Macular Degeneration: Ying GS

Metelitsina TI, Grunwald JE, DuPont JC, Ying GS. · Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, 51 North 39th Street, Philadelphia, PA 19104, USA. · Exp Eye Res. · Pubmed #16080909 No free full text.

Abstract: To investigate the effects of sildenafil citrate (Viagra) on foveolar choroidal circulation in patients with age related macular degeneration (AMD). Double-blinded, randomized, placebo-controlled, crossover study. Fifteen male AMD patients received a dose of 100 mg of sildenafil or matching placebo on two separate days. Laser Doppler flowmetry was performed to assess relative choroidal blood velocity (ChB(Vel)), volume (ChB(Vol)) and flow (ChB(Flow)) in the study eye prior to administration of the drug at baseline and 30, 90, 180, 300 min after dosing. Best corrected visual acuity (BCVA), contrast sensitivity (CS), mean arterial blood pressure (BPm), heart rate (HR), intraocular pressure (IOP) and ocular perfusion pressure (PP) were determined. In comparison to placebo, sildenafil did not cause any statistically significant changes in mean ChB(Vel) (ANOVA, P=0.12), ChB(Vol) (ANOVA, P=0.24) or ChB(Flow) (ANOVA, P=0.46). There were no statistically significant changes in CS (ANOVA, P=0.59), BCVA (P=0.58), IOP (P=0.81) or HR (P=0.07) throughout the study. Significant decreases in BPm (P=0.006) and PP (P=0.006) were observed at 30 min after sildenafil. Administration of sildenafil citrate didn't cause any statistically significant changes in the foveolar choroidal circulation of AMD patients.

Metelitsina TI, Grunwald JE, DuPont JC, Ying GS. · Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, 51 North 39th Street, Philadelphia, PA 19104, USA. · Br J Ophthalmol. · Pubmed #15548814 links to  free full text

Abstract: AIM: To investigate the effects of niacin on choroidal blood flow in age related macular degeneration (AMD). METHODS: 12 AMD patients with bilateral drusen and visual acuity of 20/40 or better in the study eye received a single oral dose of niacin (six subjects received 500 mg and six received 250 mg) or matching placebo on two separate occasions. Laser Doppler flowmetry was used to assess relative choroidal blood velocity (ChB(Vel)), volume (ChB(Vol)), and flow (ChB(Flow)) in the foveola of the study eye at baseline, 30, and 90 minutes after dosing. RESULTS: In comparison with placebo, a statistically significant 24% increase in ChB(Vol) was observed 30 minutes after niacin administration (ANOVA, p = 0.01). In comparison with placebo, a significant decrease in ChB(Vel) of 23% was observed in the 500 mg group (p = 0.04) and no significant change in ChB(Vel) was seen in the 250 mg group at 30 minutes. No significant changes in ChB(Flow) were detected at 30 or 90 minutes. Also, there were no statistically significant changes in ChB(Vol) or ChB(Vel) at 90 minutes. CONCLUSION: In comparison with placebo, a significant 24% increase in ChB(Vol) was observed 30 minutes after niacin administration. Owing to simultaneous decrease in ChB(Vel), however, no significant change in ChB(Flow) was detected.

Prenner JL, Rosenblatt BJ, Tolentino MJ, Ying GS, Javornik NB, Maguire MG, Ho AC, Anonymous00258. · Associated Retinal Consultants, Royal Oak, Michigan, USA. · Retina. · Pubmed #12824829 No free full text.

Abstract: PURPOSE: To identify risk factors for the development of choroidal neovascularization (CNV) and vision loss in the Fellow Eye Study of the Choroidal Neovascularization Prevention Trial. METHODS: Retrospective review of 121 patients enrolled in a multicentered, randomized, controlled trial. Patients had neovascular age-related macular degeneration in one eye and more than 10 large drusen in the other eye. Records of patients randomly assigned to laser treatment or observation were reviewed through 4 years of follow-up. Three candidate risk factors for the development of CNV and vision loss were evaluated. RESULTS: Eyes with hyperfluorescent drusen on fluorescein angiography at 3 minutes appeared to have a decreased risk of CNV. Patchy choroidal filling was seen in 14% of patients. Eyes with patchy choroidal perfusion showed a higher risk of developing CNV that was not statistically significant, and the increased risk was present only in treated eyes. Reticular pseudodrusen were present in only three eyes. CONCLUSIONS: Reticular pseudodrusen were rare. Late drusen fluorescence may protect against the development of CNV.

