[Show abstract][Hide abstract] ABSTRACT: To assess the incidence and outcomes of infectious endophthalmitis after intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents.
Patient records at the Bascom Palmer Eye Institute (BPEI) from January 1, 2005, through December 31, 2014, were reviewed. The largest commercial claims and encounters database in the U.S. (MarketScan) was utilized to calculate the population-based endophthalmitis rate for 2011 to 2013.
The population-based rate of endophthalmitis after anti-VEGF injections for 2011 to 2013 was 391/740,757 (0.053%). BPEI's rate was 20/121,285 (0.016%) during the study period: eight after bevacizumab (0.012%), six after ranibizumab (0.018%), and six after aflibercept (0.031%) injection. Nine BPEI cases (45%) were culture-positive: Streptococcus species (5), coagulase-negative Staphylococcus (3), and non-anthracis Bacillus (1). Final visual acuity varied from 20/25 to no light perception.
Endophthalmitis after anti-VEGF injection was uncommon in our institution and in the population-based database. Treatment outcomes were variable but generally fared better in the culture-negative cases. [Ophthalmic Surg Lasers Imaging Retina. 2015;46:643-648.].
Copyright 2015, SLACK Incorporated.
Ophthalmic Surgery Lasers and Imaging Retina 06/2015; 46(6):643-648. DOI:10.3928/23258160-20150610-08 · 1.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Age-Related Eye Disease Study (AREDS) recommended treatment with antioxidants plus zinc in patients with intermediate or advanced age-related macular degeneration in order to reduce progression risks. Recent pharmacogenetic studies have reported differences in treatment outcomes with respect to variants in genes for CFH and ARMS2, although the treatment recommendations based on these differences are controversial. Different retrospective analyses of subsets of patients from the same AREDS trial have drawn different conclusions. The practicing clinician, who is not an expert on genetics, clinical trial design, or statistical analysis, may be uncertain how to interpret these results. Based on the balance of the available literature, we suggest not changing established practice recommendations until additional evidence from clinical trials becomes available.
[Show abstract][Hide abstract] ABSTRACT: Purpose:Age-Related Macular Degeneration (AMD) is the leading cause of irreversible visual loss in developed countries. Its etiology includes genetic and environmental factors. Although VEGFA variants are associated with AMD, the joint action of variants within the VEGF pathway and their interaction with non-genetic factors has not been investigated. Methods:Affymetrix 6.0 chipsets were used to genotype 668,238 SNPs in 1,207 AMD cases and 686 controls. Environmental exposures were collected by questionnaire. A set-based test was conducted using the chi-square statistic at each SNP derived from Kraft's 2df joint test. Pathway and gene-based test statistics were calculated as the mean of all independent SNP statistics. Phenotype labels were permuted 10,000 times to generate an empirical p-value. Results: While a main effect of the VEGF pathway was not identified, the pathway was associated with neovascular AMD in women when accounting for birth control pill (BCP) use (P= 0.017). Analysis of VEGF's subpathways found that SNPs in the Proliferation subpathway were associated with neovascular AMD (P=0.029) when accounting for BCP use. Nominally significant genes within this subpathway were also observed. Stratification by BCP use revealed novel significant genetic effects in women who had taken BCPs. Conclusions: These results illustrate that some AMD genetic risk factors may only be revealed when considering complex relationships among risk factors. This shows the utility of exploring pathways of previously associated genes to find novel effects. It also demonstrates the importance of incorporating environmental exposures in tests of genetic association at the SNP, gene, or pathway level.
[Show abstract][Hide abstract] ABSTRACT: Evaluation of: Sallo FB, Leung BA, Chung M et al. MacTel Study Group. Retinal crystals in type 2 idiopathic macular telangiectasia. Ophthalmology 118, 2461–2467 (2011).
Idiopathic macular telangiectasia (MacTel) is a bilateral anomaly of retinal capillaries that involves the juxtafoveal region around the horizontal raphe. Clinical features include intraretinal crystalline deposits, subretinal pigment plaques, right-angle vessels, inner lamellar cysts and, in some cases, subretinal neovascularization. Currently, there is no effective treatment for this condition and the etiology is unknown. Funded by the Lowy Medical Research Institute Ltd., the MacTel Study Project is a worldwide multicenter endeavor dedicated to exploring the causes of MacTel and investigating possible treatments. In the featured article, the study group characterizes the intraretinal crystalline deposits associated with MacTel.
Expert Review of Ophthalmology 01/2014; 7(2). DOI:10.1586/eop.12.10
[Show abstract][Hide abstract] ABSTRACT: When delivered via a single intravitreal injection, ocriplasmin can effect proteolytic resolution of symptomatic vitreomacular adhesion (VMA). The authors describe their initial clinical experience with ocriplasmin at a large academic center.
