Endogenous Methicillin-Resistant Staphylococcus Aureus (MRSA) Endophthalmitis: A Six-year Series at a Tertiary Care Center.

PURPOSE: To investigate the clinical outcomes of methicillin-resistant Staphylococcus aureus (MRSA) endophthalmitis. METHODS: Clinical courses were reviewed for 17 eyes (15 patients) with endogenous MRSA endophthalmitis based on positive blood and vitreous culture or clinical suspicion between 2013 to 2019 at Duke University Hospitals. RESULTS: Of 17 eyes, initial VA ranged from 20/40 to light perception. Of 15 patients, 9 had predisposing risk factors for bacteremia. All eyes received intravitreal vancomycin, 13 also received ceftazidime, and 2 also received amikacin instead of ceftazidime. Nine eyes developed retinal detachment; 6 underwent vitrectomy. Final VA ranged from 20/20 to no light perception and was ≥20/200 in 8 eyes. Eleven eyes had improved VA, 2 eyes were unchanged, and 4 were worse. CONCLUSIONS: This study is the largest series on endogenous MRSA endophthalmitis to date. Patients had a higher proportion of final VA ≥20/200, similarly high rate of RD, and fewer enucleations compared to prior reports.

Clinical characteristics and mortality rates for suprachoroidal hemorrhage: seven-year experience at a tertiary eye center.

PURPOSE: To investigate comorbidities and medications associated with acute (ASCH) and delayed (DSCH) suprachoroidal hemorrhage (SCH), and to explore visual outcomes and mortality following SCH. METHODS: Retrospective review of SCH cases diagnosed at a tertiary center between 2013 and 2019. Demographics, history, surgery type, visual acuity, intraocular pressure (IOP), and mortality data were reviewed. RESULTS: Fifty eyes of 50 patients experienced SCH related to surgery: 15 (30%) ASCH and 35 (70%) DSCH. Glaucoma surgery was the most common preceding surgery, and SCH was more likely to be delayed in glaucoma surgery relative to other surgeries (p = 0.001). The proportions of patients on anticoagulant, antiplatelet, or NSAID medications were 30% (n = 15), 52% (n = 26), and 12% (n = 6), respectively. The mean preoperative IOP was 25.0 ± 10.2 mmHg. The mean final best corrected visual acuity did not significantly differ between DSCH and ASCH (logMAR 1.92 vs. 2.36; p = 0.39). After controlling for pre-drainage visual acuity, final visual acuity was not statistically significantly different between eyes that were drained versus those that were not drained (p = 0.06). Of all 50 patients, the mortality rate was 12% with a mean time to mortality after SCH of 754 ± 564 days for those who died. CONCLUSION: DSCH was more common than ASCH, with glaucoma surgery being the most common procedure to result in SCH. Visual outcomes and mortality rate were comparable between ASCH and DSCH. Further research is needed regarding the role of surgical drainage on improving visual outcomes in eyes with SCH.

Management of a rhegmatogenous retinal detachment in a pregnant patient.

PURPOSE: To describe the management of a rhegmatogenous retinal detachment (RRD) in a pregnant patient. OBSERVATIONS: A 30-year-old, 26-week pregnant female presented with curtain vision loss in the left eye. Exam findings were significant in the left eye for an inferior fovea-sparing RRD. Care was coordinated and discussed with anesthesia and OB/GYN. The patient underwent surgery with monitored anesthesia care and a 41 scleral buckle, cryotherapy and C3F8 gas. The retina remained attached at 4 months post-operatively. A healthy girl was delivered via spontaneous vaginal delivery at 39 weeks. CONCLUSION: Safe and successful treatment of RRD in pregnant patients can be achieved with careful coordination between ophthalmology, anesthesia, and obstetrics. An understanding of pregnancy specific considerations is important in order to optimize patient outcomes.

Factors Impacting Outcomes and the Time to Recovery From Malignant Glaucoma.

