Kirk H. Packo

The Age-Related Eye Disease Study (AREDS): Design Implications AREDS Report No. 1

The Age-Related Eye Disease Study (AREDS) was initially conceived as a long-term multicenter, prospective study of the clinical course of age-related macular degeneration (AMD) and age-related cataract. Data on progression rates and risk factors from the study will increase understanding of the clinical course of both conditions, generate hypotheses about etiology, and aid in the design of clinical trials of potential interventions. In addition to collecting natural history data, AREDS includes a clinical trial of high-dose vitamin and mineral supplements for AMD and a clinical trial of high-dose vitamin supplements for cataract. The clinical trials were initiated largely because of the widespread public use in the United States of commercially available pharmacologic doses of vitamins and minerals to treat these two eye conditions and the absence of definitive studies on the safety and efficacy of their use. Important design issues for the clinical trials include: defining cataract and AMD, estimating event rates, determining the type and dosage of vitamins and minerals to be tested for each condition, and identifying the parameters necessary for monitoring safety and efficacy. This paper describes the AREDS design, including the study rationale and operational structure, and the approach adopted to combine, for two diseases, clinical trials with a natural history study.

The Age-Related Eye Disease Study (AREDS) system for classifying cataracts from photographs: AREDS Report No. 4

PURPOSE To describe the system for grading cataracts from photographs in the Age-Related Eye Disease Study (AREDS). METHODS The system for grading cataracts in AREDS uses photographs taken in a standardized fashion with specially modified cameras at 11 clinical centers. The photographs are evaluated by graders for quality and cataract severity at a central reading center. The area of lens involvement is used to assess the severity of cortical and posterior subcapsular opacities. Optical density of nuclear opacity is graded against a series of seven standard photographs. Contemporaneous variability in grading is evaluated periodically by having a second examiner regrade a subset of the photographs. Temporal variability is assessed by annually regrading a subset of photographs. RESULTS Photographs of 925 eyes, most with no or early lens opacities, were regraded to assess intergrader reliability. For cortical opacities, there was an absolute difference of 10% or greater of area involved in 1.9% of the replicate gradings. For posterior subcapsular opacities an absolute difference of 5% of area involved was noted in 2.8% of the regraded photographs. For nuclear opacities, absolute differences of 1.5 or more steps were observed in 0.6% of eyes. There was little evidence of temporal drift in grading any of the three types of opacity during four annual regrades. CONCLUSIONS We have demonstrated a high degree of reliability in grading the severity of lens opacities in a large study cohort with mostly early lens changes, the type of cohort most likely to be entered in clinical trials involving cataract prevention. The Age-Related Eye Disease Study System for Classifying Cataracts From Photographs could be useful in studies where there is a need to standardize data collection over time and across different data collection sites. Limitations of the system include the cost of implementation and, currently, the limited amount of data on grading reproducibility for more advanced lens opacities.

Vitrectomy for Prevention of Macular Holes: Results of a Randomized Multicenter Clinical Trial

PURPOSE: The purpose of this study is to assess the benefit of vitreous surgery in preventing full-thickness macular holes in patients with impending (stage 1) macular holes. METHODS: A prospective randomized multicenter clinical trial was conducted on patients with full-thickness macular holes in their first eye (stage 3 or 4) and signs and symptoms of stage 1 macular holes in their fellow eye (study eye). The study eye was randomized to vitreous surgery or observation. Outcome was assessed by standardized measurement of visual acuity, detailed clinical examination, fundus photographs, and fluorescein angiography. RESULTS: A full-thickness macular hole developed in 10 (37%) of 27 patients in the vitrectomy group compared with 14 (40%) of 35 patients randomized to observation (P = 0.81). This difference of 3% has a 95% confidence interval of (-21%, 27%). CONCLUSION: The study was terminated because of low recruitment. The authors were unable to prove (or disprove) the benefit of vitreous surgery in patients with stage 1 macular holes. The authors can state, however, that should a beneficial effect from vitrectomy exist, it would probably be minimal. Considering the cost and morbidity of vitreous surgery, a conservative approach for stage 1 macular hole might be appropriate.Purpose: The purpose of this study is to assess the benefit of vitreous surgery in preventing full-thickness macular holes in patients with impending (stage 1) macular holes. Methods: A prospective randomized multicenter clinical trial was conducted on patients with full-thickness macular holes in their first eye (stage 3 or 4) and signs and symptoms of stage 1 macular holes in their fellow eye (study eye). The study eye was randomized to vitreous surgery or observation. Outcome was assessed by standardized measurement of visual acuity, detailed clinical examination, fundus photographs, and fluorescein angiography. Results: A full-thickness macular hole developed in 10 (37%) of 27 patients in the vitrectomy group compared with 14 (40%) of 35 patients randomized to observation ( P = 0.81). This difference of 3% has a 95% confidence interval of (-21%,27%). Conclusion: The study was terminated because of low recruitment. The authors were unable to prove (or disprove) the benefit of vitreous surgery in patients with stage 1 macular holes. The authors can state, however, that should a beneficial effect from vitrectomy exist, it would probably be minimal. Considering the cost and morbidity of vitreous surgery, a conservative approach for stage 1 macular hole might be appropriate.

