
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12619-9
10.1016/j.heliyon.2024.e36588
e36588
Research Article
Meta-regression of idiopathic full-thickness macular holes diameter and anatomical closure rate: Implications to intraoperative technique
Zhang Ruiheng a1
Fang Yan-Cheng b1
Shi Xuhan a
Wu Haotian a
Yu Chuyao a
Li Yitong a
Zhou Wenda a
Li Heyan a
Zhang Chuan a
Zhou Yan-Feng b
Dong Li a
Wei Wenbin weiwenbintr@163.com
a⁎
a Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Ophthalmology & Visual Sciences Key Lab, Medical Artificial Intelligence Research and Verification Key Laboratory of the Ministry of Industry and Information Technology, Beijing Tongren Hospital, Capital Medical University, 1 Dong Jiao Min Lane, Beijing, 100730, China
b Department of Ophthalmology, First Affiliated Hospital of Anhui Medical University, No.218, Jixi Road, Shushan District, Hefei, Anhui, China
⁎ Corresponding author. weiwenbintr@163.com
1 These authors contributed equally to the study.

20 8 2024
15 9 2024
20 8 2024
10 17 e3658825 8 2023
13 8 2024
19 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Purpose

Primary surgery failure of macular holes causes poor visual acuity outcomes. Several studies indicate that small-medium idiopathic full-thickness macular holes (iFTMH) have consistent and high anatomical closure rates after vitrectomy and internal limiting membrane (ILM) peeling, regardless of iFTMH diameters. However, there is no systematic analysis examining the relationship between iFTMH diameters and anatomical closure rates.

Methods

In this systematic review and meta-regression, we searched PubMed, Embase, and Web of Science databases on October 24th, 2022. We included studies regarding iFTMH, with ILM peeling/inverted flap technique, long-lasting gas tamponade, and face-down position after surgery. Univariable meta-regression with a restricted cubic spline model and component-plus-residual plot after covariables adjustment were used to explore non-linear association.

Results

A total of 7257 participants from 19 randomized controlled trials and 49 observational studies were included in this meta-analysis. In ILM peeling group, every 100-μm increment in diameter was associated with a 3.8 % (95 % confidence interval [CI], 1.8%–5.7 %, P < 0.001) relatively lower anatomical closure rate. Yet, among studies using the inverted flap technique, baseline iFTMH diameter was not associated with a lower anatomical closure rate (0.2 %, 95%CI, −4.2 %–4.5 %, P > 0.9). The restricted cubic spline model and component-plus-residual plot controlling for age, sex, and symptom duration prior to surgery showed no evident non-linearity in both surgical techniques.

Conclusions

The iFTMH diameter is linear and inversely associated with the anatomical closure rate after the ILM peeling technique, but not with the inverted flap technique. The present study supports the use of advanced techniques, e.g., inverted flap technique, in small-medium iFTMH to improve anatomical closure rates.

Keywords

Idiopathic full-thickness macular hole
Diameter
Anatomical closure rate
Internal limiting membrane peeling
Inverted flap technique
==== Body
pmc1 Introduction

A macular hole is an anatomic discontinuity of the neurosensory retina that develops in the center of the macula or fovea [1]. Based on a population-based cross-sectional study of 4346 participants aged 40 or older, the Beijing Eye Study found that the full-thickness macular hole was detected in eight eyes of seven participants, which corresponds to a prevalence of 1.6 per 1000 Chinese people in this age range [2]. Another population-based cross-sectional study of 7774 participants aged 40 or older also found that the prevalence of macular holes is 1.7 per 1000 Indian people in this age range [3]. Macular holes are mostly idiopathic and related to vitreomacular traction syndrome [4]. Trauma, high myopia, macular telangiectasia Type 2, and other retinal pathologic conditions are also responsible for a minority of macular [4]. Although the anatomical close rate of idiopathic full-thickness macular hole (iFTMH) reached about 90 %, primary surgery can still fail or a late reopening of the iFTMH may occur [5]. Such conditions lead to repeated surgery and poor visual acuity outcomes.

