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.

Mechanical factors

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.

Adhesion

Mechanical forces inside the subretinal space (SRS) include the matrix material between the NSR and RPE and the complex anatomical relationship with the outer segments of the photoreceptors.⁷

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

Pressure gradient

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

Metabolic factors

Metabolic factors that affect retinal adhesion are intricate.

Oxygenation

Retinal adhesion is markedly decreased after death ^20,²¹ 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.

Water movement

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.

An inward movement of fluid from the choroid into the vitreous could lead to retinal separation from the RPE because of retinal resistance to flow.^30,³¹

Mechanisms of impairment

Impairment of water movement

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.

An intricate synergy of these factors is primarily responsible for maintaining retinal adhesion under normal conditions.

Occurrence of detachment

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.

Most subretinal fluid is absorbed rapidly by active transport across the RPE. However, in the presence of damage to the RPE BRB, subretinal fluid is rapidly cleared by passive forces.

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

Persistence and resorption of serous detachments

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

Clinical manifestations of PED and serous retinal detachments

Serous detachments, with elevation of the retina, occur in a variety of diseases. Regardless of the mechanism, all types of retinal detachment have one characteristic in common, the accumulation of subretinal fluid. Exudative, transudative, or serous retinal detachments (SRD) are characterized by fluid accumulation in the SRS in the absence of retinal breaks or traction.

The source of the fluid is the vessels of the choroid, or the retina, or both. This can occur in a variety of vascular, inflammatory, or neoplastic diseases of the retina, RPE, and choroid ⁴⁶ in which fluid leaks outside the vessels and accumulates under the retina. It is suggested that the primary pathology in most serous retinopathy is a diffuse metabolic or vascular abnormality of RPE fluid transport, and that RPE defects or leaks are necessary but only secondary components of the disease.

Serous detachment of the neuroretina is observed under multiple circumstances: vascular diseases include malignant hypertension, toxemia of pregnancy, retinal vein occlusion, Coats’ disease, retinal angiomatous diseases, and different forms of CNV, including polypoidal choroidal vasculopathies. It is a characteristic of central serous retinopathy, which appears to be associated with focal dysfunction of the RPE secondary to dysregulation of the choroidal vasculature. Detachment of the retina from the RPE is also seen in primary choroidal disorders such as tumors, choroidal inflammation, ischemia, and in a variety of other conditions falling into the category of choroidal effusion syndrome.

Accumulation of fluid between Bruch’s membrane and the RPE is seen consistently in only one situation, PED. This occurs in the young as a manifestation of central serous retinopathy and in the elderly as a manifestation of age-related macular disease (AMD).

Serous retinal detachment associated with choroidal dysregulation

Central serous chorioretinopathy

The separation of the outer segments of photoreceptors from the RPE by subretinal fluid should slow down the exchange of all-trans and 11-cis retinal. The RPE–photoreceptor visual cycle serves mainly the rods, and cone function is supported by a separate visual cycle within the sensory retina,⁴⁷ and is thus less affected by the separation from the RPE.

Central serous chorioretinopathy (CSC) is a disease in which the NSR becomes detached, supposedly due to a single or multiple focal lesions within the RPE, which leaks into the SRS overlying dysregulation of the choroidal vasculature. With indocyanine green angiography (ICGA), it has been demonstrated that CSC primarily affects the choroidal circulation and causes multifocal areas of choroidal vascular hyperpermeability.^48,⁴⁹ PED shown by biomicroscopy, fluorescein angiography (FA), ICGA, and optical coherence tomography (OCT) can be seen in early stages of CSC, under the SRD. The location of these PEDs is the same as the location of the leakage in FA. Spontaneous resolution is the usual outcome.⁵⁰ The serous detachment extends significantly beyond the leak if the tight junctional RPE barrier under the elevated retina (except directly over the areas of leakage) is intact, since fluid would otherwise leave under hydrostatic and osmotic pressure.⁵¹

Chronic forms of CSC, defined as a persistent choroidal anomaly demonstrated on ICGA, are not the rule. In those cases, PEDs do not always accompany an SRD.⁵² ICGA has demonstrated the presence of “multiple presumed occult” PEDs in both acute and chronic stages.⁵³

