Macular Degeneration: Hawkins BS

Solomon SD, Bressler SB, Hawkins BS, Marsh MJ, Bressler NM, Anonymous00106. · Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2005, USA. · Retina. · Pubmed #15805900 links to  free full text

Abstract: PURPOSE: To describe the guidelines followed by the Submacular Surgery Trials (SST) Research Group in the interpretation of color fundus photographs and fluorescein angiograms of subfoveal choroidal neovascular lesions evaluated in the SST and to assist ophthalmologists in applying the results of the SST. METHODS: Stereoscopic color fundus photographs and fluorescein angiograms of the study eye and nonstudy eye of 1,015 patients with subfoveal choroidal neovascular lesions secondary to age-related macular degeneration, ocular histoplasmosis syndrome, or idiopathic choroidal neovascularization (CNV) were obtained and graded by certified SST fundus photograph readers at the baseline examination in three randomized clinical trials comparing surgery with observation. Adherence to the inclusion and exclusion criteria and ocular features that might affect visual outcome were documented. Stereoscopic color fundus photography and fluorescein angiography were repeated 1 month after randomization for patients assigned to surgery to provide documentation that surgery was performed and to assess compliance with the surgery protocol. Photographs and fluorescein angiograms of both the study eye and the fellow eye in all patients then were obtained 3 months, 6 months, and 12 months after randomization and then annually up to 48 months. The kappa statistic was used to evaluate interobserver reliability of photograph gradings. RESULTS: Lesion components at baseline included classic CNV, occult CNV, and features contiguous to CNV, including blood, fibrous tissue, hypofluorescence not corresponding to blood, serous detachment of the retinal pigment epithelium, and prior areas of laser photocoagulation. At follow-up, fluorescein leakage from CNV was assessed peripheral to or within the area of the retinal pigment epithelium abnormality after surgery. The lesion at follow-up could include any of the features identified at baseline as well as retinal pigment epithelium abnormalities, such as mottling of the retinal pigment epithelium with a subtle transition to normal retinal pigment epithelium or a very sharply demarcated, markedly hypopigmented area that was easily distinguished from the surrounding retinal pigment epithelium. kappa statistics for interobserver reliability ranged from good (0.47) to excellent (1.00) for features graded at baseline and follow-up. CONCLUSIONS: Although some of the definitions essential to the interpretation of the SST are similar to those used in the Macular Photocoagulation Study and randomized clinical trials of photodynamic therapy with verteporfin, this guideline provides new information regarding lesion components at baseline as well as standardized descriptions of lesions after submacular surgery. These descriptions from the SST assist in understanding what lesions were studied, when additional treatment was considered after surgery, and how anatomical results should be interpreted.

Bressler NM, Hawkins BS, Sternberg P, McDonald HR, Steinberg P. · No affiliation provided · Ophthalmology. · Pubmed #11237895 No free full text.

This publication has no abstract.

Hawkins BS, Bird A, Klein R, West SK. · The Wilmer Ophthalmological Institute, Baltimore, MD 21205-2010, USA. · Mol Vis. · Pubmed #10562650 links to  free full text

Abstract: For more than two decades, researchers have sought to identify "risk factors" for age-related macular degeneration (AMD), a major cause of irreversible vision loss in the Western world, particularly in the elderly. Two issues have complicated this search: failure to differentiate between different stages of AMD and misinterpretation of measures of association (odds ratios) and risk (risk ratios) derivable from different research designs. Fortunately, in more recent epidemiologic studies, more attention has been given to these issues. Three groups of potential "risk factors" that have been studied were reviewed: those known to be risk factors for cardiovascular disease, environmental factors, and racial and ethnic factors. Of these, only tobacco smoking, a known risk factor for cardiovascular disease, has been demonstrated to be associated with AMD consistently across many studies of different design, carried out within different populations. The available evidence supports at least a doubling of risk of late AMD associated with long-term smoking, a factor that is under the control of the individual. The preponderance of evidence has not supported other factors to the same degree. Presently, racial and ethnic factors are high priorities for further research.

Childs AL, Bressler NM, Bass EB, Hawkins BS, Mangione CM, Marsh MJ, Miskala PH, Anonymous00092. · SST Coordinating Center, 550 North Broadway, 9th Floor, Baltimore, MD 21205, USA. · Ophthalmology. · Pubmed #15522365 links to  free full text

Abstract: PURPOSE: To present and compare findings from health-related quality-of-life (HRQOL) interviews conducted with patients enrolled in the SST Group B Trial evaluating surgical removal of subfoveal choroidal neovascular lesions associated with age-related macular degeneration versus observation. DESIGN: Randomized clinical trial. PARTICIPANTS: Eligible patients had predominantly hemorrhagic subfoveal choroidal neovascular lesions (total lesion size of >3.5 disc areas, area of blood at least 50% of the lesion area, and at least 75% of blood posterior to the equator) and best-corrected visual acuity (VA) of 20/100 to <20/1600 but at least light perception in the study eye. Three hundred thirty-six patients enrolled after baseline quality-of-life interviews, 168 assigned to each of surgery or observation. METHODS: Clinical and HRQOL data were collected before randomization and at 6, 12, 24, 36, and 48 months after enrollment. Baseline clinical evidence was used to stratify patients as having unilateral or bilateral neovascularization at the time of randomization. The HRQOL interviews included the National Eye Institute Visual Function Questionnaire (NEI-VFQ), the 36-item Short Form Health Survey, and the Hospital Anxiety and Depression Scale. MAIN OUTCOMES MEASURE: Two-year change in NEI-VFQ. RESULTS: At 24 months after enrollment, overall NEI-VFQ scores had a median decrease of 1 point from baseline in the observation arm (95% confidence interval [CI]: -4 to 3 points) and no change in the surgery arm (95% CI: -3 to 3 points) (P = 0.70). Changes from baseline on NEI-VFQ subscales also were similar between treatment arms. Differences in scores by unilateral or bilateral involvement seen at baseline in each treatment arm persisted throughout follow-up for most outcomes. Planned analyses stratified by VA showed trends (P = 0.17) in favor of surgery at 24 months in the patients with baseline VA greater than 20/200 for the NEI-VFQ scale (3.5-point median increase from baseline in the surgery arm [95% CI: -4 to 7] vs. a 1-point median loss from baseline in the observation arm [95% CI: -6 to 4]). CONCLUSIONS: No difference was detected with respect to vision-targeted quality-of-life outcomes for patients randomized to surgery or observation in the SST Group B Trial. This article contains additional online-only material available at www.ophsource.com/periodicals/ophtha.

