Laurie Dustin

Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol

BACKGROUND Data suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later. However, the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation (the hormone-timing hypothesis) has not been tested. METHODS A total of 643 healthy postmenopausal women were stratified according to time since menopause (<6 years [early postmenopause] or ≥10 years [late postmenopause]) and were randomly assigned to receive either oral 17β-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intima-media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen. RESULTS After a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P=0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P=0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P=0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum. CONCLUSIONS Oral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum. (Funded by the National Institute on Aging, National Institutes of Health; ELITE ClinicalTrials.gov number, NCT00114517.).

Signal strength is an important determinant of accuracy of nerve fiber layer thickness measurement by optical coherence tomography.

PurposeTo investigate the effect of signal strength on the measurement of the retinal nerve fiber layer (RNFL) using optical coherence tomography (OCT). MethodsEyes with known or suspected glaucoma or nonglaucomatous optic atrophy were scanned twice within the same visit using Stratus OCTs Fast Nerve Fiber Layer Thickness protocol. Only those eyes with 2 high-quality scans (signal strengths of at least 5 and different from each other, no error messages, and no obvious segmentation errors) were included in the study. The RNFL thickness measurements from the initial and the repeat scans were compared and then correlated with the differences in signal strength. Subgroup analyses were performed similarly among patients with average RNFL thickness less than 90 μm and those with at least 90 μm. ResultsScans with higher signal strengths are associated with greater RNFL thickness measurements if the signal strength is less than 7. Scans with signal strength of at least 7 have higher reproducibility. This is true among all patients and subgroups divided on the basis of average RNFL thickness. Additionally, we found that the greater the variability between the initial and repeat scans, the greater the variability in the RNFL thickness measurements. Scans with higher signal strengths have less variability, especially when the optic nerve is relatively healthy. ConclusionsWhen measuring the RNFL thickness with the Stratus OCT, it is important to aim for a signal strength of at least 7. Visual field testing may be more reliable in some patients, especially when the optic nerve is significantly compromised.

Combined cataract extraction and trabeculotomy by the internal approach for coexisting cataract and open-angle glaucoma: Initial results

PURPOSE: To provide an update of the short‐term results of combined phacoemulsification and trabeculotomy by the internal approach with a follow‐up to 21 months. SETTING: Universities and private practices in the United States. METHODS: This prospective interventional case series comprised 304 consecutive eyes with open‐angle glaucoma and cataract having combined phacoemulsification and trabeculotomy with a Trabectome (NeoMedix Inc.). The Trabectome is designed to open a direct pathway for aqueous to flow from the anterior chamber into Schlemm canal collector channels. Under gonioscopic control, bipolar cautery was applied by a purpose‐designed footplate to ablate the trabecular meshwork and inner wall of Schlemm canal. The main outcome measures were intraocular pressure (IOP), glaucoma medication use, and complications. RESULTS: The mean IOP was 20.0 mm Hg ± 6.3 (SD) preoperatively, 14.8 ± 3.5 mm Hg at 6 months, and 15.5 ± 2.9 mm Hg at 1 year. There was a corresponding drop in glaucoma medications from 2.65 ± 1.13 at baseline to 1.76 ± 1.25 at 6 months and 1.44 ± 1.29 at 1 year. Subsequent secondary glaucoma procedures were performed in 9 patients. The only frequent complication, blood reflux in 239 patients (78.4%), resolved within a few days. CONCLUSIONS: Combined phacoemulsification and trabeculotomy by the internal approach using the Trabectome lowered IOP and medication use in the majority of patients. Complications were minimal and comparable to those in an earlier series of Trabectome‐only procedures.

