Dataset Information

Progression of Stargardt Disease as Determined by Fundus Autofluorescence in the Retrospective Progression of Stargardt Disease Study (ProgStar Report No. 9).

ABSTRACT: Importance:Sensitive outcome measures for disease progression are needed for treatment trials of Stargardt disease. Objective:To describe the yearly progression rate of atrophic lesions in the retrospective Progression of Stargardt Disease study. Design, Setting, and Participants:A multicenter retrospective cohort study was conducted at tertiary referral centers in the United States and Europe. A total of 251 patients aged 6 years or older at baseline, harboring disease-causing variants in ABCA4 (OMIM 601691), enrolled in the study from 9 centers between August 2, 2013, and December 12, 2014; of these patients, 215 had at least 2 gradable fundus autofluorescence images with atrophic lesion(s) present in at least 1 eye. Exposures:Areas of definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence were quantified by a reading center. 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 fundus autofluorescence. Results:A total of 251 participants (458 study eyes) were enrolled. Images from 386 eyes of 215 participants (126 females and 89 males; mean [SD] age, 29.9 [14.7] years; mean [SD] age of onset of symptoms, 21.9 [13.3] years) showed atrophic lesions present on at least 2 visits and were graded for 2 (156 eyes), 3 (174 eyes), or 4 (57 eyes) visits. A subset of 224 eyes (123 female participants and 101 male participants; mean [SD] age, 33.0 [15.1] years) had areas of DDAF present on at least 2 visits; these eyes were included in the estimation of the progression of the area of DDAF. At the first visit, DDAF was present in 224 eyes (58.0%), with a mean (SD) lesion size of 2.2 (2.7) mm2. The total mean (SD) area of decreased autofluorescence (DDAF and questionably decreased autofluorescence) at first visit was 2.6 (2.8) mm2. Mean progression of DDAF was 0.51 mm2/y (95% CI, 0.42-0.61 mm2/y), and of total decreased fundus autofluorescence was 0.35 mm2/y (95% CI, 0.28-0.43 mm2/y). Rates of progression depended on the initial size of the lesion. Conclusions and Relevance:In Stargardt disease with DDAF lesions, fundus autofluorescence may serve as a monitoring tool for interventional clinical trials that aim to slow disease progression. Rates of progression depended mainly on initial lesion size.

SUBMITTER: Strauss RW

PROVIDER: S-EPMC5710470 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Progression of Stargardt Disease as Determined by Fundus Autofluorescence in the Retrospective Progression of Stargardt Disease Study (ProgStar Report No. 9).

Strauss Rupert W RW Muñoz Beatriz B Ho Alexander A Jha Anamika A Michaelides Michel M Cideciyan Artur V AV Audo Isabelle I Birch David G DG Hariri Amir H AH Nittala Muneeswar G MG Sadda SriniVas S West Sheila S Scholl Hendrik P N HPN

JAMA ophthalmology 20171101 11

<h4>Importance</h4>Sensitive outcome measures for disease progression are needed for treatment trials of Stargardt disease.<h4>Objective</h4>To describe the yearly progression rate of atrophic lesions in the retrospective Progression of Stargardt Disease study.<h4>Design, setting, and participants</h4>A multicenter retrospective cohort study was conducted at tertiary referral centers in the United States and Europe. A total of 251 patients aged 6 years or older at baseline, harboring disease-cau ...[more]

PMID: 29049437

Similar Datasets

Project description:ImportanceSensitive outcome measures for disease progression are needed for treatment trials of Stargardt disease.ObjectiveTo 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 participantsThis 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.ExposuresAutofluorescence 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 measuresYearly rate of progression, using the growth of atrophic lesions measured by autofluorescence imaging.ResultsA 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) mm2. The mean total area of decreased autofluorescence at baseline was 4.07 (4.04) mm2. The estimated progression of definitely decreased autofluorescence was 0.76 (95% CI, 0.54-0.97) mm2 per year (P < .001), and the total area of both questionably and definitely decreased autofluorescence was 0.64 (95% CI, 0.50-0.78) mm2 per year (P < .001). Both progression rates depended on initial lesion size.Conclusions and relevanceIn Stargardt disease, autofluorescence imaging may serve as a monitoring tool and definitely decreased autofluorescence and total area as outcome measures for interventional clinical trials that aim to slow disease progression. Rates of progression depended mainly on initial lesion size.