Several techniques have been introduced to improve macular hole closure rate and postoperative visual acuity, especially the inverted internal limiting membrane (ILM) flap technique [1]. Inverted flap technique showed advantage regarding conditions including myopic macular hole, duration >6 months, and inability of the patient to keep the postoperative posturing [5,6]. Such a technique can simultaneously promote Müller cell induced-gliosis, potentially leading to delayed reconstitution of the ellipsoid zone and external limiting membrane [7,8]. In addition, inverted flap technique is time-consuming and might displace, especially during the fluid-air exchange. Thus, as for iFTMH, the inverted flap technique is primarily used in large iFTMH [9].

Several studies indicated small-medium iFTMH have consistent as well as high postoperative anatomical closure rates, regardless of iFTMH diameters [10,11], which gives less rationale to use advanced techniques, e.g., inverted flap technique, in small-medium iFTMH to further improve anatomical closure rate, because they require advanced skill and is time-consuming compared to ILM peeling alone. However, there is no systematic analysis examining the relationship between iFTMH diameters and anatomical closure rates. We here performed a meta-regress and found no evidence of threshold effect in the association between iFTMH diameter and anatomical closure rate, namely an anatomical closure rate was linear and inversely associated with iFTMH diameter. In such a way, we provide evidence that implicates potential advantages of using inverted flap techniques to improve anatomical closure rate for all iFTMH patients, including small-medium iFTMH.

2 Methods

2.1 Search strategy

This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist guideline [12]. Two authors (Zhang, and Fang) independently performed a systematic search on October 24th, 2022. We searched PubMed (published between 1946 to October 24th, 2022), Embase (published 1974 to October 24th, 2022), and Web of Science (1980 to October 24th, 2022), with keywords “macular hole”, “diameter”, and “size”. Relevant articles from the reference lists of the retrieved articles were also searched. We did not apply other restrictions to the literature search.

2.2 Inclusion and exclusion criteria

Two authors independently reviewed all studies by title and abstract. After primary selection, two authors independently screened full-text studies and considered for inclusion if they met the following criteria: (1) randomized controlled trials, prospective or retrospective cohort studies; (2) including iFTMH participants undergoing ILM peeling, with or without inverted flap covering, inverted flap plugging, or usage of autologous blood clotting, and maintained face-down position after surgery; (3) reporting minimal linear diameter and anatomy closure outcomes. We excluded studies with the following criteria: (1) with insufficient data for methodological quality assessment; (2) treated macular hole, trauma, high myopia, and other secondary macular holes; (3) tamponade with room air; (4) reviews, editorials, letters, abstracts, case reports, or practice guidelines. Any disagreements about study inclusion/exclusion that could not be resolved by discussion between two authors (Zhang and Fang) were decided by a third author (Wei).

2.3 Data extraction and definition of surgical techniques

The study design, number of eyes, mean/median of minimum linear diameter (μm) measured on OCT, surgical technique regarding ILM, tamponade, and finial anatomical closure were extracted. ILM peeling was defined as circular ILM peeling centered on the fovea after posterior vitreous detachment maneuver and staining, regardless of the extent. Inverted flap technique was defined as the peeled ILM attached at the edges, covering or plugging into the macular hole. Autologous blood clots might be alternatively applied to stabilize the inverted ILM flap.

2.4 Data processing and primary analyses

Our pre-specified primary analysis examined the association between baseline iFTMH diameter and anatomical closure rate. Each trial arm in randomized controlled trials and observation group in non-randomized studies was considered a separate observation, and intervention and control arms were included in the analysis. To minimize the dimension of trial arms and observation groups, those compared different extents of ILM peeling and gas for tamponade were further merged. We also set subgroups by patient enrollments (retrospective or prospective/randomized).

