Characteristics and Treatment Patterns of Patients with Diabetic Macular Edema Non-Responsive to Anti-Vascular Endothelial Growth Factor Treatment in Ontario, Canada.

Purpose: To understand the demographics, clinical characteristics, treatment patterns, visual and anatomic responses of patients with diabetic macular edema (DME) initially treated with anti-vascular endothelial growth factor (anti-VEGF) agents in the real-world clinical setting. Patients and Methods: This retrospective cohort study used electronic health records to identify consecutively presenting patients with DME who received their first documented anti-VEGF injection (index injection) on or after 1 October 2015 and before 30 September 2016 (index period) at 4 clinical sites in Ontario, Canada. Patients receiving anti-VEGF injections in the study eye were followed for ≥18 months. After the first 3 monthly injections, patients were classified as "responder" (≥20% reduction in central retinal thickness [CRT] from index date) or "nonresponder" (<20% reduction in CRT) to anti-VEGF treatment. Results: At 12 months, change from baseline (CFB) in best visual acuity (BVA) of responders (n = 30) was mean (SD) 12.8 (13.00) letters; CFB in nonresponders (n = 56) was 3.2 (16.3) letters. Sensitivity analyses stratified by initial BVA were supportive. Mean (SD) change in CRT (µm) was -160.4 (111.4) in responders and -62.2 (98.6) in nonresponders. While changes in anti-VEGF therapy were lower in responders versus nonresponders (10.0% vs 23.2%), mean number of injections was similar (8.3 in each cohort). Conclusion: Despite receiving a substantial number of injections and requiring changes in therapy more frequently, nonresponders showed a lack of clinically meaningful change in BVA and CRT. Nonresponders could be identified after 3 anti-VEGF injections. There remains an unmet need for treatment options in patients with DME who show a nonresponse after 3 months of anti-VEGF treatment.

Suprachoroidal and vitreous haemorrhage as a presenting feature of metastatic melanoma.

A man in his 70s presented with right ocular pain, vision loss and temporal headache 4 days after undergoing laser peripheral iridotomy. The patient had lost 10 lbs over the preceding 6 weeks and had a medical history significant for a previously excised melanoma of the left arm. During the course of investigations, the patient was referred to oncology for workup, ultimately leading to a diagnosis of metastatic melanoma. Visceral metastases were identified in the lungs, right anterior fourth rib, left femoral distal diaphysis and medial side of the right globe. The patient decompensated and died shortly after his first radiotherapy treatment.This is the first published report of suprachoroidal haemorrhage secondary to metastasis from suspected cutaneous melanoma. The case highlights the importance of considering malignancy on the differential diagnosis for a suprachoroidal haemorrhage of unknown aetiology and involving oncology early for workup and treatment.

CALRETICULIN MUTATION ASSOCIATED WITH BILATERAL CENTRAL RETINAL VEIN OCCLUSION IN A YOUNG WOMAN.

BACKGROUND: Bilateral central retinal vein occlusion (CRVO) is rare and is usually associated with an underlying systemic illness such as hypercoagulable state or systemic inflammatory disease. We present a case of bilateral CRVO in a young patent who was found to have a mutation in the calreticulin gene, which was presumed to be the culprit. METHODS: Case report. RESULTS: We report a 24-year-old woman with bilateral CRVO. Hypercoagulability work-up was positive for in-frame deletion in exon 9 of the calreticulin gene. CONCLUSION: We suggest that all young patients presenting with CRVO or any patient with bilateral CRVO have genetic testing for a limited set of known, prothrombotic mutations including the recently identified calreticulin gene.

Treatment of Diabetic Macular Edema with Aflibercept and Micropulse Laser (DAM Study).

Purpose: To investigate the safety and efficacy of micropulse (MP) macular laser in combination with intravitreal aflibercept for the treatment of center-involved diabetic macular edema (CI-DME). Methods: A single-blind prospective randomized controlled pilot trial was performed. In total, 30 eyes of 30 patients with CI-DME and best corrected visual acuity (BCVA) between, and including, 20/30 and 20/400 were enrolled. Enrolled eyes were randomized to 2 groups. Group 1 received intravitreal aflibercept injections (IVT-AFL) with sham laser. Group 2 received IVT-AFL with MP laser. Both groups were followed every 4 weeks for 48 weeks and retreatment was performed on pro re nata basis according to preset criteria. The main outcome measure was the average number of intravitreal injections for each group at 48 weeks. Secondary outcome measures included changes in BCVA and central macular thickness (CMT) at 24 and 48 weeks. Results: The average number of intravitreal injections at 48 weeks was similar between the groups (8.5±3.3 in Group 1 vs 7.9±3.6 in Group 2, p=0.61). After 48 weeks, both groups demonstrated an improvement in BCVA and CMT. However, the difference in improvement between the groups was not statistically significant (p=0.18 for BCVA and p=0.57 for CMT). Conclusion: Intravitreal injections of aflibercept led to improvements in BCVA and CMT at 24 and 48 weeks. Addition of MP laser to eyes in group 2 did not offer additional benefit in reducing treatment burden or improving CMT. Eyes that received MP laser showed a numerically greater improvement in BCVA, although this was not statistically significant. Clinicaltrialsgov Identifier: NCT03143192 March 8, 2017.

