Alan J. Ruby

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.

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.

Lutein/zeaxanthin for the treatment of age-related cataract: AREDS2 randomized trial report no. 4.

IMPORTANCE Age-related cataract is a leading cause of visual impairment in the United States. The prevalence of age-related cataract is increasing, with an estimated 30.1 million Americans likely to be affected by 2020. OBJECTIVE To determine whether daily oral supplementation with lutein/zeaxanthin affects the risk for cataract surgery. DESIGN, SETTING, AND PATIENTS The Age-Related Eye Disease Study 2 (AREDS2), a multicenter, double-masked clinical trial, enrolled 4203 participants, aged 50 to 85 years, at risk for progression to advanced age-related macular degeneration. INTERVENTIONS Participants were randomly assigned to daily placebo; lutein/zeaxanthin, 10mg/2mg; omega-3 long-chain polyunsaturated fatty acids, 1 g; or a combination to evaluate the effects on the primary outcome of progression to advanced age-related macular degeneration. MAIN OUTCOMES AND MEASURES Cataract surgery was documented at annual study examination with the presence of pseudophakia or aphakia, or reported during telephone calls at 6-month intervals between study visits. Annual best-corrected visual acuity testing was performed. A secondary outcome of AREDS2 was to evaluate the effects of lutein/zeaxanthin on the subsequent need for cataract surgery. RESULTS A total of 3159 AREDS2 participants were phakic in at least 1 eye and 1389 of 6027 study eyes underwent cataract surgery during the study, with median follow-up of 4.7 years. The 5-year probability of progression to cataract surgery in the no lutein/zeaxanthin group was 24%. For lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratios for progression to cataract surgery was 0.96 (95% CI, 0.84-1.10; P = .54). For participants in the lowest quintile of dietary intake of lutein/zeaxanthin, the hazard ratio comparing lutein/zeaxanthin vs no lutein/zeaxanthin for progression to cataract surgery was 0.68 (95% CI, 0.48-0.96; P = .03). The hazard ratio for 3 or more lines of vision loss was 1.03 (95% CI, 0.93-1.13; P = .61 for lutein/zeaxanthin vs no lutein/zeaxanthin). CONCLUSIONS AND RELEVANCE Daily supplementation with lutein/zeaxanthin had no statistically significant overall effect on rates of cataract surgery or vision loss. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00345176.

Photodynamic therapy using verteporfin for choroidal neovascularization in angioid streaks.

PURPOSE To evaluate the efficacy of photodynamic therapy with verteporfin in the management of choroidal neovascularization (CNV) associated with angioid streaks. DESIGN Retrospective case series. METHODS Eleven eyes of nine patients with subfoveal or juxtafoveal CNV due to angioid streaks underwent visual acuity testing, ophthalmic examination, color photography, and fluorescein angiography to evaluate the results of photodynamic therapy with verteporfin. Retreatment of persistent CNV was based on criteria from the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Investigation (TAP) except in one case. Follow-up ranged from 5 to 28 months (mean, 17 months). RESULTS Nine of 11 eyes had subfoveal lesions while two eyes had juxtafoveal lesions on initial examination. Conversion from a choroidal neovascular membrane (CNVM) to a fibrous disciform lesion following photodynamic therapy was observed in nine eyes. Enlargement of the CNVM was noted in seven of these eyes by fluorescein angiography at final follow-up. Initial best-corrected visual acuity (BCVA) ranged from 20/25 to counting fingers (CF) (mean, 20/400; median, 20/200). Final BCVA ranged from 20/20 to CF (mean, 20/600; median, 20/400). Seven eyes with subfoveal CNVM had an initial BCVA of at least 20/200 while only three eyes maintained this level or better at last follow-up. In one patient with a juxtafoveal CNVM in one eye, vision decreased from 20/25 to 20/400 with enlargement and fibrosis of the CNVM and subfoveal extension. In the fellow eye a juxtafoveal CNVM was initially treated and then retreated earlier than TAP criteria at 6 weeks. Vision improved to 20/20 and has remained stable 5 months after the initial treatment. CONCLUSIONS Verteporfin for choroidal neovascularization-associated with angioid streaks does not appear to significantly alter the course of this disease with most eyes undergoing enlargement and disciform transformation of the neovascular process. However, aggressive management of these patients with biomicroscopic and fluorescein angiographic examination and timely photodynamic therapy with early retreatment when indicated may be beneficial in certain cases.

