Drusen, a hallmark of ARM, are extracellular deposits between the RPE and the inner collagenous layer of Bruch’s membrane. Drusen cause a lateral stretching of the RPE and physical displacement of the RPE from its immediate vascular supply, the choriocapillaris. Therefore, they are thought to interfere with the physiological metabolite diffusion between the neurosensory retina and the choroid.

The molecular composition of drusen is complex and includes lipids and various matrix proteins, such as vitronectin, as well as constituents of the inflammatory pathways (9, 10, 11). The latter include complement activators and inhibitors, activationspecific complement fragments, and terminal pathway components, including the lytic membrane attack complex (9,12,13). Hageman and coworkers (15) showed that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the RPE. Variants in the complement factor H gene have been shown to be associated with an increased risk for AMD (14, 15, 16, 17, 18, 19).

Ophthalmoscopically, focal drusen appear as small, roundish, yellowish lesions underneath the RPE. Various drusen classifications have been proposed (20, 21, 22, 23), depending on their size, shape, appearance, and topographic distribution. Well-delineated drusen with a diameter of less than 64 μm are referred to as “hard” drusen. Drusen with a diameter of 64-124 μm are classified as “intermediate,” and those larger than 125 μm are considered “large.” The former may occur as part of the normal aging process and do not appear to increase the risk of advanced AMD. Over a 5-year period in patients with many small drusen or few intermediate drusen, the risk for progression to
advanced AMD was shown to be 1.3% (24). In contrast, the risk for progression to advanced AMD in patients with many intermediate or large drusen was 18% in the Age Related Eye Disease Study (AREDS) (24). “Soft” drusen describes the presence of amorphous and poorly demarcated lesions in the presence of thickening of the inner aspects of Bruch’s membrane. “Confluent” drusen refers to contiguous boundaries between several soft drusen. Eyes with soft, confluent drusen are more likely to progress to late-stage AMD (15.1%) (25).

The so-called “reticular drusen” have been described as a variant of soft drusen with unique features (21,26,27). The prevalence of reticular drusen seems to be higher in AMD patients than in age-matched subjects without the disease (21,26,27). Reticular drusen seem to represent an important risk factor for the development of neovascular AMD (28), although a subgroup analysis of AREDS found a higher rate of progression to geographic atrophy than to choroidal neovascularization in the presence of reticular drusen (29). Klein and colleagues (30) recently described a 15-year cumulative incidence of reticular drusen (3.0%) in a population-based (n = 4926) prospective study. Eyes with reticular drusen had a higher risk to progress to geographic atrophy (cumulative incidence 21%) or to exudative AMD (cumulative incidence 20%) than those with soft indistinct drusen. From histopathological findings in one eye with reticular drusen, it appeared that fundus changes did not correlate with the extracellular material deposited in the inner aspect of Bruch’s membrane, but did correlate with choroidal alterations; therefore, the term “pseudodrusen” was proposed (27). However, the precise histopathological changes in reticular drusen is yet unknown.

In addition to the above drusen types, a different type of material can be found deposited between the RPE cell plasma membrane and its basement membrane. This complex composite of granular electron-dense material, coated membrane bodies, and fibrous collagen was initially termed “basal linear deposit” (31,32). Based on light and electron microscopy, the deposit was later renamed “basal laminar deposit,” whereas the term “basal linear deposit” was introduced to describe vesicular material underneath the basement membrane of the RPE. Because of this confusing terminology, Loeffler and Lee (33) suggested the terms “basement membrane deposit” (BMD) for material located between the RPE cell and its basement membrane, and “basal laminar deposit” (BLD) for vesicular material located within Bruch’s membrane. However, these deposits are detected only by light and electron microscopy and remain invisible by slit-lamp biomicroscopy. Apart from these ophthalmoscopically invisible deposits, Bonanomi et al. (34) and Gass et al. (35) described basal laminar drusen in association with pseudovitelliform lesions that angiographically appear as “stars in the sky.” Histologically, these basal laminar drusen correspond to nodular, hyaline thickening of the basement membrane of the RPE (35).

Over time, drusen may be subject to dynamic changes: (i) hard drusen may enlarge and turn into soft drusen (36), (ii) soft confluent drusen may lead to a drusenoid retinal pigment epithelial detachment, (iii) drusen material may show signs of calcification, and (iv) drusen may regress with the occurrence of a corresponding area of geographic atrophy (37).