Corneal endothelial cell loss after pars plana vitrectomy and combined phacoemulsification-vitrectomy surgeries.

OBJECTIVE: To compare postoperative corneal endothelial cell density (ECD) loss in eyes undergoing pars plana vitrectomy (PPV), or combination of cataract extraction (using phacoemulsification) and intraocular lens implantation with vitrectomy (CE/IOL-PPV) surgeries. METHODS: Institutional setting. Best-corrected visual acuity (BCVA) and ECD by specular microscopy were measured preoperatively and 3 months postoperatively in both groups. Relative postoperative ECD loss was the primary outcome measure. Change in BCVA was the secondary outcome measure. RESULTS: Forty eyes of 40 patients undergoing PPV and 46 eyes of 46 patients undergoing CE/IOL-PPV were included in the final analysis. Postoperative ECD was decreased slightly more in the CE/IOL-PPV group compared with the PPV group (13.9% ± 15.5% vs 9.0% ± 14.6%), although this was not statistically significant (p = 0.10). The improvement in the logMAR BCVA was, however, statistically more significant in the CE/IOL-PPV group compared with the PPV group (-56.6% ± 24.3% vs -38.6% ± 45.5%, p = 0.04). CONCLUSIONS: PPV and the combination CE/IOL-PPV surgeries lead to modest and statistically similar postoperative decline in ECD. The combination surgery may lead to slightly more postoperative cells loss, but also more improvement in visual acuity.

Effect of distance and duration of illumination on retinal ganglion cells exposed to varying concentrations of brilliant blue green.

BACKGROUND: The objective of the study was to determine the safety parameters of using brilliant blue green (BBG) for chromovitrectomy by assessing the cytotoxicity of BBG on cultured retinal ganglion cells (RGCs) exposed to illumination. METHODS: RGCs were exposed to two concentrations of BBG (0.25 and 0.5 mg/mL) under metal halide illumination at varying distances (1 and 2.5 cm), intensities (990 and 2,000 Fc), and durations (1, 5 and 15 minutes). Cell viability was assessed using the WST-1 and CellTiter 96(®) AQueous One solution cell proliferation assays. RESULTS: Using the WST-1 assay, with high-intensity illumination, viability of RGCs ranged from 97.5±16.4% of controls with minimum BBG and light exposure (0.25 mg/mL BBG and illuminated for 1 minute at 2.5 cm distance) to 53.1±11.3% of controls with maximum BBG and light exposure (0.50 mg/mL and illuminated for 15 minutes at 1 cm distance; P < 0.01). With medium-intensity illumination, RGCs showed better viability, ranging from 95.1±7.2% of controls with minimum BBG and light exposure to 72.3±12.8% of controls with maximum BBG and light exposure. CellTiter 96(®) AQueous One assay showed similar results. CONCLUSION: RGCs seem to safely tolerate up to 5 minutes of exposure to 0.5 mg/mL BBG under diffuse medium-intensity illumination (990 Fc).

Assessment of the effect of distance and duration of illumination on retinal pigment epithelial cells exposed to varying doses of Brilliant Blue Green.

