Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease (SMART) Study: Design and Baseline Characteristics (Report No. 1).

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.

The Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Studies: Design and Baseline Characteristics: ProgStar Report No. 1.

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.

MAPPING THE DENSE SCOTOMA AND ITS ENLARGEMENT IN STARGARDT DISEASE.

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.

Equating Visual Function Scales to Facilitate Reporting of Medicare Functional G-Code Severity/Complexity Modifiers for Low-Vision Patients.

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.

Automated image alignment and segmentation to follow progression of geographic atrophy in age-related macular degeneration.

PURPOSE: To develop a computer-based image segmentation method for standardizing the quantification of geographic atrophy (GA). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Hydroxychloroquine can be resumed with close monitoring after retinopathy has developed, without major visual loss: Case Report.

PURPOSE: To present a patient with systemic lupus erythematosus on longstanding hydroxychloroquine (HCQ) use for whom HCQ was stopped due to signs of toxicity, and then resumed four years later due to dire systemic need. METHODS: Long term retrospective study. Humphrey visual fields (10-2 and 24-2), fundus autofluorescence imaging, and spectral domain OCT were used to follow progression over time. RESULTS: The patient was on HCQ for 26 years, with a cumulative dose over 3,000g. HCQ was stopped in 2011 due to macular toxicity. She remained off HCQ for four years, during which time she developed type 1 diabetes due to an immunologic attack on the pancreas, and then JC (John Cunningham) viremia after a period of treatment with mycophenolate, which put her at risk for progressive multifocal leukoencephalopathy. Mycophenolate was discontinued and HCQ was resumed with careful follow-up over the next 7 years. The toxic maculopathy showed only mild, slow progression since HCQ was resumed. CONCLUSION: Careful annual monitoring using HVF 10-2 and spectral domain OCT imaging remains the standard of care for patients on HCQ. However, it may be possible with close monitoring, when there is compelling systemic need, to resume HCQ after it has been stopped, with only slow progression of the retinopathy. This allowed the patient to have an improved quality of life and reduced the risk of severe morbidity and mortality.

Clinicopathologic Findings in Three Siblings With Geographic Atrophy.

Purpose: Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly worldwide. Clinical imaging and histopathologic studies are crucial to understanding disease pathology. This study combined clinical observations of three brothers with geographic atrophy (GA), followed for 20 years, with histopathologic analysis. Methods: For two of the three brothers, clinical images were taken in 2016, 2 years prior to death. Immunohistochemistry, on both flat-mounts and cross sections, histology, and transmission electron microscopy were used to compare the choroid and retina in GA eyes to those of age-matched controls. Results: Ulex europaeus agglutinin (UEA) lectin staining of the choroid demonstrated a significant reduction in the percent vascular area and vessel diameter. In one donor, histopathologic analysis demonstrated two separate areas with choroidal neovascularization (CNV). Reevaluation of swept-source optical coherence tomography angiography (SS-OCTA) images revealed CNV in two of the brothers. UEA lectin also revealed a significant reduction in retinal vasculature in the atrophic area. A subretinal glial membrane, composed of processes positive for glial fibrillary acidic protein and/or vimentin, occupied areas identical to those of retinal pigment epithelium (RPE) and choroidal atrophy in all three AMD donors. SS-OCTA also demonstrated presumed calcific drusen in the two donors imaged in 2016. Immunohistochemical analysis and alizarin red S staining verified calcium within drusen, which was ensheathed by glial processes. Conclusions: This study demonstrates the importance of clinicohistopathologic correlation studies. It emphasizes the need to better understand how the symbiotic relationship between choriocapillaris and RPE, glial response, and calcified drusen impact GA progression.

Oil droplet cataracts can mimic retinal disease.

