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Internal Limiting Membrane Peeling With Indocyanine Green or Trypan Blue in Macular Hole SurgeryA Randomized Trial
Julia Beutel, MD;
Gerlinde Dahmen, MSc;
Andreas Ziegler, PhD;
Hans Hoerauf, MD
Arch Ophthalmol. 2007;125(3):326-332.
ABSTRACT
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Objective To report on anatomical and visual outcomes after vitrectomy and internal limiting membrane peeling for idiopathic macular hole repair.
Methods Forty patients with stage II to IV idiopathic macular holes were randomly assigned (1:1) in a 2-arm, single-center, randomized controlled . Internal limiting membrane delamination was performed using indocyanine green (ICG) solution (n = 20) or trypan blue (TB) (n = 20). Two patients did not complete the study, for a total of 19 in each group. Follow-up examinations included Early Treatment of Diabetic Retinopathy Study visual acuity, scanning laser ophthalmoscope microperimetry, optical coherence tomography, and fluorescein angiography.
Main Outcome Measure Visual acuity 3 months after surgery.
Results Visual acuity did not show a significant difference between study groups (95% confidence interval [CI], –2 to 1 lines). The rate of macular hole closures was identical (84%; 95% CI, 60% to 97%). Within-group visual recovery was significant only in the TB group. Central scotomata despite hole closure persisted in 8 patients (42%) in the ICG group and in 5 (26%) in the TB group.
Conclusion Although no statistically significant difference was detected for the primary end point, the better visual recovery in the TB group and the higher rate of persistent central scotomata in the ICG group justify a larger clinical trial.
Application to Clinical Practice No statistically significant difference in visual acuity between ICG and TB in the used concentrations and application method could be proved in macular hole surgery.
Trial Registration clinicaltrials.gov Identifier: NCT00419185
INTRODUCTION
The positive effects of internal limiting membrane (ILM) peeling on anatomical and functional outcomes in macular hole surgery have been reported in several clinical trials.1-4 Controversies exist, however, regarding the application and possible toxic effects of dyes used to facilitate the surgical procedure. Since Kadonosono et al5 introduced indocyanine green (ICG) as a dye for ILM peeling, several researchers6-8 have reported on the advantages of dyes such as ICG and trypan blue (TB) for ILM peeling or removal. Recent experimental and clinical studies raise concerns about the safety of ICG-assisted membrane peeling. Morphologic and functional damage was described in an animal model,9 in human donor eyes,10 in cultured human pigment epithelial cells,11-12 and in clinical studies using ICG in macular surgery.13-16 The intraocular tolerance of TB has been demonstrated in rabbit eyes and in retinal pigment epithelium (RPE) cell viability studies.17-18 Higher concentrations of TB (0.6 or 4 mg/mL) lead to toxic effects on cultured RPE cells, but the application of lower clinically relevant levels did not show any significant effect.18 A recent retrospective comparative analysis by Lee et al19 indicates that TB may be the safer dye. They found better anatomical and functional results than with the use of ICG.
Therefore, the aim of this study is to compare the anatomical and functional outcomes after dye-assisted peeling of the ILM in patients with idiopathic macular holes using ICG or TB in a controlled clinical trial.
METHODS
PARTICIPANTS
Between April 3, 2003, and July 14, 2004, 40 patients with idiopathic macular holes were referred to the University Hospital Schleswig-Holstein, Campus Lübeck, for macular hole surgery using ICG or TB. Data collection was performed prospectively in consecutive patients. Patients with stage II to IV idiopathic macular holes according to the classification proposed by J. Donald M. Gass and a visual acuity (VA) of at least 20/200 entered the study. Exclusion criteria were secondary macular holes; previous intraocular surgery, except for uneventful cataract extraction; and ocular disorders that might interfere with vision, such as severe cataract, exudative age-related macular degeneration, and diabetic retinopathy. This study was approved by the local ethics committee.
INTERVENTIONS
All the patients were examined 1 day before surgery and 3 and 6 months after surgery. Examinations included Early Treatment of Diabetic Retinopathy Study (ETDRS) VA, scanning laser ophthalmoscope (SLO) microperimetry (SLO-101; Rodenstock Instruments GmbH, WECO, Düsseldorf, Germany), optical coherence tomography (OCT) (OCT III 2000; Humphrey Instruments, San Leandro, Calif), stereoscopic biomicroscopy, fluorescein angiography (FLA) (Heidelberg Retina Angiograph; Heidelberg Engineering GmbH, Heidelberg, Germany), infrared fundus photography using excitation, and barrier filters for ICG fluorescence.