Ranchod TM, Brucker AJ, Liu C, Cukras CA, Hopkins TB, Ying GS. · Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · Am J Ophthalmol. · Pubmed #19195634 No free full text.

Abstract: PURPOSE: To determine the accuracy of the photodynamic therapy (PDT) laser spot size on the retina as generated by 2 Food and Drug Administration (FDA)-approved lasers. DESIGN: Prospective observational case series. METHODS: Fundus photographs were taken of 1 eye of each of 10 subjects with the WinStation 4000 fundus photography system (OIS; Ophthalmic Imaging Systems, Sacramento, California, USA); disc size was calculated using OIS software. Slit-lamp photographs were taken of the PDT laser spot focused on the retina adjacent to the optic disc, using various spot sizes in combination with 3 different contact lenses and 2 different lasers. Spot size at the retina was determined by measuring the ratio of disc diameter to spot diameter in Adobe Photoshop (San Jose, California, USA) and applying this ratio to the OIS disc measurements. RESULTS: Spot size at the retina averaged 87% of expected spot size for the Coherent Opal laser (Coherent Inc, Santa Clara, California, USA) and 104% of expected spot size for the Zeiss Visulas laser (Carl Zeiss Meditec Inc, Dublin, California, USA)(P = .002). Multivariate analysis demonstrated that percentage of expected spot size decreased with larger spot diameter (P = .01 for Coherent laser; P = .02 for Zeiss laser). CONCLUSIONS: PDT spot size at the retina appears to be consistently smaller than expected for the Coherent laser while the spot size was consistently within 10% of expected size for the Zeiss laser. The deviation from expected size increased with larger spot size using the Coherent laser.

Ying GS, Maguire MG, Liu C, Antoszyk AN, Anonymous00057. · Department of Ophthalmology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Ophthalmology. · Pubmed #18672295 No free full text.

Abstract: OBJECTIVE: To describe baseline night vision symptoms and their association with >/=3-lines loss in visual acuity (VA), choroidal neovascularization (CNV), and geographic atrophy (GA). DESIGN: Cohort study within a multicenter randomized clinical trial. PARTICIPANTS: A total of 1052 participants with >/=10 large (>125 mu) drusen and VA >/=20/40 in each eye. METHODS: At baseline, participants self-administered a 10-item Night Vision Questionnaire (NVQ-10). VA testing was performed at baseline, 6 months, and annually. One eye of each participant was randomly assigned to laser treatment, and the contralateral eye was assigned to observation. During follow-up, trained readers identified CNV on the basis of fluorescein angiograms and end point GA, defined as >1 disc area of new GA, based on color photographs. Evaluation was performed by repeated-measures logistic regression for NVQ-10 score as a risk factor for >/=3-lines loss in VA and by survival analysis for CNV and GA, with and without adjustment for participant and ocular characteristics. Evaluations were based on observed eyes and treated eyes, considered separately and combined. MAIN OUTCOME MEASURES: A >/=3-lines loss in VA, development of CNV and end point GA. RESULTS: At baseline, NVQ-10 scores ranged from 3 to 100 with a mean of 70 (100 corresponds to no night vision symptoms). Compared with participants with the best night vision (fourth quartile of scores), participants with the worst night vision (first quartile of scores) were at increased risk of >/=3-lines loss in VA in both observed and treated eyes; odds ratios (95% confidence interval) were 2.85 (1.85-4.39) and 2.00 (1.27-3.14), respectively. The relative risk for the first quartile versus the fourth quartile for development of GA was 4.18 (1.80-9.68) in observed eyes and 2.59 (1.13-5.95) in treated eyes. The relative risk for CNV incidence was 1.99 (1.12-3.54) in observed eyes and 1.33 (0.81-2.19) in treated eyes. These relationships were maintained after adjustment for baseline participant and ocular characteristics. CONCLUSIONS: Participants who perceived the most problems in their night vision at baseline had an increased risk of >/=3-lines loss in VA, CNV, and GA. These associations are independent of established risk factors.

