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Monika Fleckenstein - One of the best experts on this subject based on the ideXlab platform.

  • determinants of quality of life in Geographic Atrophy secondary to age related macular degeneration
    Investigative Ophthalmology & Visual Science, 2020
    Co-Authors: Sandrine H Künzel, Frank G. Holz, Moritz Lindner, Lukas Goerdt, Jennifer Nadal, Matthias Schmid, Philipp T Möller, S Schmitzvalckenberg, Monika Fleckenstein
    Abstract:

    Purpose To longitudinally evaluate vision-related quality of life (VRQoL) in Geographic Atrophy (GA) secondary to age-related macular degeneration (AMD) and define its relation to visual function and structural biomarkers. Methods Patients with GA secondary to AMD were recruited in the context of the prospective, non-interventional, natural-history Directional Spread in Geographic-Atrophy study (NCT02051998). Fundus autofluorescence and infrared reflectance images were semi-automatically annotated for GA. Linear mixed-effects models were applied to investigate the association of putative determinants with the National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) VRQoL. Results A total of 87 patients with a mean age ± SD of 77.07 ± 7.49 years were included in the analysis. At baseline, median (IQR) best-corrected visual acuity (BCVA) was 0.3 (0.51) for the better eye and 0.89 (0.76) for the worse eye; 46% of the patients showed binocular and 25.3% monocular non-central GA. The VRQoL composite score was impaired: 69.96 (24.03). Sixty-six patients with a median of 2 (2) follow-up visits after 1.08 (0.78) years were examined longitudinally. Conclusions Vision-related quality of life is significantly impaired in patients with GA secondary to AMD. The cross-sectional and longitudinal association of VRQoL with visual functional and structural biomarkers supports the validity of the NEI VFQ-25 VRQoL.

  • Determinants of Quality of Life in Geographic Atrophy Secondary to Age-Related Macular Degeneration.
    Investigative ophthalmology & visual science, 2020
    Co-Authors: Sandrine H Künzel, Frank G. Holz, Monika Fleckenstein, Steffen Schmitz-valckenberg, Moritz Lindner, Lukas Goerdt, Jennifer Nadal, Matthias Schmid, Philipp T Möller, Maximilian Pfau
    Abstract:

    To longitudinally evaluate vision-related quality of life (VRQoL) in Geographic Atrophy (GA) secondary to age-related macular degeneration (AMD) and define its relation to visual function and structural biomarkers. Patients with GA secondary to AMD were recruited in the context of the prospective, non-interventional, natural-history Directional Spread in Geographic-Atrophy study (NCT02051998). Fundus autofluorescence and infrared reflectance images were semi-automatically annotated for GA. Linear mixed-effects models were applied to investigate the association of putative determinants with the National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) VRQoL. A total of 87 patients with a mean age ± SD of 77.07 ± 7.49 years were included in the analysis. At baseline, median (IQR) best-corrected visual acuity (BCVA) was 0.3 (0.51) for the better eye and 0.89 (0.76) for the worse eye; 46% of the patients showed binocular and 25.3% monocular non-central GA. The VRQoL composite score was impaired: 69.96 (24.03). Sixty-six patients with a median of 2 (2) follow-up visits after 1.08 (0.78) years were examined longitudinally. Vision-related quality of life is significantly impaired in patients with GA secondary to AMD. The cross-sectional and longitudinal association of VRQoL with visual functional and structural biomarkers supports the validity of the NEI VFQ-25 VRQoL.

  • assessment of novel genome wide significant gene loci and lesion growth in Geographic Atrophy secondary to age related macular degeneration
    JAMA Ophthalmology, 2019
    Co-Authors: Monika Fleckenstein, Felix Grassmann, Sebastian Harsch, Caroline Brandl, Christina Kiel, Peter Nurnberg, Mohammad R Toliat, Maximilian Pfau, Steffen Schmitzvalckenberg
    Abstract:

    Importance Age-related macular degeneration (AMD) is a common threat to vision loss in individuals older than 50 years. While neovascular complications in AMD are treatable, there is currently no therapy for Geographic Atrophy secondary to AMD. Geographic Atrophy lesion progression over time shows considerable interindividual variability, but little is known about prognostic factors. Objective To elucidate the contribution of common genetic variants to Geographic Atrophy lesion growth. Design, Setting, and Participants This pooled analysis combined 4 independent studies: the Fundus Autofluorescence Imaging in Age-Related Macular Degeneration (FAM) study, the Directional Spread in Geographic Atrophy (DSGA) study, the Age-Related Eye Disease Study (AREDS), and the Geographic Atrophy Treatment Evaluation (GATE) study. Each provided data for Geographic Atrophy lesion growth in specific designs. Patients with Geographic Atrophy secondary to AMD were recruited to these studies. Genotypes were retrieved through the database of Genotypes and Phenotypes (for AREDS) or generated at the Cologne Center for Genomics (for FAM, DSGA, and GATE). Main Outcomes The correlation between square root–transformed Geographic Atrophy growth rate and 7 596 219 genetic variants passing quality control was estimated using linear regression. The calculations were adjusted for known factors influencing Geographic Atrophy growth, such as the presence of bilateral Geographic Atrophy as well as the number of lesion spots and follow-up times. Main Outcomes and Measures Slopes per allele, 95% CIs, andPvalues of genetic variants correlated with Geographic Atrophy lesion growth. Results A total of 935 patients (mean [SD] age, 74.7 [7.8] years; 547 female participants [59.0%]) were included. Two gene loci with conservative genome-wide significance were identified. Each minor allele of the genome-wide associated variants increased the Geographic Atrophy growth rate by a mean of about 15% or 0.05 mm per year. Gene prioritization within each locus suggests the protein arginine methyltransferase 6 gene (PRMT6; chromosome 1; slope, 0.046 [95% CI, 0.026-0.066];P = 4.09 × 10−8) and the lanosterol synthase gene (LSS;chromosome 21; slope, 0.105 [95% CI, 0.068-0.143];P = 4.07 × 10−7) as the most likely progression-associated genes. Conclusions and Relevance These data provide further insight into the genetic architecture of Geographic Atrophy lesion growth. Geographic Atrophy is a clinical outcome with a high medical need for effective therapy. The genesPRMT6andLSSare promising candidates for future studies aimed at understanding functional aspects of Geographic Atrophy progression and also for designing novel and targeted treatment options.