PURPOSE: To assess the cytotoxicity of varying concentrations of Brilliant Blue Green (BBG) on human retinal pigment epithelial (HRPE) cells exposed to metal halide surgical endoilluminator (SE) at varying distances of illumination. METHODS: HRPE (ARPE-19) were exposed to 2 concentrations (0.25 and 0.5 mg/mL) of BBG and illuminated with SE for 1, 5, and 15 min. Illumination (measured with light meter) was positioned at varying distances (1 and 2.5 cm) to mimic surgical distance of illumination. Cell viability (WST-1 assay) as well as structural changes in cells was quantified. RESULTS: At 1 cm distance of illumination, 0.25 mg/mL BBG decreased viability of HRPE to 89.6%±4.3%, 83.9%±10.9%, and 38.9%±5.1% of controls after 1, 5, and 15 min of exposure, respectively. Similarly, 0.5 mg/mL BBG at 1 cm distance of illumination reduced the viability of HRPE to 93.7%±2.8%, 59.6%±16%, and 34.7%±3.5% of controls. At the distance of 2.5 cm, HRPE showed improved viability; cells exposed to 0.25 mg/mL BBG maintained 98.85%±3.3%, 95.31%±7.12%, and 62.07%±3.0% of viability compared with controls after 1, 5, and 15 min of exposure. Morphometric evaluation of RPE cells showed increased width (swelling) of HRPE. CONCLUSION: BBG at its clinically used concentration (0.25 mg/mL) during vitreoretinal surgery is safe and not toxic to HRPE for up to 5 min under focal illumination (1 cm) and up to 15 min under diffuse illumination (2.5 cm) from the commonly used SE. RESULTS of our study are useful in establishing safety parameters for the use of BBG dye in vitreoretinal surgery.

Miniaturized high-resolution wide-field contact lens for panretinal photocoagulation.

BACKGROUND AND OBJECTIVE: We describe a miniaturized lightweight high-refractive-index panretinal contact lens for diagnostic and therapeutic visualization of the peripheral retina. INSTRUMENT DESIGN: The miniaturized high-resolution wide-field contact lens includes three optical elements in a light (15 g) and miniaturized (16 mm footplate, 24 mm external aperture, and 21 mm vertical height) casing contributing to a total dioptric power of +171 diopters. This lens provides up to 165° visualization of the retina for diagnostic and therapeutic applications while allowing easier placement due to its miniaturization. CONCLUSION: This new lens (50% lighter and 89% smaller) improves upon earlier contact lenses for visualization of the peripheral retina.

The role of lutein in eye-related disease.

The lens and retina of the human eye are exposed constantly to light and oxygen. In situ phototransduction and oxidative phosphorylation within photoreceptors produces a high level of phototoxic and oxidative related stress. Within the eye, the carotenoids lutein and zeaxanthin are present in high concentrations in contrast to other human tissues. We discuss the role of lutein and zeaxanthin in ameliorating light and oxygen damage, and preventing age-related cellular and tissue deterioration in the eye. Epidemiologic research shows an inverse association between levels of lutein and zeaxanthin in eye tissues and age related degenerative diseases such as macular degeneration (AMD) and cataracts. We examine the role of these carotenoids as blockers of blue-light damage and quenchers of oxygen free radicals. This article provides a review of possible mechanisms of lutein action at a cellular and molecular level. Our review offers insight into current clinical trials and experimental animal studies involving lutein, and possible role of nutritional intervention in common ocular diseases that cause blindness.

Success rates of primary probing for congenital nasolacrimal obstruction in children.

PURPOSE: To determine the success rate of nasolacrimal duct probing for the treatment of congenital nasolacrimal duct obstruction and to identify the age at which the success rate decreases. METHODS: Records for probing procedures from 2005 to 2010, over a 56-month period, were reviewed. Successful probing was defined as complete resolution of epiphora 3 months after treatment. Success rates were compared between children <3 years of age and children ≥3 years of age at the time of the procedure. RESULTS: A total of 168 eyes (128 children, mean age 32.2 ± 23.8 months) had undergone a probing procedure, and the overall success rate was 72%. Children aged <36 months had a success rate of 78%; children aged ≥36 months had a success rate of 50%. Multivariate analysis demonstrated that age at the time of procedure was a significant risk factor for failed probing (P = 0.035; OR, 1.67; 95% CI, 1.04-2.69), whereas sex and bilateral surgery were not. CONCLUSIONS: The success rate of primary probing for congenital nasolacrimal duct obstruction was significantly reduced when performed on children ≥3 years of age.

Traumatic aniridia in a pseudophakic patient 6 years following surgery.

PURPOSE: To report a case of aniridia in a pseudophakic patient following blunt trauma to the eye. CASE REPORT: The traumatized eye had cataract surgery through a 3.0 mm clear corneal incision 6 years prior to the incident. While there have been previous cases of traumatic aniridia in pseudophakic eyes, previous reports have all occurred closer to the time of the cataract surgery. We believe that the most likely mechanism of loss of iris tissue is through wound dehiscence, which would suggest the relative instability of clear corneal incisions several years postoperatively. The patient's visual acuity returned to 20/20 4 weeks post-trauma, with symptoms of glare which were managed by the use of a colored contact lens. CONCLUSION: The possibility of wound dehiscence should be recognized as an important clinical entity in the immediate postoperative period, but also several years following cataract surgery.

Role of angiopoietin-2 in regulating growth and vascularity of astrocytomas.

