The evolving therapeutic landscape of diabetic retinopathy.

INTRODUCTION: Diabetic retinopathy (DR) is a leading cause of blindness worldwide. Recent decades have seen rapid progress in the management of diabetic eye disease, evolving from pituitary ablation to photocoagulation and intravitreal pharmacotherapy. The advent of effective intravitreal drugs inhibiting vascular endothelial growth factor (VEGF) marked a new era in DR therapy. Sustained innovation has since produced several promising biologics targeting angiogenesis, inflammation, oxidative stress, and neurodegeneration. AREAS COVERED: This review surveys traditional, contemporary, and emerging therapeutics for DR, with an emphasis on anti-VEGF therapies, receptor tyrosine kinase inhibitors, angiopoietin-Tie2 pathway inhibitors, integrin pathway inhibitors, gene therapy 'biofactory' approaches, and novel systemic therapies. Some of these investigational therapies are being delivered intravitreally via sustained release technologies for extended durability. Other investigational agents are being delivered non-invasively via topical and systemic routes. These strategies hold promise for early and long-lasting treatment of DR. EXPERT OPINION: The evolving therapeutic landscape of DR is rapidly expanding our toolkit for the effective and durable treatment of blinding eye disease. However, further research is required to validate the efficacy of novel therapeutics and characterize real world outcomes.

EFFECTS OF INTRAVITREAL BEVACIZUMAB THERAPY ON GLOMERULAR FILTRATION RATES IN PATIENTS TREATED FOR PROLIFERATIVE DIABETIC RETINOPATHY.

PURPOSE: To assess whether the repeated use of intravitreal bevacizumab injections in treatment of proliferative diabetic retinopathy is associated with a long-term decline in the glomerular filtration rate (GFR). METHODS: Three hundred charts were retrospectively reviewed, of which 60 patients met the criteria for inclusion. The criteria were as follows: reception of at least one bevacizumab injection, baseline GFR before initial bevacizumab injection, and end GFR 6 to 24 months after baseline. Analysis controlled for time between baseline and end GFR measurements, blood pressure, hemoglobin A1C, race, sex, age, and use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Significance testing was performed with step-wise multiple linear regression. The significance threshold was 5%, and all tests were two-sided. RESULTS: Patients received a range of 1 to 17 injections (average 3.6). The average baseline GFR was 76 ± 38 mL/minute, and the end GFR was 63 ± 39 mL/min. The number of injections patients received was not associated with end GFR ( P = 0.72), GFR reduction ( P = 0.88), or percent GFR reduction ( P = 0.49). CONCLUSION: Increased number of intravitreal bevacizumab injections at therapeutic dosage was not associated with reduced GFR in patients with proliferative diabetic retinopathy. This study supports that intravitreal antivascular endothelial growth factor agents are renally safe.

Bilateral Cystoid Macular Edema Following Bimatoprost Implants.

PURPOSE: To report the development of bilateral cystoid macular edema (CME) following bimatoprost implant (Durysta) injections in both eyes to treat primary open angle glaucoma (POAG). METHODS: Case Report. RESULTS: A 93-year-old woman with a history of POAG received bimatoprost implant (Durysta) injections in both eyes four weeks apart. The patient subsequently developed progressively decreased visual acuity in both eyes due to bilateral CME, which improved with topical corticosteroid therapy. CONCLUSIONS: Bimatoprost implant (Durysta) can cause CME in susceptible individuals. Patients who received the implant should be assessed for the presence of CME following any decline in visual acuity, particularly in high-risk patients.

Progress in the pharmacotherapy of uveitis: the art of personalized care.

INTRODUCTION: Uveitis is a heterogeneous group of inflammatory intraocular disorders that can lead to blindness, but prompt diagnosis and management can improve visual outcomes and reduce treatment burden. AREAS COVERED: In this review, the authors provide an overview of commonly used treatments for the management of noninfectious uveitis. EXPERT OPINION: Initially, the treatment of noninfectious uveitis was limited to corticosteroids, which have a broad range of adverse ocular and systemic effects. Now new delivery and therapeutic options, such as biological response modulators, represent novel yet exciting additions to this armory and have the potential to alter the course of treatment as well as prognostic outcomes for uveitis patients. Further research is needed to evaluate the efficacy of this novel class of immunomodulators in uveitis therapy.

