Macular Degeneration: Sung JU

Shah SM, Tatlipinar S, Quinlan E, Sung JU, Tabandeh H, Nguyen QD, Fahmy AS, Zimmer-Galler I, Symons RC, Cedarbaum JM, Campochiaro PA. · Retinal Imaging Research and Reading Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA. · Invest Ophthalmol Vis Sci. · Pubmed #17122137 links to  free full text

Abstract: PURPOSE: In this study, the authors sought to develop and characterize techniques for measuring changes in choroidal neovascularization (CNV) lesion size and fluorescence over time for quantitative analysis of fluorescein angiograms. METHODS: Initial assessment of the quantitative technique was made by retrospectively analyzing digital fluorescein angiograms taken before and 3 months after photodynamic therapy (PDT) for CNV (6 patients, group 1). The method was then applied prospectively to digital fluorescein angiograms (baseline and day 71) obtained on 12 patients taking part in a clinical trial investigating the effect of vascular endothelial growth factor (VEGF) Trap in CNV (group 2). Two masked observers, with the use of image processing, measured the area of hyperfluorescence and fluorescence intensity above background. Values for each image were plotted against time after dye injection to generate curves, and each area under the curve (AUC) was calculated. RESULTS: The physician who treated the patients in group 1 judged the condition of three patients to be improved and of three to be worse 3 months after PDT. Masked retrospective grading of fluorescein angiograms showed an 11% decrease in AUC for fluorescence area and a 32% decrease in AUC for fluorescence intensity in the three patients whose conditions clinically improved but increases of 131% and 292% in the three patients whose conditions clinically worsened. In group 2, a 38% decrease in AUC for fluorescence intensity and a 19% decrease in AUC for fluorescence area were observed in patients who received VEGF Trap compared with increases of 66% (P = 0.004, Mann-Whitney U test) and 21% (P = 0.07) for patients who received placebo. Macular volume decreased by 11% in VEGF Trap-treated patients and increased by 10% in placebo-treated patients (P = 0.03). CONCLUSIONS: This study reports a technique for analysis of change in fluorescence area and intensity over time during fluorescein angiography (FA) using a continuous scale and its application in a clinical setting and a clinical trial. Compared with previous techniques making use of categorical scales, this approach provides an advantage for evaluating responses to treatment that may improve the value of FA as an outcome measure in clinical trials.

Nguyen QD, Shah SM, Van Anden E, Sung JU, Vitale S, Campochiaro PA. · Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA. · Invest Ophthalmol Vis Sci. · Pubmed #14744906 links to  free full text

Abstract: PURPOSE: Diabetic macular edema (DME) is the most common cause of moderate visual disability in persons of working age in the United States. The pathogenesis of DME is poorly understood. In this study, the effect of retinal hypoxia in the development and maintenance of DME was investigated. METHODS: Five patients with chronic DME despite at least one focal laser photocoagulation treatment (nine eyes) received 4 L/min of inspired oxygen by nasal cannula for 3 months. Best corrected visual acuity (VA) and retinal thickness, assessed by optical coherence tomography (OCT), were measured at baseline, during 3 months of oxygen treatment, and for 3 months after stopping oxygen. RESULTS: After 3 months of oxygen therapy, nine of nine eyes with DME at baseline showed a reduction in thickness of the center of the macula. Foveal thickness (FTH) above the normal range was reduced by an average of 43.5% (range, 14%-100%), excess foveolar thickness (CEN) was reduced by an average of 42.1% (range, 13%-100%), and excess macular volume was reduced by an average of 54% (range, 35%-100%). Statistical analyses suggested that these changes were unlikely to be due to chance (P = 0.0077 by Wilcoxon signed-rank test). Three eyes showed improvement in VA by at least 2 lines, one by slightly less than 2 lines, and five eyes showed no change. Three months after discontinuation of oxygen, five of the nine eyes showed increased thickening of the macula compared with when oxygen was discontinued. CONCLUSIONS: Supplemental inspired oxygen may decrease macular thickness due to DME, suggesting that retinal hypoxia is involved in the development and maintenance of DME.

Rasmussen H, Chu KW, Campochiaro P, Gehlbach PL, Haller JA, Handa JT, Nguyen QD, Sung JU. · Clinical Research & Regulatory Affairs, USA. · Hum Gene Ther. · Pubmed #11727737 No free full text.