PURPOSE: Oil Droplet Cataracts in adults is an elusive diagnosis for ophthalmologist. It is difficult to diagnose, and patients can suffer for years with increasingly debilitating symptoms for what is a surgically curable condition. Additionally, patients often undergo difficult and costly medical testing as well as occasionally receive improper treatment. This case series goal is to highlight this condition, showing that with careful slit lamp examination and index of suspicion one is able to appropriately diagnose this condition and avoid unnecessary testing and harm to a patient's quality of life. METHODS: Nine cases of this diagnostically challenging condition seen by one of the authors of this paper (JSS) are included. All were referred for electrophysiological or careful testing for unexplained visual loss, by neuroophthalmologists and/or retina specialists. Three were suspected of having a retinal dystrophy. Many had already undergone MRI and extensive evaluations. RESULTS: All patients were women. The average age was 45.5 years old with a range of 32-52 years of age on at their initial visit. The average length of symptoms prior to the initial visit was 3.2 years with a range of 3 months-11 years and a median of 4 years. Six had uniocular oil droplet cataracts, and three had binocular involvement. At diagnosis of the affected eyes, visual acuity ranged from 20/30-1 to 20/160 with a median of 20/65 in the affected eyes. Five patients had monocular diplopia or triplopia. Four had myopic shifts. Six patients had cataract surgery with resolution of their symptoms and restoration of good visual acuity. One patient who had been prescribed a low vision telescope for her presumed retinal dystrophy recovered to 20/20- ou, and had normalization of her electroretinogram after cataract surgery. CONCLUSIONS: This case series shows the diagnostic difficulty of this condition and the years it could take before a definitive diagnosis is made. Slit lamp examination was able to successfully diagnose this condition, although sometimes the oil droplet cataract was not seen until a later visit. Oil droplet cataracts should be considered in the differential diagnosis for a patient presenting with unexplained visual loss or acute worsening visual difficulties, and may mimic a retinal dystrophy. Once diagnosed, cataract surgery can cure this condition.(Abraham Ifrah, Janet S Sunness; Oil Drop Cataracts Mimicking Retinal Disease. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3851).

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.

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.

Toll-like receptor 3 and geographic atrophy in age-related macular degeneration.

BACKGROUND: Age-related macular degeneration is the most common cause of irreversible visual impairment in the developed world. Advanced age-related macular degeneration consists of geographic atrophy and choroidal neovascularization. The specific genetic variants that predispose patients to geographic atrophy are largely unknown. METHODS: We tested for an association between the functional toll-like receptor 3 gene (TLR3) variant rs3775291 (involving the substitution of phenylalanine for leucine at amino acid 412) and age-related macular degeneration in Americans of European descent. We also tested for the effect of TLR3 Leu and Phe variants on the viability of human retinal pigment epithelial cells in vitro and on apoptosis of retinal pigment epithelial cells from wild-type mice and Tlr3-knockout (Tlr3(-/-)) mice. RESULTS: The Phe variant (encoded by the T allele at rs3775291) was associated with protection against geographic atrophy (P=0.005). This association was replicated in two independent case-control series of geographic atrophy (P=5.43x10(-4) and P=0.002). No association was found between TLR3 variants and choroidal neovascularization. A prototypic TLR3 ligand induced apoptosis in a greater fraction of human retinal pigment epithelial cells with the Leu-Leu genotype than those with the Leu-Phe genotype and in a greater fraction of wild-type mice than Tlr3(-/-) mice. CONCLUSIONS: The TLR3 412Phe variant confers protection against geographic atrophy, probably by suppressing the death of retinal pigment epithelial cells. Since double-stranded RNA (dsRNA) can activate TLR3-mediated apoptosis, our results suggest a role of viral dsRNA in the development of geographic atrophy and point to the potential toxic effects of short-interfering-RNA therapies in the eye.

Characteristics of Glaucoma Patients Attending a Vision Rehabilitation Service.

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.

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.

Improvement of visual acuity by refraction in a low-vision population.

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.

Abnormal Visual Function Outside the Area of Atrophy Defined by Short-Wavelength Fundus Autofluorescence in Stargardt Disease.

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.

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.

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.