Metelitsina TI, Grunwald JE, DuPont JC, Ying GS, Brucker AJ, Dunaief JL. · Department of Ophthalmology, Scheie Eye Institute, School of Medicine, University of Pennsylvania, 51 North 39th Street, Philadelphia, PA 19104, USA. · Invest Ophthalmol Vis Sci. · Pubmed #18172113 links to  free full text

Abstract: PURPOSE: To investigate in a longitudinal study whether foveolar choroidal blood flow changes are associated with the development of choroidal neovascularization (CNV) in AMD. METHODS: Relative foveolar choroidal blood velocity (ChBVel), volume (ChBVol), and flow (ChBFlow) were assessed in 135 patients with AMD, at baseline and then annually with laser Doppler flowmetry. All study eyes had visual acuity of 20/40 or better and no CNV at the time of enrollment. Comparison of foveolar choroidal circulatory measurements at baseline and their change before the development of CNV was made between eyes that had CNV and those that did not. RESULTS: CNV developed in 28 eyes during the study. Baseline average foveolar ChBVol and ChBFlow in these eyes were 24% (P < 0.0001) and 20% (P = 0.0007) lower than that observed in the 165 eyes in which CNV did not develop. In the eyes with CNV, foveolar ChBVol and ChBFlow decreased by 9.6% and 11.5% before the formation of CNV, whereas in the eyes that did not, they increased by 6.7% (P = 0.006) and 2.8% (P = 0.004), respectively. Eyes with lower baseline foveolar ChBFlow were more likely (risk ratio = 3.47, 95% CI: 1.24-8.70) to show visual loss of three or more lines than were eyes with a higher baseline ChBFlow (P = 0.005). CONCLUSIONS: The development of CNV and visual loss are associated with lower choroidal circulatory parameters at baseline. In addition, the results suggest that decreases in the foveolar choroidal circulation precede the development of CNV in AMD and may play some role in its development.

Metelitsina TI, Grunwald JE, DuPont JC, Ying GS, Liu C. · Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, 51 North 39th Street, Philadelphia, PA 19104, USA. · Exp Eye Res. · Pubmed #16530757 No free full text.

Abstract: The aim of the present study was to investigate the effect of sildenafil citrate (viagra) on retinal venous diameter in patients with age-related macular degeneration (AMD). We investigated 14 male patients in a double-masked, randomized, placebo-controlled, crossover study. In each subject, one eye with typical non-exudative AMD fundus features was studied. Each of the subjects received 100 mg dose of sildenafil or matching placebo on two separate study visits. Monochromatic fundus photographs were obtained in the study eye before dosing and then 30, 90, 180 and 300 min later. Measurements of the diameter of the major retinal veins from digitized negatives were carried out using "Vessel map" static vessel analysis program (IMEDOS GmbH, Weimar, Germany). Statistical analysis of the data comparing the effect of sildenafil and placebo on venous diameters was performed using analysis of variance (ANOVA) for repeated measures. An analysis of variance (ANOVA) comparing the effects of sildenafil citrate and placebo on retinal vein diameters showed a significant interaction between time and treatment (P = 0.03). In comparison to placebo, sildenafil citrate produced a statistically significant vasodilatation of major retinal veins of 4.7% at 90 min (P = 0.004), 5.5% at 180 min (P < 0.0001) and 5.8% at 300 min (P < 0.0001). At 30 min there was a 2.2% difference, which was not statistically significant (P=0.14). Our results suggest that in patients with age-related macular degeneration, sildenafil citrate (viagra) produces a statistically significant vasodilatation of major retinal veins that is similar to what has been reported in normal subjects. Whether this vasodilatation is associated with changes in retinal blood flow needs to be further investigated.

