Serous PED



Ugo Introini, MD, PhD
Department of Ophthalmology University Vita-Salute Scientific Institute San Raffaele Milano, Italy


Serous PED in AMD


Retinal pigment epithelial detachment (PED) is part of age-related macular degeneration (AMD) clinical spectrum.

Different types of PED have been reported in the literature, related or not with AMD.

Serous PED is defined as an area of sharply demarcated, dome-shaped serous elevation of the retinal pigment epithelium.

In AMD, serous PED is frequently associated with choroidal neovascularisation (CNV).

The presence of this lesion worsens the prognosis of the disease, preluding to the formation of a large disciform scar that ends with a poor visual outcome.

Even though no clear therapeutic indications are so far set for its treatment, the early detection of a serous PED is therefore important for the prognosis and the management of these patients.

The histopathology of a serous PED is consistent with the detachment of the RPE basement membrane along with the overlying retinal pigment epithelium from the remaining Bruch’s membrane by the accumulation of fluid(1).

Retinal pigment epithelium (RPE) monolayer is anatomically located between the external retinal layer, the outer segments apex, and the Bruch’s membrane.

RPE functions, fundamental for the photoreceptors metabolism, include the outer blood-retinal barrier formation and the fluid exchange balance, that physiologically flows from the vitreous into the choroid.

In normal conditions, RPE basement membrane is attached to the inner collagenous layer of Bruch’s membrane.

Although the correct pathology of the serous PED formation is not completely known, there are some evidences concerning AMD aspects that can at least partially explain it.

In AMD, there are degenerative changes in Bruch’s membrane that are likely implicated in the adhesion loss between these two layers and can explain the pathogenesis of the serous PED.

Aging thickening of Bruch’s membrane, more evident in AMD, has been shown to be secondary to accumulation of debris and lipids, most of them phospholipids that greatly decrease its hydraulic conductivity(2,3,4).

Moreover, the localized accumulation of basal linear deposits between the RPE basement membrane and the outer collagen layer of Bruch’s membrane, increases the pathologic damage through the drusen formation(5).

These two facts significantly combine to bring about an hydrophobic barrier that prevent the fluid outflow towards the choroid, that causes liquid accumulation in the subretinal pigment epithelium space(6-9).

In AMD, serous PED can be either associated or not with CNV, although the vascularised sort is by far the most observed.

The formation of soft drusen predispose the progression to advanced AMD, with the development of CNV.

Various theories concerning the relationship between serous PED and CNV have been proposed.

To explain its pathogenesis, firstly Gass theorized the growth of newvessels from the choroid inside the Bruch’s membrane thickness, that actively leak increasing the hydrostatic pressure causing RPE detachment among the less adherent layers(10).

This concept has been later sustained by the evidence that the development of CNV comes with inflammatory mechanisms that add more damage to Bruch’s membrane, supporting RPE separation from the inner collagenous layer(11,12,13).

When the growth of newvessels arises from the inner retina, more recently described as retino-choroidal anastomoses (RCA) or retinal angiomatous proliferation (RAP), it has been hypothesized that the serous PED formation, very frequently associated, can be reconducted to a RPE invasion by the neovascular complex(14-16).

On the contrary, other authors observed that the presence of a PED can represent a pre-existing condition that can promote the CNV’s growth through a further Bruch’s membrane damage, expression of the same disease ongoing(2,17).

Even though the pathogenesis of the PED is not completely understood, from these studies the CNVs’ formation seems to be a pivotal moment.

At fundus examination, a serous PED appears as a round or oval, distinct dome-shaped area of regular detachment of the RPE and the overlying neurosensory retina, yellow to orange color and smooth surfaced.

Margins are typically sharply demarcated; focal RPE atrophy and pigment figures are frequently observed(2,18).

However, the concurrent presence of a CNV can generate a variety of associated ophthalmoscopic aspects, such as hemorrhagic and exudative components, areas of irregular elevation of the RPE and serous detachment of the surrounding neuroretina.

A CNV located at the margin of the PED can vary its shape, resulting in a reniform or notched aspect, or a flat-sided RPE detachment(19).

