A. Bindewald

Classification of abnormal fundus autofluorescence patterns in the junctional zone of geographic atrophy in patients with age related macular degeneration

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.

Keypathophysiologic pathways in age-related macular disease.

PurposeTo review current knowledge of key pathogenetic pathways in age-related macular disease (AMD).MethodsExperimental evidence and clinical observations are reviewed.ResultsA 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.ConclusionsUnderstanding 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.

Digital simultaneous fluorescein and indocyanine green angiography, autofluorescence, and red-free imaging with a solid-state laser-based confocal scanning laser ophthalmoscope.

Purpose: To describe and to evaluate a novel confocal scanning laser ophthalmoscope (cSLO) for fluorescence angiography, fundus autofluorescence (FAF), and red-free imaging. Methods: Digital infrared, red-free, FAF, fluorescein, and indocyanine green (ICG) angiography images were obtained with a cSLO in 766 patients. An optically pumped solid-state laser generates the excitation wavelength (488 nm) required for red-free, FAF, and fluorescein angiography images. For ICG angiography and infrared imaging, diode laser sources at 790 and 820 nm are used. Further features include an internal fixation control and a focus range of −24 to +30 diopters. Results: High-image quality is achieved with a resolution of up to 5 &mgr;m per pixel in 30- x 30-degree images and allows for accurate delineation of normal and pathologic features. Simultaneous angiography offers high-contrast images. Corresponding display of quasi-simultaneous frames facilitates interpretation. A small focus difference between fluorescein and ICG scans occurs because of chromatic aberrations. Automated alignment and generation of mean images from several single frames allow for acquisition of high-resolution FAF images. Conclusion: Various laser-source related, optical, and electronic innovations improve cSLO fundus imaging for routine clinical application. A solid-state laser has advantages compared to argon gas laser sources, including less space occupation, heat emission, and noise production.

Automated analysis of digital fundus autofluorescence images of geographic atrophy in advanced age-related macular degeneration using confocal scanning laser ophthalmoscopy (cSLO)

BackgroundFundus 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.MethodsA 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.ResultsThe 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]).ConclusionThe 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.

Fundus Autofluorescence Imaging

Ophthalmic imaging technology has revolutionized fundus examination. FAF imaging represents one of various novel tools and provides information over and above fundus photography, fluorescence angiography and optical coherence tomography. This noninvasive diagnostic tool visualizes age- and disease-related metabolic changes of the retinal pigment epithelium. The autofluorescence signal mainly derives from dominant fluorophores in lipofuscin granules of the RPE. Lipofuscin accumulation represents a common downstream pathogenetic pathway in many retinal and macular disease entities.Thus FAF imaging contributes significantly to our understanding of the pathophysiology and treatment of various retinal diseases.

[OCT in age-related macular degeneration. Findings, usage in clinical routine, and assessment of treatment outcome].

ZusammenfassungDie optische Kohärenztomographie (OCT) ist ein relativ einfach durchführbares, nichtinvasives Untersuchungsverfahren, das ein zweidimensionales Schnittbild der makulären Netzhaut ermöglicht. Obwohl diese Untersuchungsmethode bei zahlreichen Erkrankungen der Makula zum Teil schon routinemäßig Einsatz findet, ist sie bei altersabhängiger Makuladegeneration (AMD) noch kein Standardverfahren. Mit Hilfe der OCT sind sowohl quantitative als auch qualitative Aussagen bei verschiedenen Manifestationsformen der AMD möglich. Die qualitative Auswertung von OCT-Bildern umfasst unter anderem die Beurteilung des Vorhandenseins intra- oder subretinaler extrazellulärer Flüssigkeitsakkumulationen inklusive intraretinaler zystoider Hohlräume, sowie von Pigmentepithelabhebungen und retinalen angiomatösen Proliferationen (RAP). Gerade für die Beurteilung des Effekts therapeutischer Interventionen bei neovaskulärer AMD wird die OCT in der klinischen Routine weiter an Bedeutung gewinnen. Zum Therapiemonitoring neuer therapeutischer Strategien ist sie bereits fester Bestandteil klinischer Studien geworden.AbstractOptical 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.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.

Lower limits of fluorescein and indocyanine green dye for digital cSLO fluorescence angiography

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.

Discovery of factors influencing the growth of geographic atrophy in patients with age-related macular degeneration.

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.

OCT bei altersabhängiger Makuladegeneration

ZusammenfassungDie optische Kohärenztomographie (OCT) ist ein relativ einfach durchführbares, nichtinvasives Untersuchungsverfahren, das ein zweidimensionales Schnittbild der makulären Netzhaut ermöglicht. Obwohl diese Untersuchungsmethode bei zahlreichen Erkrankungen der Makula zum Teil schon routinemäßig Einsatz findet, ist sie bei altersabhängiger Makuladegeneration (AMD) noch kein Standardverfahren. Mit Hilfe der OCT sind sowohl quantitative als auch qualitative Aussagen bei verschiedenen Manifestationsformen der AMD möglich. Die qualitative Auswertung von OCT-Bildern umfasst unter anderem die Beurteilung des Vorhandenseins intra- oder subretinaler extrazellulärer Flüssigkeitsakkumulationen inklusive intraretinaler zystoider Hohlräume, sowie von Pigmentepithelabhebungen und retinalen angiomatösen Proliferationen (RAP). Gerade für die Beurteilung des Effekts therapeutischer Interventionen bei neovaskulärer AMD wird die OCT in der klinischen Routine weiter an Bedeutung gewinnen. Zum Therapiemonitoring neuer therapeutischer Strategien ist sie bereits fester Bestandteil klinischer Studien geworden.AbstractOptical 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.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.

OCT bei altersabhngiger Makuladegeneration@@@OCT in age-related macular degeneration: Befunde, Einsatz in der klinischen Routine, Beurteilung des Therapieverlaufs@@@Findings, routine clinical application, and assessment of treatment effects

ZusammenfassungDie optische Kohärenztomographie (OCT) ist ein relativ einfach durchführbares, nichtinvasives Untersuchungsverfahren, das ein zweidimensionales Schnittbild der makulären Netzhaut ermöglicht. Obwohl diese Untersuchungsmethode bei zahlreichen Erkrankungen der Makula zum Teil schon routinemäßig Einsatz findet, ist sie bei altersabhängiger Makuladegeneration (AMD) noch kein Standardverfahren. Mit Hilfe der OCT sind sowohl quantitative als auch qualitative Aussagen bei verschiedenen Manifestationsformen der AMD möglich. Die qualitative Auswertung von OCT-Bildern umfasst unter anderem die Beurteilung des Vorhandenseins intra- oder subretinaler extrazellulärer Flüssigkeitsakkumulationen inklusive intraretinaler zystoider Hohlräume, sowie von Pigmentepithelabhebungen und retinalen angiomatösen Proliferationen (RAP). Gerade für die Beurteilung des Effekts therapeutischer Interventionen bei neovaskulärer AMD wird die OCT in der klinischen Routine weiter an Bedeutung gewinnen. Zum Therapiemonitoring neuer therapeutischer Strategien ist sie bereits fester Bestandteil klinischer Studien geworden.AbstractOptical 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.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.