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Background/AimsTo better understand the pattern of degeneration progression in cases with choroideremia.MethodsA cohort of genotypically confirmed choroideremia cases who underwent optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging was studied. Using HEYEX review software, the foveal centre was marked on FAF images under guidance of corresponding OCT images, followed by application of an ETDRS grid. The boundaries of preserved autofluorescence (AF) were manually segmented in each individual ETDRS subfield. The regional distribution of preserved AF was assessed by comparing its area among the various subfields.ResultsA total of 168 eyes from 84 choroideremia cases were enrolled. There was a statistically significant difference in the amount of preserved AF area between inner subfields as determined by one-way analysis of variance (F (3,668)=9.997, pConclusionThe asymmetric spatial distribution of preserved AF in choroideremia (corresponding to the stellate shaped nature of these regions) suggests that the progression of degeneration has directional preference.

Background/aimsTo systematically compare the intermodality and inter-reader agreement for two blue-light confocal fundus autofluorescence (FAF) systems.MethodsThirty eyes (21 patients) with a diagnosis of geographic atrophy (GA) were enrolled. Eyes were imaged using two confocal blue-light FAF devices: (1) Spectralis device with a 488 nm excitation wavelength (488-FAF); (2) EIDON device with 450 nm excitation wavelength and the capability for ‘colour’ FAF imaging including both the individual red and green components of the emission spectrum. Furthermore, a third imaging modality (450-RF image) isolating and highlighting the red emission fluorescence component (REFC) was obtained and graded. Each image was graded by two readers to assess inter-reader variability and a single image for each modality was used to assess the intermodality variability.ResultsThe 95% coefficient of repeatability (1.35 mm2 for the 488-FAF-based grading, 8.13 mm2 for the 450-FAF-based grading and 1.08 mm2 for the 450-RF-based grading), the coefficient of variation (1.11 for 488-FAF, 2.05 for 450-FAF, 0.92 for 450-RF) and the intraclass correlation coefficient (0.994 for 488-FAF, 0.711 for 450-FAF, 0.997 for 450-RF) indicated that 450-FAF-based and 450-RF-based grading have the lowest and highest inter-reader agreements, respectively. The GA area was larger for 488-FAF images (median (IQR) 2.1 mm2 (0.8–6.4 mm2)) than for 450-FAF images (median (IQR) 1.0 mm2 (0.3–4.3 mm2); p2 (0.8–6.8 mm2); p=1.0).ConclusionThe isolation of the REFC from the 450-FAF images allowed for a reproducible quantification of GA. This assessment had good comparability with that obtained with 488-FAF images.

Background: The safety and efficacy of subretinally transplanted human central nervous system stem cells (HuCNS-SCR) in subjects with geographic atrophy (GA). Methods: Twenty-two eyes of 11 subjects with bilateral GA due to age-related macular degeneration (AMD) were enrolled in this IRB-approved, multicenter, prospective Phase I/II open-label clinical trial. For each subject, the eye with the worst best-corrected visual acuity was selected for treatment and considered the study eye; the fellow eye was treated as a control for this analysis. A total of 0·25 X 106 or 1·0 X 106 HuCNS-SC cells were directly infused into the subretinal space, superotemporal to the fovea near the junctional zone outside the area of GA. Subjects were followed for 12 months and the GA was monitored with fundus autofluorescence (FAF) imaging. Total GA area in both eyes was measured at baseline and month 12 by certified graders and sectoral (clock hour)/directional GA progression rates with respect to the foveal center were computed, and compared between study and control eyes. Findings: Although there was a numerical difference and trend, no statistically significant difference was observed in the overall 12 month enlargement in GA area between study and fellow eyes (1·07 ± 0·84 vs. 2·08 ± 1·97 mm2, P=0·08). However, the month 12 sectoral/directional GA growth rate for the superotemporal region (i.e. toward the location of HuCNS-SC transplantation) showed a significantly slower progression rate in study eyes compared to the same region in fellow eyes (0·06 ± 0·11 vs. 0·21 ± 0·13 mm2, P=0·03). The progression rate in the superotemporal quadrant of the study eye was also significantly slower than in the other three quadrants of the study eye combined (P=0·003). Interpretation: In this Phase I/II trial, HuCNS-SC transplantation was well tolerated and appeared to be associated with slower expansion of the GA lesion in the transplanted quadrant. Trial Registration: NCT01632527. Funding Statement: The clinical study was supported in full by the original trial sponsor, StemCells, Inc. Declaration of Interests: Financial disclosure: Dr. Sadda receives research support from Carl Zeiss, Meditec, Optos, Genentech, and Allergan. He has served as a consultant for Genentech, Allergan, Alcon, Novartis, and Roche. Dr. Birch receives research support from Nightstar, Allergan, AGTC, 4D Molecular Therapeutics, and ProQR Therapeutics. He has served as a consultant for Nightstar, AGTC, Nacuity Pharmaceuticals, Editas Medicine, Acucela, Foundation Fighting Blindness, and ProQR Therapeutics. All other authors declare no conflicts of interest. Ethics Approval Statement: All study procedures were approved by the institutional review boards (IRBs) of the participating clinical centers, and the research adhered to the tenets set forth in the Declaration of Helsinki. Informed consent was obtained from all subjects after explanation of the study procedures and the expected risks and benefits.