Project description:Importance:Outcome measures that are sensitive to disease progression are needed as clinical end points for future treatment trials in Stargardt disease. Objective:To examine the incidence of atrophic lesions of the retinal pigment epithelium in patients with Stargardt disease as determined by fundus autofluorescence imaging. Design, Setting, and Participants:In this retrospective multicenter cohort study, 217 patients 6 years and older at baseline at tertiary referral centers in Europe, the United States, and the United Kingdom who were harboring disease-causing variants in the adenosine triphosphate (ATP)-binding cassette subfamily A member 4 (ABCA4) gene and who met the following criteria were enrolled: (1) at least 1 well-demarcated area of atrophy with a minimum diameter of 300 µm, with the total area of all atrophic lesions being less than or equal to 12 mm2 in at least 1 eye at the most recent visit, and (2) fundus autofluorescence images for at least 2 visits with a minimum of 6 months between at least 2 visits. Data were collected between August 22, 2013, and December 12, 2014. Data analysis was performed from March 15, 2015, through January 31, 2017. Exposures:Images were evaluated by staff at a central reading center. Areas of definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence (QDAF) were outlined and quantified. Lesion-free survival rates were estimated using Kaplan-Meier survival curves. Main Outcomes and Measures:Incidence of atrophic lesions as determined by fundus autofluorescence. Results:The 217 patients (mean [SD] age, 21.8 [13.3] years; 127 female [57.5%]; 148 white [68.2%]) contributed 390 eyes for which the mean (SD) follow-up time was 3.9 (1.6) years (range, 0.7-12.1 years). Among eyes without DDAF at first visit, the median time to develop a DDAF lesion was 4.9 years (95% CI, 4.3-5.6 years). Among eyes without QDAF, the median time to develop a QDAF lesion was 6.3 years (95% CI, 5.6-9.7 years). Eyes with a lesion of DDAF at the first visit were less likely to develop a QDAF lesion compared with eyes without a lesion of DDAF (hazard ratio, 0.19; 95% CI, 0.05-0.70; P?=?.01). Conclusions and Relevance:An estimated 50% of the eyes without DDAF at first visit will develop the lesion in less than 5 years, suggesting that incidence of DDAF could serve as an outcome measure for treatment trials.

Project description:ImportanceNew 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.ObjectiveTo measure and analyze retinal light sensitivity of the macula in STGD1 using fundus-controlled perimetry (microperimetry).Design, setting, and participantsThis 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 measuresMean sensitivity and the number of points with normal sensitivity, relative, or deep scotomas.ResultsMean (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 < .001) and 0.21 dB lower per additional year of duration of STGD1 (95% CI, -0.28 to -0.14; P < .001). Longer duration of STGD1 was associated with worse MS (β = -0.18; P < .001), with a lower number of normal test points (β = -0.71; P < .001), and with a higher number of deep scotoma points (β = -0.70; P < .001). We found 11 eyes with low MS (<6 dB) but very good best-corrected visual acuity of at least 72 Early Treatment Diabetic Retinopathy Study letter score (20/40 Snellen equivalent).Conclusions and relevanceWe provide an extensive analysis of macular sensitivity parameters in STGD1 and demonstrate their association with demographic characteristics and vision. These data suggest microperimetry testing provides a more comprehensive assessment of retinal function and will be an important outcome measure in future clinical trials.

Project description:PurposeTo determine the reliability and repeatability of quantitative evaluation of areas of decreased autofluorescence (DAF) from fundus autofluorescence (FAF) images and track disease progression in children with Stargardt disease (STGD1), and to investigate clinical and genotype correlations, disease symmetry, and intrafamilial variability.DesignProspective cohort study.MethodsChildren and adults with molecularly confirmed STGD1 (n = 90) underwent longitudinal FAF imaging with subsequent semiautomated measurement of the area of DAF and calculation of the annual rate of progression. The age of disease onset was recorded for all subjects, as well as the electroretinography (ERG) group at baseline (n = 86). Patients were grouped for analysis based on the age at baseline and age of onset, into children (n = 56), adults with childhood-onset STGD1 (n = 15), and adults with adult-onset (n = 19). Fifty FAF images were selected randomly and analyzed by 2 observers to evaluate repeatability and reproducibility. Differences between groups, interocular symmetry, genotype-phenotype correlations, and intrafamilial variability were also investigated both for baseline measurements as well as progression rates. We measured visual acuity, molecular genetics, ERG group, FAF metrics, and their correlations.ResultsThe mean age of onset ± SD was 9.6 ± 3.4 years for childhood-onset (n = 71) and 28.3 ± 7.8 years for adult-onset STGD1 (n = 19). The intra- and interobserver reliability of DAF quantification was excellent (intraclass correlation coefficients 0.995 and 0.987, respectively). DAF area was symmetric between eyes and the mean rate of progression (SD) was 0.69 (0.72), 0.78 (0.48), and 0.40 (0.36) mm2/year for children, adults with childhood-onset, and adults with adult-onset disease, respectively. Patients belonging to a group 3 ERG phenotype (generalized cone and rod dysfunction) had a significantly greater progression rate. Limited intrafamilial variability was observed.ConclusionsThis is the first large prospective study of FAF in a cohort of molecularly confirmed children with STGD1. DAF area quantification was highly reliable and may thereby serve as a robust structural endpoint. A high rate of progression was observed in childhood-onset disease, making this subtype of STGD1 ideally suited to be considered for prioritization in clinical trials.

