—  SHORT COURSE  —

OPHTHALMIC PATHOLOGY FOR THE NON-SPECIALIST


CASE 12 – AGE-RELATED MACULAR DEGENERATION

J. Godfrey Heathcote, M.B.,Ph.D.  —  Janice R. Safneck, M.D.




History
Eye removed post-mortem from an 86-year-old blind woman who died of congestive heart failure

Diagnosis
Age-related macular degeneration (disciform scar)

Histopathology
On gross examination, the retina appears opaque with an irregular elevation in the region of the macula. The centre of the opacity is black.


Case 12, Slide 31 - Age-related Macular Degeneration: Gross photograph showing irregular, elevated opacity with central pigmentation at macula
Case 12, Slide 32 - Age-related Macular Degeneration: Sub-retinal fibrous tissue (disciform scar) at macula containing proliferated retinal pigment epithelial cells.
Case 12, Slide 33 - Age-related Macular Degeneration: Fibrovascular scar with retinal pigment epithelium beneath macula.

On microscopic examination, pathological changes are concentrated in the retina. At the macula the neurosensory retina (NSR) is degenerate with extensive loss of the outer nuclear layer (ONL). Beneath this is a fibrous scar containing considerable numbers of retinal pigment epithelial (RPE) cells arranged focally in a lamellar pattern. Calcific deposits are noted within the scar and there is irregular calcification of Bruch's membrane that is worst adjacent to the optic nerve head. Several small breaks in Bruch's membrane are noted beneath the macula and on either side of the optic nerve head and, in a number of larger breaks, blood vessels are seen extending from the choroid into the scar tissue (choroidal neovascularization, CNV). A convoluted ribbon of basal laminar deposit (BLD) is seen within the scar and this continues under more normal RPE at the margins of the scar. Scattered nodular drusen are seen. On both sides of the eye there is peripheral scarring beneath the RPE that is continuous with nodular drusen. The retinal blood vessels are mildly sclerotic. The optic nerve appears normal apart from some thickening of the pial septa.

Discussion
The prevalence of visual impairment and also of legal blindness (visual acuity =/< 20/200) increases with age.1  In Western countries, age-related macular degeneration (AMD), defined as some degree of visual loss in people over 50 years of age associated with geographical atrophy of the RPE or detachment of the RPE with or without subretinal neovascularization, is a leading cause of irreversible visual loss. Its prevalence rises from 0.2% in the 55-64 year age group to 11.0% in those over 85 years.2  The cause of AMD has not been established but a number of predisposing factors have been identified including chronic exposure to visible light,3  cigarette smoking,4  a positive family history5  and an early artificial menopause.6 

Clinically there are two major types of AMD:

1. Non-exudative ('dry', 'atrophic', 'non-neovascular')
      * accounts for 80-90% of all AMD7 
      * gradual, mild - moderate visual impairment
      * slow, progressive atrophy of RPE and photoreceptors
      * "treated" with aids to low vision
2. Exudative ('wet', 'neovascular')
      * accounts for approx. 10% of AMD7 
      * causes 90% of blindness in AMD7 
      * severe visual loss may develop rapidly
      * associated with RPE detachment and subretinal neovascularization
      * treatable in approx. 10% of cases by laser photocoagulation.

Some understanding of the pathology of AMD is of value to the pathologist who performs an autopsy on an elderly blind person. Often a detailed ophthalmic assessment has been performed on the patient but is not available: the identification of a disciform scar clarifies the case. In the past eyes with disciform scars have been enucleated under the mistaken impression that they harboured choroidal melanomas.8  Nowadays, this occurs infrequently but is still a risk if the scar should develop in an extra-macular location. Occasional cases of exudative AMD are amenable to surgery and a subretinal neovascular membrane (SRNVM) may be received as a surgical pathology specimen.

Although the basic abnormality in AMD has yet to be established, the process is thought to reflect a disturbance in RPE function. In the non-exudative form the RPE cells undergo depigmentation and degeneration with accumulation of cytoplasmic lipid; this is accompanied by progressive loss of photoreceptors and disappearance of the ONL that leads to visual impairment.9  Initially the parafoveal rods disappear, possibly an exaggeration of a normal age-related phenomenon, and this is followed by progressive degeneration of cones around the fovea.10  Ultimately, foveal cones disappear.

In both forms of AMD RPE dysfunction manifests as a deposit of granular PAS-positive material on the inner surface of Bruch's membrane.11  In early studies this material was referred to as basal linear deposit and its extent correlated with the age of the patient and the severity of AMD.11,12  This deposit consists of homogeneous, finely granular material, fibrous banded material with a periodicity of approx. 120 nm, and membranous vesicles located between the plasmalemma of the RPE cells and their basement membrane. The homogeneous substance appears to contain type IV collagen but there is no evidence that the banded material is collagen, despite its resemblance to wide-spacing collagen.13,14  A similar deposit accumulates in the outer collagenous zone of Bruch's membrane with age and contributes to the formation of the intercapillary pillars.15  The introduction of the term basal laminar deposit for this material in later studies has given rise to considerable confusion. Green and Enger16  have suggested that basal laminar deposit be used for material internal to the RPE basement membrane and basal linear deposit be used to describe material located external to the RPE basement membrane and predominantly in the inner collagenous zone of Bruch's membrane. It would seem reasonable to apply the term basal laminar deposit (BLD) to this material whatever its location,17  particularly since the precise location is often difficult to establish on light microscopy. BLD arises from the release of basal portions of RPE cells and it may act as a chemoattractant for the macrophages that can be seen at the edges of breaks in Bruch's membrane in AMD.18  Its presence at the interface of the RPE and the choriocapillaris may disturb the balance of biochemical messengers in this region and contribute to the proliferation of capillaries within the choriocapillaris that extend through breaks in Bruch's membrane to the sub-RPE space.19 

