URINARY METABOLOMICS OF CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To analyze the urinary metabolomic profile of central serous chorioretinopathy cases. METHODS: In a cross-sectional study, 80 participants with central serous chorioretinopathy were compared with 80 age-matched and sex-matched controls. Urinary metabolites were measured using Metabolon's Discovery HD4 platform. RESULTS: Of 1,031 metabolites total that were measured in urine samples, 53 were upregulated and 27 downregulated in central serous chorioretinopathy participants compared with controls. After exclusion of potentially confounding xenobiotics and bile compounds that could represent digestive processes, 14 metabolites were significantly higher and 12 metabolites were significantly lower in cases compared with controls. One upregulated metabolite (tetrahydrocortisol sulfate) is involved in the corticosteroid subpathway. The downregulated metabolites are unrelated to the identified corticosteroid subpathway. CONCLUSION: The upregulation of urinary tetrahydrocortisol sulfate in central serous chorioretinopathy cases provides a precise molecular basis to further study the role of corticosteroids in producing choroidal venous congestion.

Central Serous Chorioretinopathy in African Americans at Wilmer Eye Institute.

OBJECTIVE: To evaluate the frequency of central serous chorioretinopathy (CSC) in African Americans/blacks within an academic center in a predominantly African American city, as the current belief is that CSC is rare in this population. METHODS: A retrospective review of all patients' charts diagnosed with CSC at Wilmer Eye Institute/Johns Hopkins University from August 2009-August 2015 was conducted via an electronic health record search (EPIC). The charts were categorized by self-reported race and gender. The diagnosis was confirmed by multiple physician consensus through chart and imaging review. Fluorescein angiograms were classified as single versus multiple point leakage. OCTs were evaluated for subfoveal thickness, location of fluid, presence or absence of pigment epithelial detachment. Color photos were categorized as to the extent of retinal pigment epithelial changes. RESULTS: Of the 590 charts identified via EPIC as CSC patients, 407 were confirmed as CSC through chart and imaging review. 45 patients (11.1%) were African Americans and 298 patients (73.2%) were Caucasians. Of all patients seen during the study period, 0.09% of African Americans at Wilmer had CSC and 0.18% of Caucasians had CSC. While three fold more Caucasians were seen during the study period as compared to African Americans, this study's prevalence rate in African Americans/blacks at Wilmer Eye Institute was half of that in Caucasian/whites. CONCLUSIONS: CSC has been reported as exceedingly rare in African Americans, but our study suggests that CSC may be underestimated in this population. A large nationally representative population based study is needed to determine true racial prevalence to ensure that the diagnosis of CSC is not overlooked in African Americans.

A Crossover Design for Comparative Efficacy: A 36-Week Randomized Trial of Bevacizumab and Ranibizumab for Diabetic Macular Edema.

PURPOSE: To investigate the comparative efficacy of bevacizumab (Avastin) and ranibizumab (Lucentis; both Genentech, Inc, South San Francisco, CA) for diabetic macular edema (DME) using a crossover study design. DESIGN: Randomized, double-masked, 36-week, 3-period crossover clinical trial. PARTICIPANTS: Fifty-six subjects with DME involving the center of the macula in one or both eyes. METHODS: Monthly intravitreous injections of bevacizumab (1.25 mg) or ranibizumab (0.3 mg). MAIN OUTCOME MEASURES: Comparison of mean changes in visual acuity and central retinal thickness, tested using a linear mixed-effects model. RESULTS: Based on the linear mixed-effects model, the 3-month estimated mean improvement in visual acuity was 5.3 letters for bevacizumab and 6.6 letters for ranibizumab (difference, 1.3 letters; P = 0.039). Estimated change in optical coherence tomography (OCT) central subfield mean thickness (CSMT) was -89 µm for bevacizumab and -137 µm for ranibizumab (difference, 48 µm; P < 0.001). Incorporating cumulative treatment benefit, the model yielded a predicted 36-week (9-month) average improvement in visual acuity of 7.1 letters (95% confidence interval [CI], 5.0-9.2) for bevacizumab and 8.4 letters (95% CI, 6.3-10.5) for ranibizumab, and a change in OCT CSMT of -128 µm (95% CI, -155 to -100) for bevacizumab and -176 µm (95% CI, -202 to -149) for ranibizumab. There was no significant treatment-by-period interaction (i.e., treatment difference was constant in all 3 periods), nor was there a significant differential carryover effect from one period to the next. CONCLUSIONS: This trial demonstrated a statistically significant but small relative clinical benefit of ranibizumab compared with bevacizumab for treatment of DME, using a markedly reduced sample size relative to a full comparative efficacy study. The effects on visual acuity and central retinal thickness for the 2 drugs are consistent with those reported at 1 year for the concurrent parallel-group trial by the Diabetic Retinopathy Clinical Research Network testing bevacizumab, ranibizumab, and aflibercept for DME. The 3-period crossover design allowed for meaningful and efficient comparison, suggesting that this approach may be useful for future comparative efficacy studies of anti-vascular endothelial growth factor drugs for DME.