High-Dose B Vitamin Supplementation and Progression of Subclinical Atherosclerosis A Randomized Controlled Trial

Background and Purpose— Although plasma total homocysteine (tHcy) levels are associated with cardiovascular disease, it remains unclear whether homocysteine is a cause or a marker of atherosclerotic vascular disease. We determined whether reduction of tHcy levels with B vitamin supplementation reduces subclinical atherosclerosis progression. Methods— In this double-blind clinical trial, 506 participants 40 to 89 years of age with an initial tHcy >8.5 &mgr;mol/L without diabetes and cardiovascular disease were randomized to high-dose B vitamin supplementation (5 mg folic acid+0.4 mg vitamin B12+50 mg vitamin B6) or matching placebo for 3.1 years. Subclinical atherosclerosis progression across 3 vascular beds was assessed using high-resolution B-mode ultrasonography to measure carotid artery intima media thickness (primary outcome) and multidetector spiral CT to measure aortic and coronary artery calcium (secondary outcome). Results— Although the overall carotid artery intima media thickness progression rate was lower with B vitamin supplementation than with placebo, statistically significant between-group differences were not found (P=0.31). However, among subjects with baseline tHcy ≥9.1 &mgr;mol/L, those randomized to B vitamin supplementation had a statistically significant lower average rate of carotid artery intima media thickness progression compared with placebo (P=0.02); among subjects with a baseline tHcy <9.1 &mgr;mol/L, there was no significant treatment effect (probability value for treatment interaction=0.02). B vitamin supplementation had no effect on progression of aortic or coronary artery calcification overall or within subgroups. Conclusion— High-dose B vitamin supplementation significantly reduces progression of early-stage subclinical atherosclerosis (carotid artery intima media thickness) in well-nourished healthy B vitamin “replete” individuals at low risk for cardiovascular disease with a fasting tHcy ≥9.1 &mgr;mol/L.

Postoperative use of bevacizumab as an antifibrotic agent in glaucoma filtration surgery in the rabbit.

PURPOSE To evaluate the efficacy of bevacizumab as an antifibrotic agent after trabeculectomy in rabbits. METHODS Forty-two rabbits underwent trabeculectomy and were randomly assigned to receive a postoperative course of seven subconjunctival injections of bevacizumab (1.25 mg, 25 mg/mL), 5-fluorouracil (5-FU; 5 mg, 50 mg/mL), or balanced salt solution (BSS; 0.1 mL, control). Bleb survival and characteristics were evaluated over a 30-day period. The animals were killed on postoperative day (PD)10, PD20, and PD30. Histology and immunohistochemistry of the surgical eyes was performed to evaluate and grade the amount of scarring and fibrosis in each group. RESULTS Bevacizumab significantly improved the outcome of filtration surgery in this model. Bevacizumab prolonged bleb survival compared with the 5-FU and control groups (16.0 +/- 1.3 days vs. 6.9 +/- 0.6 and 7.4 +/- 0.85 days, respectively; P < 0.001). Bevacizumab-treated eyes had significantly larger and higher blebs than the control and 5-FU-treated groups (P < 0.05). Histologic analysis revealed that eyes treated with bevacizumab had significantly less postoperative scarring at the microscopic level at PD10 and PD20 (P = 0.009). CONCLUSIONS Postoperative subconjunctival injection of bevacizumab is associated with improved trabeculectomy bleb survival in the rabbit model. Bevacizumab may be a useful agent for improving success and limiting scar tissue formation after trabeculectomy.

Frequency of Distinguishing Clinical Features in Vogt-Koyanagi-Harada Disease

PURPOSE To determine the frequency of occurrence of limited clinical features which distinguish patients with Vogt-Koyanagi-Harada (VKH) disease from those with non-VKH uveitis. DESIGN Comparative case series. PARTICIPANTS We included 1147 patients. METHODS All patients with bilateral ocular inflammatory disease presenting to any of 10 uveitis centers in the 3-month period between January 1 and March 31, 2006 (inclusive), were asked to participate. The clinical and historical features of disease were obtained from the participants via direct interview and chart review. Patients were stratified based on whether they were diagnosed with VKH disease or non-VKH uveitis for statistical analysis. MAIN OUTCOME MEASURES Presence or absence of various clinical features in the 2 populations. RESULTS Of 1147 patients, 180 were diagnosed with VKH disease and 967 with non-VKH uveitis. Hispanics and Asians were more likely to be diagnosed with VKH than non-VKH disease compared with other ethnicities. In acute disease, the finding of exudative retinal detachment was most likely to be found in VKH disease with a positive predictive value (PPV) of 100 and negative predictive value (NPV) of 88.4, whereas in chronic disease, sunset glow fundus was most likely to be found, with a PPV of 94.5 and NPV of 89.2. CONCLUSIONS Numerous clinical findings have been described in the past as important in the diagnosis of VKH. The current study reveals that of these, 2 are highly specific to this entity in an ethnically and geographically diverse group of patients with nontraumatic bilateral uveitis. These clinical findings are exudative retinal detachment during acute disease and sunset glow fundus during the chronic phase of the disease.