Metelitsina TI, Grunwald JE, DuPont JC, Ying GS. · Department of Opthalmology, Scheie Eye Institute, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. · Br J Ophthalmol. · Pubmed #16488959 links to  free full text

Abstract: AIM: To investigate the effect of systemic hypertension (SH) on the foveolar choroidal circulation in patients with age related macular degeneration (AMD). METHODS: This study included 163 study eyes with early AMD characteristics of 124 AMD patients. Study eyes had visual acuity of 20/40 or better, drusen > or =63 microm, and/or RPE hypertrophy. 56 of the AMD patients had a history of SH and 47 of these patients were receiving antihypertensive medications. Laser Doppler flowmetry (Oculix) was used to assess relative choroidal blood velocity (ChBVel), volume (ChBVol), and flow (ChBFlow) in the centre of the fovea of the study eyes. Differences in the mean haemodynamic parameters between groups of eyes were assessed using analysis of variance (ANOVA) and a test of linear trend, with adjustment for the correlation between eyes of the same patient. RESULTS: AMD patients with SH showed decreased ChBFlow in comparison with those without SH (ANOVA, p = 0.02). This association was maintained after adjustments for multiple factors (p = 0.04). CONCLUSIONS: AMD patients with SH have lower ChBFlow than those without SH. This decrease in choroidal blood circulation may help explain the mechanism by which systemic hypertension may contribute to the progression of AMD and the development of choroidal neovascularisation.

Grunwald JE, Metelitsina TI, Dupont JC, Ying GS, Maguire MG. · Department of Ophthalmology, Scheie Eye Institute, School of Medicine, University of Pennsylvania, 51 North 39th Street, Philadelphia, PA 19104, USA. · Invest Ophthalmol Vis Sci. · Pubmed #15728562 links to  free full text

Abstract: PURPOSE: In an earlier study, the authors reported that foveolar choroidal blood flow (ChBFlow) decreases in patients with AMD and drusen. To explore further the choroidal circulatory changes in patients with AMD, the relationship between ChBFlow and fundus features associated with increased risk of choroidal neovascularization (CNV) were investigated. METHODS: The study included 26 control eyes of 17 normal subjects and 163 eyes with early AMD characteristics of 123 patients with AMD. The AMD study eyes were divided into three groups according to increasing risk for development of CNV: (1) drusen > or =63 microm, no RPE hyperpigmentary changes in the study eye, and no CNV in the fellow eye; (2) drusen > or =63 microm, RPE hyperpigmentary changes in the study eye, and no CNV in the fellow eye; and (3) eyes with CNV in the fellow eye. Laser Doppler flowmetry was used to assess relative foveolar choroidal blood velocity (ChBVel), volume (ChBVol), and flow (ChBFlow). Differences in the mean circulatory parameters were assessed by analysis of variance (ANOVA) and test of linear trend. RESULTS: Mean ChBVel, ChBVol, and ChBFlow decreased with increased risk for CNV (linear trend, P < 0.05). The lowest circulatory parameters were observed in the eyes with the highest risk for CNV development. Trends for ChBVel and ChBFlow were still significant after adjustment for multiple factors. CONCLUSIONS: There is a systematic decrease in choroidal circulatory parameters with an increase in the severity of AMD features associated with risk for the development of CNV, suggesting a role for ischemia in the development of CNV.

Ibarra MS, Hsu J, Mirza N, Wu IH, Ying GS, Mainster MA, Tolentino MJ. · Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · Invest Ophthalmol Vis Sci. · Pubmed #15452076 links to  free full text

