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Homer N, Jakobiec FA, Stagner A, Cunnane ME, Freitag SK, Fay A, Yoon MK. Periocular breast carcinoma metastases: correlation of clinical, radiologic and histopathologic features. Clin Exp Ophthalmol 2017;Abstract

IMPORTANCE: To describe presenting patterns of breast cancer metastases to the orbit and eyelids BACKGROUND: To provide clinical, radiographic, and pathologic correlations of breast metastases to the orbit or eyelids and evaluate radiographic volumetric orbital changes DESIGN: Retrospective review in an academic center PARTICIPANTS: Ten female patients with periocular metastatic breast carcinoma who were seen at the Massachusetts Eye and Ear Infirmary Oculoplastics Clinic METHODS: Retrospective review of patient records, imaging and pathology findings. MAIN OUTCOME MEASURES: Presenting clinical characteristics, radiographic findings, and histopathological features were assessed and correlated to discover distinctive presenting patterns. Volumetric measurements of the tumors and orbital soft tissue structures were made on magnetic resonance imaging studies. RESULTS: The breast metastases included 9 orbital and 1 eyelid lesions. Two distinct clinical presentations were observed. The first consisted of seven patients who had either enophthalmos or euphthalmos in the setting of a retrobulbar lesion, a radiographically indistinct lesion, and a classic microscopic invasive lobular breast carcinoma (ILBC) with a prominent fibrotic stroma. The second group consisted of two proptotic patients with mass lesions on imaging and an atypical ILBC pathological subtype (pleomorphic or alveolar). One patient had diffusely indurated eyelid fullness. Volumetric analyses demonstrated variable tumor sizes with an inconsistent impact on the orbital volume and fat. CONCLUSIONS AND RELEVANCE: This correlative study provides the clinical-radiographic-histopathologic basis for separating two overarching phenotypic presentations of metastatic breast carcinoma to the orbit. Previously postulated mechanisms for the distinctive finding of tumor-induced enophthalmos are re-examined in the light of the foregoing conclusions.

English JT, Norris PC, Hodges RR, Dartt DA, Serhan CN. Identification and Profiling of Specialized Pro-Resolving Mediators in Human Tears by Lipid Mediator Metabolomics. Prostaglandins Leukot Essent Fatty Acids 2017;117:17-27.Abstract

Specialized pro-resolving mediators (SPM), e.g. Resolvin D1, Protectin D1, Lipoxin A₄, and Resolvin E1 have each shown to be active in ocular models reducing inflammation. In general, SPMs have specific agonist functions that stimulate resolution of infection and inflammation in animal disease models. The presence and quantity of SPM in human emotional tears is of interest. Here, utilizing a targeted LC-MS-MS metabololipidomics based approach we document the identification of pro-inflammatory (Prostaglandins and Leukotriene B₄) and pro-resolving lipid mediators (D-series Resolvins, Protectin D1, and Lipoxin A₄) in human emotional tears from 12 healthy individuals. SPMs from the Maresin family (Maresin 1 and Maresin 2) were not present in these samples. Principal Component Analysis (PCA) revealed gender differences in the production of specific mediators within these tear samples as the SPMs were essentially absent in these female donors. These results indicate that specific SPM signatures are present in human emotional tears at concentrations known to be bioactive. Moreover, they will help to further appreciate the mechanisms of production and action of SPMs in the eye, as well as their physiologic roles in human ocular disease resolution.

Fu Z, Gong Y, Liegl R, Wang Z, Liu C-H, Meng SS, Burnim SB, Saba NJ, Fredrick TW, Morss PC, Hellstrom A, Talukdar S, Smith LEH. FGF21 Administration Suppresses Retinal and Choroidal Neovascularization in Mice. Cell Rep 2017;18(7):1606-1613.Abstract

Pathological neovascularization, a leading cause of blindness, is seen in retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. Using a mouse model of hypoxia-driven retinal neovascularization, we find that fibroblast growth factor 21 (FGF21) administration suppresses, and FGF21 deficiency worsens, retinal neovessel growth. The protective effect of FGF21 against neovessel growth was abolished in adiponectin (APN)-deficient mice. FGF21 administration also decreased neovascular lesions in two models of neovascular age-related macular degeneration: very-low-density lipoprotein-receptor-deficient mice with retinal angiomatous proliferation and laser-induced choroidal neovascularization. FGF21 inhibited tumor necrosis α (TNF-α) expression but did not alter Vegfa expression in neovascular eyes. These data suggest that FGF21 may be a therapeutic target for pathologic vessel growth in patients with neovascular eye diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration.