There are multiple theories on the origin of CSC, none of which has been completely demonstrated. Neither RPE nor choroidal dysfunction can be effectively pointed out as the sole causative mechanism. The leakage rate corresponds to bulk fluid flow, rather than secretion and diffusion,⁵⁴ which indicates that the underlying choroid is possibly responsible and not the RPE. Focal areas of hyperpermeability visualized as tiny punctuate spots in the inner choroid may be involved in the development of SRD.⁵⁵ During the period of time in which the retina remains detached, many events occur which have to do with the change in metabolism and intercellular processes. The outer segments of photoreceptors overlying the detached area are no longer phagocytosed, the photoreceptors elongate,⁵⁶ and finally, outer segments begin to accumulate, resulting in the deposit of multiple dot-like yellow precipitates and material. This material is demonstrated by high reflectivity on OCT and hyperautofluorescence.⁵⁷ The autofluorescent fluorophores in the photoreceptor outer segments may be concentrated in precipitates or settled into the inferior SRD.⁵⁸ These could correspond to the recently described acute hypertrophic outer retinal changes.⁵⁹

The structure of the detached NSR in eyes with CSC remains preserved.⁶⁰ Photoreceptor apoptosis has been postulated as implicated in visual function in CSC, since apoptosis has been reported in experimental retinal detachment and human retinal detachment within a few days.⁶¹

Upon resolution the fluid will be reabsorbed rapidly for water and ions, whereas macromolecules will remain in the SRS and precipitate. After a long resolved episode, a hyperautofluorescent aspect remains on retinal imaging.⁶²

The high protein content of serous detachments, which is caused by oncotic pressure, has been put forward as an explanation for why subretinal fluid forms and persists in CSC. It is this continued influx, and the presence of a reduced absorptive capacity of the surrounding RPE, that maintains the detachment. Protein entering the SRS can be sequestered and concentrated by fluid absorption, but it does not directly cause or maintain the detachment. Although fluid absorption across the RPE is compromised, the underlying pathology appears often to be choroidal vascular disease.⁶³

Age-related macular degeneration

In the early stages of age-related macular degeneration (AMD), inflammation may help keep the RPE barrier intact by preventing RPE proliferation and migration, and, at the same time, choroidal cell growth may increase blood flow to the retina and the clearance of pathogens or drusen.

In chronic inflammatory diseases such as in AMD, the IFN-induced dehydration of the SRS would increase the activity of already accumulating chemokines and, thereby, help draw monocytes and neutrophils across the RPE to the SRS. Inhibition of RPE proliferation and migration by IFN also protects and maintains the RPE barrier. However, over long periods of unresolved inflammation, chronic exposure to IFN and other cytokines (e.g., interleukin-1 and tumor necrosis factor) could induce a significant decrease in transepithelial paracellular resistance and the loss of transport potential (fluid absorption).

These persistent changes, coupled with an IFN-driven increase in choroidal cell proliferation, suggest a pathway for the entry of choroidal neovascular blood vessels into the SRS via the RPE tight junctions. Neovascular AMD results in an alteration of the outer BRB. These mechanisms provide a possible basis for understanding the role of inflammation in CNV and AMD.

Serous retinal detachment in idiopathic polypoidal choroidal vasculopathy

Idiopathic polypoidal choroidal vasculopathy (PCV) is a distinct exudative disorder in which the SRD is thought to be of choroidal origin.⁶⁴ PCV is a disease in which the primary abnormality involves the inner choroidal circulation, where thin capillary vessels dilate within Bruch’s membrane, immediately under the RPE, where they form cavernous vascular channels.⁶⁵ It is distinguishable from more typical proliferations of abnormal choroidal vessels.⁶⁶

PCV is caused by inner choroidal vessel abnormalities, not CNV.⁶⁷ These lesions cause serosanguineous RPE detachments via damage to the overlying Bruch’s membrane and/or RPE The histopathological findings suggest that these lesions can be more accurately considered as a degenerated RPE–Bruch’s membrane–choriocapillaris complex and inner choroid dilated venules and arterioles, rather than an intra-Bruch’s fibrovascular membrane.⁶⁸ Both CNV and vascular polyps have been identifed as hyperreflectivity between RPE and Bruch’s membrane, in the same tissue plane as CNV.⁶⁹ It has been suggested that the underlying mechanism in these lesions is related to atherosclerosis.⁷⁰

