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International Journal of Ophthalmology logoLink to International Journal of Ophthalmology
. 2019 Dec 18;12(12):1917–1928. doi: 10.18240/ijo.2019.12.15

Internal limiting membrane peeling with different dyes in the surgery of idiopathic macular hole: a systematic review of literature and network Meta-analysis

Shan-Shan Li 1, Ran You 1, Min Li 2, Xiao-Xiao Guo 1, Lu Zhao 1, Yan-Ling Wang 1, Xi Chen 1
PMCID: PMC6901880  PMID: 31850178

Abstract

AIM

To evaluate the effect of internal limiting membrane (ILM) peeling with indocyanine green (ICG), brilliant blue G (BBG), triamcinolone acetonide (TA), trypan blue (TB), or without dye for the treatment of idiopathic macular hole (IMH).

METHODS

A search was conducted using PubMed, EMBASE, and CENTRAL (Cochrane Central Register of Controlled Trials) for related studies published before October 2018.

RESULTS

A total of 29 studies and 2514 eyes were included in this network Meta-analysis. For IMH closure, the rank from the best to the worse treatment was: BBG, TB, TA, ICG, and no dye. There was a significant difference in postoperative IMH closure rate between BBG and no dye. The rank of the best to the worse treatment to improve visual acuity was: BBG, TB, no dye, TA, and ICG. The improvement rate of visual acuity after using BBG was significantly higher than ICG. The improvement rate of visual acuity was more favorable with TB than ICG, TA, and no dye.

CONCLUSION

BBG can contribute to better anatomical and functional outcomes compared to other dyes for ILM peeling in patients with IMH. The results show that the best treatment of ILM peeling with dyes is BBG.

Keywords: idiopathic macular hole, brilliant blue G, trypan blue, internal limiting membrane peeling, network Meta-analysis

INTRODUCTION

Idiopathic macular hole (IMH) is an important condition that leads to blindness[1]. Patients with IMH have a prevalence of 8 cases per 100 000 people[2], and patients with visual impairment have an incidence of 0.2/1000 to 0.3/1000[3]–[4]. IMH has a serious impact on patients' quality of life, however, it can be repaired by the surgery of pars plana vitrectomy (PPV)[5].

In 1971, Machemer et al[6] firstly described a vitrectomy. With the development of medical technology, vitrectomy combined with inner limiting membrane (ILM) peeling shows better outcomes compared to no ILM peeling[7]–[9]. However, the ILM is thin and transparent which makes it a challenge for the surgeon, and it is difficult to distinguish the boundary and range of the peeling[10]. It is for this reason that indocyanine green (ICG) dye, which was initially used for fluorescein angiography, was firstly used for ILM staining in 2000 and improved the visualization of ILM during the surgery and promoted the development of ILM peeling[11]. Since then, ILM peeling with ICG has been widely reported to promote the surgery of MHs[12]–[13]. However, ICG could also cause damage to the retinal ganglion cells and retinal pigment epithelium (RPE) because of its toxicity, the mechanism might be related to the oxidative toxicity of ICG[14]. Brilliant blue G (BBG) is an alternative dye for staining ILM and has been frequently used throughout the world. However, in vitro, it has been shown that BBG is related to cellular toxicity[14]–[15], and other dyes applied to ILM peeling surgeries have also shown toxic effects on the retina[16]–[17], such as trypan blue (TB) and triamcinolone acetonide (TA)[2],[18].

In summary, almost all kinds of biological dyes have potential side effects on the retina. At present, there are few comparative reports of postoperative results from ICG, BBG, TB, TA, and no dye assisted ILM peeling for patients with IMH. Therefore, this network Meta-analysis study is mainly for patients with IMH, to analysis and summarize the anatomical outcome (rate of postoperative primary MH closure) and functional outcome [rate of vision improvement and best corrected visual acuity (BCVA)] for ILM peeling with ICG, BBG, TB, TA, and no dye.

MATERIALS AND METHODS

This systematic review and a Meta-analysis were conducted according to the recommendations from the Cochrane Handbook for Systematic Review of Interventions[19].

