Retinal pigment epithelial detachment (PED) is a condition in which the retinal pigment epithelium (RPE) layer separates from the underlying Bruch’s membrane, with fluid, lipids, blood, or fibrovascular tissue accumulating between them. PED itself is not an independent disease but an important clinical finding associated with many retinal diseases such as age-related macular degeneration, central serous chorioretinopathy (CSC), polypoidal choroidal vasculopathy (PCV), and choroidal neovascularization.
Age-related macular degeneration is the most common cause of PED, and it is particularly emphasized as an early biomarker of neovascular AMD (nAMD). 2) In untreated nAMD, more than 50% of cases experience a loss of 3 or more lines of visual acuity within one year. 2)
In central serous chorioretinopathy, the frequency of PED is also high, with reports of PED in 9–100% of acute CSC cases. 1)
It is a condition in which the RPE detaches from Bruch’s membrane and elevates in a dome shape. The contents (serous fluid, blood, fibrovascular tissue, etc.) vary depending on the underlying disease, and the prognosis and treatment strategy differ by type. For details, see the section on Diagnosis and Examination Methods.
Pigment epithelial detachment alone is often asymptomatic. The following symptoms appear when complicated by choroidal neovascularization or serous retinal detachment.
In pigment epithelial detachment associated with central serous chorioretinopathy, characteristic diurnal variation has been reported. Some cases show a pattern where the detachment appears and expands upon waking when cortisol levels are high, and shrinks in the afternoon. 1)
Pigment epithelial detachment is classified into four main types based on the nature of the accumulated material.
Drusenoid Type
Morphology: Dome-shaped elevation due to confluence of soft drusen.
OCT findings: Homogeneous low to medium reflectivity space between the RPE and Bruch’s membrane.
Features: Risk of progression to atrophic age-related macular degeneration. Visual acuity tends to be relatively preserved.
Serous
Morphology: Dome-shaped elevation with steep margins. Contents are serous fluid.
OCT findings: A homogeneous, non-reflective cavity beneath the RPE (optical cavity).
Features: Associated with central serous chorioretinopathy, polypoidal choroidal vasculopathy, and choroidal neovascularization. May resolve spontaneously.
Fibrovascular
Morphology: Gentle, irregular elevation. Contents are fibrovascular tissue.
OCT findings: A heterogeneous cavity with moderate reflectivity beneath the RPE.
Features: Most common in type 1 choroidal neovascularization. Treatment response is an important prognostic factor.
Hemorrhagic
Morphology: Dark red, steep elevation. Blood accumulates beneath the RPE.
OCT findings: High reflectivity beneath the RPE obscures deeper structures.
Features: Risk of RPE damage due to iron toxicity. Large cases may be candidates for surgical treatment. 3)
Multilayered pigment epithelial detachment (multilayered PED) is a special form with alternating high- and low-reflectivity layers, associated with pre-choroidal cleft in 65% of cases. 5) SS-OCTA often reveals fan-shaped type 1 choroidal neovascularization, with relatively good visual acuity and low risk of tears. 5)
Large pigment epithelial detachment is defined as PED diameter >2500 μm, which carries a particularly high risk of RPE tear and influences treatment strategy. 4)
The underlying pathology of pigment epithelial detachment is dysfunction of Bruch’s membrane, where lipid and cholesterol deposition and accumulation of metabolic waste impair fluid movement. When choroidal neovascularization forms, it can progress to fibrovascular or hemorrhagic PED.
Major risk factors include the following:
In central serous chorioretinopathy, cortisol is thought to cause pigment epithelial detachment through increased choroidal vascular permeability, direct RPE damage, upregulation of KCa2.3 channels, and suppression of collagen synthesis. 1)
The risk of RPE tear correlates with the diameter of pigment epithelial detachment; a detachment diameter >400 μm significantly increases the risk of tear. 4) In fibrovascular pigment epithelial detachment, RPE tears occur in 15-20% of cases. 4)
OCT is the most important tool for diagnosing pigment epithelial detachment, essential for type classification, size assessment, and follow-up. Multiple modalities are combined to comprehensively evaluate the condition.
OCT
Use: Evaluation of the morphology, type, and thickness of pigment epithelial detachment. Standard tool for treatment effect assessment.
EDI-OCT: Useful for evaluating choroidal thickness and choroidal vascular structure. Adjunct in diagnosing central serous chorioretinopathy and polypoidal choroidal vasculopathy.
ICGA / FA
ICGA (Indocyanine Green Angiography): Definitive diagnosis of polypoidal choroidal vasculopathy. Directly visualizes polypoidal lesions and branching vascular networks.
FA (Fluorescein Angiography): Evaluation of the type and activity of choroidal neovascularization. Confirmation of leakage patterns.
SS-OCTA
Use: Non-invasive evaluation of choroidal neovascularization and flow. Allows repeated examinations.
Multilayered pigment epithelial detachment: SS-OCTA can detect fan-shaped type 1 choroidal neovascularization. 5)
The following shows the appropriate use of each test.
| Test | Main Use | Notes |
|---|---|---|
| OCT/EDI-OCT | Type differentiation and thickness | First choice |
| ICGA | Definitive diagnosis of polypoidal choroidal vasculopathy | Important in Asians |
| FA | Choroidal neovascularization activity | Leakage pattern evaluation |
In the diagnosis of polypoidal choroidal vasculopathy, OCT criteria (AUC 0.90) have been reported to show high agreement with ICGA, and their application in screening is expected. 4)
In SS-OCTA evaluation of multilayered pigment epithelial detachment, pre-choroidal cleft (65%) and characteristic patterns of fan-shaped choroidal neovascularization provide diagnostic clues. 5)
It is not essential in all cases, but when polypoidal choroidal vasculopathy is suspected (especially in Asians, large serous pigment epithelial detachment, or thumb-shaped elevation), ICGA is indispensable for definitive diagnosis. On the other hand, the high accuracy of OCT criteria (AUC 0.90) has also been reported, and the choice depends on the situation. 4)
The treatment strategy for pigment epithelial detachment is determined by the underlying disease, type, presence of choroidal neovascularization, and lesion size.
Intravitreal injection of anti-VEGF drugs is the first-line treatment for fibrovascular and serous pigment epithelial detachments associated with choroidal neovascularization.
Chakraborty S et al. (2023) administered brolucizumab to nAMD patients with extra-large pigment epithelial detachments (>350 μm) and observed a marked reduction in sub-RPE fluid at 4 weeks. Good outcomes were achieved in an 81-year-old (final visual acuity 20/80) and a 70-year-old (final visual acuity 20/32) 2). The incidence of intraocular inflammation (IOI) in the HAWK/HARRIER trials was 4.4% 2).
In polypoidal choroidal vasculopathy cases with pigment epithelial detachment diameter >2500 μm, the risk of RPE tear is high. There are reports that a treatment strategy of half-dose PDT followed by aflibercept is more effective than anti-VEGF monotherapy.
In this report, for polypoidal choroidal vasculopathy cases with pigment epithelial detachment >2500 μm, half-dose PDT followed by aflibercept achieved a final best-corrected visual acuity of 20/20. The AUC for OCT-based diagnosis of polypoidal choroidal vasculopathy was 0.90 4).
In giant cases where hemorrhagic pigment epithelial detachment exceeds 50 disc areas, surgical treatment is considered to prevent progression of RPE damage.
Zheng F et al. (2023) performed a combination of vitrectomy, tPA (25 μg/100 μL), C3F8 (0.3 mL), and anti-VEGF for giant hemorrhagic pigment epithelial detachment (>50 disc areas). Blood disappeared within 1–2 weeks postoperatively, and a 51-year-old patient achieved a final visual acuity of 20/25. A mechanism of blood drainage through an RPE tear was suggested 3).
Vitrectomy (ILM peeling + SF6 gas) is effective for full-thickness macular holes (FTMH) associated with pigment epithelial detachment.
Meyer PS et al. (2021) achieved closure of full-thickness macular holes in 8 of 9 eyes, and no reopening was observed during a 10-year follow-up 6).
For full-thickness macular holes (hole diameter 480 μm) on drusenoid pigment epithelial detachment, the closure rate is low and reoperation may be necessary. There is a report of closure and final visual acuity of 20/40 after reoperation. 7) In eyes with drusen of AREDS2 category 3, the macular hole closure rate tends to be low, requiring modifications in surgical technique. 7)
It depends on the type and underlying disease. Drusenoid pigment epithelial detachment and serous pigment epithelial detachment associated with acute central serous chorioretinopathy are generally observed. Treatment intervention is considered for cases with choroidal neovascularization or enlarging hemorrhagic pigment epithelial detachment. Treatment selection based on RPE tear risk is important; see also the “Pathophysiology” section.
With aging, cholesterol, oxidized lipids, and complement components deposit in Bruch’s membrane, impairing transport of water and metabolites. Fluid from the choriocapillaris cannot pass through Bruch’s membrane and accumulates under the RPE, forming pigment epithelial detachment. Type 1 choroidal neovascularization proliferates under the RPE without destroying Bruch’s membrane, leading to fibrovascular pigment epithelial detachment.
In central serous chorioretinopathy, elevated cortisol due to psychological stress or steroid excess is a major trigger. Cortisol acts directly on the RPE and causes pigment epithelial detachment through the following mechanisms. 1)
Diurnal variation has been observed in which pigment epithelial detachments appear and enlarge in the morning when waking cortisol levels are high, and shrink in the afternoon. 1) When chronic, RPE atrophy progresses, leading to permanent visual loss (equivalent to 20/200). 1)
In hemorrhagic pigment epithelial detachment, iron ions produced by the breakdown of hemoglobin in the blood are directly toxic to the RPE. 3) Photoreceptor damage due to iron toxicity is irreversible, and prompt blood drainage is key to protecting visual function. In giant hemorrhagic pigment epithelial detachment, thrombolysis with tPA plus gas tamponade to drain via an RPE tear is effective. 3)
In full-thickness macular holes overlying pigment epithelial detachment, traction forces acting in the opposite direction to the vitreous adhesion to the pigment epithelial detachment are a trigger for hole formation. 6) The reasons for the lower closure rate compared to typical idiopathic full-thickness macular holes include the presence of sub-RPE fluid and weakening of the RPE and Bruch’s membrane. 7)
Multilayered pigment epithelial detachment is formed by alternating layers of fibrous tissue, matrix, and fluid components produced by type 1 choroidal neovascularization. 5) Alternating layers of high and low reflectivity and a characteristic pre-choroidal cleft (65%) are observed on SS-OCT. 5) This morphology may function as a structural buffer zone protecting the RPE.
Brolucizumab, due to its small molecule size (26 kDa) and high VEGF-A binding affinity (2:1 binding), has been suggested to be superior to existing anti-VEGF drugs in resolving subretinal and sub-RPE fluid. 2) Enrichment of comparative trials targeting extra-large pigment epithelial detachments (>350 μm) is a future challenge. Optimization of dosing protocols to reduce the incidence of IOI (4.4%) is also underway. 2)
The combination of vitrectomy + tPA + gas tamponade + anti-VEGF has shown efficacy at the case report level, but the number of cases is limited. 3) Accumulation of evidence regarding the timing of blood drainage, tPA concentration, and optimization of gas type is needed.
For large pigment epithelial detachments (>2500 μm) associated with polypoidal choroidal vasculopathy, a strategy of half-dose PDT followed by continued anti-VEGF may reduce the risk of RPE tears and improve visual prognosis. 4) Clinical implementation of OCT diagnostic criteria for polypoidal choroidal vasculopathy (AUC 0.90) is expected to improve access for cases without ICGA. 4)
Multilayered pigment epithelial detachment is considered a progressive form of type 1 choroidal neovascularization, but visual prognosis is relatively good and the risk of tears is low. 5) Data on the indication and efficacy of anti-VEGF treatment for this specific morphology are scarce, and prospective studies are needed.
Improvement of central serous chorioretinopathy-associated pigment epithelial detachment through normalization of cortisol levels (stress management, mineralocorticoid receptor antagonist eplerenone) is being explored. 1) Establishing a method for evaluating pigment epithelial detachment as a biomarker utilizing diurnal variation is also a future challenge.
Research on novel treatments targeting the cortisol pathway, complement system, KCa2.3 channels, etc., is progressing. At present, all are at the research stage and have not been established as standard treatments.
