Geographic Atrophy

Core Messages

›The advanced dry form of age-related macular degeneration (AMD) – so-called geographic atrophy – is a common cause for both moderate and severe visual loss with increasing incidence and prevalence.

›The atrophic process typically shows welldefined borders and encompasses outer neurosensory retinal layers, the retinal pigment epithelium (RPE), and the choriocapillaris.

›Atrophic areas show a continuous enlargement over time with high interindividual variability in progression.

›Distinct phenotypic patterns of abnormal fundus autofluorescence (FAF) in perilesional areas are associated with different enlargement rates, while known genetic risk factors for AMD in general as well as other risk factors including smoking appear not to have an impact on individual progression of the disease.

›While there is no exclusive dichotomy between atrophic and neovascular AMD, factors responsible for the switch to geographic atrophy vs. exudative manifestations are yet unknown.

›Visual acuity (VA) correlates poorly with the total geographic atrophy size in earlier stages and may therefore not reflect the actual visual performance of the patient including stability of fixation and reading. The fovea may be spared until late in the course of the disease. Therefore, an anatomical endpoint to assess outcome in patients in clinical trials appears more adequate than a functional parameter such as VA.

›Multiple pathways appear to be operative in the pathogenesis of geographic atrophy, which is reflected by a wide spectrum of agents with heterogeneous targets currently in preclinical or clinical development for interventions aiming at slowing progression, i.e., enlargements of atrophic areas.

M. Fleckenstein • S. Schmitz-Valckenberg • F.G. Holz (*) Department of Ophthalmology, University of Bonn, Bonn, Germany

e-mail: monika.fleckenstein@ukb.uni-bonn.de; steffen.schmitz-valckenberg@ukb.uni-bonn.de; frank.holz@ukb.uni-bonn.de

J.S. Sunness

Hoover Low Vision Rehabilitation Services,

Greater Baltimore Medical Center, Baltimore, MD, USA e-mail: jsunness@gbmc.org

8.1Introduction

Geographic atrophy (GA) is the advanced form of “dry” AMD. GA appears as sharply demarcated areas with depigmentation and enhanced visualization of deep choroidal vessels (Fig. 8.1). The term “geographic” has been introduced as a descriptive term. The initial term “GA of the retinal pigment epithelium (RPE)” is misleading in that not only RPE cells are involved but also anatomical layers anterior

Fig. 8.1 In atrophic AMD, atrophy areas appear as sharply demarcated areas with depigmentation and enhanced visualization of deep choroidal vessels on fundus photograph (left). At the corresponding fundus autofluorescence image (right), atrophic patches are clearly delineated by decreased intensity and

high-contrast to non-atrophic retina. Surrounding atrophy, in the junctional zone of atrophy, levels of marked FAF intensity are observed which are invisible on fundus photography. These abnormalities tend to precede atrophy over time and may serve as disease markers

and posterior to the RPE cell monolayer, i.e., choriocapillaris and outer neurosensory retinal layers including the photoreceptors [1]. While choroidal neovascularization (CNV) is the most common cause of severe visual loss in advanced AMD, approximately 20% of AMD patients who are legally blind have lost central vision due to GA [2–6]. Patients with primary GA tend to be older than those with neovascular forms of AMD at the time of initial manifestation. In patients aged 85 years and older, GA occurs four times as often as CNV [7]. It has been speculated that GA is the natural end stage of the AMD process, if CNV does not intervene [80].

corresponding atrophy, and it has been proposed that GA is the natural end stage in the lifecycle of a soft drusen. Calcified, crystalline deposits also appear to correlate with the occurrence of atrophy [13]. In some cases, GA develops following the collapse of serous and/or fibrovascular pigment epithelial detachments [14].

Atrophy may initially manifest as a single atrophic patch or as multifocal areas of atrophy. In the early course of the disease, atrophy is typically limited to the perifoveal region [1, 9, 15]. Over time, atrophic lesions enlarge and may coalesce, and new atrophic areas may occur. This may result in a horseshoe or ring configuration of atrophy surrounding a spared central fovea. The fovea is typically not involved until late in the course of multifocal disease. However, the atrophy

of Atrophy

GA may occur “de novo” or subsequent to other manifestations of AMD. Funduscopically visible alterations at the level of the RPE and Bruch’s membrane such as pigmentary alterations and drusen may precede the development of atrophy [1, 8–12]. Spontaneous regression of confluent soft drusen may result in

in unifocal cases.

A high symmetry between fellow eyes in both atrophy configuration and total size of atrophy in bilateral GA has been observed [6, 16, 17] (Fig. 8.2). Of note, peripapillary atrophy is observed commonly in eyes with GA and its prevalence in GA appears to be higher compared to age-matched control eyes. Very advanced stages may show large continuous areas of atrophy,

Fig. 8.2 Fundus autofluorescence images of patients with bilateral geographic atrophy (images of the right and left eye are taken at the same time point). There is a high degree of symmetry

with respect of the configuration of atrophy while there is a high degree of interindividual variability (Copyright ARVO.org. Fleckenstein et al. [17])

covering the entire posterior pole and extending to retinal areas nasal to the disc as well.