Search Strategy

The PubMed, MEDLINE, EMBASE, and CENTRAL (Cochrane Central Register of Controlled Trials) were searched for related published studies, with no language restrictions before October 2018. The terms used for the systematic search were (“brilliant blue”, OR “indocyanine green”, OR “triamcinolone acetonide”, OR “trypan blue”, OR ICG, OR TB, OR TA, OR BBG) AND (“internal limiting membrane peeling”, OR “primary macular hole”, OR “idiopathic macular hole”). We also manually collected the reference lists for the original studies and review articles were examined by internet-based search for additional eligible articles.

Eligibility Criteria

The articles taken from the internet-based search were established to screen the qualified trials. The eligible studies must have been met: 1) comparative studies; 2) contained at least two groups, with the ILM-peeling procedure and with application of ICG, or BBG, or TB, or TA, or peeling without staining; 3) included only IMH patients, and ILM peeling was conducted in case and control groups; 4) at least one of the outcomes of interest was included.

Data Extraction and Quality Assessment

The data were extracted independently by two reviewers and were rechecked after the first extraction. Any disagreement of eligibility during the extraction was discussed by the two reviewers and resolved. The extracted information from each study included the first author, year, study type, number of subjects, age, stages of MHs, preoperative BCVAs (logarithm of the minimal angle of resolution, logMAR), follow-up time, and dyes. The outcomes of interest were extracted and included the following: the primary closure rate (MH closure after the initial surgery) and the number of people with improved visual acuity. We contacted the authors for any missing data.

The quality of the retrospective studies was assessed using the Newcastle-Ottawa Scale (NOS)[20]. The NOS was used to evaluate the selection, comparability, and outcome or exposure for cohort or case-control studies. The maximum for selection was 4 stars, for comparability was 2 stars, and for outcome or exposure was 3 stars. The maximum NOS score was 9 stars, and the studies with 6 stars were considered to have a relatively high quality.

The quality of the randomized clinical trial (RCT) studies, using the methods of the Cochrane Handbook for Systematic Reviews of Interventions[21], were assesed according to the following parameters: bias in sequence generation; bias in allocation concealment; bias in masking of participants and personnel; bias due to incomplete outcome data; bias due to selection of outcome reporting; and other bias.

Statistical Analysis

Methods for direct treatment comparisons

Odds ratios (ORs) and 95% confidence intervals (CI) were calculated as effect measures. We pooled summary estimate using the random-effects method, which recognized and anchored studies as a sample of all potential studies[22]. The I2 statistic was calculated as a measure of the proportion of overall variation that was attributable to between-study heterogeneity.

Methods for indirect and mixed comparisons

To evaluate the relative efficacy of postoperative IMH closure rate and the rate of vision improvement and BCVA for ILM peeling with ICG, BBG, TB, TA, and no dye for the patients with IMH, we used a random-effects network Meta-analysis, within a frequentist frame-work taken into account simultaneously[23].

Besides, the surface under the cumulative ranking curve (SUCRA) was used to assess the ranking probabilities for all treatments on anatomical and functional outcomes in order to obtain a treatment hierarchy[24]. A loop specific approach was used to assess the presence of inconsistencies locally in network Meta-analysis models, that is, whether the information of both sources of evidence was similar enough to be combined[25]. ORs and 95%CI were also calculated as effect measures.

Funnel plot and publication bias

The difference between the observed effect size and comparison specific summary effect for each study was calculated. Then, this variable was regressed on standard error (SE) and thus, a simple linear regression line was added in the funnel plot, which could help us explore visually if there was a publication bias in the results among the original studies. All of the analyses were conducted using STATA 15.1 software (pairwise Meta-analysis, network Meta-analysis, I2 calculations, SUCRA graphs, and funnel plot). P<0.05 was considered statistically significant.

RESULTS

Selection of Studies

A total of 1425 articles were initially identified. Then, we excluded 1341 unrelated articles by screening the titles and abstracts and 55 duplicate articles were also excluded. A total of 34 articles with full text that met the inclusion criteria were assessed. Subsequently, 3 articles were from the same trial and 2 articles did not contain interest data. Finally, a total of 29 studies with full text, published between 2004 and 2014 were selected for the network Meta-analysis (Figure 1).

Figure 1. Study selection.

