December 2017

Diplopia is a disappointing and, at times, unanticipated consequence of what might otherwise be considered anatomically successful strabismus surgery. In this study, we review the existing literature regarding diplopia after strabismus surgery in the context of the senior author's experience. We divide postoperative diplopia types into cases that occur in the setting of normal binocular vision (or "normal" suppression) vs. cases that are the consequence of rare or anomalous sensorial adaptations. We then discuss how to identify patients at greatest risk based on history and preoperative testing, and we offer strategies for managing these sometimes-challenging cases.

PURPOSE: To analyse pooled data from 2 similar phase 3 noninferiority studies comparing difluprednate 0.05% versus prednisolone acetate 1% in patients with endogenous anterior uveitis. METHODS: Patients received difluprednate alternating with vehicle or prednisolone acetate for 14 days (8 drops/day in both groups), followed by tapering from day 14 to 28. All patients were observed until day 42. RESULTS: More patients on difluprednate than on prednisolone acetate were cleared of anterior chamber cells on day twenty one (71.3% vs 54.7%; p = 0.02); results were similar at the other time points. Treatment withdrawals were higher with prednisolone acetate than difluprednate (19.8% vs 7.4%; log-rank p = 0.02). Study discontinuation due to lack of efficacy was also higher with prednisolone acetate than difluprednate (14.0% vs 0%; p = 0.0002 [pre-specified exploratory analysis]). CONCLUSIONS: More difluprednate-treated eyes were quiet following 21 days of treatment, and difluprednate-treated patients were much less likely to be withdrawn from the study because of treatment failure.

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.

PURPOSE: To compare choroidal vascular density (CVD) and volume (CVV) in diabetic eyes and controls, using en face swept-source optical coherence tomography (SS-OCT). DESIGN: Prospective cross-sectional study. METHODS: Setting: Multicenter. PATIENT POPULATION: Total of 143 diabetic eyes-27 with no diabetic retinopathy (DR), 47 with nonproliferative DR (NPDR), 51 with NPDR and diabetic macular edema (DME), and 18 with proliferative DR (PDR)-and 64 age-matched nondiabetic control eyes. OBSERVATION PROCEDURES: Complete ophthalmologic examination and SS-OCT imaging. En face SS-OCT images of the choroidal vasculature were binarized. MAIN OUTCOME MEASURES: CVD, calculated as the percent area occupied by choroidal vessels in the central macular region (6-mm-diameter circle centered on the fovea), and throughout the posterior pole (12 × 9 mm). The central macular CVV was calculated by multiplying the average CVD by macular area and choroidal thickness (obtained with SS-OCT automated software). Multilevel mixed linear models were performed for analyses. RESULTS: Compared to controls (0.31 ± 0.07), central macular CVD was significantly decreased by 9% in eyes with NPDR + DME (0.28 ± 0.06; ß = -0.03, P = .02) and by 15% in PDR (0.26 ± 0.05; ß = -0.04, P = .01). The central macular CVV was significantly decreased by 19% in eyes with PDR (0.020 ± 0.005 mm3, ß = -0.01, P = .01) compared to controls (0.025 ± 0.01 mm3). CONCLUSIONS: Choroidal vascular density and volume are significantly reduced in more advanced stages of diabetic retinopathy. New imaging modalities should allow further exploration of the contributions of choroidal vessel disease to diabetic eye disease pathogenesis, prognosis, and treatment response.

Gaze-contingent displays have been widely used in vision research and virtual reality applications. Due to data transmission, image processing, and display preparation, the time delay between the eye tracker and the monitor update may lead to a misalignment between the eye position and the image manipulation during eye movements. We propose a method to reduce the misalignment using a Taylor series to predict the saccadic eye movement. The proposed method was evaluated using two large datasets including 219,335 human saccades (collected with an EyeLink 1000 system, 95% range from 1° to 32°) and 21,844 monkey saccades (collected with a scleral search coil, 95% range from 1° to 9°). When assuming a 10-ms time delay, the prediction of saccade movements using the proposed method could reduce the misalignment greater than the state-of-the-art methods. The average error was about 0.93° for human saccades and 0.26° for monkey saccades. Our results suggest that this proposed saccade prediction method will create more accurate gaze-contingent displays.

