Macular Degeneration: Dreyhaupt J

Dreyhaupt J, Dolar-Szczasny J, Bindewald A, Holz FG, Mansmann U. · Institute of Medical Biometry and Informatics, University of Heidelberg, INF 305, 69120 Heidelberg, Germany. · Methods Inf Med. · Pubmed #17694237 No free full text.

Abstract: OBJECTIVES: Identifying factors influencing the growth of geographic atrophy (GA) in patients with age-related macular degeneration (AMD). METHODS: Data on the natural course and suspected modifying factors were collected as part of the multicenter, longitudinal, observational FAM-study in 178 eyes of 114 patients with atrophic AMD. The endpoint of interest - the size of GA - was measured in fundus autofluorescence images. The influence of different putative risk factors on progression of GA is investigated with a forward selection procedure based on the likelihood ratio test. In order to interpret non-significant results of the forward selection procedure, the power of the tests used was quantified by a parametric post-hoc bootstrap approach. RESULTS: A mean increase in GA of 1.75 mm(2) per year was estimated for the given population (95% CI: [1.46; 2.02]). Patient and eye-specific random effects could be assessed. Neither patient-specific risk factors nor ocular-specific risk factors show any significant influence on GA growth. The post-hoc bootstrap procedure shows that only very strong effects can be detected on the basis of the given data. For example, the hypercholesteremia which would result in an additional increase of GA by near 4 mm(2) per year can be detected with a power of 80%. CONCLUSIONS: The use of linear mixed effects regression models offers a convenient way to explore sources of variation in the natural course of GA. Data from further follow-up examinations and data about other putative risk factors than those investigated will be needed to further investigate of the GA growth process. The procedure described in this article is easily applicable to other putative risk factors as well as to other fields of application.

Holz FG, Bindewald-Wittich A, Fleckenstein M, Dreyhaupt J, Scholl HP, Schmitz-Valckenberg S, Anonymous00266. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · Am J Ophthalmol. · Pubmed #17239336 No free full text.

Abstract: PURPOSE: To test if fundus autofluorescence (FAF) patterns around geographic atrophy (GA) have an impact on GA progression rates over time in atrophic age-related macular degeneration (AMD). DESIGN: Prospective longitudinal multicenter natural history study. METHODS: Standardized digital FAF images were obtained from 195 eyes of 129 patients with GA using confocal scanning laser ophthalmoscopy (excitation 488 nm, emission >500 nm). Areas of GA were quantified and patterns of abnormal FAF in the junctional zone were classified. Repeated FAF images were obtained over a median follow-up period of 1.80 years (interquartile range [IQR], 1.28 to 3.34). RESULTS: Areas of GA (median, 7.04 mm(2) at baseline; IQR, 3.12 to 10.0) showed a median enlargement of 1.52 mm(2)/year (IQR, 0.81 to 2.33). Progression rates in eyes with the banded (median 1.81 mm(2)/year) and the diffuse FAF pattern (1.77 mm(2)/year) were significantly higher compared to eyes without FAF abnormalities (0.38 mm(2)/year) and focal FAF patterns (0.81 mm(2)/year, P < .0001). Within the group of the diffuse pattern, eyes with a diffuse trickling pattern could be identified that exhibited an even higher spread rate (median 3.02 mm(2)/year) compared to the other diffuse types (1.67 mm(2)/year, P = .001). CONCLUSIONS: The results indicate that distinct phenotypic FAF patterns have an impact on disease progression in eyes with atrophic AMD and may therefore serve as prognostic determinants. The findings underscore the relevance of FAF imaging and the pathogenetic role of excessive retinal pigment epithelium (RPE) lipofuscin (LF) accumulation in GA. Natural history data and identification of high-risk characteristics will be helpful to design interventional studies aiming at slowing the spread of atrophy.

Schmitz-Valckenberg S, Bindewald-Wittich A, Dolar-Szczasny J, Dreyhaupt J, Wolf S, Scholl HP, Holz FG, Anonymous00317. · Department of Ophthalmology, University of Bonn, Bonn, Germany, and First Eye Hospital, University of Lublin, Poland. · Invest Ophthalmol Vis Sci. · Pubmed #16723482 links to  free full text

Abstract: PURPOSE: To test the hypothesis that the extension of areas with increased fundus autofluorescence (FAF) outside atrophic patches correlates with the rate of spread of geographic atrophy (GA) over time in eyes with age-related macular degeneration (AMD). METHODS: The database of the multicenter longitudinal natural history Fundus Autofluorescence in AMD (FAM) Study was reviewed for patients with GA recruited through the end of August 2003, with follow-up examinations within at least 1 year. Only eyes with sufficient image quality and with diffuse patterns of increased FAF surrounding atrophy were chosen. In standardized digital FAF images (excitation, 488 nm; emission, >500 nm), total size and spread of GA was measured. The convex hull (CH) of increased FAF as the minimum polygon encompassing the entire area of increased FAF surrounding the central atrophic patches was quantified at baseline. Statistical analysis was performed with the Spearman's rank correlation coefficient (rho). RESULTS: Thirty-nine eyes of 32 patients were included (median age, 75.0 years; interquartile range [IQR], 67.8-78.9); median follow-up, 1.87 years; IQR, 1.43-3.37). At baseline, the median total size of atrophy was 7.04 mm2 (IQR, 4.20-9.88). The median size of the CH was 21.47 mm2 (IQR, 15.19-28.26). The median rate of GA progression was 1.72 mm2 per year (IQR, 1.10-2.83). The area of increased FAF around the atrophy (difference between the CH and the total GA size at baseline) showed a positive correlation with GA enlargement over time (rho=0.60; P=0.0002). CONCLUSIONS: FAF characteristics that are not identified by fundus photography or fluorescein angiography may serve as a prognostic determinant in advanced atrophic AMD. As the FAF signal originates from lipofuscin (LF) in postmitotic RPE cells and since increased FAF indicates excessive LF accumulation, these findings would underscore the pathophysiological role of RPE-LF in AMD pathogenesis.

