Cynthia A. Toth

Ranibizumab and Bevacizumab for Treatment of Neovascular Age-related Macular Degeneration: Two-Year Results

OBJECTIVE To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment. DESIGN Multicenter, randomized clinical trial. PARTICIPANTS Patients (n = 1107) who were followed up during year 2 among 1185 patients with neovascular age-related macular degeneration who were enrolled in the clinical trial. INTERVENTIONS At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment. MAIN OUTCOME MEASURES Mean change in visual acuity. RESULTS Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval [CI], -3.7 to 0.8; P = 0.21). Mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; P = 0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = 0.0003; regimen, P < 0.0001). Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (-2.2 letters; P = 0.03) and a lower proportion without fluid (-19%; P < 0.0001). Rates of death and arteriothrombotic events were similar for both drugs (P > 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = 0.009). Most of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF). CONCLUSIONS Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF.

Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: The Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial

IMPORTANCE Oral supplementation with the Age-Related Eye Disease Study (AREDS) formulation (antioxidant vitamins C and E, beta carotene, and zinc) has been shown to reduce the risk of progression to advanced age-related macular degeneration (AMD). Observational data suggest that increased dietary intake of lutein + zeaxanthin (carotenoids), omega-3 long-chain polyunsaturated fatty acids (docosahexaenoic acid [DHA] + eicosapentaenoic acid [EPA]), or both might further reduce this risk. OBJECTIVES To determine whether adding lutein + zeaxanthin, DHA + EPA, or both to the AREDS formulation decreases the risk of developing advanced AMD and to evaluate the effect of eliminating beta carotene, lowering zinc doses, or both in the AREDS formulation. DESIGN, SETTING, AND PARTICIPANTS The Age-Related Eye Disease Study 2 (AREDS2), a multicenter, randomized, double-masked, placebo-controlled phase 3 study with a 2 × 2 factorial design, conducted in 2006-2012 and enrolling 4203 participants aged 50 to 85 years at risk for progression to advanced AMD with bilateral large drusen or large drusen in 1 eye and advanced AMD in the fellow eye. INTERVENTIONS Participants were randomized to receive lutein (10 mg) + zeaxanthin (2 mg), DHA (350 mg) + EPA (650 mg), lutein + zeaxanthin and DHA + EPA, or placebo. All participants were also asked to take the original AREDS formulation or accept a secondary randomization to 4 variations of the AREDS formulation, including elimination of beta carotene, lowering of zinc dose, or both. MAIN OUTCOMES AND MEASURES Development of advanced AMD. The unit of analyses used was by eye. RESULTS Median follow-up was 5 years, with 1940 study eyes (1608 participants) progressing to advanced AMD. Kaplan-Meier probabilities of progression to advanced AMD by 5 years were 31% (493 eyes [406 participants]) for placebo, 29% (468 eyes [399 participants]) for lutein + zeaxanthin, 31% (507 eyes [416 participants]) for DHA + EPA, and 30% (472 eyes [387 participants]) for lutein + zeaxanthin and DHA + EPA. Comparison with placebo in the primary analyses demonstrated no statistically significant reduction in progression to advanced AMD (hazard ratio [HR], 0.90 [98.7% CI, 0.76-1.07]; P = .12 for lutein + zeaxanthin; 0.97 [98.7% CI, 0.82-1.16]; P = .70 for DHA + EPA; 0.89 [98.7% CI, 0.75-1.06]; P = .10 for lutein + zeaxanthin and DHA + EPA). There was no apparent effect of beta carotene elimination or lower-dose zinc on progression to advanced AMD. More lung cancers were noted in the beta carotene vs no beta carotene group (23 [2.0%] vs 11 [0.9%], nominal P = .04), mostly in former smokers. CONCLUSIONS AND RELEVANCE Addition of lutein + zeaxanthin, DHA + EPA, or both to the AREDS formulation in primary analyses did not further reduce risk of progression to advanced AMD. However, because of potential increased incidence of lung cancer in former smokers, lutein + zeaxanthin could be an appropriate carotenoid substitute in the AREDS formulation. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00345176.

Automatic segmentation of seven retinal layers in SDOCT images congruent with expert manual segmentation

Segmentation of anatomical and pathological structures in ophthalmic images is crucial for the diagnosis and study of ocular diseases. However, manual segmentation is often a time-consuming and subjective process. This paper presents an automatic approach for segmenting retinal layers in Spectral Domain Optical Coherence Tomography images using graph theory and dynamic programming. Results show that this method accurately segments eight retinal layer boundaries in normal adult eyes more closely to an expert grader as compared to a second expert grader.

