Topic
To compare the visual and anatomical outcomes of vitrectomy with those of observation in eyes with lamellar macular holes associated with epiretinal proliferation (LHEP).
Clinical relevance
LHEP is increasingly recognized in clinical practice, yet uncertainty persists regarding the visual benefits and full-thickness macular hole (FTMH) progression risk of surgical versus observational management. Reliable outcome estimates are essential for patient counseling and treatment planning.
Methods
A systematic review and meta-analysis. Literature search of PubMed, Embase, Scopus, Cochrane Library, and Web of Science were performed according to PRISMA guidelines and registered prospectively on PROSPERO (CRD420251089664). Eligible studies included adult patients with lamellar macular holes and LHEP managed with either vitrectomy or observation. The primary outcome was the change in best-corrected visual acuity (BCVA, logMAR). The secondary outcomes included progression to FTMH. Random-effects meta-analyses were conducted separately for surgical and observational cohorts due to limited direct comparative data. The risk of bias was assessed via the Newcastle–Ottawa Scale and the RoB 2 tool. Publication bias was evaluated via funnel plots, Egger’s test, and trim-and-fill analysis.
Results
Seventeen studies encompassing 610 eyes met the inclusion criteria. In surgically treated eyes (14 studies; 328 eyes), vitrectomy was associated with significant visual improvement (pooled mean difference in BCVA −0.170 logMAR; 95% CI [−0.254, −0.086]; P <.001), with minimal heterogeneity (I² = 0%). In the observational cohort (5 studies; 282 eyes), no significant change in visual acuity was observed (−0.029 logMAR; 95% CI [−0.118, 0.176]; P =.695). The pooled rate of progression to FTMH was 7.5% (95% CI [4.0%,13.6%]) after vitrectomy and 4.2% (95% CI [1.4%, 11.8%]) after observation, with overlapping confidence intervals. Bias-adjusted analyses suggested a wider confidence interval for FTMH progression in the vitrectomy cohort, 12.4% (95% CI [7.4%, 20.1%]), and observational cohort, 10.1% (95% CI [3.3%, 27.2%]).
Conclusion
In eyes with LHEP, vitrectomy is associated with clinically meaningful visual acuity improvement, whereas no significant change was observed in pooled observational data, without a clear increase in progression to FTMH. These findings support consideration of surgical intervention in appropriately selected patients, guided by symptoms and OCT-based features.
INTRODUCTION
L amellar macular holes (LMHs) are a heterogeneous group of macular disorders characterized by partial-thickness defects of the fovea. According to recent advances in optical coherence tomography (OCT), the definition and classification of LMHs have been refined. The current consensus defines LMH based on specific structural OCT criteria, which include irregular central foveal thinning, and a newly recognized type of epiretinal membrane, termed epiretinal proliferation. ,
Lamellar hole associated with epiretinal proliferation (LHEP) is a specific type of epiretinal tissue typically observed in a subset of LMHs. In contrast to the classic tractional epiretinal membrane (ERM), now termed as ERM foveoschisis, LHEP appears on OCT as a homogeneous, moderately reflective, and noncontractile layer closely adherent to the retinal surface. Histological and immunohistochemical analyses indicate that epiretinal proliferations mostly comprises Müller cell-derived glial material with negligible myofibroblastic components, suggesting a degenerative or reparative origin rather than a tractional one. , However, since this new terminology was recently adapted, in most of previous studies, ERM foveoschisis and LHEP were treated both as LMHs.
The previous dichotomy between tractional and degenerative LMHs is not in conformity with the current consensus framework. Nevertheless, the structural patterns associated with these terms remain clinically relevant, particularly when considering prognosis and management. In this regard, LHEPs are frequently perceived to manifest a degenerative phenotype with glial remodeling, thus showing consequences for visual outcomes, disease progression, and treatment strategies.