Serous PED imaging study includes fluorescein angiography (FA), indocyanine green angiography (ICGA) and optical coherence tomography (OCT).

The diagnosis of a serous PED is made with fluorescein angiography.

Examined by FA, a serous PED classically shows an early uniform hyperfluorescence of the entire lesion, slightly delayed compared to the background fluorescence, that progressively increases in brightness as the examination progresses (pooling).

Serous PED’s hyperfluorescence typically does not change in size or shape during the angiographic phases.

FA can also demonstrate the presence of CNV, usually associated to a serous PED as “occult CNV”, like areas of indistinct late subretinal staining, more evident when located at the margin of the RPE detachment or corresponding to the “notch”(18).

The presence of a CNV can be also deducted by the presence of an hemorrhagic component of the PED, the dark meniscus described by Gass(19).

However, a more precise localization of the neovascular component can be obtained with digital ICGA.

Indocyanine green molecule has biophysical properties that, unlike fluorescein, make it useful to enhance vessel’s anatomy through RPE, blood and turbid exudation.

In detail, ICGA enables to better delineate the presence and the type of newvessels associated with a serous PED and for this reason is considered a fundamental tool in the management of this disease(20,-22).

On ICGA, serous PED appears as an hypofluorescent lesion, with sharply delineated margins, that remains constantly hypofluorescent during all the phases of the examination(23).

When the newvessels are not present, no signs of localized hyperfluorescent areas are detectable; the outline of the PED is sharply round and it’s therefore considered a pure serous PED.

In AMD patients, Yannuzzy found an incidence of 4% of non-vascularized PED among serous PED(22).

When the neovascular component is present, it has been suggested the term vascularized PED(22).

Its frequency accounts for approximately 24% of newly diagnosed exudative AMD(24) Newvessels associated with serous PED are represented in different subtypes.

High-speed videoangiography with scanning laser ophthalmoscope appears a precious tool that allows the ophthalmologist to identify the newvessel pattern and their angiographic behavior(25).

To recognize the different types of neovascularization by distinguish angiographic findings is mandatory for the distinct natural course, visual prognosis and specially different response to the treatments of the three main kinds of newvessels associated to serous PED in AMD.

The more common type of newvessels associated with serous PED are those of choroidal origin, or CNV(22,24) (Fig.1).

In the early phases, ICGA shows the CNV’s feeder artery vessel that arises from the choroidal circulation, and subsequently the draining venule.

At the same time the capillary network of the neovascular membrane can be detected.

Unlike fluorescein, indocyanine green leaks slightly and the CNV’s hyperfluorescence is usually minimal, with the exception of some cases that show an intense leakage, considered as very active CNV.

Frequently, in the late phases, a well-defined area of mild hyperfluorescence corresponding to the CNV network can be appreciable.

The second type of newvessels that complicate serous PED are the so-called retinal angiomatous proliferations (RAP) or more recently type 3 neovascularization(15,26-28).

These vascular lesions, as reported by various authors, are referred to invade the outer retina and to involve the RPE, through a progression that, to the best of our knowledge, has been hypothesized to originate from either the retinal circulation or the choroid.

ICGA shows the presence of a “hot-spot”, due to the early hyperfluorescence of the intraretinal neovascular complex, that increases during the angiography, with an intense leakage in the late phases.

Its brightess is enhanced by the surrounding hypofluorescence of the underlying PED (Fig. 2).

Hallmark of the RAP, the neovascular complex is typically connected with one or more retinal vessels, tortuous and dilated, that suddenly deepen toward the vascular lesion(15,26,29).

Single or multiple, the RAPs origin are classically extrafoveal, and an intraretinal hemorrhage corresponding to the neovascular lesion is frequently observed(26).

The third type of newvessels associated with serous PED in AMD is consistent with polypoidal choroidal vasculopathy (PCV)(30).

PCV is a peculiar form of choroidal neovascularization, characterized by the presence of orange, aneurismal, polyp-like round dilatations at the border of a branching vascular network from choroidal origin.