A comparison of visual results and complications in eyes with posterior chamber intraocular lens dislocation treated with pars plana vitrectomy and lens repositioning or lens exchange

PURPOSE To compare the visual results and the postoperative complications in eyes with posterior chamber intraocular lens (PCIOL) dislocation that underwent pars plana vitrectomy with lens repositioning with eyes that underwent pars plana vitrectomy with lens exchange. DESIGN Nonrandomized consecutive comparative case series. PARTICIPANTS Fifty-nine eyes (27 right eyes and 32 left eyes) of 56 subjects (28 women and 28 men) ranging in age from 59 to 90 years. Mean follow-up was 34 months. METHODS A comparison of the best-corrected preoperative visual acuities, final visual acuities, and postoperative complications in subjects with dislocated PCIOLs that underwent pars plana vitrectomy. Logarithm of the minimum angle of resolution (LogMAR)-converted visual acuities were used for comparison. Categorical data were analyzed by Fishers exact test, and population means were compared by a pooled Students t test. MAIN OUTCOME MEASURES Final mean visual acuities, change in mean visual acuities, and postoperative complications. RESULTS For all 59 eyes the mean preoperative visual acuity was 20/152, and the mean final visual acuity was 20/48. Final visual results were similar between the eyes that underwent lens repositioning (20/55) and the eyes that underwent lens exchange (20/43; P = 0.19). Final visual results were also similar between the eyes that underwent lens exchange with sutured PCIOL placement (20/51) and the eyes that underwent lens exchange with anterior chamber intraocular lens (ACIOL) placement (20/38; P = 0.26). Final mean visual acuity in eyes that received an ACIOL (20/38) was better than in eyes that underwent repositioning of the dislocated lens into the ciliary sulcus (20/65; P = 0.01). The mean increase in visual acuities was greater for eyes with ACIOL placement compared with eyes with sutured PCIOL placement (P = 0.01). For all eyes, final visual results were unaffected by a concurrent diagnosis of age-related macular degeneration (20/52; P: = 0.71), glaucoma (20/48; P = 0.95), or postoperative cystoid macular edema (20/55; P = 0.45). Final visual acuities were significantly worse in eyes with a detectable preoperative afferent pupillary defect (20/200; P<0.0001). Postoperative retinal detachments developed in 4 of 29 eyes (14%) that underwent lens repositioning and in 2 of 30 eyes (7%) that had lens exchange (P = 0.42). Postoperative lens subluxations occurred in 6 of 29 eyes (21%) that underwent lens repositioning and in 1 of 30 eyes (3%) that underwent lens exchange (P = 0.05). CONCLUSIONS The final visual results in eyes with dislocated PCIOLs that underwent pars plana vitrectomy with lens repositioning were similar to the visual results obtained in eyes that underwent pars plana vitrectomy with lens exchange. For eyes that underwent lens exchange, final visual results in eyes that received an ACIOL were similar to the visual results obtained in eyes that received a PCIOL; however, eyes with an ACIOL showed a greater increase in mean visual acuity. Eyes with a preoperative afferent pupillary defect had worse final visual results.

Incidence of retinal detachment and visual outcome in eyes presenting with posterior vitreous separation and dense fundus-obscuring vitreous hemorrhage

