Carl C. Awh

CFH and ARMS2 Genetic Polymorphisms Predict Response to Antioxidants and Zinc in Patients with Age-related Macular Degeneration

OBJECTIVE The Age-Related Eye Disease Study (AREDS) demonstrated that antioxidant and zinc supplementation decreases progression to advanced age-related macular degeneration (AMD) in patients with moderate to severe disease. We evaluated the interaction of genetics and type of nutritional supplement on progression from moderate to advanced AMD. DESIGN Genetic analysis of a randomized, prospective clinical trial. PARTICIPANTS White patients with AREDS category 3 AMD in 1 eye and AREDS categories 1 through 4 AMD in the fellow eye enrolled in the AREDS with available peripheral blood-derived DNA (995). METHODS Subjects were evaluated for known AMD genetic risk markers and treatment category. The progression rate to advanced AMD was analyzed by genotypes and AREDS treatment group using Cox regression. MAIN OUTCOME MEASURES The effect of inherited gene polymorphisms on treatment group-specific rate of progression to advanced AMD. RESULTS Over an average of 10.1 years, individuals with 1 or 2 complement factor H (CFH) risk alleles derived maximum benefit from antioxidants alone. In these patients, the addition of zinc negated the benefits of antioxidants. Treatment with zinc and antioxidants was associated with a risk ratio (RR) of 1.83 with 2 CFH risk alleles (P = 1.03E-02), compared with outcomes for patients without CFH risk alleles. Patients with age-related maculopathy sensitivity 2 (ARMS2) risk alleles derived maximum benefit from zinc-containing regimens, with a deleterious response to antioxidants in the presence of ARMS2 risk alleles. Treatment with antioxidants was associated with an RR of 2.58 for those with 1 ARMS2 risk allele and 3.96 for those with 2 ARMS2 risk alleles (P = 1.04E-6), compared with patients with no ARMS2 risk alleles. Individuals homozygous for CFH and ARMS2 risk alleles derived no benefit from any category of AREDS treatment. CONCLUSIONS Individuals with moderate AMD could benefit from pharmacogenomic selection of nutritional supplements. In this analysis, patients with no CFH risk alleles and with 1 or 2 ARMS2 risk alleles derived maximum benefit from zinc-only supplementation. Patients with one or two CFH risk alleles and no ARMS2 risk alleles derived maximum benefit from antioxidant-only supplementation; treatment with zinc was associated with increased progression to advanced AMD. These recommendations could lead to improved outcomes through genotype-directed therapy.

Treatment Response to Antioxidants and Zinc Based on CFH and ARMS2 Genetic Risk Allele Number in the Age-Related Eye Disease Study

OBJECTIVE To evaluate the impact of complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) risk alleles on the observed response to components of the Age-Related Eye Disease Study (AREDS) formulation. DESIGN Genetic and statistical subgroup analysis of a randomized, prospective clinical trial. PARTICIPANTS White patients from the AREDS with category 3 or 4 age-related macular degeneration (AMD) with available DNA (n = 989). METHODS Four genotype groups based on CFH and ARMS2 risk allele number were defined. Progression to advanced AMD was analyzed by genotype and treatment using Cox proportionate hazards estimates and 7-year events. MAIN OUTCOME MEASURES The effect of predefined genotype group on treatment-specific progression to advanced AMD. RESULTS Patients with 2 CFH risk alleles and no ARMS2 risk alleles progressed more with zinc-containing treatment compared with placebo, with a hazard ratio (HR) of 3.07 (P = 0.0196) for zinc and 2.73 (P = 0.0418) for AREDS formulation (AF). Seven-year treatment-specific progression rates were: placebo, 17.0%; zinc, 43.2% (P = 0.023); and AF, 40.2% (P = 0.039). Patients with 0 or 1 CFH risk alleles and 1 or 2 ARMS2 risk alleles benefited from zinc-containing treatment compared with placebo, with an HR of 0.514 for zinc (P = 0.012) and 0.569 for AF (P = 0.0254). Seven-year treatment-specific AMD progression rates were as follows: placebo, 43.3%; zinc, 25.2% (P = 0.020); and AF, 27.3% (P = 0.011). Zinc and AF treatment each interacted statistically with these 2 genotype groups under a Cox model, with P values of 0.000999 and 0.00366, respectively. For patients with 0 or 1 CFH risk alleles and no ARMS2 risk alleles, neither zinc-containing treatment altered progression compared with placebo, but treatment with antioxidants decreased progression (HR, 0.380; P = 0.034). Seven-year progression with placebo was 22.6% and with antioxidants was 9.17% (P = 0.033). For patients with 2 CFH risk alleles and 1 or 2 ARMS2 risk alleles, no treatment was better than placebo (48.4%). CONCLUSIONS The benefit of the AREDS formulation seems the result of a favorable response by patients in only 1 genotype group, balanced by neutral or unfavorable responses in 3 genotype groups.

