Almut Bindewald-Wittich

A Subgroup of Age-Related Macular Degeneration is Associated With Mono-Allelic Sequence Variants in the ABCA4 Gene

Purpose. Age-related macular degeneration (AMD) is a heterogeneous condition of high prevalence and complex etiology involving genetic as well as environmental factors. By fundus autofluorescence (FAF) imaging, AMD can be classified into several distinct phenotypes, with one subgroup characterized by fine granular pattern with peripheral punctate spots (GPS[+]). Some features of GPS[+] overlap with Stargardt disease (STGD1), a recessive macular dystrophy caused by biallelic sequence variants in the ATP-binding cassette transporter 4 (ABCA4) gene. The aim of this study was to investigate the role of ABCA4 in GPS[+]. Methods. The ABCA4 gene was sequenced in 25 patients with the GPS[+] phenotype and 29 with geographic atrophy (GA)-AMD but no signs of GPS (GPS[-]). In addition, frequencies of risk-increasing alleles at three known AMD susceptibility loci, including complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and complement component 3 (C3), were evaluated. Results. We demonstrate that GPS[+] is associated significantly with monoallelic ABCA4 sequence variants. Moreover, frequencies of AMD risk-increasing alleles at CFH, ARMS2, and C3 are similar in GPS[+] and STGD1 patients, with risk allele frequencies in both subcategories comparable to population-based control individuals estimated from 3,510 individuals from the NHLBI Exome Sequencing Project. Conclusions. Our data suggest that the GPS[+] phenotype is accounted for by monoallelic variants in ABCA4 and unlikely by the well-established AMD risk-increasing alleles at CFH, ARMS2, and C3. These findings provide support for a complex role of ABCA4 in the etiology of a minor proportion of patients with AMD.

Age-related structural abnormalities in the human retina-choroid complex revealed by two-photon excited autofluorescence imaging

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 Bruchs 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.

Concordance of disease progression in bilateral geographic atrophy due to AMD

PURPOSE To determine the degree of concordance for progression rate, size of atrophy, and visual acuity in patients with bilateral geographic atrophy (GA) due to age-related macular degeneration (AMD). METHODS Analysis was performed in 156 eyes of 78 patients with bilateral GA. Best corrected visual acuity was determined with ETDRS charts. GA was quantified in digital fundus autofluorescence images (excitation, 488 nm; emission, >500 nm) by semiautomated imaging analysis. A linear, two-level, random-effects model was used to assess the natural course of disease. The concordance correlation coefficient (CCC) was calculated to assess the degree of agreement between disease characteristics of the left and right eyes. Bland-Altman plots were applied to compare measurements in the eyes. RESULTS CCC between the eyes was 0.310 (95% CI, 0.097-0.495) for visual acuity, 0.706 (95% CI, 0.575-0.801) for GA size, and 0.756 (95% CI, 0.644-0.837) for GA progression rate. Although Bland-Altman plots revealed high concordance for the progression rate, there was considerable discrepancy between both eyes for GA size. [corrected] CONCLUSIONS GA progression in bilateral atrophic AMD is a symmetrical process; however, GA size may differ substantially between the eyes. High concordance in intraindividual disease progression in the presence of a high degree of interindividual variability indicates an influence by genetic and/or environmental factors rather than nonspecific ageing changes. The relatively small concordance of GA size in this cohort may indicate asymmetric evolution of the disease in affected individuals. The results may be useful in the design of future clinical trials designed to slow the rate of GA progression (Clinical Trials.gov number, NCT00393692).

Two−photon excited autofluorescence imaging of human retinal pigment epithelial cells

Degeneration of retinal pigment epithelial (RPE) cells severely impairs the visual function of retina photoreceptors. However, little is known about the events that trigger the death of RPE cells at the subcellular level. Two-photon excited autofluorescence (TPEF) imaging of RPE cells proves to be well suited to investigate both the morphological and the spectral characteristics of the human RPE cells. The dominant fluorophores of autofluorescence derive from lipofuscin (LF) granules that accumulate in the cytoplasm of the RPE cells with increasing age. Spectral TPEF imaging reveals the existence of abnormal LF granules with blue shifted autofluorescence in RPE cells of aging patients and brings new insights into the complicated composition of the LF granules. Based on a proposed two-photon laser scanning ophthalmoscope, TPEF imaging of the living retina may be valuable for diagnostic and pathological studies of age related eye diseases.

Moderne Arzneimitteltherapie der altersabhängigen Makuladegeneration

Age-related macular degeneration (AMD) is now the most common cause for blind registration in all developed countries. Epidemiologic data indicate that there are 4.5 millions affected in Germany with constant increase in incidence and prevalence with subsequent considerable health economic implications. Late manifestations of the disease result in the inability to read and to perform daily tasks. Therefore, there is an urgent need for efficacious prophylactic and therapeutic measures to prevent irreversible loss of central vision. Based on a better understanding of the underlying molecular mechanisms new therapeutic approaches have been brought forward and expand previous approaches such as thermal laser surgery or photodynamic therapy. Repeated intravitreal injection of anti-VEGF (vascular endothelial growth factor) agents as well as corticosteroids have a beneficial effect on growth and permeability of neovascular membranes. The risk for progression from early to late stages of AMD can be reduced with certain antioxidative preparations (AREDS medication) in presence of defined funduscopic signs. Early diagnosis is key for all currently available interventions since a beneficial effect can only be achieved in early stages of the disease process.