The surgical technique included a standard 3-port pars plana vitrectomy and removal of the posterior hyaloid in eyes with stage II and III macular holes using active aspiration. In the ICG group (20 patients), 0.1 mL of ICG (ICG-Pulsion; Pulsion Medical Systems, Munich, Germany) solution was dissolved in 5% glucose at a concentration of 0.05%; in the TB group (20 patients), 0.1 mL of TB (MembraneBlue; DORC International, Zuidland, the Netherlands) was used at a concentration of 0.15%. Both agents were applied over the posterior pole and under constant irrigation with Ringer solution. Immediately after application, dye remnants in the vitreous cavity or outside the central area were washed out by means of suction using a flute needle. The peeling of the ILM extended to an area of at least 2 disc diameters surrounding the macular hole. Then, the peripheral retina was checked carefully for iatrogenic peripheral retinal breaks. At the end, a complete fluid-air exchange was performed. Patients were told to maintain the facedown position for 1 week after surgery. There were no differences regarding positioning, technique, endotamponade, or any other surgical details between treatment groups. All the operations were performed by a single surgeon (H.H.).
OUTCOMES
The primary outcome was ETDRS VA (Snellen equivalent) at 2 m 3 months after surgery. Secondary outcome measures were successful hole closure, defined only as complete closure of the inner retinal dehiscence determined by means of OCT; cystoid macular edema as revealed by FLA; and postoperative scotomata shown by SLO microperimetry. Examinations were performed by a single examiner (J.B.). Data management was performed according to the CPMP/ICH Guideline for Good Clinical Practice20 and Guideline for Statistical Principles for Clinical Trials.21
SAMPLE SIZE AND RANDOMIZATION
The trial was planned as a pilot study (without sample size calculation), with the primary aim being to obtain a reliable data basis for further studies. Assignment to ICG or TB dye was performed by the Institute for Medical Biometry and Statistics of the University at Lübeck via telephone immediately before surgery. Allocation to treatment arms was performed by means of a permuted block randomization with block size 20 without stratifications. The investigator and the patients were blinded, and only the surgeon was aware of the dye used.
STATISTICAL METHODS
As the primary analysis, a nonparametric analysis of covariance (ANCOVA) with adjustment of the baseline measurement was applied for investigation on the primary outcome variable after dye application in macular hole surgery at a significance level of .05. The intention-to-treat approach was used for analysis. For the secondary end points and exploratory analyses, categorical data are given as total numbers and relative frequencies. Continuous data are given as mean ± SD. Comparisons between groups were made using the 2-sided Fisher exact test or the 2-sided exact Mann-Whitney test. Comparisons of time-related data were performed using the exact 2-sided Wilcoxon signed rank test. A P<.05 was considered significant. For the primary and secondary end points, 95% confidence intervals (CIs) were calculated, without adjustments for multiplicity. Statistical analyses were performed using the software package SAS version 9.1 (SAS Institute Inc, Cary, NC).
RESULTS
Between April 3, 2003, and July 14, 2004, 40 eyes of 40 consecutive patients (16 men and 24 women) with stage II to IV idiopathic macular holes and a VA of 20/200 or greater were included in the study. Written informed consent was obtained from all the patients. Two patients, 1 in each group, did not complete the study: 1 patient in the TB group died of myocardial infarction 2 months after surgery, and 1 patient in the ICG group did not attend follow-up visits. Nineteen patients in each group were included in the intention-to-treat analysis. The participant flowchart according to the CONSORT statement22 is shown in Figure 1. The mean postoperative follow-up time was 6 months (±2 weeks) in both groups (Table 1). Patient ages ranged from 57 to 83 years (68.3 ± 5.4 years). Baseline variables are given in Table 1. There are no statistically significant differences in baseline variables between the intervention groups.
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Figure 1. Participant flowchart for each treatment group. ICG indicates indocyanine green; TB, trypan blue.
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Table 1. Demographic Characteristics of the 40 Patients Enrolled in the Study
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PRIMARY ANALYSIS
The primary outcome was ETDRS VA (Snellen equivalent) 3 months after surgery. The median difference in ETDRS VA between ICG and TB after 3 months was 0 lines (95% CI, –2 to 1 lines). On use of the nonparametric ANCOVA there was no difference in ETDRS VA between groups at 2 m (P = .88).
VISUAL ACUITY
At 6 months there also was no difference in ETDRS VA between the ICG and TB groups (median difference, 0 lines; 95% CI, –2 to 1 lines; P = .41) at both distances. In the ICG group, 3 months after surgery VA increased at least 2 lines in 10 patients (53%), remained unchanged or gained 1 line in 6 patients (32%), and decreased in 3 patients (16%). After 6 months VA increased at least 2 lines (compared with the baseline measurement) in 11 patients (58%), remained unchanged or gained 1 line in 3 patients (16%), and decreased in 5 patients (26%). Compared with baseline, VA did not significantly improve in the ICG group using the ETDRS charts at 2 m after 3 months (P = .07) and 6 months (P = .06) or at 4 m after 3 months (P = .11) and 6 months (P = .33).
