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PURPOSE: To estimate and compare cross-sectional scotopic versus mesopic macular sensitivity losses measured by microperimetry, and to report and compare the longitudinal rates of scotopic and mesopic macular sensitivity losses in ABCA4 gene associated Stargardt Disease (STGD1). DESIGN: Multicenter prospective cohort study. METHODS: PARTICIPANTS: 127 molecular confirmed STGD1 patients enrolled from 6 centers in the USA and Europe and followed every 6 months for up to 2 years. OBSERVATION PROCEDURES: The Nidek MP-1S device was used to measure macular sensitivities of the central 20° under mesopic and scotopic conditions. The mean deviations (MD) from normal for mesopic macular sensitivity for the fovea (within 2° eccentricity) and extrafovea (4°−10° eccentricity), and the MD for scotopic sensitivity for the extrafovea were calculated. Linear mixed effects models were used to estimate mesopic and scotopic changes. MAIN OUTCOME MEASURES: Baseline mesopic mean deviation (mMD) and scotopic MD (sMD) and rates of longitudinal changes in the mMDs and sMD. RESULTS: At baseline, all eyes had larger sMD, and the difference between extrafoveal sMD and mMD was 10.7 dB (p

Purpose In this study, we describe common demographic and clinical characteristics of the glaucoma patient population attending vision rehabilitation. Design Cross-sectional study. Participants Patients attending a hospital-based vision rehabilitation center with a primary ocular diagnosis of glaucoma. Methods Participants’ charts were retrospectively reviewed. Data extracted from medical records included demographics, referring physician, ocular history, glaucoma diagnosis, past ocular surgery, intraocular pressure, optic nerve findings, results of a functional intake assessing activities of daily living, depression, visual hallucinations, best-corrected visual acuity (BCVA), mean deviation (MD) scores on visual field testing, and log contrast sensitivity (CS). Main Outcome Measures Participant demographic information, ocular history, self-reported difficulty with activities of daily living, depression, visual hallucinations, BCVA, visual field, and CS. Results The mean age of patients in this study was 77 years and ranged from 8 to 103 years. Ninety percent of patients were referred to vision rehabilitation by an ophthalmologist. Median BCVA was 20/50. Fifty-five percent of patients were functionally monocular, and for all patients, there was a median 9-line difference in BCVA between eyes. Median MD score was −13.95 decibels (dB). Median CS was 1.05. Patients reported having the greatest difficulty with reading (88%), writing (72%), and mobility (67%). Seventy-eight percent of patients stopped driving, and 12% reported difficulty driving. Among those experiencing depression, there was a 4:1 ratio of depressed patients having difficulty with mobility. One-third of patients experienced visual hallucinations. Conclusions Most glaucoma patients attending vision rehabilitation are not legally blind, but many are functionally monocular. This may cause greater difficulty performing functions that require the use of binocularity. Increasing the referral of younger glaucoma patients to vision rehabilitation may help patients learn to cope with the loss of visual function that occurs over time.

Mean sensitivity (MS) derived from a standard test grid using microperimetry is a sensitive outcome measure in clinical trials investigating new treatments for degenerative retinal diseases. This study hypothesizes that the functional decline is faster at the edge of the dense scotoma (eMS) than by using the overall MS.Multicenter, international, prospective cohort study: ProgStar Study.Stargardt disease type 1 patients (carrying at least 1 mutation in the ABCA4 gene) were followed over 12 months using microperimetry with a Humphrey 10-2 test grid. Customized software was developed to automatically define and selectively follow the test points directly adjacent to the dense scotoma points and to calculate their mean sensitivity (eMS).Among 361 eyes (185 patients), the mean age was 32.9 ± 15.1 years old. At baseline, MS was 10.4 ± 5.2 dB (n = 361), and the eMS was 9.3 ± 3.3 dB (n = 335). The yearly progression rate of MS (1.5 ± 2.1 dB/year) was significantly lower (β = -1.33; P.001) than that for eMS (2.9 ± 2.9 dB/year). There were no differences between progression rates using automated grading and those using manual grading (β = .09; P = .461).In Stargardt disease type 1, macular sensitivity declines significantly faster at the edge of the dense scotoma than in the overall test grid. An automated, time-efficient approach for extracting and grading eMS is possible and appears valid. Thus, eMS offers a valuable tool and sensitive outcome parameter with which to follow Stargardt patients in clinical trials, allowing clinical trial designs with shorter duration and/or smaller cohorts.

Objective : Stargardt Disease type 1 (STGD1) is the most common macular dystrophy. The assessment of fixation describes an important dimension of visual function but there is limited data on its progression over time. We present longitudinal changes and investigate its usefulness for clinical trials. Design : International, multicenter, prospective cohort study Participants and Main Outcome Measures : A total of 239 individuals with genetically confirmed STGD1 (≥ 1 disease-causing ABCA4 variant). We determined the fixation stability (FS) using the bivariate contour ellipse area (1 SD-BCEA) and fixation location (FL) using the eccentricity of fixation from the fovea during 5 study visits every 6 months. Results : At baseline, 239 patients (105 males, 44 %) and 459 eyes with a median age of 32 years were included. The baseline mean log BCEA was 0.70 ± 1.41 log deg 2 and the mean FL was 6.25 ± 4.40 deg. Although the mean log BCEA did not monotonically increase from visit to visit, the overall yearly increase in log BCEA was 0.124 log deg 2 (95% CI, 0.063-0.185). The rate of change was not different between the two years but increased faster in eyes without flecks outside of the vascular arcades and depended on baseline log BCEA. FL did not change statistically significantly over time. Conclusion and relevance : Fixation parameters are unlikely to be sensitive outcome measures for clinical trials in STGD1 but they may provide useful ancillary information in selected cases to longitudinally describe and understand an eye's visual function.

PURPOSE To report the yearly rate of change in macular function in patients with Stargardt disease type 1 (STGD1) over 24 months and to establish a new volumetric visual function index for use in clinical trials investigating the efficacy on retinal sensitivity. METHODS Design: International, multicenter, prospective cohort study with 5 study visits every 6 months over 24 months. PARTICIPANTS A total of 233 individuals with genetically confirmed STGD1 (≥1 disease-causing ABCA4 variant). MAIN OUTCOME MEASURES The total volume (VTOT) beneath the sensitivity surface of a 3-D model of the hill of vision and mean sensitivity (MS) derived from mesopic microperimetry performed with a white stimulus. Changes of VTOT over time and its correlation with the ABCA4 genotype and baseline features. RESULTS At baseline, 440 eyes (233 patients) with a mean (SD) age of 33.7 (15.0) years, mean (SD) visual acuity of 46.08 (16.03) ETDRS letters were analyzed with an average VTOT of 0.91 decibel-steradian (dB-sr) and an MS of 10.73 dB. The overall mean rate of decrease in sensitivity [95% confidence interval] was 0.077 [0.064, 0.090] dB-sr/y for VTOT and 0.87 [0.72, 1.02] dB/year for MS. The progression rate of VTOT depended on baseline visual function (0.029 dB-sr/year for low and 0.120 dB-sr/year for high baseline VTOT; P < .001) and exhibited a difference in the first vs second year of follow-up (0.065 dB-sr/year vs 0.089 dB-sr/year, respectively; P < .001). The absence of pigmentary abnormalities of the retinal pigment epithelium at baseline was found to be associated with a faster progression rate (P < .001), whereas a significant association with the genotype was not detected (P = .7). CONCLUSION In STGD1, both microperimetric outcomes demonstrate statistically significant and clinically meaningful changes after relatively short follow-up periods. Volumetric modeling may be useful in future interventional clinical trials that aim to improve retinal sensitivity or to slow down its decline and for structure-function correlations.