[Modern pharmacotherapy of age-related macular degeneration].

Age-related macular degeneration (AMD) is now the most common cause for blind registration in all developed countries. Epidemiologic data indicate that there are 4.5 millions affected in Germany with constant increase in incidence and prevalence with subsequent considerable health economic implications. Late manifestations of the disease result in the inability to read and to perform daily tasks. Therefore, there is an urgent need for efficacious prophylactic and therapeutic measures to prevent irreversible loss of central vision. Based on a better understanding of the underlying molecular mechanisms new therapeutic approaches have been brought forward and expand previous approaches such as thermal laser surgery or photodynamic therapy. Repeated intravitreal injection of anti-VEGF (vascular endothelial growth factor) agents as well as corticosteroids have a beneficial effect on growth and permeability of neovascular membranes. The risk for progression from early to late stages of AMD can be reduced with certain antioxidative preparations (AREDS medication) in presence of defined funduscopic signs. Early diagnosis is key for all currently available interventions since a beneficial effect can only be achieved in early stages of the disease process.

Vitreoretinale Eingriffe bei fortgeschrittener altersabhängiger Makuladegeneration

SummarySubfoveal choroidal neovascularizations are, along with geographic atrophies of the retinal pigment epithelium, the most common cause of irreversible central visual loss in patients with age-related macular degeneration (AMD). The intravitreal injection of antiangiogenic therapies now offers a highly effective, yet palliative treatment for many forms of wet AMD. Nevertheless, more complex exudative findings, and in particular, the more prevalent dry AMD patients are not amenable to the latter treatments. Advances of vitreoretinal surgical techniques have enriched the available spectrum for interventional treatment strategies in AMD. This article reviews current and future surgical options in patients with AMD.ZusammenfassungSubfoveale choroidale Neovaskularisationen (CNV) sind neben der geographischen Atrophie die häufigste Ursache für einen irreversiblen Verlust der zentralen Sehschärfe bei altersabhängiger Makuladegeneration (AMD) Mit der intravitrealen Injektion antiangiogenetischer Substanzen steht heute für viele Feuchte AMD-Formen eine palliative pharmakologische Therapie zur Verfügung. Komplexere exudative Befunde, und insbesondere der überwiegende Teil der Patienten mit trockenen Veränderungen profitieren nicht durch letztere Therapieform. Durch Weiterentwicklung vitreoretinaler chirurgischer Techniken konnte das Spektrum interventioneller Strategien bei der AMD ergänzt werden. Dieser Artikel beleuchtet derzeitige und zukünftige Möglichkeiten chirurgischer Therapien bei der AMD.

Age-related macular degeneration II-Geographic atrophy

Geographic atrophy (GA) represents the atrophic late-stage manifestation of “dry” age-related macular degeneration (AMD). It is characterised by the development of atrophic patches that may initially occur in the parafoveal area [3, 13, 16, 23]. During the natural course of the disease, atrophy slowly enlarges over time, and the fovea itself is typically not involved until later (“foveal sparing”, see Fig 12.3). The pathophysiologic mechanisms underlying the disease process are not completely understood. It is thought that the accumulation of lipofuscin in the retinal pigment epithelium (RPE) cells is a by-product of incompletely digested photoreceptor outer segments and plays a key role in the disease process (see Chap. 1). Histopathologic studies have shown that clinically visible areas of atrophy are confined to areas with cell death of the RPE and collateral tissue layers, i.e. the choriocapillaris and the outer neurosensory retina [7, 14, 15]. Another important finding is the observation of lipofuscin and melanolipofuscin-filled RPE cells in the junctional zone between the atrophic and the normal retina, while areas of atrophy itself are characterised by a loss of RPE and, therefore, lipofuscin granules. Fundus autofluorescence (FAF) findings in patients with GA secondary to AMD are in accordance with these in-vitro analyses (Fig. 12.1) [10, 27]. Due to the distinct changes of the topographic distribution of RPE lipofuscin, which is the dominant fluorophore for FAF imaging (see Chap. 2), the signal is markedly reduced over atrophic areas, while high-intensity FAF levels can be observed in the junctional zone surrounding the atrophic patches. These morphological changes are usually without any correlate on fundus photography or fluorescein angiography.

Moderne Arzneimitteltherapie der altersabhängigen Makuladegeneration@@@Modern pharmacotherapy of age-related macular degeneration

Age-related macular degeneration (AMD) is now the most common cause for blind registration in all developed countries. Epidemiologic data indicate that there are 4.5 millions affected in Germany with constant increase in incidence and prevalence with subsequent considerable health economic implications. Late manifestations of the disease result in the inability to read and to perform daily tasks. Therefore, there is an urgent need for efficacious prophylactic and therapeutic measures to prevent irreversible loss of central vision. Based on a better understanding of the underlying molecular mechanisms new therapeutic approaches have been brought forward and expand previous approaches such as thermal laser surgery or photodynamic therapy. Repeated intravitreal injection of anti-VEGF (vascular endothelial growth factor) agents as well as corticosteroids have a beneficial effect on growth and permeability of neovascular membranes. The risk for progression from early to late stages of AMD can be reduced with certain antioxidative preparations (AREDS medication) in presence of defined funduscopic signs. Early diagnosis is key for all currently available interventions since a beneficial effect can only be achieved in early stages of the disease process.