an adverse effect regarding the progression of AMD and the development of choroidal neovascularization [85, 86]. Newest data by the ARED-Study, however, showed no clear effect of cataract surgery on the risk of progression to advanced AMD [87]. Nevertheless, the findings of prospective epidemiological and larger retrospective clinical studies are inconsistent and inconclusive to date [88]. However, these studies analyzed AMD patients in general, or differentiated only between early and late AMD manifestations. A much more sensitive method for analyzing the effect of the lens status on the disease might be to quantitatively investigate the enlargement of existing atrophy as opposed to the qualitative evaluation of solely GA development as an endpoint. The preliminary analyses on GA progression from the GASand FAM-Studies suggested that cataract surgery does not confer risk for more rapid progression of preexisting GA [89].

8.7.3Ocular Risk Factors

As mentioned above, ocular risk factors for development of GA include the presence of drusen with certain characteristics, pigment alterations, or RPE detachments [49]. More recently, so-called reticular pseudodrusen have been identified as a major risk factor for the development of late-stage AMD [90, 91]. In patients with GA, this specific phenotypic pattern, which is best recognizable by infrared reflectance and fundus autofluorescence imaging, can be detected in over 60% of eyes with GA [92]. However, the exact morphological correlate of this distinct pattern remains unknown so far: Speculations are ranging from abnormalities in the inner choroid [93] to subretinal deposits [94]; the latter speculation is based on the SD-OCT changes recorded in presence of reticular pseudodrusen [40, 94, 95].

However, what are factors that influence the rate of atrophy enlargement once GA has commenced? It has been shown that the GA progression rate is fairly constant over time [34, 47, 50, 51]. As mentioned previously, Sunness and co-workers reported that knowledge of prior enlargement rate is predictive of subsequent enlargement rate [47]; however, knowledge of the previous progression rate would require long-term follow-up prior to the study onset. Significant influence of the baseline lesion size on the GA progression rate has been shown previously [34, 47] and was recently confirmed by the GAP-Study [36], i.e., eyes with small atrophic

areas tend to have a lower rate of enlargement compared to eyes with larger areas of GA. However, the dependence of the progression rate on the baseline size of GA was found to be less strong than the dependence on the prior progression rate [46, 47].

Sunness and co-workers also found a significant difference of the progression rate between patients with bilateral GA and patients with drusen in the fellow eye; however, this difference was attributable to the lower baseline area in the fellow eye drusen group [47]. In a recent analysis of the FAM-Study population, there was significant difference in the GA progression rates of the drusen-, and GA-fellow eye groups when GA at baseline was > 1 DA (Fig. 8.6) with higher progression in bilateral GA [96].

Furthermore, configuration of GA may have a predictive value for GA progression: Klein and associates reported that eyes with multifocal atrophic lesions were most likely to have a more rapid increase in atrophy and those with classic single lesions were least likely to have an increase in atrophy [49].

Another striking observation is the high degree of concordance/symmetry of progression rates between eyes in bilateral GA [17, 46, 47, 49, 50] which also appears relevant for the design of interventional trials in GA patients to slow down enlargement of atrophic areas. By including only bilateral GA patients and assigning the untreated eye as a control if a topical administration is used, the required sample size may be significantly reduced with unilateral treatment.

Furthermore, a strong impact of phenotypic features of FAF abnormalities in the junctional zone of GA on atrophy progression has been demonstrated previously (see 8.4) [48].

Natural history data and identification of high-risk characteristics (e.g., specific FAF patterns) will help to test novel interventions in future clinical trials to slow down spread of atrophy in order to ultimately preserve vision in patients with atrophic AMD.

8.8Development of CNV in Eyes with GA

CNV and GA are not mutually exclusive. Patients with “pure GA” in one eye may have CNV or a disciform scar in the fellow eye, and eyes with GA may develop CNV (Fig. 8.6). It is not understood why some eyes develop one, and some eyes the other. It is the histological finding