To evaluate manual and semiautomated grading techniques for assessing decreased fundus autofluorescence (DAF) in patients with Stargardt disease phenotype.Certified reading center graders performed manual and semiautomated (region finder-based) grading of confocal scanning laser ophthalmoscopy (cSLO) fundus autofluorescence (FAF) images for 41 eyes of 22 patients. Lesion types were defined based on the black level and sharpness of the border: definite decreased autofluorescence (DDAF), well, and poorly demarcated questionably decreased autofluorescence (WDQDAF, PDQDAF). Agreement in grading between the two methods and inter- and intra-grader agreement was assessed by kappa coefficients (κ) and intraclass correlation coefficients (ICC).The mean ± standard deviation (SD) area was 3.07 ± 3.02 mm for DDAF (n = 31), 1.53 ± 1.52 mm for WDQDAF (n = 9), and 6.94 ± 10.06 mm for PDQDAF (n = 17). The mean ± SD absolute difference in area between manual and semiautomated grading was 0.26 ± 0.28 mm for DDAF, 0.20 ± 0.26 mm for WDQDAF, and 4.05 ± 8.32 mm for PDQDAF. The ICC (95% confidence interval) for method comparison was 0.992 (0.984-0.996) for DDAF, 0.976 (0.922-0.993) for WDQDAF, and 0.648 (0.306-0.842) for PDQDAF. Inter- and intra-grader agreement in manual and semiautomated quantitative grading was better for DDAF (0.981-0.996) and WDQDAF (0.995-0.999) than for PDQDAF (0.715-0.993).Manual and semiautomated grading methods showed similar levels of reproducibility for assessing areas of decreased autofluorescence in patients with Stargardt disease phenotype. Excellent agreement and reproducibility were observed for well demarcated lesions.

BACKGROUND AND OBJECTIVE: To evaluate the spectral-domain optical coherence tomography (SD-OCT) characteristics of the junctional zone corresponding to areas of increased autofluorescence (IAF) at the margin of geographic atrophy (GA) in patients with age-related macular degeneration (AMD). PATIENTS AND METHODS: SD-OCT and fundus autofluorescence (FAF) images from untreated eyes with GA available from archived studies at Doheny Image Reading Center were evaluated. Areas of definite decreased autofluorescence (DDAF) corresponding to GA, and areas of IAF at the margins of the GA were manually segmented. Eyes with evidence of IAF were selected. Following manual registration of FAF and OCT data, areas of IAF and normal fluorescence were correlated with OCT features at these locations. RESULTS: Thirty eyes were included. The mean retinal pigment epithelium (RPE) thickness in areas of IAF was 40.6 µm ± 7.69 µm, compared to 28.8 µm ± 7.09 µm in normal adjacent areas ( P < .001). CONCLUSION: Regions of IAF at the junctional zone of GA lesions appear to correspond to thickening of the presumed RPE band on OCT. [ Ophthalmic Surg Lasers Imaging Retina . 2016;47:523–527.]

