New Grading Criteria Allow for Earlier Detection of Geographic Atrophy in Clinical Trials

Geographic atrophy (GA) is one of the advanced forms of age-related macular degeneration and a leading cause of vision loss in the United States. Nearly 1 million individuals in the United States have GA in at least one eye.1 Because the prevalence of GA rises sharply with age, the number of Americans with GA is projected to rise rapidly in the future as the U.S. population ages.2 Despite its prevalence, there is little information available regarding the earliest stages in the natural history of this progressive disease. Histopathologically, GA is a loss of the retinal pigment epithelial (RPE) cell layer and overlying retinal photoreceptors.3 It is associated with deterioration of the underlying choriocapillaris and the reduction in density of the underlying choroidal vessels.4 GA often develops as one or several small parafoveal lesions, which enlarge and coalesce over time, often sparing the fovea until late in the course of the disease.5 In its earliest stages, these small areas of evolving GA have been described, though briefly, using multiple different imaging modalities including color fundus photography (CFP), optical coherence tomography (OCT), and fundus autofluorescence (FAF).6–9 However, despite numerous studies describing the natural progression of GA for large, well-established lesions, none have systematically investigated the characteristics, natural history, and progression of the earliest stages of disease. Treatments designed to halt the progression of GA are currently under investigation. These candidate treatments would be most beneficial if targeted toward the earliest stages of disease, before large scotomas develop and while central vision is preserved. Therefore, data on the initial appearance and natural progression rates of early GA are essential to the design of a clinical trial involving these early lesions. Color fundus photographs have been used in most of the standard grading systems developed for categorizing GA for observational studies and clinical trials. The definitions of GA developed for studies using photographs alone do not lend themselves well to description of very early GA. According to the standard color fundus photograph criteria, an area of depigmentation with a diameter at least 175 μm must be present as well as at least two of the following three features: a more or less circular shape, sharply demarcated edges, and visible choroidal vessels.6,10–17 These features may not be present when the RPE cell layer first begins to recede in a discrete area of the retina as GA first develops. Furthermore, very early GA is difficult to differentiate from its precursors.18 The standard CFP criteria are not specific enough to differentiate GA from its precursors, such as depigmentation and drusen, which also appear roughly circular and have a pigment change from the background fundus. To study the earliest stages of GA, criteria that are more sensitive and specific for GA are required. One way to improve the criteria for detecting GA is to modify them to be more selective for features specific to GA. Sunness et al.,18 have noted that GA appears as an area of excavation or decreased retinal thickness when viewed stereoscopically. This characteristic of excavation can distinguish GA from its precursors, such as drusen or depigmentation, which appear elevated and flat, respectively, when viewed in stereo. By using this clinical feature in the criteria that define GA on color fundus photos, we may be able to aid in the identification of GA and improve on the CFP criteria used previously in standard grading protocols. Color fundus photography has historically been the main means of defining GA. In 1995, an international group was formed and came to a consensus on a unified definition of GA as seen in stereoscopic color photographs.19 One of the advantages of defining lesions using this imaging modality is that CFP correlates well with the clinical examination. However, color fundus photographs do not convey any direct information about the presence or absence of the RPE, because absence of the RPE does not have a consistent clinical appearance—a problem that is exacerbated by the vast variation in fundus pigmentation across subjects.18 Other imaging modalities that have been used more recently to characterize GA (i.e., fluorescein angiography [FA], FAF, spectral-domain [SD], and scanning laser ophthalmoscopy [SLO] microperimetry [MP]) do provide such information. The loss of the RPE cell layer in a discrete area appears as an absolute scotoma (retinal sensitivity of 0) on MP,20,21 as a hyporeflective area on FAF (absence of lipofuscin-laden RPE cells),22–24 as the absence of the outer hyperreflective bands (which are anatomically consistent with the RPE cell layer) in the SD-OCT signal,7,25 and as a hyperfluorescent area or window defect (absence of the RPE cell layer, which normally blocks the underlying fluorescence of the choroid) on FA.26–28 Using one of these other imaging modalities, we may be able to identify areas of GA with greater sensitivity and specificity than features that are only variably present on color photography. Authors of textbooks describe delineation of GA from FA, and one recent study has categorized GA based on FA appearance, but there are no standard criteria (Apte RS, et al. IOVS 2002;43:E-Abstract 2505).26–28 We propose a new classification system (referred to herein as revised criteria) that uses features from two imaging modalities simultaneously—color fundus photographs and fluorescein angiograms that are sensitive and specific to GA. In this report we evaluate the reliability and accuracy of the revised criteria for detecting early GA areas; compare CFP, FA, and dual-imaging modalities in the detection of the characteristic features of GA; and assess whether application of the revised criteria leads to earlier detection of GA than the previous criteria with CFP alone.