Epiretinal Proliferation

Key Points at a Glance

Key Points of This Disease

• Epiretinal proliferation (ERP) is a fibrocellular tissue on the inner surface of the retina, associated with lamellar macular holes (LMH) and full-thickness macular holes (FTMH).
• On optical coherence tomography (OCT), it appears as an iso-reflective space-filling material without traction, which is an important distinguishing feature from epiretinal membrane (ERM).
• It is thought to originate mainly from Müller cells and appears only under conditions of mid-retinal defect.
• ERP alone causes almost no subjective symptoms, and surgical indication depends on the underlying disease (e.g., FTMH).
• EP embedding or EP + internal limiting membrane (ILM) flap techniques for FTMH achieve good closure rates and visual improvement.
• It has been reported that removing ERP before FTMH surgery may increase the risk of reopening, and in recent years, techniques that actively utilize ERP have attracted attention.

1. What is epiretinal proliferation?

Epiretinal proliferation (ERP) is a fibrous cell tissue found on the inner surface of the retina. Previously, various terms such as “thick membrane,” “dense ERM,” and “lamellar hole-associated epiretinal proliferation (LHEP)” were used interchangeably, but in 2020, Hubschman et al. proposed the unified term “epiretinal proliferation” ⁴⁾.

The concept of ERP was first reported in 2006 by Witkin et al. as a “thick membrane” using ultrahigh-resolution OCT, and in 2014, Pang et al. named it “LHEP” in association with LMH ⁴⁾. Subsequent studies revealed that it also occurs in FTMH and epiretinal membrane (ERM), leading to the use of the more comprehensive term ERP.

There are multiple reports on the frequency of ERP complications. The incidence of EP in FTMH varies among reports, with 8 out of 99 eyes (8.0%) in Pang et al. and 30 out of 113 eyes (26.5%) in Lee et al.^{4, 6)}. The incidence of EP in LMH is reported as 60 out of 197 eyes (30.5%) by Pang et al.⁴⁾. In recent years, it has been proposed to classify LMH according to the Govetto classification into tractional LMH associated with epiretinal membrane and degenerative LMH associated with EP and ellipsoid zone (EZ) defects⁴⁾. Furthermore, the new definition by Hubschman et al. (2020) provided a conceptual distinction between true LMH with tissue defects and epiretinal membrane foveoschisis (tractional pseudohole)⁴⁾.

Rare cases of association with epiretinal peripheral vascular anomalous complex (ePVAC) have also been reported³⁾.

Q What is the difference between ERP and ERM?

A

ERM is depicted as a highly reflective irregular layer and is a contractile membrane with retinal traction. In contrast, ERP is depicted as a homogeneous medium-reflective substance and is a non-contractile glial tissue without traction. Intraoperatively, ERM is white and hard, whereas ERP is a sticky, yellow, soft substance that is difficult to stain with trypan blue⁴⁾. For details, see also the “Diagnosis and Examination Methods” section.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

ERP alone is usually asymptomatic. The symptoms reported by patients are primarily derived from the underlying conditions (LMH, FTMH, etc.) that are present.

• Decreased visual acuity: Associated with morphological changes in the fovea due to the underlying disease.
• Metamorphopsia: Reflects structural changes in the macula, but the contribution from ERP alone is minimal.

Case reports have recorded decreased visual acuity, such as best-corrected visual acuity (BCVA) of 20/63¹⁾ in a 64-year-old woman and BCVA of 20/40 to 20/50⁴⁾ in a 72-year-old man, both due to the effects of underlying FTMH or LMH.

Clinical Findings

OCT plays a central role in the diagnosis of ERP. The main clinical features of ERP and epiretinal membrane are shown below.

The clinical comparison between ERP and epiretinal membrane is summarized below.

Feature	ERP	Epiretinal membrane
OCT reflectivity	Homogeneous, medium reflectivity	High reflectivity, irregular
Retinal traction	None	Present
Intraoperative characteristics	Yellow, soft	White, hard

The details of OCT findings are as follows.

