The Experts below are selected from a list of 3045 Experts worldwide ranked by ideXlab platform

Rupert W Strauss - One of the best experts on this subject based on the ideXlab platform.

  • longitudinal microperimetric changes of macular sensitivity in Stargardt Disease after 12 months progstar report no 13
    JAMA Ophthalmology, 2020
    Co-Authors: Rupert W Strauss, David G Birch, Etienne M Schonbach, Eberhart Zrenner, Beatriz Munoz, Yulia Wolfson, Mohamed A Ibrahim, Janet S. Sunness
    Abstract:

    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 withABCA4-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  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
    American Journal of Ophthalmology, 2020
    Co-Authors: Janet S. Sunness, Artur V Cideciyan, Rupert W Strauss, David G Birch, Etienne M Schonbach, Mohamed A Ibrahim, Jessica L Janes, Eberhart Zrenner
    Abstract:

    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 (MP-1, Nidek Technologies) 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, 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 yrs; 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=0.02) and the number of points within both the 2° and 4° circles was larger (P<.0001). CONCLUSIONS: Our results suggest that differences in static and dynamic assessment of fixation stability are not only dependent on different test durations but also on the testing protocol of a single fixation target versus 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
    American Journal of Ophthalmology, 2020
    Co-Authors: Janet S. Sunness, Artur V Cideciyan, Rupert W Strauss, David G Birch, Etienne M Schonbach, Mohamed A Ibrahim, Jessica L Janes, Beatriz Munoz
    Abstract:

    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. Here, we hypothesize that the functional decline is faster at the edge of the dense scotoma (eMS) than using overall MS. DESIGN: Multicenter, international, prospective cohort study: ProgStar study (NCT01977846). METHODS: Stargardt Disease patients (carrying at least one mutation in ABCA4) were followed over 12 months with microperimetry using a Humphrey 10-2 test grid. Custom software was developed to automatically define and selectively follow the test points directly adjacent to dense scotoma points and to calculate their mean sensitivity (eMS). RESULTS: Among 361 eyes (185 patients), the mean age was 32.9 ± 15.1. 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/yr) was significantly lower (β = -1.33, p < .001) than for eMS (2.9 ± 2.9 dB/yr). There was no difference in progression rates using automated vs manual grading (β = .09, p = .461). CONCLUSIONS: In Stargardt Disease, 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 measure to follow Stargardt patients in clinical trials, allowing clinical trial designs with shorter duration and/or smaller cohorts.

  • progression of Stargardt Disease as determined by fundus autofluorescence over a 12 month period progstar report no 11
    JAMA Ophthalmology, 2019
    Co-Authors: Rupert W Strauss, Paul S Bernstein, Artur V Cideciyan, David G Birch, Michael S Ip, Alexander Ho, Xiangrong Kong, Sheila K West, Michel Michaelides
    Abstract:

    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 theABCA4gene 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) mm2per year (P  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
    Translational Vision Science & Technology, 2019
    Co-Authors: Xiangrong Kong, Rupert W Strauss, Beatriz Munoz, Alexander Ho, Sheila K West, Mandeep S Singh, Ann M Ervin, Jeff Buzas, Zhihong Hu, Janet K Cheetham
    Abstract:

    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.

Rando Allikmets - One of the best experts on this subject based on the ideXlab platform.

  • clinical characterization of Stargardt Disease patients with the p n1868i abca4 mutation
    Retina-the Journal of Retinal and Vitreous Diseases, 2019
    Co-Authors: Frederick T. Collison, Jana Zernant, Gerald A. Fishman, Jason J Mcanany, Jason C Park, Rando Allikmets
    Abstract:

    Purpose:To investigate the Stargardt Disease phenotype associated with an unusually common and “extremely hypomorphic” ABCA4 variant, p.N1868I.Methods:The charts of 27 patients with p.N1868I on one allele and a severe/deleterious mutation on the other allele were reviewed. Subjective age of onset, b

