Andrew P. Schachat

Verteporfin therapy of subfoveal choroidal neovascularization in pathologic myopia: 2-Year results of a randomized clinical trial - VIP report no. 3

PURPOSE To report 24-month vision and fluorescein angiographic outcomes from trials evaluating photodynamic therapy with verteporfin in patients with subfoveal choroidal neovascularization (CNV) caused by pathologic myopia. DESIGN AND SETTING Multicenter, double-masked, placebo-controlled, randomized clinical trial at 28 ophthalmology practices in Europe and North America. PARTICIPANTS Patients with subfoveal choroidal neovascular lesions caused by pathologic myopia measuring no more than 5400 micro m and best-corrected visual acuity (approximate Snellen equivalent) of 20/100 or better. METHODS Similar to methods described for 1-year results with follow-up examinations beyond 1 year, continuing every 3 months (except Photograph Reading Center evaluations only at the month 24 examination). During the second year, the same regimen (with verteporfin or placebo as applied at baseline) was used if angiography showed fluorescein leakage from CNV. MAIN OUTCOME MEASURES The primary outcome was the proportion of eyes with fewer than 8 letters (approximately 1.5 lines) of visual acuity loss at the month 24 examination, adhering to an intent-to-treat analysis and using the last observation carried forward method to impute for any missing data. RESULTS Seventy-seven of 81 patients (95%) in the verteporfin group, compared with 36 of 39 patients (92%) in the placebo group, completed the month 24 examination. At this time point, 29 of 81 verteporfin-treated patients (36%) compared with 20 of 39 placebo-treated patients (51%) lost at least 8 letters (P = 0.11). The distribution of change in visual acuity at the month 24 examination was in favor of a benefit for the cases assigned to verteporfin (P = 0.05). This included improvement by at least 5 letters (equivalent to at least 1 line) in 32 verteporfin-treated cases [40%] vs. five placebo-treated cases (13%) and improvement by at least 15 letters (equivalent to at least 3 lines) in 10 verteporfin-treated cases (12%) vs. zero placebo-treated cases. No additional photosensitivity adverse reactions or injection site adverse events were associated with verteporfin therapy in the second year of follow-up. CONCLUSIONS Verteporfin therapy for subfoveal CNV caused by pathologic myopia safely maintained a visual benefit compared with a placebo therapy through 2 years of follow-up. Although the primary outcome was not statistically significantly in favor of verteporfin therapy at 2 years as it had been at 1 year of follow-up, the distribution of change in visual acuity at the month 24 examination was in favor of the verteporfin-treated group and showed that this group was more likely to have improved visual acuity through the month 24 examination. The VIP Study Group recommends verteporfin therapy for subfoveal CNV resulting from pathologic myopia based on both the 1- and 2-year results of this randomized clinical trial.

The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: IV. Local treatment failure and enucleation in the first 5 years after brachytherapy. COMS report no. 19.

OBJECTIVE To describe the frequency and predictors of local treatment failure and enucleation after iodine 125 (I(125)) brachytherapy in patients with choroidal melanoma treated and followed up in a large randomized clinical trial. DESIGN Prospective, noncomparative, interventional case series within a randomized, multicenter clinical trial. PARTICIPANTS Patients enrolled in the Collaborative Ocular Melanoma Study (COMS) trial of enucleation versus brachytherapy between February 1987 and July 1998; tumors measured 2.5 to 10.0 mm in apical height and no more than 16.0 mm in longest basal dimension. METHODS I(125) brachytherapy was administered via episcleral plaque according to a standard protocol. Follow-up ophthalmic evaluations, including ophthalmic ultrasound and fundus photography, were performed according to a standard protocol at baseline, every 6 months thereafter for 5 years, and subsequently at annual intervals. Survival analysis methods were used to estimate the cumulative risk of postirradiation treatment failure and enucleation. Factors associated with treatment failure and enucleation of plaqued eyes were evaluated using Cox proportional hazards analysis. MAIN OUTCOME MEASURES Reports of enucleation and of local treatment failure, defined as tumor growth, recurrence, or extrascleral extension, derived from clinical reports based on echographic and photographic documentation. RESULTS As of September 30, 2000, 638 of the 650 patients randomized to brachytherapy and so treated had been followed up for 1 year or longer, and 411 had been followed up for at least 5 years. Sixty-nine eyes were enucleated during the first 5 years after brachytherapy, and treatment failure was reported for 57 eyes. The Kaplan-Meier estimate of proportion of patients undergoing enucleation by 5 years was 12.5% (95% confidence interval [CI], 10.0%-15.6%); the risk of treatment failure was 10.3% (95% CI, 8.0%-13.2%). Treatment failure was the most common reason for enucleation within 3 years of treatment; beyond 3 years, ocular pain was most common. Risk factors for enucleation were greater tumor thickness, closer proximity of the posterior tumor border to the foveal avascular zone, and poorer baseline visual acuity in the affected eye. Risk factors for treatment failure were older age, greater tumor thickness, and proximity of the tumor to the foveal avascular zone. Local treatment failure was associated weakly with reduced survival after controlling for baseline tumor and personal characteristics (adjusted risk ratio, 1.5; P = 0.08). CONCLUSIONS Local treatment failure and enucleation were relatively infrequent events after I(125) brachytherapy within the COMS. Treatment failure typically occurred early and was associated weakly with poorer survival. The COMS randomized trial documented the absence of a clinically or statistically significant difference in survival for patients randomly assigned to enucleation versus brachytherapy. This analysis documents the efficacy of brachytherapy to achieve sustained local tumor control and to conserve the globe.