PURPOSE To determine visual outcomes and the incidence of retinal detachment in eyes presenting with posterior vitreous separation and dense fundus-obscuring vitreous hemorrhage. DESIGN Retrospective consecutive noncomparative interventional case series. PARTICIPANTS Thirty-six eyes (15 right eyes and 21 left eyes) of 34 patients (18 female and 16 male) ranging in age from 42 to 94 years. Mean follow-up was 14 months. METHODS A comparison of the best-corrected initial visual acuities versus final visual acuities after spontaneous resolution of vitreous hemorrhage or surgical intervention. The number of eyes that were found to have retinal tears or that had a rhegmatogenous retinal detachment develop was documented. Logarithm of the minimum angle of resolution-converted visual acuities was used for comparison. Categorical data were analyzed by Fishers exact test, and population means were compared by Students t test. MAIN OUTCOME MEASURES Final mean visual acuities, number of eyes with at least one retinal tear, location of retinal tears, number of eyes that had retinal detachment develop, and the number of eyes repaired with scleral buckling surgery and/or pars plana vitrectomy. RESULTS Twenty-four of 36 eyes (67%) were found to have at least one retinal break (range, 0-4 breaks), with 88% of breaks located in the superior retina. Eleven eyes (31%) had more than one retinal break. Fourteen of 36 eyes (39%) had a rhegmatogenous retinal detachment develop that was repaired with pars plana vitrectomy and scleral buckling. An additional 14 eyes (39%) underwent vitrectomy for nonclearing vitreous hemorrhage. The incidence of retinal detachment in eyes with a history of retinal detachment in the contralateral eye was 75% (P = 0.04). Seven of 14 eyes (50%) with retinal detachment had coexisting proliferative vitreoretinopathy. Most retinal breaks and detachments occurred in emmetropic or myopic eyes. For all 36 eyes the mean preoperative visual acuity was 20/1233, and the mean final visual acuity was 20/62 (P < 0.0001). Eyes that had a macula-off retinal detachment develop had worse final visual outcomes (20/264; P = 0.01), as did eyes that had proliferative vitreoretinopathy develop (20/129; P = 0.04). CONCLUSIONS Acute, spontaneous, nontraumatic posterior vitreous separation with dense fundus-obscuring vitreous hemorrhage is associated with a high incidence of retinal tears and detachment. Close follow-up with clinical examination and ultrasonography is necessary, because many of these eyes may eventually require surgical intervention. Aggressive management with early vitrectomy should be considered when there is a history of retinal detachment in the contralateral eye.

Repair of primary rhegmatogenous retinal detachment using 25-gauge transconjunctival sutureless vitrectomy.

Purpose: To evaluate the anatomical and visual outcomes of primary rhegmatogenous retinal detachment repairs performed using 25-gauge transconjunctival sutureless vitrectomy. Methods: A retrospective, noncomparative interventional case series including 53 consecutive eyes of 52 patients who underwent 25-gauge transconjunctival sutureless vitrectomy to repair primary rhegmatogenous retinal detachment was performed. Variables collected for the study were patient demographics, lens status, preoperative visual acuity, and macular status. Outcome measures included single-operation anatomical success rate, final anatomical success rate, postoperative visual acuity, and surgical complications. Results: The retina was reattached with a single operation in 39 (74%) of 53 eyes. The final anatomical success rate was 100%. The mean time to redetachment was 72 days (range, 13–334 days). Proliferative vitreoretinopathy (64%) and development of new retinal breaks (43%) were the most common reasons associated with redetachment. Mean visual acuity improved from 20/100 to 20/60 (P = 0.001); 55% of eyes had final vision of 20/40 or better. Three eyes (6%) developed postoperative choroidal hemorrhage. Three eyes (6%) developed visually significant macular pucker that required surgery. No postoperative hypotony or endophthalmitis was observed. Conclusions: Repair of primary rhegmatogenous retinal detachments using 25-gauge transconjunctival sutureless vitrectomy resulted in excellent final anatomical success rate and postoperative visual outcomes. However, redetachments due to new tears and/or proliferative vitreoretinopathy resulted in a lower single-operation success rate than those reported with 20-gauge systems.

Successful closure of traumatic macular holes.

PURPOSE To establish the efficacy of vitreoretinal surgery without the use of transforming growth factor-beta or autologous platelet concentrate in the repair of traumatic macular holes. METHODS This retrospective review consisted of 16 eyes from 16 consecutive patients treated by five vitreoretinal surgeons at a single institution between 1993 and 1997. Intervention included pars plana vitrectomy with creation of posterior vitreous detachment, placement of 14% to 16% C3F8 gas, and postoperative face-down positioning. Ten eyes received intraoperative autologous plasmin to facilitate formation of posterior vitreous detachment. Main outcome measures were anatomic closure rate and visual outcome. RESULTS Anatomic closure of the macular holes was achieved in 15 (94%) of 16 eyes, with an average follow-up of 7 months. Six (38%) eyes achieved visual acuity of 20/40 or better. Visual acuity improved by 2 or more lines in 11 (69%) of 16 eyes. The average preoperative logMAR-converted visual acuity of 20/175 improved to 20/60 postoperatively. CONCLUSION Traumatic macular holes can be closed successfully with substantial visual recovery without the use of transforming growth factor-beta or platelet concentrate.