Abstract: Age-Related Macular Degeneration (AMD) is, together with Diabetic Retinopathy, the most common cause of vision loss among adults in the U.S. and other developed countries. In the U.S., at least 1.7 million people have impaired vision due to AMD. Every year, more than 165,000 people contract AMD and 16,000 go blind from it, predominantly from a rapidly progressing form of the disease called "wet" AMD. Wet AMD is characterized by serious or hemorrhagic detachment of the retinal pigment epithelium and choroidal neovascularization. The macula has the highest concentration of photoreceptors facilitating central vision and permitting high-resolution visual acuity. The damage caused by the leakage and fibrovascular scarring in wet AMD leads to profound loss of central vision and severe loss of visual acuity (usually 20/200 or worse). People with wet AMD have several limitations, including inability to read, inability to recognize faces or drive, and the disease often leads to blindness. The onset of severe visual changes in wet AMD can occur suddenly. More than 400,000 Americans are currently affected by this form of the disease, and the incidence is rising rapidly with the aging of the population. Therefore, the serious consequences of this disease along with the limited treatment options and their effectiveness make this a very good candidate for a gene transfer treatment approach. The investigational agent, Ad(GV)PEDF.11D, is an E1-, partial E3-, E4- deleted replication-deficient, adenovirus serotype 5, gene transfer vector. The transgene in this vector is the cDNA for human pigment epithelium-derived factor (PEDF). PEDF is one of the most potent known antiangiogenic proteins found in humans. While Ad(GV)PEDF.11D is able to transduce many somatic cell types, the natural barrier to other tissues created by the retina limits the ability of Ad(GV)PEDF.11D to affect tissues other than in the eye. Intravitreal administration of Ad(GV)PEDF.11D provides a convenient means of delivering PEDF to the relevant cells within the eye likely to result in a more prolonged duration of effect versus administration of the PEDF protein alone. In three murine disease models (the laser-induced choroidal neovascularization model, the VEGF transgenic model, and the retinopathy of prematurity model) significant inhibition of neovascularization (up to 85%) was demonstrated with doses of Ad(GV)PEDF vectors ranging from 1 x 10(8) to 1 x 10(9) pu. In toxicology studies performed in Cynomolgus monkeys, a dose-related inflammatory response was observed. A dose of 1 x 10(8) pu caused no adverse effects, while the inflammatory response observed at 1 x 10(9) pu was minimal and fully reversible. The observed inflammatory response at doses of 1 x 10(10) and 5 x 10(10) pu were increasingly severe. The proposed clinical trial is an open-label, dose-escalation, phase I study to investigate the safety, tolerability and potential activity of intravitreal injection of Ad(GV)PEDF.11D in patients with wet AMD. Ad(GV)PEDF.11D will be injected once via intravitreal injection into the eye with the most advanced AMD based on visual acuity. Subjects will be age 50 or over and have severe wet AMD in at least one eye defined by a best-corrected vision of 20/200 or worse. The primary objectives of this investigation are: (1) to assess the safety, tolerability and feasibility of intravitreal injection of Ad(GV)PEDF.11D in patients with severe, neovascular AMD, (2) to identify the maximum tolerated dose (MTD) of Ad(GV)PEDF.11D, and (3) to get some indication of potential activity of Ad(GV)PEDF.11D.

Campochiaro PA, Hafiz G, Shah SM, Nguyen QD, Ying H, Do DV, Quinlan E, Zimmer-Galler I, Haller JA, Solomon SD, Sung JU, Hadi Y, Janjua KA, Jawed N, Choy DF, Arron JR. · Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA. · Mol Ther. · Pubmed #18362932 No free full text.

Abstract: Macular edema is a major cause of vision loss in patients with central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO). It is not clear how much of the edema is due to hydrodynamic changes from the obstruction and how much is due to chemical mediators. Patients with macular edema due to CRVO (n = 20) or BRVO (n = 20) were randomized to receive three monthly injections of 0.3 or 0.5 mg of ranibizumab. At the primary endpoint, month 3, the median improvement in letters read at 4 m was 17 in the 0.3-mg group and 14 in the 0.5-mg group for CRVO, and 10 and 18, respectively for the BRVO group. Optical coherence tomography (OCT) showed that compared to injections of 0.3 mg, injections of 0.5 mg of ranibizumab tended to cause more rapid reductions of central retinal thickening that lasted longer between injections, but in 3 months, excess central retinal thickening which is a quantitative assessment of the macular edema, was reduced by approximately 90% in all four treatment groups. There was no correlation between the amount of improvement and duration of disease or patient age at baseline, but there was some correlation between the aqueous vascular endothelial growth factor (VEGF) level at baseline and amount of improvement. These data indicate that excess production of VEGF in the retinas of patients with CRVO or BRVO is a major contributor to macular edema and suggest that additional studies investigating the efficacy of intraocular injections of ranibizumab are needed.

Do DV, Cho M, Nguyen QD, Shah SM, Handa JT, Campochiaro PA, Zimmer-Galler I, Sung JU, Haller JA. · Retina Division, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA. · Retina. · Pubmed #17558315 No free full text.