  • prognostic value of shape descriptive factors for the progression of Geographic Atrophy secondary to age related macular degeneration
    Retina-the Journal of Retinal and Vitreous Diseases, 2019
    Co-Authors: Maximilian Pfau, Frank G. Holz, Steffen Schmitzvalckenberg, Moritz Lindner, Lukas Goerdt, Sarah Thiele, Jennifer Nadal, Matthias Schmid, Monika Fleckenstein
    Abstract:

    PURPOSE: To systematically compare the prognostic value of multiple shape-descriptive factors in the natural course of the disease. METHODS: A total of 296 eyes of 201 patients (female patients 130; mean age: 72.2 ± 13.08 years) with a median follow-up of 2.38 years from 2 prospective, noninterventional natural history studies (Fundus-Autofluorescence-in-Age-related-Macular-Degeneration [clinicaltrials.gov identifier NCT00393692], Directional-Spread-in-Geographic-Atrophy [NCT02051998]) were included in the analysis. Serial fundus autofluorescence images were annotated using semiautomated image analysis software to determine the lesion area, circularity, perimeter, and caliper diameters. These variables and the fundus autofluorescence phenotype were evaluated for prediction of the future square root progression rates using linear mixed-effects models. RESULTS: For the combined model, leave-one-out cross validation on patient level (Scenario 1: previously unknown patient) resulted in a goodness-to-fit (R value) of 0.244 and leave-one-out cross validation on visit level (Scenario 2: previous observation of the patient) in a R value of 0.391. This indicated that shape-descriptive factors could explain 24.4% of the variance in Geographic Atrophy progression in previously unknown patients and 39.1% in patients with previous observation. CONCLUSION: These findings confirm the relevance of shape-descriptive factors and previous progression as prognostic variables for Geographic Atrophy progression. However, a substantial part of the remaining variation in Geographic Atrophy progression seems to depend on other variables, some of which are visible in optical coherence tomography.

  • the progression of Geographic Atrophy secondary to age related macular degeneration
    Ophthalmology, 2017
    Co-Authors: Monika Fleckenstein, Bailey K Freund, Frank G. Holz, Srinivas R Sadda, Erin C Henry, Christopher Brittain, Paul Mitchell, Daniela Ferrara
    Abstract:

    Geographic Atrophy (GA) is an advanced form of age-related macular degeneration (AMD) that leads to progressive and irreversible loss of visual function. Geographic Atrophy is defined by the presence of sharply demarcated atrophic lesions of the outer retina, resulting from loss of photoreceptors, retinal pigment epithelium (RPE), and underlying choriocapillaris. These lesions typically appear first in the perifoveal macula, initially sparing the foveal center, and over time often expand and coalesce to include the fovea. Although the kinetics of GA progression are highly variable among individual patients, a growing body of evidence suggests that specific characteristics may be important in predicting disease progression and outcomes. This review synthesizes current understanding of GA progression in AMD and the factors known or postulated to be relevant to GA lesion enlargement, including both affected and fellow eye characteristics. In addition, the roles of genetic, environmental, and demographic factors in GA lesion enlargement are discussed. Overall, GA progression rates reported in the literature for total study populations range from 0.53 to 2.6 mm2/year (median, ∼1.78 mm2/year), assessed primarily by color fundus photography or fundus autofluorescence (FAF) imaging. Several factors that could inform an individual's disease prognosis have been replicated in multiple cohorts: baseline lesion size, lesion location, multifocality, FAF patterns, and fellow eye status. Because best-corrected visual acuity does not correspond directly to GA lesion enlargement due to possible foveal sparing, alternative assessments are being explored to capture the relationship between anatomic progression and visual function decline, including microperimetry, low-luminance visual acuity, reading speed assessments, and patient-reported outcomes. Understanding GA progression and its individual variability is critical in the design of clinical studies, in the interpretation and application of clinical trial results, and for counseling patients on how disease progression may affect their individual prognosis.

Frank G. Holz - One of the best experts on this subject based on the ideXlab platform.