• Iso-reflective material: Depicted as a space-filling homogeneous material. A thin hyperreflective line demarcates the boundary with the inner limiting membrane¹⁾.
• Continuity with the inner retina: Continuous with a defect in the middle retinal layers⁴⁾.
• Absence of tractional findings: Does not involve the retinal traction or folding characteristic of ERM⁴⁾.
• Irregular hyporeflective cystoid spaces: May be present within the LHEP³⁾.
• Absence of blood flow on OCTA: No blood flow signal is detected within the EP³⁾.

Q Does the presence of ERP reduce visual acuity?

A

ERP alone has a minimal direct impact on visual acuity. Visual acuity decline depends on the severity of concurrent LMH or FTMH. However, ERP-associated LMH tends to progress to FTMH, making follow-up of the underlying disease important (see “Pathophysiology” section for details).

3. Causes and Risk Factors

Several hypotheses have been proposed regarding the mechanism of ERP, but the Müller cell origin theory is currently the most widely supported.

• Müller cell origin theory (mainstream): Müller cells proliferate and migrate from the middle retinal layers, appearing on the inner retinal surface. This theory is consistent with histological studies and OCT findings ^{1, 4, 6)}.
• Vitreous origin theory: Vitreous collagen fibers are sometimes observed within EP, suggesting possible admixture of vitreous-derived components.
• RPE migration theory: RPE (retinal pigment epithelium) proliferates and migrates from defects in the IS/OS junction (inner segment/outer segment junction).
• Special mechanism in ePVAC cases: Müller cell necrosis is suggested to lead to vascular instability³⁾. Additionally, it has been reported that lutein and zeaxanthin may be present in EP³⁾.

Risk factors for ERP are not clearly established, but the following are associated:

• LMH (lamellar macular hole)
• FTMH (full-thickness macular hole): especially large and chronic cases
• Epiretinal membrane
• Chronicity and enlargement of macular hole ²⁾

Specialized supplement

ERP is thought to appear only under conditions of middle retinal layer defects, and structural vulnerability of the macula is considered a prerequisite for its occurrence. A major pathophysiological difference is that while ERM is a myofibroblast-dominant contractile tissue, ERP is a non-contractile glial tissue.

4. Diagnosis and Examination Methods

The diagnosis of ERP is primarily based on SD-OCT (spectral-domain OCT).

OCT Findings

• Iso-reflective space-filling material: Homogeneous medium-reflective tissue is depicted on the surface of the inner retina¹⁾.
• Hyperreflective boundary line: A thin hyperreflective line is present at the vitreous side border of the ERP¹⁾.
• Absence of traction findings: Unlike ERM, there is no retinal traction or deformation⁴⁾.

3 points for differentiation from ERM

Differentiation from ERM is important because it directly determines the treatment strategy⁴⁾.

1. OCT reflectivity: ERP is homogeneous medium reflectivity, ERM is irregular high reflectivity
2. Traction findings: ERP has no traction, ERM has traction and retinal folding
3. Intraoperative characteristics: ERP is a sticky yellow substance that is difficult to stain with trypan blue, ERM is white and hard

OCTA (Optical Coherence Tomography Angiography)

OCTA has been reported to show no blood flow signals within EP, which can be used adjunctively to differentiate it from vascular lesions ³⁾.

5. Standard Treatment

There is no medical treatment for ERP alone, and surgery is not indicated. Surgery is performed for the treatment of concurrent FTMH or LMH.

EP embedding

EP embedding is a surgical technique that actively utilizes the EP for the treatment of FTMH. While dissecting the EP centripetally, the hinge at the edge of the macular hole is preserved, and the EP is pushed into the FTMH to fill it ^{1, 6)}.

Notomi et al. (2024) reported a case in which initial vitrectomy using EP embedding successfully closed the macular hole, but postoperatively an epiretinal membrane formed, the EP reappeared, and ultimately the FTMH reopened ¹⁾. Although best-corrected visual acuity improved from 20/63 to 20/20 after the initial surgery, traction from the epiretinal membrane was considered the cause of FTMH reopening. Attention should be paid to the risk of reopening when internal limiting membrane peeling is not performed ¹⁾.