Treatment and Pathogenesis of Traumatic Chorioretinal Rupture (Sclopetaria)

Eight eyes (seven patients) with traumatic chorioretinal rupture (sclopetaria) from severe ocular trauma were examined. All seven patients were referred with diagnoses of retinal detachment, giant retinal tear, or ruptured globe. Instead, all eyes had large, peripheral, full-thickness breaks of the choroid and retina without retinal detachment. Seven of eight eyes were initially managed by observation only; one eye was treated with a scleral buckling procedure. The retina remained attached in all eyes for at least six months. Late retinal detachment (more than one year after initial injury) occurred in two eyes because of retinal breaks at a site distant from the original chorioretinal rupture. Two eyes later developed vitreous hemorrhage associated with posterior vitreous detachment and one of these eyes required vitrectomy to clear the visual axis. The pathogenesis of sclopetaria appears to be mechanical disruption and retraction of tissue rather than acute tissue dissolution. The risk of acute retinal detachment is low. We recommend nonsurgical management for the initial treatment of these patients, with continued observation for complications that may later occur.

Vitreous nonsteroidal antiinflammatory drug concentrations and prostaglandin E2 levels in vitrectomy patients treated with ketorolac 0.4%, bromfenac 0.09%, and nepafenac 0.1%.

Purpose: To assess vitreous concentrations of nonsteroidal antiinflammatory drugs (NSAIDs) and prostaglandin E2 in patients treated with NSAIDs before vitrectomy. Methods: This was an investigator-masked, randomized, multicenter study. Patients received ketorolac 0.4% 4 times a day, bromfenac 0.09% 2 times a day, nepafenac 0.1% 3 times a day, or no NSAID for 3 days before surgery. Nonsteroidal antiinflammatory drugs and prostaglandin E2 levels were determined in vitreous samples collected at the beginning of surgery. Results: Thirty-one patients were included in the analyses. The mean (SD) vitreous concentrations were as follows: ketorolac 2.8 (3.2) ng/mL, bromfenac 0.96 (0.31) ng/mL, nepafenac 1.1 (0.6) ng/mL, and amfenac 2.0 (0.8) ng/mL aligned with the initial concentrations of the topical NSAIDs. Mean (SD) vitreous prostaglandin E2 levels of the control patients and those treated with ketorolac 0.4%, bromfenac 0.09%, or nepafenac 0.1% were 270.6 (91.7) pg/mL, 189.6 (50.2) pg/mL, 247.2 (38.3) pg/mL, and 267.7 (99.7) pg/mL, respectively. Patients treated with ketorolac 0.4% had significantly lower prostaglandin E2 levels than those treated with no NSAID (P = 0.047) or nepafenac 0.1% (P = 0.028). Conclusion: All three NSAIDs penetrated into the vitreous cavity. Topical therapy with ketorolac may lower preoperative vitreous prostaglandin E2 levels, which may have a clinical impact on the management of prostaglandin-mediated diseases, including cystoid macular edema.

Novel mercury vapor illuminator combined with a 27/29-gauge chandelier light fiber for vitreous surgery.