Abstract: PURPOSE: To compare retina surgeons' recommendations for management of epiretinal membranes (ERM) and vitreomacular traction (VMT) based on clinical assessment alone with management based on clinical evaluation supplemented by optical coherence tomography (OCT). METHODS: A prospective, masked clinical case series was conducted. Surgeons first performed a complete history and physical examination on patients referred with the macular disorders under study without the benefit of adjunctive OCT, determined whether ERM, VMT, and/or macular edema were present, questionably present, or absent, and made a provisional management recommendation. The retina specialists then reviewed the OCT images for the presence or absence of ERM, VMT, and/or associated macular edema and reconsidered the final management recommendation in light of clinical evaluation combined with OCT findings. RESULTS: Eighty-four eyes of 73 patients were examined. ERM was identified in 66 (78.6%) of 84 eyes using clinical examination compared with 72 (85.7%) of 84 eyes using OCT (P = 0.06). VMT was identified in 5 (6%) of 84 eyes using clinical examination compared with 18 (21.4%) of 84 eyes using OCT (P < 0.005). Macular edema was identified in 57 (67.9%) of 84 eyes using clinical examination compared with 70 (83.3%) of 84 eyes using OCT (P = 0.003). Surgical intervention was recommended in 33 cases: 19 (57.6%) based on the history and clinical examination findings without OCT information and an additional 14 (42.4%) based on the combination of clinical evaluation and OCT findings. CONCLUSIONS: OCT is more sensitive than clinical examination in detecting ERM, VMT, and associated macular edema. Taken together with careful clinical evaluation, OCT findings influenced surgeons to recommend consideration of surgery to an additional 14 patients (42.2%) in this series.

Do DV, Cho M, Nguyen QD, Shah SM, Handa JT, Campochiaro PA, Zimmer-Galler I, Sung JU, Haller JA. · Retina Division, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Trans Am Ophthalmol Soc. · Pubmed #17471336 links to  free full text

Abstract: PURPOSE: To compare retinal surgeons' recommendations for management of epiretinal membranes (ERM) and vitreomacular traction syndrome (VMT) based on clinical examination alone, with management based on examination supplemented by optical coherence tomography (OCT). METHODS: A prospective, masked clinical case series was conducted. Surgeons first assessed, on the basis of clinical examination only, whether ERM, VMT, or macular edema was present, questionably present, or absent and made a provisional management recommendation. The retina specialist then reviewed the OCT images, determined the presence or absence of ERM, VMT, or associated macular edema, and made a final management recommendation. RESULTS: Eighty-four eyes of 73 patients were examined. ERM was identified in 66 (78.6%) of 84 using clinical examination compared to 72 (85.7%) of 84 using OCT (P = .06). VMT was identified in five (6%) of 84 using clinical examination compared to 18 (21.4%) of 84 using OCT (P < .005). Macular edema was identified in 57 (67.9%) of 84 using clinical examination compared to 70 (83.3%) of 84 using OCT (P =.003). Surgical intervention was recommended in 33 cases: 19 (57.6%) based on clinical examination alone and 14 (42.4%) based on the combination of clinical examination and OCT findings. CONCLUSIONS: OCT is more sensitive than clinical examination in detecting ERM, VMT, and associated macular edema. OCT influenced the recommendation for surgical intervention in 42.4% of patients scheduled for surgery.

Do DV, Shah SM, Sung JU, Haller JA, Nguyen QD. · Vitreoretinal Service, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. · Am J Ophthalmol. · Pubmed #15808156 No free full text.

Abstract: PURPOSE: To assess the correlation between persistent diabetic macular edema and hemoglobin A1c (HbA1C). DESIGN: Retrospective study. METHODS: Records of type 2 diabetic patients who received eye care for persistent clinically significant macular edema (CSME) from January 2002 to January 2004 were reviewed. Subjects who met one of two criteria were identified: 1) persistent CSME, detected by contact lens biomicroscopy and fluorescein angiography, despite at least two focal laser photocoagulations (FLP) performed at least 3 months before the current diagnosis, or 2) a history of CSME with resolution of macular edema at the time of examination. Patients also needed to have had their HbA1C measured at the Johns Hopkins Hospitals within 3 months of meeting these criteria. RESULTS: The study identified 92 patients (152) eyes with persistent CSME and 32 patients (56 eyes) with resolved CSME. HbA1C values ranged from 5.3% to 15.6% (mean, 8.9%; median, 8.7%) and 5.3% to 9.7% (mean, 6.7%; median, 6.6%) among patients with persistent and resolved edema (P = .0005). Among the 32 patients with persistent unilateral CSME, mean HbA1C was 8.6% (median 8.5%), and among the 60 patients with bilateral CSME, mean HbA1C was 9.1% (median, 8.9%). Of patients with persistent CSME, 74% had HbA1C greater than 7.5% compared with 12.5% of the patients with resolved CSME (P = .0005). CONCLUSIONS: Persons with type 2 diabetes and persistent CSME have higher HbA1C at time of their disease than patients with resolved CSME. Patients with bilateral disease have more elevated HbA1C than those with unilateral disease.

Apte RS, Sung JU, DiBernardo C, Feuer-Greenberg E. · No affiliation provided · Br J Ophthalmol. · Pubmed #12770991 links to  free full text

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