Constituents of bile, bilirubin and TUDCA, protect against oxidative stress-induced retinal degeneration.

Two constituents of bile, bilirubin and tauroursodeoxycholic acid (TUDCA), have antioxidant activity. However, bilirubin can also cause damage to some neurons and glial cells, particularly immature neurons. In this study, we tested the effects of bilirubin and TUDCA in two models in which oxidative stress contributes to photoreceptor cell death, prolonged light exposure and rd10+/+ mice. In albino BALB/c mice, intraperitoneal injection of 5 mg/kg of bilirubin or 500 mg/kg of TUDCA prior to exposure to 5000 lux of white light for 8 h significantly reduced loss of rod and cone function assessed by electroretinograms. Both treatments also reduced light-induced accumulation of superoxide radicals in the outer retina, rod cell death assessed by outer nuclear layer thickness, and disruption of cone inner and outer segments. In rd10+/+ mice, intraperitoneal injections of 5 or 50 mg/kg of bilirubin or 500 mg/kg of TUDCA every 3 days starting at postnatal day (P) 6, caused significant preservation of cone cell number and cone function at P50. Rods were not protected at P50, but both bilirubin and TUDCA provided modest preservation of outer nuclear layer thickness and rod function at P30. These data suggest that correlation of serum bilirubin levels with rate of vision loss in patients with retinitis pigmentosa could provide a useful strategy to test the hypothesis that cones die from oxidative damage in patients with retinitis pigmentosa. If proof-of-concept is established, manipulation of bilirubin levels and administration of TUDCA could be tested in interventional trials.

Antagonism of vascular endothelial growth factor for macular edema caused by retinal vein occlusions: two-year outcomes.

PURPOSE: To determine the long-term effects of intraocular antagonism of vascular endothelial growth factor (VEGF) in patients with macular edema caused by retinal vein occlusions (RVOs). DESIGN: Prospective randomized trial. PARTICIPANTS: Twenty patients with macular edema caused by branch RVOs (BRVOs) and 20 patients with central RVOs (CRVOs). METHODS: After the month 3 primary end point, patients were seen every 2 months and received injections of an anti-VEGF agent as needed for recurrent edema. MAIN OUTCOME MEASURES: Mean change from baseline best-corrected visual acuity (BCVA) at month 24 with assessment of other parameters of visual function and center subfield thickness (foveal thickness [FTH]). RESULTS: For 17 patients with BRVO who completed 2 years of follow-up, the mean improvement from baseline in BCVA at month 24 was 17.8 letters compared with 15.6 letters at month 3. Improvement by at least 6, 3, or 2 lines occurred in 18%, 59%, and 76% of patients, respectively. The Snellen equivalent BCVA at month 24 was 20/40 or better in 10 patients. With an average of 2 injections of ranibizumab during year 2, the mean FTH at month 24 was 245.8 µm compared with 217.1 µm at month 3 and 481.5 µm at baseline. For 14 patients with CRVO who completed 2 years of follow-up, the mean improvement in BCVA at month 24 was 8.5 letters compared with 12.0 letters at month 3. Improvement by at least 6, 3, or 2 lines occurred in 14%, 21%, and 43% of patients, respectively. The Snellen equivalent BCVA at month 24 was 20/40 or better in 4 patients. With an average of 3.5 injections of ranibizumab in year 2, mean FTH at month 24 was 338 µm compared with 278 µm at month 3 and 533 µm at baseline. Duration of RVO >1 year at study entry and nonperfusion of perifoveal capillaries for 360 degrees correlated with reduced visual outcomes. CONCLUSIONS: Antagonism of VEGF provides substantial long-term benefit to patients with macular edema caused by RVO, but frequent injections are required in some patients with BRVO and most patients with CRVO.

Ranibizumab for macular edema due to retinal vein occlusions: implication of VEGF as a critical stimulator.

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.

Dynamic and quantitative analysis of choroidal neovascularization by fluorescein angiography.

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.

Persistent diabetic macular edema is associated with elevated hemoglobin A1c.

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.

Panuveitis in association with pseudotumor cerebri.

We report a case of an 11-year-old girl with bilateral panuveitis in association with pseudotumor cerebri. The patient underwent complete ophthalmologic, neurologic, and laboratory evaluations and was treated with therapy for pseudotumor cerebri. The patient met the diagnostic criteria for pseudotumor cerebri and also had panuveitis. Symptoms and findings of pseudotumor cerebri and panuveitis improved significantly after combination therapy of oral acetazolamide and weight reduction. The index case illustrates that pseudotumor cerebri can be associated with panuveitis. Therapy for pseudotumor cerebri might also help with the resolution of uveitis.

Supplemental oxygen improves diabetic macular edema: a pilot study.

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.

Impact of optical coherence tomography on surgical decision making for epiretinal membranes and vitreomacular traction.

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.

The impact of optical coherence tomography on surgical decision making in epiretinal membrane and vitreomacular traction.

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.