Clinical Features, Laboratory Investigations, and Survival in Ocular Reticulum Cell Sarcoma

The authors report 32 cases of histologically proven ocular reticulum cell sarcoma (RCS). Follow-up data are available for all patients. Twenty-six patients (81%) have died and the mean survival time was 20 months from the time of diagnosis of RCS. Diagnosis of ocular involvement was made by vitreous biopsy in 56% of cases, enucleation in 13%, and postmortem examination in 31%. The mean age at the time of diagnosis was 60 years. Central nervous system (CNS) involvement was present in 56% of patients, visceral involvement in 16%, and both CNS and visceral involvement in 6%. Isolated ocular disease occurred in 22% of patients. Results of head computed tomography (CT) and cerebrospinal fluid examination more often disclosed evidence of RCS than did body CT or nuclear medicine scans. Responses to treatment were variable, but prognosis for survival is poor.

Frequency of Adverse Systemic Reactions after Fluorescein Angiography: Results of a Prospective Study

Intravenous fluorescein angiography is a commonly performed and extraordinarily valuable diagnostic procedure. The frequency of adverse reactions after angiography has varied considerably in previous reports. In a prospective study of 2789 angiographic procedures in 2025 patients, the authors found that the percentage of adverse reactions depended strongly on the patients angiographic history. Overall, adverse reactions followed 4.8% of the angiographic procedures. These reactions included nausea (2.9%), vomiting (1.2%), flushing/itching/hives (0.5%), and other reactions (dyspnea, syncope, excessive sneezing) (0.2%). No cases of anaphylaxis, myocardial infarction, pulmonary edema, or seizures occurred. The percentage of reactions was 1.8% for patients who had had previous angiography without ever having had an adverse reaction. In contrast, the percentage of reactions was 48.6% for patients who had had an adverse reaction to angiography previously.

Verteporfin therapy for subfoveal choroidal neovascularization in age-related macular degeneration: three-year results of an open-label extension of 2 randomized clinical trials--TAP Report no. 5

