Table 6.1 Clinical manifestations of age-related macular degeneration

Table 6.2 Probability of the development of advanced agerelated macular degeneration (AMD) with visual loss (in the presence of bilateral drusen in both eyes, in the presence of unilateral late-stage lesion in the fellow eye)

subretinal fibrosis

Fig. 6.1 Focal and diffuse drusen taking the form of abnormal material deposits between retinal pigment epithelium and Bruch’s membrane predispose to the development of late-stage atrophic or neovascular lesions of age-related macular degeneration associated with severe visual loss

20% of the patients who develop severe visual loss do so because of geographic atrophy – with an increasing tendency. Particularly for clinical studies, sophisticated systems of classification have been developed, which also include quantitative parameters such as the size of drusen (Age-Related Eye Disease Study Research Group [2]: ARED study classification; [3]: International Classification and Grading System for Age-Related Maculopathy and Age-Related Macular Degeneration; [4]: Rotterdam study classification).

6.2Drusen

The presence of specific drusen types indicates a risk of development of late-stage AMD (Fig. 6.1) [5–7]. Depending on the method of examination and definition, up to 80% of all patients over 60 years of age have evidence of drusen, usually in the macular and paramacular regions. At the same time,

drusen of Bruch’s membrane are not by any means a specific sign for AMD. However, as a common pathogenetic pathway, they occur in association with various acquired and genetically determined retinal and choroidal diseases.In AMD, drusen as hallmarks of disease are assumed to primarily develop on the genetic basis of risk polymorphisms in the complement factor H (CFH) gene. Several studies indicate an early influence of the CFH gene in the development of AMD and suggest a role in developing already early stages of AMD – in addition to the influence on the progression of more clinically relevant late stages of AMD [8]. The observation of diffuse deposits below the RPE [9] and vitronectin might be relevant to disease progression. Vitronectin is an extracellular matrix protein that is a major constituent of drusen [10] and an important inactivator of complement produced after complement stimulation by RPE cells [11] (see Chap. 5). In contrast, the AMD-associated risk variant in the ARMS2 gene appears to be more important in advanced forms of AMD and may support the formation of respectively the progression to late stages of AMD [12]. Thereby, the risk polymorphism in the ARMS2 gene appears to primarily influence the progression to exudative AMD rather than to geographic atrophy, while for the CFH risk variant, no differences in progression to different forms of late AMD have been shown [13]. This genetic predisposition for early AMD includes two aspects: The highly bilateral symmetry of drusen, comparable to a fingerprint, indicates a genetic basis of drusen development that goes beyond the association to genetic risk polymorphisms. Secondly, due to the genetic basis and the genetic identity of both eyes, there is an elevated risk of progression of early AMD to unilateral or bilateral late AMD (Table 6.2).

In the absence of atrophy or exudative manifestation, patients with drusen usually have good visual function. However, detailed questioning may reveal functional deficits, such as abnormal dark adaptation or reading problems in dim light. The latter symptoms would not be detected by conventional tests of visual acuity. Other, more refined, psychophysical examinations allow both detection and quantification of such deficits [14, 15]. These include color-contrast vision deficits, blue-cone functions being the ones primarily affected [16]. These are relevant in daily life, since the ability to drive a car at night is impaired [17].

Various types of drusen can be distinguished on the basis of ophthalmoscopic, histological, and angiographic criteria classification of drusen:

6.2.1Classification of Drusen

•Hard (nodular) drusen

•Soft (exudative) drusen

•Basal linear deposits (diffuse drusen)

•Cuticular drusen (previous term: basal laminar drusen)

•Reticular pseudodrusen (reticular drusen, subretinal drusenoid deposits)

Different types of drusen can be present in the same

eye. While various characteristics suggest that the type

Fig. 6.2 Fundus photograph (a) with multiple hard drusen showing up as well-defined window defects owing to corresponding thinning of the retinal pigment epithelium (reduced content of intracellular melanin granules) seen on fluorescein angiography (b)

and distribution of drusen at the posterior pole can vary markedly between individuals, there is usually a high degree of symmetry between the two eyes of the same patient [18].

6.2.2Possible Spontaneous Modifications of Drusen

•Enlargement of hard drusen including progression of hard drusen to soft drusen (“drusen softening”)

•Detachment of the retinal pigment epithelium due to confluence of soft drusen

•Calcification

•Spontaneous regression

•Disappearance with subsequent corresponding atrophy

Hard drusen are usually <50 mm in diameter and

are seen as small, well-defined, yellowish deposits on ophthalmoscopy. Drusen of this type are associated with very little risk of progression to late-stage AMD with visual loss. Therefore, some authors interpreted such drusen as “normal” changes of aging (Fig. 6.2) [3]. However, findings in the Beaver Dam Eye Study indicate that the presence of a high number of hard drusen (more than eight) is associated with an increased risk of the occurrence of soft drusen or late-stage disease over a review period of 10 years [6].

Soft drusen are larger and usually ill defined (Fig. 6.3). Soft drusen are associated with a higher risk of progression to late-stage AMD such as choroidal neovascularization. Ophthalmoscopic detection should prompt the ophthalmologist to advise regular central visual field testing with the Amsler grid. Soft drusen may enlarge over time to become confluent and cause detachments of the retinal pigment epithelium (“drusenoid retinal pigment epithelial detachment”). They may also disappear spontaneously; this

is usually associated with the development of corresponding atrophy of outer retinal layers.

Basal linear deposits are extensive deposits between the basal membrane of the RPE and the inner collagenous zone of Bruch’s membrane. Their diffuse occurrence can be readily identified only in histological sections. Clinically, they might be identified indirectly by choroidal perfusion analysis (see Sect. 6.4). Basal linear deposits are sometimes referred to as “diffuse drusen” because they primarily consist of

Fig. 6.5 Reticular pseudodrusen (subretinal drusenoid deposits) on fundus photograph (a) and fundus autofluorescence image (b) in association with central geographic atrophy. This type of drusen is readily identified with confocal scanning laser ophthalmoscopy

and shows a uniform netlike structure. Using spectral domain optical coherence tomography (SD-OCT) techniques (c), corresponding hyperreflective changes are found above the cell layers of the RPE

membranous material that is similar to that found in soft drusen which are also located between the basal membrane of RPE and the inner collagenous zone of Bruch’s membrane [19].

Cuticular drusen are classified as a special variant of drusen, which usually occur in middle age and are associated with a relatively good prognosis [20]. They may be associated with a peculiar “vitelliform” lesion at the posterior pole (Fig. 6.4), i.e., accumulations of yellowish subretinal fluid in the macula. On angiographic examination, this type of drusen has a “stars-in-the- sky” appearance with myriads of small, equally sized, round hyperfluorescent window defects corresponding

to the stars. First, these drusen were histologically thought to represent nodular hyaline thickenings of the basal membrane of the RPE and were termed as basal laminar drusen [20]. After they were shown to contain the same constituents as soft drusen, they were renamed as cuticular drusen [21, 22].

Reticular pseudodrusen can, under certain conditions, be seen on fundus photography, but they are best visualized by confocal scanning laser ophthalmoscopy (cSLO) using near-infrared reflectance or autofluorescence imaging. They appear as uniform, small, netlike structures (Fig. 6.5). By using spectral domain optical coherence tomography (SD-OCT),