Zhou C, Robert M-C, Kapoulea V, Lei F, Stagner AM, Jakobiec FA, Dohlman CH, Paschalis EI. Sustained Subconjunctival Delivery of Infliximab Protects the Cornea and Retina Following Alkali Burn to the Eye. Invest Ophthalmol Vis Sci 2017;58(1):96-105.Abstract

Purpose: Tumor necrosis factor (TNF)-α is upregulated in eyes following corneal alkali injury and contributes to corneal and also retinal damage. Prompt TNF-α inhibition by systemic infliximab ameliorates retinal damage and improves corneal wound healing. However, systemic administration of TNF-α inhibitors carries risk of significant complications, whereas topical eye-drop delivery is hindered by poor ocular bioavailability and the need for patient adherence. This study investigates the efficacy of subconjunctival delivery of TNF-α antibodies using a polymer-based drug delivery system (DDS). Methods: The drug delivery system was prepared using porous polydimethylsiloxane/polyvinyl alcohol composite fabrication and loaded with 85 μg of infliximab. Six Dutch-belted pigmented rabbits received ocular alkali burn with NaOH. Immediately after the burn, subconjunctival implantation of anti-TNF-α DDS was performed in three rabbits while another three received sham DDS (without antibody). Rabbits were followed with photography for 3 months. Results: After 3 months, the device was found to be well tolerated by the host and the eyes exhibited less corneal damage as compared to eyes implanted with a sham DDS without drug. The low dose treatment suppressed CD45 and TNF-α expression in the burned cornea and inhibited retinal ganglion cell apoptosis and optic nerve degeneration, as compared to the sham DDS treated eyes. Immunolocalization revealed drug penetration in the conjunctiva, cornea, iris, and choroid, with residual infliximab in the DDS 3 months after implantation. Conclusions: This reduced-risk biologic DDS improves corneal wound healing and provides retinal neuroprotection, and may be applicable not only to alkali burns but also to other inflammatory surgical procedures such as penetrating keratoplasty and keratoprosthesis implantation.

Torkildsen G, Abelson MB, Gomes PJ, McLaurin E, Potts SL, Mah FS. Vehicle-Controlled, Phase 2 Clinical Trial of a Sustained-Release Dexamethasone Intracanalicular Insert in a Chronic Allergen Challenge Model. J Ocul Pharmacol Ther 2017;33(2):79-90.Abstract

PURPOSE: To evaluate the efficacy and safety of a sustained-release dexamethasone intracanalicular insert (Dextenza™) in a model of allergic conjunctivitis. METHODS: This was a randomized, double-masked, vehicle-controlled, Phase 2 study. Subjects had to have a positive conjunctival allergen challenge (CAC) reaction to allergen (bilateral +2 itching and redness on 5-point, 0-4 scales) at Visit 1, and for 2 of 3 time points on subsequent visits. Subjects who met entry criteria were randomized to receive Dextenza or PV (vehicle insert). Challenges occurred over 42 days, with efficacy assessed at 14 (primary endpoint visit), 28, and 40 days postinsertion. Outcome measures included the evaluation of ocular itching, redness, tearing, chemosis, eyelid swelling, rhinorrhea, and congestion. RESULTS: Twenty-eight subjects completed the study in the Dextenza group and 31 in the vehicle group. At 14 days postinsertion, Dextenza was statistically superior to PV, with least square mean differences for ocular itching of -0.76, -0.97, and -0.87 at 3, 5, and 7 min post-CAC, and for conjunctival redness of -0.46, -0.66, and -0.68 at 7, 15, and 20 min post-CAC. Clinical significance, defined as a 1-U decrease from PV, was not met for primary efficacy. Secondary endpoints, including number of subjects reporting itching and conjunctival redness, indicated superior performance of Dextenza compared with vehicle. Eleven Dextenza-treated (35.5%) and 10 vehicle-treated (30.3%) subjects each experienced a single adverse event. CONCLUSION: This Phase 2 study demonstrated preliminary efficacy and safety data of Dextenza for treatment of allergic conjunctivitis.