Observation seems appropriate for eyes with intact vision, minor symptoms, or stable LMH with LHEP, but vitrectomy is typically warranted in cases of progressive visual loss, metamorphopsia, or morphological decline. ,, Despite growing optimism about surgery, published studies on LHEP are heterogeneous and retrospective, often lacking observational comparators. Consequently, clinicians are uncertain whether surgery alters the natural history of LHEP or merely accelerates anatomical remodeling.
Therefore, the aim of this study was to specifically evaluate LHEP as a distinct OCT-defined phenotype. Rather than addressing LMH as a single entity, we focused on this clinically relevant subgroup to better understand its behavior and response to treatment. The primary objective was to determine whether vitrectomy yields superior benefits compared with observation alone by analyzing changes in visual acuity and, secondarily, progression to full-thickness macular hole (FTMH). Importantly, this study does not aim to inform the management of LMH as a whole, and its findings should not be extrapolated to other LMH subtypes.
METHODS
A systematic review and meta-analysis were conducted according to the American Journal of Ophthalmology guidance, Cochrane Handbook, and the results were reported according to the PRISMA guidelines. ,, This research adhered to the tenets of the Declaration of Helsinki; no institutional review board approval was needed since we used data from the available published literature. This study was registered prior to data extraction in the International Prospective Register of Systematic Reviews (PROSPERO) under number CRD420251089664, no amendments were performed, and review material can be found by contacting the corresponding author.
SEARCH STRATEGY
A literature search without filters was conducted in PubMed, Embase, Scopus, Cochrane, and Web of Science databases up to September 2025 via Boolean logic and Medical Subject Heading terms with the following search strategy: (“LHEP” OR “Lamellar hole-associated epiretinal proliferation” OR “degenerative lamellar macular hole” OR “lamellar hole epiretinal proliferation”) AND (“vitrectomy” OR “surgery” OR “surgical treatment” OR “observation” OR “conservative management”) AND (“retinal morphology” OR “visual acuity” OR “anatomic” OR “anatomy” OR “progression” OR “full-thickness macular hole” OR “FTMH” OR “outcome” OR “OCT” OR “Optical Coherence Tomography”). The results were exported to Mendeley (Elsevier©, Netherlands), and duplicates were excluded.
INCLUSION AND EXCLUSION CRITERIA
The literature search strategy and research question were designed using the patient–intervention–comparator–outcome (PICO) framework. This study was specifically designed to evaluate LHEP as a distinct OCT-defined phenotype. Eligible studies included adult patients with LMH presenting LHEP who underwent vitrectomy, regardless of surgical technique. Patients with LMH without LHEP or with other associated retinal conditions were excluded. Patients with LMH and LHEP who were managed conservatively were included as comparators.
The primary outcome was change in visual acuity, and the secondary outcome was the rate of conversion to full-thickness macular hole (FTMH). Both prospective and retrospective studies, including randomized and nonrandomized designs, were eligible given the limited number of available studies. No restrictions were applied regarding publication date or geographic location; however, only studies with full text available in English were included. Studies were excluded if they were case reports, conference abstracts or proceedings, systematic reviews, meta-analyses, or theses.
Studies were excluded from quantitative synthesis if outcome data could not be extracted in a format compatible with meta-analysis (eg, absence of baseline and final visual acuity values, lack of discrete FTMH event reporting, or nonstandardized outcome reporting formats). To ensure methodological consistency and validity of pooled estimates, only studies with extractable and standardized quantitative outcomes were included, which may have led to the exclusion of studies reporting results in noncomparable formats.
DATA EXTRACTION AND RISK OF BIAS
Four independent reviewers comprehensively reviewed the titles and abstracts of all the publications. Full-text articles that met the inclusion criteria were retrieved and assessed for eligibility. Discrepancies in the inclusion of the studies were discussed with a fifth reviewer to reach a consensus. The following information was collected from the included studies and added to a Microsoft Excel (Microsoft, USA) spreadsheet: first author, year of publication, location of the study, vitrectomy technique, number of patients who underwent vitrectomy, vitrectomy technique, number of patients observed, patients’ mean age and SD (SD) (vitrectomy group and observation group), mean and SD of the baseline visual acuity in logMAR (vitrectomy group and observation group), mean and SD of the final visual acuity in logMAR (vitrectomy group and observation group), number of patients who developed FTMH at the end of the follow-up period (vitrectomy group and observation group), and mean and SD follow-up time (vitrectomy group and observation group).