EP + Internal Limiting Membrane Flap Technique (Recommended Procedure)

This is a surgical technique that uses the EP as a tissue filler while covering it with an inverted flap of the internal limiting membrane. A synergistic effect is expected, with the EP maintaining its position and the internal limiting membrane promoting healing and providing additional tissue volume ⁶⁾.

Dervenis et al. (2024) performed EP combined with inverted internal limiting membrane flap in 16 eyes with large full-thickness macular holes, achieving closure in all 16 eyes (100%) ²⁾. The mean maximum linear diameter (MLD) of the holes was 707.63 μm. Best-corrected visual acuity significantly improved from 1.11 logMAR preoperatively to 0.45 logMAR postoperatively.

Fukushima et al. (2023) reported successful closure in two cases of secondary macular holes that developed after vitrectomy, using EP embedding combined with inverted internal limiting membrane technique ⁶⁾.

Comparison of EP-related surgical outcomes is shown below.

Procedure	Closure rate	Visual improvement
EP embedding	Case report (good)	Best corrected visual acuity 20/63→20/201)
EP + internal limiting membrane flap	16/16 cases (100%)2)	1.11→0.45 logMAR2)
EP removal (vitrectomy + ILM peeling)	Case report	20/50→20/254)

EP removal (conventional method)

Conventionally, vitrectomy (PPV) with EP peeling and internal limiting membrane peeling was performed⁴⁾. However, it has been pointed out that EP removal may increase the risk of FTMH development after surgery⁶⁾, and currently, there is a shift toward surgical methods that actively utilize ERP.

Treatment of ePVAC-complicated cases

In ERP cases complicated by ePVAC, anti-VEGF drugs (aflibercept) provide some effect, but long-term efficacy may be insufficient. Dexamethasone intravitreal implant has been reported to be more effective³⁾.

Precautions in treatment

• If internal limiting membrane peeling is omitted during EP embedding, there is a risk of FTMH reopening due to epiretinal membrane formation postoperatively ¹⁾.
• Preoperative removal of ERP may increase the risk of FTMH recurrence after surgery ⁶⁾.
• Active use of EP (embedding) requires careful case selection and should be decided at a specialized facility.

Q Should ERP be removed or left during surgery?

A

Recent findings indicate a trend toward actively utilizing ERP as a useful tissue to promote FTMH closure. Good outcomes have been reported, such as EP embedding and EP plus internal limiting membrane flap achieving 100% closure rates ²⁾, and utilization rather than removal is recommended. EP removal may also increase the risk of FTMH recurrence ⁶⁾.

6. Pathophysiology and Detailed Mechanism of Onset

The pathology of ERP is understood primarily through the behavior of Müller cells.

Müller Cell Origin Theory

The most widely supported theory is that Müller cells proliferate and migrate from the middle retinal layers (inner nuclear layer and outer plexiform layer) to appear on the inner retinal surface ^{1, 4, 6)}. The finding that ERPs appear only under conditions of mid-retinal defects supports this hypothesis ⁴⁾.

ERPs are fundamentally different in pathological nature from epiretinal membranes.

• ERP (glial type): A non-contractile tissue composed mainly of Müller cells. It does not cause retinal traction.
• Epiretinal membrane (fibrous type): A contractile tissue composed mainly of myofibroblasts. It causes retinal traction and deformation.

Relationship between ERP and FTMH

It has been suggested that ERP may promote spontaneous closure of FTMH⁵⁾. On the other hand, there are reports that contraction of the epiretinal membrane is involved in the reopening of FTMH⁵⁾.

Watanabe et al. (2021) reported a case in which a stage 2 macular hole and LHEP coexisted, and after spontaneous closure of the FTMH, it progressed to a stage 4 FTMH ⁵⁾. LMH with ERP may have a tendency to progress to FTMH.

Mechanism of progression from LMH to FTMH

It has been pointed out that LMH with ERP (degenerative LMH) has a higher tendency to progress to FTMH compared to LMH with ERM (tractional LMH)⁴⁾. It is inferred that a defect in the middle retinal layers allows the appearance of ERP, and further enlargement of this defect leads to progression to FTMH.