OBJECTIVE To report vision and safety outcomes from an extension of a 2-year investigation evaluating verteporfin photodynamic therapy in patients with age-related macular degeneration with subfoveal choroidal neovascularization (CNV). DESIGN AND SETTING Open-label extension of selected patients from 2 multicenter, double-masked, placebo-controlled, randomized clinical trials, the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Investigation, at 22 ophthalmology practices in Europe and North America. PARTICIPANTS Patients enrolled in the TAP Investigation and followed up for at least 24 months in whom verteporfin therapy to CNV might reduce the risk of further vision loss. METHODS Before receiving verteporfin therapy in the extension, eligible patients signed a written informed consent form accompanied by an oral consent process approved by local institutional review boards. Methods were similar to those described for 1- and 2-year results, with follow-up examinations beyond 2 years continuing at 3-month intervals with a few exceptions, including that extension patients with fluorescein leakage from CNV were to receive open-label verteporfin therapy irrespective of their original treatment assignment. RESULTS Of 402 patients in the verteporfin group, 351 (87.3%) completed the month 24 examination; 320 (91.2%) of these enrolled in the extension study. The enrolled participants included 124 (78.0%) of the 159 verteporfin-treated patients with lesions composed of predominantly classic CNV at baseline, of whom 105 (84.7%) completed the month 36 examination. Verteporfin-treated patients with this lesion composition at baseline who participated in the extension study, with or without a month 36 examination, appeared more likely to have a younger age, better level of visual acuity, absence of fluorescein leakage from classic CNV, or no progression of classic CNV beyond the baseline boundaries of the lesion at the month 24 examination compared with those who did not enroll in the extension. For the 105 patients with a predominantly classic baseline lesion composition who completed the month 36 examination, an average of 1.3 treatments were given from the month 24 examination up to, but not including, the month 36 examination. A letter score loss in the study eye of at least 15 from baseline for these patients occurred in 39 (37.5%) at the month 24 examination compared with 44 (41.9%) of these patients at the month 36 examination. Visual acuity changed little from the month 24 examination (mean, -1.9 lines) to the month 36 examination (mean, -2.0 lines) for these eyes. Verteporfin-treated patients had little change in the mean visual acuity lost and few or no additional instances of infusion-related back pain or photosensitivity reactions from month 24 to month 36. Two patients originally assigned to placebo had acute severe vision decrease within 7 days after verteporfin treatment during the extension. One patient originally assigned to verteporfin had acute severe vision decrease after verteporfin treatment of the fellow eye during the extension. CONCLUSIONS Vision outcomes for verteporfin-treated patients with predominantly classic lesions at baseline remained relatively stable from month 24 to month 36, although only approximately one third of the verteporfin-treated patients originally enrolled with this lesion composition had a month 36 examination. From these results, the TAP Study Group identified no safety concerns to preclude repeating photodynamic therapy with verteporfin. Additional treatment was judged likely to reduce the risk of further vision loss. Caution appears warranted in the absence of comparison with an untreated group during the extension and since not all patients in the TAP Investigation participated in the TAP Extension.

Prevalence and causes of visual impairment in the Barbados eye study

OBJECTIVE To determine the prevalence and causes of low vision and blindness in a predominantly black population. DESIGN Population-based prevalence study of a simple random sample of Barbados-born citizens aged 40 to 84 years. PARTICIPANTS Four thousand seven hundred nine persons (84% participation). METHODS The standardized protocol included best-corrected visual acuity (with a Ferris-Bailey chart), automated perimetry, lens gradings (LOCS II), and an interview. Participants with visual acuity of worse than 20/30, other positive findings, and a 10% sample also had an ophthalmologic examination that evaluated the cause and extent of vision loss (resulting from that cause), if any. MAIN OUTCOME MEASURES Low vision and blindness were defined as visual acuity in the better eye between 6/18 and 6/120 and visual acuity worse than 6/120, respectively (World Health Organization [WHO] criteria). RESULTS Of the 4631 participants with complete examinations, 4314 (93%) reported their race as black, 184 (4%) reported their race as mixed (black and white), and 133 (3%) reported their race as white or other. Low vision was found in 5.9% of the black, 2.7% of the mixed, and 3.0% of white or other participants. Bilateral blindness was similar for black and mixed race participants (1.7% and 1.6%, respectively) and was not found in whites. Among black and mixed participants, the prevalence of low vision increased with age (from 0.3% at 40-49 years to 26.8% at 80 years or older). The prevalence of blindness was higher (P < 0.001) for men than women at each age group (0.5% versus 0.3% at ages 40-49 and 10.9% versus 7.3% at 80 years or more). Sixty percent of blindness was due to open-angle glaucoma and age-related cataract, each accounting for more than one fourth of cases. Other major causes were optic atrophy or neuropathy and macular and other retinal diseases. Few cases of blindness were due to diabetic retinopathy (1.4%), and none were due to age-related macular degeneration. CONCLUSIONS Using the WHO criteria, prevalence of visual impairment was high in this African-origin population, particularly at older ages. Most blindness was due to open-angle glaucoma and cataract, with open-angle glaucoma causing a higher proportion of blindness than previously reported. The increased prevalence of blindness in men may be due to the increased male prevalence of glaucoma in this population and warrants further investigation. Results underline the need for blindness prevention programs, with emphasis on effective treatment of age-related cataract and enhancing strategies for early detection and treatment of open-angle glaucoma.