  • determinants of quality of life in Geographic Atrophy secondary to age related macular degeneration
    Investigative Ophthalmology & Visual Science, 2020
    Co-Authors: Sandrine H Künzel, Frank G. Holz, Moritz Lindner, Lukas Goerdt, Jennifer Nadal, Matthias Schmid, Philipp T Möller, S Schmitzvalckenberg, Monika Fleckenstein
    Abstract:

    Purpose To longitudinally evaluate vision-related quality of life (VRQoL) in Geographic Atrophy (GA) secondary to age-related macular degeneration (AMD) and define its relation to visual function and structural biomarkers. Methods Patients with GA secondary to AMD were recruited in the context of the prospective, non-interventional, natural-history Directional Spread in Geographic-Atrophy study (NCT02051998). Fundus autofluorescence and infrared reflectance images were semi-automatically annotated for GA. Linear mixed-effects models were applied to investigate the association of putative determinants with the National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) VRQoL. Results A total of 87 patients with a mean age ± SD of 77.07 ± 7.49 years were included in the analysis. At baseline, median (IQR) best-corrected visual acuity (BCVA) was 0.3 (0.51) for the better eye and 0.89 (0.76) for the worse eye; 46% of the patients showed binocular and 25.3% monocular non-central GA. The VRQoL composite score was impaired: 69.96 (24.03). Sixty-six patients with a median of 2 (2) follow-up visits after 1.08 (0.78) years were examined longitudinally. Conclusions Vision-related quality of life is significantly impaired in patients with GA secondary to AMD. The cross-sectional and longitudinal association of VRQoL with visual functional and structural biomarkers supports the validity of the NEI VFQ-25 VRQoL.

  • Determinants of Quality of Life in Geographic Atrophy Secondary to Age-Related Macular Degeneration.
    Investigative ophthalmology & visual science, 2020
    Co-Authors: Sandrine H Künzel, Frank G. Holz, Monika Fleckenstein, Steffen Schmitz-valckenberg, Moritz Lindner, Lukas Goerdt, Jennifer Nadal, Matthias Schmid, Philipp T Möller, Maximilian Pfau
    Abstract:

    To longitudinally evaluate vision-related quality of life (VRQoL) in Geographic Atrophy (GA) secondary to age-related macular degeneration (AMD) and define its relation to visual function and structural biomarkers. Patients with GA secondary to AMD were recruited in the context of the prospective, non-interventional, natural-history Directional Spread in Geographic-Atrophy study (NCT02051998). Fundus autofluorescence and infrared reflectance images were semi-automatically annotated for GA. Linear mixed-effects models were applied to investigate the association of putative determinants with the National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) VRQoL. A total of 87 patients with a mean age ± SD of 77.07 ± 7.49 years were included in the analysis. At baseline, median (IQR) best-corrected visual acuity (BCVA) was 0.3 (0.51) for the better eye and 0.89 (0.76) for the worse eye; 46% of the patients showed binocular and 25.3% monocular non-central GA. The VRQoL composite score was impaired: 69.96 (24.03). Sixty-six patients with a median of 2 (2) follow-up visits after 1.08 (0.78) years were examined longitudinally. Vision-related quality of life is significantly impaired in patients with GA secondary to AMD. The cross-sectional and longitudinal association of VRQoL with visual functional and structural biomarkers supports the validity of the NEI VFQ-25 VRQoL.

  • Light Sensitivity Within Areas of Geographic Atrophy Secondary to Age-Related Macular Degeneration.
    Investigative Ophthalmology & Visual Science, 2019
    Co-Authors: Maximilian Pfau, Steffen Schmitz-valckenberg, Moritz Lindner, Sarah Thiele, Jennifer Nadal, Matthias Schmid, Philipp T Möller, Leon Von Der Emde, Chantal Dysli, Frank G. Holz
    Abstract:

    Purpose: To investigate residual sensitivity within Geographic Atrophy (GA) secondary to age-related macular degeneration. Methods: Mesopic and dark-adapted (DA) cyan and red light sensitivity (Goldmann III) were investigated using fundus-controlled perimetry (microperimetry). Test points were placed within GA along an "iso-hull" with a distance of -0.645° to the Atrophy boundary. The false-positive response rate was determined with suprathreshold stimuli to the optic disc (Heijl-Krakau method) and used to compute the expected sensitivity measurements for the assumption of absolute scotomata. The outermost visible retinal layer on spectral-domain optical coherence tomography at the location of each test point was determined. Results: Thirty eyes of 36 patients (75.55 ± 7.93 years; 19 female) from the prospective natural history study Directional Spread in Geographic Atrophy (NCT02051998), with a total of 1380 threshold determinations were analyzed. The measured sensitivities were significantly (P < 0.01) higher than the expected values for absolute scotomata (mean ± standard error of +6.92 ± 0.86 dB for mesopic, +2.57 ± 0.56 dB for DA cyan, and +4.93 ± 0.74 dB for DA red testing). For mesopic testing and DA red testing, the presence of a residual outer nuclear layer had a significant effect on this discrepancy (P < 0.001). There was no effect of fixation stability or any other reliability index on this discrepancy. Conclusions: Measured sensitivities within the inner junctional zone of GA may not be purely explained by patient-specific false-positive response rates or other reliability indices. The marked influence of the outer retinal configuration on measured sensitivity may be indicative of residual cone function within GA at the inner junctional zone.

  • prognostic value of shape descriptive factors for the progression of Geographic Atrophy secondary to age related macular degeneration
    Retina-the Journal of Retinal and Vitreous Diseases, 2019
    Co-Authors: Maximilian Pfau, Frank G. Holz, Steffen Schmitzvalckenberg, Moritz Lindner, Lukas Goerdt, Sarah Thiele, Jennifer Nadal, Matthias Schmid, Monika Fleckenstein
    Abstract:

