Scott C. N. Oliver

VEGF Trap-Eye for the treatment of neovascular age-related macular degeneration

Background: Age-related macular degeneration (AMD) affects > 14 million individuals worldwide. Although 90% of patients with AMD have the dry form, neovascular AMD accounts for the vast majority of patients who develop legal blindness. Until recently, few treatment options existed for treatment of neovascular AMD. The advent of anti-VEGF therapy has significantly improved the safe and effective treatment of neovascular AMD. In addition to two anti-VEGF drugs currently in widespread use, ranibizumab and bevacizumab, a number of medications that interrupt angiogenesis are currently under investigation. One promising new drug is aflibercept (VEGF Trap-Eye), a fusion protein that blocks all isoforms of VEGF-A and placental growth factors-1 and -2. Objective: To review the current literature and clinical trial data regarding VEGF Trap-Eye for the treatment of neovascular AMD. Methods: Literature review. Results/conclusion: VEGF Trap-Eye is a novel anti-VEGF therapy, with Phase I and II trial data indicating safety, tolerability and efficacy for the treatment of neovascular AMD. Two Phase III clinical trials (VIEW-1 and VIEW-2) comparing VEGF Trap-Eye to ranibizumab are currently continuing and will provide vital insight into the clinical applicability of this drug.

Ultra Wide-Field Angiographic Characteristics of Branch Retinal and Hemicentral Retinal Vein Occlusion

PURPOSE To study the peripheral angiographic features of branch retinal vein occlusions (BRVO) and hemicentral retinal vein occlusions (HRVO) and explore associations with macular edema and neovascularization. DESIGN Retrospective observational case series. PARTICIPANTS Seventy-eight outpatients. METHODS An imaging database of angiograms performed at a single academic institution was searched for patients with a diagnosis of BRVO or HRVO. Images were graded for the presence of untreated nonperfusion (areas without evidence of laser photocoagulation), late peripheral vascular leakage (LPVL), neovascularization, macular edema, and prior laser treatment. Optical coherence tomography images were reviewed for all patients to confirm the presence of macular thickening and to exclude eyes with vitreomacular traction. MAIN OUTCOME MEASURES Angiographic evidence of nonperfusion, neovascularization, macular edema, LPVL, and prior laser treatment. RESULTS Angiograms from 80 eyes of 78 patients were analyzed with a diagnosis of BRVO (86%) or HRVO (14%). Angiographic macular edema (80%), untreated nonperfusion (82%), neovascularization (21%), and LPVL (58%) were observed. Untreated nonperfusion at any location was significantly associated with macular edema (P = 0.043). Untreated nonperfusion anterior to the globe equator was significantly associated with macular edema (P = 0.007). Untreated nonperfusion was significantly associated with the presence of neovascularization (P = 0.033). Late peripheral vascular leakage was not associated with other angiographic or clinical findings studied. CONCLUSIONS Ultra wide-field angiography provides visualization of peripheral retinal pathology in BRVO and HRVO patients, which may be useful in their evaluation and treatment. Our findings support the hypothesis that areas of untreated retinal nonperfusion may be the source of production of biochemical mediators that promote neovascularization and macular edema. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Endophthalmitis after Pars Plana Vitrectomy: A 20- and 25-Gauge Comparison

