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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 Measures 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

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.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.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.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.Development of advanced AMD. The unit of analyses used was by eye.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.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.clinicaltrials.gov Identifier: NCT00345176.

In reply Since the publication of "Sudden Visual Loss Associated With Sexual Activity," 1 I have been deluged with requests for more detailed information about the risks for "blindness" occurring during sexual activity. Although our series was too small to provide meaningful incidence data, the risk for visual loss must be extremely small. Furthermore, none of the patients reported permanent damage. Your article was unfortunately not referenced because of its unique but rather obscure title. In it you outlined the development of ocular pain precipitated by sexual intercourse in a patient with gonioscopically narrow angles and suggested that such activity may even serve as a provocative test. Ocular mydriasis itself is part of the normal sexual response. Levi 2 has shown that there is an increase in the excretion of catecholamines during emotional and sexual excitement. Furthermore, pupillographic studies have been conducted and in some cases have been used as

• Dense inflammatory fibrocellular membranes may develop over the iris in an eye with endophthalmitis, completely obliterating any view of the posterior segment and hindering vitrectomy. To remove this debris, the edge of the membrane is first lifted from the surface of the iris with a small microvitreoretinal blade inserted through a limbal wound. The membrane is then engaged with an iris hook that is rotated until the debris is tightly wound on the shaft of the instrument. The iris hook is then removed from the anterior segment, delivering the inflammatory debris en bloc. This technique limits possible surgical trauma to the anterior segment and provides an excellent specimen for culture.

• Ocular rigidity is the change in intraocular pressure produced by an incremental change in intraocular volume. Ocular rigidity was determined in 14 donor eyes by injecting small increments of a balanced salt solution through the limbus, while continually monitoring the intraocular pressure with a transducer. A buckling procedure was then performed in these eyes with the use of various solid silicone or stainless steel encircling elements, and the experiments were repeated. Buckled eyes were significantly less rigid than unbuckled eyes, and eyes with higher buckles were significantly less rigid than those with shallower buckles. The observed changes in rigidity are likely secondary to changes in the shape and stress distribution of the scleral shell and are only to a small degree related to the elasticity of the encircling element. Greater volumes of vitreous substitutes, gases, or antibiotics may be injected into buckled eyes compared with unbuckled eyes before excessive intraocular pressures are reached.

• Visual loss is uncommon in thrombosis of the cavernous sinus. A patient observed closely in the acute stages developed high intraocular and intraorbital pressures. Although the retinal vasculature remained patent, total unilateral blindness occurred within 48 hours. To our knowledge this is the first documented case in which ischemic optic neuropathy caused blindness in a patient suffering from cavernous sinus thrombosis.

The penetration of indomethacin labeled with radioactive carbon (14C) into all ocular tissues and fluids was determined at various intervals in both phakic and aphakic rabbit eyes after either single or multiple (every 12 hours for three days) topical application (50 microL) regimens. More indomethacin was found in the vitreous of aphakic eyes compared with phakic eyes after single- or multiple-drop administration. Retinal and choroidal indomethacin concentrations were equal in both phakic and aphakic eyes after either drug regimen and are much greater than those of the vitreous. A pathway other than diffusion through the vitreous exists for the drug to reach these tissues. The concentration of indomethacin reaching the retina and choroid is not sufficient to inhibit prostaglandin formation locally. The concentrations of indomethacin are high enough to inhibit the biotransformation of prostaglandin precursor only in the anterior segment.

• We measured aqueous angiotensin-converting enzyme (ACE) activity in 37 patients. Patients with granulomatous uveitis and probable sarcoidosis (based on increased serum ACE activity or characteristic radiologic findings) had a significant increase in aqueous ACE activity compared with normal subjects. Aqueous ACE activity was also significantly elevated in patients with sarcoid who had normal serum ACE activity. We believe that measurement of aqueous ACE activity should be considered in patients with uveitis who have normal serum ACE activity and are suspected of having sarcoidosis.

• A patient with decreased visual acuity had small, glistening white particles that were scattered over both posterior poles. Monochromatic fundus photography revealed ghost vessels and intraluminal particulate matter in small retinal vessels. Fluorescein angiography demonstrated nonperfusion of small arterioles and macular capillaries. The patient admitted to multiple intravenous injections of crushed methylphenidate (Ritalin) hydrochloride tablets, which contain talc 18 months prior to examination. To our knowledge, visual loss and irreversible macular ischemia from talc emboli have not been previously documented.