Photoreceptor Layer Thinning over Drusen in Eyes with Age-Related Macular Degeneration Imaged In Vivo with Spectral-Domain Optical Coherence Tomography

PURPOSE Detect changes in the neurosensory retina using spectral-domain optical coherence tomography (SD OCT) imaging over drusen in age-related macular degeneration (AMD). Quantitative imaging biomarkers may aid in defining risk of disease progression. DESIGN Cross-sectional, case-control study evaluating SD OCT testing in AMD. PARTICIPANTS AND CONTROLS Seventeen eyes of 12 subjects with nonneovascular AMD and drusen and 17 eyes of 10 age-matched control subjects. METHODS Spectral-domain OCT imaging across the fovea in the study eye with multiple 10- to 12-mm scans of 1000 A scans each. MAIN OUTCOME MEASURES In summed SD OCT scans, the height of individual retinal layers either over drusen or at corresponding locations in the control eye and qualitative changes in retinal layers over drusen. Secondary measures included photoreceptor layer (PRL) area, inner retinal area, and retinal pigment epithelium (RPE)/drusen area. RESULTS The PRL was thinned over 97% of drusen, average PRL thickness was reduced by 27.5% over drusen compared with over a similar location in controls, and the finding of a difference was valid and significant (P=0.004). Photoreceptor outer segments were absent over at least 1 druse in 47% of eyes. Despite thinning of the PRL, inner retinal thickness remained unchanged. We observed 2 types of hyperreflective abnormalities in the neurosensory retina over drusen. Distinct hyperreflective speckled patterns occurred over drusen in 41% of AMD eyes and never in control eyes. A prominent hyperreflective haze was present in the photoreceptor nuclear layer over drusen in 67% of AMD eyes and more subtly in the photoreceptor nuclear layer in 18% of control eyes (no drusen). CONCLUSIONS With SD OCT as used in this study, we can easily detect and measure changes in PRL over drusen. Decreased PRL thickness over drusen suggests a degenerative process, with cell loss leading to decreased visual function. The hyperreflective foci overlying drusen are likely to represent progression of disease RPE cell migration into the retina and possible photoreceptor degeneration or glial scar formation. A longitudinal study using SD OCT to examine and measure the neurosensory retina over drusen will resolve the timeline of degenerative changes relative to druse formation.

Diagnosis of vitreoretinal adhesions in macular disease with optical coherence tomography.

Purpose: To compare the relative incidence of vitreoretinal adhesions associated with partial vitreous separation within the macula diagnosed with optical coherence tomography (OCT) with that of those diagnosed with biomicroscopy. Methods: The authors obtained linear cross‐sectional retinal images using OCT in patients with selected macular diseases. Additional studies included biomicroscopy, fundus photography, fluorescein angiography, and B‐scan ultrasonography. Results: Optical coherence tomography was performed on 132 eyes of 119 patients. Vitreoretinal adhesions within the macula were identified using OCT in 39 eyes (30%) with the following diagnoses: idiopathic epiretinal membrane (n = 13), diabetic retinopathy (n = 7), idiopathic macular hole (n = 7), cystoid macular edema (n = 7), and vitreomacular traction syndrome (n = 5). Biomicroscopy identified vitreoretinal adhesions in only 11 eyes (8%). Two distinct vitreoretinal adhesion patterns were identified with OCT, each associated with partial separation of the posterior hyaloid face: focal (n = 25) and multifocal (n = 14). Conclusions: Optical coherence tomography is more sensitive than biomicroscopy in identifying vitreoretinal adhesions associated with macular disease.

Pars plana vitrectomy, subretinal injection of tissue plasminogen activator, and fluid–gas exchange for displacement of thick submacular hemorrhage in age-related macular degeneration☆

