Thomas R. Friberg

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.

Intraocular and Episcleral Venous Pressure Increase During Inverted Posture

We measured intraocular and episcleral venous pressure in 11 subjects in both the supine and the head-down vertical position. Gonioscopy was performed in eight subjects. The intraocular pressure changes were correlated with the alterations in episcleral venous pressure using linear regression analysis. We found that for each 0.83 +/- 0.21 mm Hg increase in episcleral venous pressure there was a rise of 1 mm Hg in intraocular pressure (r = .80, P = .003). Upon inversion, blood appeared in Schlemms canal in half of the eyes studied with gonioscopy, suggesting that it refluxed into the canal from increased episcleral venous pressure. The mechanism of a sustained intraocular pressure rise during gravity inversion appears to be closely related to increased venous pressure in the orbit.

The treatment of macular disease using a micropulsed and continuous wave 810-nm diode laser

OBJECTIVE The purpose of the study is to determine whether the 810-nm diode wavelength using a rectangular waveform is clinically effective in the treatment of choroidal neovascularization from age-related macular degeneration and to determine whether macular edema secondary to branch vein occlusion or diabetic retinopathy can be effectively treated with this laser using the micropulse waveform. DESIGN Review of consecutive nonrandomized patients whose eyes were treated with the diode laser over a 30-month period. PARTICIPANTS Fifty-three patients with an initial presentation of choroidal neovascularization located subfoveally (77%), extrafoveally (17%), and juxtafoveally (6%); 14 patients with macular edema from a branch vein occlusion; and 59 patients with diabetic macular edema, 40 of which were treated for the first time. INTERVENTION Ablative rectangular wave laser photocoagulation was applied to the choroidal neovascular membranes and very light threshold treatment was applied in a macular grid to treat retinal edema. Microaneurysms were not targeted. MAIN OUTCOME MEASURES Anatomic resolution of macular edema or choroidal neovascularization and visual acuity. RESULTS Sixty percent of eyes treated for choroidal neovascularization had no persistence or recurrence at 6 months, and 72% achieved visual stabilization. In 8% of eyes, some localized bleeding occurred during photocoagulation. Clinical resolution of macular edema from branch vein occlusion occurred by 6 months in 92% of eyes, and 77% had stabilization of visual acuity. At 6 months, 76% of newly treated patients with diabetic macular edema and 67% of previously treated patients had clinical resolution of their edema. Vision was improved or stabilized in 91% and 73% of newly treated and retreated patients at 6 months, respectively. CONCLUSIONS The micropulsed 810-nm diode laser is clinically effective in the treatment of macular edema from venous occlusion and diabetic retinopathy, and the rectangular (normal) mode diode laser can be used in many eyes with choroidal neovascularization.

Migration of silicone oil into the brain: a complication of intraocular silicone oil for retinal tamponade

PURPOSE To report a case in which intravitreal silicone oil migrated along the intracranial portion of the optic nerve and into the lateral ventricles of the brain after the repair of a retinal detachment secondary to cytomegalovirus retinitis. METHODS A 42-year-old man with acquired immunodeficiency syndrome (AIDS) developed a rhegmatogenous retinal detachment in his left eye secondary to a cytomegalovirus infection of the retina. The detachment was repaired using 5000 cs intraocular silicone oil for a long-term tamponade. Subsequently, the affected eye developed glaucoma, which was poorly controlled. Fifteen months after the retinal surgery, he developed a peripheral neuropathy that was thought to be AIDS related. Computed tomography and magnetic resonance imaging of the head were performed to investigate the neuropathy. RESULTS The patient was found to have a foreign substance within his lateral ventricles that shifted with position and was identical with respect to its imaging properties to the remaining intraocular silicone oil. Additional material was found along the intracranial portion of his optic nerve. CONCLUSION Under certain circumstances, intraocular silicone oil may migrate out of the eye, along the intracranial portion of the optic nerve, and into the lateral ventricles of the brain.

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.