The risk of bias for individual studies was independently assessed by 2 reviewers, with the Newcastle–Ottawa Scale for case‒control studies, prospective longitudinal studies, and cohort studies. RoB2 was used to assess risk of bias in randomized clinical trials. , Article bias was also assessed by visual analysis of the funnel plot for evidence asymmetry and Egger’s test P value. To explore the potential impact of funnel plot asymmetry on the pooled estimate, the trim-and-fill method was employed.
STATISTICAL ANALYSIS AND DATA INTERPRETATION
Statistical analysis was performed via IBM SPSS version 30.0 (IBM, Inc., Chicago, IL). Continuous outcomes (visual acuity) were reported as the mean ± SD, mean difference (final– baseline), and SD of change according to the formula , and the correlation factor was considered 0.7, according to previously described methods. , Binary outcomes (progression to FTMH) were reported as the total number of events. Individual effect size and SE (SE) were estimated via logit transformation with continuity correction to lead with zeros ( ; , where P = the proportion of patients progressing to FTMH, n = the total number of patients, and 0.5 was used for continuity correction), according to previous methods. The pooled rate was calculated by the overall effect size ( ), according to previously described methods. A 95% CI (CI) was also calculated for effect size. Homogeneity between the included studies was assessed via Q statistics and its P value, and heterogeneity was assessed via I 2. The results are illustrated in forest plots and were considered significant if the P value <.05.
RESULTS
Literature search revealed 262 potential studies, of which 39 were duplicates; thus, 223 were screened. After screening and applying the inclusion and exclusion criteria, 17 studies were included in the review and meta-analysis according to the flow diagram in Figure 1 . The characteristics of the included studies are shown in Table 1 . There were 2 multicenter studies with more than one continent encompassing Europe, Asia, and North America; , 7 studies were developed in Asia (Japan, South Korea, India, and Taiwan); ,,,,,, 5 studies were developed in Europe only (Italy, Germany, Spain); ,,,, and 3 studies were solely developed in the USA. ,, Most of the studies were retrospective case series (82%), 2 were prospective case series, and one was a randomized comparative pilot study.
Flow diagram of the study selection process.
TABLE 1
Characteristics of the Selected Studies.
| First Author | Year | Country | Study Design | Study Group | Sample Size, Eyes | Age, years | Visual Acuity change, logMAR | Progression to FTMH, % (n) | Follow up, months | Bias Score |
|---|---|---|---|---|---|---|---|---|---|---|
| Ismael Chehaibou et al. | 2023 | Multicenter (France, USA, Italy, Spain, Germany, Japan, Austria, Serbia, Belgium, and United Kingdom) | Retrospective and consecutive case series | Vitrectomy (86.2% Peeling ILM, 7.7% ILM foveal sparing, 6.1% no ILM peeling) | 89 | 71.2 ± 9.8 | −0.11 ± 0.20 | 8.9 (8) | 24.1 ± 30.1 | 7 |