Effect of ranibizumab on high-speed indocyanine green angiography and minimum intensity projection optical coherence tomography findings in neovascular age-related macular degeneration.

PURPOSE: The purpose of this 1-year prospective study was to investigate how induction/pro re nata ranibizumab intravitreal treatment of eyes with neovascular age-related macular degeneration affects the anatomy of choroidal neovascularization (CNV) and the overlying outer retinal tissue. METHODS: High-speed indocyanine green (HS-ICG) angiography measurements provided quantification of the CNV size in 60 patients followed for 1 year. Minimum intensity projection optical coherence tomography (MinIP OCT), a novel algorithm assessing minimum optical intensity between the internal limiting membrane and retinal pigment epithelium, measured the area of outer retinal disruption overlying the CNV. Fluorescein angiography was also assessed to evaluate late retinal leakage. RESULTS: After 1 year, the mean area of CNV measured with indocyanine green angiography decreased by 5.8%. The mean area of MinIP OCT of outer retinal disruption overlying the CNV decreased by 4.2%. Mean area of fluorescein angiography leakage decreased by 6.3%. Both the area of outer retinal disruption measured with MinIP OCT and the area of leakage on fluorescein angiography typically exceeded the area of CNV on indocyanine green angiography at baseline and 1 year. CONCLUSION: Choroidal neovascularization treated with induction/pro re nata intravitreal ranibizumab for 1 year essentially remained static. Minimum intensity projection optical coherence tomography suggests that the area of outer retinal disruption overlying the CNV may be greater than the CNV itself and often correlates with the leakage area on fluorescein angiography. Additionally, there was minimal change in the area of outer retinal disruption on MinIP OCT even when fluid resolved. Measurements of the extent of CNV lesions based on indocyanine green angiography and MinIP OCT may provide useful outcome variables to help assess the CNV complex longitudinally and warrant further validation.

Suggestive association between PLA2G12A single nucleotide polymorphism rs2285714 and response to anti-vascular endothelial growth factor therapy in patients with exudative age-related macular degeneration.

PURPOSE: The use of anti-vascular endothelial growth factor (anti-VEGF) therapy, with drugs such as ranibizumab and bevacizumab, to treat neovascular age-related macular degeneration (nAMD) produces an effective but widely variable response. Identifying markers that predict differentiated response could serve as a valuable assay in developing more personalized medicine. This study aimed to identify single nucleotide polymorphisms (SNPs) that influence the outcome of treatment with anti-VEGF therapy for AMD. METHODS: One hundred six patients with nAMD were treated with either ranibizumab or bevacizumab as needed over a period of 12 months. Visual acuity and the presence of macular fluid were measured with optical coherence tomography at baseline, six months, and 12 months. Patients were then classified as good or poor responders based on change in visual acuity and macular fluid on follow-up visits. DNA extracted from blood was genotyped with a TaqMan-based allelic discrimination SNP assay for 21 SNPs in six candidate genes (PLAG12A, IL23R, STAT3, VEGFA, KDR, and HIF1A). The SNPs were primarily selected based on previously reported associations with AMD and functional involvement in angiogenesis pathways. SNPs shown to be promising for association with anti-VEGF therapy were then assessed in an independent AMD case-control cohort. RESULTS: Of the 106 patients with nAMD, 77 were classified as good responders and 29 as poor responders. For rs2285714 (PLA2G12A), the frequency of minor allele T was 40.1% for good responders compared to 51.7% for poor responders (odds ratio: 1.60, 95% confidence interval of odds ratio: 0.87-2.94, p=0.13). Genetic model analysis of rs2285714 (PLA2G12A) demonstrated an association between rs2285714 (PLA2G12A) and therapy response in a dominant genotypic model. Patients carrying at least one T allele of rs2285714 were 2.79 times (95% confidence interval=1.02-7.69, p<0.05) more likely to be poor responders (79.3% of poor responders) than good responders (57.3% of good responders). However, after adjusting for multiple testing by the false discovery rate or Bonferroni correction, the initially observed association was no longer statistically significant. No association was identified between the remaining SNPs and response status. The SNP rs2285714 of PLA2G12A was not significantly associated with AMD in an independent AMD case-control cohort. CONCLUSIONS: Data suggest a possible weak association between rs2285714 (PLA2G12A) and response to anti-VEGF therapy, but the association must be confirmed in additional cohorts with larger patient samples. Identifying factors that predict the differentiated response could provide a valuable assay for developing approaches in personalized medicine.