Purpose Sensitive, reproducible visual function biomarkers are necessary to evaluate the efficacy of emerging treatments for Stargardt disease type 1 in clinical trials. We previously demonstrated that fixation stability may serve as a secondary outcome parameter for visual function loss. However, the test duration and protocol have an unknown effect on the assessment of fixation stability. Here, we hypothesize that separate fixation testing with a single target is different from combined fixation testing using the same target with simultaneous perimetry testing. Design International, multicenter, prospective, cross-sectional study. Methods Microperimetry data from the international, multicenter, prospective Progression of Atrophy Secondary to Stargardt Disease (ProgStar, NCT01977846 ) study were analyzed. Patients underwent various types of fixation testing including static testing and dynamic testing, and a duration-corrected dynamic test was generated (30sEpoch). Results A total of 437 eyes from 235 patients were included (mean age, 33.8 ± 15.1 years; 55.3% female). The mean 1SD-BCEA (bivariate contour ellipse area), which is the smallest ellipse encompassing 1 standard deviation of all fixation events, was smaller for the static fixation test compared to the 30sEpoch (4.5 ± 6.9 deg2 vs 5.3 ± 7.0 deg2; P = .02) and the number of points within both the 2-degree and 4-degree circles was larger (P Conclusions Our results suggest that differences in static and dynamic assessment of fixation stability are dependent not only on different test durations but also on the testing protocol of a single fixation target vs fixation target plus simultaneous perimetry testing and provide information on the conduct of fixation testing for clinical trials.

Purpose To investigate the natural history of Stargardt disease (STGD1) using fixation location and fixation stability. Design Multicenter, international, prospective cohort study. Methods Fixation testing was performed using the Nidek MP-1 microperimeter as part of the prospective, multicenter, natural history study on the Prog ression of Star gardt disease (ProgStar). A total of 238 patients with ABCA4-related STGD1 were enrolled at baseline (bilateral enrollment in 86.6%) and underwent repeat testing at months 6 and 12. Results Outcome measures included the distance of the preferred retinal locus from the fovea (PRL) and the bivariate contour ellipse area (BCEA). After 12 months of follow-up, the change in the eccentricity of the PRL from the anatomic fovea was −0.0014 degrees (95% confidence interval [CI], −0.27 degrees, 0.27 degrees; P = .99). The deterioration in the stability of fixation as expressed by a larger BCEA encompassing 1 standard deviation of all fixation points was 1.21 degrees squared (deg2) (95% CI, −1.23 deg2, 3.65 deg2; P = .33). Eyes with increases and decreases in PRL eccentricity and/or BCEA values were observed. Conclusions Our observations point to the complexity of fixation parameters. The association of increasingly eccentric and unstable fixation with longer disease duration that is typically found in cross-sectional studies may be countered within individual patients by poorly understood processes like neuronal adaptation. Nevertheless, fixation parameters may serve as useful secondary outcome parameters in selected cases and for counseling patients to explain changes to their visual functionality.

Background/aimsTo describe the genetic characteristics of the cohort enrolled in the international multicentre progression of Stargardt disease 1 (STGD1) studies (ProgStar) and to determine geographic differences based on the allele frequency.Methods345 participants with a clinical diagnosis of STGD1 and harbouring at least one disease-causing ABCA4 variant were enrolled from 9 centres in the USA and Europe. All variants were reviewed and in silico analysis was performed including allele frequency in public databases and pathogenicity predictions. Participants with multiple likely pathogenic variants were classified into four national subgroups (USA, UK, France, Germany), with subsequent comparison analysis of the allele frequency for each prevalent allele.Results211 likely pathogenic variants were identified in the total cohort, including missense (63%), splice site alteration (18%), stop (9%) and others. 50 variants were novel. Exclusively missense variants were detected in 139 (50%) of 279 patients with multiple pathogenic variants. The three most prevalent variants of these patients with multiple pathogenic variants were p.G1961E (15%), p.G863A (7%) and c.5461-10 T>C (5%). Subgroup analysis revealed a statistically significant difference between the four recruiting nations in the allele frequency of nine variants.ConclusionsThere is a large spectrum of ABCA4 sequence variants, including 50 novel variants, in a well-characterised cohort thereby further adding to the unique allelic heterogeneity in STGD1. Approximately half of the cohort harbours missense variants only, indicating a relatively mild phenotype of the ProgStar cohort. There are significant differences in allele frequencies between nations, although the three most prevalent variants are shared as frequent variants.

The purpose of the present article is to describe the evaluation and treatment processes for glaucoma patients with functional challenges related to their vision. Studies of glaucoma patients demonstrate a decline in the ability to perform vision-related activities. Low vision therapy has proven to have a positive impact for many of these patients. We review the most recent literature in this area and also report on the characteristics of glaucoma patients enrolled in low vision services. Glaucoma is a significant cause of visual impairment and blindness. Low vision rehabilitation complements traditional medical and surgical care by working with patients to identify losses in and improve functionality. A battery of testing to assess visual acuity, contrast sensitivity, visual field, psychological well-being, and ambulation is performed in order to categorize deficits in vision-related tasks. Training and education on the use of visual aids have helped many patients improve independent function.

Purpose To determine fixation location and fixation stability in Stargardt disease (STGD1) and their association with best-corrected visual acuity (BCVA). Design Cross-sectional analysis within the multicenter, prospective ProgStar study. Participants A total of 238 patients and 440 eyes with ABCA4-related STGD1. Methods Patients underwent testing with the Nidek MP-1 microperimeter (Nidek Technologies Inc., Gamagōri, Japan). Fixation location was expressed as the eccentricity of the preferred retinal locus (PRL) from the anatomic fovea, fixation stability was expressed as the bivariate contour ellipse area (BCEA), and BCVA was expressed as Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Linear models with generalized estimating equations were used for statistical analysis while accounting for between-eye correlations. Main Outcome Measures Fixation location and fixation stability. Results Median PRL eccentricity from the fovea was 6° (mean, 6.3°; range, 0°–25°) and median BCEA was 6.31°2 (mean, 12.31°2; range, 0.03°2–365.63°2). Each year of later onset of symptoms of STGD1 was associated with 0.14° more central fixation location (P Conclusions We provide the first extensive database of continuous fixation parameters in STGD1 and demonstrate their association with vision. These measures allow for a more comprehensive assessment of retinal function and may serve as potential secondary outcome measures for future treatment trials for STGD1 and other macular diseases.