Novel Mercury Vapor Illuminator Combined With a 27/29-Gauge Chandelier Light Fiber for Vitreous Surgery W ith the recent popularity and widespread use of small-gauge vitrectomy instruments and panoramic viewing systems, adequate and safe endoillumination has become especially important. To overcome the insufficient illumination of conventional light sources for these surgical procedures, brighter illuminators (e.g., xenon light source) have been developed recently. The increased power of xenon lights is substantial even with 25-gauge and 27-gauge light probes, and the intraocular illumination is equal to or brighter than the illumination achievable with 20-gauge probes with conventional halogen or metal halide light bulbs.1,2 Although the new xenon illuminators are useful and have an integrated filter system to improve safety by cutting off high levels of ultraviolet illumination, no commercially available light sources, including xenon lights, are safe for long periods of exposure with respect to photochemical retinal damage.3 To obtain a more powerful illumination source with minimal phototoxicity to the retina, a mercury vapor illuminator (PhotonII; Synergetics, Inc., St. Charles, MO) has been newly developed. This instrument features a dual-output pathway from one mercury vapor bulb, which is compatible with an integrated laser pathway for use with an illuminating laser probe (Fig. 1). Spherical reflectors are adopted to generate homogenized illumination and sharpen the focus spot of the illumination (Fig. 1). The luminous efficacy of the mercury vapor illuminator reaches 402 lumens/W of optical power, which is brighter than any commercially available xenon light illuminators (range, 277– 355 lumens/W). The actual output level of the mercury vapor illuminator can be enhanced to 56 lumens through a 25-gauge chandelier fiber, which is approximately twice as bright as that of the xenon light source that maximally enhances only up to 29 lumens through the same chandelier fiber. This novel illumination system incorporates a 435-nm cutoff filter to substantially reduce the ultraviolet and blue light. After passing through the cutoff filter, the output of the mercury vapor illuminator has only two spectral output peaks at 550 nm and 580 nm, and the entire spectral output curve is mostly confined within the range of the photopic spectral system (Fig. 2). The hazard efficacy, which represents the magnitude of theoretical phototoxicity, is 2,200 lumens/hazard W in the mercury vapor illuminator, which is much higher than the hazard efficacy measured in a xenon or halogen light source (range, 1,150–1,900 lumens/hazard W). These data suggest that this novel illuminator has favorable efficiency and safety superior to any other conventional illuminators. Because of the higher illumination capabilities of the mercury vapor illuminator, high levels of endoilFrom the *Department of Ophthalmology, Osaka University Medical School, Suita, Osaka, Japan; the †Department of Ophthalmology, University of Toronto, Toronto, Ontario, Canada; and ‡Retina–Vitreous Associates, Nashville, Tennessee. Supported in part by Research Grants from the Ministry of Education, Science and Culture, Tokyo, Japan. None of the authors have received royalties from the sale of the devices mentioned in this article, nor are they patent holders for these devices. Drs. Chow and Awh are paid consultants to Synergetics, Inc. (St. Charles, MO). Supplemental figures. A, Intraoperative view under 27/29-gauge chandelier endoillumination driven by a mercury vapor light source in a case of epiretinal membrane. The membrane can be visualized clearly under the green yellowish illumination. B, The magnified posterior view under 27/29-gauge chandelier endoillumination in a case of proliferative diabetic retinopathy. Preretinal hemorrhage and whitish fibrovascular membranes are well observed under the chandelier illumination. Reprint requests: Yusuke Oshima, MD, PhD, Department of Ophthalmology, Osaka University Medical School, 2-2 Yamadaoka, E-7, Suita, Osaka 565-0871 Japan; e-mail: oshima@ophthal. med.osaka-u.ac.jp)

Prophylactic Treatment of Age-Related Macular Degeneration Report Number 2: 810-Nanometer Laser to Eyes With Drusen: Bilaterally Eligible Patients