  • A non-retinoid antagonist of retinol-binding protein 4 rescues phenotype in a model of Stargardt Disease without inhibiting the visual cycle
    Journal of Biological Chemistry, 2018
    Co-Authors: Boglarka Racz, Paul G. Pearson, Christopher L. Cioffi, Jian Kong, Rando Allikmets, Graham Johnson, András Váradi, Konstantin Petrukhin
    Abstract:

    A primary pathological defect in the heritable eye disorder Stargardt Disease is excessive accumulation of cytotoxic lipofuscin bisretinoids in the retina. Age-dependent accumulation of lipofuscin in the retinal pigment epithelium (RPE) matches the age-dependent increase in the incidence of the atrophic (dry) form of age-related macular degeneration (AMD) and therefore may be one of several pathogenic factors contributing to AMD progression. Lipofuscin bisretinoid synthesis in the retina depends on the influx of serum retinol from the circulation into the RPE. Formation of the tertiary retinol-binding protein 4 (RBP4)–transthyretin–retinol complex in the serum is required for this influx. Herein, we report the pharmacological effects of the non-retinoid RBP4 antagonist, BPN-14136. BPN-14136 dosing in the Abca4−/− mouse model of increased lipofuscinogenesis significantly reduced serum RBP4 levels and inhibited bisretinoid synthesis, and this inhibition correlated with a partial reduction in visual cycle retinoids such as retinaldehydes serving as bisretinoid precursors. BPN-14136 administration at doses inducing maximal serum RBP4 reduction did not produce changes in the rate of the visual cycle, consistent with minimal changes in dark adaptation. Abca4−/− mice exhibited dysregulation of the complement system in the retina, and BPN-14136 administration normalized the retinal levels of proinflammatory complement cascade components such as complement factors D and H, C-reactive protein, and C3. We conclude that BPN-14136 has several beneficial characteristics, combining inhibition of bisretinoid synthesis and reduction in retinaldehydes with normalization of the retinal complement system. BPN-14136, or a similar compound, may be a promising drug candidate to manage Stargardt Disease and dry AMD.

  • HYPERREFLECTIVE DEPOSITION IN THE BACKGROUND OF ADVANCED Stargardt Disease.
    Retina-the Journal of Retinal and Vitreous Diseases, 2017
    Co-Authors: Lyam Ciccone, Stephen H Tsang, Jana Zernant, Koji Tanaka, Kaspar Schuerch, Rando Allikmets
    Abstract:

    PURPOSE: To describe an unusual manifestation of hyperreflective deposits in the subretinal space in a group of patients with clinically and genetically confirmed Stargardt Disease. METHODS: Retrospective review of color fundus, autofluorescence, infrared reflectance, red-free images, and spectral domain optical coherence tomography in 296 clinically diagnosed and genetically confirmed (2 expected Disease-causing mutations in ABCA4) patients with Stargardt Disease. Full-field electroretinogram (ffERG), medical history, and genotype data (in silico predictions) were further analyzed from the selected cohort. RESULTS: Eight of 296 patients (2.7%) were found to exhibit small crystalline deposits that were detectable on certain imaging modalities, such as color, infrared reflectance and red-free images, but not autofluorescence. The deposits were most prevalent in the superior region of the macula, and spectral domain optical coherence tomography revealed their presence in the subretinal space. All patients presented with these findings at a notably advanced Disease stage with abnormal ffERG and a high proportion of highly deleterious ABCA4 alleles. CONCLUSION: Hyperreflective subretinal deposits may be a manifestation of advanced ABCA4 Disease, particularly in regions susceptible to Disease-related changes, such as lipofuscin accumulation.

  • Recessive Stargardt Disease phenocopying hydroxychloroquine retinopathy.
    Graefes Archive for Clinical and Experimental Ophthalmology, 2015
    Co-Authors: Kalev Nõupuu, Jana Zernant, Stephen H Tsang, Vivienne C. Greenstein, Rando Allikmets
    Abstract:

    Purpose To describe a series of patients with Stargardt Disease (STGD1) exhibiting a phenotype usually associated with hydroxychloroquine (HCQ) retinopathy on spectral domain-optical coherence tomography (SD-OCT).