Treatment of nonneovascular idiopathic macular telangiectasia type 2 with intravitreal ranibizumab: results of a phase II clinical trial.

PURPOSE: To evaluate the safety and preliminary efficacy of intravitreal ranibizumab for nonneovascular idiopathic macular telangiectasia Type 2. METHODS: Single-center, open-label Phase II clinical trial enrolling five participants with bilateral nonneovascular idiopathic macular telangiectasia Type 2. Intravitreal ranibizumab (0.5 mg) was administered every 4 weeks in the study eye for 12 months with the contralateral eye observed. Outcome measures included changes in best-corrected visual acuity, area of late-phase leakage on fluorescein angiography, and retinal thickness on optical coherence tomography. RESULTS: The study treatment was well tolerated and associated with few adverse events. Change in best-corrected visual acuity at 12 months was not significantly different between treated study eyes (0.0 ± 7.5 letters) and control fellow eyes (+2.2 ± 1.9 letters). However, decreases in the area of late-phase fluorescein angiography leakage (-33 ± 20% for study eyes, +1 ± 8% for fellow eyes) and in optical coherence tomography central subfield retinal thickness (-11.7 ± 7.0% for study eyes and -2.9 ± 3.5% for fellow eyes) were greater in study eyes compared with fellow eyes. CONCLUSION: Despite significant anatomical responses to treatment, functional improvement in visual acuity was not detected. Intravitreal ranibizumab administered monthly over a time course of 12 months is unlikely to provide a general and significant benefit to patients with nonneovascular idiopathic macular telangiectasia Type 2.

Finasteride for chronic central serous chorioretinopathy.

PURPOSE: To evaluate the safety and efficacy of finasteride, an inhibitor of dihydrotestosterone synthesis, in the treatment of chronic central serous chorioretinopathy. METHODS: Five patients with chronic central serous chorioretinopathy were prospectively enrolled in this pilot study. Patients were administered finasteride (5 mg) daily for 3 months, after which study medication was withheld and patients were observed for 3 months. Main outcome measures included best-corrected visual acuity, central subfield macular thickness, and subretinal fluid volume as assessed by optical coherence tomography. Serum dihydrotestosterone, serum testosterone, and urinary cortisol were also measured. RESULTS: There was no change in mean best-corrected visual acuity. Mean center-subfield macular thickness and subretinal fluid volume reached a nadir at 3 months and rose to levels that were below baseline by 6 months. The changes in both optical coherence tomography parameters paralleled those in serum dihydrotestosterone level. In four patients, center-subfield macular thickness and/or subretinal fluid volume increased after discontinuation of finasteride. In the remaining patient, both optical coherence tomography parameters normalized with finasteride and remained stable when the study medication was discontinued. CONCLUSION: Finasteride may represent a novel medical treatment for chronic central serous chorioretinopathy. Larger controlled clinical trials are needed to further assess the efficacy of finasteride for the treatment of central serous chorioretinopathy.

Patient Use of Dietary Supplements, Home Monitoring, or Genetic Testing for Nonneovascular Age-Related Macular Degeneration.