BACKGROUND AND OBJECTIVES: To evaluate retinal sensitivity (RS) by mesopic and scotopic microperimetry (MP-1S) in an elderly Amish population with age-related macular degeneration (AMD). PATIENTS AND METHODS: Mesopic and scotopic microperimetric testing was performed in 148 eyes of 77 elderly Amish subjects (age > 50 years) from Pennsylvania using a retinal function analyzer. Scotopic testing was performed using a 2.0 log unit neutral density filter following 30 minutes of dark adaptation. All subjects underwent complete ophthalmic examinations, including spectral-domain optical coherence tomography, fundus autofluorescence, infrared reflectance imaging, and flash color fundus photography. Certified graders at Doheny Image Reading Center identified subjects with evidence of AMD as defined by the Beckman classification and quantified drusen volume. RS in subjects with and without AMD was compared. Correlations between RS and drusen burden were analyzed. Ten eyes with incomplete MP-1S exams were excluded from the final analysis. RESULTS: Among the 138 eyes from 77 subjects included in the final analysis, 42 eyes from 29 subjects had evidence of early or intermediate AMD. The mean age of subjects with AMD was 69.65 years ± 13.81 years versus 63.04 years ± 12.69 years in those without AMD (P = .06). Mesopic RS was 18.8 dB ± 2.1 dB in subjects with AMD and 19.6 dB ± 1.4 dB in those without AMD (P = .07). Scotopic RS was significantly lower (P = .04) in subjects with AMD (15.9 dB ± 2.9 dB) compared with those without AMD (17.3 dB ± 2.4 dB). There was no relationship between mesopic RS and either drusen area (r = −0.06; P = .32) or drusen volume (r = −0.08; P = .30). There was a trend for an association between scotopic RS and both drusen area (r = −0.39; P = .24) and drusen volume (r = −0.36; P = .30). CONCLUSIONS: In an elderly Amish population, eyes with early or intermediate AMD show a greater reduction in scotopic RS than mesopic RS, suggesting that rod function is more severely affected than cone function. Drusen area and volume measurements better correlated with scotopic RS. [ Ophthalmic Surg Lasers Imaging Retina . 2019;50:e236–e241.]

Purpose To quantify the extent of topographic correspondence between baseline (BSL) choroidal neovascularization (CNV) and macular atrophy (MA) at follow-up in eyes with neovascular age-related macular degeneration (NVAMD). Design Post hoc analysis of randomized controlled clinical trial data. Methods Sixty treatment-naive NVAMD patients from the TREX-AMD trial were followed for 18 months. Regions of month 18 macular atrophy (MA) were graded on fundus autofluorescence (FAF) with guidance of spectral-domain optical coherence tomography (SDOCT). CNV lesions were graded manually on fluorescein angiography (FA) with lesion components including classic and occult CNV delineated. FAF and FA images were registered to quantitate area and location of overlap between CNV and MA. Outcome measures included overlap of month 18 MA to BSL CNV subtype and progression of MA from BSL to month 18. Results Twenty-six eyes had both MA at month 18 and CNV at BSL. A total of 84.6% of eyes showed evidence of MA and CNV overlap. MA appeared by month 18 in regions corresponding to BSL classic CNV in 36.4% of eyes and occult CNV in 40.9%, and in both regions in 22.7%, with more area of MA (AMA) in regions of occult than classic CNV. MA position at BSL corresponded to BSL classic CNV in 76.9% of eyes and occult CNV in 61.5%, and to both regions in 15.4%, with more AMA in regions of occult than classic CNV. Among eyes with MA and CNV at BSL but with no overlap, 50% progressed to involve regions with BS -CNV. Six eyes had no BSL MA but developed MA at month 18 within regions of BSL CNV. Conclusions In ranibizumab-treated eyes with NVAMD, more MA lesions develop within the region of baseline CNV (type 1, CNV-based MA) than outside (type 2, CNV-independent MA). Baseline-MA also tends to be located within regions of CNV in the pretreatment phase.

BACKGROUND AND OBJECTIVE: To evaluate scaling and measurement differences between flash and scanning laser fundus images. PATIENTS AND METHODS: The authors analyzed fundus autofluorescence images of patients with geographic atrophy secondary to age-related macular degeneration imaged with both 30º confocal scanning laser ophthalmoscope (cSLO) and 50º flash fundus camera (FFC). Multiple vessel-crossing points served as landmarks. RESULTS: The mean (± SD; range) scaling factor between cSLO and FFC images (by GRADOR) for the horizontal dimension was 1.217 (± 0.0487; 1.0474-1.272) versus 1.138 (± 0.0311; 1.0841-1.193) for the vertical dimension. The mean percentage difference between horizontal and vertical scaling factors was 7.48 (± 2.29; 2.30–10.70). Refractive error (focus) and aperture size (or field of view of the image) were positively correlated and aspect ratio was negatively correlated with landmark pair measurements. CONCLUSION: Inherent image-scaling differences between fundus autofluorescence imaging systems are not restricted to simple pixel-to-millimeter calibration variances, but appear to vary depending on measurement orientation. Differences should be considered when comparing measurements obtained using different imaging systems, particularly for clinical trials. [ Ophthalmic Surg Lasers Imaging Retina . 2015;46:872–879.]