    PURPOSE: To systematically compare the prognostic value of multiple shape-descriptive factors in the natural course of the disease. METHODS: A total of 296 eyes of 201 patients (female patients 130; mean age: 72.2 ± 13.08 years) with a median follow-up of 2.38 years from 2 prospective, noninterventional natural history studies (Fundus-Autofluorescence-in-Age-related-Macular-Degeneration [clinicaltrials.gov identifier NCT00393692], Directional-Spread-in-Geographic-Atrophy [NCT02051998]) were included in the analysis. Serial fundus autofluorescence images were annotated using semiautomated image analysis software to determine the lesion area, circularity, perimeter, and caliper diameters. These variables and the fundus autofluorescence phenotype were evaluated for prediction of the future square root progression rates using linear mixed-effects models. RESULTS: For the combined model, leave-one-out cross validation on patient level (Scenario 1: previously unknown patient) resulted in a goodness-to-fit (R value) of 0.244 and leave-one-out cross validation on visit level (Scenario 2: previous observation of the patient) in a R value of 0.391. This indicated that shape-descriptive factors could explain 24.4% of the variance in Geographic Atrophy progression in previously unknown patients and 39.1% in patients with previous observation. CONCLUSION: These findings confirm the relevance of shape-descriptive factors and previous progression as prognostic variables for Geographic Atrophy progression. However, a substantial part of the remaining variation in Geographic Atrophy progression seems to depend on other variables, some of which are visible in optical coherence tomography.

  • the progression of Geographic Atrophy secondary to age related macular degeneration
    Ophthalmology, 2017
    Co-Authors: Monika Fleckenstein, Bailey K Freund, Frank G. Holz, Srinivas R Sadda, Erin C Henry, Christopher Brittain, Paul Mitchell, Daniela Ferrara
    Abstract:

    Geographic Atrophy (GA) is an advanced form of age-related macular degeneration (AMD) that leads to progressive and irreversible loss of visual function. Geographic Atrophy is defined by the presence of sharply demarcated atrophic lesions of the outer retina, resulting from loss of photoreceptors, retinal pigment epithelium (RPE), and underlying choriocapillaris. These lesions typically appear first in the perifoveal macula, initially sparing the foveal center, and over time often expand and coalesce to include the fovea. Although the kinetics of GA progression are highly variable among individual patients, a growing body of evidence suggests that specific characteristics may be important in predicting disease progression and outcomes. This review synthesizes current understanding of GA progression in AMD and the factors known or postulated to be relevant to GA lesion enlargement, including both affected and fellow eye characteristics. In addition, the roles of genetic, environmental, and demographic factors in GA lesion enlargement are discussed. Overall, GA progression rates reported in the literature for total study populations range from 0.53 to 2.6 mm2/year (median, ∼1.78 mm2/year), assessed primarily by color fundus photography or fundus autofluorescence (FAF) imaging. Several factors that could inform an individual's disease prognosis have been replicated in multiple cohorts: baseline lesion size, lesion location, multifocality, FAF patterns, and fellow eye status. Because best-corrected visual acuity does not correspond directly to GA lesion enlargement due to possible foveal sparing, alternative assessments are being explored to capture the relationship between anatomic progression and visual function decline, including microperimetry, low-luminance visual acuity, reading speed assessments, and patient-reported outcomes. Understanding GA progression and its individual variability is critical in the design of clinical studies, in the interpretation and application of clinical trial results, and for counseling patients on how disease progression may affect their individual prognosis.

Glenn J Jaffe - One of the best experts on this subject based on the ideXlab platform.

  • natural history of Geographic Atrophy progression secondary to age related macular degeneration Geographic Atrophy progression study
    Ophthalmology, 2016
    Co-Authors: Steffen Schmitzvalckenberg, Monika Fleckenstein, Josealain Sahel, Ronald P Danis, Glenn J Jaffe, Sebastian Wolf, Christian Pruente, Frank G. Holz
    Abstract:

    Purpose The Geographic Atrophy Progression (GAP) study was designed to assess the rate of Geographic Atrophy (GA) progression and to identify prognostic factors by measuring the enlargement of the atrophic lesions using fundus autofluorescence (FAF) and color fundus photography (CFP). Design Prospective, multicenter, noninterventional natural history study. Participants A total of 603 participants were enrolled in the study; 413 of those had gradable lesion data from FAF or CFP, and 321 had gradable lesion data from both FAF and CFP. Methods Atrophic lesion areas were measured by FAF and CFP to assess lesion progression over time. Lesion size assessments and best-corrected visual acuity (BCVA) were conducted at screening/baseline (day 0) and at 3 follow-up visits: month 6, month 12, and month 18 (or early exit). Main Outcome Measures The GA lesion progression rate in disease subgroups and mean change from baseline visual acuity. Results Mean (standard error) lesion size changes from baseline, determined by FAF and CFP, respectively, were 0.88 (0.1) and 0.78 (0.1) mm 2 at 6 months, 1.85 (0.1) and 1.57 (0.1) mm 2 at 12 months, and 3.14 (0.4) and 3.17 (0.5) mm 2 at 18 months. The mean change in lesion size from baseline to month 12 was significantly greater in participants who had eyes with multifocal atrophic spots compared with those with unifocal spots ( P P  = 0.001). The mean (standard deviation) decrease in visual acuity was 6.2 ± 15.6 letters for patients with image data available. Atrophic lesions with a diffuse (mean 0.95 mm 2 ) or banded (mean 1.01 mm 2 ) FAF pattern grew more rapidly by month 6 compared with those with the "none" (mean, 0.13 mm 2 ) and focal (mean, 0.36 mm 2 ) FAF patterns. Conclusions Although differences were observed in mean lesion size measurements using FAF imaging compared with CFP, the measurements were highly correlated with one another. Significant differences were found in lesion progression rates in participants stratified by hyperfluorescence pattern subtype. This large GA natural history study provides a strong foundation for future clinical trials.