Figure 1

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Baseline Characteristics of the Included Studies

Table 1 shows the baseline characteristics of the included studies. Among 29 of the included studies, 6 articles were RCTs, 4 articles were three-arm trials, and 23 articles were retrospective trials. A total of 2514 eyes were included, with 1132 in the ICG group, 340 in the BBG group, 89 in the TB group, 236 in the TA group, and 717 in the no dye group. The follow-up duration was between 6 and 19mo. MH was stage 2-4. The concentration of ICG was 0.05-2.5mg/mL. TB was 0.025-0.25 mg/mL, and BBG was 0.25-0.5 mg/mL (Table 1). The different dyes were assessed by studies that compared ICG vs BBG vs TB (n=1), ICG vs TA vs no dye (n=1), ICG vs BBG vs TA (n=2), BBG vs TA (n=1), BBG vs no dye (n=2), ICG vs no dye (n=12), ICG vs TA (n=2), ICG vs BBG (n=4), and ICG vs TB (n=4; Figure 1).

Table 1. Baseline characteristics of the included studies.

Study Trial type No. of eyes Age (y) Gender (M/F) Treatment group Preoperative BCVA Follow-up months MH stage
Shukla, 2011[26] Retrospective 50 (15:20:15) 59.5±7.3; 58.8±7.7; 58.7±7.9 24/26 BBG 0.5 mg/mL TB 0.15%; ICG 1.25 mg/mL 0.2±0.13; 0.19±0.09; 0.18±0.08 6 s3-s4
Christensen, 2009[27] Randomized 77 (34:18) 66.9/66.6 8:27/9:9 ICG 0.05%; TB 0.15% 50.5±5.9; 49.9±6.5 12 s2-s3
Bellerive, 2013[28] Randomized 25 (11:14) 64.5±9.4; 65.4±4.9 5:6/3:11 ICG 2.5 mg/mL; TB 0.06% 38.9±8.5; 39.8±5 12 s2-s4
Lee, 2005[29] Retrospective 37 (19:18) 70.7/68.6 NA ICG 0.05%-0.5%; TB 0.15% 0.91/0.85 >6 s2-s4
Beutel, 2007[30] Randomized 40 (19:19) 67.2±4.7; 69.3±5.9 7:13/9:11 ICG 0.05%; TB 0.15% 20/40; 20/50 6 s2-s4
Baba, 2012[31] Retrospective 73 (28:35) 65.7±7.3; 67.1±4.8 9:19/17:18 ICG 1.25 mg/mL; BBG 0.25 mg/mL 0.8±0.3; 0.8±0.3 6 s2-s4
Williamson, 2014[32] Retrospective 318 (209:109) 68.9 107/211 ICG 0.5 mg/mL; BBG; NA 0.97±0.45 6 s2-s4
Fukuda, 2011[33] Retrospective 53 (22:31) 68/67 12:10/14:17 ICG 1.25 mg/mL; BBG 0.25 mg/mL 0.59±0.27; 0.61±0.29 6 s2-s4
Horio, 2004[34] Randomized 40 (20:20) 64.7±6.9; 63.5±6.9 7:12/5:15 ICG 0.125%; no dye 0.92±0.25; 0.92±0.24 >12 s2-s4
Ando, 2004[35] Retrospective 97 (28:21) 64.5/65.3 8:20/7:14 ICG 0.5%; no dye 0.77±0.53; 0.98±0.43 >12 s2-s4