  • psychophysical measurement of rod and cone thresholds in Stargardt Disease with full field stimuli
    Retina-the Journal of Retinal and Vitreous Diseases, 2014
    Co-Authors: Frederick T. Collison, Jana Zernant, Gerald A. Fishman, Jason J Mcanany, Rando Allikmets
    Abstract:

    Purpose:To investigate psychophysical thresholds in Stargardt Disease with the full-field stimulus test (FST).Methods:Visual acuity, spectral domain optical coherence tomography, full-field electroretinogram, and FST measurements were made in 1 eye of 24 patients with Stargardt Disease. Dark-adapted

Etienne M Schonbach - One of the best experts on this subject based on the ideXlab platform.

  • longitudinal microperimetric changes of macular sensitivity in Stargardt Disease after 12 months progstar report no 13
    JAMA Ophthalmology, 2020
    Co-Authors: Rupert W Strauss, David G Birch, Etienne M Schonbach, Eberhart Zrenner, Beatriz Munoz, Yulia Wolfson, Mohamed A Ibrahim, Janet S. Sunness
    Abstract:

    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 withABCA4-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  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
    American Journal of Ophthalmology, 2020
    Co-Authors: Janet S. Sunness, Artur V Cideciyan, Rupert W Strauss, David G Birch, Etienne M Schonbach, Mohamed A Ibrahim, Jessica L Janes, Eberhart Zrenner
    Abstract:

    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 (MP-1, Nidek Technologies) 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, 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 yrs; 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=0.02) and the number of points within both the 2° and 4° circles was larger (P<.0001). CONCLUSIONS: Our results suggest that differences in static and dynamic assessment of fixation stability are not only dependent on different test durations but also on the testing protocol of a single fixation target versus 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
    American Journal of Ophthalmology, 2020
    Co-Authors: Janet S. Sunness, Artur V Cideciyan, Rupert W Strauss, David G Birch, Etienne M Schonbach, Mohamed A Ibrahim, Jessica L Janes, Beatriz Munoz
    Abstract:

    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. Here, we hypothesize that the functional decline is faster at the edge of the dense scotoma (eMS) than using overall MS. DESIGN: Multicenter, international, prospective cohort study: ProgStar study (NCT01977846). METHODS: Stargardt Disease patients (carrying at least one mutation in ABCA4) were followed over 12 months with microperimetry using a Humphrey 10-2 test grid. Custom software was developed to automatically define and selectively follow the test points directly adjacent to dense scotoma points and to calculate their mean sensitivity (eMS). RESULTS: Among 361 eyes (185 patients), the mean age was 32.9 ± 15.1. 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/yr) was significantly lower (β = -1.33, p < .001) than for eMS (2.9 ± 2.9 dB/yr). There was no difference in progression rates using automated vs manual grading (β = .09, p = .461). CONCLUSIONS: In Stargardt Disease, 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 measure to follow Stargardt patients in clinical trials, allowing clinical trial designs with shorter duration and/or smaller cohorts.

  • a workshop on measuring the progression of atrophy secondary to Stargardt Disease in the progstar studies findings and lessons learned
    Translational Vision Science & Technology, 2019
    Co-Authors: Annmargret Ervin, Rupert W Strauss, Mohamed Ahmed, David G Birch, Janet K Cheetham, Frederick L Ferris, Michael S Ip, Glenn J Jaffe, Maureen G Maguire, Etienne M Schonbach
    Abstract:

    : 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.

  • scotopic microperimetric assessment of rod function in Stargardt Disease smart study design and baseline characteristics report no 1
    Ophthalmic Research, 2019
    Co-Authors: Rupert W Strauss, Annmargret Ervin, Mohamed Ahmed, Etienne M Schonbach, Beatriz Munoz, Alexander Ho, Michel Michaelides, Xiangrong Kong, Millena Bittencourt, David G Birch
    Abstract:

    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.

Michel Michaelides - One of the best experts on this subject based on the ideXlab platform.