2.5 Statistics

Since the proportion of anatomical closure rate is close to or at 1 in some studies, we enabled the Freeman-Tukey double arcsine transformation to stabilize the variance without continuity correction [13]. The possibility of publication bias was assessed using Egger's test. We first generate inverse-variance weights from a random-effects model to detect any non-linear associations between iFTMH diameter and anatomical closure rate. A two-line piecewise linear model with a single change point was estimated by trying all possible values for the change point. Then, a restricted cubic spline model with four knots was applied during meta-regression. In multivariate random-effects adjustment, median imputation replaced the missing value. The component-plus-residual plot was used to identify non-linearity after adjusting for covariables. We repeated this analysis for different surgical techniques. A p-value <0.05 was considered statistically significant. All analyses were performed with STATA version 17.0 (StataCorp, College Station, Texas) and R (version 4.1.1; R Foundation for Statistical Computing, Vienna, Austria).

3 Result

3.1 Literature search

Through systemic research, we identified 1325 unique studies. After reviewing the titles and abstracts of these articles, a further 1156 were excluded. Among the remaining 169 full-text studies, 68 of them were in the final meta-analysis (Fig. 1). In all, a total of 7257 participants from 19 randomized controlled trials and 49 observational studies were included in the final meta-analysis (Table 1) [11,[14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80]]. 6112 patients received ILM peeling and 1145 patients inverted flap technique. The mean or median minimum linear diameters of iFTMH ranged from 227.0 to 803.3 μm. The diameter of iFTMH that received inverted flap technique (628.3 μm, interquartile range [IQR]: 456.4–663.4 μm) showed significantly larger compared received ILM peeling alone (452.2 μm, IQR: 359.5–519.9 μm, Kruskal-Wallis H test: P < 0.001). All patients received gas tamponade, including sulfur hexafluoride, perfluoroethane, or perfluoropropane, and were required to maintain the face-down position for at least three days. Egger's test did not find publication bias among studies using ILM peeling (P = 0.55) and inverted flap technique (P > 0.9).Fig. 1 Flowgram of included study. ILM, internal limiting membrane.

Fig. 1

Table 1 Characteristics of included studies.

