Chapter 30 Pathogenesis of Serous Detachment of the Retina and Pigment Epithelium
Retinal detachment is defined as the accumulation of fluid between the neurosensory retina (NSR) and the underlying retinal pigment epithelium (RPE) in the remnant of the embryonic optic vesicle. Retinal pigment epithelial detachment (PED) results from a separation between the RPE basement membrane and the inner collagenous layer of Bruch’s membrane.1,2 These abnormalities imply a dysfunction of the RPE that may be caused by choroidal or retinal diseases or both.
The blood–retinal barrier (BRB) is a particularly restrictive physiological barrier that regulates the flow of nutrients, metabolic waste products, ions, proteins, and water flux into and out of the retina. The main component is the RPE, a single polarized monolayer of cells that forms the outer BRB (the inner BRB being formed of tight junctions between retinal capillary endothelial cells). The outer BRB is located at the tight junctions between the apical lateral membranes of the RPE cells. Its integrity is fundamentally important for the health and integrity of the inner retina.3
It is believed there are structural connections between the RPE and Bruch’s membrane. The inner portion of Bruch’s membrane is the basement membrane of the pigment epithelial cells, to which the cells adhere. Local electron-dense areas can be seen in this basement membrane, and it is thought these represent sites of insertion of collagen fibers from the inner collagenous layer of Bruch’s membrane into the basement membrane. The outer limit of Bruch’s membrane is the basement membrane of the choriocapillaries, the collagenous and elastic layers lying in front.
The choriocapillaris is a continuous plexus of large capillaries (50 µm in diameter) that lie in a single plane beneath the RPE. The wall of the choriocapillaris facing Bruch’s membrane is fenestrated with circular openings (fenestrae) measuring approximately 800 Å. The fenestrae of the choriocapillaries are unique in that they have a diaphragm covering them, unlike those seen in the renal glomerulus.
These fenestrae allow easy movement of large macromolecules into the extracapillary compartment. Fluid and macromolecules escaping from these leaky vessels percolate through Bruch’s membrane and have access to the basal side of the RPE.4
The RPE plays a critical role in the visual cycle and photoreceptor outer-segment phagocytosis. Futhermore, it is the main transport pathway between the inner retina and the choriocapillaris.5 The mechanisms by which the retina is normally maintained in apposition to the pigment epithelium, and the pigment epithelium to Bruch’s membrane, have not been defined, although many factors have been identified. Mechanical and metabolic factors intervene in the attachment from the RPE to the photoreceptors on one side and to Bruch’s membrane on the other side.
The physiological mechanisms of adhesion of the neural retina to the RPE are highly synergistic and complex and involve mechanical and metabolic factors.6 Briefly, these include the active and passive metabolism of the RPE, the properties of the interphotoreceptor matrix (IPM), and established pressure gradients between the retina and choroid.
The IPM occupies the interface between the photoreceptor outer segments. It is composed of glycoproteins, proteoglycans, and glycosaminoglycans.8 This matrix may act as a glue binding the NSR and the RPE. Cones and rods are surrounded by a specialized matrix.9 The IPM also has structural components that remain attached to both the RPE and the cones and become apparent when the RPE is peeled off.10,11
Cell adhesion molecules or receptors may be involved in this interaction between the matrix and the cellular membranes.12 Factors that affect the physicochemical properties of the IPM and enzymes that degrade some of its components such as proteoglycan-degrading enzymes (given intravitreally or directly into the IPM in primate eyes) weaken retinal adhesion.13 Similarly, hyaluronidase and neuraminidase degrade chondroitin sulfate proteoglycan and sialoglycoconjugates, respectively. This decreased adhesion suggests that the IPM plays a role in normal retina–RPE adhesion.14
The mechanism by which interdigitations of RPE apical villous processes and photoreceptor outer segments contribute to retinal adhesion is not yet clear. They play a crucial role in disc phagocytosis and renewal, but their role in adhesion is uncertain.15 They may provide a frictional resistance or an electrostatic force that opposes separation, but the magnitude of this is unknown.15 However, three mechanisms have been proposed. These include the continuous process of phagocytosis of photoreceptor outer segments by RPE cells during which the two cells are intimately connected,16 the frictional forces that result from the interdigitations and the possible presence of electrostatic interaction between the cell membranes.17
Passage of fluid from the vitreous, across the retina and RPE, and out of the SRS is associated with a pressure gradient from the vitreous. Mechanical forces include active transport across the RPE, and passive hydrostatic and oncotic forces. It has been generally considered that the hydrostatic pressure in the choroid is higher than in the neuroretina; however, most evidence suggests that the reverse is true. Hydrostatic and osmotic forces drive fluid towards the choroid (by active transport across the RPE and by passive hydrostatic and oncotic forces), which is blocked in the normal eye by the RPE tight junction barrier.
