November 2017

Thomson BR, Souma T, Tompson SW, Onay T, Kizhatil K, Siggs OM, Feng L, Whisenhunt KN, Yanovitch TL, Kalaydjieva L, Azmanov DN, Finzi S, Tanna CE, Hewitt AW, Mackey DA, Bradfield YS, Souzeau E, Javadiyan S, Wiggs JL, Pasutto F, Liu X, John SWM, Craig JE, Jin J, Young TL, Quaggin SE. Angiopoietin-1 is required for Schlemm's canal development in mice and humans. J Clin Invest 2017;Abstract
Primary congenital glaucoma (PCG) is a leading cause of blindness in children worldwide and is caused by developmental defects in 2 aqueous humor outflow structures, Schlemm's canal (SC) and the trabecular meshwork. We previously identified loss-of-function mutations in the angiopoietin (ANGPT) receptor TEK in families with PCG and showed that ANGPT/TEK signaling is essential for SC development. Here, we describe roles for the major ANGPT ligands in the development of the aqueous outflow pathway. We determined that ANGPT1 is essential for SC development, and that Angpt1-knockout mice form a severely hypomorphic canal with elevated intraocular pressure. By contrast, ANGPT2 was dispensable, although mice deficient in both Angpt1 and Angpt2 completely lacked SC, indicating that ANGPT2 compensates for the loss of ANGPT1. In addition, we identified 3 human subjects with rare ANGPT1 variants within an international cohort of 284 PCG patients. Loss of function in 2 of the 3 patient alleles was observed by functional analysis of ANGPT1 variants in a combined in silico, in vitro, and in vivo approach, supporting a causative role for ANGPT1 in disease. By linking ANGPT1 with PCG, these results highlight the importance of ANGPT/TEK signaling in glaucoma pathogenesis and identify a candidate target for therapeutic development.
Rahman SI, Turalba A. Anticoagulation in Glaucoma Surgery. Semin Ophthalmol 2017;:1-4.Abstract
Anticoagulation medications are used commonly, particularly in an elderly population. There are many systemic diseases and scenarios that require modulation of coagulation to prevent serious adverse outcomes. While there is some consensus about their use in cataract surgery, there is less certainty about their management with glaucoma surgery. Glaucoma surgery presents a unique challenge when considering anticoagulation. Currently, there is great diversity in surgeon practices regarding anticoagulation in glaucoma surgery. Based on available evidence, it is unclear whether it is beneficial to hold anticoagulation, with or without bridging therapy, leading up to a planned surgery. Considering the potential serious adverse outcomes related to holding anticoagulation therapy, altering these medications for glaucoma surgery should be done sparingly and in consultation with the primary prescriber of such medications.
Indaram M, VanderVeen DK. Postoperative Refractive Errors Following Pediatric Cataract Extraction with Intraocular Lens Implantation. Semin Ophthalmol 2017;:1-8.Abstract
PURPOSE: Advances in surgical techniques allow implantation of intraocular lenses (IOL) with cataract extraction, even in young children. However, there are several challenges unique to the pediatric population that result in greater degrees of postoperative refractive error compared to adults. METHODS: Literature review of the techniques and outcomes of pediatric cataract surgery with IOL implantation. RESULTS: Pediatric cataract surgery is associated with several sources of postoperative refractive error. These include planned refractive error based on age or fellow eye status, loss of accommodation, and unexpected refractive errors due to inaccuracies in biometry technique, use of IOL power formulas based on adult normative values, and late refractive changes due to unpredictable eye growth. CONCLUSIONS: Several factors can preclude the achievement of optimal refractive status following pediatric cataract extraction with IOL implantation. There is a need for new technology to reduce postoperative refractive surprises and address refractive adjustment in a growing eye.