  • Risk of Geographic Atrophy in the comparison of age-related macular degeneration treatments trials.
    Ophthalmology, 2013
    Co-Authors: Juan E. Grunwald, Maureen G. Maguire, Glenn J Jaffe, Gui-shuang Ying, Barbara A. Blodi, Ebenezer Daniel, Jiayan Huang, Cynthia A. Toth, Stuart L. Fine, Michael L. Klein
    Abstract:

    Purpose To evaluate the growth of Geographic Atrophy (GA) during anti–vascular endothelial growth factor (VEGF) therapy. Design Cohort within a clinical trial. Participants Patients included in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). Methods Participants were randomly assigned to injections of ranibizumab or bevacizumab and to a 2-year dosing regimen of monthly or pro re nata (PRN) or to monthly for 1 year and PRN the following year. Digital color photographs and fluorescein angiograms at baseline and 1 and 2 years were evaluated for GA, and the total area of GA was measured by 2 graders masked to treatment; differences were adjudicated. Multivariate linear mixed models of the annual change in the square root of the area included baseline demographic, treatment, and ocular characteristics on imaging as candidate risk factors. Main Outcome Measures Geographic Atrophy growth rate. Results Among 1185 participants, 86 (7.3%) had GA at baseline, 120 (10.1%) developed GA during year 1, and 36 (3.0%) developed GA during year 2. Among 194 eyes evaluable for growth, the rate was 0.43 mm/yr (standard error [SE], ±0.03 mm/year). In multivariate analysis, the growth rate was 0.37 mm/year in eyes receiving bevacizumab and 0.49 mm/year in eyes receiving ranibizumab (difference, 0.11 mm/yr; 95% confidence interval [CI], 0.01–0.22; P  = 0.03). Growth rate did not differ between eyes treated monthly and PRN ( P  = 0.85). Eyes with subfoveal choroidal neovascularization (CNV) lesions had a lower growth rate than eyes with nonsubfoveal CNV lesions (difference, 0.12; 95% CI, 0.01–0.22; P  = 0.03). Eyes with GA farther from the fovea had higher growth rates by 0.14 (95% CI, 0.01–27) mm/year for every millimeter farther from the fovea. The growth rate was 0.58 mm/year for eyes with predominantly classic lesions, 0.41 mm/year for eyes with minimally classic lesions, and 0.30 mm/year for eyes with occult only lesions ( P P  = 0.03) than in eyes without GA in the fellow eye. Eyes with epiretinal membrane had a higher growth rate than eyes without epiretinal membrane (difference, 0.16; 95% CI, 0.03–0.30; P  = 0.02). Conclusions Geographic Atrophy growth depends on several ocular factors. Ranibizumab may accelerate GA growth.

  • spectral domain optical coherence tomography determined morphologic predictors of age related macular degeneration associated Geographic Atrophy progression
    Retina-the Journal of Retinal and Vitreous Diseases, 2013
    Co-Authors: Kareem Moussa, Sandra S Stinnett, Glenn J Jaffe
    Abstract:

    Purpose:To correlate spectral domain optical coherence tomography (SD OCT)–determined morphologic alterations in eyes with Geographic Atrophy because of age-related macular degeneration with lesion size, enlargement rate, and the presence of multifocal patches of Atrophy.Methods:Forty-three eyes of

  • topography of Geographic Atrophy in age related macular degeneration
    Investigative Ophthalmology & Visual Science, 2012
    Co-Authors: Matthias M Mauschitz, Frank G. Holz, Arno P. Göbel, Monika Fleckenstein, Glenn J Jaffe, Sofia Fonseca, Petrus Chang, Steffen Schmitzvalckenberg
    Abstract:

    PURPOSE: To determine the topographic distribution and progression of Geographic Atrophy (GA) in patients with AMD. METHODS: Fundus autofluorescence images (excitation 488, emission 500-700 nm) from 413 eyes of 413 subjects (median age, 77.0 years; inter quartile range [IQR], 72.0-82.0 years) of the Geographic Atrophy Progression (GAP) study were retrospectively analyzed. Using a modified Early Treatment Diabetic Retinopathy Study grid to divide the posterior pole into nine different subfields plus periphery, the localization, size, and progression of atrophic patches were determined. Subfields, zones (center, inner and outer), and slices (nasal, temporal, inferior, superior) were compared using the Friedman test. RESULTS: The center and inner zones were involved in almost all eyes (>95%), while Atrophy was less common in the outer zone subfields (76%). Inner zone Atrophy size (median 4.00 mm(2)) and progression rate (0.67 mm(2)/year) were significantly greater than in the outer zone (0.60 mm(2) and 0.42 mm(2)/year; P < 0.001). There was a trend toward outer zone subfield and periphery involvement with increasing total size of Atrophy. In addition, the superior outer subfield was significantly more affected by Atrophy as compared with the other three outer subfields of the grid (P < 0.001). CONCLUSIONS: Distribution and progression of existing GA patches depended both on the eccentricity from the center and total GA size. Central macular areas appeared most susceptible for the occurrence and expansion of GA. Refined analysis of distribution and directional spread is important to understand the natural history of the disease. This information will likely be helpful to design interventional GA clinical trials and associated anatomical outcome measures. (ClinicalTrials. gov number, NCT00599846.).

Steffen Schmitzvalckenberg - One of the best experts on this subject based on the ideXlab platform.