The high oncotic pressure in the choroid, when compared to the vitreous, maintains the necessary fluid dynamics for intact retinal attachment in causing outward movement of the water. In addition, osmolarity modifies the spontaneous resolution speed in experimental nonrhegmatogenous retinal detachments induced by subretinal injection.
Formed vitreous acts in maintaining adhesion between the retina and RPE.18 Whether the vitreous plays a direct role in retinal adhesion is yet to be determined, although some studies suggest the physical structure of the vitreous might be of importance in maintaining retinal apposition.18,19
Retinal adhesion is markedly decreased after death20,21 and is restored with oxygenation.22 This can either be due to the effect of released RPE lysosomal enzymes on IPM23 or due to the effect of ischemia on active RPE fluid transport.24 The importance of metabolic factors in retinal adhesion is also inferred from the effect of many drugs that interfere with the pH and RPE fluid transport activity.
The RPE actively transports water from the SRS to the choroid. This active transport, as well as dehydrating the SRS, is a crucial factor in maintaining adhesion. RPE fluid transport is normally limited by the retina, which resists water flow from the vitreous. Fluid exits the eye through the trabecular meshwork; however, a small proportion tends to exit from the vitreous to the choroid by virtue of the intraocular and choroidal oncotic pressures.25
In addition, the high osmotic pressure in the choroid causes outward movement of water.26–28 Also, the RPE is constantly moving ions toward the choroid with the associated movement of water.29
This constant water movement induces the apposition of the tissues. In human fetal (hf) RPE cells, acute exposure to interferon (IFN)-γ increased net transepithelial fluid absorption from the retinal to the choroidal side of the tissue. In addition, the IFN-cystic fibrosis transmembrane conductance regulator (CFTR) pathway in RPE is also activated by nitric oxide, which is continually produced in large amounts by the inner retina and perhaps by the choriocapillaris. Therefore, normal retinal metabolism helps dehydrate the SRS and maintain a close anatomical relationship between the photoreceptors and RPE.
The retina will stay attached whether or not the RPE is intact, but retinal function requires the RPE barrier. Clinical serous detachments are unlikely to form solely as a result of small RPE defects or leaks, since the active and passive transport systems for removing subretinal fluid are both strong. The primary pathology in most cases of serous retinopathy is a diffuse metabolic or vascular abnormality of RPE fluid transport, and RPE defects or leaks are necessary, but only secondary, components of the disease.32
The development of a retinal PED is related to disorders in fluid outflow between the sensory retina and Bruch’s membrane.33 The normal nonvascular nature of Bruch’s membrane is due to suppression by RPE of inward growth of choroidal blood vessels. This change occurs in response to aging. The stimulus to change in growth factor production by RPE is unknown, but it is surmised that it may be due to lack of metabolic supply from plasma as a result of reduced diffusion of material through the thickened Bruch’s membrane, or from reduced oxygen supply consequent upon changes in the choroidal capillaries.34
The pathogenetic theory is that of reduced hydraulic conductivity of Bruch’s membrane. The mechanisms underlying this process are attributed to increased deposition of lipids, enhanced collagen crosslinking, and alteration in the ratio of tissue-dissolving enzymes and their inhibitors. Detachment of the RPE is likely to be the consequence of increased resistance of Bruch’s membrane to water flow due to deposition of lipids.35
In hypotony, in which it is assumed that water movement across the retina is severely reduced, clinically detectable detachment of the neuroretina from the pigment epithelium is extremely rare; it is much more characteristic under these circumstances for fluid to accumulate within the choroid.