IMPORTANCE: Sensitive outcome measures for disease progression are needed for treatment trials of Stargardt disease. OBJECTIVE: To estimate the progression rate of atrophic lesions in the prospective Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) study over a 12-month period. DESIGN, SETTING, AND PARTICIPANTS: This multicenter prospective cohort study was conducted in an international selection of tertiary referral centers from October 21, 2013, to February 15, 2017. Patients who were affected by Stargardt disease, aged 6 years and older at baseline, and harboring disease-causing variants of the ABCA4 gene were enrolled at 9 centers in the United States, United Kingdom, and continental Europe. Data analysis occurred from November 2016 to January 2017. EXPOSURES: Autofluorescence images obtained with a standard protocol were sent to a central reading center, and areas of definitely decreased autofluorescence, questionably decreased autofluorescence, and the total combined area of decreased autofluorescence were outlined and quantified. Progression rates were estimated from linear mixed models with time as the independent variable. MAIN OUTCOMES AND MEASURES: Yearly rate of progression, using the growth of atrophic lesions measured by autofluorescence imaging. RESULTS: A total of 259 study participants (488 eyes; 230 individuals [88.8%] were examined in both eyes) were enrolled (mean [SD] age at first visit, 33.3 [15.1] years; 118 [54.4%] female). Gradable images were available for evaluation for 480 eyes at baseline and 454 eyes after 12 months. At baseline, definitely decreased autofluorescence was present in 306 eyes, and the mean (SD) lesion size was 3.93 (4.37) mm(2). The mean total area of decreased autofluorescence at baseline was 4.07 (4.04) mm(2). The estimated progression of definitely decreased autofluorescence was 0.76 (95% CI, 0.54-0.97) mm(2) per year (P

Purpose To describe the design and baseline characteristics of patients enrolled into 2 natural history studies of Stargardt disease (STGD1). Design Multicenter retrospective and prospective cohort studies. Participants Three hundred sixty-five unique patients aged 6 years and older at baseline harboring disease-causing variants in the ABCA4 gene and with specified ocular lesions were enrolled from 9 centers in the United States and Europe. Methods In the retrospective study, patients contributed medical record data from at least 2 and up to 4 visits for at least 1 examination modality: fundus autofluorescence (FAF), spectral-domain (SD) optical coherence tomography (SD OCT), and/or microperimetry (MP). The total observational period was at least 2 years and up to 5 years between single visits. Demographic and visual acuity (VA) data also were obtained. In the prospective study, eligible patients were examined at baseline using a standard protocol, with 6-month follow-up visits planned for a 2-year period for serial Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected VA, SD OCT, FAF, and MP. Main Outcome Measures Design and rationale of a multicenter study to determine the progression of STGD1 in 2 large retrospective and prospective international cohorts. Detailed baseline characteristics of both cohorts are presented, including demographics, and structural and functional retinal metrics. Results Into the retrospective study, 251 patients (458 eyes) were enrolled; mean follow-up ± standard deviation was 3.9±1.6 years. At baseline, 36% had no or mild VA loss, and 47% of the study eyes had areas of definitely decreased autofluorescence (DDAF) with an average lesion area of 2.5±2.9 mm 2 (range, 0.02–16.03 mm 2 ). Two hundred fifty-nine patients (489 eyes) were enrolled in the prospective study. At baseline, 20% had no or mild VA loss, and 64% had areas of DDAF with an average lesion area of 4.0±4.4 mm 2 (range, 0.03–24.24 mm 2 ). The mean retinal sensitivity with MP was 10.8±5.0 dB. Conclusions The ProgStar cohorts have baseline characteristics that encompass a wide range of disease severity and are expected to provide valuable data on progression based on serial quantitative measurements derived from multiple methods, which will be critical to the design of planned clinical trials.

Objective To present a method of estimating and equating scales across functional assessment instruments that appropriately represents changes in a patient's functional ability and can be meaningfully mapped to changes in Medicare G-code severity modifiers. Design Previously published measures of patients' overall visual ability, estimated from low-vision patient responses to 7 different visual function rating scale questionnaires, are equated and mapped onto Medicare G-code severity modifiers. Setting Outpatient low-vision rehabilitation clinics. Participants The analyses presented in this article were performed on raw or summarized low-vision patient ratings of visual function questionnaire (VFQ) items obtained from previously published research studies. Interventions Previously published visual ability measures from Rasch analysis of low-vision patient ratings of items in different VFQs (National Eye Institute Visual Functioning Questionnaire, Index of Visual Functioning, Activities of Daily Vision Scale, Visual Activities Questionnaire) were equated with the Activity Inventory (AI) scale. The 39 items in the Self-Report Assessment of Functional Visual Performance (SRAFVP) and the 48 items in the Veterans Affairs Low Vision Visual Functioning Questionnaire (VA LV VFQ) were paired with similar items in the AI in order to equate the scales. Main Outcome Measures Tests using different observation methods and indicators cannot be directly compared on the same scale. All test results would have to be transformed to measures of the same functional ability variable on a common scale as described here, before a single measure could be estimated from the multiple measures. Results Bivariate regression analysis was performed to linearly transform the SRAFVP and VA LV VFQ item measures to the AI item measure scale. The nonlinear relationship between person measures of visual ability on a logit scale and item response raw scores was approximated with a logistic function, and the 2 regression coefficients were estimated for each of the 7 VFQs. These coefficients can be used with the logistic function to estimate functional ability on the same interval scale for each VFQ and for transforming raw VFQ responses to Medicare's G-code severity modifier categories. Conclusions The principle of using equated interval scales allows for comparison across measurement instruments of low-vision functional status and outcomes, but can be applied to any area of rehabilitation.

Purpose To examine the extent of visual function abnormality outside the dark lesion on short-wavelength fundus autofluorescence (SW-AF), and its correlation with background SW-AF features and optical coherence tomography (OCT) in recessive Stargardt disease (STGD1). Methods Forty-nine eyes of 25 participants in the ProgStar (the Natural History of the Progression of Atrophy Secondary to Stargardt Disease) study at our center were included. Patients underwent microperimetry (both threshold and dense scotoma mapping), OCT, SW-AF, and visual acuity testing. The Fisher's exact test, the χ2 test, and unpaired t-tests were used to analyze the data. Results Of 40 eyes without central fixation, 33 (82%) placed fixation remote (most ≥5°) from the dense scotoma edge, despite good intervening retinal sensitivity. OCT findings accounted for the remote fixation in 75%. Eighteen (37%) of all 49 eyes had dense scotoma extending past the dark lesion border. OCT was not adequate to define the edge of the scotoma. Of the 49 eyes, 28 (57%) had the mottled background pattern, 10 (20%) had the uniform pattern, and 11 (22%) had the other pattern, with >75% of eyes in each pattern having remote fixation. The dense scotoma exceeded the dark lesion primarily in the mottled pattern. The two eyes of each patient were concordant in all features. Conclusions Functional abnormalities in STGD1 extend past the SW-AF dark lesion. The disruption of the ellipsoid zone shows that photoreceptor abnormality extends peripheral to the dark lesion, and it explains in part the remote fixation pattern and the dense scotoma exceeding the dark lesion. This has implications for clinical trials for STGD1.