  • progression of Stargardt Disease as determined by fundus autofluorescence over a 12 month period progstar report no 11
    JAMA Ophthalmology, 2019
    Co-Authors: Rupert W Strauss, Paul S Bernstein, Artur V Cideciyan, David G Birch, Michael S Ip, Alexander Ho, Xiangrong Kong, Sheila K West, Michel Michaelides
    Abstract:

    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 theABCA4gene 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) mm2per year (P  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.

  • scotopic microperimetric assessment of rod function in Stargardt Disease smart study design and baseline characteristics report no 1
    Ophthalmic Research, 2019
    Co-Authors: Rupert W Strauss, Annmargret Ervin, Mohamed Ahmed, Etienne M Schonbach, Beatriz Munoz, Alexander Ho, Michel Michaelides, Xiangrong Kong, Millena Bittencourt, David G Birch
    Abstract:

    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.

  • progression of Stargardt Disease as determined by fundus autofluorescence in the retrospective progression of Stargardt Disease study progstar report no 9
    JAMA Ophthalmology, 2017
    Co-Authors: Rupert W Strauss, Isabelle Audo, Artur V Cideciyan, David G Birch, Beatriz Munoz, Alexander Ho, Michel Michaelides, Amir H Hariri, Muneeswar Gupta Nittala
    Abstract:

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

  • incidence of atrophic lesions in Stargardt Disease in the progression of atrophy secondary to Stargardt Disease progstar study report no 5
    JAMA Ophthalmology, 2017
    Co-Authors: Rupert W Strauss, Artur V Cideciyan, David G Birch, Beatriz Munoz, Michel Michaelides, Amir H Hariri, Muneeswar Gupta Nittala, Alex Ho, Saddek Mohandsaid, Srinivas R Sadda
    Abstract:

    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.

  • progression of visual acuity and fundus autofluorescence in recent onset Stargardt Disease progstar study report 4
    Ophthalmology Retina, 2017
    Co-Authors: Xiangrong Kong, Artur V Cideciyan, Rupert W Strauss, Mohamed Ahmed, Beatriz Munoz, Alexander Ho, Michel Michaelides, Sheila K West, Etienne M Schonbach
    Abstract:

    Purpose To investigate the impact of areas of decreased fundus autofluorescence (AF) on visual acuity (VA) in molecularly confirmed Stargardt Disease (STGD1) with recent symptom onset, and investigate the association between these structural and functional measures over time. Design Prospective, international, multicenter observational study of Stargardt Disease. Participants Sixty-four patients (124 eyes) aged ≥6 years at first study visit, with onset of symptoms ≤2 years before the first visit. Methods AF images were graded for the presence and areas of definitely decreased AF (DDAF), questionably decreased AF (QDAF), and total decreased AF (DAF). First-visit images were also graded for presence of these lesions and for the presence of increased AF in the fovea. VA was measured as best-corrected or presenting acuity and converted to logarithm of the minimum angle of resolution (logMAR). Cross-sectional associations were measured using linear models with generalized estimating equations. Longitudinal linear mixed effects models were used to estimate yearly progression rates of VA and AF lesion areas. Main outcome measures were rate of change in VA and rate of change of decreased AF area. Results In cross-sectional analyses at baseline, VA was not significantly associated with area of DDAF (P = 0.86), or QDAF (P = 0.11), but was significantly associated with lesion involvement in the fovea (P Conclusions In recent-onset STGD1, the rate of VA loss was not significantly associated with the rate of increase in area of DDAF, QDAF, or DAF. For DDAF, the growth rate depended on the initial size of the lesion, a finding that will be helpful in stratifying these patients for intervention.

Artur V Cideciyan - One of the best experts on this subject based on the ideXlab platform.