Bressler NM, Bressler SB, Childs AL, Haller JA, Hawkins BS, Lewis H, MacCumber MW, Marsh MJ, Redford M, Sternberg P, Thomas MA, Williams GA, Anonymous00091. · SST Coordinating Center, Wilmer Clinical Trials and Biometry, 550 North Broadway, 9th Floor, Baltimore, MD 21205-2010, USA. · Ophthalmology. · Pubmed #15522364 links to  free full text

Abstract: PURPOSE: To present best-corrected visual acuity (BCVA) findings and other clinical outcomes from eyes of patients enrolled in one of the Submacular Surgery Trials (SST) evaluating surgical removal versus observation of predominantly hemorrhagic subfoveal choroidal neovascularization (CNV) associated with age-related macular degeneration. DESIGN: Randomized clinical trial (SST Group B Trial). PARTICIPANTS: Eligible patients had subfoveal choroidal neovascular lesions greater than 3.5 disk areas (8.9 mm2) composed of at least 50% blood (either blood or CNV underlying the center of the foveal avascular zone) and BCVA of 20/100 to light perception in the study eye. INTERVENTION: Patients were assigned randomly at time of enrollment to observation or surgical removal of blood and any associated CNV. MAIN OUTCOME MEASURE: A successful outcome was defined a priori as either improvement in visual acuity (VA), no change in VA, or a decline in VA of no more than 1 line (7 letters) from baseline to the 24-month examination based on an intent-to-treat analysis. RESULTS: Of 336 patients enrolled, 168 were assigned to each treatment arm; treatment arms were balanced by baseline characteristics. Of 1501 expected examinations 3 months through 36 months after baseline, 1370 (91%) were performed. Loss of > or =2 lines (> or =8 letters) of VA occurred in 56% of surgery eyes, versus 59% of observation eyes examined at 24 months. Although severe loss of VA was not the primary outcome of interest, surgery more often prevented such loss: 36% in the observation arm versus 21% in the surgery arm at the 24-month examination (chi2 P = 0.004). Of initially phakic eyes, the cumulative percentage that had undergone cataract surgery by 24 months was 44% in the surgery arm, compared with 6% in the observation arm. Twenty-seven eyes (16%) in the surgical arm, compared with 3 eyes (2%) in the observation arm, had a rhegmatogenous retinal detachment (RD). CONCLUSIONS: Submacular surgery as performed in the SST Group B Trial did not increase the chance of stable or improved VA (the primary outcome of interest) and was associated with a high risk of rhegmatogenous RD, but did reduce the risk of severe VA loss in comparison with observation. This article contains additional online-only material available at http://www.ophsource.com/periodicals/ophtha.

Miskala PH, Bass EB, Bressler NM, Childs AL, Hawkins BS, Mangione CM, Marsh MJ, Anonymous00090. · SST Coordinating Center, 550 North Broadway, 9th Floor, Baltimore, MD 21205-2010, USA. · Ophthalmology. · Pubmed #15522363 links to  free full text

Abstract: PURPOSE: To describe health-related quality of life (HRQOL), overall and in patients with unilateral or bilateral choroidal neovascularization (CNV), in a clinical trial (Group N Trial) comparing observation and surgical removal of subfoveal CNV secondary to age-related macular degeneration (AMD). DESIGN: Randomized clinical trial. PARTICIPANTS: Eligible patients had untreated subfoveal CNV and AMD, best-corrected visual acuity (VA) of 20/100 to 20/800, classic CNV on fluorescein angiography, and a total subfoveal lesion size of < or =9.0 disc areas in the study eye. METHODS: Health-related quality of life data (the National Eye Institute Visual Function Questionnaire [NEI-VFQ], 36-item Short Form Health Survey [SF-36], and Hospital Anxiety and Depression Scale [HADS]) and clinical data were collected at baseline and at 6, 12, 24, 36, and 48 months. Patients were divided into unilateral and bilateral CNV subgroups based on fluorescein angiographic and clinical evidence. MAIN OUTCOME MEASURE: Two-year change in the NEI-VFQ. RESULTS: Of 454 patients enrolled, 228 were assigned to observation and 226 to surgery. At baseline, median overall NEI-VFQ scores were 67 in the observation group and 69 in the surgery group; by 2 years, the observation group had lost a median of 3 points (95% confidence interval [CI]: -6 to -2), and the surgery group gained a median of 1 point (CI: -1 to 3). The largest difference was observed for the mental health subscale, where the observation group lost a median of 5 points (CI: -5 to 0), and the surgery group gained a median of 5 points (CI: 0-10) by 2 years. Treatment differences in median 2-year changes in NEI-VFQ scores favored surgery by up to 10 points for unilateral cases and up to 8 points for bilateral cases. No treatment difference in 2-year change was observed for the SF-36 physical component summary; 2-year change in the mental component summary favored surgery by 2 points. Few patients (2%-4%) had HADS definite anxiety or depression at baseline or at 24 months. CONCLUSIONS: Although HRQOL outcomes were better in the submacular surgery arm than in the observation arm, surgery (per protocol) is not recommended because VA outcomes (reported elsewhere) were similar in the treatment arms. This article contains additional online-only material available at http://www.ophsource.com/periodicals/ophtha.