BACKGROUND AND OBJECTIVE To determine the prophylactic and therapeutic value of a single subthreshold 810-nanometer laser treatment in patients with high risk drusen as a manifestation of dry age-related macular degeneration in both eyes. PATIENTS AND METHODS The Prophylactic Treatment of Age-related Macular Degeneration study enrolled 1,278 eyes of 639 participants who were 50 years or older with at least 5 drusen 63 microm or more in diameter in each eye. Treatment consisted of the placement of an annular grid of 48 extrafoveal, subthreshold 810-nm diode laser applications centered at but sparing the foveola in one eye of each participant, with the fellow eye serving as a control. Development of choroidal neovascularization and change in best-corrected visual acuity were compared between treated and untreated eyes. RESULTS Subthreshold laser treatment did not decrease the incidence of choroidal neovascularization in treated versus untreated eyes. A modest visual acuity benefit in treated eyes was found at 24 months (1.5 letter difference; P = .04) and in the treated eyes of participants with a baseline visual acuity between 20/32 and 20/63 (4.0 letter difference; P = .0034). However, this treatment effect was not sustained at 3 years. CONCLUSION A single subthreshold 810-nanometer laser treatment to eyes of participants with bilateral high risk drusen is not an effective prophylactic strategy against choroidal neovascularization.

A 29/30-gauge dual-chandelier illumination system for panoramic viewing during microincision vitrectomy surgery.

From the *Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan; and †Tennessee Retina, Nashville, Tennessee. Chandelier endoillumination, a useful tool to facilitate bimanual manipulation in challenging cases, is highly compatible with the recent widespread use of wide-angle viewing systems during vitreous surgery. Owing to the recent advances in the development of powerful light sources such as xenon and mercury vapor illuminators, various types of chandelier illumination fibers have been manufactured, the sizes of which have become increasingly smaller and suitable for modern microincision vitrectomy. Chandelier illumination with one optic fiber currently is popular among surgeons because of its easy use in the transconjunctival setting. However, instrument shadows projected onto the fundus by the illumination may be distracting during delicate intraocular manipulations. Multiport illumination using the 27-gauge Twinlight chandelier fiber designed by Eckardt et al may be a good alternative to decrease the shadowrelated concerns. However, setting up the small-gauge chandelier fiber transconjunctivally without a preloaded cannula can be challenging and requires special techniques. In addition, if the fiber is inadvertently withdrawn during surgery, the sclerotomy is no longer aligned with the conjunctiva, making it difficult or practically impossible to reinsert the fiber into the original wound. To address these problems, we developed a new trocar-cannula–based dual-chandelier illumination system comprising two 30-gauge optic fibers with two 29-gauge trocar-cannulas and a cord management strip. The tip of the optical fiber is cone shaped to provide diffuse illumination. Each fiber passes through a rubber stopper positioned approximately 5 mm to 6 mm posterior to the fiber tip (Figure 1A). Our technique for positioning the dual-chandelier fibers is as follows: after displacing the conjunctiva, a 29-gauge trocar-cannula (Figure 1B) is inserted transconjunctivally 3.5 mm or 4.0 mm posterior to the corneal limbus. Either an oblique or perpendicular insertion technique can be used, because the 29-gauge size is sufficiently small to allow the

CFH and ARMS2 genetic risk determines progression to neovascular age-related macular degeneration after antioxidant and zinc supplementation