Although PCV afflicts more frequently middle-age black and Asian populations, its clinical spectrum is expanded to whites, where it has been found to be present in 8-13% of patients with concomitant AMD lesions.

In these cases, when the manifestations attributable to both PCV and AMD are present, some authors consider PCV as a subtype of CNV in AMD(30,31).

Hemorrhagic manifestation are common in patients with PCV.

Serous PED associated with PCV show frequently a blood level in the lower portion of the detachment. ICGA is the state-of-the-art examination to distinguish the typical features of the two vascular components.

The vascular network is characterized by the presence of one or more aneurismal lesions that show a bright fluorescence since the early phases, followed in the late phases by a clearing of the dye, called “wash-out”, typical of this disease (Fig. 3).

Nevertheless, some polyp-like structure can actively leake showing late staining of their walls and surrounding exudation.

The polypoidal lesions are usually located at the margin of the serous PED(32). Recognition of these lesions appears fundamental because clinical course, prognosis and treatment response of PCV and RAP are different from that of CNV.

Optical coherence tomography (OCT) provides images that allows an exact correlation with both the angiographic exams findings.

In OCT cross-sectional scans, serous PED appears as an optically empty dome-shaped elevation of the external high reflective band – the RPE -, that steeply detaches from Bruch’s membrane(33).

The overlying retina, usually adherent to the bullous PED, at the margins of the lesion can be slightly detached from the underlying RPE. More additional information can be provided by OCT in vascularized PED(34).

The tomographic sections, guided by FA and ICGA in the area corresponding to the CNV, show a smoother elevation of the RPE, continuous with the serous detachment, with a deeper backscattering, due to the presence of the fibrovascular tissue.

Hyporeflective areas of homogeneous optically empty spaces referable to fluid accumulation are frequently present in the intraretinal and subretinal spaces(35).

Intraretinal optically empty spaces are more pronounced when the serous PED is associated with a RAP, specially with cystic shape.

By positioning the scan line corresponding to the “hot-spot”, the neovascular abnormality is represented as a dense or hyperreflective pre-epithelial zone in the inner retinal layers, where the outer hyperreflectant layers are no longer detectable(36).

The RPE close to that lesion shows frequently effractions or interruptions in its hyperreflective layer(37). The retinal topographic measurement sustains an increased retinal thickness.

Even though it has been hypothesized that the intraretinal neovascularization should be connected to the choroid with an anastomotic vessel, no clear enough images that can bear its presence in the optical free area under the PED can be detected by OCT (Fig. 4-A).

In eyes with serous PED and PCV, the polypoidal ectasies show a sharp protrusion of RPE, similar to the PED but steeply sloped.

The polyps cavity, usually optically empty, is contiguous to irregular RPE elevation, expression of the occult neovascular component of the lesion(38,39).

Subretinal and intraretinal fluid, observed as hypofluorescent optical empty areas, are related to the PCV’s activity (Fig. 4-B).

Serous PED natural course depends on the presence or not of the neovascular component(40).

In pure serous PED there is generally a slow enlargement of the lesion, with a minimal progression of visual loss over a long period (months or years).

However, many of them can subsequently develop neovascularization, that worsens their prognosis(8).

Different natural course occurs indeed in vascularized PED, and it’s related to the type of newvessels associated.

The most common acute complication is the tearing of the RPE(6,41-43). It usually occurs at the edge of the PED, at the intersection of the detached and attached RPE.

Clinically, a RPE tear or rip appears as a well-defined area of bare choroid, contiguous to a darker hyperpigmented rugate area, that corresponds to the mound of the RPE that has torn away(44,45).

The ripped RPE usually rolls towards the occult CNV, and its propensity to tear can be predicted by the observation of pre-tear characteristics, such as an increase in the size and a modification in the shape, the presence of small holes at the PED margins, the presence of hemorrhages or subretinal fluid, but the most noteworthy aspect is the irregular filling of the PED visible at the FA(46).

RPE tears occurs either spontaneously, either after a treatment, formally laser photocoagulation, photodynamic therapy and intravitreal injection of steroids or anti-VEGF agents(47- 57).