Laser treatment in fellow eyes with large drusen: Updated findings from a pilot randomized clinical trial

PURPOSE To update the findings from the Choroidal Neovascularization Prevention Trial (CNVPT) with respect to resolution of drusen, incidence of choroidal neovascularization, and visual function. DESIGN A multicenter, randomized, controlled, pilot clinical trial. PARTICIPANTS The 120 patients enrolled in the CNVPT. Patients had signs of choroidal neovascularization or retinal pigment epithelial detachment in 1 eye and had >/=10 large (>63- micro m) drusen in the contralateral, or fellow, eye. INTERVENTION The fellow eye of 59 patients was assigned randomly to argon green laser treatment consisting of multiple 100- micro m spots at least 750 micro m from the center of the fovea. The fellow eye of the remaining 61 patients was assigned randomly to observation. MAIN OUTCOME MEASURES Change in visual acuity was the primary outcome measure. Incidence of choroidal neovascularization, resolution of drusen, change in contrast threshold, change in critical print size for reading, and incidence of geographic atrophy were secondary outcome measures. RESULTS Throughout 4 years of follow-up, there were no statistically significant differences in change in visual acuity, contrast threshold, critical print size, or incidence of geographic atrophy. With additional follow-up, the large increase in the incidence of choroidal neovascularization observed within 18 months of treatment was maintained; however, by 30 months, the incidence in the two treatment groups was the same. Most drusen resolution in treated eyes occurred within 24 months of the initial treatment. Treated eyes that received higher-intensity laser burns had an increased risk of choroidal neovascularization. Among eyes developing choroidal neovascularization in each treatment group, most lesions (two thirds or more) were composed of occult neovascularization only. CONCLUSIONS Laser treatment as applied in the CNVPT caused an excess risk of choroidal neovascularization in the first year or so after treatment. The increased early incidence of choroidal neovascularization was not associated with either a harmful or beneficial effect in this pilot study.

Preservation of anterior capsule during vitrectomy and lensectomy for retinal detachment with proliferative vitreoretinopathy

PURPOSE To report a series of 15 eyes with rhegmatogenous retinal detachment and proliferative vitreoretinopathy (PVR) or at high risk for advanced PVR, which underwent pars plana vitrectomy (PPV) and lensectomy (PPL) with preservation of the anterior capsule. DESIGN Retrospective noncomparative case series. PARTICIPANTS Fifteen consecutive patients with retinal detachment and varying degrees of PVR in one eye. METHODS All eyes had undergone PPV and PPL with preservation and polishing of the anterior capsule and had at least 6 months of follow-up. Of the 15 eyes, grade C PVR was present preoperatively in 11 and was anterior in 5. Seven of 15 eyes had gas and 8 of 15 had silicone oil tamponade. Eight of 15 eyes had subsequent posterior chamber intraocular lens (PCIOL) placement; 5 eyes had simultaneous silicone oil removal. One eye had a PCIOL placed at the time of the PPL. MAIN OUTCOME MEASURES Visual acuity, retinal reattachment, complications of gas or silicone oil tamponade, and anterior capsular clarity. RESULTS Fourteen eyes had complete retinal reattachment at the final visit (1 of 15 had macular redetachment only). Final visual acuity was better or equal to preoperative acuity in all eyes, improving by 4 +/- 4 lines overall. No eyes had corneal decompensation, pupillary block, or other vision-threatening anterior segment complication. The anterior capsule remained centrally clear in the 13 eyes that did not have a primary central capsulotomy. One eye with minimal preoperative PVR developed hypotony. CONCLUSIONS Vitreoretinal surgeons can preserve the anterior capsule in eyes with retinal detachment and PVR to help prevent intraoperative and postoperative complications of gas or silicone oil, simplify future PCIOL placement, and maintain a normal iris appearance.