Complications of Vitreous Surgery for Diabetic Retinopathy: I. Intraoperative Complications

One hundred seventy-nine eyes were analyzed to determine the incidence of intraoperative complications during vitrectomy for proliferative diabetic retinopathy. Inadvertent corneal epithelial defects occurred in 51 eyes (28%). The lens was removed in 42 (25%) of 170 phakic eyes. This was done through a pars plana approach. Accidental mechanical lens damage occurred in one eye, and mild pharmacologic lens damage occurred in two eyes. Some bleeding from fibrovascular tissue occurred in nearly every case, but this was controlled with diathermy except in seven eyes (4%) in which severe bleeding required premature termination of the operation. Latrogenic retinal tears occurred in 36 (20%) of the 179 eyes. Fifteen (34%) of the total of 44 retinal tears were anterior to the equator, and 11 (73%) of the 15 anterior tears were located posterior to the sclerotomy through which the vitrectomy probe was introduced. Twenty-nine (66%) of the 44 retinal tears were posterior to the equator, and 19 of the 29 occurred within 15 degrees radius of the fovea.

Choroidal Neovascularization after Laser Photocoagulation for Diabetic Macular Edema

Choroidal neovascular membranes (CNVMs) developed in eight patients after photocoagulation for clinically significant diabetic macular edema (DME). The CNVMs developed in areas where Bruchs membrane was ruptured and were diagnosed 2 weeks to 5 months after treatment. Only six patients had symptoms. The CNVMs were treated in four patients; final visual acuity was poor in all eight patients. This serious complication that follows laser treatment for DME may be related to the use of repeated small-size, short-duration laser or intense laser burns, or both.

Diabetes, hypertension, and central obesity as cataract risk factors in a black population. The Barbados Eye Study

OBJECTIVE The increased cataract prevalence of black populations, especially of cortical cataract, remains unexplained. The authors evaluate the relationships of diabetes, hypertension, and obesity patterns to lens opacities, by age, among 4314 black participants in the Barbados Eye Study. DESIGN AND PARTICIPANTS Prevalence study of a random sample of the Barbados population, ages 40 to 84 years (84% participation). MAIN OUTCOME MEASURES Associations with age-related lens changes (grade > or = 2 in the Lens Opacities Classification System II at the slit lamp) were evaluated in logistic regression analyses by age (persons < 60 years and > or = 60 years). Results are presented as odds ratios (OR) with 95% confidence intervals. RESULTS Of the 1800 participants with lens changes, most had cortical opacities. Diabetes history (18% prevalence) was related to all lens changes, especially at younger ages (age < 60 years: OR = 2.23 [1.63, 3.04]; age > or = 60 years: OR = 1.63 [1.22, 2.17]). Diabetes also increased the risk of cortical opacities (age < 60 years: OR = 2.30 [1.63, 3.24]; age > or = 60 years: OR = 1.42 [1.03, 1.96]); additional risk factors were high diastolic blood pressure (age < 60 years: OR = 1.49 [1.00, 2.23]) and higher waist/hip ratio (all ages: OR = 1.36 [1.00, 1.84]). Diabetes was also related to posterior subcapsular opacities. Glycated hemoglobin levels were positively associated with cortical and posterior subcapsular opacities. Overall, 14% of the prevalence of lens changes could be attributed to diabetes. CONCLUSIONS The high prevalence of cortical opacities was related to diabetes, hypertension, and abdominal obesity, which also are common in this and other black populations. Interventions to modify these risk factors, especially in populations in which they are highly prevalent, may have implications to control visual loss from cataract, which is the first cause of blindness worldwide.

Massive Hemorrhage Complicating Age-Related Macular Degeneration: Clinicopathologic Correlation and Role of Anticoagulants

Reported are 15 cases of age-related macular degeneration (AMD) complicated by massive subretinal and/or vitreous hemorrhage. Clinicopathologic correlation is presented in four of the seven cases studied histopathologically. Salient histologic findings include: subretinal and subretinal pigment epithelium (sub-RPE) fibrovascular scar in the posterior pole; discontinuities in Bruchs membrane with choroidal neovascularization; extensive hemorrhagic detachment of the RPE and sensory retina; and vitreous hemorrhage. In three cases, a choroidal artery, emerging from breaks in Bruchs membrane, had ruptured walls. The authors have reviewed the previously reported cases of AMD complicated by massive hemorrhage and found that 19% of the patients were taking Coumadin (warfarin) or aspirin treatment when the bleeding occurred. Forty percent had a positive history of systemic hypertension and cardiovascular diseases. Although the occurrence of hypertension is expected in the aged population with AMD, use of anticoagulants or antithrombotics by such patients may predispose them to serious ocular hemorrhagic complications.