Retrospective review of all patients with symptomatic VMA treated with ocriplasmin from January 2013 through May 2013 at a single center.
Nineteen patients with symptomatic VMA received intravitreal ocriplasmin. Eight patients (42%) exhibited resolution of VMA. Macular holes in three of six patients (50%) closed after injection. A higher proportion of VMA resolution was observed in patients with the following baseline characteristics: age less than 65 years, focal adhesions less than or equal to 1,500 μm, presence of macular hole, phakic status, and absence of epiretinal membrane.
Initial clinical outcomes using ocriplasmin in this study are consistent with those reported in the phase 3 clinical trials. Improved clinical results can be achieved with careful case selection based on specific baseline characteristics. [Ophthalmic Surg Lasers Imaging Retina. 2013;44:334-343.].
Ophthalmic Surgery Lasers and Imaging Retina 07/2013; 44(4):334-43. DOI:10.3928/23258160-20130715-05 · 1.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Variations in a locus at chromosome 10q26 are strongly associated with the risk of age-related macular degeneration (AMD). The most significantly associated haplotype includes a nonsynonymous SNP rs10490924 in the exon 1 of ARMS2 and rs11200638 in the promoter region of HTRA1. It is under debate which gene(s), ARMS2, HTRA1 or some other genes are functionally responsible for the genetic association. To verify whether the associated variants correlate with a higher HTRA1 expression level as previously reported, HTRA1 mRNA and protein were measured in a larger human retina-RPE-choroid samples (n = 82). Results show there is no significant change of HTRA1 mRNA level among genotypes at rs11200638, rs10490924 or an indel variant of ARMS2. Furthermore, two AMD-associated synonymous SNPs rs1049331 and rs2293870 in HTRA1 exon 1 do not change its protein level either. These results suggest that the AMD-associated variants in the chromosome 10q26 locus do not significantly affect the expression of HTRA1.
Experimental Eye Research 05/2013; 112. DOI:10.1016/j.exer.2013.04.019 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Relatively little is known about the interaction between genes and environment in the complex etiology of age-related macular degeneration (AMD). This study aimed to identify novel factors associated with AMD by analyzing gene-smoking interactions in a genome-wide association study of 1207 AMD cases and 686 controls of Caucasian background with genotype data on 668,238 single nucleotide polymorphisms (SNPs) after quality control. Participants' history of smoking at least 100 cigarettes lifetime was determined by a self-administered questionnaire. SNP associations modeled the effect of the minor allele additively on AMD using logistic regression, with adjustment for age, sex, and ever/never smoking. Joint effects of SNPs and smoking were examined comparing a null model containing only age, sex, and smoking against an extended model including genotypic and interaction terms. Genome-wide significant main effects were detected at three known AMD loci: CFH (P = 7.51×10(-30) ), ARMS2 (P = 1.94×10(-23) ), and RDBP/CFB/C2 (P = 4.37×10(-10) ), while joint effects analysis revealed three genomic regions with P < 10(-5) . Analyses stratified by smoking found genetic associations largely restricted to nonsmokers, with one notable exception: the chromosome 18q22.1 intergenic SNP rs17073641 (between SERPINB8 and CDH7), more strongly associated in nonsmokers (OR = 0.57, P = 2.73 × 10(-5) ), with an inverse association among smokers (OR = 1.42, P = 0.00228), suggesting that smoking modifies the effect of some genetic polymorphisms on AMD risk.
Annals of Human Genetics 05/2013; 77(3):215-31. DOI:10.1111/ahg.12011 · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10-8. These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10-8 for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.
[Show abstract][Hide abstract] ABSTRACT: To identify genetic associations between specific risk genes and bilateral advanced age-related macular degeneration (AMD) in a retrospective, observational case series of 1,003 patients: 173 patients with geographic atrophy in at least 1 eye and 830 patients with choroidal neovascularization in at least 1 eye.
Patients underwent clinical examination and fundus photography. The images were subsequently graded using a modified grading system adapted from the Age-Related Eye Disease Study. Genetic analysis was performed to identify genotypes at 4 AMD-associated variants (ARMS2 A69S, CFH Y402H, C3 R102G, and CFB R32Q) in these patients.
There were no statistically significant relationships between clinical findings and genotypes at CFH, C3, and CFB. The genotype at ARMS2 correlated with bilateral advanced AMD using a variety of comparisons: unilateral geographic atrophy versus bilateral geographic atrophy (P = 0.08), unilateral choroidal neovascularization versus bilateral choroidal neovascularization (P = 9.0 × 10(-8)), and unilateral late AMD versus bilateral late AMD (P = 5.9 × 10(-8)).
