Macular Degeneration: Bindewald A

Dolar-Szczasny J, Mackiewicz J, Bindewald A, Holz FG, Zagórski Z. · Z Katedry i I Kliniki Okulistyki Akademii Medycznej w Lublinie. · Klin Oczna. · Pubmed #16417019 No free full text.

Abstract: PURPOSE: To present application of a confocal Scanning Laser Ophthalmoscope (cSLO) for fundus autofluorescence examination, as a new method of visualization of retinal pigment epithelium and its possible significance in the diagnosis of different retinal diseases. MATERIAL AND METHODS: Typical autofluorescence images in age-related macular degeneration (AMD), Stargardt disease, Best disease and pattern dystrophies are presented, based on the own experience and literature data. Autofluorescence images were obtained with a cSLO using an argon laser for generation of excitation light at 488 nm and a barrier filter >500 nm for the detection of the emitted signals. RESULTS: A variety of autofluorescence patterns, associated with the accumulation of lipofuscin in RPE cells, was found in the above entities. CONCLUSIONS: Presented method of fundus autofluorescence examination gives new possibilities in studying the pathogenetic mechanisms in various retinal diseases and may be useful in monitoring the follow-up and the effects of the treatment.

Eter N, Bindewald A, Roth F, Holz FG. · Augenklinik, Universität, Bonn. · Ophthalmologe. · Pubmed #15459788 No free full text.

Abstract: Optical coherence tomography (OCT) represents a fast and noninvasive examination technique that generates two-dimensional sections of the posterior pole in vivo. Although this method is now widely applied in the diagnosis of various heterogeneous macular diseases, its role in patients with age-related macular degeneration (AMD) is less well established. OCT allows for quantitative as well as qualitative assessment of various AMD phenotypes. Qualitative assessment comprises the evaluation of intra- or subretinal fluid, intraretinal cystoid spaces, and retinal pigment epithelial detachments. However, together with the clinical findings and fluorescence angiography, it can provide useful additional information including monitoring of treatment effects.

Roth F, Bindewald A, Holz FG. · Department of Ophthalmology, University of Bonn, Ernst-Abbestrasse 2, 53127 Bonn, Germany. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #15309554 No free full text.

Abstract: PURPOSE: To review current knowledge of key pathogenetic pathways in age-related macular disease (AMD). METHODS: Experimental evidence and clinical observations are reviewed. RESULTS: A number of common downstream pathophysiologic pathways appear to be relevant in AMD manifestations irrespective of primary heterogeneous etiologies. These include sequelae of oxidative damage, retinal pigment epithelium (RPE) cell dysfunction with accumulation of lipofuscin and impairment of lysosomal functions, deposition of subsequently incompletely degraded material at the basal RPE cell side and alterations in Bruch's membrane extracellular matrix, immunologic responses to extracellular material (drusen) with subsequent growth of drusen, induction of choroidal neovascularization as a result of imbalance between anti-angiogenetic and proangiogenetic factors as well as cell death (geographic atrophy) without prior neovascular events. CONCLUSIONS: Understanding is expanding regarding the sequence of events that lead to early and late lesions in AMD. Therapeutic approaches that focus on the molecular mechanisms are more likely to succeed than currently available treatment options as exemplified by the management of choroidal neovascularisations.

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.

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.

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.

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.

Bindewald A, Jorzik JJ, Roth F, Holz FG. · Augenklinik und Poliklinik, Universität, Bonn. · Ophthalmologe. · Pubmed #15490188 No free full text.

Abstract: BACKGROUND: Fundus autofluorescence (FAF) originates from age- and disease-dependent accumulation of lipofuscin in the lysosomal compartment of the retinal pigment epithelium (RPE). FAF imaging is a noninvasive method to detect intrinsic RPE fluorescence in vivo. We describe features of a novel confocal scanning laser ophthalmoscope (cSLO) for FAF imaging and compare images to the previous cSLO system.METHODS: FAF images were obtained with a cSLO using an optically pumped solid state laser (OPSL) instead of an argon laser for generation of excitation light at 488 nm. For detection of emitted FAF signals >500 nm a barrier filter was used.RESULTS: The novel cSLO allows FAF imaging with a resolution of up to 5 microm/pixel to delineate normal and pathological features in various retinal pathologies including early-stage and advanced atrophic or neovascular age-related macular degeneration, macular edema, and retinal dystrophies. Further technical improvements include an internal fixation target and an enlarged optical focus adaption range.CONCLUSIONS: Improved image quality using the novel cSLO for FAF imaging is of clinical relevance for diagnosis and precise phenotyping of retinal diseases. This method may also be useful to monitor therapeutic effects targeting RPE lipofuscin accumulation as a common pathogenetic pathway in various degenerative and hereditary retinal diseases.

Bindewald A, Roth F, Van Meurs J, Holz FG. · Universitäts-Augenklinik, Bonn. · Ophthalmologe. · Pubmed #15316735 No free full text.

Abstract: Neovascular age-related macular degeneration (AMD) has become the leading cause for severe visual loss in all industrialized nations. Surgical excision of choroidal neovascularizations (CNV) is technically feasible but invariably associated with inadvertent removal of corresponding retinal pigment epithelium (RPE) and subsequent atrophy of the choriocapillaris, with the latter two layers being a prerequisite for normal photoreceptor function. To cover the RPE defect both heterologous and homologous RPE cell suspensions have been injected into the subretinal space. The lack of functional improvement has been attributed to various factors including RPE cell dedifferentiation, failure of adherence to Bruch's membrane as well as development of a regular RPE cell monolayer. Therefore, techniques for translocating intact autologous RPE cell sheets have been sought and preservation of foveal neurosensory functions has recently been successfully demonstrated. Besides translocation of a full-thickness RPE/Bruch's membrane/choroid patch outside the macular area, superfluous choroidal tissue may be ablated intraocularly using an excimer laser prior to translocation. Besides recent pharmacological approaches including anti-VEGF agents, these surgical developments open new perspectives for patients with neovascular AMD.

Holz FG, Bindewald A, Schutt F, Specht H. · Universitäts-Augenklinik Heidelberg Im Neuenheimer Feld 400 D-69120 Heidelberg. · Biomed Tech (Berl). · Pubmed #12749285 No free full text.

Abstract: Age-related macular degeneration (AMD) is the leading cause of legal blindness in the western nations beyond 50 years of age. The most frequent cause for severe visual loss is the growth of neovascular membrances from the choroid into the subretinal space. This usually results in irreversible degeneration of the overlying retina. Surgical removal of the membrane is feasible, however, usually results in functional loss of apposing retinal photoreceptors since retinal pigment epithelial (RPE) cells are removed concurrently due to their tight adherence to the neovascular complex. Therefore, various attempts have been undertaken to fill the resulting RPE cell defect with either heterologous or autologous RPE cell transplants. So far cell survival, function and subsequent visual function has been disappointing. To minimize trauma and resulting dedifferentiation harvesting in the eye and transplantation in whole sheets and without temporary removal from the eyes would be desirable. This may be achieved by isolating grafts consisting of choroid, Bruch's membrance and RPE cells from the peripheral retina and transplantation of this graft under the neurosensory retina after removal of the choroidal neovascularization. However, the choroidal component of such a graft would be expected to interfere with diffusion of metabolites to and from the retina. Therefore, outcome would be expected to be better if the choroidal tissue would be removed before translocation. In preclinical experiments we used a 308 nm UV AIDA excimer laser to microablate choroidal tissue from such a graft in human donor eyes.