Table 1Study (Author, year)	Country	Study design	Mean age	Female percentage	Symptom duration (month)	Number of Eyes	Mean/median of Minimum linear diameter (μm)	Surgical technique regarding ILM	Tamponade	Anatomical closure	
Randomized trials	
Agrawal 2022	India	Randomized	64.2	NA	3.4	75	749.7 ± 167.6	ILM peeling	20 % SF6	70/75 (93.3 %)	
65.4	NA	3.9	75	765.6 ± 77.0	Inverted flap plugging	20 % SF6	75/75 (100 %)	
Alberti 2016	Denmark	Randomized	69.8	58.8 %	8.0	34	394 ± 150	ILM peeling	15 % C3F8	33/34 (97.1 %)	
Babu 2020	India	Randomized	59.4	63.3 %	NA	30	803.3 ± 120.6	Inverted flap plugging	20 % SF6	27/30 (90.0 %)	
Bae 2016	South Korea	Randomized	64.0	76.7 %	NA	65	328.2 ± 150.6	ILM peeling	20 % SF6
14 % C3F8	63/65 (96.9 %)	
Briand 2015	Canada	Randomized	68.8	76.3 %	3.1	59	436.6 ± 144.4	ILM peeling	20 % SF6/15 % C3F8	54/59 (91.5 %)	
Cacciamani 2020	Italy	Randomized	67.5	50.0 %	NA	14	351 (310–438)	Inverted flap covering	20 % SF6	14/14 (100 %)	
66.5	64.3 %	NA	14	456 (298–536)	Inverted flap plugging	20 % SF6	14/14 (100 %)	
Elwan 2022	Egypt	Randomized	67.3	72.0 %	NA	25	589.8 ± 77.3	Inverted flap covering	20 % SF6	22/25 (88.0 %)	
Iovino 2018	Italy	Randomized	71.0	55.0 %	NA	20	664.6	Inverted flap covering	20 % SF6	20/20 (100 %)	
Kannan 2018	India	Randomized	61.2	43.3 %	NA	30	760.0 ± 85.0	ILM peeling	SF6	23/30 (76.7 %)	
Khodabande 2020	Iran	Randomized	65.9	45.0 %	NA	40	486.3 ± 145.3	ILM peeling	20 % SF6	31/40 (77.5 %)	
Lange 2012	U.K	Randomized	66.8	60.0 %	6.0	15	470 ± 165	ILM peeling	14 % C3F8	14/15 (93.3 %)	
Leisser 2022	Austria	Randomized	67.0	77.8 %	NA	9	244 ± 101	ILM peeling	20 % SF6	9/9 (100 %)	
71.0	57.1 %	NA	7	275 ± 90	Inverted flap covering	20 % SF6	7/7 (100 %)	
Manasa 2018	India	Randomized	61.0	NA	12.6	48	657.5	ILM peeling	20 % SF6	42/48 (87.5 %)	
63.4	NA	11.4	43	673	Inverted flap covering	20 % SF6	41/43 (95.3 %)	
Modi 2017	India	Randomized	64.6	68.0 %	9.5	50	397.5	ILM peeling	20 % SF6	36/50 (72.0 %)	
Pasu 2020	U.K	Randomized	69.0	75.6 %	5.0	88	517 (460–588)	ILM peeling	14 % C3F8	84/88 (95.5 %)	
Rishi 2022	India	Randomized	61.9	59.0 %	6.8	159	548.8 ± 229.7	ILM peeling	18 % SF6/16 % C2F6/12 % C3F8	119/159 (74.8 %)	
Sinawat 2021	Thailand	Randomized	62.4	75.0 %	12.2	100	633.0 ± 129.8	ILM peeling	20 % SF6	64/100 (64.0 %)	
Velez‐Montoya 2018	Mexico	Randomized	61.8	NA	3.9	12	522.2 ± 82.7	ILM peeling	18 % SF6/14 % C3F8	11/12 (91.7 %)	
			61.1	NA	3.2	12	608.9 ± 213	Inverted flap covering	18 % SF6/14 % C3F8	11/12 (91.7 %)	
Yao 2019	China	Randomized	64.6	74.4 %	4.7	121	484.5 ± 202.5	ILM peeling	20 % SF6	105/121 (86.8 %)	
Non-Randomized trials	
Baumann 2020	U.K	Retrospective	NA	NA	NA	68	560 ± 104	Inverted flap covering	12 % C3F8	67/68 (98.5 %)	
			NA	NA	NA	49	504 ± 106	ILM peeling	12 % C3F8	43/49 (87.8 %)	
Bleidiβel 2022	Germany	Retrospective	67.0	66.0 %	3.3	91	395 ± 147	Inverted flap covering	12 % C3F8	91/91 (100 %)	