In this series, in patients with geographic atrophy or choroidal neovascularization in at least 1 eye, the ARMS2 A69S substitution strongly associated with geographic atrophy or choroidal neovascularization in the fellow eye. The ARMS2 A69S substitution may serve as a marker for bilateral advanced AMD.
[Show abstract][Hide abstract] ABSTRACT: Over the past few years, antivascular endothelial growth factor (VEGF) therapy has become a standard treatment for neovascular age-related macular degeneration (AMD). During this time, treatment strategies have evolved from a monthly dosing schedule to individualized regimens. This paper will review the currently available anti-VEGF agents and evidence-based treatment strategies.
Journal of Ophthalmology 02/2012; 2012(3):786870. DOI:10.1155/2012/786870 · 1.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the rate of infectious endophthalmitis and to describe the clinical and microbiological features of eyes that develop clinically suspected endophthalmitis after an intravitreal injection of vascular endothelial growth factor antagonists.
The medical records of patients undergoing intravitreal injections of anti-vascular endothelial growth factor agents from January 1, 2005, through December 31, 2010, at a single university referral center and associated satellite clinics were retrospectively analyzed to determine the rate of infectious endophthalmitis after intravitreal anti-vascular endothelial growth factor injections.
Twelve cases (11 patients) of clinically suspected endophthalmitis were identified after a total of 60,322 injections (0.02%; 95% confidence interval, 0.0114%-0.0348%). Of the 12 cases, 11 presented within 3 days of the injection. Of the 7 culture-positive cases, 5 were because of Streptococcus species. In 4 of the 5 Streptococcus cases, final visual acuity was hand motions or worse. The rate of clinically suspected endophthalmitis was 0.018% after bevacizumab and 0.027% after ranibizumab injections.
A very low rate of endophthalmitis after intravitreal injections of anti-vascular endothelial growth factor agents was observed. Patients typically presented within 3 days of injection. Streptococcus species was the most common bacteria isolated, and it was generally associated with poor visual outcomes.
[Show abstract][Hide abstract] ABSTRACT: Persistent placoid maculopathy is a rare entity characterized by bilateral well-delineated whitish plaque-like lesions in the macula. Secondary choroidal neovascularization and extensive retinal pigment epithelial damage, highlighted by spectral domain optical coherence tomography and autofluorescence imaging, can limit visual prognosis. Aggressive immunosuppression can preserve vision and perhaps delay the onset of choroidal neovascularization.
Ophthalmic Surgery Lasers and Imaging 11/2010; 41 Suppl:S101-3. DOI:10.3928/15428877-20101031-11 · 1.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10(-75)), ARMS2 (P < 10(-59)), C2/CFB (P < 10(-20)), C3 (P < 10(-9)), and CFI (P < 10(-6)). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10(-11)), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10(-7); CETP, P = 7.4 x 10(-7)) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 x 10(-3)) and ABCA1 (P = 5.6 x 10(-4)). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.
Proceedings of the National Academy of Sciences 04/2010; 107(16):7401-6. · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To report the first case of endophthalmitis after Descemet's stripping with automated endothelial keratoplasty caused by Mycobacterium abscessus.
Observational case report.
An immunocompetent 88-year-old woman presented with endophthalmitis 2 months after a routine Descemet's stripping with automated endothelial keratoplasty resulting in decreased visual acuity and persistent vitreous opacities despite aggressive medical treatment. She underwent eventual pars plana vitrectomy with explantation of the posterior chamber intraocular lens and tube shunt. Operative cultures isolated Mycobacterium abscessus. With continued antibiotic therapy, the endophthalmitis eventually resolved with significant improvement of visual acuity.
We report a case of endophthalmitis as a complication of Descemet's stripping with automated endothelial keratoplasty. Although a rare pathogen in endophthalmitis, M. abscessus is difficult to culture and treat. Surgical hypotony combined with contamination of intraoperative materials and/or postsurgical drops are the likely mechanisms of infection.
[Show abstract][Hide abstract] ABSTRACT: Age-related macular degeneration (AMD) is a complex degenerative retinal disease influenced by both genetic and environmental risk factors. We assessed whether single nucleotide polymorphisms (SNPs) in the NOS2A gene increase risk and modulate the effect of smoking in AMD. 998 Caucasian subjects (712 AMD cases and 286 controls) were genotyped for 17 SNPs in NOS2A. Multivariable logistic regression models containing SNP genotypes, age, sex, smoking status and genotype/smoking interaction were constructed. SNP rs8072199 was significantly associated with AMD (OR = 1.3; 95% CI : 1.02, 1.65; P = 0.035). A significant interaction with smoking was detected at rs2248814 (P = 0.037). Stratified data by genotypes demonstrated that the association between AMD and smoking was stronger in carriers of AA genotypes (OR = 35.98; 95% CI: 3.19, 405.98) than in carriers of the AG genotype (OR = 3.05; 95% CI: 1.36, 6.74) or GG genotype (OR = 2.1; 95% CI: 0.91, 4.84). The results suggest a possible synergistic interaction of AA genotype with smoking, although the result bears replication in larger samples. Our data suggests that SNPs in the NOS2A gene are associated with increased risk for AMD and might modulate the effect of smoking on AMD.
