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PATHOGENESIS OF AGE-RELATED MACULAR DEGENERATION
RAHUL A SHROFF
Shroff Eye Clinic, 86B, Netaji Subhash Road, Mumbai 400 002.
Drusen, retinal pigment epithelial (RPE) detachment and subretinal neovascularization are important clinical findings in macular degeneration. This review article outlines the pathogenesis based on experimental and clinical studies of macular degeneration.
INTRODUCTION
Most Ophthalmic investigators attribute age-related macular degeneration to a genetically compromised retinal pigment epithelium (RPE) adversely affected by environmental pressure.[23] Several candidate genes have been proposed[24] and the search is on for more. Photic stress,[25] dietary deficiency of antioxidants,[26,27] and cardiovascular risk factors have been implicated as pathogenetic.
PIGMENT EPITHELIAL DETACHMENT
It was originally considered that RPE detachment was induced by weakening of the physical attachment of the pigment epithelium to Bruch’s membrane by accumulation of debris on the inner surface of Bruch’s.[1] The RPE detachment then followed due to passive movement of fluid from the choroid through Bruch’s membrane into the subpigment epithelial space.[2]
Alternatively, Gass[3] postulated that fluid might be derived from blood vessels that grow on the inner surface of Bruch’s membrane. These vessels may be obscured by subretinal fluid such that they may not always be evident on fluorescein angiography. However, the data suggest that subpigment epithelial neovascularization, though common, is not universal in pigment epithelial detachments.[4]
Recently, it has been suggested that fluid in the subpigment epithelial space may be derived, at least partly, from the pigment epithelium rather than from the choroid. Fluid crosses the RPE from the neurosensory retina toward Bruch’s membrane as a result of active transport of ions, such that some of the fluid must be derived from the pigment epithelium.[5] As the Bruch’s membrane becomes thicker with age, there is an increase in the resistance to water flow resulting in fluid accumulation in the subpigment epithelial space. The resistance to fluid flow is resulting in fluid accumulation in the subpigment epithelial space. The resistance to fluid flow is further compromised by deposition of non-polar neutral lipid on the inner surface of Bruch’s membrane. Recently, analysis has shown that lipid extracted from Bruch’s membrane increases with the age of the donor and the total quantity and ratio of neutral fats to phospholipids varied over the age of 60 years.[6]
The lipid content of drusen may be identified by fluorescein angiography. Deposits containing predominantly polar phospholipids were hydrophilic allowing the entry of water soluble eye resulting in hyperfluorescence on fluorescein angiography, while neutral lipids were hydrophobic so the dye could not enter the tissues resulting in hypofluorescence.[7]
It is believed that RPE detachments that are destined to tear tend to become progressively larger and more highly detached, generating sufficient tangential stress to cause a rupture[8] implying that these lesions are highly resistant to water flow across the Bruch’s membrane. These lesions are hypofluorescent on fluorescein angiography, the drusen being hydrophobic and limiting entry of fluorescein into the lesion.
Evidence to data suggests that detachment of the pigment epithelium from Bruch’s membrane is initiated by active pumping by the pigment cells in the presence of high resistance to water flow at the level of Bruch’s membrane and that subpigment epithelial neovascularization occurs as secondary phenomenon in the sequence of events. Even if subpigment epithelial blood vessels contribute to the detachment, they would not do so unless Bruch’s membrane became hydrophobic.[9]
Clinical phenomena, namely loss of sensitivity, slow dark adaptation, and changes in the choriocapillaris indicate the presence of diffuse deposits, which are sufficiently thick and hydrophobic due to the presence of neutral fats. These impair the free diffusion through Bruch’s membrane of large molecule complexes as they pass from the choriocapillaris to the RPE, thus impairing the metabolic exchange between the choroid and retina.[10] These clinical observation support the concept of change in hydraulic conductivity of Bruch’s membrane with age leading to a reduction of water movement and metabolic exchange between the RPE and choriocapillaris.
Pathogenesis of Drusen
During life, the RPE cells continuously ingest debris, particularly receptor outer segments, which in time, virtually fill a cell. Studies described RPE apoptosis,[11] a process by which cells cast off a part of their cytoplasm leading to formation of drusen. This is supported by studies of primate retina,[12,13] which describe several stages of RPE budding protruding into the RPE space that lead to formation of drusen. The buds were surrounded by a basement membrane containing organelles and showed cytoplasmic continuity with the parent cell. The cytoplasm showed various stages of degeneration ranging from clearly cytoplasmic to drusenoid in appearance.[14] Although the connection between drusen and subretinal neovascularisation is one of associations, both processes involved degenerative changes of the RPE.
PATHOGENESIS OF SUBRETINAL NEOVASCULARISATION
Recent studies by Glaser and co-workers have suggested the importance of the RPE in the development of subretinal neovascularisation. They report that-1. Retinal pigment epithelial cells release factors that inhibit growth of vascular endothelial cells.[15]
2. Substances derived from the retina stimulate the growth of RPE cells, Fibroblasts[16] and vascular cells.[17]
3. The vitreous of patients with proliferative vitreoretinopathy contains factors that stimulate RPE cell migration.[18] Normal vitreous causes RPE cells to transform into fibrocyte-like cells. Normal vitreous inhibits stimulation of vascular cells by retinal extracts.[19]
4. RPE cells produce many of the components of Bruch’s membrane, which could act as a barrier to the spread of new vessels from the choroid into the subretinal space.[20]
These findings suggest that choroidal vascular cells, in the absence of a barrier and inhibitory facors released by the normal RPE, may be exposed to mitogenic and chemotaxic retinal factors that stimulate development of subretinal neovascularisation. These influences must be in balance in the normal retina, but diseases of the RPE, inflammation, or breach of Bruch’s membrane may disturb the balance, thereby initiating subretinal neovascularisation. It is not required for Bruch’s membrane to be broken for subretinal neovascularisation. It is not required for Bruch’s membrane to be broken for subretinal neovascularisation to develop. Laser light and subretinal injection of autologous vitreous, treatments that are without obvious effects on Bruch’s membrane, can cause RPE proliferation and subretinal neovascularisation.[21] Laser treatment initiates a mild inflammation, macrophage invasion and RPE proliferation.[22]The macrophages release some of the factors that lead to development of subretinal neovascularisation. Penetration through Bruch’s membrane may result from RPE changes that lead to their proliferation.
Subretinal, neovascularisation, which results in a central disciform scar and loss of central vision, remains a major clinical problem. It is important that studies on subretinal neovascularisation continue so that improved methods of treatment can be designed, probably based on restoration of the natural balance of inhibitory and stimulating factors.
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