PURPOSE: To identify factors associated with the successful treatment of malignant glaucoma (MG). DESIGN: Retrospective case series. METHODS: Setting: single institution; study population: 64 eyes (55 subjects) with MG; observation procedure(s): chart review; main outcome measures: anatomy, intraocular pressure (IOP), best visual acuity (BVA). RESULTS: 87.5% (n=56/64) of eyes with MG required surgical intervention. Vitrectomy was more likely to be successful in eyes with a history of <3 incisional surgeries, <3 glaucoma drops, or IOP ≤30 mm Hg (P < .05). If vitrectomy was performed within 30 days, recovery of anatomy, BVA, and IOP occurred sooner (P < .05). IOP reduction was greater in subjects treated with oral carbonic anhydrase inhibitors (P = .016) or Nd:YAG laser hyaloidotomy (P = .007), and without a history of MG (P = .007). Time to maximal improvement was significantly longer for IOP and BVA than anatomy (P < .001). Treatment of MG with an oral carbonic anhydrase inhibitor hastened anatomic recovery (P = .01). Time to improvement in BVA was significantly faster in men and African Americans (P < .05). Time to maximal reduction in IOP occurred sooner in eyes that underwent anterior chamber reformation in clinic (P < .002). Trabeculectomy surgery prior to MG was associated with prolonged recovery of anatomy, BVA, and IOP (P < .05). CONCLUSIONS: Earlier vitrectomy may shorten recovery times for MG. Nd:YAG laser hyaloidotomy and oral carbonic anhydrase inhibitors may lead to greater IOP reduction. The time to maximal improvement in IOP and BVA may be longer than the time to anatomic resolution. Although trabeculectomy may impede time to recovery from MG, oral carbonic anhydrase inhibitors may shorten the time to anatomic recovery and anterior chamber reformation may hasten IOP recovery.

Comparison of Visual Outcomes in Coats' Disease: A 20-Year Experience.

PURPOSE: To report differences in visual acuities among patients with Coats' disease who sought treatment at a tertiary care university-based practice. DESIGN: Single-center retrospective cohort study. PARTICIPANTS: Patients with Coats' disease diagnosed clinically, angiographically, or both from 1995 through 2015. METHODS: Patients were divided into 2 groups based on date of presentation: decade 1 (1995-2005) and decade 2 (2006-2015). MAIN OUTCOME MEASURES: Visual acuity (VA). RESULTS: Thirty-nine eyes of 39 patients were included with 19 eyes presenting in decade 1 and 20 eyes presenting in decade 2. Three patients demonstrated bilateral disease, but only the worse eye was included for analysis. Forty-seven percent of eyes in decade 1 demonstrated advanced stages of disease (stage 3B or worse) compared with 20% of eyes in decade 2. There was a trend for the mean initial presenting VA (±standard deviation) for decade 1 eyes to be worse (2.05±1.29 logarithm of the minimum angle of resolution [logMAR]) than for decade 2 eyes (1.45±0.99 logMAR; P = 0.1). From initial to final follow-up visit, mean VA also worsened for decade 1 eyes (P = 0.03), but remained stable for decade 2 eyes (P = 1.0). At the end of follow-up, there was a trend for mean VA for decade 1 eyes (2.28±1.17 logMAR) to be worse than for decade 2 eyes (1.60±1.15 logMAR; P = 0.07). Eight eyes were observed initially in decade 1 compared with 1 eye in decade 2, and only 1 of the observed eyes (in decade 2) developed painful glaucoma requiring enucleation. Decade 2 eyes had a higher average number of procedures per eye (6.5±4.9) compared with decade 1 eyes (1.4±1.7; P < 0.001). CONCLUSIONS: The earlier presentation of disease in decade 2 suggests improvements in disease detection over time. Furthermore, there was a trend for eyes to have better final VA in this decade. This is due to a combination of factors, including earlier presentation of disease, fewer eyes being observed without treatment, and eyes, when treated, receiving a higher number of procedures.

Preclinical evaluation and intraoperative human retinal imaging with a high-resolution microscope-integrated spectral domain optical coherence tomography device.