Hawkins BS, Bressler NM, Miskala PH, Bressler SB, Holekamp NM, Marsh MJ, Redford M, Schwartz SD, Sternberg P, Thomas MA, Wilson DJ, Anonymous00089. · SST Coordinating Center, Wilmer Clinical Trials and Biometry, 550 North Broadway, 9th Floor, Baltimore, MD 21205-2010, USA. · Ophthalmology. · Pubmed #15522362 links to  free full text

Abstract: PURPOSE: To present visual acuity (VA) and related findings from patients enrolled in one of the Submacular Surgery Trials (SST) evaluating surgical removal versus observation of subfoveal choroidal neovascularization secondary to age-related macular degeneration (SST Group N Trial). DESIGN: Randomized clinical trial. PARTICIPANTS: Eligible patients had age-related macular degeneration with subfoveal choroidal neovascularization, some with a classic pattern on fluorescein angiography, and best-corrected VA (BCVA) of 20/100 to 20/800 in one eye (study eye) that had received no treatment in the macula. Any contiguous blood had to account for <50% of the total area occupied by the subfoveal lesion (maximum size, 9.0 disc areas [22.9 mm2]). METHODS: Randomization was stratified by VA and by clinical center. All patients were scheduled for study examinations at 3, 6, 12, and 24 months after enrollment for assessment of study outcomes. MAIN OUTCOME MEASURE: A successful outcome was defined a priori to be either improvement of BCVA or VA no more than 1 line (7 letters) worse than baseline at the 24-month examination. RESULTS: Of 454 patients enrolled, 228 study eyes were assigned to observation and 226 to surgery. The percentages of eyes that had successful outcomes were similar in the 2 arms: 44% assigned to observation and 41% assigned to surgery. Median VA losses from baseline to the 24-month examination were 2.1 lines (10.5 letters) in the observation arm and 2.0 lines (10 letters) in the surgery arm. Median VA declined from 20/100 at baseline to 20/400 at 24 months in both arms. No subgroup of patients was identified in which submacular surgery led to better VA outcomes. In the surgery arm, 55 (39%) of 142 initially phakic eyes had cataract surgery by the 24-month examination, compared with 6 (5%) of 133 eyes in the observation arm. Rhegmatogenous retinal detachment occurred in 12 surgery eyes (5%) and 1 observation eye. CONCLUSIONS: Submacular surgery, as performed in this clinical trial, did not improve or preserve VA for 24 months in more eyes than observation and is not recommended for patients with similar lesions. This article contains additional online-only material available at http://www.ophsource.com/periodicals/ophtha.

Dong LM, Childs AL, Mangione CM, Bass EB, Bressler NM, Hawkins BS, Marsh MJ, Miskala P, Jaffee HA, McCaffrey LA, Anonymous00315. · Wilmer Clinical Trials and Biometry, The Wilmer Ophthalmologic Institute, 550 N. Broadway, 9th Floor, Baltimore, MD 21205-2010, USA. · Am J Ophthalmol. · Pubmed #15234287 No free full text.

Abstract: PURPOSE: To describe the effect of subfoveal choroidal neovascularization (CNV) from age-related macular degeneration (AMD) on health-related quality of life (HRQOL) of patients at enrollment in two randomized clinical trials; to examine the relation of visual acuity to HRQOL; to compare HRQOL scores between participants with unilateral and bilateral CNV independent of other characteristics. DESIGN: Randomized clinical trials. METHODS: Two Submacular Surgery Trials (SST) recruited patients with AMD and either new subfoveal CNV (Group N Trial) or predominantly hemorrhagic CNV (Group B Trial). Health-related quality of life interviews included the National Eye Institute Visual Function Questionnaire [NEI-VFQ], the SF-36 Health Survey, and the Hospital Anxiety and Depression Scale [HADS]. Linear correlation and regression analyses were used to relate baseline HRQOL scores to visual acuity and bilateral disease. RESULTS: Interview data were analyzed for 789 AMD patients: 454 patients in the Group N Trial and 335 patients in the Group B Trial. Participants reported poor vision-related functioning in many domains measured by the NEI-VFQ (mean overall scores of 65 for Group N and 63 for Group B). Visual acuity of the better eye was strongly associated with NEI-VFQ scores but not with SF-36 or HADS scores. After adjusting for visual acuity of the better eye and other factors, bilateral cases had NEI-VFQ overall scores six points lower than unilateral cases in Group N Trial and 10 points lower than unilateral cases in the Group B Trial. CONCLUSIONS: Subfoveal CNV profoundly affects vision-related quality of life. The effect is more pronounced with bilateral disease, even after controlling for visual acuity.