Purpose: To describe the study design and characteristics at first visit of participants in the longitudinal Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease (SMART) study. Methods: Scotopic microperimetry (sMP) was performed in one designated study eye in a subset of participants with molecularly proven ABCA4-associated Stargardt disease (STGD1) enrolled in a multicenter natural history study (ProgStar). Study visits were every 6 months over a period ranging from 6 to 24 months, and also included fundus autofluorescence (FAF). Results: SMART enrolled 118 participants (118 eyes). At the first visit of SMART, the mean sensitivity in mesopic microperimetry was 11.48 (±5.05; range 0.00–19.88) dB and in sMP 11.25 (±5.26; 0–19.25) dB. For FAF, all eyes had a lesion of decreased autofluorescence (mean lesion size 3.62 [±3.48; 0.10–21.46] mm2), and a total of 76 eyes (65.5%) had a lesion of definitely decreased autofluorescence with a mean lesion size of 3.46 (±3.60; 0.21–21.46) mm2. Conclusions: Rod function is impaired in STGD1 and can be assessed by sMP. Testing rod function may serve as a potential outcome measure for future clinical treatment trials. This is evaluated in the SMART study.

Background/purpose Foveal hypoplasia is associated with low vision in a variety of conditions. We report and show imaging studies for a series of five patients with foveal hypoplasia who had visual acuity ranging from 20/25 to 20/60. Methods Observational case series. Patients This series includes five patients aged 5 to 18 years who presented to the Greater Baltimore Medical Center, Hoover Low Vision Clinic. All patients showed a partial or complete absence of the fovea in both eyes on examination. Results Eight eyes exhibited absence of foveal depression on spectral domain optical coherence tomography (Cirrus high-definition OCT; Carl Zeiss Meditec). Four eyes exhibited Grade 3 foveal hypoplasia, two eyes exhibited Grade 4 foveal hypoplasia, and two eyes exhibited Grade 1 foveal hypoplasia. For two eyes (one patient), the optical coherence tomography was no longer available for grading, but was interpreted as foveal hypoplasia in both eyes in the chart. Visual acuities ranged from 20/25 to 20/60. Only two of five patients showed signs of albinism. Conclusion Despite the presence of foveal hypoplasia, patients can retain a high level of visual acuity, which suggests that a foveal depression is not essential for the development of good visual acuity.

PUPOSE To document acute thioridazine toxicity from the symptoms only, through the development of ophthalmoscopic signs and recovery of dark adaptation and electroretinogram responses. These findings support the thesis that visual loss is metabolic and reversible if diagnosed early. METHODS Case Report. RESULTS A case is presented of acute thioridazine toxicity with documentation of the development of symptoms before any ophthalmoscopic evidence of toxicity. This case uniquely shows the time course of dark adaptation, showing both delay in adaptation and elevated final threshold, it includes full electrophysiologic studies from within the first weeks of symptoms and regular follow-up demonstrating marked recovery of dark adaptation in terms of both delay and final threshold, a nearly normal electroretinography and normal color vision within 10 months. CONCLUSION Our findings give support to the thesis that functional visual disturbance is primarily metabolic and reversible if detected early in the course of toxicity.

To determine fixation location and fixation stability in Stargardt disease (STGD1) and their association with best-corrected visual acuity (BCVA).Cross-sectional analysis within the multicenter, prospective ProgStar study.A total of 238 patients and 440 eyes with ABCA4-related STGD1.Patients underwent testing with the Nidek MP-1 microperimeter (Nidek Technologies Inc., Gamagōri, Japan). Fixation location was expressed as the eccentricity of the preferred retinal locus (PRL) from the anatomic fovea, fixation stability was expressed as the bivariate contour ellipse area (BCEA), and BCVA was expressed as Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Linear models with generalized estimating equations were used for statistical analysis while accounting for between-eye correlations.Fixation location and fixation stability.Median PRL eccentricity from the fovea was 6° (mean, 6.3°; range, 0°-25°) and median BCEA was 6.31°We provide the first extensive database of continuous fixation parameters in STGD1 and demonstrate their association with vision. These measures allow for a more comprehensive assessment of retinal function and may serve as potential secondary outcome measures for future treatment trials for STGD1 and other macular diseases.

Purpose To describe the enlargement of the dense scotoma over time in Stargardt disease and to highlight methodologic issues in tracking enlargement. Methods Retrospective study of patients with full mapping of the border of the dense scotoma using the MP-1 for at least two visits. Results 14 eyes of 7 patients met this criterion. Patients had median of 3 visits (range 2-5), with median total follow-up of 4.5 years (range 1.5-8). Mean baseline visual acuity was 20/56 (range 20/25-20/200), mean baseline dense scotoma area was 2.23 mm (range 0.41-5.48), and mean dense scotoma enlargement rate was 1.36 mm/year (range 0.22-2.91). The younger patients tended to have more rapid loss of visual acuity, which tended to plateau when the visual acuity was 20/100 or worse. The patients who developed Stargardt before age 20 years, and the single patient who developed Stargardt disease after age 40 years, had more rapid enlargement rates, with preservation of central vision in the oldest patient. The ability to precisely define the dense scotoma area was dependent on the density location of the points tested; this led to significant variability in the assessment of the scotoma enlargement rate in three of the seven patients. The dense scotoma was not described adequately by the extent of the homogeneous dark area on fundus autofluorescence imaging. Conclusion Microperimetry is necessary for mapping the scotoma in patients with Stargardt disease, because current imaging is not adequate. Standardized grid testing, plus a standardized procedure for refining the border of the dense scotoma, should allow more precise testing and longitudinal assessment of enlargement rates.

To examine the association between characteristics of Stargardt disease and visual acuity (VA), to estimate the longitudinal rate of VA loss, and to identify risk factors for VA loss.Retrospective, multicenter cohort study.A total of 176 patients (332 eyes) with molecularly and clinically confirmed Stargardt disease enrolled from the United States and Europe.Standardized data report forms were used to collect retrospective data on participants' characteristics and best-corrected or presenting VA from medical charts. Linear models with generalized estimating equations were used to estimate the cross-sectional associations, and linear mixed effects models were used to estimate the longitudinal VA loss.Yearly change in VA.The median duration of observation was 3.6 years. At baseline, older age of symptom onset was associated with better VA, and a longer duration of symptoms was associated with worse VA. Longitudinal analysis estimated an average of 0.3 lines loss (P0.0001) per year overall, but the rate varied according to baseline VA: (1) eyes with baseline VA ≥20/25 (N = 53) declined at a rate of approximately 1.0 line per year; (2) eyes with VA between 20/25 and 20/70 (N = 65) declined at a rate of approximately 0.9 lines per year; (3) eyes with VA between 20/70 and 20/200 (N = 163) declined at a rate of 0.2 lines per year; and (4) eyes with VA worse than 20/200 (n = 49) improved at a rate of 0.5 lines per year. Older age of onset was associated with slower VA loss: Patients with onset age30 years showed 0.4 lines slower change of VA per year (P = 0.01) compared with patients with onset age ≤14 years.Given the overall slow rate of VA loss, VA is unlikely to be a sensitive outcome measure for treatment trials of Stargardt disease. However, given the faster decline in younger patients and those with no or mild visual impairment, VA may be a potential outcome measure for trials targeting such subgroups of patients. These observations will need to be assessed in a prospective study bearing in mind the inherent limitations of retrospective datasets.