Nakamura, 2009[36] Retrospective 75 (16:38) 64.5±1.4; 64.5±0.8 6:10/12:26 ICG 0.25%; no dye 0.81±0.07; 0.82±0.05 >12 s2-s4
Shiono, 2013[37] Retrospective 34 (19:15) 66.3±9.3; 66.3±9.3 NA ICG 2.5 mg/mL; no dye 0.77±0.34; 0.65±0.4 6 s2-s4
Ferencz, 2006[38] Retrospective 30 (21:9) 65.7±5.8; 70.0±4.9 7:14/2:7 ICG 0.125%; no dye 0.83±0.27; 0.89±0.23 >6 s2-s4
Kumagai, 2006[39] Retrospective 190 (96/94) 65.3±7.3; 65.3±6.7 33:63/28:66 ICG 0.1%; no dye 0.7±0.34; 0.78±0.33 >12 s2-s4
Schaal, 2009[40] Retrospective 240 (90:66) 69/63 NA ICG 0.5%; no dye 20/60-20/150 >12 s2-s4
Lochhead, 2004[41] Retrospective 68 (34:34) 69.9/67.5 10:24/10:24 ICG 0.5%; no dye 1.00/0.99 <12 s3-s4
Nagai, 2007[42] Retrospective 53 (35:18) 65.3±6.6; 64.3±5.5 8:27/6:12 ICG NA; no dye 0.83±0.27; 0.89±0.23 >12 s2-s4
Mochizuki, 2014[43] Retrospective 97 (61:15:21) 65.9±8.6; 68.6±7.4; 63.2±7.6 16/32 ICG 2.5 mg/mL; BBG 0.025% TA NA 12 s2-s4
Karacorlu, 2005[44] Retrospective 30 (15:15) 64.6/64.5 8:7/9:6 ICG 0.05%; TA NA >6 s3-s4
Nomoto, 2008[45] Retrospective 67 (27:40) 65.8±7.7; 61.7±9.3 5:22/14:26 ICG 0.25%; TA 0.81±0.4; 0.78±0.3 12 s2-s4
Tsipursky, 2013[46] Retrospective 430 (119:97:209) 68.7±8.0; 67.5±8.0; 67.4±8.1 NA ICG 0.125%; TA 40 mg/mL; no dye 0.86±0.38; 0.78±0.31 0.86±0.63 12 NA
Machida, 2014[47] Randomized 48 (16:16:16) 64.6 ±7.62 16/32 ICG 2.5 mg/mL; BBG 0.25mg/mL; TA NA 12 NA
Caramoy, 2012[48] Randomized 56 (15:11) NA NA ICG 0.5 mg/mL; BBG 0.25 mg/mL 0.5±0.08; 0.55±0.1 12 NA
Fu, 2014[49] Retrospective 83 (41:42) 56.74±3.62 9:33/7:34 BBG 0.25 mg/mL; no dye 0.10±0.052; 0.13±0.046 6 s2-s4
Kumar, 2011[50] Retrospective 94 (47:47) 60.8±3.71; 60.3±3.92 NA BBG 0.05%; TA 1.15±0.38 >12 s2-s4
Selton, 2012[51] Retrospective 40 (20:20) 69.2±7.8; 66.4±7.0 NA BBG NA; no dye NA 6 s2-s4
Rüfer, 2007[52] Retrospective 61 (36:25) NA 15:46 ICG NA; no dye 0.71±0.30 12 s2-s4
Meyer, 2008[53] Retrospective 91 (46:45) NA NA ICG NA; no dye NA 19 s2-s4
Brasil, 2006[54] Retrospective 142 (81:61) 64.46±8.45; 65.04±7.26 17/64; 17/44 ICG 2.5mg/mL; no dye 0.12±0.15; 0.18±0.18 NA s2-s4
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BCVA: Best corrected visual acuity; NA: Not available; ICG: Indocyanine green; BBG: Brilliant blue G; TB: Trypan blue; TA: Triamcinolone acetonide.