Miskala PH, Hawkins BS, Mangione CM, Bass EB, Bressler NM, Dong LM, Marsh MJ, McCaffrey LD, Anonymous00023. · Submacular Surgery Trials Coordinating Center, Wilmer Clinical Trials and Biometry, Baltimore, MD 21205, USA. · Arch Ophthalmol. · Pubmed #12695250 links to  free full text

Abstract: BACKGROUND: The National Eye Institute Visual Function Questionnaire (NEI-VFQ) measures vision-targeted quality of life, but it is unclear whether it is sensitive to changes within individuals over time. OBJECTIVE: To determine the responsiveness of the NEI-VFQ to "within-individual" changes in visual acuity in patients who had subfoveal choroidal neovascularization in at least one eye secondary to age-related macular degeneration, ocular histoplasmosis syndrome, or idiopathic causes, and who participated in randomized trials of submacular surgery. METHODS: Trained telephone interviewers administered the NEI-VFQ as part of annual follow-up data collection for pilot trials and larger clinical trials of submacular surgery. Best-corrected visual acuity was measured by local vision examiners at 12 months after enrollment and, typically, by central "traveling" vision examiners at 24 months after enrollment. Changes in visual acuity and NEI-VFQ scores from 12 to 24 months were analyzed using linear regression methods. RESULTS: Two-hundred eighteen patients had both interviews and visual acuity measurements at 12 and 24 months after enrollment. Changes in the overall NEI-VFQ score and in 9 of the subscales (near activities, dependency, driving, role difficulties, distance activities, mental health, general vision, peripheral vision, and social functioning) were related to changes in visual acuity of the better-seeing eye based on linear regression analysis (P<.05). In our analysis, a 3-line decrease in the visual acuity of the better-seeing eye was associated with 3.6- to 16.2-point decreases in the overall NEI-VFQ score and 9 subscale scores. CONCLUSIONS: Most of the NEI-VFQ subscales were responsive to changes in the visual acuity of the better-seeing eye over a 12-month interval in this patient population. Thus, the NEI-VFQ can be used to measure change in vision-targeted quality of life over time to augment clinical measurements of visual acuity.

Dong LM, Hawkins BS, Marsh MJ. · Wilmer Clinical Trials and Biometry, 550 N Broadway, Ninth Floor, Baltimore, MD 21205-2010, USA. · Arch Ophthalmol. · Pubmed #12427067 No free full text.

Abstract: OBJECTIVE: To investigate the consistency of visual acuity (VA) scores measured at 2 different distances in patients with or at risk for choroidal neovascularization. METHODS: Best-corrected VA scores measured at 2 distances for the same eyes at the same examinations were collected from 4 sets of randomized clinical trials among patients with or at risk of choroidal neovascularization. Within each trial, the pairs of VA scores were compared and their relationship was explored. RESULTS: After adjustment for test distance, VA scores obtained at the closer distance were found to be systematically lower than those obtained at the farther distance in all data sets. In the Submacular Surgery Trials pilot study, the average discrepancy between 2- and 0.5-m VA scores was 7.5 letters. In an ancillary study of the Macular Photocoagulation Study, the discrepancy between 10-ft and 5-ft VA scores was 3.1 letters. In the Laser to Drusen Trial pilot study, the discrepancy between 3.2- and 1-m VA scores was 7.3 letters. In the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy Study, in which the VA scores at the closer test distance were censored, the estimated discrepancy between 2- and 1-m VA scores was 8.2 letters. Reduction in visual angle at closer test distance did not explain the discrepancy completely. Features of the macular lesion, poor accommodation of the elderly population with age-related macular degeneration, or the test charts did not account for the discrepancies. CONCLUSION: The VA scores at distances less than 2 m were lower than expected in all 4 studies. The observed discrepancy was consistent with findings from a study among healthy young subjects, suggesting that the phenomenon is real and common.

Orr PR, Cramer LD, Hawkins BS, Bressler NM. · The Johns Hopkins University School of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205-2010, USA. · Invest Ophthalmol Vis Sci. · Pubmed #11157881 links to  free full text

Abstract: PURPOSE: To compare the results from manifest refraction using trial lenses and a standard visual acuity protocol to results from autorefraction for obtaining refractive error and best corrected visual acuity in patients enrolled in a randomized clinical trial. METHODS: During a 4-month period, 29 patients with subfoveal choroidal neovascularization (CNV), who were enrolled in the Submacular Surgery Trials (SSTs) Pilot Study at the Wilmer Ophthalmological Institute, gave verbal consent to participate in this study. Best corrected visual acuity was obtained using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity charts and standardized room lighting after performance of manifest refraction, according to the SST protocol, and autorefraction. Refractive error (spherical equivalent) and visual acuity scores were obtained in both eyes of all patients. RESULTS: On average, manifest refraction gave a spherical equivalent that was 1.04 D more plus than autorefraction (95% limits of agreement = 0.74, 1.34). On average, the visual acuity score was 1.5 letters better after manifest refraction than after autorefraction (95% limits of agreement = 0, 3.0).The comparison of the two methods of refraction was subdivided according to visual acuity level and eye disease (age-related macular degeneration or ocular histoplasmosis syndrome). CONCLUSIONS: Despite large differences in spherical equivalent between manifest refraction and autorefraction, the visual acuity scores were close (mean difference, 1.5 letters). Other studies comparing subjective refraction and autorefraction have shown similar results. Autorefraction in patients with subfoveal CNV may be a satisfactory alternative to manifest refraction in clinical trials and field studies in which best corrected visual acuity is of interest.

