Deep phenotyping of PROM1-associated retinal degeneration.

BACKGROUND/AIMS: The purpose of this study was to investigate retinal structure in detail of subjects with autosomal-dominant (AD) and autosomal-recessive (AR) PROM1-associated retinal degeneration (PROM1-RD), study design: institutional, cross-sectional study. METHODS: Four eyes from four subjects (three with AD and one with AR) PROM1-RD were investigated by ophthalmic examination including best-corrected visual acuity (BCVA) and multimodal retinal imaging: fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT) and adaptive optics scanning light ophthalmoscopy. Quantitative assessment of atrophic lesions determined by FAF, thickness of individual retinal layers and cone photoreceptor quantification was performed. RESULTS: BCVA ranged from 20/16 to 20/200. Initial pathological changes included the presence of hyperautofluorescent spots on FAF imaging, while later stages demonstrated discrete areas of atrophy. In all patients, thinning of the outer retinal layers on SD-OCT with varying degrees of atrophy could be detected depending on disease-causing variants and age. Cone density was quantified both in central and/or at different eccentricities from the fovea. Longitudinal assessments were possible in two patients. CONCLUSIONS: PROM1-RD comprises a wide range of clinical phenotypes. Depending on the stage of disease, the cone mosaic in PROM1-RD is relatively preserved and can potentially be targeted by cone-directed interventions.

Progression of PROM1-Associated Retinal Degeneration as Determined by Spectral-Domain Optical Coherence Tomography Over a 24-Month Period.

PURPOSE: To evaluate the progression of atrophy as determined by spectral-domain optical coherence tomography (SD-OCT) in patients with molecularly confirmed PROM1-associated retinal degeneration (RD) over a 24-month period. DESIGN: International, multicenter, prospective case series. METHODS: A total of 13 eyes (13 patients) affected with PROM1-associated RD were enrolled at 5 sites and SD-OCT images were obtained at baseline and after 24 months. Loss of mean thickness (MT) and intact area were estimated after semi-automated segmentation for the following individual retinal layers in the central subfield (CS), inner ring, and outer ring of the ETDRS grid: retinal pigment epithelium (RPE), outer segments (OS), inner segments (IS), outer nuclear layer (ONL), inner retina (IR), and total retina (TR). RESULTS: Statistically significant losses of thickness of RPE and TR were detected in the CS and inner ring and of ONL and IS in the outer ring (all P < .05); a statistically significant decrease in the intact area of RPE and IS was observed in the inner ring, and of ONL in the outer ring (all P < .05); the change in MT and the intact area of the other layers showed a trend of decline over an observational period of 24 months. CONCLUSIONS: Significant thickness losses could be detected in outer retinal layers by SD-OCT over a 24-month period in patients with PROM1-associated retinal degeneration. Loss of thickness and/or intact area of such layers may serve as potential endpoints for clinical trials that aim to slow down the disease progression of PROM1-associated retinal degeneration.

Progression of Stargardt Disease as Determined by Fundus Autofluorescence Over a 24-Month Period (ProgStar Report No. 17).

PURPOSE: To estimate the progression rate of atrophic lesions in Stargardt disease derived from fundus autofluorescence (FAF). DESIGN: International, multicenter, prospective cohort study. METHODS: A total of 259 participants aged ≥6 years with disease-causing variants in the ABCA4 gene were enrolled from 9 centers and followed over a 24-month period. FAF images were obtained every 6 months, and areas of definitely decreased autofluorescence (DDAF) and decreased autofluorescence (DAF) were quantified. Progression rates were estimated from linear mixed models with time as the independent variable. RESULTS: A total of 488 study eyes of 259 participants (88.8% with both eyes) were enrolled and images from 432 eyes were followed for 24 months. The overall estimated progression of DDAF was 0.74 mm2/y (95% CI 0.64-0.85, P < .0001) and that of DAF was 0.64 mm2/y (95% CI 0.57-0.71) over a 24-month period in univariate analysis. Growth rates were strongly dependent on baseline lesion area. After square root transformation, the DDAF growth rate was not dependent on baseline lesion radius (P = .11), whereas the DAF growth rate was dependent (P < .0001). Genotype was not found to significantly impact the growth rate of DDAF or DAF lesions. CONCLUSIONS: FAF may serve as a convenient monitoring tool and suitable end point for interventional clinical trials that aim to slow disease progression. DDAF and DAF lesion sizes at baseline are strong predicting factors for lesion area growth and can be partially accounted for by square root transformation.