Background/aims Inflammation has been implicated in age-related macular degeneration (AMD). This study investigates the association of mast cells (MCs), a resident choroidal inflammatory cell, with pathological changes in AMD. Methods Human donor eyes included aged controls (n=10), clinically diagnosed with early AMD (n=8), geographic atrophy (GA, n=4) and exudative AMD (n=11). The choroids were excised and incubated for alkaline phosphatase (APase; blood vessels) and non-specific esterase activities (MCs). Degranulated (DG) and non-degranulated MCs in four areas of posterior choroid (nasal, non-macular, paramacular and submacular) were counted in flat mounts (4–6 fields/area). Choroids were subsequently embedded in JB-4 and sectioned for histological analyses. Results The number of MCs was significantly increased in all choroidal areas in early AMD (p=0.0006) and in paramacular area in exudative AMD (139.44±55.3 cells/mm 2 ; p=0.0091) and GA (199.08±82.0 cells/mm 2 ; p=0.0019) compared with the aged controls. DG MCs were also increased in paramacular (p=0.001) and submacular choroid (p=0.02) in all forms of AMD. Areas with the greatest numbers of DG MCs had loss of choriocapillaris (CC). Sections revealed that the MCs were widely distributed in Sattler9s and Haller9s layer in the choroidal stroma in aged controls, whereas MCs were frequently found in close proximity with CC in GA and exudative AMD and in choroidal neovascularisation (CNV). Conclusion Increased MC numbers and degranulation were observed in all AMD choroids. These results suggest that MC degranulation may contribute to the pathogenesis of AMD: death of CC and retinal pigment epithelial and CNV formation. The proteolytic enzymes released from MC granules may result in thinning of AMD choroid.

Purpose Refraction often may be overlooked in low-vision patients, because the main cause of vision decrease is not refractive, but rather is the result of underlying ocular disease. This retrospective study was carried out to determine how frequently and to what extent visual acuity is improved by refraction in a low-vision population. Design Cross-sectional study. Participants Seven hundred thirty-nine low-vision patients seen for the first time. Methods A database with all new low-vision patients seen from November 2005 through June 2008 recorded presenting visual acuity using an Early Treatment Diabetic Retinopathy Study chart; it also recorded the best-corrected visual acuity (BCVA) if it was 2 lines or more better than the presenting visual acuity. Retinoscopy was carried out on all patients, followed by manifest refraction. Main Outcome Measures Improvement in visual acuity. Results Median presenting acuity was 20/80 –2 (interquartile range, 20/50–20/200). There was an improvement of 2 lines or more of visual acuity in 81 patients (11% of all patients), with 22 patients (3% of all patients) improving by 4 lines or more. There was no significant difference in age or in presenting visual acuity between the group that did not improve by refraction and the group that did improve. When stratified by diagnosis, the only 2 diagnoses with a significantly higher rate of improvement than the age-related macular degeneration group were myopic degeneration and progressive myopia (odds ratio, 4.8; 95% confidence interval [CI], 3.0–6.7) and status post–retinal detachment (odds ratio, 7.1; 95% CI, 5.2–9.0). For 5 patients (6% of those with improvement), the eye that was 1 line or more worse than the fellow eye at presentation became the eye that was 1 line or more better than the fellow eye after refraction. Conclusions A significant improvement in visual acuity was attained by refraction in 11% of the new low-vision patients. Improvement was seen across diagnoses and the range of presenting visual acuity. The worse-seeing eye at presentation may become the better-seeing eye after refraction, so that the eye behind a balance lens should be refracted as well. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

PURPOSE: The goal of this study was to see how the availability of ranibizumab affected the referral patterns for low vision (LV) evaluation. METHODS: This study used a retrospective review and a comparison of all patients newly referred from retinal Practice 1 (J.T.T., R.N.S.) for LV consultation, from July 2005 to June 2006 (Year 1, preranibizumab) and from July 2006 to June 2007 (Year 2, ranibizumab available), and a retrospective review of patients referred by retinal Practice 2 (M.J.E.) since February 2007. RESULTS: Practice 1: In Year 1, 24 patients with choroidal neovascularization were referred for LV, and in Year 2, only 12 were referred. There was a trend for those patients referred in Year 2 to have worse visual acuity and Pelli-Robson contrast sensitivity than those in Year 1. In Years 1 and 2, 18 and 11 patients with other conditions were referred for LV consultation, respectively. For these patients without choroidal neovascularization, there was no significant difference between groups for visual acuity or contrast sensitivity. Practice 2: The mean best-corrected visual acuity of patients with bilateral choroidal neovascularization referred was 20/145, and no patient had visual acuity > or =20/100. CONCLUSION: Although the use of antivascular endothelial growth factor agents puts visual acuity in a zone more favorable for successful LV intervention, patients with better acuities may not be referred for LV evaluation despite their residual visual impairments and their scotomas, and despite the fact that without LV intervention, they are having difficulty with reading and other activities of daily living. The frequent visits required for monthly injection, the tendency to wait until a course of therapy is complete before referring patients, and a lesser appreciation for the need for LV intervention in patients with only moderate visual loss may be factors in explaining this.