Quality Assessment of the Included Studies

For the Newcastle-Ottawa Scale, 18 retrospective studies had scores ≥6 and 4 retrospective studies had 5 (Table 2). For RCT studies, bias could be considered low in six RCTs (Figure 2).

Table 2. Quality assessment of the retrospective studies.

Study Country Study quality (NOS Scale)
Selection Comparability Expose Total score
Shukla, 2011[26] India 4 2 1 7
Lee, 2005[29] New Zealand 3 2 1 6
Baba, 2012[31] Japan 4 1 1 6
Williamson, 2014[32] UK 4 2 1 7
Fukuda, 2011[33] Japan 4 1 1 6
Ando, 2004[35] Japan 3 2 2 7
Nakamura, 2009[36] Japan 3 2 2 7
Shiono, 2013[37] Japan 4 1 1 6
Ferencz, 2006[38] Hungary 3 2 1 6
Kumagai, 2006[39] Japan 3 1 1 5
Schaal, 2009[40] US 3 1 2 6
Lochhead, 2004[41] UK 4 1 1 6
Nagai, 2007[42] Japan 3 2 1 6
Mochizuki, 2014[43] Japan 3 2 1 6
Karacorlu, 2005[44] Turkey 3 1 1 5
Nomoto, 2008[45] Japan 3 1 2 6
Tsipursky, 2013[46] US 4 1 2 7
Fu, 2014[49] China 3 2 1 6
Kumar, 2011[50] India 4 1 1 6
Selton, 2012[51] France 3 2 1 6
Brasil, 2006[54] Brazil 3 2 1 6
Rüfer, 2007[52] Germany 3 1 1 5
Meyer, 2008[53] Germany 3 1 1 5
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NOS Scale: Newcastle-Ottowa Scale.

Figure 2. Bias assessment of the six randomized clinical trial studies were performed by “Cochrane Collaboration's tool for assessing the risk of bias”.

Figure 2

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Network Plots

Figure 3 presents the corresponding structure of network, where 5 treatments formed 10 different pairs of comparisons. The network plots whose nodes were weighted corresponding to the sample size that showed direct comparison of different dyes, such as BBG, ICG, TB, TA, and no dye. The number of included trials for specific direct comparison decides the thickness of straight lines. The line between the two treatments indicates evidence of direct comparison. Figure 3A shows the network relationship of the IMH closure rate. The line indicates that there were 8 direct comparisons and the remaining 2 lines had no direct comparison. Figure 3B shows the improvement rate of visual acuity after ILM peeling. The connection indicates that there were 6 direct comparisons and the remaining 4 had no direct comparison evidence. Figure 3C shows the result of BCVA in postoperative patients. The connection indicates that there were 5 direct comparisons, and the remaining 4 had no direct comparison evidence.

Figure 3. Network structure for different treatments was included in the network Meta-analysis.

Figure 3

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A: Primary IMH closure rate; B: Rate of improved visual acuity; C: Postoperative visual acuity (logMAR). ICG: Indocyanine green; BBG: Brilliant blue G; TB: Trypan blue; TA: Triamcinolone acetonide; logMAR: Logarithm of the minimal angle of resolution.

Forest Plots of the Pairwise and Network Meta-Analysis

Forest plot of the pairwise Meta-analyses shows the result of the MH closure of dyes had no significant difference. The result of improved visual acuity shows that ILM peeling BBG was better than ICG (OR 0.12, 95%CI 0.02-0.66, heterogeneity I2=0). The results of BCVA after ILM peeling with TA and BBG were better than ICG (OR 0.08, 95%CI 0.02-0.14, heterogeneity I2=0, P=0.536; OR 0.10, 95%CI 0.02-0.17, heterogeneity I2=53.5%, P=0.072; Figure 4).

Figure 4. Forest plot of results of the pairwise Meta-analysis.

Figure 4

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A: Primary MH closure rate; B: Rate of improved visual acuity; C: Postoperative visual acuity (logMAR). WMD: Weighted mean difference.

Figure 5 presents the results of network Meta-analysis. It shows the result of MH closure rate after ILM peeling. For no dye vs BBG, the rate of BBG assisted IMH closure was higher than no dye, significantly (OR: 0.36, 95%CI: 0.14-0.92). Other comparisons was no statistical significance. Figure 5 B shows the result of the rate of improved visual acuity after ILM peeling. For ICG vs BBG, TB vs ICG, TB vs TA, and no dye vs TB, the difference was statistically significant (OR 0.19, 95%CI 0.04-0.9; OR 4.57, 95%CI 1.46-14.32; OR 3.53, 95%CI 1.03-12.13; OR 0.29, 95%CI 0.09-0.96, respectively). It shows that the improvement rate of visual acuity after using BBG was higher than ILM peeling with ICG. The improvement rate of visual acuity of TB was higher than ILM peeling with ICG, TA, and no dye (Figure 5B, Table 3). The difference of BCVA after surgery was not statistically significant (Figure 5C, Table 3).

Figure 5. Odds relative with 95%CI of the network Meta-analysis for different dyes in the surgery of IMH.