Witkin AJ, Chang DF, Jumper MJ, Charles S, Eliott D, Hoffman RS, Mamalis N, Miller KM, Wykoff CC. Vancomycin-Associated Hemorrhagic Occlusive Retinal Vasculitis: Clinical Characteristics of 36 Eyes. Ophthalmology 2017;124(5):583-595.Abstract

PURPOSE: To expand understanding of presentation, diagnosis, and outcomes of hemorrhagic occlusive retinal vasculitis (HORV). DESIGN: Retrospective case series. PARTICIPANTS: Thirty-six eyes of 23 patients. METHODS: The American Society of Cataract and Refractive Surgery (ASCRS) and the American Society of Retina Specialists (ASRS) formed a joint task force to define clinical characteristics of HORV and to study its prevalence, cause, treatment, and outcomes. An online registry was established on both societies' web sites. Surveys were e-mailed to members of both societies soliciting cases of suspected HORV. A literature search was performed to uncover additional cases. MAIN OUTCOME MEASURES: Historical data including intraoperative characteristics, images, treatment regimens, and visual and anatomic outcomes. RESULTS: Characteristic findings of HORV included unremarkable postoperative day 1 undilated examination, delayed-onset painless vision loss, mild anterior chamber and vitreous inflammation, sectoral retinal hemorrhages in areas of ischemia, and predilection for venules and peripheral involvement. Based on predetermined diagnostic criteria, 36 eyes of 23 patients were diagnosed with HORV. All eyes received intraocular vancomycin via intracameral bolus (33/36), via intravitreal injection (1/36), or through the irrigation bottle (2/36). Patients sought treatment with HORV 1 to 21 days after surgery or intravitreal injection. Visual results usually were poor: 22 of 36 eyes (61%) had 20/200 or worse visual acuity and 8 of 36 eyes (22%) had no light perception (NLP). Neovascular glaucoma developed in 20 of 36 eyes (56%). Seven eyes received additional intravitreal vancomycin after surgery; 5 of these 7 eyes had NLP visual acuity at the most recent examination. Three eyes received intravitreal corticosteroids and had final visual acuities of 20/40, 20/70, and hand movements. CONCLUSIONS: Hemorrhagic occlusive retinal vasculitis is a rare, potentially devastating condition that can develop after cataract surgery or intraocular injection. All cases in this series were associated with intraocular vancomycin. Disease course and findings suggest that HORV is caused by a delayed hypersensitivity reaction to vancomycin. Early treatment with corticosteroids likely is beneficial. Subsequently, anti-vascular endothelial growth factor injections and panretinal photocoagulation are important to prevent neovascular glaucoma, a common complication. Avoidance of additional intravitreal vancomycin is recommended if HORV is suspected.

Springelkamp H, Iglesias AI, Mishra A, Höhn R, Wojciechowski R, Khawaja AP, Nag A, Wang YX, Wang JJ, Cuellar-Partida G, Gibson J, Cooke Bailey JN, Vithana EN, Gharahkhani P, Boutin T, Ramdas WD, Zeller T, Luben RN, Yonova-Doing E, Viswanathan AC, Yazar S, Cree AJ, Haines JL, Koh JY, Souzeau E, Wilson JF, Amin N, Müller C, Venturini C, Kearns LS, Kang JH, Kang JH, Tham YC, Zhou T, van Leeuwen EM, Nickels S, Sanfilippo P, Liao J, van der Linde H, Zhao W, van Koolwijk LME, Zheng L, Rivadeneira F, Baskaran M, van der Lee SJ, Perera S, de Jong PTVM, Oostra BA, Uitterlinden AG, Fan Q, Hofman A, Tai E-S, Vingerling JR, Sim X, Wolfs RCW, Teo YY, Lemij HG, Khor CC, Willemsen R, Lackner KJ, Aung T, Jansonius NM, Montgomery G, Wild PS, Young TL, Burdon KP, Hysi PG, Pasquale LR, Wong TY, Klaver CCW, Hewitt AW, Jonas JB, Mitchell P, Lotery AJ, Foster PJ, Vitart V, Pfeiffer N, Craig JE, Mackey DA, Hammond CJ, Wiggs JL, Cheng C-Y, van Duijn CM, Macgregor S. New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics. Hum Mol Genet 2017;Abstract

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increase risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

Woods SE, Lieberman MT, Lebreton F, Trowel E, de la Fuente-Núñez C, Dzink-Fox J, Gilmore MS, Fox JG. Characterization of Multi-Drug Resistant Enterococcus faecalis Isolated from Cephalic Recording Chambers in Research Macaques (Macaca spp.). PLoS One 2017;12(1):e0169293.Abstract

