Low serum testosterone and increased diastolic ocular perfusion pressure: a risk for retinal microvasculature.

BACKGROUND: Low levels of testosterone in men and changes in retinal microvascular calibre are both associated with hypertension and cardiovascular disease risk. Sex hormones are also associated with blood flow in microvascular beds which might be a key intermediate mechanism in the development of hypertension. Whether a direct association between endogenous testosterone and retinal microvascular calibre exists is currently unknown. We aimed to determine whether testosterone is independently associated with ocular perfusion via a possible association with retinal vascular calibre or whether it plays only a secondary role via its effect on blood pressure in a bi-ethnic male cohort. PROBANDS AND METHODS: A total of 72 black and 81 white men (28-68 years of age) from the follow-up phase of the Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) study were included in this sub-study. Ambulatory pulse pressure and intraocular perfusion pressures were obtained, while metabolic variables and testosterone were measured from fasting venous blood samples. Retinal vascular calibre was quantified from digital photographs using standardised protocols. RESULTS: The black men revealed a poorer cardiometabolic profile and higher pulsatile pressure (>50 mm Hg), intraocular pressure and diastolic ocular perfusion pressure than the white men (p≤0.05). Only in the white men was free testosterone positively associated with retinal calibre, i.e. arterio-venular ratio and central retinal arterial calibre and inversely with central retinal venular calibre. These associations were not found in the black men, independent of whether pulse pressure and ocular perfusion pressure were part of the model. CONCLUSIONS: These results suggest an independent, protective effect of testosterone on the retinal vasculature where an apparent vasodilatory response in the retinal resistance microvessels was observed in white men.

Predictors for the development of referral-warranted retinopathy of prematurity in the telemedicine approaches to evaluating acute-phase retinopathy of prematurity (e-ROP) study.

IMPORTANCE: Detection of treatment-requiring retinopathy of prematurity (ROP) involves serial eye examinations. An ROP prediction model using predictive factors could identify high-risk infants and reduce required eye examinations. OBJECTIVE: To determine predictive factors for the development of referral-warranted (RW) ROP. DESIGN, SETTING, AND PARTICIPANTS: This multicenter observational cohort study included secondary analysis of data from the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity Study. Infants included in the study had a birth weight (BW) of less than 1251 g. EXPOSURES: Serial ROP examinations of premature infants who had 2 or more ROP examinations. MAIN OUTCOMES AND MEASURES: Incidence of RW-ROP (defined as the presence of plus disease, zone I ROP, or ROP stage 3 or greater in either eye) and associations with predictive factors. RESULTS: Among 979 infants without RW-ROP at first study-related eye examination (median postmenstrual age, 33 weeks; range, 29-40 weeks) who underwent at least 2 eye examinations, 149 (15.2%) developed RW-ROP. In a multivariate model, significant predictors for RW-ROP were male sex (odds ratio [OR], 1.80; 95% CI, 1.13-2.86 vs female), nonblack race (OR, 2.76; 95% CI, 1.50-5.08 for white vs black race and OR, 4.81; 95% CI, 2.19-10.6 for other vs black race), low BW (OR, 5.16; 95% CI, 1.12-7.20 for ≤500 g vs >1100 g), younger gestational age (OR, 9.79; 95% CI, 3.49-27.5 for ≤24 weeks vs ≥28 weeks), number of quadrants with preplus disease (OR, 7.12; 95% CI, 2.53-20.1 for 1-2 quadrants and OR, 18.4; 95% CI, 4.28-79.4 for 3-4 quadrants vs no preplus disease), stage 2 ROP (OR, 4.13; 95% CI, 2.13-8.00 vs no ROP), the presence of retinal hemorrhage (OR, 4.36; 95% CI, 1.57-12.1 vs absence), the need for respiratory support (OR, 4.99; 95% CI, 1.89-13.2 for the need for controlled mechanical ventilator; OR, 11.0; 95% CI, 2.26-53.8 for the need for high-frequency oscillatory ventilation vs no respiratory support), and slow weight gain (OR, 2.44; 95% CI, 1.22-4.89 for weight gain ≤12 g/d vs >18 g/d). These characteristics predicted the development of RW-ROP significantly better than BW and gestational age (area under receiver operating characteristic curve, 0.88 vs 0.78; P < .001). CONCLUSIONS AND RELEVANCE: When controlling for very low BW and prematurity, the presence of preplus disease, stage 2 ROP, retinal hemorrhage, and the need for ventilation at time of first study-related eye examination were strong independent predictors for RW-ROP. These predictors may help identify infants in need of timely eye examinations.