To the Editor. —Serpiginous choroiditis is a recurrent, bilateral, multifocal inflammatory disease. Branch vein occlusion, retinal phlebitis, optic disc drusen, and elevated toxoplasmosis titers were unusual associated findings in the case described below. Report of a Case. —A healthy 42-year-old man noted blurring of the vision in his right eye. Visual acuity was 6/24 OD and 6/9 OS. Funduscopic examination disclosed multiple, oval, atrophic choroidal lesions and small optic disc drusen in both eyes. In the right eye, intraretinal hemorrhage characteristic of a branch vein occlusion was seen superotemporally along with focal areas of periphlebitis (Fig 1). In the left eye, an active gray-white lesion contiguous with a geographic zone of choroidal atrophy was present inferior to the macula along with periphlebitis (Fig 2). No cells were present in the vitreous cavity or in the anterior segment. The sedimentation rate, serum fluorescent treponomal antibody absorption, VDRL, and angiotensin-converting enzyme, complete

To determine the ocular manifestations of inverting the human body into a head-down vertical position, we evaluated normal volunteers with applanation tonometry, fundus photography, fluorescein angiography, and ophthalmodynamometry. Compared with data obtained in the sitting position, the intraocular pressure more than doubled on inversion (35.6 ±4v14.1±2.8 mm Hg, n=16), increasing to levels well within the glaucomatous range. Pressures in the central retinal artery underwent similar increases, while the caliber of the retinal arterioles decreased substantially. External ocular findings associated with gravity inversion included orbital congestion, conjunctival hyperemia, petechiae of the eyelids, excessive tearing (epiphora), and subconjunctival hemorrhage. We suggest that patients with retinal vascular abnormalities, macular degeneration, ocular hypertension, glaucoma, and similar disorders refrain from inversion altogether. Whether normal individuals will suffer irreversible damage from inversion is uncertain, but it seems prudent to recommend that prolonged periods of inverted posturing be avoided. (JAMA1985;253:1755-1757)

THE VITREOUS is altered pathologically in numerous ocular and systemic diseases. Hence, most physicians will encounter patients whose vision has been impaired by vitreous opacities or by the formation of membranes within the vitreous cavity. Only recently has the successful treatment of vitreous pathology become commonplace, primarily because of the development of specialized microsurgical techniques. To appreciate the importance of vitreous surgery in reducing the prevalence of blindness, a basic understanding of the disease processes affecting the vitreous is necessary. VITREOUS DISORDERS The human vitreous is normally an optically clear gel consisting of 99% water and containing collagen and hyaluronic acid.1The vitreous collagen is firmly attached to the internal limiting membrane of the retina anteriorly near the pars plana; weaker vitreoretinal attachments occur at the macula and at the optic disc. Vitreous Collapse With increasing age, the vitreous gel often collapses and separates from the posterior retinal surface.

• Two eyes were enucleated for angle-closure associated with familial exudative vitreoretinopathy. Characteristic features included total retinal detachment, peripheral retinal vascular proliferation, and a fibrovascular preretinal membrane. Angle-closure glaucoma developed in one case when sudden massive subretinal hemorrhage, associated with abnormal intraretinal vessels, produced anterior displacement of the lens-iris diaphragm; in the second case, angle-closure was associated with the development of rubeosis iridis. Intraretinal inflammatory cells and exudates were also seen in the enucleated eyes.

In Reply.— We agree with Dr Sadun that increases in intracranial arterial and venous pressure undoubtedly occur with inversion and are reflected by the increase in ophthalmic artery pressure as measured by ophthalmodynamometry. As he points out, one of the most important circulatory effects of the inverted posture is elevation of venous pressure. 1 We are alarmed by the close association of a subdural hematoma with gravity inversion and are unaware of any other such reports. Patients with glaucoma and ocular hypertension show elevation of intraocular pressure with gravity inversion as do normal subjects. 2 We share the concerns of Drs O'Connor and Poirier that inverted posturing achieved using gravity-inversion devices or slant boards or by performing head stands may raise intraocular pressures to harmful levels. Their case documents progressive field loss in a patient whose daily exercise routine substantially increased his intraocular pressure. While a direct cause and effect