Nonhuman primates are commonly used for cognitive neuroscience research and often surgically implanted with cephalic recording chambers for electrophysiological recording. Aerobic bacterial cultures from 25 macaques identified 72 bacterial isolates, including 15 Enterococcus faecalis isolates. The E. faecalis isolates displayed multi-drug resistant phenotypes, with resistance to ciprofloxacin, enrofloxacin, trimethoprim-sulfamethoxazole, tetracycline, chloramphenicol, bacitracin, and erythromycin, as well as high-level aminoglycoside resistance. Multi-locus sequence typing showed that most belonged to two E. faecalis sequence types (ST): ST 4 and ST 55. The genomes of three representative isolates were sequenced to identify genes encoding antimicrobial resistances and other traits. Antimicrobial resistance genes identified included aac(6')-aph(2"), aph(3')-III, str, ant(6)-Ia, tetM, tetS, tetL, ermB, bcrABR, cat, and dfrG, and polymorphisms in parC (S80I) and gyrA (S83I) were observed. These isolates also harbored virulence factors including the cytolysin toxin genes in ST 4 isolates, as well as multiple biofilm-associated genes (esp, agg, ace, SrtA, gelE, ebpABC), hyaluronidases (hylA, hylB), and other survival genes (ElrA, tpx). Crystal violet biofilm assays confirmed that ST 4 isolates produced more biofilm than ST 55 isolates. The abundance of antimicrobial resistance and virulence factor genes in the ST 4 isolates likely relates to the loss of CRISPR-cas. This macaque colony represents a unique model for studying E. faecalis infection associated with indwelling devices, and provides an opportunity to understand the basis of persistence of this pathogen in a healthcare setting.

Thanos A, Todorich B, Hypes SM, Yonekawa Y, Thomas B, Randhawa S, Drenser KA, Trese MT. RETINAL VASCULAR TORTUOSITY AND EXUDATIVE RETINOPATHY IN A FAMILY WITH DYSKERATOSIS CONGENITA MASQUERADING AS FAMILIAL EXUDATIVE VITREORETINOPATHY. Retin Cases Brief Rep 2017;11 Suppl 1:S187-S190.Abstract

PURPOSE: To report a novel presentation of dyskeratosis congenita masquerading as familial exudative vitreoretinopathy. METHODS: Observational case series involving single family and literature review. RESULTS: A brother and sister were diagnosed with familial exudative vitreoretinopathy at ages 4 and 2, respectively. Both patients were managed with laser photocoagulation. Eight years after the initial presentation, both siblings developed pancytopenia secondary to bone marrow failure. Laboratory work-up revealed severely shortened telomere length in both patients, and genetic testing revealed a missense mutation in the gene that encodes the reverse transcriptase component of telomerase, confirming the diagnosis of dyskeratosis congenita. The father of both children was a carrier of the same mutation, who exhibited marked retinal vascular tortuosity of the second-order vessels. CONCLUSION: Dyskeratosis congenita is a severe multisystem disorder, which should be considered in cases of pediatric exudative retinopathies with concurrent signs and/or symptoms of bone marrow failure.

Wan MJ, Mantagos IS, Shah AS, Kazlas M, Hunter DG. Comparison of Botulinum Toxin With Surgery for the Treatment of Acute-Onset Comitant Esotropia in Children. Am J Ophthalmol 2017;176:33-39.Abstract

PURPOSE: To determine whether botulinum toxin is as effective as strabismus surgery in the treatment of acute-onset comitant esotropia in children. DESIGN: Retrospective, nonrandomized, comparative clinical study. METHODS: Setting: Tertiary care pediatric hospital. STUDY POPULATION: Forty-nine children with acute-onset comitant esotropia. INTERVENTION: Treatment with either botulinum toxin ("chemodenervation group") or standard incisional strabismus surgery ("surgery group"). MAIN OUTCOME MEASURE: Success rate at 6 months (total horizontal deviation of 10 prism diopters or less and evidence of binocular single vision). RESULTS: There were 16 patients in the chemodenervation group and 33 patients in the surgery group. The success rate was not significantly different at 6 months (81% vs 61%, P = .20) or at 18 months (67% vs 58%, P = .74). The median angle of deviation and median stereoacuity were not significantly different at 6 or 18 months. The chemodenervation procedure was not inferior to incisional strabismus surgery at 6 months. The duration of general anesthesia (5 vs 71 min, P < .001) and time in the post-anesthesia care unit (37 vs 93 min, P < .001) were significantly shorter in the chemodenervation group. Botulinum toxin injection payment averaged $874 per procedure compared with $2783 for strabismus surgery. CONCLUSIONS: Botulinum toxin is at least as effective as surgery in the treatment of acute-onset comitant esotropia at 6 months while reducing the duration of general anesthesia and healthcare costs.