Dreyhaupt J, Mansmann U, Pritsch M, Dolar-Szczasny J, Bindewald A, Holz FG. · Department of Medical Biometry and Informatics, University of Heidelberg, Germany. · Ophthalmic Epidemiol. · Pubmed #16283987 No free full text.

Abstract: PURPOSE: To model the natural course of geographic atrophy (GA) in patients with age-related macular degeneration (AMD). METHODS: Data on the natural course of GA were collected in the multi-center, longitudinal, prospective observational FAM study. The size of GA was measured by autofluorescence scanning laser ophthalmoscopy. The natural course of GA is modelled by two different mixed effect models (MEM). Both models are compared with respect to the correctness of the model assumptions, goodness of fit, and predictive behavior. RESULTS: The linear model results in better prediction, the non-linear model is more in agreement with the model assumptions. The non-linear model fits the data for small and large areas of GA better, while the linear model seems to be more adequate for the medial areas. More data will be needed to study the interplay of both models in more detail. CONCLUSIONS: The natural course of GA varies extremely between individuals. However, reliable factors for the explanation of this variability have so far not been established. MEM are useful for describing "inter-individual" as well as "intra-individual" influences without the need for precise knowledge of the influencing factors. Using MEM to evaluate data on the natural history of GA allows one to derive parameter estimates, which could be used to design interventional trials for modes of therapy with a potential to reduce or stop the progression of GA in patients with AMD.

Bindewald A, Bird AC, Dandekar SS, Dolar-Szczasny J, Dreyhaupt J, Fitzke FW, Einbock W, Holz FG, Jorzik JJ, Keilhauer C, Lois N, Mlynski J, Pauleikhoff D, Staurenghi G, Wolf S. · Department of Ophthalmology, University of Bonn, Ernst-Abbe-Strasse 2, 53127 Bonn, Germany. · Invest Ophthalmol Vis Sci. · Pubmed #16123434 links to  free full text

Abstract: PURPOSE: To describe and classify patterns of abnormal fundus autofluorescence (FAF) in eyes with early nonexudative age-related macular disease (AMD). METHODS: FAF images were recorded in eyes with early AMD by confocal scanning laser ophthalmoscopy (cSLO) with excitation at 488 nm (argon or OPSL laser) and emission above 500 or 521 nm (barrier filter). A standardized protocol for image acquisition and generation of mean images after automated alignment was applied, and routine fundus photographs were obtained. FAF images were classified by two independent observers. The kappa statistic was applied to assess intra- and interobserver variability. RESULTS: Alterations in FAF were classified into eight phenotypic patterns including normal, minimal change, focal increased, patchy, linear, lacelike, reticular, and speckled. Areas with abnormal increased or decreased FAF signals may or may not have corresponded to funduscopically visible alterations. For intraobserver variability, kappa of observer I was 0.80 (95% confidence interval [CI]0.71-0.89) and of observer II, 0.74. (95% CI, 0.64-0.84). For interobserver variability, kappa was 0.77 (95% CI, 0.67-0.87). CONCLUSIONS: Various phenotypic patterns of abnormal FAF can be identified with cSLO imaging. Distinct patterns may reflect heterogeneity at a cellular and molecular level in contrast to a nonspecific aging process. The results indicate that the classification system yields a relatively high degree of intra- and interobserver agreement. It may be applicable for determination of novel prognostic determinants in longitudinal natural history studies, for identification of genetic risk factors, and for monitoring of future therapeutic interventions to slow the progression of early AMD.

Schmitz-Valckenberg S, Bültmann S, Dreyhaupt J, Bindewald A, Holz FG, Rohrschneider K. · Department of Ophthalmology, University of Bonn, Abbe-Strasse 2, D-53127 Bonn, Germany. · Invest Ophthalmol Vis Sci. · Pubmed #15557456 links to  free full text

Abstract: PURPOSE: To investigate retinal sensitivity in the junctional zone of geographic atrophy (GA), with variations in fundus autofluorescence (FAF) in patients with advanced age-related macular degeneration (AMD). METHODS: The spatial distribution and intensity of FAF were recorded with a confocal scanning laser ophthalmoscope (SLO). Eyes had normal background FAF (group 1) or increased FAF (group 2) surrounding the atrophic patches. Retinal sensitivity was assessed by applying light stimuli with static automated full-threshold fundus perimetry with a modified SLO. Threshold sensitivities were compared with age-matched normal sensitivities. RESULTS: Thirty-nine eyes of 39 patients with GA were included. Group 2 had a higher percentage of all test points outside the GA area, with decreased retinal sensitivity (44.9% +/- 28.7%) compared with group 1 (20.7% +/- 12.7%; P = 0.0063; multiple regression model; outcome variable is retinal sensitivity; covariates are group affiliation and GA area). Within group 2, the average percentage of stimuli in areas of normal FAF with reduced sensitivity was 38.0% +/- 33.0%, whereas the average percentage of stimuli in areas of elevated FAF with reduced sensitivity was 52.6% +/- 29.7% (P = 0.023, Wilcoxon signed rank test). CONCLUSIONS: Areas of increased FAF outside GA may be associated with variable degrees of loss of retinal sensitivity and suggest a functional correlate of excessive accumulation of retinal pigment epithelium lipofuscin in AMD. Combining in vivo recording of FAF and retinal sensitivity, using SLO technology, may give important clues in the understanding of mechanisms of disease.