Bressler NM, Bressler SB, Hawkins BS, Marsh MJ, Sternberg P, Thomas MA, Anonymous00036. · No affiliation provided · Am J Ophthalmol. · Pubmed #11024412 No free full text.

Abstract: PURPOSE: To report complications and changes in vision during 2 years of follow-up of patients with age-related macular degeneration assigned randomly to surgical removal or to laser photocoagulation of subfoveal recurrent neovascular lesions in a pilot trial designed to test methods, to refine estimates of outcome rates, and to project patient accrual rates for a larger multicenter randomized trial to evaluate submacular surgery. PATIENTS AND METHODS: Eligible patients with previous laser photocoagulation of extrafoveal or juxtafoveal choroidal neovascularization secondary to age-related macular degeneration were enrolled at 15 collaborating clinical centers. Assignments to treatment arm were made by personnel at a central coordinating center. Adherence to eligibility criteria and treatment assignment was assessed centrally at a photograph reading center. Patients were examined at 3, 6, 12, and 24 months after treatment for data collection purposes. Outcome measures reported include treatment complications, adverse events, requirements for additional treatment, and 2-year changes in visual acuity from baseline. RESULTS: Of 70 patients enrolled, 36 were assigned to laser photocoagulation and 34 to submacular surgery; all were treated as assigned. One patient in each group died before the 2-year examination. Visual acuity was measured at the 2-year examination for 31 of the surviving patients (89%) in the laser arm and for 28 of the surviving patients (85%) in the surgery arm. The 2-year measurements for 36 of the 59 patients (61%) were made by an examiner masked to treatment assignment and to the identity of the study eye. Improvements and losses of visual acuity were observed in both treatment arms; 20 of 31 study eyes (65%) in the laser arm and 14 of 28 study eyes (50%) in the surgery arm had visual acuity 2 years after enrollment that was better than or no more than 1 line worse than the baseline level. Changes in visual acuity and the size of the central macular lesions from baseline to the 2-year examination were similar in the treatment arms. Few serious complications were observed in either arm at the time of initial treatment; serious adverse events were rare. During follow-up, 11 laser-treated eyes and 18 surgically treated eyes had additional intraocular procedures. CONCLUSIONS: The data from this pilot trial suggest no reason to prefer submacular surgery over laser photocoagulation for treatment of patients with age-related macular degeneration who have lesions similar to those studied in this pilot trial. Any clinical trial designed to compare submacular surgery with laser photocoagulation in eyes with age-related macular degeneration and subfoveal recurrent neovascular lesions must enroll several hundred patients in order to reach a statistically valid conclusion regarding differences between these two methods of treatment with respect to either changes in visual acuity or complication rates.

Solomon SD, Dong LM, Haller JA, Gilson MM, Hawkins BS, Bressler NM, Anonymous00207. · Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Retina. · Pubmed #19516120 No free full text.

Abstract: OBJECTIVE: To identify risk factors associated with the development of rhegmatogenous retinal detachment (RRD) in patients enrolled in the Submacular Surgery Trials. METHODS: One thousand fifteen patients with eligible subfoveal neovascular lesions in the study eye were assigned randomly to observation or to surgery. Eyes were examined at 3 months, 6 months, 12 months, and 24 months after enrollment to assess study outcomes and adverse events, including RRDs. Adverse events also were reported at other times as clinical personnel became aware of them. Potential risk factors for the development of RRD in study eyes were evaluated using recursive partitioning and logistic regression analysis. RESULTS: Among 506 eyes assigned to surgery, RRD developed in 44 (8.7%) compared with 4 (0.8%) of 509 eyes assigned to observation. Of the 44 eyes in which RRD developed, 27 had age-related macular degeneration (AMD) and large (>3.5 MPS disk areas) hemorrhagic subfoveal neovascular lesions at baseline and represented 16.1% of all eyes with such lesions assigned to surgery. Eyes with AMD and larger hemorrhagic lesions (>16 MPS disk areas) together with relatively poor visual acuity (best-corrected visual acuity < or =20/1280) had a higher risk of RRD (odds ratio = 6.2, 95% confidence interval: 2.2-16.7) compared with those with smaller lesions and better visual acuity at baseline. CONCLUSION: Poor visual acuity and very large, predominantly hemorrhagic subfoveal neovascular AMD lesion type were the greatest risk factors for RRD after submacular surgery. Submacular surgery should be undertaken in such eyes with full awareness of the risk of RRD during subsequent follow-up.

Hawkins BS, Bressler NM, Reynolds SM. · Wilmer Eye Institute, School of Medicine, Johns Hopkins University, 550 N Broadway, Room 930, Baltimore, MD 21205-2010, USA. · Arch Ophthalmol. · Pubmed #19506188 No free full text.

Abstract: OBJECTIVE: To compare 2-year visual acuity outcomes between similar participants assigned to sham and no-treatment control arms in randomized clinical trials. METHODS: We retrospectively matched sham controls from 2 randomized trials to no-treatment controls (no sham or placebo) from 3 trials on 8 baseline prognostic criteria (full matches) or on 4 to 7 criteria (partial matches). Outcomes were compared using data from those who had 2-year visual acuity measurements and also using the last observation carried forward method to impute missing 2-year measurements. RESULTS: A full match to a no-treatment control was identified for 72 of 321 sham controls (22%); a partial match was identified for another 93 sham controls (29%). Among the fully matched pairs, no important difference in 2-year visual acuity outcomes was observed. However, 2-year outcomes differed somewhat between sham and no-treatment controls within the partially matched pairs. CONCLUSIONS: Findings from fully matched pairs suggest that sham treatment to mask participants in clinical trials may be unnecessary when visual acuity is the outcome of interest. However, findings from the partially matched pairs do not fully support this conclusion. This analysis challenges the necessity for sham (placebo) controls in randomized clinical trials in ophthalmology when visual acuity is the primary outcome of interest.