OBJECTIVE Recent retrospective analyses have suggested that postoperative endophthalmitis may be more frequent with 25- than 20-gauge pars plana vitrectomy (PPV). Because the infection risk may depend on the suturing status of the sclerotomy, and the perioperative anti-infection protocol, we compared the incidence rate of endophthalmitis after sutureless 25-gauge versus sutured 20-gauge PPV on a large cohort of patients operated with a standardized perioperative anti-infection protocol. DESIGN Retrospective comparative case series. PARTICIPANTS Consecutive patients who underwent 20- or 25-gauge PPVs at a single center over a multi-year period. METHODS We analyzed 3597 consecutive PPVs. Patients with a pre-PPV diagnosis of endophthalmitis, PPVs performed for implantation of drug delivery devices, or 25-gauge PPVs with all sclerotomies sutured closed were excluded. Patients with > or =1 week of follow-up were divided into 2 study groups by sclerotomy status at the end of surgery: the 20-gauge group had 3 sutured 20-gauge sclerotomies, and the 25-gauge group had > or =1 unsutured 25-gauge sclerotomy. Endophthalmitis was defined by clinical criteria independent of microbiological results. MAIN OUTCOME MEASURES The incidence of endophthalmitis was compared between 25- versus 20-gauge groups. RESULTS Of 3372 PPV surgeries meeting inclusion and exclusion criteria, 1948 and 1424 surgeries were 20- and 25-gauge PPVs, respectively. Average age (+/- standard deviation) of patients was 54.6 (+/- 22.6) and 64.4 (+/- 16.5) years in the 20- and 25-gauge PPV groups, respectively (P<0.0001). Median post-PPV follow-up time was not significantly different between the 2 groups (12.5 vs 13.0 months; P = 0.69). Endophthalmitis was observed in 1 patient (0.07%; 95% confidence interval, 0%-0.21%) from the 25-gauge group and none in the 20-gauge group (P = 0.42; Fisher exact test, 2-tailed). The use of air/gas endotamponade (P<0.0001) and intravitreal triamcinolone (P<0.001) was more common in 25- versus 20-gauge PPV. CONCLUSIONS The incidence of endophthalmitis was low in both groups. We were unable to show a significant difference in the incidence of endophthalmitis between sutureless 25-gauge and sutured 20-gauge PPV, and conclude that a careful perioperative anti-infection protocol may reduce 25-gauge PPV endophthalmitis risk to that of 20-gauge PPV.

Ischemic index and neovascularization in central retinal vein occlusion.

Purpose: To explore the association of angiographic nonperfusion with anterior segment and posterior segment neovascularization in central retinal vein occlusion (CRVO). Methods: An imaging database at one institution was searched for the diagnosis of central retinal vein occlusion. Ultra wide field fluorescein angiograms were graded for image quality, the presence of retinal neovascularization, and the quantity of nonperfusion; an ischemic index (ISI) was calculated. Charts were reviewed to exclude eyes with previous treatment and to determine which eyes had anterior segment or posterior segment neovascularization on the day of the angiogram. Time from onset to presentation could not accurately be ascertained. Results: In a 39-month period, there were 69 eyes that met inclusion criteria. The mean ISI was 25% (SD, 26%; range, 0-100%), and 15 eyes (21%) with neovascularization had a mean ISI of 75% (range, 47-100%) compared with eyes without neovascularization that had an ISI of 6% (range, 0-43%). Ischemic index significantly correlated to neovascularization, and eyes that had evidence of neovascularization had an ISI >45% (P < 0.0001). Conclusion: Ultra wide field fluorescein angiography provides visualization of nonperfusion in eyes with central retinal vein occlusion. Eyes with neovascularization on the day of the angiogram were found to have significantly larger areas of retinal nonperfusion compared with eyes without neovascularization. A prospective study is indicated to know if early treatment of peripheral retinal nonperfusion in CRVO improves outcomes.

Current knowledge and trends in age-related macular degeneration: genetics, epidemiology, and prevention.

Purpose: To address the most dynamic and current issues concerning human genetics, risk factors, pharmacoeconomics, and prevention regarding age-related macular degeneration. Methods: An online review of the database Pubmed and Ovid was performed, searching for the key words: age-related macular degeneration, AMD, pharmacoeconomics, risk factors, VEGF, prevention, genetics and their compound phrases. The search was limited to articles published since 1985 to date. All returned articles were carefully screened and their references were manually reviewed for additional relevant data. The webpage www.clinicaltrials.gov was also accessed in search of relevant research trials. Results: A total of 366 articles were reviewed, including 64 additional articles extracted from the references and 25 webpages and online databases from different institutions. At the end, only 244 references were included in this review. Conclusion: Age-related macular degeneration is a complex multifactorial disease that has an uneven manifestation around the world but with one common denominator, it is increasing and spreading. The economic burden that this disease poses in developed nations will increase in the coming years. Effective preventive therapies need to be developed in the near future.