PURPOSE The junctional zone at the border of areas of geographic atrophy (GA) in eyes with nonneovascular age-related macular degeneration is an important target region for future therapeutic strategies. The goal of this study was to perform a detailed classification and quantitative characterization of the junctional zone using spectral domain optical coherence tomography. METHODS Spectral domain optical coherence tomography volume cube scans (Spectralis OCT, 1024 × 37, Automatic Real Time > 9) were obtained from 15 eyes of 11 patients with GA because of nonneovascular age-related macular degeneration. Volume optical coherence tomography data were imported into previously described validated grading software (3D-OCTOR), and manual segmentation of the retinal pigment epithelium (RPE) and photoreceptor layers was performed on all B-scans (total of 555). Retinal pigment epithelium and photoreceptor defect maps were produced for each case. The borders of the photoreceptor defect area and RPE defect area were delineated individually on separate annotation layers. The two outlines were then superimposed to compare the areas of overlap and nonoverlap. The perimeter of the RPE defect area was calculated by the software in pixels. The superimposed outline of the photoreceptor defect area and the RPE defect area was scrutinized to classify the overlap configuration of the junctional zone into one of three categories: Type 0, exact correspondence between the edge of the RPE defect and photoreceptor defect; Type 1, loss of photoreceptors outside and beyond the edge of the RPE defect; Type 2, preservation of photoreceptors beyond the edge of the RPE defect. The relative proportion of the various border configurations was expressed as a percentage of the perimeter of the RPE defect. Each configuration was then classified into four subgroups according to irregularity of the RPE band and the presence of debris. RESULTS Fifteen eyes of 11 patients (mean age: 79.3 ± 4.3 years; range: 79-94 years) were included in this study. Seventeen GA lesions were analyzed. Two hundred and thirty-two B-scans were found to pass through the GA lesions, yielding 612 individual GA borders which were separately analyzed and classified. The mean area of the RPE defect was 4.0 ± 4.4 mm, which was significantly smaller than that of the photoreceptor defect which measured 4.4 ± 4.1 mm (paired t test, P = 0.037). On average, 18.0 ± 9.6% (range, 2.3-36.6%) of the junctional zone was of the Type 0 configuration, 57.3 ± 19.0% (range, 21.3-96.8%) was Type 1, and 24.7 ± 18.0% (range, 0.9-64.4%) was Type 2. Type 1 was more prevalent than Type 0 and 2 (analysis of variance, P = 0.000). Debris was present at the margin of the defect in 24.3% (149 of 612) of all assessed junctional zones; 20.0% (14 of 70) of Type 0 junctions, 28.7% (120 of 418) of Type 1, and 12.1% (15 of 124) of Type 2. Debris was more common in Type 1 than Type 2 junctions (P < 0.001). Retinal pigment epithelial irregularity was present at the margin of the defect in 34.8% (213 of 612) of all assessed junctional zones; 52.9% (37 of 70) of Type 0 junctions, 38.0% (159 of 418) of Type 1, and 13.7% (17 of 124) of Type 2. Retinal pigment epithelial irregularity was present more often at Type 0 and Type 1 than at Type 2 junctions (P < 0.001 for both). CONCLUSION The size of the optical coherence tomography-visible RPE and photoreceptor defect in GA lesions differ significantly. There were significant areas where the photoreceptor outer segments were preserved despite the absence of visible RPE cells, and also areas of photoreceptor outer segment loss despite apparent RPE preservation. These findings have implications for development of therapeutic strategies, particularly cell-replacement approaches.