The characteristic histopathological features of exudative AMD include serous detachment of the RPE and/or NSR (found in 68% of eyes with AMD), CNV (38%) and atrophy of the RPE (37%).16  The organization of serous and hemorrhagic detachments of the RPE and NSR in association with CNV gives rise to a fibrous disciform scar at the macula. This is found in 41% of eyes with AMD and varies from a thin, avascular layer of fibrous tissue beneath the RPE to a dome-shaped mass of fibrovascular tissue showing dystrophic calcification and even metaplastic bone.16  In Green and Enger's series of 760 eyes with AMD, there were 310 scars ranging in diameter from 0.1-20.0 mm (mean 3.73 mm) and in thickness from 0-4.0 mm (mean 0.27 mm).16  RPE hyperplasia was a prominent feature in 9.0% of these scars and a band of RPE and BLD may be seen in the centre of the scar. Accompanying these changes there was extensive and often total atrophy of the photoreceptor cells, with only 5% of eyes showing no loss of the ONL. Macular cysts in the NSR were seen in 2.6% of eyes.16 

The cause of the breaks in Bruch's membrane and the stimulus to CNV are two key questions in the pathogenesis of AMD. The occasional presence of multinucleated giant cells on both surfaces of Bruch's membrane adjacent to the breaks suggested a role for inflammatory cells in this process. Bruch's membrane contains tissue inhibitor of metalloproteinases-3 (TIMP-3) and a mutation in the gene for this protein has been detected in Sorsby's fundus dystrophy, a rare disease associated with early-onset CNV.20  Since TIMP-3 has anti-angiogenic properties21  an inactive mutant form may lead to proteolysis of Bruch's membrane, release of angiogenic factors and CNV. However, no mutations in the gene for TIMP-3 have yet been identified in AMD.22  TIMP-3 inhibits the migration of human endothelial cells in response to vascular endothelial growth factor (VEGF)21  and expression of VEGF by macrophages and RPE cells is increased in an experimental model of CNV induced by laser photocoagulation.23  Increased levels of VEGF have been detected in human eyes with subretinal neovascular membranes.24  Mutations in a gene termed ABCR have now been identified in Stargardt disease, a juvenile form of macular degeneration, as well as classical AMD.25 

Subretinal neovascular membranes may develop in humans following inappropriate laser photocoagulation, in the presumed ocular histoplasmosis syndrome, in severe myopia and in association with choroidal naevi. In recent years surgical excision of these membranes has been undertaken in carefully selected patients, often with improvement in visual acuity.26  Pathological examination of the excised membranes has not revealed evidence of significant damage to the NSR although photoreceptor elements may be associated with the fibrovascular scar.27  Fibroblasts and RPE cells are the principal cellular elements and BLD may be present. Attempts to replace damaged RPE by transplantation of human fetal RPE following removal of SRNVMs are in progress.28 

Drusen represent a heterogeneous group of degenerative changes of the RPE - choriocapillaris complex and have been classified morphologically into 4 types.29  Alone they are not sufficient for a diagnosis of AMD but they are one of the earliest features to be clinically detectable.
i Hard drusen are small, discrete, hyaline, nodular deposits beneath the RPE that are PAS-positive. Although they may be associated with pigmentary changes, their number does not increase significantly with age and they do not predispose to CNV.30  Hard drusen are often most obvious beneath the peripheral RPE but they are also seen in the macula.
ii Soft drusen, larger and with poorly defined edges, represent small detachments of the RPE over pale, granular, eosinophilic material.30  They increase in number with age and are associated with CNV and atrophy of the RPE.16 
iii Dffuse drusen is the name given to BLD (although basal linear deposit according to the terminology of Green)16  and, as discussed above, this material is a key feature of AMD.
iv Papillary drusen are the lobulated structures generally associated with chronic inflammatory or degenerative diseases, including retinal detachment and phthisis bulbi.

Retinitis Pigmentosa
Disciform scars may occur in an extra-macular location and, if pigmented, may mimic choroidal melanoma. Pigmentary changes may develop within the NRS from other causes, the most important of which is retinitis pigmentosa. This term refers to a large group of inherited retinal diseases characterised by a progressive loss of photoreceptor function and the migration of RPE cells to surround blood vessels within the NRS.31  The degenerate retina is said to show "bone spicule pigmentation" and this is most pronounced in the mid-periphery.