Peripheral vessel leakage (PVL): a new angiographic finding in diabetic retinopathy identified with ultra wide-field fluorescein angiography.

Purpose: To characterize the relationship between peripheral vessel leakage and other angiographic features of diabetic retinopathy. Design: Retrospective, consecutive case series. Methods: Consecutive ultra wide-field angiographs obtained at a single institution for diabetic retinopathy were graded for angiographic characteristics including macular edema, retinal neovascularization, retinal vascular perfusion abnormalities, and retinal vascular staining and leakage. Results: Angiographic characteristics of 264 eyes of 143 patients were evaluated. Findings included focal and diffuse angiographic macular edema (150/264, 57%), neovascularization (107/264, 41%), late peripheral vascular leakage (PVL) (107/264, 41%), and peripheral non-perfusion (142/264, 54%). Amongst all subjects untreated peripheral non-perfusion was associated with anterior neovascularization (78% vs. 48%, p = 0.0001, Fisher exact test) and posterior neovascularization (78% vs. 43%, p < 0.0001), but not with macular edema (p = 0.71). PVL was associated with peripheral non-perfusion (78% vs. 38%, p < 0.0001) and posterior neovascularization (53% vs. 35%, p = 0.01), but not with macular edema (p = 0.449). However, focal macular edema was strongly associated with PVL (33% vs. 13%, p = 0.008) in eyes without peripheral non-perfusion. Amongst untreated eyes with non-proliferative retinopathy and macular edema, there was a trend for association between macular edema and peripheral non-perfusion (p = 0.065). Conclusion: Untreated peripheral non-perfusion and late peripheral vascular leakage detected using ultra wide-field FA are associated with neovascularization in diabetic retinopathy. PVL may be associated with focal diabetic macular leakage in this cohort.

Current knowledge and trends in age-related macular degeneration: today's and future treatments.

Purpose: To address the most dynamic and current issues concerning today’s treatment options and promising research efforts regarding treatment for age-related macular degeneration. This review is aimed to serve as a practical reference for more in-depth reviews on the subject. Methods: An online review of the database PubMed and Ovid were performed, searching for the key words age-related macular degeneration, AMD, VEGF, treatment, PDT, steroids, bevacizumab, ranibizumab, VEGF-trap, radiation, combined therapy, as well as their compound phrases. The search was limited to articles published since 1985. All returned articles were carefully screened, and their references were manually reviewed for additional relevant data. The web page www.clinicaltrials.gov was also accessed in search of relevant research trials. Results: A total of 363 articles were reviewed, including 64 additional articles extracted from the references. At the end, only 160 references were included in this review. Conclusion: Treatment for age-related macular degeneration is a very dynamic research field. While current treatments are mainly aimed at blocking vascular endothelial growth factor, future treatments seek to prevent vision loss because of scarring. Promising efforts have been made to address the dry form of the disease, which has lacked effective treatment.

Treatment of intractable posterior uveitis in pediatric patients with the fluocinolone acetonide intravitreal implant (Retisert).

