Prevalence and morphology of druse types in the macula and periphery of eyes with age-related maculopathy

Abstract

Purpose: Macular drusen are hallmarks of age-related maculopathy (ARM), but these focal extracellular lesions also appear with age in the peripheral retina. The present study was conducted to determine regional differences in morphology that contribute to the higher vulnerability of the macula to advanced disease.

Methods: Drusen from the macula (n = 133) and periphery (n = 282) were isolated and concentrated from nine ARM-affected eyes. A semiquantitative light microscopic evaluation of 1-mum-thick sections included 12 parameters.

Results: Significant differences were found between the macula and periphery in ease of isolation, distribution of druse type, composition qualities, and substructures. On harvesting, macular drusen were friable, with liquefied or crystallized contents. Peripheral drusen were resilient and never crystallized. On examination, soft drusen appeared in the macula only, had homogeneous content without significant substructures, and had abundant basal laminar deposits (BlamD). Several substructures, previously postulated as signatures of druse biogenesis, were found primarily in hard drusen. Specific to hard drusen, which appeared everywhere, were central subregions and reduced RPE coverage. Macular hard drusen with a rich substructure profile differed from primarily homogeneous peripheral hard drusen. Compound drusen, found in the periphery only, exhibited a composition profile that was not intermediate between hard and soft.

Conclusions: The data confirm regional differences in druse morphology, composition, and physical properties, most likely based on different formative mechanisms that may contribute to macular susceptibility for ARM progression. Two other reasons that only the macula is at high risk despite having relatively few drusen are the exclusive presence of soft drusen and the abundant BlamD in this region.

Figure 1

Gross appearance of drusen in the macula and periphery of donor eyes. In the specimens (A) the retinal vasculature was visible. Prominent in all panels are the major choroidal vessels, which empty at death and appear as lighter stripes in contrast to the heavily pigmented intervening choroidal stroma. The neurosensory retina is in place in the specimens in (A) and (C) and is removed in all other panels. (A) Right macula of case 6R with abundant large drusen. Arrowhead: crystalline druse. (B) The same macula (retina off) as in (A). Arrowhead: the same crystalline druse, which is whiter and more glistening relative to the other drusen in the field. (C) Right macula of case 7R with large drusen. Drusen are less white than in (A) and have a stippled surface indicating overlying RPE. Arrowhead: one druse. Semicircular area of depigmentation at right, blurred due to the overlying retina, indicates atrophy of the RPE and choroid around the optic nerve head (not visible). (D) Same macula (retina off) as (C), with the same druse indicated. (E, F) Pair of images of the macula of case 7L from which a soft druse has been removed. X, the fovea. A druse and surrounding RPE (bordered in yellow) has been punctured, releasing oily contents diffusely (cloudy area delimited by gray dashed line in E) into the surrounding buffer. (F) The druse has been cleaved from Bruch's membrane, leaving a window in the RPE through which the underlying choroid is visible. The druse, still bordered by yellow, has been inverted so that its basal aspect is now apparent. (G) Periphery of case 3L showing abundant drusen, some large (arrowhead). (H) Periphery of case 1L showing less abundant drusen. The largest drusen (arrowhead) are smaller than those in (G). Bars, 1 mm.

Figure 2

Druse types. One-micrometer-thick sections stained with toluidine blue and imaged with a 60× oil immersion objective. All 415 drusen were assigned to one druse type. (A) Soft druse, typically loose, amorphous material; sloped shoulders; (B, C) hard drusen, (B, macular, C, peripheral), round or dome-shaped, well-defined borders, hyalinized content; (D) compound drusen, hyalinized material mixed with loose amorphous contents, not assigned to the two previous types.

Figure 3

Examples of evaluated druse parameters. One-micrometer-thick sections stained with toluidine blue and imaged with a 60× oil immersion objective. The images depict the evaluated parameters (Table 2). Examples are marked with an arrowhead and a number: 1, vertical section plane; 2, nonvertical section plane; 3, full integrity; 4, reduced integrity; 5, empty druse; 6, homogeneous content; 7, inhomogeneous content; 8, reduced RPE coverage; 9, full RPE coverage; 10, BlamD; 11, shell; 12, central subregion; 13, remodeling recess; 14, internal cells; 15, pigment granules; 16, amyloid assemblies; 17, calcification; and 18, inclusions. Soft drusen (C, E, H); macular hard drusen (A, B); peripheral hard drusen (D, top; F, I, J, K, L); compound drusen (D, bottom; G).

Figure 4

Druse diameters, by druse type. Diameters were determined for drusen sectioned in the vertical and nonvertical planes separately and then pooled. Box plot: the median and quartiles; bars, minimum and maximum diameter for each type.