Figure 5

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Different dyes in the middle block (in blue) divide the graph into upper and lower triangles, for the lower triangle, the efficacy estimate is the ratio of the column interventions to the row interventions. A, B: In case that 95%CI does not include 1, if OR>1, it favors the column interventions, in contrast, if OR<1, it favors the row interventions. C: It is different from A and B, in case that the 95%CI does not include 0, if OR<0, it favors the column interventions, in contrast, if OR>0, it favors the row interventions. The upper triangle is symmetrical to the lower triangle. The efficacy estimate is the ratio of the row interventions to the column interventions. The results are mutually reciprocal. Boxes highlighted show significant difference. OR: Odds relative; CI: Credible intervals; IMH: Idiopathic macular hole; ICG: Indocyanine green; BBG: Brilliant blue G; TB: Trypan blue; TA: Triamcinolone acetonide; logMAR: Logarithm of the minimal angle of resolution.

Table 3. Summary of main findings of pairwise and network-analysis.

Parameters Direct pairwise Meta-analysis
 Network Meta-analysisOR/WMD (95%CI)
No. of samples OR/WMD (95%CI) P Heterogeneity I2
Primary MH closure rate
 IGG vs BBG 572 0.51 (0.18-1.40) 0.229 30.5% 0.6 (0.26-1.38)
 TA vs BBG 162 1.06 (0.33-3.34) 0.623 0 0.74 (0.26-2.08)
 TB vs BBG 35 2.38 (0.09-62.7) - 100% 0.88 (0.21-3.67)
 No dye vs BBG 12 2.05 (0.34-12.48) 0.526 0 0.36 (0.14-0.92)
 TA vs ICG 427 0.93 (0.35-2.50) 0.833 0 1.23 (0.47-3.17)
 TB vs ICG 187 0.64 (0.20-2.04) 0.912 0 1.46 (0.44-4.84)
 No dye vs ICG 1171 1.87 (0.78-4.47) 0.008 63.1% 0.59 (0.32-1.09)
 TB vs TA - - - - 1.19 (0.26-5.44)
 No dye vs TA 306 2.19 (0.72-6.66) - 0 0.48 (0.17-1.35)
 No dye vs TB - - - - 0.41 (0.11-1.56)
Rate of improved visual acuity
 IGG vs BBG 30 0.12 (0.02-0.66) - 0 0.19 (0.04-0.90)
 TA vs BBG - - - - 0.24 (0.05-1.25)
 TB vs BBG 35 0.71 (0.12-4.11) - 100% 0.85 (0.17-4.34)
 No dye vs BBG - - - - 0.24 (0.05-1.24)
 TA vs ICG 313 0.81 (0.50-1.31) 0.46 0 1.29 (0.81-2.07)
 TB vs ICG 73 0.22 (0.04-1.24) 0.126 57.3% 4.57 (1.46-14.32)
 No dye vs ICG 518 0.76 (0.51-1.14) 0.428 0 1.32 (0.09-1.94)
 TB vs TA - - - - 3.53 (1.03-12.13)
 No dye vs TA 306 1.00 (0.62-1.62) - 0 1.02 (0.65-1.60)
 No dye vs TB - - - - 0.29 (0.09-0.96)
Postoperative visual acuity (logMAR)
 IGG vs BBG 531 0.10 (0.02-0.17) 0.072 53.5% 0.33 (-0.28-0.95)
 TA vs BBG 36 -0.09 (-0.24-0.06) - 100% 0.01 (-0.88-0.89)
 No dye vs BBG - - - - -0.08 (-0.86-0.70)
 TA vs ICG 365 0.08 (0.02-0.14) 0.536 0 -0.33 (-1.05-0.40)
 No dye vs ICG 648 0.06 (-0.03-0.14) 0.00 79.4% -0.41 (-0.91-0.08)
 No dye vs TA 306 -0.01 (-0.07-0.05) - 100% -0.09 (-0.91-0.73)
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OR: Odds ratio; WMD: Weighted mean difference.