PURPOSE: The authors have recently developed a high-resolution microscope-integrated spectral domain optical coherence tomography (MIOCT) device designed to enable OCT acquisition simultaneous with surgical maneuvers. The purpose of this report is to describe translation of this device from preclinical testing into human intraoperative imaging. METHODS: Before human imaging, surgical conditions were fully simulated for extensive preclinical MIOCT evaluation in a custom model eye system. Microscope-integrated spectral domain OCT images were then acquired in normal human volunteers and during vitreoretinal surgery in patients who consented to participate in a prospective institutional review board-approved study. Microscope-integrated spectral domain OCT images were obtained before and at pauses in surgical maneuvers and were compared based on predetermined diagnostic criteria to images obtained with a high-resolution spectral domain research handheld OCT system (HHOCT; Bioptigen, Inc) at the same time point. Cohorts of five consecutive patients were imaged. Successful end points were predefined, including ≥80% correlation in identification of pathology between MIOCT and HHOCT in ≥80% of the patients. RESULTS: Microscope-integrated spectral domain OCT was favorably evaluated by study surgeons and scrub nurses, all of whom responded that they would consider participating in human intraoperative imaging trials. The preclinical evaluation identified significant improvements that were made before MIOCT use during human surgery. The MIOCT transition into clinical human research was smooth. Microscope-integrated spectral domain OCT imaging in normal human volunteers demonstrated high resolution comparable to tabletop scanners. In the operating room, after an initial learning curve, surgeons successfully acquired human macular MIOCT images before and after surgical maneuvers. Microscope-integrated spectral domain OCT imaging confirmed preoperative diagnoses, such as full-thickness macular hole and vitreomacular traction, and demonstrated postsurgical changes in retinal morphology. Two cohorts of five patients were imaged. In the second cohort, the predefined end points were exceeded with ≥80% correlation between microscope-mounted OCT and HHOCT imaging in 100% of the patients. CONCLUSION: This report describes high-resolution MIOCT imaging using the prototype device in human eyes during vitreoretinal surgery, with successful achievement of predefined end points for imaging. Further refinements and investigations will be directed toward fully integrating MIOCT with vitreoretinal and other ocular surgery to image surgical maneuvers in real time.

The ARMS2 A69S variant and bilateral advanced age-related macular degeneration.

PURPOSE: 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. METHODS: 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. RESULTS: 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)). CONCLUSION: 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.

Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.

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.

Analysis of single nucleotide polymorphisms in the NOS2A gene and interaction with smoking in age-related macular degeneration.

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.

Analysis of the indel at the ARMS2 3'UTR in age-related macular degeneration.

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.

Overall diet quality and age-related macular degeneration.

PURPOSE: To examine overall diet quality in relation to advanced age-related macular degeneration (AMD). METHODS: This case-control study identified 437 advanced AMD patients and 259 unrelated controls using stereoscopic color fundus photographs. Participants were predominantly non-Hispanic White men and women from North Carolina and Tennessee. A 97-item Block food frequency questionnaire was used to gather diet information, and overall diet quality was measured using the Healthy Eating Index (HEI) and Alternate Healthy Eating Index (AHEI). RESULTS: Participants in the highest quartile of diet quality had significantly reduced odds of AMD according to the AHEI score (0.54, 95% confidence interval 0.30-0.99) and non-significantly reduced odds of AMD according to the HEI (0.75, 0.41-1.38). Odds of AMD were also 51% lower in the highest quartile of fish intake compared to the lowest quartile (odds ratio = 0.49, 0.26-0.90). CONCLUSIONS: We found that advanced AMD was significantly related to overall diet quality. The AHEI score may be a useful instrument for assessing AMD risk due to diet, and it could potentially be improved by incorporating more specific information regarding micronutrient intake.

Inverse association of female hormone replacement therapy with age-related macular degeneration and interactions with ARMS2 polymorphisms.

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.

Rapid and sensitive method for detection of Y402, H402, I62, and V62 variants of complement factor H in human plasma samples using mass spectrometry.

PURPOSE: Variations in the complement factor H (CFH) gene are tightly associated with age-related macular degeneration (AMD) across diverse populations. Of the many nonsynonymous coding variants in CFH, two are most strongly associated with increased risk of AMD: isoleucine 62 to valine (I62V) and tyrosine 402 to histidine (Y402H). Detection of these variations in a patient's blood is important for a risk assessment of AMD and disease prognosis. However, traditional methods of genetic analysis cannot be used for measuring CFH allotypes in some sources of human plasma and other biological fluids not containing DNA. The purpose was to develop a protein-based method of detecting CFH allotypes. METHODS: A combination of a single-step affinity enrichment of CFH, gel separation, and mass spectrometry identification of the CFH peptides spanning amino acids at positions 62 and 402 was used to identify individual CFH allotypes. RESULTS: The CFH isoforms V62, I62, H402, and Y402 were reliably detected based on identification of tryptic peptides with masses of 1148.59 Da, 1162.60 Da, 2031.88 Da, and 2057.88 Da, respectively, using MALDI-TOF-TOF. The presence or absence pattern of these peptides in mass spectra of different CFH samples robustly correlated with all nine genotypes of CFH, as a result of variations at positions 62 and 402. CONCLUSIONS: A rapid and sensitive method has been developed for detection of V62, I62, H402, and Y402 variants of CFH in human plasma samples using mass spectrometry. This method can be used in clinical laboratories equipped with a basic inexpensive mass spectrometer capable of performing peptide fingerprinting.