Patient preferences in retinal drug delivery.

Retinal vascular diseases (RVDs) are often treated with intravitreally (IVT) injected drugs, with relatively low patient compliance and potential risks. Ongoing research explores alternative RVD treatments, including eye drops and oral tablets. This study surveyed RVD patients treated with IVT injections to establish factors influencing low compliance rates while gauging treatment delivery method preferences. Demographics, perspectives, and treatment preferences were collected via IRB-approved, self-administered survey sent to Glick Eye Institute patients treated via IVT injections. Demographics, diagnoses, and treatments were ascertained from respondents' medical records. Gender, age, and number of IVT injections received were used as stratifications. Five-level Likert-style scales and t-tests evaluated responses and stratification comparisons. The most common diagnoses in the respondent population (n = 54; response rate = 5%) were age-related macular degeneration, macular edema, and diabetic retinopathy. Respondents had varying levels of education, income, and age. Most (83%) admitted feeling anxious prior to their first IVT injection, but 80% reported willingness to receive IVT injections indefinitely, with a preference for ophthalmologist visits every 1-3 months. Eye drops would be preferred over IVT injections by 76% of respondents, while 65% preferred oral tablets, due to several perceived negative factors of IVT injections and positive factors for eye drops. Stratified groups did not differ in responses to survey questions. RVD patients will accept IVT injections for vision preservation, but alternative delivery methods like eye drops or oral tablets would be preferred. Thus, development of eye drop and oral therapeutics for RVD treatment is further emphasized by these findings.

International multi-center study of iatrogenic retinal tears in pars plana vitrectomy.

AIM: To study and compare the effect of different surgical settings on the development of iatrogenic retinal tears (IRT) in conventional (20-gauge) and microincisional vitrectomy. METHODS: An international retrospective comparative study of 394 patients who had simple vitrectomy at three tertiary centers. Surgeries were performed by four retina surgeons using different viewing systems. Two groups of eyes were compared: microincisional vitrectomy (327 eyes) and conventional (67 eyes) vitrectomy. An iatrogenic tear was defined as the occurrence of one or more peripheral retinal tears during surgery or at any visit in the first 6wk postoperatively. RESULTS: Mean age was 67±12y and 55% were female. Iatrogenic tears occurred in 11/394 (2.8%) of eyes. The rate of tears was similar among different surgeons and viewing systems (P=0.93 and P=0.76, respectively). Surgical indication, preexisting pseudophakia/aphakia, induction of posterior vitreous detachment (PVD) during surgery, and the use triamcinolone acetonide didn't significantly affect the rate of tears (P>0.1 for all factors). A higher rate of tears was found in the conventional group compared to the microincisional group (respectively, 7.5%, 1.8%, P=0.02). CONCLUSION: The rate of IRT in vitrectomy is not significantly affected by surgical indication, preexisting PVD or pseudophakia, or use of triamcinolone or different viewing systems but is significantly higher in conventional vitrectomy. Microincisional platforms improve the safety of vitrectomy regardless of the viewing system used.

Common and Rare Ocular Side-effects of the Dexamethasone Implant.

PURPOSE: Expanding indications for use, and overall increased use of the slow-release dexamethasone (DEX) implant yields an opportunity to study the reported ocular side-effects and adverse events associated with this drug. METHODS: A PubMed.gov (US National Library of Medicine, National Institutes of Health) review of literature for the search terms, "Ozurdex and complication," through December 2015. RESULTS: Ocular hypertension and cataract are the main long-term sequelae identified in large, randomized clinical trials. Case reports have emerged regarding implant migration, complications with implantation, infection, and posterior segment sequelae, including vitreomacular traction. CONCLUSION: DEX implant overall is well-tolerated and, with careful monitoring, can be a useful adjunct to treating macular edema associated with diabetes, retinal vein occlusion, and chronic uveitis.

QUIESCENT HERPES SIMPLEX KERATITIS REACTIVATION AFTER INTRAVITREAL INJECTION OF DEXAMETHASONE IMPLANT.