Jefferys JL, Alexander J, Hiner CJ, Javornik NB, Smith RE, Bressler NM, Hawkins BS. · The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Ophthalmic Epidemiol. · Pubmed #18569815 No free full text.

Abstract: PURPOSE: To assess the reproducibility of the evaluation of color photographs and fluorescein angiograms of the macula of each eye for patients enrolled in the Macular Photocoagulation Study (MPS) trials of laser photocoagulation of subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration. METHODS: A total of 65 pre-enrollment and 26 posttreatment sets of photographs were regraded. The two gradings were compared on selected items judged to be of primary importance with respect to the role of the MPS Reading Center. RESULTS: Agreement on eligibility of the neovascular lesion for an MPS trial was 88% (kappa statistic = 0.59); agreement on the size of the lesion was 86% (kappa statistic = 0.80); agreement on whether the lesion was covered by heavy treatment was 69% (kappa statistic = 0.35); and agreement on whether the treatment was in compliance with the study protocol was 73% (kappa statistic = 0.06). CONCLUSIONS: Interpretation of photographs of eyes with CNV secondary to age-related macular degeneration for eligibility and size of the lesion was reproducible in the MPS. However, adequacy of laser photocoagulation treatment could not be determined reliably from photographs.

Sunness JS, Rubin GS, Broman A, Applegate CA, Bressler NM, Hawkins BS. · The Richard E Hoover Rehabilitation Services for Low Vision and Blindness, Greater Baltimore Medical Center, Baltimore, Maryland 21204, USA. · Ophthalmology. · Pubmed #18486216 No free full text.

Abstract: OBJECTIVE: To show that low luminance visual dysfunction is predictive of subsequent visual acuity (VA) loss in eyes with geographic atrophy (GA) resulting from age-related macular degeneration (AMD). DESIGN: Cohort study examining the prospective natural history study of GA from 1992 through 2000 at the Wilmer Eye Institute. PARTICIPANTS: Ninety-one participants with GA resulting from AMD without choroidal neovascularization in at least 1 eye who completed a 2-year study examination. METHODS: Annual examinations included measurement of best-corrected VA, low luminance VA, Pelli-Robson contrast sensitivity, reading speed, examination, and fundus photography. The total GA area was quantified, as was the GA within a 10.2-mm(2) circle centered on the fovea. MAIN OUTCOME MEASURES: Visual acuity loss at 2 years and risk factors for visual loss. RESULTS: Participants with baseline VA of 20/50 or more had a 40% 2-year rate of VA loss of 3 lines or more, compared with 13% for the participants with worse baseline acuities. The baseline low-luminance deficit (LLD) in VA was a strong predictor of subsequent VA loss for all levels of baseline VA. Within the good baseline VA group, the relative risk (RR) of 3-line loss for the worse LLD group compared with the better LLD group was 2.88 (95% confidence interval [CI], 1.13-7.35). The LLD is a stable and reproducible measure. Other significant visual function predictors of subsequent VA loss in eyes with good baseline VA included foveal dark-adapted sensitivity (RR, 4.20; 95% CI, 1.39-12.71) and reduced reading rate (RR, 2.43; 95% CI, 1.11-5.31). The rate of VA loss within the good acuity group was higher when the GA included 25% to 75% of the central 10.2 mm(2) than in eyes with GA including less than 25% or more than 75% of the central 10.2 mm(2). The following were not significant predictors of subsequent VA loss among these participants: age, gender, fellow eye diagnosis, fellow eye VA, baseline GA area, and GA enlargement rate. CONCLUSIONS: Visual function measures can predict the risk of future VA loss in subjects with GA and good baseline VA. They may allow identification of the highest risk group for VA loss, enabling more efficient design of clinical trials. They also may be appropriate surrogate measures of foveal health in short-term treatment trials.

Anonymous00076, Solomon SD, Jefferys JL, Hawkins BS, Bressler NM. · Johns Hopkins University School of Medicine, 550 N Broadway, Ste 115, Baltimore, MD 21205-2005, USA. · Arch Ophthalmol. · Pubmed #17923538 links to  free full text

Abstract: OBJECTIVE: To describe incident choroidal neovascular lesions in fellow eyes of participants in the Submacular Surgery Trials who had age-related macular degeneration (AMD). METHODS: Review of baseline fluorescein angiograms confirmed the absence of neovascular AMD in fellow eyes of 364 participants at risk. Subjects were eligible for a minimum of 2 years of follow-up with angiograms of eyes at risk reevaluated to estimate incidence rates of choroidal neovascularization (CNV) and to characterize these lesions. MAIN OUTCOME MEASURES: Incidence of CNV during follow-up, characteristics of the incident lesion (composition, size, and location), and visual acuity at the time of incidence. RESULTS: Incident lesions were confirmed in 98 fellow eyes of participants, yielding 2- and 4-year cumulative incidence rates of 22% and 37%. Incident lesions were predominantly CNV in 87 fellow eyes (90%), extrafoveal in 29 fellow eyes (30%), and juxtafoveal in 9 fellow eyes (9%). Occult without classic CNV lesions were found in 64 eyes (67%), minimally classic CNV and predominantly classic CNV lesions in 12 eyes (13%) each, and predominantly blood lesions in 4 eyes (4%). Nearly two-thirds of all incident lesions were 3 disc areas or smaller in size. Median visual acuity decreased from 20/25 at baseline to 20/250 at the 4-year follow-up in fellow eyes with incident CNV. CONCLUSIONS AND APPLICATION TO CLINICAL PRACTICE: Frequent angiographic follow-up of fellow eyes at risk for CNV may lead to earlier detection and treatment of neovascular AMD and better visual acuity outcomes.