Optical coherence tomography-based ranibizumab monotherapy for retinal angiomatous proliferation in Korean patients.

PURPOSE: To evaluate the visual outcome of optical coherence tomography-based ranibizumab monotherapy in Korean patients with retinal angiomatous proliferation and identify prognostic factors of visual outcome. METHODS: A prospective single-arm clinical study of 31 retinal angiomatous proliferation patients who underwent 3 consecutive monthly intravitreal ranibizumab injections was conducted. Additional treatment was given based on optical coherence tomography at monthly follow-ups over 24 months. RESULTS: Best-corrected visual acuity improved from 48.7 ± 19.3 to 56.3 ± 19.1 letters at 24 months (P = 0.010). Total cumulative numbers of injection were 5.5 ± 2.2 and 7.7 ± 3.4 times at 12 and 24 months, respectively. Older age, larger choroidal neovascularization size, and poor initial best-corrected visual acuity were associated with poor visual outcome. Final best-corrected visual acuity was significantly worse with Stage 3 disease (70.4 ± 5.1, 62.3 ± 11.6, 46.2 ± 22.3 letters improved in each stage; P = 0.015). Among factors associated with poor visual outcome, only the stage of retinal angiomatous proliferation remained statistically significant on multiple linear regression analysis (P = 0.006). Although baseline best-corrected visual acuity was similar, Stage 3 patients exhibited limited visual improvement despite anatomical improvement, and more recurrences requiring more injections. CONCLUSION: Retinal angiomatous proliferation may be successfully managed with ranibizumab monotherapy in Korean patients, with the number of treatments required comparable to other forms of neovascular age-related macular degeneration. However, visual improvement was limited in late-stage RAP.

FLT1 genetic variation predisposes to neovascular AMD in ethnically diverse populations and alters systemic FLT1 expression.

PURPOSE: Current understanding of the genetic risk factors for age-related macular degeneration (AMD) is not sufficiently predictive of the clinical course. The VEGF pathway is a key therapeutic target for treatment of neovascular AMD; however, risk attributable to genetic variation within pathway genes is unclear. We sought to identify single nucleotide polymorphisms (SNPs) associated with AMD within the VEGF pathway. METHODS: Using a tagSNP, direct sequencing and meta-analysis approach within four ethnically diverse cohorts, we identified genetic risk present in FLT1, though not within other VEGF pathway genes KDR, VEGFA, or VASH1. We used ChIP and ELISA in functional analysis. RESULTS: The FLT1 SNPs rs9943922, rs9508034, rs2281827, rs7324510, and rs9513115 were significantly associated with increased risk of neovascular AMD. Each association was more significant after meta-analysis than in any one of the four cohorts. All associations were novel, within noncoding regions of FLT1 that do not tag for coding variants in linkage disequilibrium. Analysis of soluble FLT1 demonstrated higher expression in unaffected individuals homozygous for the FLT1 risk alleles rs9943922 (P = 0.0086) and rs7324510 (P = 0.0057). In silico analysis suggests that these variants change predicted splice sites and RNA secondary structure, and have been identified in other neovascular pathologies. These data were supported further by murine chromatin immunoprecipitation demonstrating that FLT1 is a target of Nr2e3, a nuclear receptor gene implicated in regulating an AMD pathway. CONCLUSIONS: Although exact variant functions are not known, these data demonstrate relevancy across ethnically diverse genetic backgrounds within our study and, therefore, hold potential for global efficacy.

Risk factors for proliferative diabetic retinopathy in a Latino American population.