Annals of Human Genetics 03/2010; 74(3):195-201. DOI:10.1111/j.1469-1809.2010.00570.x · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Controversy remains as to which gene at the chromosome 10q26 locus confers risk for age-related macular degeneration (AMD) and statistical genetic analysis is confounded by the strong linkage disequilibrium (LD) across the region. Functional analysis of related genetic variations could solve this puzzle. Recently, Fritsche et al. reported that AMD is associated with unstable ARMS2 transcripts possibly caused by a complex insertion/deletion (indel; consisting of a 443 bp deletion and an adjacent 54 bp insertion) in its 3'UTR (untranslated region). To validate this indel, we sequenced our samples. We found that this indel is even more complex and is composed of two side-by-side indels separated by 17 bp: (1) 9 bp deletion with 10 bp insertion; (2) 417 bp deletion with 27 bp insertion. The indel is significantly associated with the risk of AMD, but is also in strong LD with the non-synonymous single nucleotide polymorphism rs10490924 (A69S). We also found that ARMS2 is expressed not only in placenta and retina but also in multiple human tissues. Using quantitative PCR, we found no correlation between the indel and ARMS2 mRNA level in human retina and blood samples. The lack of functional effects of the 3'UTR indel, the amino acid substitution of rs10490924 (A69S), and strong LD between them suggest that A69S, not the indel, is the variant that confers risk of AMD. To our knowledge, it is the first time it has been shown that ARMS2 is widely expressed in human tissues. Conclusively, the indel at 3'UTR of ARMS2 actually contains two side-by-side indels. The indels are associated with risk of AMD, but not correlated with ARMS2 mRNA level.
Human Genetics 02/2010; 127(5):595-602. DOI:10.1007/s00439-010-0805-8 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose: To describe hypertensive optic neuropathy and choroidopathy caused by renal failure in an 18-year-old woman.
Methods: The clinical and angiographic findings of a young patient with hypertensive optic neuropathy and choroidopathy caused by hypertensive emergency secondary to renal failure are described.
Results: The patient's visual acuity, bilateral optic nerve swelling, and macular edema improved with blood pressure control. Several small areas of exudative retinal detachment remain.
Conclusion: Accelerated or malignant hypertension is a common cause of bilateral optic nerve swelling and exudative retinal detachments. Treatment of systemic hypertension is essential in reversing the ocular manifestations of the condition.
[Show abstract][Hide abstract] ABSTRACT: Purpose. To investigate whether female reproductive history and hormone replacement therapy (HRT) or birth control pills (BCPs) influence risk for age-related macular degeneration (AMD) and whether genetic factors interact with HRT to modulate AMD risk. Methods. Related and unrelated female participants (n = 799) were examined and data were analyzed with generalized estimating equations with adjustment for age and smoking. Individuals with AMD grades 1 to 2 were considered to be unaffected (n = 239) and those with grades 3 to 5 were considered affected (n = 560). Results. When comparing all cases with controls, significant inverse associations were observed for HRT (odds ratio [OR] = 0.65, 95% CI 0.48-0.90, P = 0.008) and BCPs (OR = 0.60, 95% CI 0.36-0.10, P = 0.048). When analyses were stratified by AMD severity (early versus geographic atrophy versus neovascular), the inverse association remained significant (HRT OR = 0.45, 95% CI 0.30-0.66, P < 0.0001; BCP OR = 0.55, 95% CI 0.32-0.96, P = 0.036) only when comparing neovascular AMD with the control. All pair-wise HRT-genotype and BCP-genotype interactions were examined, to determine whether HRT or BCP modifies the effect of established genetic risk factors. The strongest interactions were observed for HRT x ARMS2 coding SNP (R73H) rs10490923 (P = 0.007) and HRT x ARMS2 intronic SNP rs17623531 (P = 0.019). Conclusions. These findings provide the first evidence suggesting that ARMS2 interacts with HRT to modulate AMD risk and are consistent with previous reports demonstrating a protective relationship between exogenous estrogen use and neovascular AMD. These results highlight the genetic and environmental complexity of the etiologic architecture of AMD; however, further replication is necessary to validate them.