Anonymous00228, Mann AL, Bressler SB, Hawkins BS, Holekamp N, Bressler NM. · Submacular Surgery Trials Chair's Office, Wilmer Eye Institute, Johns Hopkins University, 550 North Broadway, Suite 115, Baltimore, MD 21205, USA. · Ophthalmology. · Pubmed #17574675 No free full text.

Abstract: PURPOSE: To describe and compare methods used to monitor development and progression of presumed vision-limiting lens opacity in study eyes of Submacular Surgery Trials (SST) patients. DESIGN: Prospective study of patients enrolled in a set of randomized clinical trials. PARTICIPANTS: Patients enrolled in the SST who were phakic in the study eye at the time of enrollment (n = 690). In a subset of 114 patients, lens photographs were obtained at baseline and 2 years after enrollment. METHODS: Data collection at baseline and annual follow-up examinations included ocular history, ophthalmologic examination including the SST ophthalmologist's assessment of presence or absence of vision-limiting opacity, fundus photography, and lens photography (13 of 27 clinics only). All photographs were assessed by masked graders centrally using the Lens Opacities Classification System III (LOCS III). kappa statistics were calculated to compare LOCS III cataract classifications with fundus photograph quality and with the ophthalmologist's assessment of lens opacity, with the LOCS III classification considered the gold standard. MAIN OUTCOME MEASURE: Incidence of cataract in study eyes. RESULTS: Baseline lens photographs were available and graded for 312 (45%) of 690 patients with phakic study eyes; 2-year lens photographs were available for 156 (23%) of 690 initially phakic eyes. Both baseline and 2-year lens photographs were available for 114 eyes that remained phakic. Submacular surgery was associated with significant progression of nuclear color and nuclear opalescence characteristics within 2 years of enrollment. The reliability of fundus photograph quality versus cataract classification using a 4.5 LOCS III score threshold for cataract was poor to good at each time point and for all groups (kappa, 0-0.51), but sensitivity of the photograph quality score as a surrogate was low, and both positive and negative predictive values were low. Agreement between the ophthalmologists' assessments of lens opacity and the 4.5 LOCS III score threshold for cataract was good (kappa, 0.42-0.78). CONCLUSIONS: In the SST, clinical identification of severe cataract (LOCS III scores of 4.5 or worse for nuclear opacity or nuclear color) by the examining ophthalmologist was valid based on comparison with LOCS III scores and may be an adequate method to use in similar trials.

Sunness JS, Applegate CA, Bressler NM, Hawkins BS. · Richard E. Hoover Rehabilitation Services for Low Vision and Blindness, Greater Baltimore Medical Center, Baltimore, Maryland 21204, USA. · Retina. · Pubmed #17290203 No free full text.

Abstract: PURPOSE: To derive information from the Geographic Atrophy (GA) Natural History Study that is relevant to recruiting patients and designing clinical trials for GA. METHODS: A prospective natural history study with annual follow-up enrolled patients with GA and no choroidal neovascularization (CNV) in at least one eye. Characteristics of recruited and enrolled patients are analyzed, in the context of progression data from the study. RESULTS: The data show that GA from age-related macular degeneration (AMD) was seen in 82% of the referred patients, there was an attrition rate of 14%, and 60% of the patients with GA from AMD had bilateral GA without CNV. Within the 83 patients in the bilateral GA group with follow-up, 50 patients (60%) met both the proposed visual acuity and the proposed GA area criteria for a treatment trial in one or both eyes. CONCLUSION: These data should be helpful in planning future treatment trials for GA.

Sunness JS, Margalit E, Srikumaran D, Applegate CA, Tian Y, Perry D, Hawkins BS, Bressler NM. · Richard E. Hoover Rehabilitation Services for Low Vision and Blindness, Greater Baltimore Medical Center, Baltimore, Maryland 21204, USA. · Ophthalmology. · Pubmed #17270676 links to  free full text

Abstract: PURPOSE: To report the enlargement rate of geographic atrophy (GA) over time, its relationship to size of atrophy at baseline and to prior enlargement rate, and the implications for designing future treatment trials for GA. DESIGN: Prospective natural history study of GA resulting from age-related macular degeneration. PARTICIPANTS: Two hundred twelve eyes of 131 patients were included in the analysis. METHODS: Annual follow-up included stereo color fundus photographs. The areas of GA were identified and measured, and the rate of enlargement of the atrophy was assessed. Sample sizes for clinical trials using systemic treatment and uniocular treatment were determined. MAIN OUTCOME MEASURE: Rate of enlargement of the atrophy. RESULTS: The median overall enlargement rate was 2.1 mm2/year (mean, 2.6 mm2/year). Eyes with larger areas of atrophy at baseline tended to have larger enlargement rates, but knowledge of prior rates of enlargement was the most significant factor in predicting subsequent enlargement rates. There was high concordance between the enlargement rates in the 2 eyes of patients with bilateral GA (correlation coefficient, 0.76). To detect a 25% reduction in enlargement rate for a systemic treatment (alpha, 0.05; power, 0.80; losses to follow-up, 15%), 153 patients each in a control and treatment group would be required for a trial with a 2-year follow-up period for each patient. For a uniocular treatment, 38 patients with bilateral GA would be required, with the untreated eye serving as a control for the treated eye. CONCLUSIONS: Treatment trials for GA with an outcome variable of change in enlargement rate are feasible.