PURPOSE: To assess the personal and demographic risk factors for proliferative diabetic retinopathy in Latino Americans in Los Angeles County. METHODS: In this prospective, non-interventional, cross-sectional case control study, seven hundred and twenty-nine subjects from Los Angeles County University of Southern California Medical Center (LAC + USC), Los Angeles, CA, were enrolled. All patients were recruited prospectively from the LAC + USC Medical Center and affiliated clinics between June 2008 and June 2011. Complete personal data and results from systemic and ophthalmic examinations were collected for all enrolled subjects. Laboratory tests such as glycosylated hemoglobin, creatinine levels, and cholesterol levels were collected prospectively by drawing blood at the time of each patient's clinic visit. The main outcome measures were age, gender, type of diabetes mellitus (DM I or II) duration of diabetes mellitus, history of hypertension, history of insulin use, height, weight, and body mass index, smoking history, glycosylated hemoglobin, creatinine levels, and cholesterol levels. RESULTS: The mean age of subjects with no diabetic retinopathy was 56.38 years (SD, 10.16), whereas that of patients with proliferative diabetic retinopathy was 57.43 years (SD, 9.63). Parameters that conferred a statistically significant increased risk for proliferative diabetic retinopathy in the multivariate model included gender (men were at higher risk: odds ratio [OR], 4.11; 95% confidence interval [CI], 2.56-6.58), insulin use (OR, 1.85; 95% CI, 1.13-3.03), history of hypertension (OR, 1.64; 95% CI, 1.02-2.63), and duration (>25 years vs. 10-15 years) of diabetes (OR, 22.00; 95% CI, 9.76-49.60). CONCLUSION: In this case-control study in a Latino population, duration of diabetes and male gender were the strongest risk factor for the development of proliferative diabetic retinopathy followed by insulin use and hypertension. Interestingly, smoking and glycosylated hemoglobin levels did not confer additional significant risk in this cohort.

Efficacy of the screening algorithm WINROP in a Korean population of preterm infants.

OBJECTIVE: To investigate the efficacy of WINROP (https://winrop.com), an algorithm based on serial measurements of neonatal body weight to predict proliferative retinopathy of prematurity (ROP), in a Korean population of preterm infants. METHODS: The records of preterm infants with gestational age less than 32 weeks who were admitted to the neonatal intensive care unit at Chonnam National University Hospital, Gwangju, South Korea, from October 2006 to November 2010 were reviewed. The body weight of infants was measured weekly and entered into a computer-based surveillance system, WINROP, and the outcome was analyzed. RESULTS: A total of 314 preterm infants participated in the study. The mean gestational age was 29 weeks (range, 25-32 weeks). The mean body weight was 1263 g (range, 590-2260 g). For 166 of 314 infants (52.9%), a high-risk alarm was noted. In the high-risk alarm group, 36 infants developed type 1 ROP, according to the Early Treatment for Retinopathy of Prematurity criteria, and they were treated for ROP. The remaining 148 infants (47.1%) had a low-risk alarm. In the low-risk alarm group, 3 infants with bronchopulmonary dysplasia and intraventricular hemorrhage, a risk factor for ROP, and 1 infant without any risk factors for ROP developed type 1 ROP and were treated. CONCLUSIONS: In a Korean population, the WINROP algorithm had a sensitivity of 90% for identifying infants with type 1 ROP. Although some limitations are present, adjustment to the WINROP algorithm for a specific population may improve the efficacy of predicting proliferative ROP and reduce the frequency of retinal examinations.

Combination therapy of ranibizumab and photodynamic therapy for retinal angiomatous proliferation with serous pigment epithelial detachment in Korean patients: twelve-month results.