| Observation | 79 | 72.2 ± 9.7 | 0.03 ± 0.14 | 11.4 (9) | 45.7 ± 33.3 | |||||
| Su et al. | 2023 | Taiwan | Retrospective consecutive case series | Vitrectomy (Peeling ILM + embedding) | 30 | 61.1 ± 12.2 | −0.22 ± 0.29 | 0.0 | 61.4 ± 37.2 | 6 |
| Fukushima et al. | 2023 | Japan | Retrospective case series | Vitrectomy (Peeling ILM + embedding) | 4 | 72.2 ± 8.9 | −0.25 ± 0.09 | 0.0 | 12.0 ± 0.0 | 7 |
| Masanori Kanai et al. | 2023 | Japan | Retrospective case series | Vitrectomy (Peeling ILM + embedding) | 23 | 75.5±10.2 | −0.20±0.20 | 0.0 | 16.1±20.8 | 7 |
| Vitrectomy (Peeling ILM only) | 17 | 70.2±12.0 | 0.08±0.16 | 29.4 (5) | 32.5±23.3 | 7 | ||||
| Kumar et al. | 2021 | India | Retrospective case series | Vitrectomy (Peeling ILM + embedding) | 10 | 65.8 ± 5.3 | −0.37 ± 0.21 | 0.0 | 7.9 ± 0.9 | 4 |
| Morescalchi et al. | 2020 | Italy | Prospective, randomized, comparative pilot study. | Vitrectomy (Peeling LHEP and ILM foveal sparing) | 24 | 72.1 ± 8.3 | −0.27 ± 0.11 | 0.0 | 6.0 ± 0.0 | Some Concerns* |
| Observation | 10 | 70.5 ± 7.1 | 0.02 ± 0.15 | 0.0 | 6.0 ± 0.0 | |||||
| Tzyy-Chang Ho et al. | 2019 | Taiwan | Retrospective case series | Vitrectomy (Peeling ILM + embedding) | 11 | 67.0 ± 8.2 | −0.10 ± 0.21 | 0.0 | 28.2 ± 8.2 | 6 |
| Kosuke Takahashi et al. | 2019 | Japan | Retrospective case series | Vitrectomy (Peeling ILM + embedding) | 34 | 69.6 ± 10.1 | −0.21 ± 0.19 | 0.0 | 30.0 ± 17.7 | 6 |
| Marta S. Figueiroa et al. | 2018 | Multicenter (Spain, United Kingdom, and USA) | Retrospective observational study | Peeling ILM + ERM | 26 | 67.0 ± 8.9 | −0.17 ± 0.20 | 7.7 (2) | 8.0 ± 1.7 | 7 |
| Won Seok Choi et al. | 2018 | USA | Retrospective case series | Peeling ILM + ERM | 11 | 71.8 ± 7.9 | −0.10 ± 0.21 | 27.3 (3) | 23.4 ± 17.2 | 6 |
| Marco Frederico Marques et al. | 2017 | Portugal | Retrospective case series | Vitrectomy (Peeling ILM + ERM) | 13 | 73.0 ± 13.1 | −0.17 ± 0.23 | 0.0 | 7.3 ± 2.9 | 6 |
| Observation | 49 | Not mentioned | Not mentioned | 0.0 | 32.2 ± 19.2 | |||||
| Jaesang Ko et al. | 2017 | South Korea | Retrospective case series | Vitrectomy (Peeling ILM) | 15 | 67.4 ± 9.5 | −0.05 ± 0.30 | 0.0 | 22.3 ± 14.3 | 6 |
| Denise Compera et al. | 2017 | Multicenter (Germany and Italy) | Retrospective case series | Observation | 34 | 76.5 ± 9.0 | 0.02 ± 0.15 | 2.9 (1) | 40.5 ± 26.2 | 6 |
| Andrea Govetto et al. | 2016 | USA | Retrospective case series | Observation | 48 | 73.2±10.0 | 0.05±0.19 | Not mentioned | 38.2±21.0 | 7 |
| Denise Compera et al. | 2015 | Germany | Prospective case series | Vitrectomy (Peeling ILM + ERM) | 10 | 70 ± 6.0 | −0.07 ± 0.0 | 0.0 | 8.6 ± 3.0 | 4 |
| Claudine E. Pang et al. | 2015 | USA | Retrospective case series | Observation | 62 | 71.3 ± 14.1 | 0.10± | 1.6 (1) | 26.7 ± 23.0 | 6 |
| Denise Compera et al. | 2015 | Germany | Prospective case series | Vitrectomy (Peeling ILM + ERM) | 11 | 70.0 ± 6.3 | −0.13 ± 0.14 | 0.0 | 11.0 ± 3.2 | 7 |
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