In choroidal effusion syndrome, fluid accumulates between the choroid and the neuroretina in the absence of a retinal hole. Accumulation of fluid between the neuroretina and pigment epithelium is most commonly associated with a retinal hole; in this instance the subretinal fluid is thought to be derived from the hyaloid cavity and to enter the SRS through the hole.
A serous detachment will form if there are conditions that drive fluid against the normal gradients into the SRS and that limit its subsequent removal by active and passive transport. As long as the RPE is able to pump the leaking fluid into the choroidal circulation, no fluid accumulates in the SRS and no retinal detachment occurs. However, if the process continues and the normal RPE pump activity becomes overwhelmed, or if the RPE activity decreases because of RPE loss or decreased metabolic supply (e.g., ischemia), then fluid starts to accumulate and a retinal detachment occurs.36 This type of retinal detachment can be also due to accumulation of blood in the SRS (hemorrhagic retinal detachment).
A continued influx and the presence of a reduced absorptive capacity of the surrounding RPE maintain the detachment. Protein will diffuse continuously out of the SRS, and high subretinal protein content will be maintained only if there is continued entry of new fluid with protein.
IFN-γ receptors localized to the basolateral membrane of human RPE inhibit, when activated, cell proliferation and migration, decrease RPE mitochondrial membrane potential, alter transepithelial potential and resistance, but also significantly increase transepithelial fluid absorption. In vivo experiments showed that IFN-γ can remove extra fluid deposited in the extracellular or SRS between the retinal photoreceptors and RPE.5 Removal of this extra fluid can be blocked by a combination of inhibitors injected into the SRS. In addition, the IFN-CFTR pathway in RPE is activated by nitric oxide, which is continually produced in large amounts by the inner retina and, perhaps, by the choriocapillaris. IFN-γ regulates retinal hydration across the outer BRB, helps dehydrate the SRS, and maintains a close anatomical relationship between the photoreceptors and RPE.37
When the retina separates from the RPE secondary to retinal detachment of any type, the outer retina becomes ischemic due to loss of its blood supply from the choroid. Photoreceptor cell degeneration has been shown to increase as the distance between the RPE layer and the photoreceptor layer increases. The earliest light microscopic manifestations include accumulation of subretinal fluid with loss of photoreceptor outer segments, and if the process persists, the entire photoreceptor cell layer becomes atrophic.38–40
Apoptosis appears to play an important role in the time-dependent photoreceptor cell degeneration that occurs following retinal detachment.41 In cases of chronic detachment, more prominent changes occur, including cystic and macrocystic retinal degeneration, retinal thinning, RPE alterations, demarcation lines, large drusen, choroidal neovascularization (CNV) at the ora serrata, and iris neovascularization secondary to angiogenic factor elaboration by the ischemic detached retina. As the detachment is mostly centered on the macula, the foveal cones at a distance from the RPE are less likely to receive adequate oxygenation and other nutrients from the choriocapillaris. After retinal reattachment, photoreceptor atrophy in the fovea typically occurs after a long duration.42
Subretinal fluid is removed both by active transport across the RPE and by passive hydrostatic and oncotic forces that work most effectively when the RPE barrier has been damaged. Saline subretinal fluid is removed across the RPE into the choroidal space primarily by RPE metabolic activity.43 cGMP, acetazolamide, and hyperosmotic agents experimentally facilitate its resorption. Clinical retinal detachments invariably contain protein, which slows the absorption of fluid. The biochemical interplay between the RPE and the retinal photoreceptors is affected.43
Potential sources of variation in the dynamics of precipitation and resorption of subretinal lipid include the surface area of the source of leakage and its effective pore size, the surface area of the site(s) of resorption, the active fluid and salt resorption capacity of the RPE, the phagocytic activity of the RPE and infiltrating macrophages, and the degree of infiltration of phagocytic cells in the SRS.44
The effects of intraocular pressure, vitreous pressure, and gravity on the resorption of small experimental retinal detachments (blebs) made with Hanks’ solution or autologous serum was shown to be limited to normal subretinal fluid absorption. Neither liquefaction of the vitreous nor retinal weight has a significant influence on fluid absorption.45