Purpose: To evaluate the efficacy and safety of the fluocinolone acetonide intravitreal implant in pediatric patients with intractable noninfectious posterior uveitis. Methods: A retrospective chart review was performed on all patients aged <18 years on whom a fluocinolone implant was used to treat intractable posterior uveitis at our institution. Conventional treatment with topical and systemic steroids and/or systemic steroid-sparing agents failed in all patients before proceeding with an implant. Each implant contained 0.59 mg of fluocinolone acetonide. Implants were placed in the inferonasal quadrant through a pars plana incision and sutured in place with 8-0 proline suture. Postoperatively, patients were followed for improvement in Snellen visual acuity, control of inflammation, and development of complications such as infection or uncontrolled intraocular pressure in the eyes. Results: The study included six eyes of four patients. Mean age at implant placement was 9.2 years (range, 6–13 years). Four eyes were pseudophakic at the time of surgery; one eye had pars plana lensectomy at the time of surgery. Mean follow-up duration was 698 days (range, 376–1,189 days). Postoperative visual acuity improved by ≥3 lines in 3 eyes. Four eyes had postoperative intraocular spikes ≥30 mmHg, with 2 eyes having ≥40 mmHg. Two of these patients required glaucoma shunting procedures postoperatively for intraocular pressure control. Inflammation was well controlled postoperatively in all six eyes with all eyes successfully weaned off of topical steroids. The single phakic eye developed a visually significant cataract 18 months postoperatively requiring cataract extraction. There were no cases of postoperative infection. There were no postoperative complications of surgical technique including no instances of wound leakage or implant dislocation. Conclusion: The fluocinolone implant can be used effectively for control of posterior inflammation in pediatric patients. As in adults, concerns for development of cataract and secondary glaucoma remain. No other safety concerns were evident in this pilot study.

Attenuation of iodine 125 radiation with vitreous substitutes in the treatment of uveal melanoma.

OBJECTIVE To demonstrate attenuation of radiation from iodine 125 ((125)I) to intraocular structures using liquid vitreous substitutes. METHODS Four candidate vitreous substitutes were tested for attenuation using empirical measurement and theoretical calculation. In vitro and ex vivo cadaveric dosimetry measurements were obtained with lithium fluoride thermoluminescent dosimeters to demonstrate the attenuation effect of vitreous substitution during (125)I simulated plaque brachytherapy. Theoretical dosimetry calculations were based on Monte Carlo simulation. RESULTS In a cylindrical phantom at a 17-mm depth, liquid vitreous substitutes as compared with saline showed significant reduction of radiation penetration (48% for 1000-centistoke [cSt] silicone oil [polydimethyl-n-siloxane], 47% for 5000-cSt silicone oil [polydimethyl-n-siloxane], 40% for heavy oil [perfluorohexyloctane/polydimethyl-n-siloxane], and 35% for perfluorocarbon liquid [perfluoro-n-octane]). Human cadaveric ex vivo measurements demonstrated a 1000-cSt silicone oil to saline dose ratio of 35%, 52%, 55%, and 48% at arc lengths of 7.6, 10.6, 22.3, and 28.6 mm from the plaque edge, respectively, along the surface of the globe. Monte Carlo simulation of a human globe projected attenuation as high as 57% using 1000-cSt silicone oil. CONCLUSIONS Intraocular vitreous substitutes including silicone oil, heavy oil, and perfluorocarbon liquid attenuate the radiation dose from (125)I. Cadaveric ex vivo measurements and Monte Carlo simulation both demonstrate radiation attenuation using 1000-cSt silicone oil at distances corresponding to vital ocular structures. Clinical Relevance Attenuation of radiation with silicone oil endotamponade in the treatment of uveal melanoma may significantly reduce radiation-induced injury to vital ocular structures.

Ultrawide angle angiography for the detection and management of diabetic retinopathy.

For the last 50 years, fluorescein angiography (FA) has played a pivotal role in the evaluation and management of retinal diseases including diabetes. Patterns of hyperfluorescence and hypofluorescence provide insights into the pathophysiologic processes and guide treatment. Despite recent advances in other imaging techniques, including indocyanine green angiography and optical coherence tomography, FA still plays a primary role. FA remains a vital method to assess indications and outcomes of treatment methods including laser photocoagulation, intraocular pharmacologic therapy such as steroid and antivascular endothelial growth factor (anti-VEGF) agents, and surgical intervention. The ability to capture a single image of the entire ocular fundus has been limited until recently. Standard FA using film or digital cameras typically capture an image 30 degrees across. A new fluorescein imaging technique that captures fundus images up to 200 degrees in breadth is discussed herein. Optomap fa dynamic ultrawide field angiography is a digital panoramic technique performed with the Optos P200 MA scanning laser ophthalmoscope (Optos plc, Dunfermline, UK). The ability to image the peripheral retina using Optomap fa provides a more comprehensive assessment of the extent of a retinal disease process, and