PURPOSE: To report reactivation of herpes simplex virus keratitis after the injection of dexamethasone implant (Ozurdex) and to raise the awareness of this potentially vision threatening side effect. METHODS: A 90-year-old man presented with ocular pain and tearing in the left eye 3 weeks after receiving a dexamethasone implant (Ozurdex) for the treatment of macular edema associated with branch retinal vein occlusion. The patient had a history of herpes simplex virus keratitis that was quiescent for more than 30 years. RESULTS: Clinical examination of the left eye showed arborizing epithelial ulcer with terminal bulbs consistent with herpes simplex virus keratitis. CONCLUSION: Quiescent herpes simplex virus keratitis can be reactivated after dexamethasone implant (Ozurdex). Prophylactic antiviral therapy might be indicated in individuals who have a high risk of recurrent herpetic disease.

Sequential Chorioretinal Changes in Presumed Ocular Histoplasmosis Syndrome Analyzed Using Spectral Domain Optical Coherence Tomography.

PURPOSE: To analyze sequential chorioretinal changes in presumed ocular histoplasmosis syndrome (POHS) using volumetric spectral-domain optical coherence tomography (SD-OCT). METHODS: A total of 28 treatment-naive eyes of 20 POHS patients were characterized as: no choroidal neovascular membrane (CNVM) at initial SD-OCT but CNVM development during follow-up (primary group); CNVM at initial SD-OCT (progressive group); and contralateral asymptomatic eyes (control group). RESULTS: The primary group (4/28 eyes) initially demonstrated external limiting membrane (ELM), ellipsoid zone and retinal pigment epithelium (RPE)/Bruch's disruption in 100%, and pigment epithelial detachment (PED) in 75% of eyes. CNVM developed in 100% of eyes during follow-up. Progressive group (8/28 eyes) showed CNVM in 100% of eyes. Control group (16/28 eyes) showed ELM disruption in two and PED in three additional eyes on follow-up from initial analysis. CONCLUSIONS: SD-OCT is a useful tool to sequentially follow eyes with POHS for subtle chorioretinal changes that may suggest impending CNVM development, and thus benefit from closer clinical monitoring.

POSTCATARACT ENDOPHTHALMITIS TREATED WITH SMALL GAUGE VITRECTOMY.

PURPOSE: To discuss the use of minimally invasive, small gauge vitrectomy for acute postcataract endophthalmitis in patients with better than light-perception vision. PATIENT: 71-year-old man presented with redness, pain, and decreased vision of his left eye 11 days after cataract extraction. His visual acuity was counting fingers at 1 foot and slit-lamp examination revealed severe conjunctival injection, corneal edema, and hypopyon. The clinical impression was of acute postcataract endophthalmitis. METHODS: Patient was taken for immediate vitrectomy with simultaneous vitreous tap for culture, PCR, and injection of intravitreal vancomycin and ceftazidime. RESULTS: Culture and PCR of vitreous sample were positive for Staphylococcus epidermidis. Vision improved to 20/20 1 month postoperatively with complete resolution of vitreous inflammation and retinal vasculitis. CONCLUSION: In postcataract endophthalmitis with dense vitritis and diffuse retinal vasculitis, immediate, 25-gauge vitrectomy may result in return of baseline visual acuity.

Detection of GNAQ mutations and reduction of cell viability in uveal melanoma cells with functionalized gold nanoparticles.

BACKGROUND: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Early treatment may improve any chances of preventing metastatic disease, but diagnosis of small UM is challenging. Up to 95 % of all UMs carry somatic mutations in the G-coupled proteins GNAQ and GNA11 promoting anchorage-independent growth and proliferation. About 50 % of UMs are fatal. Once metastatic, patients have limited options for successful therapy. METHODS: We have developed functionalized gold nanoparticles (AuNPs) to visualize transcripts of mutant GNAQ mRNA in living cells. In addition to their suitability as a specific tool for GNAQ mutation detection, we have developed a novel linker that enables conjugation of siRNAs to AuNPs allowing for greater and more rapid intracellular release of siRNAs compared to previously described approaches. RESULTS: Binding of modified AuNPs to matching target mRNA leads to conformational changes, resulting in a detectable fluorescent signal that can be used for mutation detection in living cells. Knockdown of GNAQ with siRNA-AuNPs effectively reduced downstream signals and decreased cell viability in GNAQ mutant uveal melanoma cells. CONCLUSION: AuNPs may in future be developed to serve as sensors for mutations of vital importance. The new release system for siRNA-AuNP improves previous systems, which conceivably will be useful for future therapeutic gene regulatory approaches.