This finding however might be related to the overlapping areas of multiple lesions rather than the simple expanding growth of a single lesion and the possibility that growth rates may slow as the lesion expands out of the macular region. Longer follow-up intervals are needed to finally reveal the mode of progression in GA.

Results of a large prospective, multicenter, natural history study on GA progression (GAP-Study) have recently been reported [35, 36]. In this study, 413 eyes of 413 patients were measured based on FAF imaging and a mean progression rate of 1.77 mm2/year was reported. Lesion growth was significantly correlated with baseline lesion size, and it was confirmed that perilesional FAF patterns were predictive of lesion growth rates.

Based on the natural history data of these studies, it appears that the GA progression rate has been approved by the FDA as primary outcome measure in clinical trials on GA [52]. Furthermore, FAF imaging now appears to be accepted as a suitable tool to measure GA size longitudinally with a high degree of reproducibility. Furthermore, in contrast to manual outlining of atrophic areas, area measurements on digital FAF images can be performed using semiautomated image analysis software.

An alternative approach to determine GA progression has been recently demonstrated by using simultaneous cSLO and OCT imaging: The lateral spread of GA and the reduction in retinal thickness were confirmed as surrogate markers for disease progression at the GA border that were both quantifiable and corresponded to loss of outer retinal layers. However, an increase in retinal thickness was also observed that was related to confounders such as epiretinal membrane formation or marked collateral changes such as development of RPE elevations or sub-RPE deposits. Furthermore, it was shown in patients with Stargardt’s macular dystrophy that reduced retinal thickness (i.e., atrophy of retinal layers) did not correlate with the

transverse extent of photoreceptor loss [53]. These observations indicate that tracking of GA progression by changes in retinal thickness measurements alone should be interpreted with caution.

8.7Risk Factors

As the advanced dry form of AMD – GA – represents a multifactorial, complex disease involving genetic, other endogenous and exogenous risk factors. Population-based studies have examined both the prevalence and potential risk factors of GA also in comparison to CNV [2, 3, 5, 49, 54, 55]. More recently, genetic as well as natural history studies have given more insight into potential risk factors of GA and their results are promising to better elucidate the pathogenesis of GA and to develop future treatments for this disease.

8.7.1Genetic Factors

Various early reports have pointed toward the important role of genetic factors in AMD [3, 56–58]. The role of the alternative complement pathway in the AMD pathogenesis was subsequently documented by the discovery [59–62] and replication [63, 64] of the CFH association as well as reports of three additional risk loci in this pathway: CFB/C2 on chromosome 6 [64, 65], C3 on chromosome 19 [66, 67], and CFI on chromosome 4 [68]. Together with strongly associated variants in the ARMS2/HTRA1 region on chromosome 10 [69, 70], these multiple loci have been estimated to explain approximately one-half of the heritability of AMD [64], and combined with demographic, ocular, and environmental factors, they have potential predictive power [71]. More recently, a genome-wide association study of advanced age-related macular

degeneration identified the role of the hepatic lipase gene (LIPC) [72].

Looking specifically at GA, no significant difference in the genetic polymorphism between the occurrence of GA and CNV could be conclusively determined so far. A previously reported protection against GA conferred by a Toll-like-receptor 3 (TLR3) variant [73] could not be confirmed by genotyping this variant (rs3775291) in eight well-known case–control studies involving data from a total of 1,080 patients of European descent with GA and 2,669 matched controls (The International Age-related Macular Degeneration Genetics Consortium) [74].

Regarding the potential association of genotype and GA progression, two independent studies were published recently: In the first study, 99 individuals with bilateral GA were followed by FAF imaging. The investigators found an association of variants in CFH (Y402H), ARMS2 (A69S), and C3 (R102G) with the presence of GA, but no correlation with the progression of GA [75]. In the second study, growth rates of GA (114 individuals) calculated from digitized serial fundus photographs showed no association with variants in the CFH, C2, C3, APOE, or TLR3 genes. There was a nominally significant association with the LOC387715/ARMS2/HTRA1 genotype, although this finding was not supported by analyses of secondary measures of GA progression [76].

8.7.2Systemic Risk Factors

Extensive studies have been performed to examine possible relationships between AMD and systemic factors, such as hypertension, smoking, alcohol intake, and cholesterol level. Despite a significant risk of smoking in developing AMD, the findings are not consistent [55]. Even more important, only a few studies have distinguished different stages and manifestation of AMD and have separately analyzed the occurrence of GA due to AMD.

For example, the Blue Mountain Eye Study has shown that for women, current or past smoking was a significant risk factor for the presence of GA; for men, this did not reach statistical significance. Large prospective natural history studies on GA patients have demonstrated that neither hypertension and hyperlipidemia nor body mass index > 30 kg/m2 are risk factors for a more rapid atrophy progression [34, 47, 49, 50].

No significant correlation between actual and previous history of smoking could be shown; however, there was a weak trend for smokers to have more rapid enlargement of atrophy.

Divergent views have been brought forward with regard to the role of light exposure for the pathogenesis of GA [77]. Ultraviolet or visible light can induce generation of reactive oxygen species in the retina which may cause lipid peroxidation of photoreceptor outer segment membranes potentially contributing to LF accumulation in the RPE and, eventually, to the development of AMD. These assumptions have been partly confirmed in cell cultures and animal experiments [24, 78, 79]. However, until now, clinical and epidemiological studies have not been able to provide sound support for the view that cumulative sunlight exposure is associated with AMD [80–82]. However, it is difficult to accurately determine the amount of light exposure during the life span for a person who is 55 years and older and, the likely age to develop AMD.

For example, the ARED-Study could not show that high-dose intake of vitamins and mineral supplements significantly decreases the risk of the development of GA in the fellow eye of participants with unilateral advanced AMD or in participants without GA in any eye at baseline. Therefore, this large placebo-controlled, randomized study was unable to provide strong data for the hypothesis that reactive oxygen species might be involved in the GA disease process which could be potentially scavenged by antioxidant vitamins [83]. Furthermore, regarding the effect of AREDS treatment on GA growth, the data suggest no great benefit of AREDS-type supplements on the progression of GA. Tests for overall treatment effect, antioxidant main effect, and zinc main effect were not significant [50].

The ophthalmologist is often confronted with the question whether or not cataract surgery should be performed in eyes with GA. There has been speculation on a possible association between cataract and AMD. Both are the most frequent causes of visual impairment in the elderly and their prevalence is strongly age related [3]. Furthermore, both share common potential risk factors including smoking and sun light exposure [81].

Cataract extraction, i.e., the exchange of an opaque, yellow and, therefore, blue-light filtering natural lens to a clear artificial lens, would consequently expose the macula relatively to more blue light than preoperatively [84]. Anecdotal reports and non-randomized case series suggest that cataract surgery in AMD patients may have