References

  1. Rubin GS, et al. A comprehensive assessment of visual impairment in a population of older Americans. The SEE study. Invest Ophthalmol Vis Sci 1997;38:557-568.
  2. Vingerling JR, et al. The prevalence of age-related maculopathy in the Rotterdam study. Ophthalmology 1995;102:205-210.
  3. Taylor HR, et al. The long-term effects of visible light on the eye. Arch Ophthalmol 1992;110:99-104.
  4. Smith W, et al. Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology 2001;108:697-704.
  5. Klaver CCW, et al. Genetic risk of age-related maculopathy. Population-based familial aggregation study. Arch Ophthalmol 1998;116:1646-1651.
  6. Vingerling JR, et al. Macular degeneration and early menopause: a case-control study. BMJ 1995;310:1570-1571.
  7. Ferris III, FL, Fine SL, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol 1984;102:1640-1642
  8. Berkow JW, Font RL. Disciform macular degeneration with subpigment epithelial hematoma. Arch Ophthalmol 1969;82:51-56.
  9. Green WR. Age-related macular degeneration. In "Ophthalmic Pathology: An Atlas and Textbook". Ed., Spencer WH, 4th Ed. 1996, pp 982-1050.
  10. Curcio CA, Medeiros NE, Millican CL. Photoreceptor loss in age-related macular degeneration. Invest Ophthalmol Vis Sci 1996;37:1236-1249.
  11. Sarks, SH. New vessel formation beneath the retinal pigment epithelium in senile eyes. Br J Ophthalmol 1973;57:951-965.
  12. Sarks SH. Ageing and degeneration in the macular region: a clinico-pathological study. Br J Ophthalmol 1976;60:324-341.
  13. van der Schaft TL, Mooy CM, de Bruijn WC, Bosman FT, de Jong PTVM. Immunohistochemical light and electron microscopy of basal laminar deposit. Graefe's Arch Clin Exp Ophthalmol 1994;232:40-46.
  14. Marshall GE, Konstas AGP, Reid GG, Edwards JG, Lee WR. Collagens in the aged human macula. Graefe's Arch Clin Exp Ophthalmol 1994;232:133-140.
  15. Killingsworth MC. Age-related components of Bruch's membrane in the human eye. Graefe's Arch Clin Exp Ophthalmol 1987;225:406-412.
  16. Green WR, Enger C. Age-related macular degeneration histopathologic studies. Ophthalmology 1993;100:1519-1535.
  17. van der Schaft TL, et al. Histologic features of the early stages of age-related macular degeneration. Ophthalmology 1992;99:278-286.
  18. Killingsworth MC, Sarks JP, Sarks SH. Macrophages related to Bruch's membrane in age-related macular degeneration. Eye 1990;4:613-621.
  19. Spraul CW, Lang G, Grossniklaus HE. Morphometric analysis of the choroid, Bruch's membrane and retinal pigment epithelium in eyes with age-related macular degeneration. Invest Ophthalmol Vis Sci 1996;37:2724-2735.
  20. Fariss RN, Apte SS, Olsen BR, Iwata K, Milam AH. Tissue inhibitor of metalloproteinases-3 is a component of Bruch's membrane of the eye. Amer J Pathol 1997;150:323-328.
  21. Anand-Apte B, et al. Inhibition of angiogenesis by tissue inhibitor of metalloproteinase-3. Invest Ophthalmol Vis Sci 1997;38:817-823.
  22. Felbor U, Doepner D, Schneider U, Zrenner E, Weber BHF. Evaluation of the gene encoding the tissue inhibitor of metalloproteinases-3 in various maculopathies. Invest Ophthalmol Vis Sci 1997;38:1054-1059.
  23. Ishibashi T, et al.Expression of vascular endothelial growth factor in experimental choroidal neovascularization. Graefe's Arch Clin Exp Ophthalmol 1997;235:159-167.
  24. Wells JA, et al. Levels of vascular endothelial growth factor are elevated in the vitreous of patients with subretinal neovascularization. Br J Ophthalmol 1996;80:363-366.
  25. Allikmets R, et al. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science 1997;1805-1807.
  26. Lambert HM, et al. Surgical excision of subfoveal neovascular membranes in age-related macular degeneration. Amer J Ophthalmol 1992;113:257-262 .
  27. Lopez PF, et al. Pathologic features of surgically excised subretinal neovascular membranes in age-related macular degeneration. Amer J Ophthalmol 1991;112:647-656.
  28. Algvere PV, et al. Transplantation of RPE in age-related macular degeneration: observations in disciform lesions and dry RPE atrophy. Graefe's Arch Clin Exp Ophthalmol 1997;235:149-158.
  29. Tso MOM. Pathogenetic factors of aging macular degeneration. Ophthalmology 1985;92:628-635.
  30. Coffey AJH, Brownstein S. The prevalence of macular drusen in postmortem eyes. Amer J Ophthalmol 1986;102:164-171.
  31. Li Z-Y, Possin DE, Milam AH. Histopathology of bone spicule pigmentation in retinitis pigmentosa. Ophthalmology 1995;102:805-816.