(Schmitz-Valckenberg et al. 2004). Similar to identifiable patterns in early AMD, different patterns of FAF have been identified in the junctional zone outside GA separating atrophic and normal retina. These patterns are present with a high degree of symmetry in patients with bilateral geographic atrophy, pointing towards specific genetic contributions rather than non-specific aging processes. Different patterns may predict different rates of spread of pre-existing atrophy (Bindewald et al. 2005; Holz et al. 2007). Holz and colleagues recently stratified progression rates of GA according to FAF pattern type, and demonstrated in a subset analysis that there was significant difference between none/focally increased FAF and diffusely increased FAF (Holz et al. 2007). About 195 eyes from 129 patients were followed with repeated FAF imaging over a median follow-up of 1.8 years, and progression rates in eyes with the banded (1.81 mm2/year) and diffusely increased (1.77 mm2/year) pattern types demonstrated significantly faster rates of progression compared to eyes without FAF abnormalities (0.38 mm2/year) and focally increased patterns (0.81 mm2/year, P < 0.0001) (Holz et al. 2007). We propose a simpler categorical scheme, as well as a novel parameter called rim area focal hyperautofluorescence, or RAFH (Fig. 45.2).

45.5 Progression of Geographic Atrophy

Past studies of natural history progression of GA using color fundus photos reveals a mean progression rate of 2.6 mm2/year, and median of 2.1 mm2/year (Sunness et al. 2007). There is a high concordance rate between enlargement rates in 2 eyes of patients with bilateral GA (correlation coefficient, 0.76), and knowledge of prior rates of enlargement is the most significant factor in predicting subsequent enlargement rates (Sunness et al. 2007). Quantification of enlargement in this study was based on fundus photographs and involved several magnification steps (Sunness et al. 1999). Measurements of GA progression with FAF images reveals a mean progression of 1.74 mm2/year (median, 1.52 mm2/year) (Holz et al. 2007).

45.6 Mechanisms of Progression

Progression is best studied in the junctional zone at the margin of intact and dead RPE, where increased FAF may be noted in varying levels. Higher lipofuscin content as evidenced by increased FAF has demonstrated faster progression of RPE death (Holz et al. 2007). This increase in FAF is attributable to autophagy, phagocytosis of discarded photoreceptor cells and byproducts, and phagocytosis of dead RPE. In the area overlying increased FAF, there appears to be impaired photoreceptor function (Schmitz-Valckenberg et al. 2004; Scholl et al. 2004). A2E is the major fluorophore that has been identified as toxic by its detergent and phototoxic effects (Sparrow et al. 2003).

Fig. 45.2 Example of categorical scheme used to quantitate rim area focal hyperautofluorescence (RAFH). In category 1 (a), ≤ 1/3 of the 500 μm zone bordering the geographic atrophy (GA) had increased autofluorescence. For category 2 eyes (b), between 1/3 and 2/3, and in category 3 (c), ≥ 2/3 of this area had increased autofluorescence

45.7 Research to Prevent Progression

Several trials of new pharmacologic agents to slow progression of established GA have been proposed or initiated. One study investigates OT-551 (Othera Pharmaceuticals, Inc), a topical antioxidant eye drop which is now in phase II of clinical study. This agent, when metabolized to Tempol-H by corneal esterases, acts as a free-radical scavenger. In animal models of AMD, topical administration has demonstrated anti-inflammatory and anti-angiogenic effects (Wang et al. 1995). Ciliary neurotrophic factor (CNTF) is another agent in phase II of clinical study for atrophic AMD as well as advanced retinitis pigmentosa. In an animal model, CNTF slows the progression of photoreceptor degeneration (Sieving et al. 2006). Major advances in genetic knowledge implicate alterations in the inflammatory pathways in both wet and dry AMD, however this is not yet directly modifiable (Shaumberg et al. 2007).

Another new area of research to slow GA involves the reduction of serum retinol. Sirion Pharmaceuticals has initiated a randomized, double-masked and placebo controlled study of the safety and efficacy of 100 and 300 mg of fenretinide in the treatment of geographic atrophy. The active ingredient in fenretinide, N-(4-hydroxyphenyl) retinamide, promotes clearance of retinol and reduces the total retinol available for visual processing. This compound competes for binding sites on retinol binding protein (RBP), and may prevent binding of transthyretin. The altered moiety is then cleared through the urine by glomerular filtration. By reducing lipofuscin and A2E accumulation, this agent is theorized to reduce fundus autofluorescence and slow the progression of geographic atrophy (Radu et al. 2005). This 2 year trial has a targeted enrollment of 225 patients with three to five disc areas of geographic atrophy in at least one eye. The primary endpoint will be the deterioration of scotoma size or depth, defined as at least 5 points/loci losing light sensitivity from baseline by a clinically significant amount as measured by microperimetry. A secondary outcome is change from baseline in the area and intensity of fundus autofluorescence.

45.8 Discussion

Several ongoing clinical trials of GA are using FAF imaging as a clinical endpoint. Based on our studies, FAF imaging is likely to have a major impact in how we follow and predict geographic atrophy progression (studies submitted for publication). By potentially stratifying risk and enrolling patients at high risk of progression, the use of FAF imaging could further optimize clinical trial design for GA.

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