Ranking Probability of Therapeutic Effects

Figure 6 shows the ranking probability of each treatment. The larger the area under the curve was the better treatment effect. Figure 6A shows the rate of MH closure after ILM peeling. The area under the BBG group was the largest, the effect of TB group was the second, and the TA group was the third. The rate of MH closure after ILM peeling with no dye was the worst. Figure 6B shows the rate of improvement of visual acuity. The effect of ILM peeling with BBG group was the first and the effect of TB group was the second. The effect was similar between TA and the no dye group which were the third, and the effect of the ICG group was the worst. Figure 6C shows the result of postoperative BCVA, which was different from A and B. Therefore, Figure 6C shows the larger area under the curve, the larger logMAR value was the worse treatment effect. The result of treatment effect after ILM peeling with no dye was similar to the BBG and TA groups, which were better than the ICG group.

Figure 6. Ranking of therapeutic effects included in the network Meta-analysis.

Figure 6

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A: Primary MH closure rate; B: Rate of improved visual acuity; C: Postoperative visual acuity (logMAR).

Inconsistent Test Results

We did an inconsistency test for the closure of the IMH, forming 5 triangular closed loops, namely BBG-ICG-TA, BBG-ICG-no dye, BBG-TA-no dye, BBG-ICG-TB, and ICG-TA-no dye. The result of the inconsistency test showed that the impact factor (IF) was in the range of 0.12-0.95 and 95%CI was in the range of 0.00-3.92. Inconsistent test results of postoperative visual acuity improvement showed two closed loops, BBG-ICG-TB and ICG-TA-no dye. The results of the IF were in the range of 0.09-1.78 and 95%CI was in the range of 0.00-4.69. The results of BCVA showed two triangular closed loops, BBG-ICG-TA and ICG-TA-no dye. The results of the IF were in the range of 0.17-0.27 and 95%CI was in the range of 0.00-2.30.

Funnel Plot and Publication Bias

The different points in the funnel plot represented a direct comparison between the five treatments, and the number of identical color points represented the same pairwise direct comparison from the original study. Comparison adjusted funnel plots were roughly symmetrical for the outcome Figure 7, it showed that there was a small possibility of small sample size effects or publication bias.

Figure 7. A comparison-adjusted funnel plot representing the same pairwise direct comparison from the original study.

Figure 7

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A: Primary MH closure rate; B: Rate of improved visual acuity; C: Postoperative visual acuity (logMAR).

DISCUSSION

This network Meta-analysis study was mainly for patients with IMH, to analyze and summarize the postoperative primary MH closure rate and the rate of vision improvement and BCVA for ILM peeling with ICG, BBG, TB, TA, and no dye. It included 2514 eyes from 29 studies. Forest plots showed the postoperative IMH closure effect of BBG was better than no dye and it was statistically significant. The improvement rate of visual acuity after using BBG was significantly higher than the ICG group, and the TB group was significantly higher than the ICG, TA, and no dye groups. The differences between groups were not statistically significant. Ranking probability of therapeutic effects showed that for the rate of IMH closure, the rank from the best to the worse treatment was BBG, TB, TA, ICG, and no dye. The rank of the rate of improvement for visual acuity from the best to the worse treatment was BBG, TB, no dye, TA, and ICG. The results for visual acuity after ILM peeling with no dye were similar to the BBG and TA groups, but better than the ICG group. Comparison adjusted funnel plots were roughly symmetrical and showed that there was only a small possibility of small sample size effects or publication bias.

In 1996, Yooh et al[55] performed ultrastructural analysis of ILM tissue exfoliated during MH surgery, which suggested that ILM tissue became the only pulling force in stage 4 MH with posterior vitreous detachment or after posterior vitreous detachment[31]. ILM acted as a proliferating scaffold for various cellular components, such as RPE cells[56]. ILM peeling released tangential traction around the macula, which could cause centripetal motion of the tissue to close the MH[57].

In 2002, TB was firstly used in vitreoretinal surgery[58]. TB is a high molecular weight reactive dye with a weight of 960.8, which makes the lens anterior capsule, preretinal membrane[59]–[60], and ILM more visible and able to form a high affinity with the retinal epithelium, improving the surgical effect[61]. Brazitikos et al[62] observed 35 eyes of intraoperative TB-assisted ILM peeling, and showed that ILM peeling with TB did not cause any changes in the thickness of the retinal nerve fiber layer at six months after surgery. TA is a kind of water-insoluble glucocorticoid[63]. As an anti-inflammatory drug[64]–[65], it has been used for the treatment of various ophthalmic diseases[61], and also for staining the posterior vitreous membrane and ILM. The deposition of TA particles on the surface of the retina acts as a “stain” because there are no white spots on the ILM, allowing the surgeon to see where the ILM is peeling[45]. Similarly, studies have found that TA has toxic effects on the RPE and retinal ganglion cells[66]. Furthermore, some studies have reported that ICG is more likely to cause a decrease in retinal function than other dyes such as TB and TA[67].