Aschard H, Kang JH, Iglesias AI, Hysi P, Cooke Bailey JN, Khawaja AP, Allingham RR, Ashley-Koch A, Lee RK, Moroi SE, Brilliant MH, Wollstein G, Schuman JS, Fingert JH, Budenz DL, Realini T, Gaasterland T, Scott WK, Singh K, Sit AJ, Igo RP, Song YE, Hark L, Ritch R, Rhee DJ, Gulati V, Haven S, Vollrath D, Zack DJ, Medeiros F, Weinreb RN, Cheng C-Y, Chasman DI, Christen WG, Pericak-Vance MA, Liu Y, Kraft P, Richards JE, Rosner BA, Hauser MA, Hauser MA, Klaver CCW, van Duijn CM, Haines J, Wiggs JL, Pasquale LR. Genetic correlations between intraocular pressure, blood pressure and primary open-angle glaucoma: a multi-cohort analysis. Eur J Hum Genet 2017;25(11):1261-1267.Abstract
Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14-1.21), P=1.8 × 10-27) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 × 10-5); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG.
Riau AK, Venkatraman SS, Dohlman CH, Mehta JS. Surface Modifications of the PMMA Optic of a Keratoprosthesis to Improve Biointegration. Cornea 2017;36 Suppl 1:S15-S25.Abstract
Biointegration of a keratoprosthesis (KPro) is critical for the mitigation of various long-term postoperative complications. Biointegration of a KPro occurs between the haptic skirt (corneal graft) and the central optic [poly(methyl methacrylate) (PMMA)]. Various studies have highlighted common problems associated with poor bonding and biointegration between these 2 incompatible biomaterials. Resolution of these issues could be achieved by surface modification of the inert material (PMMA). A calcium phosphate (CaP) coating deposited on dopamine-activated PMMA sheets by simulated body fluid incubation (d-CaP coating) was shown to improve adhesion to collagen type I (main component of corneal stroma) compared with untreated PMMA and PMMA with other surface modifications. However, the d-CaP coating could easily undergo delamination, thereby reducing its potential for modification of KPro optical cylinders. In addition, the coating did not resemble the Ca and P composition of hydroxyapatite (HAp). A novel dip-coating method that involves the creation of cavities to trap and immobilize HAp nanoparticles on the PMMA surface was introduced to address the problems associated with the d-CaP coating. The newly obtained coating offered high hydrophilicity, resistance to delamination, and preservation of the Ca and P composition of HAp. These advantages resulted in improved adhesion strength by more than 1 order of magnitude compared with untreated PMMA. With respect to biointegration, human corneal stromal fibroblasts were able to adhere strongly and proliferate on HAp-coated PMMA. Furthermore, the new coating technique could be extended to immobilization of HAp nanoparticles on 3-mm-diameter PMMA cylinders, bringing it closer to clinical application.
Learned D, Eliott D. Management of Delayed Suprachoroidal Hemorrhage after Glaucoma Surgery. Semin Ophthalmol 2017;:1-5.Abstract
PURPOSE: To review the most current treatment recommendations and outcomes for delayed suprachoroidal hemorrhages. METHODS: Article review of management and outcomes of suprachoroidal hemorrhages, with emphasis on delayed suprachoroidal hemorrhages in the setting of glaucoma surgery. CONCLUSION: Time of drainage of suprachoroidal hemorrhages remains controversial. Earlier drainage should be considered with high intraocular pressure, expulsion of intraocular content, or retinal detachment. In clinically stable eyes with suprachoroidal hemorrhage, recommendations range from observation to immediate drainage. Clot lysis occurs at roughly 14 days.