Blindness and visual impairment in Central Europe.

PURPOSE: To assess the prevalence and causes of visual impairment and blindness in a Central European country. The findings may have implications for the planning of further research and development of therapies in order to prevent blindness. SETTING: Department of Ophthalmology, Medical University of Graz, Austria. DESIGN: Retrospective, epidemiological study. METHODS: The database of the Main Confederation of Austrian Social Insurances was searched for patients with visual impairment, legal blindness or deaf-blindness. This database gathers data from patients of all insurance providers in the country who receive care due to visual impairment and blindness. To determine the prevalence of these conditions, the number of all entries recorded in February 2019 was evaluated. Additionally, all new entries between (January 1st,) 2017, and (December 31st,) 2018, were analysed for distinct characteristics, such as sex, the cause of blindness/visual impairment, and age. Since health care allowances can provide a considerable source of income (459.90€-936.90€ per month), good coverage of practically all patients who are blind and visually impaired in the country can be assumed. RESULTS: On February 2nd, 2019, 17,730 patients with visual impairments, blindness or deaf-blindness were registered in Austria, resulting in a prevalence of these diagnoses of 0.2% in the country. During the observational period from 2017 to 2018, 4040 persons met the inclusion criteria. Of these, 2877 were female (65.3%), and 1527 were male (34.7%). The mean age was 75.7 ± 18.0 years (median 82). Most patients (n = 3675, 83.4%) were of retirement age, while 729 (16.6%) were working-age adults or minors. In total, an incidence of 25.0 (95% confidence limit (CL) 24.3-25.8) per 100,000 person-years was observed from 2017 to 2018. A higher incidence was observed for females (32.2, 95% CL 31.0-33.3) than for males (17.7, 95% CL 16.8-18.5). Incidences where higher for males in lower age groups (e.g. 10-14 years: rate ratio RR = 2.7, 95% CL 1.1-6.8), and higher for females in higher age groups (e.g. 70-74 years: RR = 0.6, 95% CL 0.5-0.8). In total, the most frequent diagnoses were macular degeneration (1075 persons, 24.4%), other retinal disorders (493 persons, 11.2%) and inherited retinal and choroidal diseases (IRDs) (186 persons, 4.2%). Persons with IRDs were significantly younger compared to persons with macular degeneration or retinal disorders (IRDs: median 57, range 2-96 vs 83, 5-98 and 82, 1-98 years, p<0.001). For persons of retirement age, macular degeneration, other retinal disorders and glaucoma were the three most frequent diagnoses. In contrast, among working-aged adults and children, IRDs were the leading cause of visual impairment and blindness (103 persons, 14.1%). CONCLUSION: These data show that IRDs are the leading cause of blindness and visual impairment in working-aged persons and children in Austria. Thus, these findings suggest to draw attention to enhance further research in the fields of emerging therapies for IRDs.

Longitudinal Changes in Scotopic and Mesopic Macular Function as Assessed with Microperimetry in Patients With Stargardt Disease: SMART Study Report No. 2.