Retinal Thickness Analysis by Race, Gender, and Age Using Stratus OCT

PURPOSE To detect differences in retinal thickness among patients of different race, gender, and age using Stratus OCT. DESIGN Cross-sectional study. METHODS In a multicenter, university-based study, 126 patients with no history of ocular disease were enrolled (78 diabetics without retinopathy and 48 nondiabetics). Optical coherence tomography measurements were performed using Stratus OCT. Statistical comparisons of center point foveal thickness and mean foveal thickness were made using generalized estimating equations adjusting for diabetic status, race, age, and gender. RESULTS The study population consisted of 36% male subjects, 39% Caucasian, 33% African-American, and 28% Hispanic. Mean foveal thickness was 191.6 +/- 2.7 microm and 194.5 +/- 2.7 microm for diabetics and nondiabetics, respectively (P = .49). Mean foveal thickness in male subjects was significantly larger than in female (201.8 +/- 2.7 microm and 186.9 +/- 2.6 microm, respectively; P < .001). Mean foveal thickness was 200.2 +/- 2.7 microm for Caucasian, 181.0 +/- 3.7 microm for African-American, and 194.7 +/- 3.9 microm for Hispanic subjects. Mean foveal thickness was significantly less for African-American than Caucasian (P < .0001) or Hispanic subjects (P = .005). Center point foveal thickness and mean foveal thickness showed a significant increase with age. CONCLUSIONS There are statistically significant differences in retinal thickness between subjects of different race, gender, and age. When compared to Caucasian and Hispanic subjects, African-American race is a predictor of decreased mean foveal thickness; and male sex (regardless of race) is a significant predictor of increased mean foveal thickness. Mean foveal thickness is similar among diabetics and nondiabetics when data are controlled for age, race, and sex. These results suggest that studies comparing OCT measurements should carefully control for age-based, race-based, and gender-based variations in retinal thickness.

Macular thickness measurements in normal eyes with time-domain and Fourier-domain optical coherence tomography.

Purpose: To compare macular thickness measurements using time-domain optical coherence tomography (OCT) and Fourier-domain OCT. Methods: Thirty-two eyes from 32 normal patients underwent complete ophthalmic evaluation. Macular scanning using the StratusOCT and the RTVue-100 OCT were performed for a total of three times each on the same visit. The average retinal thicknesses of the nine macular sectors as defined by the Early Treatment Diabetic Retinopathy Study, along with the foveal center point and macular volume, were recorded. The SD, the coefficient of variation, and the intraclass correlation coefficient were calculated for each parameter studied. Comparisons were made between the two OCTs in terms of retinal thicknesses measurements, their reproducibility, and macular regional differences. Correlations between retinal thickness and demographic variables (age and gender) were also investigated. Due to known differences in segmentation algorithms of the two OCTs, software calipers were used to measure the distance from the internal limiting membrane to the photoreceptor inner segment–outer segment junction at the foveal center point on all RTVue scans to allow a more fair comparison. Results: The RTVue yielded greater retinal thickness measurements in nearly all macular subfields compared with the StratusOCT. Even after accounting for differences in segmentation algorithms, significant disparities were still evident with the RTVue measurements less than those of the StratusOCT at the foveal center. On both machines, the macula was thinnest at the fovea and thickest within the 3 mm ring. There were some consistent regional variations in macular thickness evident on both OCTs. Compared with the StratusOCT, the RTVue generally had lower coefficients of variation and higher intraclass coefficients, suggesting better reproducibility. Age and gender also appeared to be important determinants in some macular thickness parameters. Conclusion: Compared with StratusOCT, the RTVue fourier-domain OCT yields greater retinal thickness measurements with greater reproducibility, presumably due to different segmentation algorithms, increased sampling density, and greater resolution. However, regional differences across the macula can be consistently observed with both devices.

