Macular Degeneration: Schmitz-Valckenberg S

Schmitz-Valckenberg S, Fleckenstein M, Scholl HP, Holz FG. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · Surv Ophthalmol. · Pubmed #19171212 No free full text.

Abstract: Fundus autofluorescence imaging is an imaging method that provides additional information compared to conventional imaging techniques. It permits to topographically map lipofuscin distribution of the retinal pigment epithelial cell monolayer. Excessive accumulation of lipofuscin granules in the lysosomal compartment of retinal pigment epithelium cells represents a common downstream pathogenetic pathway in various hereditary and complex retinal diseases including age-related macular degeneration (AMD). This comprehensive review contains an introduction in fundus autofluorescence imaging, including basic considerations, the origin of the signal, different imaging methods, and a brief overview of fundus autofluorescence findings in normal subjects. Furthermore, it summarizes cross-sectional and longitudinal fundus autofluorescence findings in patients with AMD, addresses the pathophysiological significance of increased fundus autofluorescence, and characterizes different fundus autofluorescence phenotypes as well as fundus autofluorescence alterations with disease progression.

Schmitz-Valckenberg S, Holz FG, Bird AC, Spaide RF. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · Retina. · Pubmed #18327131 No free full text.

Abstract: Fundus autofluorescence (FAF) imaging is a novel imaging method that allows topographic mapping of lipofuscin distribution in the retinal pigment epithelium cell monolayer as well as of other fluorophores that may occur with disease in the outer retina and the subneurosensory space. Excessive accumulation of lipofuscin granules in the lysosomal compartment of retinal pigment epithelium cells represents a common downstream pathogenetic pathway in various hereditary and complex retinal diseases, including age-related macular degeneration. FAF imaging has been shown to be useful with regard to understanding of pathophysiologic mechanisms, diagnostics, phenotype-genotype correlation, identification of predictive markers for disease progression, and monitoring of novel therapies. FAF imaging gives information above and beyond that obtained by conventional imaging methods, such as fundus photography, fluorescein angiography, and optical coherence tomography. Its clinical value coupled with its simple, efficient, and noninvasive nature is increasingly appreciated. This review summarizes basic principles and FAF findings in various retinal diseases.

Schmitz-Valckenberg S, Jorzik J, Unnebrink K, Holz FG, Anonymous00191. · Department of Ophthalmology, University of Heidelberg, Germany. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #11933894 No free full text.

Abstract: BACKGROUND: Fundus autofluorescence (AF) imaging using confocal scanning laser ophthalmoscopy (cSLO) has been shown to be superior to fundus photography or angiography for delineating areas of geographic atrophy (GA) in retinal pigment epithelium (RPE) and for recording variation over time. We have evaluated a method for automated computerized detection and quantitation of RPE atrophy. METHODS: AF images in vivo were recorded with a confocal scanning laser ophthalmoscope (exc. 488 nm, em. >500 nm; Heidelberg Retina Angiograph). The intensity of AF in atrophic areas was markedly decreased. Two independent readers analysed these areas in 24 right eyes manually by outlining GA areas using a mouse-driven arrow (method A) and automatically by image analysis software (Global Lab Image/2) after subjective adjustment of thresholding (method B). Agreement between observers and between methods A and B was assessed by the Bland-Altman design for method-comparison studies. RESULTS: Larger areas were measured using method A than B by both readers (agreement A/B: reader 1 mean difference 1.04 mm, 95% CI [0.66,1.42]; reader 2 mean difference 0.62 mm, 95% CI [0.43,0.81]). The agreement between the readers was mean difference 0.39 mm (95% CI [0.02,0.76]) for A and mean difference -0.03 mm (95% CI [-0.23,0.18]) for B. Features making the delineation of borders of GA difficult included large choroidal vessels with autofluorescent properties in the GA area and media opacities. CONCLUSIONS: Fundus AF cSLO imaging provides a reliable means to delineate areas of GA. The automated image analysis allows more accurate detection and quantitative documentation of atrophic areas than manual outlining. This method will be useful in longitudinal natural history studies and for monitoring effects of future therapeutic interventions to slow down GA progression in patients with advanced atrophic ARMD and other retinal diseases associated with outer retinal atrophy.

Fleckenstein M, Charbel Issa P, Helb HM, Schmitz-Valckenberg S, Scholl HP, Holz FG. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · Arch Ophthalmol. · Pubmed #18852430 No free full text.

This publication has no abstract.

Schmitz-Valckenberg S, Fleckenstein M, Göbel AP, Sehmi K, Fitzke FW, Holz FG, Tufail A. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · Am J Ophthalmol. · Pubmed #18514607 No free full text.