The exact pathogenesis of RPE tears is poorly understood.

Concerning PEDs’ natural course, it has been hypothesized that tangential shearing forces in the PED can cause the break of the RPE basement membrane at the edge of the detachment; however it is more likely the result of several variables, where the presence of a CNV plays a major role.

When RPE tear occurs after a treatment, various other causal relationships have been reported, varying from the heat generated by photocoagulation, to an abrupt increase of intra-PED fluid, a contraction of the associated CNV or the concomitant sudden resolution of the sub RPE fluid.

The combining presence of a vitreomacular traction and the deformation of the globe due to the mechanical trauma by the needle have also been reported as causative agents(58).

After RPE rips, the majority of patients complain a sudden severe visual decrease.

In a small percentage of eyes, where the tear spares the fovea, patients can even experience a temporary preservation of good visual function(59).

However, in the long term, the progression of a subretinal scar leads to a severe visual decrease. In the prognosis of serous PED, it must be also considered the high risk of bilaterality, with symmetrical behavior(60).

Treatment of serous PED, associated or not with CNV, has always been a challenge and so far there are no recommended guidelines for their management.

Pure serous PEDs have been treated in the past with laser grid or scattered photocoagulation, nevertheless with disappointing results(61).

No other approaches have been attempted to treat these lesions.

On the other hand, when a neovascular net is present, treatment of serous PED has been focused on CNVs management.

However, given that vascularized PEDs have never been included in the major RCTs, we must establish our treatment decision on published small series, often retrospective, that hint different therapeutic approaches.

By and large, in the antiangiogenic therapy era, all the previous employed treatments appear unsatisfactory to the occasion.

Laser photocoagulation, far-back widely employed, can still have a limited indication when an ICG-well defined CNV lies remote to the detached RPE(62).

Verteporfin photodynamic therapy alone has been proved to be harmful, increasing the risk of RPE tear, hemorrhages and sudden visual acuity decrease(43, 48, 49, 63) (Fig. 5).

On the contrary, PDT combined with intravitreal triamcinolone acetonide injection has been demonstrated as potentially capable of visual acuity stabilization and recurrences reduction(64).

However, the high rate complications (cataract and glaucoma) has reduced the intravitreal triamcinolone use.

The optimistic results obtained with the anti-VEGF intravitreal therapy in the treatment of occult CNV have extended its employment to the vascularized PED, however with disappointing results(65-68).

As a matter of fact, both acute complications and scanty response to the treatment frequently invalidate our attempts to heal the lesion.

RPE tears and subretinal hemorrhages are reported to complicate ranibizumab and bevacizumab treatments(51-57).

Moreover, the sub-RPE fluid hardly responds to the anti-VEGF therapy, probably due to the hydroconductivity changes of Bruch’s membrane(68).

In a recent retrospective case series of 328 patients treated with bevacizumab, ranibizumab, pegaptanib and PDT+IVTA respectively, after a mean follow-up of 42, 4 weeks the authors reported a significant stabilization of visual acuity in each group, better in the bevacizumab and ranibizumab ones compared to the other two, and an overall RPE tears frequency of 12,5%.

However, they conclude that with these treatments, only a partial regression of the lesions can be obtained, and the risk of RPE tears is not avoided(68).

In the future, new combination therapies and new therapeutic strategies, tested in multicentric clinical trials specifically designed, will help to improve the prognosis of the patients affected by vascularized PED.

>> Figure 1 - Vascularized PED with choroidal neovascularization

>> Figure 2 - Vascularized PED with retinal angiomatous proliferation: fluorescein angiography, indocyanine green angiography early and late phases

>> Figure 3 - Vascularized PED with PCV: fluorescein angiography and early, mid and late phase ICGA

>> Figure 4 - Retinal Angiomatous Proliferation (right) and Polypoidal Choroidal Vasculopathy (left): ICGA and OCT patterns

>> Figure 5 - Vascularized PED with choroidal neovascularization before and after PDT: RPE tear (fluorescein angiography and OCT)


>> References