Boral 2021	India	Retrospective	64.8	NA	NA	62	632.0 ± 146.6	ILM peeling	12 % C3F8	58/62 (93.6 %)	
			62.0	NA	NA	65	677.2 ± 152.1	Inverted flap covering	12 % C3F8	63/65 (96.8 %)	
Boral 2020	India	Retrospective	NA	54.3 %		75	618.4 ± 143.4	ILM peeling	12 % C3F8	67/75 (89.3 %)	
	NA	30	273.5 ± 64.6	ILM peeling	12 % C3F8	30/30 (100 %)	
Brasil 2019	Brazil	Retrospective	64.0	83.0 %	3.0	46	457 (135–954)	ILM peeling	15 % C3F8	42/46 (91.3 %)	
Chou 2022	Taiwan	Retrospective	NA	NA	NA	53	261.6 ± 99.7	Inverted flap covering	20 % SF6
15 % C3F8	52/53 (98.1 %)	
NA	NA	NA	62	251.9 ± 76.7	ILM peeling	20 % SF6
15 % C3F8	60/62 (96.7 %)	
Ch'ng 2018	U.K	Retrospective	71.4	69.8 %	NA	258	558 (400–1416)	ILM peeling	20 % SF6
14 % C3F8	232/258 (89.9 %)	
Chandra 2017	U.K	Retrospective	NA	68.9 %	NA	222	434.6 ± 186.4	ILM peeling	SF6
C3F8	193/222 (86.9 %)	
Chen 2018	China	Retrospective	57.9	76.8 %	NA	86	333.8 ± 148.0	ILM peeling	15 % C3F8	79/86 (91.9 %)	
112	403.6 ± 148.0	ILM peeling	15 % C3F8	102/112 (91.1 %)	
Chen 2016	China	Prospective, non-randomized	65.8	50.0 %	NA	8	629.0 ± 172.0	Inverted flap plugging	14 % C3F8	8/8 (100 %)	
El-Baha 2019	Egypt	Prospective, non-randomized	65.3	76.2 %	2.1	42	646	Inverted flap covering	20 % SF6	40/42 (95.2 %)	
Essex 2016	Australian	Prospective, non-randomized	69.1	65.6 %	3.0	2330	281 (200–400)	ILM peeling	SF6/C2F6/C3F8	2214/2330 (95.0 %)	
Feist 2014	U.K	Retrospective	NA	65.0 %	NA	57	408	ILM peeling	SF6/C3F8	55/57 (96.5 %)	
Forsaa 2013	Norway	Retrospective	68.4	75.8 %	10.6	33	456 ± 148	ILM peeling	SF6/C2F6	30/33 (90.9 %)	
Ghassemi 2019	U.S	Prospective, non-randomized	67.2	59.7 %	NA	72	545.5 ± 20.6	Inverted flap covering	20 % SF6	67/72 (93.1 %)	
Grewal 2015	U.S	Retrospective	68.5	62.8 %	NA	45	276.5 ± 161.4	ILM peeling	30 % SF6/14 % C3F8	45/45 (100 %)	
Hasegawa 2009	Japan	Retrospective	65.6	NA	NA	91	352 ± 155	ILM peeling	20 % SF6	82/91 (90.1 %)	
Hu 2020	China	Retrospective	64.4	77.8 %	64.4	25	754.4 ± 238.4	Inverted flap + autologous blood clot	15 % C3F8	24/25 (96.0 %)	
27	732.0 ± 143.4	Inverted flap plugging	15 % C3F8	25/27 (92.5 %)	
Hu 2018	China	Retrospective	62.1	NA	NA	12	657.8 ± 164.4	Inverted flap covering	15 % C3F8/Silicon oil	11/12 (91.7 %)	
Huang 2021	China	Retrospective	61.5	80.0 %	6.5	10	649.7	Inverted flap covering	15 % C3F8	10/10 (100 %)	
Jenisch 2017	Germany	Retrospective	70.0	68.0 %	NA	225	381 ± 168	ILM peeling	SF6/C2F6/C3F8	194/225 (86 %)	
Kazmierczak 2018	Poland	Retrospective	68.8	70.0 %	8.0	44	468.8	ILM peeling	C3F8	42/44 (95.45 %)	
Kumar 2018	India	Retrospective	56.8	40.0 %	NA	25	501 ± 162	ILM peeling	25 % SF6	25/25 (100 %)	
Kumari 2017	Pakistan	Retrospective	57.4	60.0 %	4.2	30	452.2 ± 242.3	ILM peeling	SF6	29/30 (96.7 %)	
Major 2020	U.S	Retrospective	63.8	75.0 %	NA	8	529 ± 101	Inverted flap covering	20–24 % SF6	8/8 (100 %)	