Abstract: PURPOSE: To compare fundus autofluorescence images (FAF) between a modified fundus camera (mFC) and a confocal scanning laser ophthalmoscope (cSLO). DESIGN: Evaluation of diagnostic technology. METHODS: Thirty-two eyes of 16 patients with age-related geographic atrophy (GA) treated in an institutional setting were included. FAF images were obtained with both the cSLO (excitation, 488 nm; emission, > 500 nm) and the mFC (excitation, approximately 500 to 610 nm; emission, approximately 675 to 715 nm). Using established algorithms, images were graded by two independent observers and agreements were evaluated. The main outcome measures were image quality, quantification of total atrophy, and classification of FAF patterns. RESULTS: In two eyes with advanced cataract (lens grade 7 according to the Age-Related Eye Disease Study classification), FAF image quality with both systems was not sufficient for any meaningful analysis. In the remaining 30 eyes, the mean differences of the interobserver agreements for atrophy quantification were 0.16 mm2 (95% confidence interval [CI], 0.07 to 0.38) for mFC and 0.15 mm2 (95% CI, -0.04 to 0.33) for cSLO images. Because of inferior signal-to-noise ratios, FAF pattern classification was possible in a lower number of mFC images (69%) compared with cSLO images (88%). CONCLUSIONS: This study suggests that the agreements for atrophy quantification are similar with both devices. The lesser visualization of FAF patterns with the mFC and thus inferior determination of disease markers may be the result of the nonconfocality and the use of single instead of mean images compared with the cSLO. These findings may be important for the design of interventional trials as well as the routine use of FAF imaging in age-related geographic atrophy.

Fleckenstein M, Charbel Issa P, Helb HM, Schmitz-Valckenberg S, Finger RP, Scholl HP, Loeffler KU, Holz FG. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · Invest Ophthalmol Vis Sci. · Pubmed #18487363 No free full text.

Abstract: PURPOSE: To describe morphologic variations in outer retinal layers in eyes with atrophic age-related macular degeneration (AMD) using high-resolution, spectral-domain optical coherence tomography (SD-OCT). METHODS: SD-OCT scans were obtained with a combined confocal scanning laser ophthalmoscope (cSLO) and SD-OCT for simultaneous tomographic and topographic in vivo imaging. A total of 81 eyes of 56 patients (mean age, 77.8 +/- 7.4 years) with geographic atrophy (GA) were examined. Morphologic alterations were analyzed and classified in the perilesional zone, at the junction between GA and nonatrophic retina, and in the atrophic area itself. RESULTS: In the perilesional zone, distinct morphologic alterations included elevations of the outer retinal layers, thickening, and spikes of the outer hyperreflective band as well as clumps at different neurosensory retinal levels. At the junction, highly variable transitions of the outer retinal layers were present with different degrees of loss of the normal hyperreflective bands. Within the actual GA, hyperreflective clumps at different retinal levels, segmented plaques of the outer band and elevations with variable reflectivity were visualized. CONCLUSIONS: SD-OCT imaging in eyes with GA revealed a wide spectrum of morphologic alterations, both in the surrounding retinal tissue and in the atrophic area. These alterations may reflect different disease stages or, alternatively, heterogeneity on a cellular and molecular level. Longitudinal studies using in vivo SD-OCT imaging may allow evaluation of the relevance of these phenotypic changes as potential predictive markers for the progression of disease (i.e., enlargement rates of GA over time) and may be used for monitoring of future therapeutic interventions.

Han M, Giese G, Schmitz-Valckenberg S, Bindewald-Wittich A, Holz FG, Yu J, Bille JF, Niemz MH. · University of Heidelberg, Mannheim Biomedical Engineering Laboratories, Faculty of Clinical Medicine, Heidelberg, Germany. · J Biomed Opt. · Pubmed #17477727 No free full text.

Abstract: The intensive metabolism of photoreceptors is delicately maintained by the retinal pigment epithelium (RPE) and the choroid. Dysfunction of either the RPE or choroid may lead to severe damage to the retina. Two-photon excited autofluorescence (TPEF) from endogenous fluorophores in the human retina provides a novel opportunity to reveal age-related structural abnormalities in the retina-choroid complex prior to apparent pathological manifestations of age-related retinal diseases. In the photoreceptor layer, the regularity of the macular photoreceptor mosaic is preserved during aging. In the RPE, enlarged lipofuscin granules demonstrate significantly blue-shifted autofluorescence, which coincides with the depletion of melanin pigments. Prominent fibrillar structures in elderly Bruch's membrane and choriocapillaries represent choroidal structure and permeability alterations. Requiring neither slicing nor labeling, TPEF imaging is an elegant and highly efficient tool to delineate the thick, fragile, and opaque retina-choroid complex, and may provide clues to the trigger events of age-related macular degeneration.

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.