Abstract: PURPOSE: To study the risk of adverse events in transpupillary thermotherapy (TTT) for age-related macular degeneration by measuring how laser-induced retinal temperature increase is affected experimentally by subretinal blood, choroidal blood flow, and chorioretinal pigmentation. METHODS: An ultrafine thermocouple technique was developed to measure retinal temperature increase during TTT in albino and pigmented rabbit eyes. TTT was performed with 60-second, 0.78-mm spot size, 810-nm infrared diode laser exposures with power settings ranging from 50 to 950 mW. Intraretinal and subretinal temperature increases were measured in pigmented and albino rabbits, with or without subretinal blood and choroidal blood flow. RESULTS: Threshold power settings for visible lesions in albino and pigmented rabbits were 950 and 90 mW, respectively, corresponding to retinal temperature increases of 11.8 degrees C and 5.28 degrees C, respectively. Power settings required to produce threshold lesions in albino rabbits caused retinal temperature increases in pigmented rabbits that were five times higher than in the albino rabbits. Temperature increases in albino rabbits were 1.5 times higher with subretinal blood than without it. Choroidal blood flow generally did not affect measured retinal temperature increases. CONCLUSIONS: The results confirm prior theoretical recommendations that clinicians should consider decreasing TTT power settings in darkly pigmented eyes and proceed with caution in those with subretinal hemorrhage or pigment clumping.

Dunaief JL, Dentchev T, Ying GS, Milam AH. · 305 Stellar Chance Labs, University of Pennsylvania, Philadelphia, PA 19104, USA. · Arch Ophthalmol. · Pubmed #12427055 No free full text.

Abstract: OBJECTIVE: To investigate apoptosis in human age-related macular degeneration (AMD). METHODS: Postmortem retinas with AMD and normal retinas were studied by terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) to identify dying cells, and by immunocytochemistry with cell-specific antibodies to identify rods and cones. Sections were also labeled for Fas, a cell surface receptor that triggers apoptosis in other cell types. The maculas with AMD had geographic atrophy (GA) or exudative AMD. RESULTS: Maculas with AMD had statistically significant increases in TUNEL-positive cells in the inner choroid, retinal pigment epithelium (RPE), photoreceptors, and inner nuclear layers compared with normal retinas. In eyes with GA, TUNEL-positive rod and RPE cell nuclei were present near edges of RPE atrophy. Photoreceptors in the maculas of eyes with AMD were strongly Fas-positive, while normal photoreceptors were only weakly labeled. CONCLUSIONS: Evidence in this study suggests that in human AMD, RPE, photoreceptors, and inner nuclear layer cells die by apoptosis. Most TUNEL-positive RPE and photoreceptor cells were at edges of atrophy, correlating with clinically observed expansion of atrophic areas with vision loss in patients with GA. Increased Fas labeling in AMD photoreceptors indicates that the Fas/Fas ligand system may be involved in photoreceptor apoptosis. This information is essential for developing rational therapy for AMD.

Tolentino MJ, Brucker AJ, Fosnot J, Ying GS, Wu IH, Malik G, Wan S, Reich SJ. · Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, 51 North 39th Street, Philadelphia, PA 19104, USA. · Retina. · Pubmed #15076954 No free full text.

Abstract: PURPOSE: To determine the safety and efficacy of small interfering RNA (siRNA) directed against vascular endothelial growth factor (VEGF) in a nonhuman primate model of laser-induced choroidal neovascularization (CNV). METHODS: Each animal received laser rupture of Bruch's membrane to induce CNV in both eyes. Each animal was then randomized to receive 0.05 mL of either vehicle alone or VEGF siRNA at 70 microg, 150 microg, or 350 microg in both eyes by intravitreal injection. Eyes were monitored weekly by ophthalmic examination, color photography, and fluorescein angiography for 36 days after laser injury. Electroretinograms were measured at baseline and at 5 weeks after laser. CNV on fluorescein angiograms were measured for area and graded for clinically significant leakage in a standardized, randomized, and double-masked fashion on days 15, 22, 29, and 36 after laser. RESULTS: VEGF siRNA did not cause any change in electroretinographic, hemorrhage, inflammation, or clinical signs of toxicity. A single administration of VEGF siRNA significantly inhibited growth of CNV and attenuated angiographic leakage in a dose-dependent manner. CONCLUSION: Intravitreal injection of VEGF siRNA is capable of inhibiting the growth and vascular permeability of laser-induced CNV in a nonhuman primate in a dose-dependent manner. This study demonstrates preclinical proof of a principle that supports proceeding to clinical studies of VEGF siRNA in patients with exudative age-related macular degeneration.