Penicillin-binding proteins (PBPs) are enzymes involved in the assembly of the bacterial cell wall, a major target for antibiotics. These proteins are classified by mass into high-molecular-weight PBPs, which are transpeptidases that form peptidoglycan cross-links, and low-molecular-weight PBPs, which are typically hydrolases. We report a functionally unique family of low-molecular-weight PBPs that act as transpeptidases rather than hydrolases, but they do not cross-link peptidoglycan. We show that these PBPs can exchange d-amino acids bearing chemical tags or affinity handles into peptidoglycan precursors, including Lipid II, enabling biochemical studies of proteins involved in cell wall assembly. We report that, in two organisms, the PBPs incorporate lysine into cellular peptidoglycan and that, further, the PBPs have the unprecedented ability to transfer the primary ε-amine of lysine to peptidoglycan.

A 38-year-old woman presented with multiple bilateral recurrent eyelid cysts. Her medical history was notable for Gorlin (nevoid basal cell carcinoma) syndrome. Histopathologic and immunohistochemical examinations revealed that the lesions were intratarsal keratinous cysts. They were similar in appearance to sporadic intratarsal keratinous cysts and closely resembled odontogenic keratocysts of the jaw. Eyelid cysts occur in up to 40 percent of patients with Gorlin syndrome; however, their description has been cursory and for the most part, outside of the ophthalmic literature. Although ophthalmologists are familiar with the periocular basal cell carcinomas that occur in patients with Gorlin syndrome, up to 10 percent of patients never develop a basal cell carcinoma, but may manifest other ophthalmic findings. Awareness of these other features may contribute to the earlier diagnosis of the syndrome. We discuss the clinical and histopathologic features of intratarsal keratinous cysts in Gorlin syndrome, comparing them to sporadic intratarsal keratinous cysts, other eyelid cysts, and jaw cysts that also characterize this syndrome. We briefly review the ocular and systemic manifestations of Gorlin syndrome and recent genetic and therapeutic developments so that the eyelid cysts may be appreciated within the appropriate context of Gorlin syndrome as a whole.

Purpose: Pathologic angiogenesis is a component of many diseases, including neovascular age-related macular degeneration, proliferation diabetic retinopathy, as well as tumor growth and metastasis. The purpose of this project was to examine whether the system of adeno-associated viral (AAV)-mediated CRISPR (clustered regularly interspaced short palindromic repeats)-associated endonuclease (Cas)9 can be used to deplete expression of VEGF receptor 2 (VEGFR2) in human vascular endothelial cells in vitro and thus suppress its downstream signaling events. Methods: The dual AAV system of CRISPR/Cas9 from Streptococcus pyogenes (AAV-SpGuide and -SpCas9) was adapted to edit genomic VEGFR2 in primary human retinal microvascular endothelial cells (HRECs). In this system, the endothelial-specific promoter for intercellular adhesion molecule 2 (ICAM2) was cloned into the dual AAV vectors of SpGuide and SpCas9 for driving expression of green fluorescence protein (GFP) and SpCas9, respectively. These two AAV vectors were applied to production of recombinant AAV serotype 5 (rAAV5), which were used to infect HRECs for depletion of VEGFR2. Protein expression was determined by Western blot; and cell proliferation, migration, as well as tube formation were examined. Results: AAV5 effectively infected vascular endothelial cells (ECs) and retinal pigment epithelial (RPE) cells; the ICAM2 promoter drove expression of GFP and SpCas9 in HRECs, but not in RPE cells. The results showed that the rAAV5-CRISPR/Cas9 depleted VEGFR2 by 80% and completely blocked VEGF-induced activation of Akt, and proliferation, migration as well as tube formation of HRECs. Conclusions: AAV-CRISRP/Cas9-mediated depletion of VEGFR2 is a potential therapeutic strategy for pathologic angiogenesis.

Despite recent advances in the medical management of diabetic retinal disease, there remain established indications for vitreoretinal surgery in the treatment of severe proliferative diabetic retinopathy. These include non-clearing vitreous hemorrhage and tractional retinal detachment. Advances in surgical instrumentation, technique, and experience have led to improved visual outcomes, as well as a corresponding decrease in the incidence of postoperative complications. However, the presence of systemic and ocular factors in diabetic patients increases the risk of adverse events compared to non-diabetic individuals. This review will focus on the most important postoperative complications following pars plana vitrectomy, with specific considerations for the diabetic patient.