  • the effect of attention on fixation stability during dynamic fixation testing in Stargardt Disease
    American Journal of Ophthalmology, 2020
    Co-Authors: Janet S. Sunness, Artur V Cideciyan, Rupert W Strauss, David G Birch, Etienne M Schonbach, Mohamed A Ibrahim, Jessica L Janes, Eberhart Zrenner
    Abstract:

    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 (MP-1, Nidek Technologies) 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, 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 yrs; 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=0.02) and the number of points within both the 2° and 4° circles was larger (P<.0001). CONCLUSIONS: Our results suggest that differences in static and dynamic assessment of fixation stability are not only dependent on different test durations but also on the testing protocol of a single fixation target versus 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
    American Journal of Ophthalmology, 2020
    Co-Authors: Janet S. Sunness, Artur V Cideciyan, Rupert W Strauss, David G Birch, Etienne M Schonbach, Mohamed A Ibrahim, Jessica L Janes, Beatriz Munoz
    Abstract:

    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. Here, we hypothesize that the functional decline is faster at the edge of the dense scotoma (eMS) than using overall MS. DESIGN: Multicenter, international, prospective cohort study: ProgStar study (NCT01977846). METHODS: Stargardt Disease patients (carrying at least one mutation in ABCA4) were followed over 12 months with microperimetry using a Humphrey 10-2 test grid. Custom software was developed to automatically define and selectively follow the test points directly adjacent to dense scotoma points and to calculate their mean sensitivity (eMS). RESULTS: Among 361 eyes (185 patients), the mean age was 32.9 ± 15.1. 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/yr) was significantly lower (β = -1.33, p < .001) than for eMS (2.9 ± 2.9 dB/yr). There was no difference in progression rates using automated vs manual grading (β = .09, p = .461). CONCLUSIONS: In Stargardt Disease, 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 measure to follow Stargardt patients in clinical trials, allowing clinical trial designs with shorter duration and/or smaller cohorts.

  • progression of Stargardt Disease as determined by fundus autofluorescence over a 12 month period progstar report no 11
    JAMA Ophthalmology, 2019
    Co-Authors: Rupert W Strauss, Paul S Bernstein, Artur V Cideciyan, David G Birch, Michael S Ip, Alexander Ho, Xiangrong Kong, Sheila K West, Michel Michaelides
    Abstract:

    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 theABCA4gene 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) mm2per year (P  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.

  • progression of Stargardt Disease as determined by fundus autofluorescence in the retrospective progression of Stargardt Disease study progstar report no 9
    JAMA Ophthalmology, 2017
    Co-Authors: Rupert W Strauss, Isabelle Audo, Artur V Cideciyan, David G Birch, Beatriz Munoz, Alexander Ho, Michel Michaelides, Amir H Hariri, Muneeswar Gupta Nittala
    Abstract:

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

  • towards treatment of Stargardt Disease workshop organized and sponsored by the foundation fighting blindness
    Translational Vision Science & Technology, 2017
    Co-Authors: Avery E Sears, Srinivas R Sadda, Carel B. Hoyng, Paul S Bernstein, Artur V Cideciyan, Peter Charbel Issa, Krzysztof Palczewski, Philip J Rosenfeld, Ulrich Schraermeyer, Janet R Sparrow
    Abstract:

    : Accumulation of fluorescent metabolic byproducts of the visual (retinoid) cycle is associated with photoreceptor and retinal pigment epithelial cell death in both Stargardt Disease and atrophic (nonneovascular) age-related macular degeneration (AMD). As a consequence of this observation, small molecular inhibitors of enzymes in the visual cycle were recently tested in clinical trials as a strategy to protect the retina and retinal pigment epithelium in patients with atrophic AMD. To address the clinical translational needs for therapies aimed at both Diseases, a workshop organized by the Foundation Fighting Blindness was hosted by the Department of Pharmacology at Case Western Reserve University on February 17, 2017, at the Tinkham Veale University Center, Cleveland, OH, USA. Invited speakers highlighted recent advances in the understanding of the pathophysiology of Stargardt Disease, in terms of its clinical characterization and the development of endpoints for clinical trials, and discussed the comparability of therapeutic strategies between atrophic age-related macular degeneration (AMD) and Stargardt Disease. Investigators speculated that reducing the concentrations of visual cycle precursor substances and/or their byproducts may provide valid therapeutic options for the treatment of Stargardt Disease. Here we review the workshop's presentations in the context of published literature to help shape the aims of ongoing research endeavors and aid the development of therapies for Stargardt Disease.