Purpose: This work evaluated the use and type of dietary supplements and home monitoring for nonneovascular age-related macular degeneration (AMD), as well as the prevalence of genetic testing among patients with AMD. Methods: A cross-sectional study was conducted of 129 participants older than 50 years who completed self-administered questionnaires regarding usage and type of dietary supplements and home monitoring, as well as the participants' use of genetic testing for AMD. Results: Of 91 participants with AMD, 83 (91.2%) took vitamins, including 55 (60.4%) who used an Age-Related Eye Disease Study (AREDS) or AREDS2 formulation. Of 38 without AMD, 31 (81.6%) took vitamins (difference from participants with AMD = 9.6% [95% CI, 0%-23.2%]), including 2 on an AREDS formulation. Among 82 participants with AMD who were AREDS candidates (intermediate or advanced AMD in 1 or both eyes), 51 (62.2%; 95% CI, 51.7%-72.7%) took an AREDS or AREDS2 formulation, and 31 (37.8%) did not (5 were unsure). Additionally, 50 (61.0%; 95% CI, 50.4%-71.6%) AREDS candidates did some type of home monitoring. Only 1 (1.2%; 95% CI, 0%-3.6%) underwent genetic testing for AMD. Among 9 with AMD who were not AREDS candidates, 4 (44.4%) used an AREDS formulation, 4 (44.4%) did not, and 1 (11.1%) was unsure; only 1 (11.1%) of these 9 performed home monitoring. Conclusions: Despite similar results from past surveys and AREDS2 data supporting supplement use in 2013 and home monitoring in 2014, these findings suggest about one-third of AREDS candidates do not do so, providing further support for improving education regarding appropriate supplement and home monitoring usage. Genetic testing for AMD also appears infrequent.

Relationship between photoreceptor outer segment length and visual acuity in diabetic macular edema.

PURPOSE: The purpose of this study was to quantify photoreceptor outer segment (PROS) length in 27 consecutive patients (30 eyes) with diabetic macular edema using spectral domain optical coherence tomography and to describe the correlation between PROS length and visual acuity. METHODS: Three spectral domain-optical coherence tomography scans were performed on all eyes during each session using Cirrus HD-OCT. A prototype algorithm was developed for quantitative assessment of PROS length. Retinal thicknesses and PROS lengths were calculated for 3 parameters: macular grid (6 x 6 mm), central subfield (1 mm), and center foveal point (0.33 mm). Intrasession repeatability was assessed using coefficient of variation and intraclass correlation coefficient. The association between retinal thickness and PROS length with visual acuity was assessed using linear regression and Pearson correlation analyses. The main outcome measures include intrasession repeatability of macular parameters and correlation of these parameters with visual acuity. RESULTS: Mean retinal thickness and PROS length were 298 mum to 381 microm and 30 microm to 32 mum, respectively, for macular parameters assessed in this study. Coefficient of variation values were 0.75% to 4.13% for retinal thickness and 1.97% to 14.01% for PROS length. Intraclass correlation coefficient values were 0.96 to 0.99 and 0.73 to 0.98 for retinal thickness and PROS length, respectively. Slopes from linear regression analyses assessing the association of retinal thickness and visual acuity were not significantly different from 0 (P > 0.20), whereas the slopes of PROS length and visual acuity were significantly different from 0 (P < 0.0005). Correlation coefficients for macular thickness and visual acuity ranged from 0.13 to 0.22, whereas coefficients for PROS length and visual acuity ranged from -0.61 to -0.81. CONCLUSION: Photoreceptor outer segment length can be quantitatively assessed using Cirrus HD-OCT. Although the intrasession repeatability of PROS measurements was less than that of macular thickness measurements, the stronger correlation of PROS length with visual acuity suggests that the PROS measures may be more directly related to visual function. Photoreceptor outer segment length may be a useful physiologic outcome measure, both clinically and as a direct assessment of treatment effects.

Complementary angiographic and autofluorescence findings in pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is a systemic disease with characteristic findings on fundus examination. The fundus findings may be difficult to detect with ophthalmoscopy. A case report is described as follows. A PXE patient had subtle retinal findings on fundoscopy that were more prominently seen using a combination of both fundus autofluorescence (FAF) imaging and indocyanine green (ICG) angiography. The fundus features visualized using each of these two modalities appeared different from each other. FAF imaging and ICG angiography may be able to more prominently detect pathology at the level of the retinal pigment epithelium and Bruch's membrane, respectively. The use of these imaging modalities together may be complementary and useful in the evaluation of patients with PXE.