50% of the eyes. Retention of the initial keratoprosthesis was 100%. The results of this study seem to be similar to those reported internationally. The anatomical and visual functions of the eyes were stable after keratoprosthesis implantation, though for a longer follow-up period, additional surgical procedures may be required.
Ziaei A, Schmedt T, Chen Y, Jurkunas UV. Sulforaphane decreases endothelial cell apoptosis in fuchs endothelial corneal dystrophy: a novel treatment. Invest Ophthalmol Vis Sci. 2013;54 (10) :6724-34.Abstract
PURPOSE: Fuchs endothelial corneal dystrophy (FECD) is an oxidative stress disorder that leads to age-related and gradual loss of corneal endothelial cells resulting in corneal edema and loss of vision. To date, other than surgical intervention, there are no treatment options for patients with FECD. We have shown that in FECD, there is a deficiency in nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated antioxidant defense due to decreased Nrf2 nuclear translocation and activation of antioxidant response element (ARE). In this study, we used sulforaphane (SFN) and D3T to investigate a strategy of targeting Nrf2-ARE in FECD. METHODS: FECD and normal ex vivo corneas and human corneal endothelial cell lines were pretreated with SFN or D3T and exposed to oxidative stress with tert-Butyl hydroperoxide (tBHP). Apoptosis was detected with TUNEL. Cellular localization of Nrf2 and p53 was assessed by immunohistochemistry. Effect of SFN was determined by using DCFDA assay, Western blot and real-time PCR. RESULTS: After pretreatment with SFN, oxidative stress was induced with tBHP. In ex vivo FECD specimens, SFN decreased CEC apoptosis by 55% in unstressed group and by 43% in tBHP-treated specimens. SFN enhanced nuclear translocation of Nrf2 in FECD specimens and decreased p53 staining under oxidative stress. Pretreatment with SFN enhanced cell viability by decreasing intracellular reactive oxygen species production. Upregulation of Nrf2 levels led to increased synthesis of DJ-1, heme oxygenase 1, and nicotinamide adenine dinucleotide quinone oxidoreductase-1. SFN significantly upregulated major ARE-dependent antioxidants and ameliorated oxidative stress-induced apoptosis in FECD. CONCLUSIONS: Our results suggest that targeting Nrf2-ARE pathway may arrest degenerative cell loss seen in FECD.