  • assessment of novel genome wide significant gene loci and lesion growth in Geographic Atrophy secondary to age related macular degeneration
    JAMA Ophthalmology, 2019
    Co-Authors: Monika Fleckenstein, Felix Grassmann, Sebastian Harsch, Caroline Brandl, Christina Kiel, Peter Nurnberg, Mohammad R Toliat, Maximilian Pfau, Steffen Schmitzvalckenberg
    Abstract:

    Importance Age-related macular degeneration (AMD) is a common threat to vision loss in individuals older than 50 years. While neovascular complications in AMD are treatable, there is currently no therapy for Geographic Atrophy secondary to AMD. Geographic Atrophy lesion progression over time shows considerable interindividual variability, but little is known about prognostic factors. Objective To elucidate the contribution of common genetic variants to Geographic Atrophy lesion growth. Design, Setting, and Participants This pooled analysis combined 4 independent studies: the Fundus Autofluorescence Imaging in Age-Related Macular Degeneration (FAM) study, the Directional Spread in Geographic Atrophy (DSGA) study, the Age-Related Eye Disease Study (AREDS), and the Geographic Atrophy Treatment Evaluation (GATE) study. Each provided data for Geographic Atrophy lesion growth in specific designs. Patients with Geographic Atrophy secondary to AMD were recruited to these studies. Genotypes were retrieved through the database of Genotypes and Phenotypes (for AREDS) or generated at the Cologne Center for Genomics (for FAM, DSGA, and GATE). Main Outcomes The correlation between square root–transformed Geographic Atrophy growth rate and 7 596 219 genetic variants passing quality control was estimated using linear regression. The calculations were adjusted for known factors influencing Geographic Atrophy growth, such as the presence of bilateral Geographic Atrophy as well as the number of lesion spots and follow-up times. Main Outcomes and Measures Slopes per allele, 95% CIs, andPvalues of genetic variants correlated with Geographic Atrophy lesion growth. Results A total of 935 patients (mean [SD] age, 74.7 [7.8] years; 547 female participants [59.0%]) were included. Two gene loci with conservative genome-wide significance were identified. Each minor allele of the genome-wide associated variants increased the Geographic Atrophy growth rate by a mean of about 15% or 0.05 mm per year. Gene prioritization within each locus suggests the protein arginine methyltransferase 6 gene (PRMT6; chromosome 1; slope, 0.046 [95% CI, 0.026-0.066];P = 4.09 × 10−8) and the lanosterol synthase gene (LSS;chromosome 21; slope, 0.105 [95% CI, 0.068-0.143];P = 4.07 × 10−7) as the most likely progression-associated genes. Conclusions and Relevance These data provide further insight into the genetic architecture of Geographic Atrophy lesion growth. Geographic Atrophy is a clinical outcome with a high medical need for effective therapy. The genesPRMT6andLSSare promising candidates for future studies aimed at understanding functional aspects of Geographic Atrophy progression and also for designing novel and targeted treatment options.

  • prognostic value of shape descriptive factors for the progression of Geographic Atrophy secondary to age related macular degeneration
    Retina-the Journal of Retinal and Vitreous Diseases, 2019
    Co-Authors: Maximilian Pfau, Frank G. Holz, Steffen Schmitzvalckenberg, Moritz Lindner, Lukas Goerdt, Sarah Thiele, Jennifer Nadal, Matthias Schmid, Monika Fleckenstein
    Abstract:

    PURPOSE: To systematically compare the prognostic value of multiple shape-descriptive factors in the natural course of the disease. METHODS: A total of 296 eyes of 201 patients (female patients 130; mean age: 72.2 ± 13.08 years) with a median follow-up of 2.38 years from 2 prospective, noninterventional natural history studies (Fundus-Autofluorescence-in-Age-related-Macular-Degeneration [clinicaltrials.gov identifier NCT00393692], Directional-Spread-in-Geographic-Atrophy [NCT02051998]) were included in the analysis. Serial fundus autofluorescence images were annotated using semiautomated image analysis software to determine the lesion area, circularity, perimeter, and caliper diameters. These variables and the fundus autofluorescence phenotype were evaluated for prediction of the future square root progression rates using linear mixed-effects models. RESULTS: For the combined model, leave-one-out cross validation on patient level (Scenario 1: previously unknown patient) resulted in a goodness-to-fit (R value) of 0.244 and leave-one-out cross validation on visit level (Scenario 2: previous observation of the patient) in a R value of 0.391. This indicated that shape-descriptive factors could explain 24.4% of the variance in Geographic Atrophy progression in previously unknown patients and 39.1% in patients with previous observation. CONCLUSION: These findings confirm the relevance of shape-descriptive factors and previous progression as prognostic variables for Geographic Atrophy progression. However, a substantial part of the remaining variation in Geographic Atrophy progression seems to depend on other variables, some of which are visible in optical coherence tomography.

  • Geographic Atrophy semantic considerations and literature review
    Retina-the Journal of Retinal and Vitreous Diseases, 2016
    Co-Authors: Steffen Schmitzvalckenberg, Monika Fleckenstein, Srinivas R Sadda, Giovanni Staurenghi, Emily Y Chew, Frank G. Holz
    Abstract:

    Purpose:There is a lack of agreement regarding the types of lesions and clinical conditions that should be included in the term “Geographic Atrophy.” Varied and conflicting views prevail throughout the literature and are currently used by retinal experts and other health care professionals.Methods:W

  • natural history of Geographic Atrophy progression secondary to age related macular degeneration Geographic Atrophy progression study
    Ophthalmology, 2016
    Co-Authors: Steffen Schmitzvalckenberg, Monika Fleckenstein, Josealain Sahel, Ronald P Danis, Glenn J Jaffe, Sebastian Wolf, Christian Pruente, Frank G. Holz
    Abstract:

    Purpose The Geographic Atrophy Progression (GAP) study was designed to assess the rate of Geographic Atrophy (GA) progression and to identify prognostic factors by measuring the enlargement of the atrophic lesions using fundus autofluorescence (FAF) and color fundus photography (CFP). Design Prospective, multicenter, noninterventional natural history study. Participants A total of 603 participants were enrolled in the study; 413 of those had gradable lesion data from FAF or CFP, and 321 had gradable lesion data from both FAF and CFP. Methods Atrophic lesion areas were measured by FAF and CFP to assess lesion progression over time. Lesion size assessments and best-corrected visual acuity (BCVA) were conducted at screening/baseline (day 0) and at 3 follow-up visits: month 6, month 12, and month 18 (or early exit). Main Outcome Measures The GA lesion progression rate in disease subgroups and mean change from baseline visual acuity. Results Mean (standard error) lesion size changes from baseline, determined by FAF and CFP, respectively, were 0.88 (0.1) and 0.78 (0.1) mm 2 at 6 months, 1.85 (0.1) and 1.57 (0.1) mm 2 at 12 months, and 3.14 (0.4) and 3.17 (0.5) mm 2 at 18 months. The mean change in lesion size from baseline to month 12 was significantly greater in participants who had eyes with multifocal atrophic spots compared with those with unifocal spots ( P P  = 0.001). The mean (standard deviation) decrease in visual acuity was 6.2 ± 15.6 letters for patients with image data available. Atrophic lesions with a diffuse (mean 0.95 mm 2 ) or banded (mean 1.01 mm 2 ) FAF pattern grew more rapidly by month 6 compared with those with the "none" (mean, 0.13 mm 2 ) and focal (mean, 0.36 mm 2 ) FAF patterns. Conclusions Although differences were observed in mean lesion size measurements using FAF imaging compared with CFP, the measurements were highly correlated with one another. Significant differences were found in lesion progression rates in participants stratified by hyperfluorescence pattern subtype. This large GA natural history study provides a strong foundation for future clinical trials.

  • choroidal thickness in Geographic Atrophy secondary to age related macular degeneration
    Investigative Ophthalmology & Visual Science, 2015
    Co-Authors: Moritz Lindner, Frank G. Holz, Christian K. Brinkmann, Steffen Schmitzvalckenberg, Athanasios Bezatis, Joanna Czauderna, Eva Becker, Rolf Fimmers, Monika Fleckenstein
    Abstract:

    Abstract To analyze choroidal thickness (CT) in eyes with Geographic Atrophy (GA) secondary to age-related macular degeneration (AMD). A total of 72 eyes of 72 patients (mean age, 75.97 ± 7.09 years) with GA and 37 eyes of 37 healthy controls (73.89 ± 6.19 years) were examined by confocal scanning laser ophthalmoscopy and enhanced depth imaging (EDI) spectral-domain optical coherence tomography. Choroidal thickness was measured at 25 defined points in horizontal and vertical scans. Geographic Atrophy size was determined in fundus autofluorescence (FAF) images and GA subtypes were classified based on abnormal FAF in the perilesional zone. In GA, subfoveal CT (fCT) was significantly thinner compared to controls (173.03 ± 90.22 vs. 253.95 ± 69.19 μm, P

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  • Determinants of Quality of Life in Geographic Atrophy Secondary to Age-Related Macular Degeneration.
    Investigative ophthalmology & visual science, 2020
    Co-Authors: Sandrine H Künzel, Frank G. Holz, Monika Fleckenstein, Steffen Schmitz-valckenberg, Moritz Lindner, Lukas Goerdt, Jennifer Nadal, Matthias Schmid, Philipp T Möller, Maximilian Pfau
    Abstract:

    To longitudinally evaluate vision-related quality of life (VRQoL) in Geographic Atrophy (GA) secondary to age-related macular degeneration (AMD) and define its relation to visual function and structural biomarkers. Patients with GA secondary to AMD were recruited in the context of the prospective, non-interventional, natural-history Directional Spread in Geographic-Atrophy study (NCT02051998). Fundus autofluorescence and infrared reflectance images were semi-automatically annotated for GA. Linear mixed-effects models were applied to investigate the association of putative determinants with the National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) VRQoL. A total of 87 patients with a mean age ± SD of 77.07 ± 7.49 years were included in the analysis. At baseline, median (IQR) best-corrected visual acuity (BCVA) was 0.3 (0.51) for the better eye and 0.89 (0.76) for the worse eye; 46% of the patients showed binocular and 25.3% monocular non-central GA. The VRQoL composite score was impaired: 69.96 (24.03). Sixty-six patients with a median of 2 (2) follow-up visits after 1.08 (0.78) years were examined longitudinally. Vision-related quality of life is significantly impaired in patients with GA secondary to AMD. The cross-sectional and longitudinal association of VRQoL with visual functional and structural biomarkers supports the validity of the NEI VFQ-25 VRQoL.