To report a genotype-phenotype correlation study of patients with retinitis pigmentosa (RP) based on ultra-widefield (UWF) fundus autofluorescence (FAF) imaging.Case series.Thirty-four patients with RP.This retrospective study included RP patients with confirmed causative genetic variants and UWF FAF imaging data. Qualitative grading criteria including the pattern of macular abnormal autofluorescence, decreased autofluorescence (DAF), and its extent and distribution were applied to evaluate the genotype-phenotype correlation.The main parameters measured were increased or decreased patterns and extent of autofluorescence.Thirty-four unrelated patients 38±19 years of age (range, 9-82 years) were enrolled. Mutations in 17 different genes were detected in patients, including 7 patients having mutations in USH2A, 4 in DHDDS, 4 in RPGR, 3 in PRPF31, and 3 in RP1. Patients with nummular DAF and widespread DAF were significantly older (59±14 years and 56±19 years, respectively). All 3 patients with PRPF31 mutations showed an abnormal macular ring hyperautofluorescence and a circular pattern of coarse DAF distributed in Early Treatment Diabetic Retinopathy Study fields 1, 2, and 3 with sparing of the far periphery. In other genotypes, no specific DAF or macular abnormal autofluorescence pattern could be discerned.Specific UWF FAF characteristics in RP patients were correlated strongly with patient age and stage of the disease. Particular UWF FAF characteristics were found to be more prominent in a unique genotype.

BACKGROUND AND OBJECTIVE: To compare macular thickness measurement algorithms of two different spectral-domain optical coherence tomography (SD-OCT) devices in eyes affected by dry age-related macular degeneration (AMD). PATIENTS AND METHODS: Patients with dry AMD and healthy volunteers from the retina clinic of the Doheny Eye Center – UCLA were imaged using two different SD-OCT devices: the RS-3000 Advance (Nidek, Padova, Italy) and the Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA). All patients had been previously diagnosed with drusen or geographic atrophy due to AMD. The commercial instrument software was used to generate the macular retinal thickness measurements, and measurements were compared between devices. RESULTS: Eighty-five diseased eyes from 49 patients and 16 healthy control eyes from eight normal volunteers were included in this study. The macular thickness measurements generated by the two instruments in eyes with AMD differed significantly in mean retinal thickness in the foveal center subfield (257.34 μm ± 51.72 μm using the Nidek OCT vs. 238.20 μm ± 51.89 μm using the Cirrus OCT; P < .001). The mean difference in macular thickness between the two devices was 19.14 μm ± 5.84 μm for diseased eyes and 17.06 μm ± 5.28 μm in normal control eyes, and this was not statistically different between the two groups ( P > .05). The macular thickness measurements in diseased eyes, as evaluated by the two different instruments, however, showed excellent correlation (r = 0.99; P < .001), with an intraclass correlation coefficient of 0.99 (95% confidence interval, 0.98–0.99). Post hoc evaluation of cases with larger differences also showed differences in foveal center selection and variabilities in boundary selection with specific pathology. CONCLUSION: Macular thickness measurements provided by the Nidek and Cirrus OCT instruments in eyes with dry AMD are highly correlated but show a consistent difference, which may allow the use of a standard correction factor to be applied to better interrelate measurements between the devices. [ Ophthalmic Surg Lasers Imaging Retina . 2018;49:410–415.]

BACKGROUND AND OBJECTIVE: To determine the correlation between mesopic retinal sensitivity and optical coherence tomographic metrics of the outer retina in patients with intermediate age-related macular degeneration (AMD). PATIENTS AND METHODS: Participants with nonatrophic dry AMD underwent mesopic MP-3 microperimetry (Nidek, Padova, Italy) and both Nidek and Cirrus (Carl Zeiss Meditec, Dublin, CA) spectral-domain optical coherence tomography (SD-OCT). The volume of the outer retinal layers was measured on the Nidek SD-OCT scans using the automatic segmentation algorithm of Navis-EX software. In addition, drusen area and volume within a 5-mm circle centered on the fovea were determined using the Cirrus Advanced RPE Analysis Tool. The mean retinal sensitivity at 8° and 10° of fixation (5-mm and 6-mm circles) was calculated for every eye. The correlation between retinal sensitivity and patient age, outer retinal layer volume, drusen area, and drusen volume was assessed. RESULTS: Thirty-seven eyes from 25 patients with non-atrophic dry AMD were included in the study. The mean age of the patients was 76 years ± 9 years. The mean sensitivity across the whole tested retinal area was 24.9 dB ± 2.4 dB, with a sensitivity of 25.1 dB ± 2.4 dB within the central 5-mm circle. Drusen area within the central 5-mm circle was 0.7 mm 2 ± 0.89 mm 2 with a drusen volume of 0.03 mm 3 ± 0.04 mm 3 . Retinal pigment epithelium and photoreceptor outer segment (RPE + OS) volume was 1.96 mm 3 ± 0.1 mm 3 , and outer nuclear layer (ONL) volume was 1.91 mm 3 ± 0.17 mm 3 . There was a significant correlation between RPE + OS volume and retinal sensitivity, as well as between patients' age and retinal sensitivity. There was no significant correlation between drusen area or volume and retinal sensitivity, nor between ONL volume and retinal sensitivity. CONCLUSION: In eyes with nonatrophic AMD, retinal sensitivity is correlated with the RPE + OS volume, but not the ONL volume or the area or volume of drusen. [ Ophthalmic Surg Lasers Imaging Retina. 2017;48:312–318.]