Central scotomas from macular diseases, such as age-related macular degeneration (AMD), that necessitate the use of the eccentric retina have a major impact on reading, the recognition of faces, and the performance of other activities of daily living that require fine vision. Since the fovea is specialized for fine resolution and excellent visual acuity in a way that the peripheral retina is not, a person with a central scotoma must use magnification or large-print text. Likewise, with the loss of central vision, there is a drop in contrast sensitivity, and improved contrast and lighting are often required. However, the third important component in restoring optimal vision to a person with a central scotoma has not been as easy to quantify or address—the impact of having a blind spot in the central field of vision. If a person places what he or she wants to see at the location of the (now blind) fovea and within the scotomatous area, he or she will not be able to see it. If a person cannot establish a way to use the peripheral retina as a “pseudo-fovea” (Guez, Gargasson, Rigaudiere, & O’Regan, 1993; White & Bedell, 1990)—that is, to direct the object of interest to the eccentric preferred retinal locus (PRL) for fixation—the person will waste time and effort scanning, moving his or her head in all different directions, and having letters and words appear and disappear as they enter and emerge from the scotoma. Some persons with central scotomas are able to adopt a regular and reliable fixation pattern; they look to the side or above the object of interest in a consistent way and thereby move the central scotoma out of the way. They may or may not be consciously aware of what they do, but they do it consistently. Other persons cannot seem to place the object of interest on the seeing retina regularly and, according to anecdotal evidence, have their visual acuity measured at levels that are far worse than one would expect from the observed retinal lesions. Most persons seem to fall in the middle; they have a PRL, but it is not strongly established. They may, for example, keep missing the first letters on the line in the acuity chart, implying that they are moving the scotoma to the left to read, but they do not compensate for this situation and may not do it consistently. With the development of fundus perimeters (more commonly called microperimeters), such as the Rodenstock scanning laser ophthalmoscope (SLO) and the Nidek MP-1, the clinician can see the actual site of the PRL on the retina, evaluate how stable it is, and measure the size and location of the scotoma relative to the location of the PRL (Fletcher & Schuchard, 1997; Rohrschneider et al., 1995; Timberlake et al., 1986). Studies that have used microperimeters in geographic atrophy (GA) from AMD have shown that with the acquisition of a PRL over time, measured visual acuity can actually improve despite progressive enlargement of the atrophy (Sunness, Applegate, & Gonzalez-Baron, 2000). These microperimeters are the gold standard for characterizing the PRL and fixation pattern relative to the central scotoma and give the clinician or low vision provider an awareness of the PRL that can be strengthened through verbal coaching and specific exercises. However, microperimeters are not widely available; the Rodenstock SLO is no longer being manufactured, and the MP-1 costs about $48,000, so that most low vision providers do not have access to them. Therefore, simpler inexpensive ways to assess fixation are desirable, particularly ways that can be used both in a clinic and at a person’s home, where low vision instruction may be taking place. It has long been recognized that, presumably because of perceptual completion (or “filling in”), more than 40% of persons with definite scotomas in their central visual field cannot detect them on an Amsler grid (Fine et al., 1986; Schuchard, 1993). In addition, despite an effort to be clear in the instructions to persons who use the grid, clinicians often do not know whether these persons are centering their fixation (using the corners of the grid, for example) at the fovea or whether they are using an eccentric PRL to fixate the center spot (Schuchard & Raasch, 1992). Even if a person reports an abnormality, it is difficult to interpret its location clearly. Conventional visual field testing that does not correct for eye movements cannot accurately measure the location of the PRL or the size of the scotoma (Sunness, Schuchard et al., 1995). In examinations of persons with low vision, it is clear that they are aware of the blurring of facial features that is associated with their scotomas. It is easy and quick to do a “face field”—to map out where the blurred areas of the face are relative to fixation. As is described later, the face field is a much simpler and more familiar task than is using clock hours and numbers for looking for PRLs (Watson, 1999). To validate the face field technique, a retrospective study was performed of persons with central scotomas who, during a single visit, underwent first face fields and then SLO or MP-1 analysis.

Foveal-sparing scotomas are common in advanced dry macular degeneration (geographic atrophy). Foveal preservation may be present for a number of years. Despite good visual acuity, these patients have reduced reading rates. Magnification may not be effective if the text becomes too large to “fit” within the central spared area.

OBJECTIVE To determine the relationship between reduced retinal autofluorescence and the dense scotomas in Stargardt disease. METHOD Retrospective review of patients with Stargardt disease seen between 2000 and 2004 at a tertiary referral center. PATIENTS All 32 patients with Stargardt who underwent both autofluorescence (AF) imaging and scotoma mapping were included. RESULTS Forty-seven percent of eyes had dense scotomas corresponding to the areas of loss of AF (27% corresponding to the area of uniform loss of AF, and 20% corresponding to the area of uniform plus mottled loss of AF). Fifty-three percent of eyes did not have a good correlation of the dense scotoma with the area of loss of AF. Both eyes were judged to be in the same group in 75% of patients. CONCLUSIONS Areas of reduced AF are measurable, but are not equivalent to the area of dense scotoma in 53% of patients. Measures of retinal sensitivity and scotomas are necessary for defining retinal functional involvement in Stargardt disease.

To describe, in a group of patients with moderately advanced retinitis pigmentosa (RP), the prevalence of cystoid macular edema (CME), the variation in foveal thickness over a 48-week period, the correlation of visual acuity (VA) with retinal thickness, and the lack of response of CME to lutein administration.Optical coherence tomography (OCT) imaging of the macula and clinical examination were evaluated for 77 eyes of 39 patients with RP over 11 months, with a scan done every 6 weeks.The prevalence of CME, defined by cysts visible on OCT, was 49%. Bilateral CME was present in 44% of patients (17 of 39), and an additional two patients had unilateral CME. Central retinal thickness varied little over the 48 weeks. Sixty-six percent of the eyes with CME had VA of 20/40 or better. The eyes with CME with VA worse than 20/40 had either greater degrees of thickening or in fact had lower thickness measures. For the eyes without CME, the eyes with VA worse than 20/40 tended to have lower retinal thickness than the eyes with VA of 20/40 or better. VA was highly concordant between eyes, and did not differ significantly between the groups with and without CME. Lutein did not show a statistically significant effect on retinal thickness in the patients with or without CME, nor was such an effect observed in subgroups of patients with vision better or worse than 20/40.The prevalence rate of CME is higher than in previous reports, perhaps because the patients had some preserved macular vision and because of the use of a definition based on OCT findings. Retinal thickness remains fairly stable over time, both in eyes with CME and in eyes without CME.

PURPOSE To show that the area of atrophy seen on ophthalmoscopy may not correspond with the area of scotoma in some macular diseases. METHODS Three cases are presented, one with geographic atrophy (GA) from age-related macular degeneration, one with Stargardt disease, and one with a macular dystrophy. Nidek MP-1 microperimetry was performed and the correspondence of the dense scotoma to the visible atrophy is reported. RESULTS In the GA patient, the dense scotoma corresponds with the atrophy. In the patient with Stargardt disease, the dense scotoma is larger than the area of visible atrophy. In the patient with a macular dystrophy, the dense scotoma is smaller than the area of visible atrophy. CONCLUSIONS In GA from age-related macular degeneration, the dense scotoma generally corresponds with the atrophy, so that measurement of the enlargement rate of the atrophy is a direct measure of enlargement of the scotoma. This may not be true of other macular diseases.

To derive information from the Geographic Atrophy (GA) Natural History Study that is relevant to recruiting patients and designing clinical trials for GA.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.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.These data should be helpful in planning future treatment trials for GA.

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 mm 2 /year (mean, 2.6 mm 2 /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 (α, 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.