PURPOSE To evaluate a new procedure for displacement of large, thick submacular hemorrhage in patients with age-related macular degeneration. METHODS Retrospective review of 11 eyes of 11 patients with age-related macular degeneration and thick submacular hemorrhage (defined as causing retinal elevation detectable on stereo fundus photographs) treated with vitrectomy, subretinal injection of tissue plasminogen activator (25 or 50 microg), and fluid-gas exchange with postoperative prone positioning. Outcome measures included displacement of hemorrhage from the fovea, best postoperative visual acuity, and final postoperative visual acuity. RESULTS In the 11 affected eyes of 11 patients (seven men and four women; mean age, 76 years), preoperative visual acuity ranged from 20/200 to hand motions. With surgery, subretinal hemorrhage was displaced from the fovea in all 11 cases. Mean postoperative follow-up was 6.5 months (range, 1 to 15 months). Best postoperative visual acuity varied from 20/30 to 5/200, with improvement in nine (82%) cases and no change in two cases. Eight eyes (73%) measured 20/200 or better, with four of these eyes (36%) 20/80 or better. Final postoperative visual acuity ranged from 20/70 to light perception, with improvement in eight (73%) cases, no change in one case, and worsening in two cases. A statistically significant difference was found between preoperative and best postoperative visual acuity (P =.004) but not between preoperative and final visual acuity (P =.16). Hemorrhage recurred in three (27%) eyes, causing severe visual loss in one eye. CONCLUSIONS This technique displaces submacular hemorrhage from the fovea and can improve vision in patients with age-related macular degeneration. However, recurrence of hemorrhage occurred in 27% of eyes and caused severe visual loss in one eye. A randomized, prospective clinical trial is necessary to determine the efficacy of this technique in comparison with other proposed treatments.

Secondary Analyses of the Effects of Lutein/Zeaxanthin on Age-Related Macular Degeneration Progression: AREDS2 Report No. 3

IMPORTANCE The Age-Related Eye Disease Study (AREDS) formulation for the treatment of age-related macular degeneration (AMD) contains vitamin C, vitamin E, beta carotene, and zinc with copper. The Age-Related Eye Disease Study 2 (AREDS2) assessed the value of substituting lutein/zeaxanthin in the AREDS formulation because of the demonstrated risk for lung cancer from beta carotene in smokers and former smokers and because lutein and zeaxanthin are important components in the retina. OBJECTIVE To further examine the effect of lutein/zeaxanthin supplementation on progression to late AMD. DESIGN, SETTING, PARTICIPANTS The Age-Related Eye Disease Study 2 is a multicenter, double-masked randomized trial of 4203 participants, aged 50 to 85 years, at risk for developing late AMD; 66% of patients had bilateral large drusen and 34% had large drusen and late AMD in 1 eye. INTERVENTIONS In addition to taking the original or a variation of the AREDS supplement, participants were randomly assigned in a factorial design to 1 of the following 4 groups: placebo; lutein/zeaxanthin, 10 mg/2 mg; omega-3 long-chain polyunsaturated fatty 3 acids, 1.0 g; or the combination. MAIN OUTCOMES AND MEASURE S Documented development of late AMD by central, masked grading of annual retinal photographs or by treatment history. RESULTS In exploratory analysis of lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratio of the development of late AMD was 0.90 (95% CI, 0.82-0.99; P = .04). Exploratory analyses of direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.82 (95% CI, 0.69-0.96; P = .02) for development of late AMD, 0.78 (95% CI, 0.64-0.94; P = .01) for development of neovascular AMD, and 0.94 (95% CI, 0.70-1.26; P = .67) for development of central geographic atrophy. In analyses restricted to eyes with bilateral large drusen at baseline, the direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.76 (95% CI, 0.61-0.96; P = .02) for progression to late AMD, 0.65 (95% CI, 0.49-0.85; P = .002) for neovascular AMD, and 0.98 (95% CI, 0.69-1.39; P = .91) for central geographic atrophy. CONCLUSION AND RELEVANCE The totality of evidence on beneficial and adverse effects from AREDS2 and other studies suggests that lutein/zeaxanthin could be more appropriate than beta carotene in the AREDS-type supplements. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00345176.

Baseline Predictors for One-Year Visual Outcomes with Ranibizumab or Bevacizumab for Neovascular Age-related Macular Degeneration