Angiopoietins and Tie2 are angiogenic-specific ligand and receptor complex that have been shown to play a critical role in tumor angiogenesis. Angiopoietin-2 (Ang2) is one of four ligands for receptor Tie2 and it is the naturally occurring antagonist to Tie2, inhibiting the action of Angiopoietin-1 (Ang1). Over the last decade, significant research has focused on elucidating the role of Ang2 in cancer biology and its exact role in tumor angiogenesis remains elusive. In this study we have focused on establishing the role of Ang2 in angiogenesis of malignant astrocytomas. We have demonstrated that Ang2 significantly enhances the vascular growth of malignant astrocytomas and constant upregulation of Ang2 throughout all phases of tumor growth generates abnormal vascular structures that are not typically seen in human astrocytomas, suggesting that Ang2 plays a tumor stage-dependent role and is not a consistently elevated throughout all growth stages of malignant astroctyomas.

Digital photography as a novel technique of measuring ocular surface dimensions.

PURPOSE: To introduce a novel technique for measuring ocular surface dimensions using digital photography and computerized image analysis in the context of ptosis repair surgery. METHODS: Digital photographs and patient questionnaires on dry eye symptoms were obtained from 31 patients before and after ptosis repair. Patients were examined preoperatively and at 1 and 6 weeks postoperatively. Adobe Photoshop 7.0 (Adobe Systems Incorporated, 345 Parkl Avenue, San Jose, CA 95110-2704, USA) was used to digitally measure palpebral fissure height, fissure width, and ocular surface area (OSA). Similar digital measurements were obtained on 30 control subjects as well. Digital calculations of OSA for control, preoperative, and postoperative groups were compared with other published techniques. RESULTS: Graphical comparison between our method of measuring OSA and the mathematical estimations proposed by previous studies suggests that our method is more precise in measuring OSA, and that it is also better able to identify individual variations of OSA from general population trends. CONCLUSION: Digital ocular photography combined with computerized image analysis is a fast, easy to use, and reliable method of measuring ocular surface dimensions. In addition to ptosis surgery, this method can be used in other ocular surface studies.

Regulation of the pathological vasculature of malignant astrocytomas by angiopoietin-1.

Malignant astrocytomas are the most common and highly vascularized of all primary adult brain tumors. The histopathological hallmarks of malignant astrocytomas are microvascular proliferation and formation of vascular entities, which are referred to as "glomeruloid bodies." The significance of glomeruloid bodies and the molecular mechanisms driving the abnormal vascular architecture in malignant astrocytomas are not understood. We have observed that overexpression of angiopoietin-1 (Ang1) in both subcutaneous and intracranial xenograft models of malignant astrocytomas reproduces many of the vascular features of these tumors, including glomeruloid bodies. To confirm that the formation of glomeruloid bodies was directly dependent on Ang1, we performed experiments where levels of Ang1 expression were regulated under tetracycline control, and we found a direct correlation between levels of Ang1 expression and the occurrence of glomeruloid bodies in xenografts. Additionally, we inhibited the action of Ang1 by blocking its cognate receptor Tie2, and we found that the formation of glomeruloid bodies was inhibited. Collectively, these results support our hypothesis that Ang1 is a key molecular regulator of pathological vascularization characteristic of malignant astrocytomas.

Role of Ang1 and its interaction with VEGF-A in astrocytomas.

Angiopoietins (Ang1 and Ang2) modulate the activity of the endothelial cell (EC)-specific receptor tyrosine kinase Tie2, which together with vascular endothelial growth factor (VEGF-A) and its EC-specific receptors, VEGFR1 and VEGFR2, regulate normal physiological vessel development. The functional role of angiopoietins in tumor angiogenesis, in particular astrocytoma angiogenesis, remains unclear. In this study, we focus on the specific contribution of Ang1 to the vascular growth of glioblastoma multiforme (GBM) and its interactive role with VEGF-A. Subcutaneous and intracranial GBM xenografts were generated using 3 established astrocytoma cell lines (U87, U373, and U343) that were transfected to stably over-express Ang1. GBM xenografts were also generated to express low levels of VEGF-A and high Angl. We found that Ang1 increases the vascular growth of both subcutaneous and intracranial xenografts of GBM by approximately 3-fold. However, the increased vascular growth was only seen in xenografts with concurrent VEGF-A elevation, since decreasing VEGF-A expression resulted in a loss of the pro-angiogenic growth advantage seen with Ang1. Collectively, our data suggest that Ang1 regulates GBM vascularity in a VEGF-A dependent manner, synergizing the initial pro-angiogenic response that is triggered by VEGF-A and promoting the vascular growth of GBM.