Quantitative Subanalysis of Cystoid Spaces and Outer Nuclear Layer Using Optical Coherence Tomography in Age-Related Macular Degeneration

PURPOSE To use optical coherence tomography (OCT) to quantify intraretinal cystoid spaces (ICSs) and the outer nuclear layer (ONL) in patients with neovascular age-related macular degeneration (AMD) and to investigate the correlation of these parameters with visual acuity. METHODS StratusOCT (Carl Zeiss Meditec, Inc., Dublin, CA) images were collected from 53 patients receiving their initial treatment with intravitreous ranibizumab. Images were analyzed with custom software (OCTOR) that allows accurate manual segmentation of OCT B-scans and provides thickness/volume measurements of ICS, ONL, neurosensory retina, pigment epithelial detachments (PEDs), subretinal fluid (SRF), and subretinal tissue (SRT). Univariate and multivariate analyses were used to correlate OCT parameters with best corrected Snellen visual acuity. Reproducibility was assessed with weighted kappa statistics and intraclass correlation coefficients. RESULTS A multivariate linear regression model with adjusted R(2) showed that ONL volume and SRT thickness significantly correlated with Snellen visual acuity (R(2) = 0.15, P = 0.002 and R(2) = 0.19, P = 0.001, respectively) with an overall model R(2) of 0.34. Adjustment of ONL volume for ICS did not improve correlation with visual acuity, and ICS volume did not independently correlate with visual acuity. Weighted kappa statistics showed excellent intergrader agreement for both ICS and ONL measurements. CONCLUSIONS The results suggest that an increased total volume of the ONL is associated with decreased visual acuity in neovascular AMD and that the total volume of ICS does not correlate with visual acuity. Although the correlations detected in this study are modest, quantitative subanalysis of OCT images may be of greater clinical relevance in the context of more advanced OCT technology.

Cognitive effects of estradiol after menopause A randomized trial of the timing hypothesis

Objective: To test the hypothesis that effects of estrogen-containing hormone therapy on cognitive abilities differ between postmenopausal women near to, and further from, menopause. Methods: In this randomized, double-blind, placebo-controlled trial, healthy women within 6 years of menopause or 10+ years after menopause were randomly assigned to oral 17β-estradiol 1 mg/d or placebo. Women with a uterus received cyclic micronized progesterone vaginal gel or placebo. The primary outcome assessed at 2.5 and 5 years, compared between treatment groups, was change in a standardized composite of neuropsychological test scores assessing verbal episodic memory. Secondary outcomes assessed executive functions and global cognition. Results: A total of 567 women were included in modified intention-to-treat analyses after a mean treatment duration of 57 months. For verbal memory, the mean estradiol minus placebo standardized difference in composite scores (−0.06, 95% confidence interval −0.22 to 0.09) was not significant (2-tailed p = 0.33). Differences were similar in early and late postmenopause groups (2-tailed interaction p = 0.88). Interactions between postmenopause groups and differences between treatment groups were not significant for executive functions or global cognition. Conclusions: Estradiol initiated within 6 years of menopause does not affect verbal memory, executive functions, or global cognition differently than therapy begun 10+ years after menopause. Estradiol neither benefits nor harms these cognitive abilities regardless of time since menopause. Classification of evidence: This study provides Class I evidence that estradiol initiated within 6 years of menopause does not affect cognition at 2.5 years differently than estradiol initiated 10+ years after menopause.