To describe the design and baseline characteristics of patients enrolled into 2 natural history studies of Stargardt disease (STGD1).Multicenter retrospective and prospective cohort studies.Three hundred sixty-five unique patients aged 6 years and older at baseline harboring disease-causing variants in the ABCA4 gene and with specified ocular lesions were enrolled from 9 centers in the United States and Europe.In the retrospective study, patients contributed medical record data from at least 2 and up to 4 visits for at least 1 examination modality: fundus autofluorescence (FAF), spectral-domain (SD) optical coherence tomography (SD OCT), and/or microperimetry (MP). The total observational period was at least 2 years and up to 5 years between single visits. Demographic and visual acuity (VA) data also were obtained. In the prospective study, eligible patients were examined at baseline using a standard protocol, with 6-month follow-up visits planned for a 2-year period for serial Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected VA, SD OCT, FAF, and MP.Design and rationale of a multicenter study to determine the progression of STGD1 in 2 large retrospective and prospective international cohorts. Detailed baseline characteristics of both cohorts are presented, including demographics, and structural and functional retinal metrics.Into the retrospective study, 251 patients (458 eyes) were enrolled; mean follow-up ± standard deviation was 3.9±1.6 years. At baseline, 36% had no or mild VA loss, and 47% of the study eyes had areas of definitely decreased autofluorescence (DDAF) with an average lesion area of 2.5±2.9 mm(2) (range, 0.02-16.03 mm(2)). Two hundred fifty-nine patients (489 eyes) were enrolled in the prospective study. At baseline, 20% had no or mild VA loss, and 64% had areas of DDAF with an average lesion area of 4.0±4.4 mm(2) (range, 0.03-24.24 mm(2)). The mean retinal sensitivity with MP was 10.8±5.0 dB.The ProgStar cohorts have baseline characteristics that encompass a wide range of disease severity and are expected to provide valuable data on progression based on serial quantitative measurements derived from multiple methods, which will be critical to the design of planned clinical trials.

To illustrate the confounding factors when assessing visual acuity and color vision in a patient with a bullseye macular scotoma in one eye and a horseshoe of atrophy sparing the fovea in the fellow eye. Case report. Visual acuity, color vision, and scanning laser ophthalmoscope analysis. The patient with geographic atrophy from age-related macular degeneration in both eyes had visual acuity of 20/40– in the right eye and 20/40+ in the left eye. She reported that she could read newsprint but not news headlines. She could not identify any color plates, but had only minor errors using a color cap (large D-15) test. She had a macular ring scotoma (bullseye scotoma) in the right eye, and a horseshoe-shaped area of atrophy surrounding the fovea in the fellow eye. Scotomas surrounding but sparing the fovea can lead to difficulty reading large letters, because these letters do not fit in the spared foveal region. Care must be taken in measuring visual acuity in these patients so that the testing does not stop when the patient cannot read the largest letters. The presence of scotomas in the central field may not allow the whole figure on color plate testing to be integrated and identified, leading to a possible misdiagnosis of cone dystrophy. Color cap testing avoids this problem.

To study whether fixation patterns changed over time in patients with central scotomas from geographic atrophy from age-related macular degeneration.Prospective cohort study.setting: Institutional. patient or study population: Prospective natural history study of geographic atrophy included 34 eyes of 25 patients with baseline acuity between 20/80 and 20/200 and with subsequent follow-up. observation procedures: Baseline and annual follow-up visits included best-corrected visual acuity, scanning laser ophthalmoscope macular perimetry, reading rate, and clinical evaluation. main outcome measures: Location of eccentric preferred retinal locus for fixation (PRL).At baseline, 77% of study eyes had a PRL. At the final visit (median follow-up, 5.3 years), 91% of study eyes had a PRL, with 81% of the eyes retaining the baseline PRL location. Fixation with the scotoma to the right and fixation with the scotoma superior were the first and second most common fixation patterns, respectively. Reading rates of50 words/min were present in 54% of eyes. Eyes fixating with the scotoma to the left tended to have lower reading rates than eyes fixating with right or superior patterns.Fixation with right pattern remained the most common fixation pattern, both in patients with a PRL at baseline and in patients who had a PRL during follow-up. Eyes with a PRL at baseline generally retained this pattern. The reading rate data suggest an advantage of fixation with right or superior pattern, rather than left. Reading rate declined further during follow-up in most patients.

Purpose To describe retinotopic mapping of the visual cortex when a central scotoma is present. Design Single observational case report. Methods Scanning laser ophthalmoscope perimetry was used to define the site and stability of fixation and the area of dense scotoma. Functional magnetic resonance imaging of the visual cortex was performed while the patient viewed an expanding annular stimulus. Results Retinotopic mapping of the visual cortex for a patient with a horseshoe scotoma from geographic atrophy involving the macular region showed a loss of stimulation to the cortical areas representing the site of the atrophic lesion. Conclusions Cortical retinotopic mapping can be performed successfully in patients with central scotomas from macular disease. This study can serve as a basis for the future investigation of cortical plasticity in visual cortex.

Purpose To compare different metrics and acquisition modes of fixation stability as a new visual function biomarker in a large cohort of patients with ABCA4-related Stargardt disease from the multicenter prospective ProgStar study. Methods Fixation was tested during a separate fixation exam and also dynamically during a sensitivity exam, using fundus-tracking microperimetry (Nidek MP-1). Fixation data were analyzed using the bivariate contour ellipse area (BCEA), the 2/4 degree method, and the Fujii classification. Results In a total of 235 patients, the mean BCEA was larger when measured during the sensitivity exam (418 eyes; 12.5 vs. 4.6 deg2 during the fixation task in 427 eyes). Correlations between the two tests were generally weak. Fixation stability during the sensitivity test was significantly correlated with visual acuity. Comparing the BCEA values and the corresponding Fujii categories for these eyes revealed ranges of overlap where an eye with one defined BCEA value can fall into each of the three Fujii categories. Conclusions Patients may have limited ability to fixate over defined time periods, which leads to significant differences between shorter and longer measurements of fixation stability. The most appropriate way to use this functional biomarker appears to be using continuous metrics for fixation stability, such as the BCEA, during a macular sensitivity test.

IMPORTANCE: New outcome measures for treatment trials for Stargardt disease type 1 (STGD1) and other macular diseases are needed. Microperimetry allows mapping of light sensitivity of the macula and provides topographic information on visual function beyond visual acuity. OBJECTIVE: To measure and analyze retinal light sensitivity of the macula in STGD1 using fundus-controlled perimetry (microperimetry). DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter prospective cohort study. A total of 199 patients and 326 eyes with molecularly confirmed (ABCA4) STGD1 underwent testing with the Nidek MP-1 microperimeter as part of the multicenter, prospective Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) study. Sensitivity of 68 retinal loci was tested, and the mean sensitivity (MS) was determined; each point was categorized as “normal,” “relative,” or “deep” scotoma. MAIN OUTCOMES AND MEASURES: Mean sensitivity and the number of points with normal sensitivity, relative, or deep scotomas. RESULTS: Mean (SD) patient age was 34.2 (14.7) years, mean (SD) best-corrected visual acuity of all eyes was 47.8 (16.9) Early Treatment Diabetic Retinopathy Study letter score (approximately 20/100 Snellen equivalent), and mean MS of all eyes of all 68 points was 11.0 (5.0) dB. The median number of normal points per eye was 49 (mean [SD], 41.3 [20.8]; range, 0-68); abnormal sensitivity and deep scotomas were more prevalent in the central macula. Mean sensitivity was lower in the fovea (mean [SD], 2.7 [4.4] dB) than in the inner (mean [SD], 6.8 [5.8] dB) and outer ring (mean [SD], 12.7 [5.3] dB). Overall MS per eye was 0.086 dB lower per year of additional age (95% CI, −0.13 to −0.041; P

To develop a computer-based image segmentation method for standardizing the quantification of geographic atrophy (GA).The authors present an automated image segmentation method based on the fuzzy c-means clustering algorithm for the detection of GA lesions. The method is evaluated by comparing computerized segmentation against outlines of GA drawn by an expert grader for a longitudinal series of fundus autofluorescence images with paired 30° color fundus photographs for 10 patients.The automated segmentation method showed excellent agreement with an expert grader for fundus autofluorescence images, achieving a performance level of 94 ± 5% sensitivity and 98 ± 2% specificity on a per-pixel basis for the detection of GA area, but performed less well on color fundus photographs with a sensitivity of 47 ± 26% and specificity of 98 ± 2%. The segmentation algorithm identified 75 ± 16% of the GA border correctly in fundus autofluorescence images compared with just 42 ± 25% for color fundus photographs.The results of this study demonstrate a promising computerized segmentation method that may enhance the reproducibility of GA measurement and provide an objective strategy to assist an expert in the grading of images.