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: This was a multicenter prospective cohort study. METHODS: Participants comprised 127 molecularly confirmed STGD1 patients enrolled from 6 centers in the United States and Europe and followed up every 6 months for up to 2 years. 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 were 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 < .001). Longitudinally, all eyes showed a statistically significant worsening trend: the rates of foveal mMD and extrafoveal mMD and sMD changes were 0.72 (95% CI = 0.37-1.07), 0.86 (95% CI = 0.58-1.14), and 1.12 (95% CI = 0.66-1.57) dB per year, respectively. CONCLUSIONS: In STGD1, in extrafovea, loss of scotopic macular function preceded and was faster than the loss of mesopic macular function. Scotopic and mesopic macular sensitivities using microperimetry provide alternative visual function outcomes for STGD1 treatment trials.

Longitudinal Changes of Fixation Stability and Location Within 24 Months in Stargardt Disease: ProgStar Report No. 16.

PURPOSE: Stargardt disease type 1 (STGD1) is the most common macular dystrophy. The assessment of fixation describes an important dimension of visual function, but data on its progression over time are limited. We present longitudinal changes and investigate its usefulness for clinical trials. DESIGN: International, multicenter, prospective cohort study. METHODS: Included were 239 individuals with genetically confirmed STGD1 (one or more disease-causing ATP binding cassette subfamily A member 4 [ABCA4] variant). We determined the fixation stability (FS) using 1 SD of the bivariate contour ellipse area (1 SD-BCEA) and fixation location (FL) using the eccentricity of fixation from the fovea during five 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 logBCEA was 0.70 ± 1.41 log deg2 and the mean FL was 6.25° ± 4.40°. Although the mean logBCEA did not monotonically increase from visit to visit, the overall yearly increase in the logBCEA was 0.124 log deg2 (95% CI, 0.063-0.185 log deg2). The rate of change was not different between the 2 years but increased faster in eyes without flecks outside of the vascular arcades and depended on baseline logBCEA. FL did not change statistically significantly over time. CONCLUSIONS: Fixation parameters are unlikely to be sensitive outcome measures for clinical trials in STGD1 but may provide useful ancillary information in selected cases to longitudinally describe and understand an eye's visual function.

The Progression of Stargardt Disease Using Volumetric Hill of Vision Analyses Over 24 Months: ProgStar Report No.15.

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.

A Swept source optical coherence tomography angiography study: Imaging artifacts and comparison of non-perfusion areas with fluorescein angiography in diabetic macular edema.

PURPOSE: Swept Source Optical coherence tomography angiography (SS-OCTA) is a novel technique to visualize perfusion and vascular changes like ischemia in patients with diabetic retinopathy. The aim of this study was to compare non-perfusion areas on conventional fluorescein angiography (FA) with those on SS-OCTA using detailed manual annotation in patients with diabetic macular edema (DME) and to evaluate possible artifacts caused by DME on SS-OCTA. METHODS: 27 eyes of 21 patients with DME were analyzed in this prospective, cross-sectional study; on all, standard ophthalmological examination, SS-OCTA and FA imaging were performed. Early-phase FA and SS-OCTA images were analyzed for capillary dropout and foveal avascular zone (FAZ) was measured on both modalities. Artifacts in SS-OCTA imaging caused by DME were marked and analyzed. RESULTS: The mean age of the patients was 62.6 ± 11.5 years. On FA the mean size of the annotated non-perfusion areas was 0.14 ± 0.31 mm2 whereas the mean size in SS-OCTA was 0.04 ± 0.13 mm2; areas marked on FA were statistically significantly larger than on SS-OCTA (p<0.01). Mean size of FAZs was similar between FA and OCTA images. (p = 0.91). Seven eyes (25.9 percent) showed imaging artifacts due to DME in SS-OCTA. CONCLUSION: SS-OCTA is a valid tool to analyze capillary perfusion status of patients with DME, although areas of non-perfusion were measured smaller than in conventional FA. More non-perfusion areas were found on SS-OCTA images. FAZ measurements were similar using the two modalities. However, SS-OCTA is prone to artifacts and therefore requires reviewing of imaging results: up to 25 percent of the analyzed eyes showed artifacts on OCTA, which occurred in the areas of diabetic macular edema and did not correspond to capillary drop out.