OBJECTIVE To determine the baseline predictors of visual acuity (VA) outcomes 1 year after treatment with ranibizumab or bevacizumab for neovascular age-related macular degeneration (AMD). DESIGN Cohort study within the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). PARTICIPANTS A total of 1105 participants with neovascular AMD, baseline VA 20/25 to 20/320, and VA measured at 1 year. METHODS Participants were randomly assigned to ranibizumab or bevacizumab on a monthly or as-needed schedule. Masked readers evaluated fundus morphology and features on optical coherence tomography (OCT). Visual acuity was measured using electronic VA testing. Independent predictors were identified using regression techniques. MAIN OUTCOME MEASURES The VA score, VA score change from baseline, and ≥3-line gain at 1 year. RESULTS At 1 year, the mean VA score was 68 letters, mean improvement from baseline was 7 letters, and 28% of participants gained ≥3 lines. Older age, larger area of choroidal neovascularization (CNV), and elevation of retinal pigment epithelium (RPE) were associated with worse VA (all P<0.005), less gain in VA (all P<0.02), and a lower proportion gaining ≥3 lines (all P<0.04). Better baseline VA was associated with better VA at 1 year, less gain in VA, and a lower proportion gaining ≥3 lines (all P<0.0001). Predominantly or minimally classic lesions were associated with worse VA than occult lesions (66 vs. 69 letters; P=0.0003). Retinal angiomatous proliferans (RAP) lesions were associated with more gain in VA (10 vs. 7 letters; P=0.03) and a higher proportion gaining ≥3 lines (odds ratio, 1.9; 95% confidence interval, 1.2-3.1). Geographic atrophy (GA) was associated with worse VA (64 vs. 68 letters; P=0.02). Eyes with total foveal thickness in the second quartile (325-425 μm) had the best VA (P=0.01) and were most likely to gain ≥3 lines (P=0.004). Predictors did not vary by treatment group. CONCLUSIONS For all treatment groups, older age, better baseline VA, larger CNV area, predominantly or minimally classic lesion, absence of RAP lesion, presence of GA, greater total fovea thickness, and RPE elevation on optical coherence tomography were independently associated with less improvement in VA at 1 year. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Imaging the Infant Retina with a Hand-held Spectral-Domain Optical Coherence Tomography Device

PURPOSE To evaluate and treat infant retina through the use of a hand-held spectral-domain optical coherence tomography (SD OCT) device in selected cases of Shaken Baby syndrome (SBS). DESIGN Observational case series. METHODS A novel SD OCT system was optimized and evaluated for infant imaging. An adult eye was imaged with both a standard clinical SD OCT system and the hand-held system. Four eyes of two infants with a history of SBS were imaged with the hand-held system. One infant was imaged again during follow-up examinations. Robust image processing algorithms were developed to create high-quality images. Images were assessed for usefulness in demonstrating pertinent morphologic features. RESULTS The novel SD OCT unit proved effective for data acquisition and comparable with conventional chin-rest SD OCT. Rapid data acquisition limited motion artifact within the B-scan, although there was slight motion between B scans. The SD OCT images provided previously unseen details with regard to the morphologic features of retinal lesions in these infant eyes. This information influenced prognosis and management. CONCLUSIONS As with adults, the hand-held customized SD OCT proved to be an invaluable tool in the differentiation of disease processes or injury in these eyes under study. SD OCT imaging systems may be considered a useful adjunct to RetCam fundus photography for assessment and clinical management in cases of SBS.

Validated Automatic Segmentation of AMD Pathology Including Drusen and Geographic Atrophy in SD-OCT Images

PURPOSE To automatically segment retinal spectral domain optical coherence tomography (SD-OCT) images of eyes with age-related macular degeneration (AMD) and various levels of image quality to advance the study of retinal pigment epithelium (RPE)+drusen complex (RPEDC) volume changes indicative of AMD progression. METHODS A general segmentation framework based on graph theory and dynamic programming was used to segment three retinal boundaries in SD-OCT images of eyes with drusen and geographic atrophy (GA). A validation study for eyes with nonneovascular AMD was conducted, forming subgroups based on scan quality and presence of GA. To test for accuracy, the layer thickness results from two certified graders were compared against automatic segmentation results for 220 B-scans across 20 patients. For reproducibility, automatic layer volumes were compared that were generated from 0° versus 90° scans in five volumes with drusen. RESULTS The mean differences in the measured thicknesses of the total retina and RPEDC layers were 4.2 ± 2.8 and 3.2 ± 2.6 μm for automatic versus manual segmentation. When the 0° and 90° datasets were compared, the mean differences in the calculated total retina and RPEDC volumes were 0.28% ± 0.28% and 1.60% ± 1.57%, respectively. The average segmentation time per image was 1.7 seconds automatically versus 3.5 minutes manually. CONCLUSIONS The automatic algorithm accurately and reproducibly segmented three retinal boundaries in images containing drusen and GA. This automatic approach can reduce time and labor costs and yield objective measurements that potentially reveal quantitative RPE changes in longitudinal clinical AMD studies. (ClinicalTrials.gov number, NCT00734487.).