Mitochondrial DNA polymorphism A4917G is independently associated with age-related macular degeneration.

The objective of this study was to determine if MTND2*LHON4917G (4917G), a specific non-synonymous polymorphism in the mitochondrial genome previously associated with neurodegenerative phenotypes, is associated with increased risk for age-related macular degeneration (AMD). A preliminary study of 393 individuals (293 cases and 100 controls) ascertained at Vanderbilt revealed an increased occurrence of 4917G in cases compared to controls (15.4% vs.9.0%, p = 0.11). Since there was a significant age difference between cases and controls in this initial analysis, we extended the study by selecting Caucasian pairs matched at the exact age at examination. From the 1547 individuals in the Vanderbilt/Duke AMD population association study (including 157 in the preliminary study), we were able to match 560 (280 cases and 280 unaffected) on exact age at examination. This study population was genotyped for 4917G plus specific AMD-associated nuclear genome polymorphisms in CFH, LOC387715 and ApoE. Following adjustment for the listed nuclear genome polymorphisms, 4917G independently predicts the presence of AMD (OR = 2.16, 95%CI 1.20-3.91, p = 0.01). In conclusion, a specific mitochondrial polymorphism previously implicated in other neurodegenerative phenotypes (4917G) appears to convey risk for AMD independent of recently discovered nuclear DNA polymorphisms.

C3 R102G polymorphism increases risk of age-related macular degeneration.

Inflammation has long been suspected to play a role in the pathogenesis of age-related macular degeneration (AMD). Association of variants in the complement factor H (CFH) and complement factor B (CFB) genes has targeted the search for additional loci to the alternative complement cascade, of which C3 is a major component. Two non-synonymous coding polymorphisms within C3, R102G and L314P, have previously been strongly associated with increased risk. These variants are in strong linkage disequilibrium (LD), making the contribution of this locus to AMD even more difficult to ascertain. We sought to determine whether the C3 association resulted primarily from only one of these two variants or from a combined effect of both in 223 families and an independent dataset of 701 cases and 286 unrelated controls. The C3 polymorphisms were in strong LD (r(2) = 0.85), and both were associated in the family-based and case-control datasets (R102G genoPDT P = 0.02, case-control genotypic P = 0.004; L314P genoPDT P = 0.001, case-control genotypic P = 0.04). In conditional analyses in the case-control dataset, R102G remained associated with disease in the L314P risk allele carriers (P = 0.01), but there was no effect of L314P in the R102G risk allele carriers (P = 0.2). After adjusting for age, smoking, CFH Y402H, LOC387715 A69S, and CFB R32Q, the effect of R102G remained strong [P = 0.015, odds ratio = 1.55, 95% confidence interval 1.09 to 2.21, adjusted PAR(population attributable risk) = 0.17]. Therefore, while the strong LD between R102G and L314P makes it difficult to disentangle their individual effects on disease risk, the R102G polymorphism acting alone provides the best model for disease in our data.

Peripheral reticular pigmentary change is associated with complement factor H polymorphism (Y402H) in age-related macular degeneration.

OBJECTIVE: To examine phenotypes of age-related macular degeneration (AMD) patients with the complement factor H (CFH) variant (Y402H, C allele at rs1061170). DESIGN: Clinic-based case series study. PARTICIPANTS: The data set contained a total of 956 unrelated cases of AMD. METHODS: Age-related macular degeneration phenotypes of 796 carriers of the CFH Y402H variant were compared with the AMD phenotypes of 160 noncarriers. MAIN OUTCOME MEASURES: Presence or absence of 34 phenotypic features. RESULTS: Of the 34 features analyzed, only peripheral reticular pigmentary change (PRPC) was associated with this CFH variant (P = 0.0006). The proportion of AMD cases with PRPC correlated with the number of CFH risk C alleles in a dose-response fashion. CONCLUSIONS: The CFH Y402H polymorphism is associated with PRPC, suggesting that AMD changes are not limited to the macula. Current AMD grading methods assess only the macula and should consider incorporating peripheral retinal changes. Phenotypes that suggest a high-risk genotype may prove valuable for diagnostic, therapeutic, and research purposes.