To evaluate the response to aflibercept therapy for Type 1 and Type 3 neovascularization in pigment epithelial detachments associated with treatment-naive, neovascular age-related macular degeneration.In this multicentered, prospective study, eligible eyes underwent an intravitreal aflibercept injection protocol for 12 months. Visual acuity and morphologic features of the pigment epithelial detachments were compared at baseline and follow-up intervals between eyes with Type 1 versus Type 3 neovascularization.Thirty-six eyes were analyzed. At 12 months, Type 1 lesions showed a 4.5 ± 23 Early Treatment of Diabetic Retinopathy Study letter improvement (P = 0.1665) versus a 14 ± 11 (P = 0.0072) letter improvement with Type 3 lesions. Both Type 1 and 3 eyes showed a significant decrease in pigment epithelial detachment size, subretinal fluid, and subretinal hyperreflective material; however, Type 3 eyes had a greater reduction in pigment epithelial detachment size and subretinal hyperreflective material, as well as a reduction in central retinal thickness. Type 1 eyes required an average of 1.636 (range, 1-4) injections to resolve fluid, which was greater than Type 3 eyes, which required an average of 1.143 (range, 1-2) injections (P = 0.0251).Intravitreal aflibercept injections were efficacious for pigment epithelial detachments, but baseline and follow-up anatomical and functional outcomes differed in Type 1 versus Type 3 neovascularization. The better response of Type 3 eyes with fewer injections suggests that differentiation of the neovascularization subtype at the initial diagnosis may allow for a more tailored, optimal therapy.

Importance New methods are needed to quantify the change in the outer retinal structures in retinitis pigmentosa (RP). Objective To implement an alternate method for tracking ellipsoid zone (EZ) changes in RP by quantifying the EZ area on en face spectral domain–optical coherence tomographic (SD-OCT) images. Design, Setting, and Participants Data for this observational case study were collected at the Department of Ophthalmology, University of California, Los Angeles, from May 1 to July 30, 2015, and included SD-OCT images of a subset of patients from the Trial of Oral Valproic Acid for Retinitis Pigmentosa. To be eligible for the en face OCT subanalysis, the preserved EZ area was required to be limited to the SD-OCT scanning field. Cases in which the EZ band extended to the margins of any B-scan or the most superior or inferior B-scan were excluded. The SD-OCT images of all included cases were imported into the manufacturer’s software to generate en face images at the level of the EZ. Two certified SD-OCT graders independently delineated the boundaries of the preserved EZ on the en face images. Main Outcomes and Measures Comparison of the 2 masked gradings of the generated en face images of patients with RP for agreement between the graders and the validity of the method. Results Of the 43 available patients with volume SD-OCT data, 45 eyes of 24 patients met the eligibility criteria and were included in this subanalysis. Every patient had 2 visits that were 1 year apart, which included a total of 90 en face OCT images that were graded. The mean (SD) absolute difference and percentage difference between the 2 independent graders for each visit were 0.08 (0.10) mm 2 and 4.5% (5.9%), respectively. The EZ area determined by the 2 graders showed excellent agreement with an intraclass correlation coefficient of 0.996 (95% CI, 0.995-0.997; P Conclusions and Relevance Quantification of the preserved EZ area on en face SD-OCT images of patients with RP is a valid and reproducible method. En face SD-OCT quantification may be a useful tool for monitoring the EZ changes of patients with advanced RP and a useful outcome measurement variable in therapeutic trials.

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 inABCA4(OMIM601691), 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.

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 mm 2 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.