Bindewald A, Stuhrmann O, Roth F, Schmitz-Valckenberg S, Helb HM, Wegener A, Eter N, Holz FG. · Department of Ophthalmology, University of Bonn, Ernst-Abbe-Strasse 2, D-53127 Bonn, Germany. · Br J Ophthalmol. · Pubmed #16299141 links to  free full text

Abstract: BACKGROUND: With the advent of digital confocal scanning laser ophthalmoscopy it is possible to detect low levels of fluorescence. Here we used a novel confocal scanning laser ophthalmoscope (cSLO) to determine lower limits of dye required for fluorescein (FL) and indocyanine green (ICG) angiography. METHODS: A cSLO (Heidelberg retina angiograph 2, Heidelberg Engineering, Dossenheim, Germany) with an optically pumped solid state laser (488 nm) for FL and a diode laser (790 nm) for ICG angiography (FL/ICG-A) was used. 62 FL-As were performed in 53 patients and 45 ICG-As were performed in 39 patients with neovascular age related macular degeneration. The volume and overall dye content of bolus injections was gradually tapered (FL: 500 mg, 250 mg, 200 mg, 166 mg, 100 mg; ICG: 25 mg, 20 mg, 15 mg, 10 mg, 5 mg, 2.5 mg), while dye concentrations were kept constant at 100 mg/ml for FL and at 5 mg/ml for ICG. Images were obtained 1, 5, 15, and 30 minutes after dye injection. Image quality was evaluated by two independent readers using standardised criteria. RESULTS: For amounts down to 166 mg for FL and to 5 mg for ICG, sufficient image quality was achieved during all phases following injection. Only late phase images showed less contrast compared to typically used dye amounts, which was irrelevant for interpretation and clinical management. CONCLUSIONS: With the increased sensitivity of this novel cSLO system, amounts of injected dye during FL-A can be reduced to one third for FL and to one fifth for ICG without relevant loss of image quality or information compared to conventionally used dye levels. These amounts can be used for routine angiography and allow relevant savings for units performing FL-A.

Bindewald A, Schmitz-Valckenberg S, Jorzik JJ, Dolar-Szczasny J, Sieber H, Keilhauer C, Weinberger AW, Dithmar S, Pauleikhoff D, Mansmann U, Wolf S, Holz FG. · Department of Ophthalmology, University of Bonn, Ernst-Abbe-Strasse 2, D-53127 Bonn, Germany. · Br J Ophthalmol. · Pubmed #15965170 links to  free full text

Abstract: AIM: To describe and classify patterns of abnormal fundus autofluorescence (FAF) in the junctional zone of geographic atrophy (GA) in patients with age related macular degeneration. METHODS: Digital FAF images were recorded in 164 eyes of 107 patients using a confocal scanning laser ophthalmoscope (cSLO; excitation 488 nm, detection above 500 nm) as part of a prospective multicentre natural history study (FAM Study). FAF images were obtained in accordance with a standardised protocol for digital image acquisition and generation of mean images after automated alignment. RESULTS: Image quality was sufficient for classification of FAF patterns in 149 eyes (90.9%) with lens opacities being the most common reason for insufficient image quality. Abnormal FAF outside GA in 149 eyes was classified into four patterns: focal (12.1%), banded (12.8%), patchy (2.0%), and diffuse (57.0%), whereby 12.1% had normal background FAF in the junctional zone. In 4% there was no predominant pattern. The diffuse pattern was subdivided into four groups including reticular (4.7%), branching (27.5%), fine granular (18.1%), and fine granular with peripheral punctate spots (6.7%). CONCLUSIONS: Different phenotypic patterns of abnormal FAF in the junctional zone of GA can be identified with cSLO FAF imaging. These distinct patterns may reflect heterogeneity at a cellular and molecular level in contrast with a non-specific ageing process. A refined phenotypic classification may be helpful to identify prognostic determinants for the spread of atrophy and visual loss, for identification of genetic risk factors as well as for the design of future interventional trials.

Deckert A, Schmitz-Valckenberg S, Jorzik J, Bindewald A, Holz FG, Mansmann U. · Institute of Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany. · BMC Ophthalmol. · Pubmed #15813972 links to  free full text

Abstract: BACKGROUND: Fundus autofluorescence (AF) imaging using confocal scanning laser ophthalmoscopy (cSLO) provides an accurate delineation of areas of geographic atrophy (GA). Automated computer-assisted methods for detecting and removing interfering vessels are needed to support the GA quantification process in longitudinal studies and in reading centres. METHODS: A test tool was implemented that uses region-growing techniques to segment GA areas. An algorithm for illuminating shadows can be used to process low-quality images. Agreement between observers and between three different methods was evaluated by two independent readers in a pilot study. Agreement and objectivity were assessed using the Bland-Altman approach. RESULTS: The new method (C) identifies vascular structures that interfere with the delineation of GA. Results are comparable to those of two commonly used procedures (A, B), with a mean difference between C and A of -0.67 mm2 (95% CI [-0.99, -0.36]), between B and A of -0.81 mm2, (95% CI [-1.08, -0.53]), and between C and B of 0.15 mm2 (95% CI [-0.12, 0.41]). Objectivity of a method is quantified by the mean difference between observers: A 0.30 mm2 (95% CI [0.02, 0.57]), B -0.11 mm2 (95% CI [-0.28, 0.10]), and C 0.12 mm2 (95% CI [0.02, 0.22]). CONCLUSION: The novel procedure is comparable with regard to objectivity and inter-reader agreement to established methods of quantifying GA. It considerably speeds up the lengthy measurement process in AF with well defined GA zones.

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.