An Investigation of the Hospital Charges Related to the Treatment of Endophthalmitis in the Endophthalmitis Vitrectomy Study

PURPOSE The purpose of the study is to assess the hospital charges associated with the treatment of endophthalmitis using a sample of patients from the Endophthalmitis Vitrectomy Study (EVS). METHODS The Endophthalmitis Vitrectomy Study was a multicenter, randomized clinical trial with a two-by-two factorial design to compare immediate pars plana vitrectomy to tap-biopsy and to compare the use of systemic antibiotics (intravenous) to no intravenous antibiotics in the management of postoperative endophthalmitis. Hospital charge data were collected retrospectively from 129 patients from the 4 clinical centers participating in this ancillary study. This represents 31% of the total Endophthalmitis Vitrectomy Study population. An analysis of variance was used to compare hospital charges across center and treatment. A charge-effectiveness analysis compared measures the effectiveness across treatment groups. The annual savings of hospital charges in the United States was estimated for a range of annual incidence rates of endophthalmitis. RESULTS The use of intravenous antibiotics significantly increased hospital charges. Patients undergoing vitrectomy had significantly higher hospital charges than did patients undergoing tap-biopsy. The most charge-effective treatment for patients presenting with light perception only vision was immediate vitrectomy, whereas the most charge-effective treatment for patients presenting with better vision was tap-biopsy. Factors other than treatment independently associated with hospital charges were female sex, history of diabetes, symptom of red eye, and baseline vision of light perception only. CONCLUSIONS Assuming the results of the Endophthalmitis Vitrectomy Study were used as a guide for the treatment of endophthalmitis, the estimated annual nationwide reduction of hospital charges would be between

Acanthamoeba Endophthalmitis Following Penetrating Keratoplasty for Acanthamoeba Keratitis

7.6 million and

Intrusion of Retinal Tacks

40.0 million.

Chronic central serous chorioretinopathy responsive to rifampin.

membrane bilaterally. Fundus examination revealed no pigmentation. Dental, oral mucosal, skin, and nail pigmentation were evident (Figure 1F). The diagnosis of argyrosis was confirmed by conjunctival biopsy. It was possibly due to occupational inhalation of silver. The Scheimpflug image displayed hyperreflectivity corresponding to corneal pigment accumulation areas at the superficial layers (Figure 2A and B). Histopathologic examination of the incisional biopsy material revealed subepithelial extracellular silver particles in the lamina propria, which supported the diagnosis of argyrosis (Figure 2C and D). Systemic evaluation results were normal except for the presence of fatty degeneration of the liver.

Long-Term Macular Changes in the First Proband of Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC) Due to a Newly Identified Mutation in BEST1.

We examined nine patients in whom retinal tacks intruded into the eye and lodged in the subretinal space, preretinal space, vitreous cavity, or anterior chamber. Complications included retinal pigment epithelium atrophy; retinal phlebitis; vitreous hemorrhage; focal corneal, iris, and retinal injury; and corneal edema. The intrusion of the retinal tacks did not apparently cause, but was associated with retinal redetachment in five patients. Factors associated with intrusion of the retinal tacks included absence of a barb at the end of the tack to anchor it to the sclera, absence of a groove in the tack, a short shaft, incomplete penetration of the retina, choroid, and sclera by the tack, self-inflicted trauma to the eye, placing a scleral buckle after inserting the tacks, and reproliferation of periretinal membranes. In four patients the intruded tacks did not cause any complications. In four patients the intruded tacks were removed without complications and in the remaining five patients, they were left in the eye.