Purpose To report ocular and renal findings specific to the inheritable entity called papillorenal (also known as renal-coloboma) syndrome and relate these to a common cause. Design Observational case series and genetic study. Participants Two unrelated probands presenting with absent central retinal vessels and 11 available family members. Testing Doppler ultrasonographic imaging of the optic nerves and kidneys, fluorescein angiography, and genetic testing for PAX2 mutations were performed. In selected cases, indocyanine green angiography, scanning laser ophthalmoscope perimetry, Retinal Thickness Analyzer measurements, visual evoked potentials, and magnetic resonance imaging were also performed. Main outcome measures Better defined characteristics of the papillorenal syndrome. Results Numerous cilioretinal vessels were present with rudimentary or absent central retinal vessels. Superonasal visual field defects, typical for papillorenal syndrome, corresponded to inferotemporal areas of anomalous retinal and choroidal perfusion and hypoplastic retina. Renal hypoplasia was discovered in two affected members of one family (with previously unsuspected renal failure in one case), and recurrent pyelonephritis was discovered in four affected members of the other family. No PAX2 mutations were detected. Conclusions In the papillorenal syndrome, the hereditary absence of central retinal vessels may be missed, leading to confusion with isolated coloboma, low-tension glaucoma, and morning glory anomaly. Greater awareness of this syndrome will avoid unneeded glaucoma therapy, allow earlier recognition of renal diseases, and allow genetic counseling. We propose that the papillorenal syndrome is a primary dysgenesis that causes vascular abnormalities predominantly affecting the eye, kidney, and urinary tract, leading to hypoplasia of these structures. The absence of defects in the PAX2 gene in these families suggests that mutations in other genes may also be responsible for this syndrome.

PURPOSE To study the improvement in visual acuity over time in patients with central scotomas. METHODS In a prospective natural history study of geographic atrophy (GA) from age-related macular degeneration (ARMD) with annual follow-up, 36 patients with bilateral GA completed 3 years of follow-up. Protocol visual acuity (VA) measurements were performed. Scanning laser ophthalmoscopy (SLO) was performed, and the areas of GA were measured from fundus photographs. RESULTS Six eyes of six patients with VA ranging from 20/80 to 20/500 had a VA improvement of two or more lines (mean, 3.2 lines). This was found only in the worse-seeing eyes of the patients and was contemporaneous with the deterioration in VA of the better-seeing eyes. Four of six eyes that improved in acuity had an improvement in the ability to find and hold the fixation target in an area of seeing retina, as assessed by SLO at follow-up, and a fifth eye changed from one fixation site that had little functional retina to another site. CONCLUSIONS Spontaneous improvement in VA in eyes with bilateral GA and central scotomas may occur. It appears to be related to deterioration in VA of the better-seeing fellow eye and is associated with improvement of fixation in the worse-seeing eye. The worse-seeing eye of a patient with bilateral ARMD may have the potential for better vision than measured VA indicates. This finding may have implications for the choice of patients in treatment trials, for interpretation of long-term results, and for planning and assessment of low vision intervention.

Objective To describe the progression of geographic atrophy (GA) from age-related macular degeneration (AMD) with respect to visual acuity (VA) loss and enlargement of atrophy. Design A prospectively observed case series. Setting Tertiary retinal referral center. Participants One hundred twenty-three patients with GA due to AMD who completed at least 1 year of follow-up (median follow-up, 3 years) were examined annually. Methods At each examination, a protocol best-corrected VA of each eye was measured, a clinical examination was performed, and color fundus photographs were taken. The areas of atrophy were drawn and measured. Main outcome measures Visual acuity loss and enlargement of total and central atrophy. Results At baseline, median VA was poorer with larger areas of atrophy, but there was wide variation related to sparing of the fovea. Thirty-one percent of all study eyes suffered a three-line VA loss from baseline by 2 years, and 53% had a three-line loss by 4 years. Those eyes with VA better than 20/50 had the highest rate of acuity loss; 27% of these eyes had acuities of 20/200 or worse at 4 years. Visual acuity loss in the GA study eye was similar in patients with bilateral GA and in those with choroidal neovascularization in the fellow eye. Total atrophy enlarged a median of 1.8 Macular Photocoagulation Study disc areas (DA) at 2 years; atrophy within a 4-DA circle centered on the fovea enlarged a median of 0.9 DA. Two (22%) of nine patients with GA in one eye and only drusen without advanced AMD in the fellow eye developed GA in the fellow eye at 2 years. Conclusions Geographic atrophy is associated with a significant decline in VA over time in many eyes. Areas of atrophy continue to enlarge over time, even when already large at baseline. The combination of reduced VA with enlargement of atrophy, occurring bilaterally in most patients, can lead to significant impairment of visual function.

Objective To determine the rate of developing choroidal neovascularization (CNV) in eyes with geographic atrophy (GA) from age-related macular degeneration (AMD) and the characteristics of the CNV in these eyes. Design Prospective natural history study with cohort analysis. Participants One hundred fifty-two patients with GA and no CNV by fluorescein angiography in at least 1 eye, with annual follow-up. Main outcome measures The development of CNV. Results Thirteen eyes with GA developed CNV. For patients with bilateral GA and no CNV at baseline, 2% developed CNV by 2 years and 11% by 4 years. For patients with CNV in the fellow eye, 18% developed CNV in the study eye with GA by 2 years and 34% by 4 years. The eyes that developed CNV experienced more acuity loss than did the eyes with only GA. Within the fellow eye CNV group, those study eyes with GA that had less central atrophy (and better acuity) at baseline were more likely to develop CNV. The CNV developed at a peripheral border of GA in nine eyes, in the spared foveal region in two eyes, and in both center and border in one eye. No eye developed CNV in the area of atrophy itself. The appearance of CNV was evanescent in some cases and had a final appearance of an enlarged area of GA. Twelve other eyes had hemorrhages without definite evidence of CNV; three were thought to be suspicious for CNV and the remainder were thought to be hemorrhages that may be seen in elderly patients. Conclusion An eye with GA whose fellow eye has CNV is at significant risk for the development of CNV in the GA eye. A patient with bilateral GA and no evidence of CNV is at relatively low risk for developing CNV. The CNV may be evanescent and may not be detected. Intraretinal hemorrhages unrelated to CNV are relatively common in this older population.