Significance Age-related macular degeneration (AMD) is the leading cause of severe vision loss in the elderly and has major economic and quality-of-life impact. Prophylactic high-dose zinc and antioxidant supplements treatments are typically recommended with the assumption of homogeneously distributed benefit and risk of developing neovascular AMD. We show that individual variation at complement factor H and age-related maculopathy susceptibility 2, genes which predispose to AMD, also determines the effectiveness of nutritional prophylaxis. Some individuals paradoxically experience worsening disease with treatment, while others experience greater than average benefit. These divergent responses are difficult to identify when treatment effects have long latency. Understanding individual variations in prophylactic treatment response should inform future research and optimize health outcomes. We evaluated the influence of an antioxidant and zinc nutritional supplement [the Age-Related Eye Disease Study (AREDS) formulation] on delaying or preventing progression to neovascular AMD (NV) in persons with age-related macular degeneration (AMD). AREDS subjects (n = 802) with category 3 or 4 AMD at baseline who had been treated with placebo or the AREDS formulation were evaluated for differences in the risk of progression to NV as a function of complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genotype groups. We used published genetic grouping: a two-SNP haplotype risk-calling algorithm to assess CFH, and either the single SNP rs10490924 or 372_815del443ins54 to mark ARMS2 risk. Progression risk was determined using the Cox proportional hazard model. Genetics–treatment interaction on NV risk was assessed using a multiiterative bootstrap validation analysis. We identified strong interaction of genetics with AREDS formulation treatment on the development of NV. Individuals with high CFH and no ARMS2 risk alleles and taking the AREDS formulation had increased progression to NV compared with placebo. Those with low CFH risk and high ARMS2 risk had decreased progression risk. Analysis of CFH and ARMS2 genotype groups from a validation dataset reinforces this conclusion. Bootstrapping analysis confirms the presence of a genetics–treatment interaction and suggests that individual treatment response to the AREDS formulation is largely determined by genetics. The AREDS formulation modifies the risk of progression to NV based on individual genetics. Its use should be based on patient-specific genotype.

Reply to Vickers: Pharmacogenetics and progression to neovascular age-related macular degeneration—Evidence supporting practice change

Vickers (1) offers little substantive criticism, but we address three items he mentions: ( i ) our choice of clinical endpoint, ( ii ) the potential for multiple-testing false positives, and ( iii ) the need for additional study. An important distinction of our study (2) is the use of neovascular AMD (nvAMD) as the endpoint. In 2001, the Age-Related Eye Disease Study (AREDS) showed that nutritional supplements reduce progression to overall advanced AMD. This main effect was due to reduced progression to nvAMD, with no impact on progression to the geographic atrophy (GA) form of advanced AMD (3). As Vickers notes (1), Seddon et al. (4) confirmed this pharmacogenetic interaction. However, he misquotes or misunderstands Seddon’s conclusion, who states that “similar results were seen for NV subtype but not GA” (4). Vickers notes that work by Awh et … [↵][1]1To whom correspondence should be addressed. Email: tibs{at}stanford.edu. [1]: #xref-corresp-1-1

Progression From No AMD to Intermediate AMD as Influenced by Antioxidant Treatment and Genetic Risk: An Analysis of Data From the Age-Related Eye Disease Study Cataract Trial

Purpose: To investigate the impact of antioxidant treatment and genetic risk on the development of intermediate age-related macular degeneration (AMD) in patients without baseline AMD, using data from the Age-Related Eye Disease Study (AREDS) Cataract Trial. Methods: Genetic risk and antioxidant treatment were analyzed as independent and interacting risk factors for the development of intermediate AMD in 554 AREDS individuals for whom genotyping was available. Genetic risk was determined using an allele dosage model based on the total number of complement factor H and age-related maculopathy sensitivity 2 risk alleles. Results: Overall, 14% of patients developed intermediate AMD over approximately 8 years. The risk of developing intermediate AMD varied from 6.5% for patients with 0 risk alleles to 39% for those with 3 or 4 risk alleles (P < .0001). Antioxidants had no impact on the development of intermediate AMD overall. However, antioxidant treatment had a significant impact on progression to intermediate AMD for patients with low or high genetic risk. Patients with 0 or 1 risk alleles had increased risk of progression to intermediate AMD (hazard ratio [HR] = 2.31, P = .017) if treated with antioxidants compared to placebo. Patients with 3 or 4 risk alleles had decreased risk of progression to intermediate AMD (HR = 0.27, P = .0008) if treated with antioxidants compared to placebo. Conclusion: On average, antioxidant treatment has no impact on the development of intermediate AMD in patients without AMD. However, antioxidant treatment may increase the risk of developing intermediate AMD in patients with low genetic risk and may reduce the risk of developing intermediate AMD in patients with high genetic risk. Since patients with high genetic risk have the greatest risk of progressing from intermediate to advanced AMD, genotype-directed antioxidant treatment of patients without AMD may ultimately lead to fewer cases of advanced AMD.