Special Pathology of Cases with ePVAC

In cases with ePVAC (perivascular anomalous complex), it is suggested that Müller cell necrosis leads to instability of surrounding blood vessels³⁾. It has also been reported that lutein and zeaxanthin may be present within the EP, and their association with macular pigment is being investigated³⁾.

Q Is there a risk of progression from LMH to FTMH?

A

LMH complicated by ERP (LHEP) has been suggested to have a tendency to progress to FTMH, making follow-up important ⁴⁾. According to the Govetto classification, “degenerative LMH” with ERP has a different pathophysiology and progression risk from “tractional LMH” with ERM. Regular OCT monitoring of morphological changes is recommended.

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7. Latest Research and Future Perspectives (Research-stage Reports)

For Patients: Please Read Carefully

The following content is currently at the research stage or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Development of the EP + Internal Limiting Membrane Composite Flap Technique

Dervenis et al. (2024) reported excellent results with the EP + internal limiting membrane inverted flap technique, achieving closure in all 16 eyes (100%) with large FTMH (mean MLD 707.63 μm) ²⁾. While the EP alone embedding method carries a risk of reopening ¹⁾, combining it with the internal limiting membrane may provide stable closure. Future large-scale prospective studies are expected to validate these findings.

Use of EP for Secondary Macular Holes

The effectiveness of EP embedding combined with the internal limiting membrane inversion method for secondary MH (macular hole) occurring after vitrectomy has been reported⁶⁾, and its application to refractory macular holes is expected.

Dexamethasone intravitreal implant for ePVAC

In ERP cases complicated by ePVAC, dexamethasone intravitreal implant has been reported to be more effective than aflibercept³⁾. It is thought to act on the vascular inflammatory component of ePVAC, but further evidence accumulation is needed.

Dósa et al. (2025) reported that using a dexamethasone intravitreal implant in LHEP cases complicated by ePVAC resulted in better long-term outcomes than aflibercept ³⁾.

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8. References

1. Notomi S, Kubo Y, Ishikawa K, Shiose S, Koh-Hei S. A Recurrent Case of Full-Thickness Macular Hole After Successful Closure With Primary Vitrectomy and Epiretinal Proliferation Embedding. Cureus. 2024;16(8):e66232. doi:10.7759/cureus.66232. PMID:39238726; PMCID:PMC11374924.
2. Dervenis N, Vagiakis I, Papadopoulou EP, Dervenis P, Sandinha T.. Combined Epiretinal Proliferation and Internal Limiting Membrane Inverted Flap for the Treatment of Large Macular Holes. Vision (Basel). 2024;8(4):63. doi:10.3390/vision8040063. PMID:39449396; PMCID:PMC11503290.
3. Dósa G, Fuller JM, Zetterberg M, Breimer M, Kalaboukhova L.. Long-term follow-up and treatment of lamellar hole-associated epiretinal proliferation presenting with exudative perivascular anomalous complex. Am J Ophthalmol Case Rep. 2025;40:102446. doi:10.1016/j.ajoc.2025.102446. PMID:41140347; PMCID:PMC12547451.
4. Asaad SZ. Full-Thickness Macular Hole Progressing from Lamellar Macular Hole with Epiretinal Proliferation. Case reports in ophthalmology. 2021;12(1):134-141. doi:10.1159/000514526. PMID:33976670; PMCID:PMC8077453.
5. Watanabe M, Yokota H, Aso H, Hanazaki H, Hanaguri J, Yamagami S, Nagaoka T.. Development of Stage 4 Macular Hole after Spontaneous Closure in a Patient with Stage 2 Macular Hole and a Lamellar Macular Hole-Associated Epiretinal Proliferation. Case Rep Ophthalmol. 2021;12(2):481-484. doi:10.1159/000513132. PMID:34177545; PMCID:PMC8215963.
6. Fukushima M, Kato T, Hayashi A. Epiretinal proliferation embedding combined with internal limiting membrane flap inversion for secondary macular hole: Two case reports. Am J Ophthalmol Case Rep. 2023;29:101774. doi:10.1016/j.ajoc.2022.101774. PMID:36544753; PMCID:PMC9761376.