Marlow 2022	China	Retrospective	64.0	71.4 %	NA	7	681 ± 295	Inverted flap covering	SF6	6/7 (85.7 %)	
Nishitsuka 2021	Japan	Retrospective	55.6	NA	NA	10	278.3 ± 165.2	ILM peeling	Not mentioned	10/10 (100 %)	
Nourinia 2021	Iran	Prospective, non-randomized	62.3	76.5 %	NA	17	651.1 ± 141.1	Inverted flap covering	SF6	17/17 (100 %)	
Park 2019	South Korea	Retrospective	65.7	88.5 %	4.1	26	657.1 ± 121.8	Inverted flap covering	18 % SF6	26/26 (100 %)	
66.3	60.0 %	7.1	15	662.1 ± 120.9	Inverted flap plugging	18 % SF6	15/15 (100 %)	
Patel 2020	U.S	Retrospective	67.2	67.3 %	3.1	211	475.9	ILM peeling	SF6/C3F8	162/171 (94.7 %)	
Peng 2020	China	Retrospective	61.2	65.4 %	3.0	26	524.2 ± 147.9	ILM peeling	15 % C3F8	25/26 (96.2 %)	
Ra 2019	South Korea	Retrospective	66.2	76.9 %	6.2	26	641.9 ± 124.2	Inverted flap plugging	14 % C3F8	26/26 (100 %)	
Roth 2021	Germany	Retrospective	67.0	71.4 %	1.6	189	299	ILM peeling	C2F6	164/189 (86.8 %)	
Ruiz-Moreno 2008	Spain	Retrospective	69.0	54.3 %	NA	46	415.7 ± 183.7	ILM peeling	14 % C3F8	44/46 (95.7 %)	
Salter 2012	U.S	Retrospective	NA	65.0 %	4.1	153	474.0 ± 245.0	ILM peeling	14 % C3F8	143/153 (93.5 %)	
Shpak 2016	Russia	Retrospective and Prospective	65.7	88.5 %	NA	170	378.1 ± 150.5	ILM peeling	Not mentioned	155/170 (91.2 %)	
Schaub 2020	Germany	Retrospective	67.3	65.0 %	3.7	105	579.8 ± 160.0	ILM peeling	20 % SF6	88/105 (83.8 %)	
Shukla 2022	United Arab Emirates	Retrospective	63.6	81.0 %	9.8	21	602	ILM peeling	15 % C3F8	20/21 (95.2 %)	
Silva 2021	Portugal	Retrospective	70.0	65.0 %	NA	76	447 ± 189	Inverted flap plugging	SF6/C3F8	70/76 (92.1 %)	
Sinawat 2021	Thailand	Retrospective	62.9	73.5 %	12.6	158	644.9 ± 136.8	ILM peeling	20 % SF6/14 % C3F8	97/158 (61.4 %)	
Tao 2020	China	Retrospective	66.0	67.9 %	3.0	53	421.0 ± 170.9	ILM peeling	C3F8	52/53 (98.1 %)	
Toklu 2022	Turkey	Retrospective	70.0	30.0 %	NA	9	456.7 ± 150.0	Inverted flap covering	20 % SF6	9/9 (100 %)	
Usui 2013	Japan	Retrospective	60.2	72.7 %	2.8	11	303 ± 98	ILM peeling	20 % SF6	11/11 (100 %)	
Veith 2020	Czech	Retrospective	72.4	NA	NA	53	358.7	ILM peeling	20 % SF6	26/27 (96.3 %)	
Wilczyński 2019	Poland	Prospective, non-randomized	68.3	67.9 %	NA	28	446.1	ILM peeling	SF6	28/28 (100 %)	
Wons 2022	Switzerland	Retrospective	68.8	61.0 %	NA	100	325 ± 170	ILM peeling	15%SF6	100/100 (100 %)	
Yamada 2022	Japan	Retrospective	66.6	NA	2.0	21	278.6 ± 80.7	Inverted flap covering	SF6	19/21 (90.5 %)	
			66.2	NA	2.0	21	276.0 ± 84.5	ILM peeling	SF6	21/21 (100 %)	
Yamashita 2014	Japan	Retrospective	66.3	58.4 %	NA	149	328.4 ± 115.3	ILM peeling	15 % SF6	143/149 (96.0 %)	
Yan 2021	China	Retrospective	67.9	84.2 %	6.9	29	533.4 ± 245.0	Inverted flap covering	20 % C2F6	29/29 (100 %)	
64.3	59.4 %	11.6	19	502.8 ± 128.6	ILM peeling	20 % C2F6	18/19 (100 %)	
ILM, internal limiting membrane. SF6, sulfur hexafluoride; C2F6, perfluoroethane; C3F8, perfluoropropane.