Grossniklaus HE, Miskala PH, Green WR, Bressler SB, Hawkins BS, Toth C, Wilson DJ, Bressler NM. · Montgomery Ophthalmic Pathology Labotratory, BT0428 Emory Eye Center, 1365 Clifton Road NE, Atlanta, GA 30322, USA. · Arch Ophthalmol. · Pubmed #16009831 No free full text.

Abstract: OBJECTIVES: To identify the histologic and ultrastructural features of surgically excised subfoveal choroidal neovascular lesions from patients enrolled in the Submacular Surgery Trials and to compare them with clinical data. METHODS: Surgically excised subfoveal choroidal neovascular lesions from patients enrolled in the Submacular Surgery Trials group N trial (lesion predominantly choroidal neovascularization [CNV] with evidence of classic CNV from age-related macular degeneration), group B trial (lesion predominantly hemorrhagic from age-related macular degeneration), and group H trial (idiopathic subfoveal CNV or subfoveal CNV from ocular histoplasmosis syndrome) between October 1, 1999, and September 1, 2001, were submitted to the pathology center. The lesion growth pattern (subretinal pigment epithelial [sub-RPE], subretinal, combined, or indeterminate) and the cellular and extracellular constituents were classified independently. Demographic, clinical, and fluorescein angiographic characteristics of patients, eyes, and lesions, respectively, were compared with the pathologic features. RESULTS: Of 269 patients assigned to surgery during the 24 months that pathologic specimens were collected, surgical specimens from study eyes of 199 were submitted to the pathology center. Of the 199 routine histologic specimens processed, 144 (72%) were classified as CNV, 51 (26%) as fibrocellular tissue, and 4 (2%) as hemorrhage. The median specimen size was smaller in group H (932 x 208 mum) than in groups N (1980 x 325 mum) and B (1800 x 395 mum). The CNV growth pattern was determined in 91 (46%) of 199 specimens. Of 159 group N and group B lesions, 76 (48%) had an indeterminate growth pattern, 28 (18%) had a sub-RPE growth pattern, and 33 (21%) had sub-RPE and subretinal growth patterns. Of 40 group H lesions, 32 (80%) had an indeterminate growth pattern, 7 (18%) had a subretinal growth pattern, and 1 (2%) had a combined sub-RPE and subretinal pattern. Based on electron microscopy, the most common cellular lesion components were RPE, macrophages, erythrocytes, fibrocytes, and vascular endothelium; the most common extracellular components were 24-nm collagen and fibrin. Basal laminar and linear deposits were found in 80% (40/50) and 16% (8/49) of group N specimens, 66% (43/65) and 5% (3/65) of group B specimens, and 8% (2/26) and 0% (0/26) of group H specimens, respectively. CONCLUSIONS: Most surgically excised subfoveal specimens had evidence of CNV or tissue associated with CNV. The constituents in CNV were consistent with granulation tissue proliferation. The presence of basal deposits in surgically excised specimens suggested a clinical diagnosis of age-related macular degeneration, even when blood was the predominant component of the lesion. Correlation of growth patterns above or below the RPE with fluorescein angiographic patterns of classic or occult CNV was limited because most specimens had insufficient material to determine these patterns.

Orr PR, Marsh MJ, Hawkins BS, Hawse PL, Bressler NM, Anonymous00177. · The Wilmer Ophthalmological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2010, USA. · Ophthalmic Epidemiol. · Pubmed #15848920 No free full text.

Abstract: PURPOSE: To describe methods and results and to assess the value of a Traveling Vision Examiner (TVE) Program designed to provide masked vision measurements by expert vision examiners who were independent of, and traveled to, local clinical centers. METHODS: The Submacular Surgery Trials (SST) Pilot Study was conducted to refine the design and methods for a set of multicenter, randomized clinical trials to evaluate submacular surgery in patients with subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) or ocular histoplasmosis (OHS), or idiopathic CNV in which the primary study outcome would be change in 2-year best-corrected vision from baseline. As part of the SST Pilot Study, the feasibility and value of a TVE Program was assessed. The goal of the program was to obtain unbiased vision measurements, according to a standard protocol, of best-corrected visual acuity, reading speed, and contrast threshold, of each patient at 2 and 4 years after enrollment. RESULTS: Eighty-three visits by TVEs were made to 16 centers participating in the SST Pilot Study; 239 patients had at least one masked vision examination. Comparison of pairs of vision measurements of the traveling vision examiners and local vision examiners for 71 patients made on the same day showed good agreement overall (intraclass correlation coefficient > or = 0.81). CONCLUSIONS: The proposed TVE Program was judged to be a feasible and useful method of providing standardized, unbiased, masked vision measurements. This approach was incorporated into the larger clinical trials conducted by the SST Research Group.

Haller JA, Hawkins BS, Hillis AI. · No affiliation provided · Ophthalmology. · Pubmed #16650686 No free full text.

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