Early alterations in retinal microvasculature on swept-source optical coherence tomography angiography in acute central serous chorioretinopathy.

The purpose of the study was to evaluate the retinal blood flow in patients with acute central serous chorioretinopathy (CSC) over an observational period of 1 month using swept-source optical coherence tomography (SS-OCTA), focusing especially on changes in the area of subretinal fluid (A-SRF). We correlated these findings with conventional indocyanine green angiography (ICGA). ICGA and SS-OCTA images were collected and analyzed of 12 eyes of 12 patients. The A-SRF was annotated and a qualitative analysis of choriocapillaris, the vessel density (VD) and perfusion density (PD) of the retinal superficial capillary plexus (SCP) and the deep capillary plexus (DCP) was performed in A-SRF and the unaffected remaining area (RA). The VD and PD in the DCP were statistically significantly lower in A-SRF than in the RA at baseline. (VD: p = 0.014; PD: p = 0.036). After 1 month, there was a statistically significant difference in the VD and PD of the DCP (VD: p = 0.015; PD: p = 0.014), and for the PD of the SCP between the A-SRF and the RA (p = 0.015), with lower values in the A-SRF. We found low perfused areas in choriocapillaris corresponding to hypofluorescent areas on ICGA. In conclusion there is a difference in VD and VD of the DCP in the area of SRF in acute CSC. These alterations may lead to a chronic change in the microvasculature and potentially to morphological changes.

Longitudinal Microperimetric Changes of Macular Sensitivity in Stargardt Disease After 12 Months: ProgStar Report No. 13.

Importance: Functional end points for clinical trials investigating the efficacy of emerging treatments for Stargardt disease type 1 (STGD1) are needed. Objective: To assess the yearly rate of change of macular function in patients with STGD1 using microperimetry. 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. 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. Exposure: ABCA4-related STGD1 with a minimum lesion size on fundus autofluorescence and a minimum visual acuity. Main Outcomes and Measures: Changes in overall macular sensitivity (MS), deep scotoma count, number of points that tested normal, and location-specific sensitivity changes. Results: Among 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 Relevance: This 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.

The Effect of Attention on Fixation Stability During Dynamic Fixation Testing in Stargardt Disease.

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 < .0001). 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.

Faster Sensitivity Loss around Dense Scotomas than for Overall Macular Sensitivity in Stargardt Disease: ProgStar Report No. 14.

PURPOSE: 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. DESIGN: Multicenter, international, prospective cohort study: ProgStar Study. METHODS: 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). RESULTS: 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 (ß = -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 (ß = .09; P = .461). CONCLUSIONS: 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.

Prospective Cohort Study of Childhood-Onset Stargardt Disease: Fundus Autofluorescence Imaging, Progression, Comparison with Adult-Onset Disease, and Disease Symmetry.

PURPOSE: To 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. DESIGN: Prospective cohort study. METHODS: Children 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. RESULTS: The 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. CONCLUSIONS: This 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.

Progression of Stargardt Disease as Determined by Fundus Autofluorescence Over a 12-Month Period: ProgStar Report No. 11.

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) 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 RELEVANCE: In 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.

Reproducibility of Measurements of Retinal Structural Parameters Using Optical Coherence Tomography in Stargardt Disease.