3.2 Univariable meta-regressions

In random-effects linear meta-regression analysis, there was a significant inverse relationship between baseline iFTMH diameter and the anatomical closure rate, such that every 100-μm increment in diameter was associated with a 3.8 % (95 % confidence interval [CI], 1.8%–5.7 %, P < 0.001) relatively lower anatomical closure rate in ILM peeling group. Yet, among studies using inverted flap technique, baseline iFTMH diameter did not associate with a lower anatomical closure rate (0.2 % for every 100-μm increment in diameter, 95 % CI, −4.2 %–4.5 %, P > 0.9, Fig. 2). Neither the two-line piecewise linear model (P > 0.2 for all points) nor non-linear meta-regression based on the restricted cubic spline model (P > 0.7 for all knots) found any non-linear association in both surgical techniques, indicating that there was no threshold effect of iFTMH diameter on anatomical closure rate (Fig. 3).Fig. 2 Linear Association between baseline iFTMH diameter and anatomical closure rate.

Baseline iFTMH diameter and anatomical closure rate among studies using ILM peeling technique (A) and inverted flap technique (B). ILM, internal limiting membrane.

Fig. 2

Fig. 3 Non-Linear regression between baseline iFTMH diameter and anatomical closure rate.

Restricted cubic spline model for detecting non-linear association between baseline iFTMH diameter and anatomical closure rate among studies using ILM peeling technique (A) and inverted flap technique (B). ILM, internal limiting membrane.

Fig. 3

3.3 Sensitive analysis

We then performed a sensitive analysis to minimize retrospective selection bias by including randomized controlled trials and prospective non-randomized studies. Three thousand seven hundred seventy-one patients from 26 included studies were finally included for analysis. In random-effects linear meta-regression analysis, there was a significant inverse relationship between baseline iFTMH diameter and the anatomical closure rate (4.0 % for every 100-μm increment in diameter, 95 % CI 1.4%–6.7 %, P = 0.03) relatively lower anatomical closure rate in ILM peeling group. Yet, among studies using inverted flap technique, baseline iFTMH diameter did not associate with a lower anatomical closure rate (0.0 % for every 100-μm increment in diameter, 95 % CI, −8.3 %–8.4 %, P > 0.9). Similarly, non-linear meta-regress did not find any non-linear association in both surgical techniques (Supplementary Figs. 1–2).

3.4 Multivariate adjustment and component-plus-residual plot analysis

In the univariate regression models, age and symptom duration prior to surgery were associated with anatomical closure rate (Supplementary Table 1). After controlling for age, sex and symptom duration prior to surgery, the component-plus-residual plot showed no evident non-linear association in both surgical techniques (Fig. 4).Fig. 4 Component-plus-residual plot of the association between baseline iFTMH diameter and anatomical closure rate, adjusting for age, sex and duration prior to surgery.

The component-plus-residual plot showed no evident non-linear association among studies using ILM peeling technique (A) and inverted flap technique (B). ILM, internal limiting membrane.

Fig. 4

4 Discussion

The present study exhibited a significant linear and inverse association between baseline iFTMH diameter and anatomical closure rate among studies using ILM peeling technique, but not the inverted flap technique. It indicates that the successful anatomical closure would be affected by greater iFTMH diameter after ILM peeling, even in small-medium iFTMH.

There is no direct evidence regarding the benefits of using inverted flap technique in small-medium iFTMH, compared to ILM peeling alone. Recently, an individual participant data study of randomized controlled trials revealed that ILM peeling, inverted flap use and smaller iFTMH size were associated with increased odds of primary closure [81]. By using multilevel logistic regression, Murphy's study found ILM peeling (OR = 18.16, 95%CI, 8.14–40.47, P < 0.001) and inverted flap use (OR = 3.656, 95%CI, 1.673–7.988, P = 0.001) could improve anatomical closure [81]. Yet, such a finding was concluded based on 940 patients with a median minimum linear diameter of 492 μm. It is still unclear whether the inverted flap technique is beneficial in small-medium iFTMH, given that it requires advanced skill and is time-consuming compared to ILM peeling alone.