Di Zazzo A, Roberti G, Mashaghi A, Abud TB, Pavese D, Bonini S. Use of Topical Cannabinomimetic Palmitoylethanolamide in Ocular Surface Disease Associated with Antiglaucoma Medications. J Ocul Pharmacol Ther 2017;33(9):670-677.Abstract
PURPOSE: Chronic use of topical hypotensive therapies in glaucoma patients leads to chronic inflammation of the ocular surface, which decreases the success rate of long-term glaucoma management. The aim of this study is to evaluate the effect of topical palmitoylethanolamide (PEA) (Defluxa©), a well-known anti-inflammatory and analgesic agent, in suppressing the ocular surface inflammation associated with the use of hypotensive eye drops. METHODS: In a pilot clinical trial, we enrolled 15 glaucomatous patients who received topical PEA (Defluxa) in addition to the current antiglaucoma drugs, while 15 glaucomatous patients did not receive any additional treatment. At 3 different time points (day 0, 15, and 30), signs of ocular surface involvement, adverse events, visual acuity, and intraocular pressure were assessed. RESULTS: Topical PEA (Defluxa) was effective in increasing the Schirmer test (P < 0.05) and the tear film breakup time (T-BUT) (P < 0.0001), and improving the conjunctival hyperemia (P < 0.0001) by day 30, compared to baseline. Compared to control, by day 15, the conjunctival hyperemia score was significantly decreased in the PEA (Defluxa) group (P < 0.01), while the T-BUT and the Schirmer Test achieved a significant improvement by day 30 (P < 0.05; P < 0.01). DISCUSSION: Our data suggests that topical PEA (Defluxa) is a safe, effective, and generally well-tolerated treatment to prevent or suppress ocular surface inflammation attributable to chronic glaucoma treatment.
Zhang Q, Jing S, Cheng Z, Yu Z, Dehghan S, Shamsaddini A, Yan Y, Li M, Seto D. Comparative genomic analysis of two emergent human adenovirus type 14 respiratory pathogen isolates in China reveals similar yet divergent genomes. Emerg Microbes Infect 2017;6(11):e92.Abstract
Human adenovirus type 14 (HAdV-B14p) was originally identified as an acute respiratory disease (ARD) pathogen in The Netherlands in 1955. For approximately fifty years, few sporadic infections were observed. In 2005, HAdV-B14p1, a genomic variant, re-emerged and was associated with several large ARD outbreaks across the U.S. and, subsequently, in Canada, the U.K., Ireland, and China. This strain was associated with an unusually higher fatality rate than previously reported for both this prototype and other HAdV types in general. In China, HAdV-B14 was first observed in 2010, when two unrelated HAdV-B14-associated ARD cases were reported in Southern China (GZ01) and Northern China (BJ430), followed by three subsequent outbreaks. While comparative genomic analysis, including indel analysis, shows that the three China isolates, with whole genome data available, are similar to the de Wit prototype, all are divergent from the U.S. strain (303600; 2007). Although the genomes of strains GZ01 and BJ430 are nearly identical, as per their genome type characterization and percent identities, they are subtly divergent in their genome mutation patterns. These genomes indicate possibly two lineages of HAdV-B14 and independent introductions into China from abroad, or subsequent divergence from one; CHN2012 likely represents a separate sub-lineage. Observations of these simultaneously reported emergent strains in China add to the understanding of the circulation, epidemiology, and evolution of these HAdV pathogens, as well as provide a foundation for developing effective vaccines and public health strategies, including nationwide surveillance in anticipation of larger outbreaks with potentially higher fatality rates associated with HAdV-B14p1.
Starks V, Freitag SK. Postoperative Complications of Dermis-Fat Autografts in the Anophthalmic Socket. Semin Ophthalmol 2017;:1-4.Abstract
Reconstruction of the anophthalmic socket allows the use of an ocular prosthesis and rehabilitation of facial appearance. Dermis-fat grafting is one option in volume augmentation of the anophthalmic socket and presents unique benefits, including increased surface area within the socket and the ability to grow with pediatric patients. Postoperative complications of this procedure are relatively common. Minor complications, such as graft hirsutism, keratinization, and conjunctival cysts or granulomas, are managed easily by observation or simple intervention. Major complications, such as graft atrophy, infection, or ulceration, may prevent good prosthesis fit and may require return to the operating room.
Peterson SR, Silva PA, Murtha TJ, Sun JK. Cataract Surgery in Patients with Diabetes: Management Strategies. Semin Ophthalmol 2017;:1-8.Abstract
Diabetes is a chronic systemic disease that affects nearly one in eight adults worldwide. Ocular complications, such as cataract, can lead to significant visual impairment. Among the worldwide population, cataract is the leading cause of blindness, and patients with diabetes have an increased incidence of cataracts which mature earlier compared to the rest of the population. Cataract surgery is a common and safe procedure, but can be associated with vision-threatening complications in the diabetic population, such as diabetic macular edema, postoperative macular edema, diabetic retinopathy progression, and posterior capsular opacification. This article is a brief review of diabetic cataract and complications associated with cataract extraction in this population of patients.
