|Molecular Vision 1999;
Received 24 May 1999 | Accepted 2 November 1999 | Published 3 November 1999
Histopathology of age-related macular degeneration
W. Richard Green
Departments of Ophthalmology and Pathology, Johns Hopkins Medical Institutions, Baltimore, MD
Correspondence to: W. Richard Green, MD, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD, 21287; Phone: (410) 955-3455; FAX: (410) 614-3457; email: email@example.com
Age-related macular degeneration is a diffuse condition involving the retinal pigment epithelium, the photoreceptor cell layer, and perhaps the choriocapillaris. The early morphologic change is the development of basal deposits of two distinct types. This phase is not ophthalmoscopically detectable but psychophysical testing may demonstrate reduced function. The process becomes detectable with the occurence of secondary changes in the pigment epithelium, soft drusen formation, and choroidal neovascularization. A reparative response results in disciform scars. The various morphologic forms of age-related macular degeneration are interrelated.
Histopathologic and clinicopathologic correlative studies have delineated most of the morphologic features of age-related macular degeneration (AMD) [1-6] and the interrelationship of the various morphologic forms . Figure 1 is a flow diagram that shows the interrelationships of the various morphologic features of AMD . The entire area centralis may be involved but the most marked changes often occur in the central area inclusive of the parafoveal area.
The earliest morphologic feature of AMD is the development of basal deposits external to the RPE, originally termed "diffuse drusen" . It now seems clear that two distinct types of deposits occur, basal laminar (BLamD) and basal linear (BLinD) . This terminology was put forward in an attempt to reduce the confusion generated by previous conflicting terms. BLamD is composed of granular material with wide-spaced collagen located between the plasma membrane and the basal lamina of the RPE  (Figure 2). BLinD is composed of material with coated and non-coated vesicles and some membranous profiles that is located external to the basal lamina of the RPE, that is, in the inner collagenous zone of Bruch's membrane (Figure 3). This early stage of AMD may not be evident by ophthalmoscopic examination but can be inferred by reduced retinal function and, in some cases, by a very faint, late fluorescein staining.
The presence of basal deposit becomes ophthalmoscopically evident by secondary changes in the RPE, and by the development of soft drusen, choroidal neovascularization and disciform scarring.
The RPE changes, often described as "pigment modeling," consist of RPE attenuation with depigmentation, hypertrophy, hyperplasia and atrophy [1,7] (Figure 4). Accumulation of pigmented cells in the subretinal space contributes to the appearance of clumping.
The second major feature is the development of soft (large) drusen [1,7]. These are usually larger than nodular drusen and have a less discrete margin. Several types of soft drusen have been observed and include localized detachment of BLamD with or without BLinD . Localized accumulation of basal linear material is emerging as the most frequent form of soft drusen  (Figure 5).
A third major feature is the development of choroidal neovascularization (CNV), which begins in the choroid and extends into a plane between BLamD along with RPE and the remainder of Bruch's membrane  (Figure 6). Only rarely do the vessels extend through the RPE and into the subretinal space. In the early stages of AMD, these vessels are capillary-like  (Figure 7) and with time evolve into arteries and veins [1,5] (Figure 8). The number of points of origin of choroidal CNV varies from 1 to 12. Study of serial sections throughout the macular area of 63 eyes with CNV disclosed an average of 2.2 sources per eye (Unpublished data, WR Green, July 1998). CNV may in turn lead to serous and/or hemorrhagic detachment of the RPE and/or retina, pigment modeling, exudation and RPE tears. CNV may be promoted by cellular breakdown of Bruch's membrane (Figure 9) . This early phase of CNV is observed in a small percentage of eyes. Most eyes with CNV are clinically occult as defined by fluorescein angiographic features: fluorescein leakage of undetermined origin  (Figure 10) and fibrovascular RPE detachment  (Figure 11). Findings of CNV by indocyanine green angiography include late, plaque-like staining (Figure 12) and a "hot spot" [12,13] (Figure 13).
The fourth major feature is the development of disciform scarring. In a study of a large series of disciform scars, Green and Enger  found that the scar was non-vascularized in 25%, vascularized in 75%, and had a variable histologic pattern. The scar was thin, nonvascularized and located between the BLamD and the remainder of Bruch's membrane in 6.5% of eyes (Figure 14) and was a thin fibrovascular sub-RPE with BLamD in 13.2% of eyes (Figure 6). The scar had a single subretinal component in 32.2% of the cases (Figure 15) and two components (subretinal and sub-RPE with BLamD) in 48.1% of cases (Figure 16). In those scars with two components, the subretinal portion was larger in 47.7% of eyes, the sub-RPE with BLamD was larger in 34.2% and the two components were about the same size in 18.1% of the cases. Of the 231 eyes with vascularized lesions, the new vessels were from the choroid only in 223 (96%), from the retina and choroid in 6(2.5%) and from the retina only in 2 (0.6%). The mean diameter and thickness of the scars was 3.73 mm and 0.44 mm, respectively . A tear of RPE and BLamD was present in 6.8% of eyes with disciform scars [1-5] (Figure 17). RPE and photoreceptor cell degeneration was progressively greater as the diameter and thickness of the disciform scar increased. Scars of 200 µm or more in thickness had remaining photoreceptor cells in only about 25% of the surface over the scar.
In two-component disciform scars, the intraBruch's membrane component with blood vessels may extend into the subretinal component through small defects in BLamD and any residual RPE [1,14] (Figure 18). Larger defects in BLamD/RPE (RPE tears) [1,2] is an additional situation in which the two components become continuous [1,2] and blood vessels may extend into the subretinal component from the intraBruch's membrane component. In 8 of 310 (2.6%) of eyes with disciform scars, retinal vessels extended into the disciform scar [1,15] (Figure 19).
Some form of detachment was observed in 79 (10.4%) of 760 eyes with AMD . The detachments were sub-RPE with BLamD in 13 of 79 (16.5%) eyes, serous neurosensory in 35 (44.3%), hemorrhagic neurosensory in 3 (3.8%), serosanguineous RPE in 3 (3.8%) and serosanguineous neurosensory in 7 (8.9%). Massive hemorrhage was present in 6 eyes (7.6%)  and was often associated with the use of aspirin or other anticoagulants [1,16].
RPE atrophy was present in 282 (37.1%) of 760 eyes . Of the 282 eyes, areolar atrophy was associated with disciform scars in 95 (33.7%). Atrophy was unassociated with disciform scars in 187 (24.6%) of 760 eyes. Twenty-one (11.2%) of the 187 eyes with areolar atrophy (2.8% 760 eyes) had no disciform scarring or neovascularization (Figure 20). This form of AMD has been referred to as the "dry form" of AMD. BLamD, BLinD and soft drusen are often present in such eyes.
The various morphologic forms of AMD are a continuum. Points of therapeutic intervention include prevention with micronutrients, antioxidants, and reduced light exposure ; antiangiogenesis; destruction of CNV [8,18-23]; antiinflammatory agents; surgical removal of membranes [24-27]; and macular translocation . The morphologic features of AMD give little hope that surgery (submacular membranectomy) will be of much benefit.
Supported in part by the Independent Order of Odd Fellows, Winston-Salem, NC and the Macula Foundation, New York, NY.
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