Several studies proved that BBG has less toxic effects on the retina than other dyes such as TB, ICG, and TA, the results of these studies were consistent with the current network meta-analysis[67]. Some experiments demonstrated that BBG had less retinal toxicity than ICG and other dyes[63]. Ejstrup et al[68] injected BBG, ICG, and TA into the eyes of pigs and found that the toxicity of ICG on the retina was much higher than that of BBG and TA. Creuzot-Garcher et al[69] injected BBG, TB, ICG, and TA into the eyes of rats. After one month it was observed that the electroretinogram of the rats had returned to normal in the BBG, TB, and TA groups. However, the rats being injected with ICG took a longer time to recover. Ueno et al[70] compared the toxicity of BBG, TB, and ICG, and found that BBG had the lowest toxicity on the retina, with the toxicity of BBG being lower than TB and the toxicity of TB being lower than ICG. The results of several clinical studies differed from our findings. Shukla et al[26] compared surgical outcomes with three dyes, BBG, TB, and ICG, six months postoperatively, visual improvement occurred in 80%, 85%, and 33% eyes (P=0.005). However, the results of our study found that the effect of BBG was better than the TB group, and the effect of TB was better than the ICG group. Nomoto et al[45] reported the results of MH surgery with TA-assisted ILM peeling and ICG-assisted ILM peeling. The rate of MH closure was similar with 98% for the TA group and 100% for the ICG group. The results of improved BCVA in the TA group were better than the ICG group, and the results of BCVA with 20/40 or better in the TA group were better than 59% in the ICG group, which was similar to our findings. Previous results of meta-analysis were also consistent with the results of this network meta-analysis. In 2016, Azuma et al[67] performed a systematic review showing that the BCVA in the BBG group was better than the ICG group and the BBG-free group. In 2012, another meta-analysis reported that VA improvement was less in the ICG group. The toxicity of visual field defects was greater in the ICG group compared with the non-ICG group[71]. However, these traditional meta-analyses only compared two therapeutic measures, and do not accurately compare multiple therapeutic measures.

Of the 29 studies included, the relevant qualified RCTs were numbered, the sample size was not sufficient and the RCTs did not clearly describe clearly how masking and allocation were completed. The other 24 studies were retrospective studies. The differences in the concentrations of BBG, ICG, and TB, and the time of face down position after surgery may also affect the results. There were few related studies on TB, and there was insufficient data in this meta-analysis. Some large samples randomized controlled and double-blind trials would be the best choice for inclusion in network meta-analysis, but there were few high-quality studies on topics related to this research. Overall, some more high quality RCTs with a longer duration and more comprehensive endpoints should be carried out in the future.

In conclusion, the results showed that the rate of MH closure after ILM peeling with dyes was better than without dyes. The dye with the highest safety was BBG, and TB was second, followed by TA which was better than ICG. This network meta-analysis systematically and objectively evaluated the efficacy of ICG, BBG, TB, TA, and no dye-assisted ILM peeling in the treatment of IMH. It allowed clear and comprehensive understanding of these dyes, which was beneficial in the selection of the best dye for ILM peeling of IMH.

Acknowledgments

Authors' contributions: Li SS, You R, Guo XX and Zhao L: data collection; Li SS, Li M, Wang YL and Chen X: data analysis; Wang YL and Chen X: project planning; Li SS and Chen X: manuscript writing.

Foundations: Supported by the National Natural Science Foundation of China (No.81870686); the Natural Science Foundation of Beijing Municipal (No.7184201); the Capital's Funds for Health Improvement and Research (No.2018-1-2021).

Conflicts of Interest: Li SS, None; You R, None; Li M, None; Guo XX, None; Zhao L, None; Wang YL, None; Chen X, None.

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