  • determinants of quality of life in Geographic Atrophy secondary to age related macular degeneration
    Investigative Ophthalmology & Visual Science, 2020
    Co-Authors: Sandrine H Künzel, Frank G. Holz, Moritz Lindner, Lukas Goerdt, Jennifer Nadal, Matthias Schmid, Philipp T Möller, S Schmitzvalckenberg, Monika Fleckenstein
    Abstract:

    Purpose To longitudinally evaluate vision-related quality of life (VRQoL) in Geographic Atrophy (GA) secondary to age-related macular degeneration (AMD) and define its relation to visual function and structural biomarkers. Methods Patients with GA secondary to AMD were recruited in the context of the prospective, non-interventional, natural-history Directional Spread in Geographic-Atrophy study (NCT02051998). Fundus autofluorescence and infrared reflectance images were semi-automatically annotated for GA. Linear mixed-effects models were applied to investigate the association of putative determinants with the National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) VRQoL. Results A total of 87 patients with a mean age ± SD of 77.07 ± 7.49 years were included in the analysis. At baseline, median (IQR) best-corrected visual acuity (BCVA) was 0.3 (0.51) for the better eye and 0.89 (0.76) for the worse eye; 46% of the patients showed binocular and 25.3% monocular non-central GA. The VRQoL composite score was impaired: 69.96 (24.03). Sixty-six patients with a median of 2 (2) follow-up visits after 1.08 (0.78) years were examined longitudinally. Conclusions Vision-related quality of life is significantly impaired in patients with GA secondary to AMD. The cross-sectional and longitudinal association of VRQoL with visual functional and structural biomarkers supports the validity of the NEI VFQ-25 VRQoL.

  • Light Sensitivity Within Areas of Geographic Atrophy Secondary to Age-Related Macular Degeneration.
    Investigative Ophthalmology & Visual Science, 2019
    Co-Authors: Maximilian Pfau, Steffen Schmitz-valckenberg, Moritz Lindner, Sarah Thiele, Jennifer Nadal, Matthias Schmid, Philipp T Möller, Leon Von Der Emde, Chantal Dysli, Frank G. Holz
    Abstract:

    Purpose: To investigate residual sensitivity within Geographic Atrophy (GA) secondary to age-related macular degeneration. Methods: Mesopic and dark-adapted (DA) cyan and red light sensitivity (Goldmann III) were investigated using fundus-controlled perimetry (microperimetry). Test points were placed within GA along an "iso-hull" with a distance of -0.645° to the Atrophy boundary. The false-positive response rate was determined with suprathreshold stimuli to the optic disc (Heijl-Krakau method) and used to compute the expected sensitivity measurements for the assumption of absolute scotomata. The outermost visible retinal layer on spectral-domain optical coherence tomography at the location of each test point was determined. Results: Thirty eyes of 36 patients (75.55 ± 7.93 years; 19 female) from the prospective natural history study Directional Spread in Geographic Atrophy (NCT02051998), with a total of 1380 threshold determinations were analyzed. The measured sensitivities were significantly (P < 0.01) higher than the expected values for absolute scotomata (mean ± standard error of +6.92 ± 0.86 dB for mesopic, +2.57 ± 0.56 dB for DA cyan, and +4.93 ± 0.74 dB for DA red testing). For mesopic testing and DA red testing, the presence of a residual outer nuclear layer had a significant effect on this discrepancy (P < 0.001). There was no effect of fixation stability or any other reliability index on this discrepancy. Conclusions: Measured sensitivities within the inner junctional zone of GA may not be purely explained by patient-specific false-positive response rates or other reliability indices. The marked influence of the outer retinal configuration on measured sensitivity may be indicative of residual cone function within GA at the inner junctional zone.

  • prognostic value of shape descriptive factors for the progression of Geographic Atrophy secondary to age related macular degeneration
    Retina-the Journal of Retinal and Vitreous Diseases, 2019
    Co-Authors: Maximilian Pfau, Frank G. Holz, Steffen Schmitzvalckenberg, Moritz Lindner, Lukas Goerdt, Sarah Thiele, Jennifer Nadal, Matthias Schmid, Monika Fleckenstein
    Abstract:

    PURPOSE: To systematically compare the prognostic value of multiple shape-descriptive factors in the natural course of the disease. METHODS: A total of 296 eyes of 201 patients (female patients 130; mean age: 72.2 ± 13.08 years) with a median follow-up of 2.38 years from 2 prospective, noninterventional natural history studies (Fundus-Autofluorescence-in-Age-related-Macular-Degeneration [clinicaltrials.gov identifier NCT00393692], Directional-Spread-in-Geographic-Atrophy [NCT02051998]) were included in the analysis. Serial fundus autofluorescence images were annotated using semiautomated image analysis software to determine the lesion area, circularity, perimeter, and caliper diameters. These variables and the fundus autofluorescence phenotype were evaluated for prediction of the future square root progression rates using linear mixed-effects models. RESULTS: For the combined model, leave-one-out cross validation on patient level (Scenario 1: previously unknown patient) resulted in a goodness-to-fit (R value) of 0.244 and leave-one-out cross validation on visit level (Scenario 2: previous observation of the patient) in a R value of 0.391. This indicated that shape-descriptive factors could explain 24.4% of the variance in Geographic Atrophy progression in previously unknown patients and 39.1% in patients with previous observation. CONCLUSION: These findings confirm the relevance of shape-descriptive factors and previous progression as prognostic variables for Geographic Atrophy progression. However, a substantial part of the remaining variation in Geographic Atrophy progression seems to depend on other variables, some of which are visible in optical coherence tomography.

  • Geographic Atrophy Secondary to Age-Related Macular Degeneration
    Spectral Domain Optical Coherence Tomography in Macular Diseases, 2016
    Co-Authors: Moritz Lindner, Steffen Schmitz-valckenberg, Monika Fleckenstein, Julia S. Steinberg, Frank G. Holz
    Abstract:

    Geographic Atrophy (GA) represents a common end stage of various retinal diseases including advanced age-related macular degeneration (AMD). While choroidal neovascularization (CNV) is the most common cause of acute severe visual loss in AMD, approximately 20 % of AMD patients who are legally blind have lost central vision due to GA (Friedman et al. 2004; Klaver et al. 1998; Klein et al. 2002; Mitchell et al. 1995; Sunness et al. 1999).