Guerriero RM, Patel AA, Walsh B, Baumer FM, Shah AS, Peters JM, Rodan LH, Agrawal PB, Pearl PL, Takeoka M. Systemic Manifestations in Pyridox(am)ine 5'-Phosphate Oxidase Deficiency. Pediatr Neurol 2017;76:47-53.Abstract
OBJECTIVE: Pyridoxine is converted to its biologically active form pyridoxal-5-phosphate (P5P) by the enzyme pyridox(am)ine 5'-phosphate oxidase and serves as a cofactor in nearly 200 reactions in the central nervous system. Pyridox(am)ine 5'-phosphate oxidase deficiency leads to P5P dependent epilepsy, typically a neonatal- or infantile-onset epileptic encephalopathy treatable with P5P or in some cases, pyridoxine. Following identification of retinopathy in a patient with pyridox(am)ine 5'-phosphate oxidase deficiency that was reversible with P5P therapy, we describe the systemic manifestations of pyridox(am)ine 5'-phosphate oxidase deficiency. METHODS: A series of six patients with homozygous mutations of PNPO, the gene coding pyridox(am)ine 5'-phosphate oxidase, were evaluated in our center over the course of two years for phenotyping of neurological and systemic manifestations. RESULTS: Five of six were born prematurely, three had anemia and failure to thrive, and two had elevated alkaline phosphatase. A movement disorder was observed in two children, and a reversible retinopathy was observed in the most severely affected infant. All patients had neonatal-onset epilepsy and were on a continuum of developmental delay to profound encephalopathy. Electroencephalographic features included background slowing and disorganization, absent sleep features, and multifocal and generalized epileptiform discharges. All the affected probands carried a homozygous PNPO mutation (c.674 G>T, c.686 G>A and c.352G>A). CONCLUSION: In addition to the well-described epileptic encephalopathy, pyridox(am)ine 5'-phosphate oxidase deficiency causes a range of neurological and systemic manifestations. A movement disorder, developmental delay, and encephalopathy, as well as retinopathy, anemia, and failure to thrive add to the broadening clinical spectrum of P5P dependent epilepsy.
Tu Y, Jakobiec FA, Leung K, Freitag SK. Distinguishing Benign from Malignant Circumscribed Orbital Tumors in Children. Semin Ophthalmol 2017;:1-10.Abstract
An orbital neoplasm in children is an uncommon clinical finding. Clinical suspicion should be based on many factors, including its location, the nature of onset, associated systemic signs and symptoms, family and social histories, examination findings, and radiographic characteristics. We present two cases of young children of similar age with a rapid-onset orbital mass. In both cases, a circumscribed round lesion was found in the superomedial orbit. An orbital schwannoma, a benign and usually slow growing tumor, was found in the first patient. In contrast, the biopsy of the second patient, who was nearly asymptomatic, revealed a rhabdomyosarcoma. In this review, we have explored the differential diagnosis of relatively common circumscribed round orbital tumors in the pediatric population from both the radiographic (magnetic resonance imaging, MRI) and histopathologic perspectives. A review of highly unusual orbital tumors in children is also provided.
Rahmani S, Eliott D. Postoperative Endophthalmitis: A Review of Risk Factors, Prophylaxis, Incidence, Microbiology, Treatment, and Outcomes. Semin Ophthalmol 2017;:1-7.Abstract
Postoperative endophthalmitis is one of the most feared complications of intraocular surgery. The most common types of intraocular surgeries performed worldwide are cataract extraction, glaucoma drainage implants/trabeculectomy, and pars plana vitrectomy. This review will focus on the clinical features, risk factors, prophylaxis, and treatment of endophthalmitis in these three main intraocular surgeries.

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