Posterior Vitreous Detachment With Microplasmin Alters the Retinal Penetration of Intravitreal Bevacizumab (Avastin) in Rabbit Eyes

Purpose: Intravitreal bevacizumab (BV) (Avastin, Genentech Inc., South San Francisco, CA) is frequently used for the treatment of age-related macular degeneration. Previous studies have demonstrated full-thickness retinal penetration. Intravitreal recombinant microplasmin (MP) has been shown to successfully induce a posterior vitreous detachment (PVD) and vitreous liquefaction in animals. It has been suggested that a PVD may alter the retinal penetration of molecules in the vitreous cavity. The aim of this study was to compare BV retinal penetration in rabbit eyes with and without an MP-induced PVD. Methods: Twelve adult rabbits were injected with 0.1 mL (0.4 mg) of MP into the vitreous cavity of 1 eye. One week later, the rabbits were injected with 0.05 mL (1.25 mg) of BV into both eyes. Both eyes of 3 rabbits were harvested at 6 hours, 12 hours, 24 hours, and 72 hours after the BV injection. Frozen retinal cross sections were prepared, and BV retinal penetration was evaluated with immunohistochemistry using a fluorescence-labeled antibody against BV. Two eyes from one rabbit were not injected with either agent and used as controls to compare the background autofluorescence. Peripapillary retinal sections were recorded with a digital camera, and intraretinal BV fluorescence-labeled antibody was measured by qualitative photographic interpretation. Two additional rabbits received an intravitreal injection of 0.1 mL of MP in 1 eye. One week later, both eyes from each rabbit were enucleated, and frozen retinal sections were prepared and analyzed with light microscopy to evaluate histologic damage. Results: Full-thickness BV retinal penetration was observed throughout the retina in both eyes of each rabbit. All the MP-injected eyes exhibited increased antibody labeling in retinas evaluated at 6 hours, 12 hours, and 24 hours after BV injection when compared with the contralateral non-MP-injected eyes. By 3 days after BV injection, all eyes demonstrated decreased antibody labeling compared with earlier periods. At 3 days, 1 rabbit showed increased antibody labeling in the retina of the non-MP-injected eye compared with the contralateral MP-injected eye, and 2 rabbits exhibited similar antibody labeling in both eyes. When compared with control eyes, light microscopy demonstrated normal retinal histologic findings in eyes injected only with MP. Conclusion: Increased BV retinal penetration is observed initially in eyes with an MP-induced PVD, and the mechanism is likely multifactorial. By 3 days, retinal penetration is similar in eyes with and without a PVD. Although it is difficult to directly extrapolate to humans, our study suggests that a PVD may alter the retinal penetration of BV.

Intraoperative acetazolamide in the prevention of intraocular pressure rise after pars plana vitrectomy with fluid-gas exchange.

PURPOSE To assess the effect of intraoperative acetazolamide (Diamox) on postoperative intraocular pressure (IOP) in gas-filled, vitrectomized eyes. METHODS We conducted a prospective randomized clinical trial of 63 consecutive patients undergoing pars plana vitrectomy with total fluid-gas exchange and long-acting intraocular gas tamponade. Patients were randomized by a blind draw to receive either intravenous 500 mg acetazolamide (Diamox) (Group 1) or no treatment (Group 2) at the conclusion of the operative procedure. Intraocular pressures at the conclusion of surgery (IOP-1), 4-8 hours following surgery (IOP-2), and on the first postoperative day (IOP-3) were measured using an Oculab Tono-Pen. RESULTS Patients in Groups 1 and 2 showed similar mean IOP on postoperative day 1 (20.48+/-7.84 mmHg versus 19.89+/-7.89 mmHg). A similar incidence of IOP-2 greater than 30 mmHg (1 versus 3 patients with high IOP) and IOP-3 greater than 30 mmHg (4 versus 3 patients with high IOP) was seen. Patients in Group 1 had a lower mean IOP at 4-8 hours postoperatively (16.25+/-6.47 mmHg) than those in Group 2 (20.13+/-6.33 mmHg). No correlation could be demonstrated between IOP-1 and subsequent IOP. However, IOP on the first postoperative day (IOP-3) was strongly correlated with IOP 4-8 hours after surgery (IOP-2) (P = 0.0001). No protective effect of Diamox could be demonstrated on either IOP-2 or IOP-3. CONCLUSIONS No protective effect against pressure rise could be demonstrated for intraoperative acetazolamide (Diamox) in the prophylaxis of IOP rise following pars plana vitrectomy and total fluid-gas exchange with long-acting intraocular gas.