Wolkow N, Jakobiec FA, Stagner AM, Cunnane ME, Piantadosi AL, Basgoz N, Lefebvre D. Chronic orbital and calvarial fungal infection with Apophysomyces variabilis in an immunocompetent patient. Surv Ophthalmol 2017;62(1):70-82.Abstract

Apophysomyces is a rare fungal organism causing rhino-orbito-cerebral mycotic infections with high morbidity and mortality, typically in immunocompetent individuals. Several cases of Apophysomyces elegans orbital disease have been reported. Herein, we report a case of Apophysomyces variabilis infection involving the orbit, sinuses, and calvarium in an immunocompetent 74-year-old woman, with a review of the literature. Unlike prior cases of A. elegans classic rhino-orbito-cerebral infection, our case included diffuse calvarial lytic lesions and overlying soft tissue nodules, but without parenchymal intracranial involvement. There was radiographic and clinical evidence of infarction of the orbital contents and cavernous sinus thrombosis. Anastomoses between the superior orbital (ophthalmic) vein and diploic veins of the calvarium are believed to be primarily responsible for the unusual mode of spread on the extradural surface of the brain. Although the patient stabilized without definitive surgical intervention, her disease slowly and intermittently progressed for over a year after presentation, requiring multiple courses of antifungal treatment.

Shi Y, Wang H, Yin J, Zhang X, Li M, Xin C, Chen X, Wang N. Outcomes of microcatheter-assisted trabeculotomy following failed angle surgeries in primary congenital glaucoma. Eye (Lond) 2017;31(1):132-139.Abstract

PurposeTo report surgical outcomes of microcatheter-assisted trabeculotomy following failed angle surgeries, and compare those with no previous angle surgery, in primary congenital glaucoma (PCG).MethodsThe early postoperative (12 months) results of 42 eyes of 36 patients who underwent microcatheter-assisted trabeculotomy by single surgeon for PCG were retrospectively analyzed. Group 1, 20 eyes of 16 patients, had no previous angle surgery. Group 2, 22 eyes of 20 patients, had one or two previous failed angle surgeries. Success was defined as an intraocular pressure (IOP) <21 mm Hg with at least a 30% reduction from preoperative IOP with (qualified success) or without (complete success) the use of antiglaucoma medication.ResultsMean IOP decreased from 31.5±7.2 mm Hg on 3 (median, range: 1-5) medications in Group 1 and 34.6±7.3 mm Hg on 3 (median, range: 1-4) medications in Group 2 preoperatively to 15.6±3.1 mm Hg on 0 (median, range: 0-4) medications in Group 1 and 16.0±4.6 mm Hg on 0 (median, range: 0-2) medications in Group 2 postoperatively at 12 months (both P<0.001), respectively. The mean percentage of IOP reduction from preoperative to last postoperative visit was 46.0±20.1% in Group 1 and 45.5±25.0% in Group 2, P=0.947. Qualified and complete successes were comparable between Group 1 and Group 2 (qualified success: 90.0% vs 77.3%, P=0.294; complete success: 78.9% vs 77.3%, P=0.853). Complications were minimal.ConclusionsMicrocatheter-assisted trabeculotomy achieved significant pressure-lowering effects with a reduction in medication use in PCG, and it represents a reasonable choice of initial and repeat surgical treatment for PCG.

Li Y, Andereggen L, Yuki K, Omura K, Yin Y, Gilbert H-Y, Erdogan B, Asdourian MS, Shrock C, de Lima S, Apfel U-P, Zhuo Y, Hershfinkel M, Lippard SJ, Rosenberg PA, Benowitz L. Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration. Proc Natl Acad Sci U S A 2017;114(2):E209-E218.Abstract

Retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate their axons once the optic nerve has been injured and soon begin to die. Whereas RGC death and regenerative failure are widely viewed as being cell-autonomous or influenced by various types of glia, we report here that the dysregulation of mobile zinc (Zn(2+)) in retinal interneurons is a primary factor. Within an hour after the optic nerve is injured, Zn(2+) increases several-fold in retinal amacrine cell processes and continues to rise over the first day, then transfers slowly to RGCs via vesicular release. Zn(2+) accumulation in amacrine cell processes involves the Zn(2+) transporter protein ZnT-3, and deletion of slc30a3, the gene encoding ZnT-3, promotes RGC survival and axon regeneration. Intravitreal injection of Zn(2+) chelators enables many RGCs to survive for months after nerve injury and regenerate axons, and enhances the prosurvival and regenerative effects of deleting the gene for phosphatase and tensin homolog (pten). Importantly, the therapeutic window for Zn(2+) chelation extends for several days after nerve injury. These results show that retinal Zn(2+) dysregulation is a major factor limiting the survival and regenerative capacity of injured RGCs, and point to Zn(2+) chelation as a strategy to promote long-term RGC protection and enhance axon regeneration.

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