Project description:ObjectiveTo study the longitudinal changes in autofluorescence in Stargardt disease to reveal aspects of disease progression not previously evident. Changes in autofluorescence reflect changing fluorophore compositions of lipofuscin and melanin in retinal pigment epithelial cells, which has been hypothesized to contribute to Stargardt disease pathogenesis.MethodsWe examined the temporospatial patterns of fundus autofluorescence with excitation at both 488 nm (standard fundus autofluorescence) and 795 nm (near-infrared autofluorescence) in a longitudinal case series involving 8 eyes of 4 patients (range of follow-up, 11-57 months; mean, 39 months). Image processing was performed to analyze spatial and temporal cross-modality associations.ResultsLongitudinal fundus autofluorescence imaging of fleck lesions revealed hyperautofluorescent lesions that extended in a centrifugal direction from the fovea with time. Patterns of spread were nonrandom and followed a radial path that left behind a trail of diminishing autofluorescence. Longitudinal near-infrared autofluorescence imaging also demonstrated centrifugal lesion spread but with fewer hyperautofluorescent lesions, suggestive of more transient hyperautofluorescence and more rapid decay at longer wavelengths. Fundus autofluorescence and near-infrared autofluorescence abnormalities were spatially correlated with each other, and together they reflect systematic progressions in fleck distribution and fluorophore composition occurring during the natural history of the disease.ConclusionsStargardt disease fleck lesions do not evolve randomly in location but instead follow consistent patterns of radial expansion and a systematic decay of autofluorescence that reflect changing lipofuscin and melanin compositions in retinal pigment epithelial cells. These progressive foveal-to-peripheral changes are helpful in elucidating molecular and cellular mechanisms underlying Stargardt disease and may constitute potential outcome measures in clinical trials.

Project description:ImportanceFunctional end points for clinical trials investigating the efficacy of emerging treatments for Stargardt disease type 1 (STGD1) are needed.ObjectiveTo assess the yearly rate of change of macular function in patients with STGD1 using microperimetry.Design, setting, and participantsThis multicenter prospective cohort study was conducted in an international selection of tertiary referral centers from October 21, 2013, to February 15, 2017. The study included participants with ABCA4-related STGD1 who were enrolled in the Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) study at baseline. Data were analyzed from February 16, 2017, to December 1, 2019.ExposureABCA4-related STGD1 with a minimum lesion size on fundus autofluorescence and a minimum visual acuity.Main outcomes and measuresChanges in overall macular sensitivity (MS), deep scotoma count, number of points that tested normal, and location-specific sensitivity changes.ResultsAmong the 359 eyes from 200 patients (87 [43.5%] men; mean [SD] age, 33.3 [15.2] years) who underwent microperimetry examination graded at baseline and month 12, the mean (SD) yearly change in MS was -0.68 (2.04) dB (95% CI, -0.89 to -0.47 dB; P < .001), and deep scotoma points increased by a mean (SD) of 1.56 (5.74) points per year. The points with sensitivity of 12 dB or higher decreased in sensitivity by a mean (SD) of -3.01 (9.84) dB (95% CI, -4.03 to -1.99 dB; P < .001). The mean (SD) yearly change in MS was not significantly different between the eyes with a grading of good or fair pattern placement at both visits (-0.67 [2.1] dB) and the eyes with a poor pattern placement during at least 1 visit (-0.64 [2.2] dB) (P = .91).Conclusions and relevanceThis study showed that MS and the number of deep scotoma points had measurably changed after follow-up of approximately 1 year. Microperimetry may serve as a useful functional outcome parameter for clinical trials aimed at slowing the progression of STGD1.

Dataset Information

Progression of Stargardt Disease as Determined by Fundus Autofluorescence in the Retrospective Progression of Stargardt Disease Study (ProgStar Report No. 9).

Publications

Progression of Stargardt Disease as Determined by Fundus Autofluorescence in the Retrospective Progression of Stargardt Disease Study (ProgStar Report No. 9).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets