PPE
Pachychoroid Pigment Epitheliopathy: The mildest form, presenting only RPE changes over pachyvessels without subretinal fluid. Often asymptomatic.
Pachychoroid Spectrum
Key Points at a Glance
Section titled “Key Points at a Glance”1. What is Pachychoroid Spectrum?
Section titled “1. What is Pachychoroid Spectrum?”Pachychoroid spectrum (PPS) is a group of diseases sharing abnormally dilated choroidal vessels (pachyvessels) as a common pathological basis. This concept was first proposed by Warrow and Freund in 2013 1).
Pachyvessels are mainly located in the Haller layer, thinning the surrounding choriocapillaris and impairing nutrient supply to the retinal pigment epithelium (RPE) 1). This choroidal venous congestion leads to RPE dysfunction and fluid accumulation.
The main subtypes included in PPS are shown below.
Central Serous Chorioretinopathy (CSC)
Central Serous Chorioretinopathy: Serous retinal detachment occurs through a break in the RPE. More common in men (male-to-female ratio 6:1), with peak incidence in the 40s to 50s.
PNV
Pachychoroid Neovasculopathy: A condition in which type 1 choroidal neovascularization (MNV) develops over pachyvessels. It accounts for about half of nAMD (neovascular age-related macular degeneration) cases in Japan 10).
Polypoidal Choroidal Vasculopathy (PCV)
Polypoidal Choroidal Vasculopathy: Polyp-like dilated lesions form at the ends of type 1 macular neovascularization. Common in Asians. Pachyvessels are found in about 90% of cases 1).
In addition, hemorrhagic subtypes such as PEHCR (pachychoroid-associated epiretinal membrane and hemorrhage choroidal rupture) have been reported 5). Also, PPE with PEVAC (perifoveal exudative vascular anomalous complex) has been described 9), and PPS may encompass even more diverse subtypes.
The disease concept and nomenclature are still under international debate, and a comprehensive reorganization with conventional central serous chorioretinopathy and polypoidal choroidal vasculopathy is ongoing 1).
Q
How is pachychoroid spectrum different from age-related macular degeneration?
A
Typical age-related macular degeneration is based on drusen and geographic atrophy, and the choroid tends to be thinner. In contrast, PPS is characterized by choroidal thickening and pachyvessels, and also occurs in younger patients. However, about half of nAMD cases in Japan are considered PPS-related 10), and the boundary between the two concepts is not clear.
2. Main Symptoms and Clinical Findings
Section titled “2. Main Symptoms and Clinical Findings”Subjective Symptoms
Section titled “Subjective Symptoms”The presence and nature of symptoms vary by disease subtype.
- PPE: Often asymptomatic. May be discovered incidentally.
- Central Serous Chorioretinopathy: Main symptoms are metamorphopsia (distorted vision), central scotoma, and decreased visual acuity. More common in men, with a male-to-female ratio of about 6:1 1). Steroid use, sleep disorders, and type A personality are associated factors.
- PNV: When exudation occurs, metamorphopsia and decreased visual acuity appear. It is accompanied by a characteristic OCT finding called SIRE (subretinal irregular reflective exudate)1).
- Polypoidal choroidal vasculopathy: Sudden decrease in visual acuity and metamorphopsia. Often accompanied by hemorrhage and serous exudation.
Clinical Findings
Section titled “Clinical Findings”Major OCT findings are shown by disease type.
| Finding | Central serous chorioretinopathy | PNV | Polypoidal choroidal vasculopathy |
|---|---|---|---|
| Serous retinal detachment | ○ | △ | ○ |
| Type 1 macular neovascularization | − | ○ | ○ |
| Polypoidal dilation | − | − | ○ |
| Pachyvessels | ○ | ○ | Approximately 90%1) |
Regarding choroidal thickness (CT), the normal mean CT has been reported as 267.5 μm2). In PPS, subfoveal CT is markedly increased. In PPS cases, the nasal CT tends to be significantly larger, and there are case reports of nasal CT reaching 550 μm3).
Studies using LSFG (laser speckle flowgraphy) have shown that choroidal blood flow (N value) in PPS eyes is 0.76, higher than 0.71 in healthy eyes4). Furthermore, the macular blood flow ratio (MBR ratio) in PNV eyes was 1.45, exceeding that of normal eyes, indicating a hyperperfusion state of the PPS choroid4).
Q
Does PPE require treatment?
A
PPE is often asymptomatic and is generally managed by observation. However, because it may progress to central serous chorioretinopathy or other disease types8), regular ophthalmologic follow-up is important.
3. Causes and Risk Factors
Section titled “3. Causes and Risk Factors”Choroidal Venous Stasis and Scleral Factors
Section titled “Choroidal Venous Stasis and Scleral Factors”The basic pathophysiology of PPS is stasis and hyperperfusion of the choroidal venous system1). Anastomoses to the vortex vein are found at high rates in each PPS subtype: 90% in central serous chorioretinopathy, 95% in PNV, and 98% in polypoidal choroidal vasculopathy2).
As the Haller layer of the choroid expands, the inner choriocapillaris becomes thin and ischemic, impairing oxygen and nutrient supply to the RPE 2). Scleral stiffness and compression are thought to be involved in this process, leading to the scleral factor hypothesis 1).
Furthermore, a choroidal flow defect known as CCFD (central choroidal flow defect) is considered useful for diagnosing PPS 2).
Steroids and Genetic Predisposition
Section titled “Steroids and Genetic Predisposition”Use of steroids (systemic, topical, inhaled) increases the risk of PPS, particularly central serous chorioretinopathy 1, 4). The mechanism is thought to involve increased choroidal vascular permeability induced by steroids.
Genetic predispositions include associations with CFH (complement factor H) and VIPR2 (vasoactive intestinal peptide receptor 2) 5).
4. Diagnosis and Examination Methods
Section titled “4. Diagnosis and Examination Methods”Key Imaging Tests
Section titled “Key Imaging Tests”Diagnosis of PPS involves combining multiple modalities.
| Test | Main Use | Features |
|---|---|---|
| EDI-OCT / SS-OCT | CT measurement, pachyvessel confirmation | Non-invasive, repeatable |
| ICGA | Confirmation of vortex veins and polyps | Essential for definitive diagnosis of polypoidal choroidal vasculopathy |
| OCTA | Detection of macular neovascularization | Sensitivity 97%1) |
| LSFG | Quantification of choroidal blood flow | Research use4) |
APOIS Classification and CCFD
Section titled “APOIS Classification and CCFD”The APOIS (Asian Pacific Ocular Imaging Society) classification has been proposed for the diagnosis of polypoidal choroidal vasculopathy, and is used as a morphological evaluation criterion for polypoidal lesions on ICGA2).
CCFD is a finding indicating areas of choroidal blood flow deficit in the late phase of ICGA, and is considered useful for the diagnosis and disease assessment of central serous chorioretinopathy and PNV2).
Role of OCTA
Section titled “Role of OCTA”OCTA shows a sensitivity of 97% for detecting macular neovascularization (choroidal neovascularization)1), and can visualize type 1 macular neovascularization that is difficult to detect with conventional FA or ICGA. It is also useful for monitoring disease type changes from PPE to PNV.
Q
How are central serous chorioretinopathy and PNV differentiated on OCT?
A
In central serous chorioretinopathy, serous fluid leaks under the retina from a break in the retinal pigment epithelium (RPE), and subretinal fluid (SRF) is the main feature. In PNV, type 1 macular neovascularization is present, and subretinal irregular reflective material called SIRE is a characteristic finding 1). Confirming the macular neovascular flow signal on OCTA is useful for differentiation.
5. Standard Treatment
Section titled “5. Standard Treatment”Treatment Strategy by Disease Type
Section titled “Treatment Strategy by Disease Type”Treatment options differ depending on the disease type.
PPE: Basically observation. Spontaneous resolution has been reported 6).
Central serous chorioretinopathy: In the acute phase (within 3 months), spontaneous improvement is expected, so observation is the principle. In chronic cases (persisting for 3 months or more), photodynamic therapy (half-dose PDT) is effective.
PNV: Anti-VEGF therapy is the first choice. Japanese guidelines recommend anti-VEGF drugs (aflibercept, brolucizumab, faricimab, etc.) 10).
Polypoidal choroidal vasculopathy: Anti-VEGF therapy alone or in combination with PDT. Genetic polymorphisms of ARMS2/CFH are associated with polypoidal choroidal vasculopathy 10) and may influence individual differences in treatment response.
Medications Used
Section titled “Medications Used”Options for anti-VEGF drugs are shown below.
- Aflibercept: Widely used for PPS with type 1 macular neovascularization (PNV, polypoidal choroidal vasculopathy). A case of bilateral PPS achieving VA 20/20 after 4 injections has been reported 5).
- Brolucizumab: Expected to have higher anti-VEGF effect and extended dosing intervals 2).
- Faricimab: Dual inhibitor of VEGF and Ang-2 2).
- Bevacizumab: Has been reported for use in PPS with macular neovascularization (including cases with vitreous hemorrhage), with improvement after 4 injections in some cases 3).
6. Pathophysiology and Detailed Pathogenesis
Section titled “6. Pathophysiology and Detailed Pathogenesis”Multi-hit Theory
Section titled “Multi-hit Theory”The progression of PPS is conceptualized as the multi-hit theory, which describes five sequential pathological changes1).
Stage 1: Pachyvessel Formation
Section titled “Stage 1: Pachyvessel Formation”Genetic and environmental factors cause abnormal dilation of choroidal vessels in the Haller layer, leading to the formation of pachyvessels.
Stage 2: Inner Choroidal Changes
Section titled “Stage 2: Inner Choroidal Changes”The choriocapillaris overlying the pachyvessels becomes thinned, and blood flow decreases. Disappearance of the Sattler layer may also be observed7).
Stage 3: RPE Damage
Section titled “Stage 3: RPE Damage”Ischemia of the choriocapillaris impairs oxygen and nutrient supply to the RPE, leading to RPE degeneration and detachment (PPE).
Stage 4: Serous Exudation (Central Serous Chorioretinopathy)
Section titled “Stage 4: Serous Exudation (Central Serous Chorioretinopathy)”When the RPE barrier breaks down, serous fluid from the choroid leaks into the subretinal space, causing central serous chorioretinopathy.
Stage 5: Neovascularization (PNV → Polypoidal Choroidal Vasculopathy)
Section titled “Stage 5: Neovascularization (PNV → Polypoidal Choroidal Vasculopathy)”As a reparative response to chronic RPE and choriocapillaris damage, type 1 macular neovascularization (PNV) forms, which may further progress to polypoidal choroidal vasculopathy with polypoidal dilations.
Conversion from PPE to Polypoidal Choroidal Vasculopathy
Section titled “Conversion from PPE to Polypoidal Choroidal Vasculopathy”PPE is a relatively stable disease type, with 82.6% remaining stable, but 17.4% progress to central serous chorioretinopathy 8). Seven cases of PPE converting to polypoidal choroidal vasculopathy have been reported, with a mean conversion period of 49.6 months 8). This is an important first report providing longitudinal evidence supporting the multi-hit theory.
Paradox of Choroidal Hyperperfusion and Ischemia
Section titled “Paradox of Choroidal Hyperperfusion and Ischemia”In LSFG studies, choroidal blood flow in PPS eyes was higher than in healthy eyes (MBR ratio 1.45) 4). Meanwhile, the choriocapillaris directly above the pachyvessels becomes ischemic. This paradoxical state of “large vessel hyperperfusion and microvascular ischemia” is the core of PPS pathology 4).
Choroidal Cavitation in Childhood-Onset Cases
Section titled “Choroidal Cavitation in Childhood-Onset Cases”In a case of onset at age 7, choroidal cavitation (CC) at sites corresponding to pachyvessels and disappearance of the Sattler layer were observed 7). Geographic atrophy (GA) has been reported in 12.5% of PPS patients 7).