PURPOSE: To assess the reproducibility of retinal measurements from optical coherence tomography (OCT) in ABCA4-related Stargardt disease (STGD1). METHODS: The international multicenter Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study enrolled 259 STGD1 patients. OCT images were graded by the study reading center (RC). Semiautomatic segmentation with manual adjustments was used to segment the layers of retinal pigmentation epithelium, outer segments, inner segments (ISs), outer nuclear layer (ONL), inner retina, and the total retina (TR). The images were overlaid to the Early Treatment Diabetic Retinopathy Study (ETDRS) grid. For each layer, the thickness and the intact area of the ETDRS central subfield, inner ring, and outer ring were recorded, respectively. A different set of RC graders regraded 30 independent ProgStar images to evaluate measurement reproducibility. Reproducibility was assessed graphically and using statistics including intraclass correlation (ICC) and relative absolute difference (RAD). RESULTS: Across all layers, measurements of the ETDRS central subfield had low ICC and/or large RAD. The outer-ring region was not fully captured in some images. For inner ring, good reproducibility was observed for intact area in the IS (ICC = 0.99, RAD = 4%), thicknesses of the ONL (ICC = 0.93, RAD = 6%), and TR (ICC = 0.99, RAD = 1%). CONCLUSIONS: STGD1's complex morphology made outer retina segmentation challenging. Measurements of the inner ring, including the intact area of IS (i.e., the ellipsoid zone [EZ]) and ONL and TR thicknesses, had good reproducibility and showed anatomical impairment. TRANSLATIONAL RELEVANCE: ONL and TR thicknesses and the EZ intact area in the ETDRS inner ring hold potential as structural endpoints for STGD1 trials. Structure-function relationships need to be further established.

A Workshop on Measuring the Progression of Atrophy Secondary to Stargardt Disease in the ProgStar Studies: Findings and Lessons Learned.

The Progression of Atrophy Secondary to Stargardt Disease (ProgStar) studies were designed to measure the progression of Stargardt disease through the use of fundus autofluorescence imaging, optical coherence tomography, and microperimetry. The overarching objectives of the studies were to document the natural course of Stargardt disease and identify the most appropriate clinical outcome measures for clinical trials assessing the efficacy and safety of upcoming treatments for Stargardt disease. A workshop organized by the Foundation Fighting Blindness Clinical Research Institute was held on June 11, 2018, in Baltimore, MD, USA. Invited speakers discussed spectral-domain optical coherence tomography, fundus autofluorescence, and microperimetry methods and findings in the ProgStar prospective study. The workshop concluded with a panel discussion of optimal endpoints for measuring treatment efficacy in Stargardt disease. We summarize the workshop presentations in light of the most current literature on Stargardt disease and discuss potential clinical outcome measures and endpoints for future treatment trials.

Cross-Sectional and Longitudinal Assessment of the Ellipsoid Zone in Childhood-Onset Stargardt Disease.

PURPOSE: To evaluate the reliability of ellipsoid zone (EZ) loss width and area measurements from spectral-domain optical coherence tomography (SD-OCT) images and track disease progression in childhood-onset Stargardt disease (STGD1). METHODS: Children with molecularly confirmed STGD1 (n = 46, mean age 12.4 years) underwent SD-OCT for the measurement of the transverse (width) loss of the EZ and en face analysis to quantify the area of EZ loss. All scans were analyzed twice by two graders to evaluate reliability. The annual rate of EZ width and area loss were calculated. RESULTS: The intra- and intergrader reliability of transverse EZ loss and area of EZ loss measurements at baseline for both graders was 0.99. The mean annual rate of transverse EZ loss (±standard deviation) was 279.5 ± 259.9 µm/y. The mean rate of area of EZ loss (±standard deviation) was 1.20 ± 1.29 mm2/y. The percentage transverse EZ loss was 10.2 ± 9.9%/y, which was significantly lower than the area of EZ loss at 19.4 ± 16.3%/y. High degree of interocular symmetry was observed. CONCLUSIONS: This is a prospective study on the quantification of EZ loss in children with STGD1 and highlights the reliability of SD-OCT in measuring EZ loss. High intra- and intergrader reliability was observed, with good ability to detect changes over time. TRANSLATIONAL RELEVANCE: Measuring the area of EZ loss was more sensitive compared with transverse EZ width loss measurements and will be valuable for natural history studies and clinical trials requiring sensitive and reliable structural endpoints.

Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8.

BACKGROUND/AIMS: To 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. METHODS: 345 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. RESULTS: 211 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. CONCLUSIONS: There 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.