8.3Histology and Pathogenesis of Geographic Atrophy

Histologically, areas of GA are characterized by loss of the RPE, of outer layers of the neurosensory retina, and the choriocapillaris [12, 18]. The initiating event in GA development, however, is still unknown: The loss of photoreceptors appears to be secondary to changes of and beneath the RPE. It is assumed that alterations in the photoreceptor layer do not occur independently of changes in the RPE and the reduction in photoreceptor nuclei appears to parallel loss of the RPE [12]. However, recent morphological studies in a series of donor eyes with GA by Bird and Hageman disclosed that marked photoreceptor loss may be present outside GA with corresponding normal appearing RPE cells (personal communication). Furthermore, the development of AMD has been ascribed to narrowing of the choriocapillaris [8]. However, in histological preparations, the choroidal capillaries persist for a time after loss of the RPE so that vascular changes are regarded to occur

secondary to the reduced requirements of the outer retina or to the loss of some trophic factor provided by the RPE [8, 19, 20]. The fact, however, that patches of RPE atrophy may sometimes correspond in size to choriocapillary lobules also raises the possibility of a choroidal contribution to the disease process [15, 21]. Furthermore, changes in the structure of Bruch’s membrane may contribute to the evolution of GA [22].

Since genetic risk factors for AMD are present from birth and on, but the disease does not manifest until older age, various pathways may play a role in parallel for the development of cell death including oxidative damage, inflammatory processes, and ageing changes in postmitotic RPE cells.

8.4Fundus Autofluorescence Imaging in Geographic Atrophy

Several lines of experimental and clinical evidence indicate that the RPE plays an important role in the pathogenesis of GA associated with AMD. In postmitotic RPE cells, lipofuscin (LF) accumulates in the lysosomal compartment with age and also in various complex and monogenetic retinal diseases including Best’s disease,

Stargardt’s disease, and AMD [23]. LF is thought to be mainly derived from the chemically modified residues of incompletely digested photoreceptor outer segment discs. Experimental findings suggest that certain molecular compounds of LF such as N-retinylidene-N- retinylethanolamine (A2-E) possess toxic properties and may interfere with normal cell function [24].

The accumulation of LF in postmitotic human RPE cells and its harmful effects on normal cell function has been largely studied in vitro with fluorescence microscopic techniques [23]. Delori and co-workers have shown that fundus autofluorescence (FAF) in vivo is mainly derived from RPE LF [25]. With the advent of confocal scanning laser ophthalmoscopy (cSLO), it is possible to document FAF and its spatial distribution and intensity over large retinal areas in the living human eye [26–29]. FAF imaging gives additional information above and beyond conventional imaging tools such as fundus photography, fluorescein angiography, or optical coherence tomography.

Due to the lack of RPE cells and, therefore, LF, FAF imaging shows markedly decreased FAF intensity corresponding with atrophic patches (Fig. 8.1). Areas of atrophy can be accurately delineated, quantified with image analysis software, and atrophy progression rates can be calculated [30, 31]. Therefore, FAF imaging is an easy feasible, non-invasive method which is a useful tool for following GA patients and progression over time.

Furthermore, it has been shown that areas with increased FAF intensities and, therefore, excessive RPE LF load surrounding atrophy, in the so-called junctional zone of atrophy, can be identified [27, 29].

Areas of increased FAF have been shown to precede the development of new areas of GA or the enlargement of preexisting atrophic patches [32] (Fig. 8.3). In a natural history study – FAM (Fundus Autofluorescence in Age-related Macular Degeneration) Study – it has been shown that eyes with larger areas of increased FAF outside atrophy were associated with higher rates of GA progression over time compared to eyes with smaller areas of increased FAF outside atrophy at baseline [33]. These findings suggest that the area of increased FAF surrounding the atrophy at baseline is positively correlated with the degree of spread of GA over time. A more recent analysis of the FAMStudy of 195 eyes of 129 patients shows that variable rates of progression of GA are dependent on the specific phenotype of abnormal FAF pattern at baseline [34] (Fig. 8.4). Atrophy enlargement was the slowest in eyes with no abnormal FAF pattern (median 0.38 mm2/year), followed by eyes with the focal FAF pattern (median 0.81 mm2/year), then by eyes with the diffuse FAF pattern (median 1.77 mm2/ year) and by eyes with the banded FAF pattern (1.81 mm2/year). The difference in atrophy progression between the groups of no abnormal and focal FAF patterns and the groups of the diffuse and banded FAF patterns was statistically significant (p < 0.0001). These results have subsequently been confirmed in another large-scale natural history study (GAP-Study) [35, 36]. These findings underscore the importance of abnormal FAF intensities around atrophy and the pathophysiological role of increased RPE LF accumulation in patients with GA due to AMD.