The juxtaperipapillary lesions resemble small serous PEDs on biomicroscopy, and are visible on ICGA as hyperfluorescent nodules in early phases with a “washout” effect on very late phases.⁷¹ Multifocal choroidal hyperfluorescence might be one of the risk factors of PCV.⁷⁰ These PEDs regress incompletely and may recur despite treatment with photodynamic therapy or bevacizumab.⁷¹ About one-third of patients have PCV lesions that resemble CNV both clinically and angiographically.

Serous retinal detachment in uveitis: exudative retinal detachment

During inflammation, loss of the BRB and a diminished outflow of the choroid and choriocapillaris result in the accumulation of liquid in the SRS. The sustained pressure exerted from the choroid is responsible for the accumulation of fluid between the RPE and the retina and then may evolve into edema of the inner retinal layers, resulting in cystoid or diffuse macular edema.

Later, when more inflammatory damage develops and/or fluid volume increases, retinal resistance may become insufficient, and the fluid may enter the neuroretinal tissue and form cysts. The transient aspect of a subfoveal SRD in uveitis and favorable response to treatment support this hypothesis. A subfoveal SRD may also be documented in patients with normal neuroretinal tissue and without edema.⁷²

In the acute phase of Vogt–Koyanagi–Harada disease, fluorescein angiography has shown increased permeability of the chorioretinal vessels and of the BRB, and delayed circulation of the choriocapillaris.^73,⁷⁴

NSR serous detachment of the macula resulting from focal retinochoroiditis has been reported previously in patients with Bartonella-associated neuroretinitis. SRD may precede the formation of a macular star in a minority of patients with neuroretinitis.⁷⁵ The macular exudates may take months to resolve.⁷⁶

Detachment of retinal origin

Serous retinal detachment in diabetic retinopathy

Diabetic macular edema (DME) is thought to be caused by hyperpermeability in the retinal vasculature, leading to dysfunction of the neuroglial cells and concomitant visual disturbance. Macular SRD occurs in 15–30% of patients with diabetic maculopathy.^77,⁷⁸ SRD in DME is diagnosed on OCT even when the neuroretinal tissue above the SRD is normal.⁷⁹ Retinal functionality in these types of SRD is controversial.⁸⁰ It has been reported that macular SRD in diabetic patients is more often correlated with high levels of HbA1c, and that this might break both the inner and the outer BRB.⁸¹

Transient SRD may represent a step in the process of macular edema absorption. Its evolution is not related to the severity of DME, and it sometimes disappears before resorption of retinal fluid. The elongation of the photoreceptors is not visualized in diabetic retinopathy-associated SRD, suggesting that the pathogenesis of this disease might be different.⁸² The high protein content of the fluid in these SRDs could alter the oxygenation and elimination of metabolites from the photoreceptor layer, thus decreasing retinal sensibility.

The involvement of the RPE is also thought to play a role in the hydrodynamics of fluid accumulation into the SRS, where hypoxia might impede its normal pump function. RPE impairment has already been proven in human and experimental diabetes.⁸³ Thus SRD in diabetic maculopathy is linked not only to the limited drainage of the vascular system (both retinal and choroidal) but also to impairment in the function of the RPE.

Severe retinal detachment in central or branch retinal vein occlusion

Severe retinal vein occlusion may be accompanied by extensive SRD.⁸⁴ SRD can be demonstrated in approximately 80% of central retinal vein occlusion patients with cystoid macular edema.⁸⁵ It appears that SRD is more frequent in major branch retinal vein occlusion (BRVO) than in macular BRVO.⁸⁶ In cases of major BRVO, a positive correlation with vascular endothelial growth factor and the presence of SRD has been reported.⁸⁷ The major complication of serous detachment is the deposit of macular hard exudates, which may result in poor visual outcome.⁸⁸