Macular hole diameter is a strong indicator of anatomical closure and vision outcome [11,62]. Some studies indicated a threshold effect of iFTMH diameter on anatomical closure rate, namely an anatomical closure rate that remained constant within a specific diameter and decreased beyond such diameter. For example, Steel et al. analyzed 1483 idiopathic iFTMH and found that the anatomical closure rate remained above 95 % among patients with diameters smaller than 500 μm [10]. The surgery failed closure rates significantly increased among patients with diameters larger than 500 μm [10]. The study from Ch'ng et al. reached a similar finding, with the threshold near 650 μm [11]. If such a threshold effect exists, it might favor ILM peeling alone with threshold iFTMH diameter. However, the present study did not support a threshold effect in the association between baseline iFTMH diameter and anatomical closure rate.

In the present study, we excluded studies tamponade with room air to minimize heterogeneity because long-lasting gas tamponade showed significant benefits of anatomical closure [81]. We also excluded studies (arms) that did not require patients to maintain face-down position, as several studies found postoperative face-forward position might be inferior to face-down position [31,56]. We found no publication bias among the 68 included studies. Using univariable meta-regression analysis, we found no evidence of non-linearity in the association baseline iFTMH diameter and the anatomical closure rate. To minimize retrospective selection bias and reduce heterogeneity, we performed sensitive analysis by including prospective enrolled studies and made multivariate adjustments for age and symptom duration prior to surgery. Through such analysis, the present study exhibited no non-linear association between iFTMH diameter and anatomical closure, which further indicates that the chance of anatomical closure decreases as iFTMH diameter increases among small-medium iFTMH after standard ILM peeling. Inverted flap technique is advantageous and prefers to myopic, refractory, and large iFTMH to support anatomical closure [5,6]. It further showed additional benefits for visual acuity outcomes [81]. Thus, the present study support the use of the inverted flap technique in small-medium iFTMH to achieve a better chance of anatomical closure.

These are some limitations that should be analyzed. First, because of an absence of studies comparing ILM peeling and inverted flap technique in small-medium size iFTMH, we cannot directly draw the conclusion that inverted flap technique is superior to ILM peeling in small-medium size iFTMH. Further studies are needed to validate the present conclusion. Yet, because of the high success rate of small-medium iFTMH, it requires a large sample size to reduce the chance of Type II error. Second, we merged study arms that compared different extents of ILM peeling and gas for tamponade during data extraction, which may inevitably invite heterogeneity. Thirdly, the anatomical closure of iFTMH is influenced by several factors, such as surgeon skills and compliance of face-down position. Access to individual patient data would allow a more robust analysis.

5 Conclusion

Baseline iFTMH diameter is linear and inversely associated with anatomical closure rate among studies using the ILM peeling technique, but not the inverted flap technique. The present study supports for using inverted flap technique in small-medium iFTMH to achieve a better chance of anatomical closure.

Ethics statement

Ethical approval for this systematic review and meta-analysis is not applicable since the data was collected from previously published literature.

Data availability statement

Data used in this study was collected from previously published literature. Extracted data are available within the paper and its supplementary material.

CRediT authorship contribution statement

Ruiheng Zhang: Writing – review & editing, Writing – original draft, Methodology, Data curation, Conceptualization. Yan-Cheng Fang: Writing – review & editing, Methodology, Formal analysis, Data curation. Xuhan Shi: Writing – original draft, Formal analysis, Data curation. Haotian Wu: Formal analysis, Data curation. Chuyao Yu: Formal analysis, Data curation. Yitong Li: Resources, Methodology. Wenda Zhou: Methodology, Formal analysis. Heyan Li: Methodology, Formal analysis. Chuan Zhang: Validation, Data curation. Yan-Feng Zhou: Software, Methodology, Formal analysis. Li Dong: Visualization, Formal analysis, Data curation. Wenbin Wei: Writing – review & editing, Writing – original draft, Supervision, Funding acquisition, Formal analysis, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A Supplementary data

The following is the supplementary data to this article:Multimedia component 1

Multimedia component 1

Acknowledgments

This study was supported by the 10.13039/501100001809 National Natural Science Foundation of China (82220108017 , 82141128 ), the Capital Health Research and Development of Special (2020-1-2052 ), and the Science & Technology Project of 10.13039/501100009592 Beijing Municipal Science & Technology Commission (Z201100005520045 , Z181100001818003 ).

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.heliyon.2024.e36588.
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