PURPOSE: The purpose of this study was to evaluate the safety and efficacy of combination therapy with intravitreal ranibizumab and photodynamic therapy in the treatment of retinal angiomatous proliferation (RAP) with serous pigment epithelial detachment. METHODS: Ten eyes of nine consecutive patients with newly diagnosed RAP were enrolled in this prospective pilot study. A course of combination therapy consisted of three ranibizumab injections at monthly intervals and a single photodynamic therapy, guided by indocyanine green angiography, about 1 week after the first injection. The patients were followed every month for 12 months. Retreatment was administered when a persistent, recurrent, or new RAP lesion was confirmed. RESULTS: Eight of the 9 patients (9 eyes) completed 12 months of follow-up. At the 3-month visit, 8 of the 9 eyes (89%) showed favorable initial responses. After 6 months, recurrent lesions developed in 2 eyes (25%) and a new lesion in one other eye; all showed favorable responses to retreatment. At the 12-month visit, 7 eyes (78%) showed regression of the RAP lesions, among which 5 eyes (56%) required only a single session of combination treatment. The mean best-corrected visual acuity was improved from 20/125 at baseline to 20/63 (P = 0.021), and the mean central foveal thickness was reduced from 353 µm at baseline to 169 µm (P = 0.017). The mean improvement in the best-corrected visual acuity was 3.86 lines. No patient had vision-threatening adverse events. CONCLUSION: Ranibizumab and photodynamic therapy combination therapy appears to be safe and effective for anatomical and functional improvement in patients with RAP with pigment epithelial detachment. Further evaluation with a larger patient sample and a long-term controlled study is required to compare treatment efficacy with antivascular endothelial growth factor monotreatment.

Clinical characteristics of exudative age-related macular degeneration in Japanese patients.

PURPOSE: To clarify the clinical characteristics of exudative age-related macular degeneration (AMD) in Japanese patients. DESIGN: Retrospective, observational, consecutive case series. METHODS: Two hundred and eighty-nine patients with neovascular AMD were examined. RESULTS: The authors classified the patients into three subtypes of neovascular AMD: polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP), and typical AMD. One hundred and fifty-eight patients (54.7%) were diagnosed with PCV and 102 patients (35.3%) with typical AMD. RAP was observed in 13 patients (4.5%). In 16 patients (5.5%), one eye had PCV and the other eye had typical AMD. Most patients with PCV and typical AMD had unilateral disease (81.6% and 94.1%, respectively) with a male preponderance (77.8% and 71.6%, respectively). Nine of 13 patients with RAP were female (69.2%). Patients with RAP were older (mean, 80.3 years for men and 75.3 years for women) than patients with other subtypes. Serous and hemorrhagic pigment epithelial detachment developed in 69 patients (43.7%) with PCV, 22 patients (21.6%) with typical AMD, and nine patients (69.2%) with RAP. In the patients with unilateral disease in each subtype, large drusen in the unaffected eye were seen in 24.0% with PCV, 30.2% with typical AMD, and 77.8% with RAP. CONCLUSIONS: Neovascular AMD in Japanese patients has different demographic features compared with that in White patients. In Japanese patients, there is a preponderance of PCV, male gender, unilaterality, and absence of drusen in the second eye, with the exception of RAP.

Subtype lesions of neovascular age-related macular degeneration in Chinese patients.

PURPOSE: To identify the subtype frequency and clinical features of neovascular age-related macular degeneration (AMD) in Chinese patients. METHODS: From January 2003 to August 2006, we investigated prospectively 155 newly diagnosed patients with presumed neovascular AMD. Fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) were performed in both eyes of all patients. Subtype frequency and clinical features were recorded according to their angiograms. RESULTS: Three subtypes of lesion were noted, which were polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP) and mixed lesions. Of the 155 patients, 105 (67.7%) had choroidal neovascularization (CNV) of the typical type seen in AMD, 38 (24.5%) had PCV and seven (4.5%) had RAP. In five (3.2%) additional cases, mixed lesions were noted. In 38 cases (47 eyes) with PCV, the rates of subfoveal, juxtafoveal and extrafoveal lesion were respectively 29.8% (14 eyes), 8.5% (four eyes), and 61.7% (29 eyes), compared with 75.6%, 14.6% and 9.8% for CNV lesion (P < 0.01). The percentage of subfoveal lesion in PCV group was significantly lower than that in the CNV group (P < 0.01). The location of the RAP lesion was subfoveal in two (28.6%) eyes, juxtafoveal in three (42.9%) eyes and extrafoveal in two (28.6%) eyes. The five eyes with mixed lesions were all PCV coexisting with CNV at the same eye, and in all of the five cases, CNV was subfoveal while PCV was extrafoveal. CONCLUSIONS: In this hospital-based study, PCV accounts for 24.5% of neovascular AMD and is the most common subtype, RAP is less frequent (4.5%), and mixed lesions are much less common in Chinese patients. PCV is least likely to involve the fovea in neovascular AMD.