Serous retinal detachment resembling central serous chorioretinopathy following organ transplantation

Two patients developed unilateral serous retinal detachments of the macula resembling idiopathic center serous chorioretinopathy within 9 months of cardiac transplantation, while one renal transplant recipient developed bilateral serous detachments within 6 months of surgery. In two cases (three eyes), dense, yellow, fibrlin-like exudates were present in the subretinal fluid. At the time of presentation, each of the three patients had a modest elevation of blood urea nitrogen. Laser photo-coagulation was performed in three eyes with limited success, although ultimately the detachments resolved leaving only mild visual impairment (6/9 vision). The differential diagnosis of visual loss in the transplant population includes serous detachment of the sensory retina as well as more serious chorioretinal infections related to immunosuppression.

Vitreous Cultures in Suspected Endophthalmitis: Biopsy or Vitrectomy?

BACKGROUND Isolation of bacteria from vitreous biopsy often guides therapy in suspected endophthalmitis. Therapeutic vitrectomy provides an additional source of culture material. The authors compared the ability of these two techniques to isolate organisms from patients with acute endophthalmitis. METHODS In a large ophthalmic microbiology laboratory during a 4-year period, the authors analyzed 206 microbial culture results from patients with suspected endophthalmitis. RESULTS Two hundred six cases were evaluated. While cultures of vitreous biopsy specimens obtained using a needle and syringe were positive in 91 (53.8%) of 169 patients, culturing the contents of the vitrectomy cassettes produced positive cultures in 29 (74.8%) of 39 patients. Both techniques were performed on 23 patients. Vitreous biopsy allowed isolation of the causative organism in 43% of these patients, whereas vitrectomy was 76% successful. Both comparisons were significant at the P < 0.01 level. No positive vitreous biopsy cultures had associated negative vitrectomy cultures. CONCLUSION Culturing the contents of the vitrectomy cassette significantly increases the likelihood of obtaining a positive culture compared with merely culturing a vitreous biopsy.

Intravitreal Ranibizumab and Bevacizumab: A Review of Risk

Ranibizumab (Lucentis®), a recombinant monoclonal antibody, blocks all active forms of vascular endothelial growth factor A and was the first treatment for age-related macular degeneration shown to improve visual acuity in a substantial percentage of patients rather than slowing visual loss. Bevacizumab (Avastin®) has a similar action, is related to the ranibizumab compound with respect to its structure, but has not been approved by the FDA for intravitreal use and therefore must be utilized only in an off-label setting. While ranibizumab was approved by the FDA at a dose of 0.5 mg per intravitreal injection, the manufacturer recently issued a letter to physicians warning of the increased risk of stroke at the FDA-approved dose as compared to a lower studied dose of 0.3 mg. An interim analysis of the ongoing SAILOR study revealed a 1.2% risk of stroke in the 0.5 mg arm versus 0.3% in the 0.3 mg arm (p = 0.02). It is unclear whether the trend toward a higher risk of stroke in patients receiving 0.5 mg dose of ranibizumab would persist in the final analysis, but details such as causality, topography, and severity of stroke in the SAILOR study should also be delineated. The risks of intraocular use of bevacizumab remain largely unknown at this time.

Ischemic index and neovascularization in central retinal vein occlusion.

Purpose: To explore the association of angiographic nonperfusion with anterior segment and posterior segment neovascularization in central retinal vein occlusion (CRVO). Methods: An imaging database at one institution was searched for the diagnosis of central retinal vein occlusion. Ultra wide field fluorescein angiograms were graded for image quality, the presence of retinal neovascularization, and the quantity of nonperfusion; an ischemic index (ISI) was calculated. Charts were reviewed to exclude eyes with previous treatment and to determine which eyes had anterior segment or posterior segment neovascularization on the day of the angiogram. Time from onset to presentation could not accurately be ascertained. Results: In a 39-month period, there were 69 eyes that met inclusion criteria. The mean ISI was 25% (SD, 26%; range, 0-100%), and 15 eyes (21%) with neovascularization had a mean ISI of 75% (range, 47-100%) compared with eyes without neovascularization that had an ISI of 6% (range, 0-43%). Ischemic index significantly correlated to neovascularization, and eyes that had evidence of neovascularization had an ISI >45% (P < 0.0001). Conclusion: Ultra wide field fluorescein angiography provides visualization of nonperfusion in eyes with central retinal vein occlusion. Eyes with neovascularization on the day of the angiogram were found to have significantly larger areas of retinal nonperfusion compared with eyes without neovascularization. A prospective study is indicated to know if early treatment of peripheral retinal nonperfusion in CRVO improves outcomes.