Zhioua Braham et al. (2023) reported a case of a 42-year-old man with PPS complicated by retinal neovascularization and vitreous hemorrhage (first report) 3). Nasal CT showed marked thickening of 550 μm, and macular neovascularization was confirmed on OCTA. After four injections of bevacizumab, vitreous hemorrhage and macular neovascularization resolved.
7. Latest Research and Future Perspectives (Investigational Reports)
Section titled “7. Latest Research and Future Perspectives (Investigational Reports)”Development of Disease Concept and Nomenclature
Section titled “Development of Disease Concept and Nomenclature”The disease concept of PPS is not yet internationally unified. Cheung et al. (2025) pointed out the limitations of current nomenclature and proposed a new classification system (including PVM) that more accurately reflects the disease spectrum 1). Future international consensus formation is expected.
Pathological Assessment Using LSFG and OCTA
Section titled “Pathological Assessment Using LSFG and OCTA”Saito et al. (2024) quantitatively evaluated choroidal blood flow in PPS eyes using LSFG and reported differences in blood flow characteristics among disease types 4). Multimodal assessment combined with OCTA is being applied for early disease type determination and treatment effect evaluation in PPS.
Prediction of Conversion from PPE to Polypoidal Choroidal Vasculopathy
Section titled “Prediction of Conversion from PPE to Polypoidal Choroidal Vasculopathy”The report of 7 conversion cases by Tang et al. (2022) 8) may provide evidence for positioning PPE as a high-risk group. Identifying biomarkers to predict which PPE cases will progress is a future research challenge.
Novel anti-VEGF drugs and treatment strategies
Section titled “Novel anti-VEGF drugs and treatment strategies”Clinical trials of brolucizumab (6 mg monotherapy or 8-week dosing) and faricimab (dual inhibition mechanism) for PNV/polypoidal choroidal vasculopathy are ongoing 2). The goals are to extend dosing intervals and reduce treatment burden.
In Case 1 of Saito et al. (2024), progression to PNV was observed during LSFG follow-up 4), suggesting that regular multimodal evaluation is key to PPS management.
8. References
Section titled “8. References”- Cheung CMG, Lai TYY, Ruamviboonsuk P, et al. Pachychoroid spectrum: review and update. Eye. 2025;39:819-834.
- Sen P, Bhende P, Gupta A, et al. Pachychoroid spectrum of diseases: a review. Clin Ophthalmol. 2023;17:53-70.
- Zhioua Braham I, Bouchami O, Limaiem R. Pachychoroid spectrum disease associated with retinal neovascularization and vitreous hemorrhage: a case report. J Med Case Rep. 2023; [PMC10875186].
- Saito M, Iida T, Matsumoto CS. Laser speckle flowgraphy in eyes with pachychoroid spectrum disease. PLoS One. 2024; [PMC12886512].
- Kitagawa Y, Ueta T, Iriyama A, et al. Bilateral pachychoroid disease with polypoidal choroidal vasculopathy, pachychoroid-associated epiretinal membrane and hemorrhagic choroidal rupture, and central serous chorioretinopathy. Am J Ophthalmol Case Rep. 2021;24:101168. [PMC8418046]
- Hubschman JP, Quiroz-Mercado H, Bourla D, et al. Spontaneous resolution of pachychoroid spectrum disease with severe cystoid macular edema. Am J Ophthalmol Case Rep. 2022;25:101334. [PMC8810369]
- Pederzolli M, Staurenghi G, Cereda M, et al. Pachychoroid disease in a 7-year-old patient. Am J Ophthalmol Case Rep. 2022;26:101509. [PMC8968018]
- Tang LY, Yao M, Duan HF, et al. Conversion from pachychoroid pigment epitheliopathy to polypoidal choroidal vasculopathy: a first report of seven cases. Ophthalmol Ther. 2022;11:1891-1901. [PMC9210595]
- Herda A, Staurenghi G, Borrelli E, et al. Perifoveal exudative vascular anomalous complex associated with pachychoroid pigment epitheliopathy. Am J Ophthalmol Case Rep. 2022;27:101653. [PMC9449734]
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