In the TB group, after 3 months VA increased at least 2 lines in 12 patients (63%), remained unchanged or gained 1 line in 4 patients (21%), and decreased in 3 patients (16%). After 6 months VA increased at least 2 lines in 10 patients (53%), remained unchanged or gained 1 line in 6 patients (32%), and decreased in 3 patients (16%). In contrast, the TB group showed significant improvement in VA at 2 m after 3 and 6 months (P = .04 for both) and at 4 m after 3 months (P = .002) and 6 months (P = .006). The VA results are presented in Figure 2.
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Figure 2. Visual acuity (VA) results for each treatment group at 3 and 6 months compared with preoperative values. Horizontal bars represent median values; boxes, 25th and 75th percentiles; and whiskers, minimum and maximum values. ETDRS indicates Early Treatment of Diabetic Retinopathy Study; ICG, indocyanine green; TB, trypan blue.
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SLO MICROPERIMETRY
The SLO microperimetry detected postoperative persistent central scotomata in 9 patients (47%; 95% CI, 25% to 71%) after 3 months and in 8 patients (42%; 95% CI, 20% to 67%) after 6 months in the ICG group. These scotomata were found in 6 patients (32%; 95% CI, 13% to 57%) after 3 months and in 5 patients (26%; 95% CI, 9% to 51%) after 6 months in the TB group. There were no significant differences between treatment groups after 3 (P = .51) and 6 months (P = .50).
Three months after surgery paracentral scotomata were detected in 2 patients in the ICG group and in 3 patients in the TB group in areas that were normal before surgery. After 6 months paracentral scotomata were found in 2 more patients in the ICG group and in 3 more patients in the TB group. Between treatment groups there was no significant difference for paracentral scotomata after 3 and 6 months (P>.99). None of the detected central or paracentral scotomata changed in size or shape during the postoperative period.
FLA AND ICG FLUORESCENCE
In 3 eyes (16%) in the ICG group and in 1 eye (5%) in the TB group cystoid changes around the macular hole had already been present before surgery. Three months after surgery FLA revealed cystoid changes around the preexistent hole in 11 eyes (58%; 95% CI, 34% to 80%) each in the ICG and TB groups. Six months after surgery these changes in FLA were found in 14 patients (74%; 95% CI, 49% to 91%) in the ICG group and in 9 patients (47%; 95% CI, 24% to 71%) in the TB group (Figure 3). Three and 6 months after surgery, no difference in cystoid macular edema as revealed by FLA was detected (P>.99 for 3 months; P = .18 for 6 months). In 1 patient in the ICG group the cystoid edema might be related to cataract extraction during follow-up.
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Figure 3. Fluorescein angiograms (late phase) of a patient in the indocyanine green group before surgery showing central hyperfluorescence due to a stage II macular hole (A) and 6 months after successful macular hole closure revealing perimacular cystoid changes (arrow) (B).
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Infrared fundus photographs using excitation and barrier filters for ICG showed persistent ICG fluorescence in 14 eyes in the ICG group (74%; 95% CI, 49% to 91%) after 3 months and in 8 eyes (42%; 95% CI, 20% to 67%) after 6 months.
OPTICAL COHERENCE TOMOGRAPHY
The rate of primary macular hole closure after a single surgery as evaluated by means of OCT was 16 (84%; 95% CI, 60% to 97%) of 19 eyes in both groups (P>.99). Patients with a persistent macular hole underwent repeated vitrectomy, with fluid-gas exchange and additional application of autologous platelet concentrate as adjuvants. Because 1 patient in the ICG group refused to provide consent for further surgical attempts, an overall closure rate of 95% was achieved in the ICG group. After the second surgery a 100% success rate was achieved in the TB group. Despite complete closure of the macular hole, OCT revealed a slight detachment between the RPE and the outer retinal layers up to 3 months after surgery in 3 patients (16%) in the ICG group and in 4 patients (21%) in the TB group (Figure 4). At the 6-month OCT examination this phenomenon disappeared in all the eyes. Furthermore, OCT showed a persistent superficial defect of the inner retinal layers in 2 patients (11%) in the ICG group and in 1 patient (5%) in the TB group. The postoperative OCT findings are summarized in Table 2.
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Figure 4. Optical coherence tomographs of a patient in the trypan blue group before surgery showing a stage III macular hole with an operculum (A) and 3 months after surgery showing a small dehiscence between the retinal pigment epithelium and the retinal layers (arrow) (B).
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Table 2. Postoperative Optical Coherence Tomography Findings
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POSTOPERATIVE COMPLICATIONS
The most common postoperative complication was the progression of nuclear cataract in all phakic eyes at the end of follow-up. Three eyes had cataract surgery during follow-up, and surgery was scheduled in 30 patients immediately after the 6-month visit. A postoperative retinal detachment occurred in 1 patient in each group and was treated successfully by means of encircling band, revitrectomy, and silicone oil tamponade. No macular pucker, RPE atrophy, late reopening, or other complications were observed during follow-up.
COMMENT
There has been intense debate highlighting the possible toxic effects of ICG during ILM delamination in macular hole surgery. A literature review of selected studies (reporting VA results in gain in lines of at least 2 and anatomical success rate) showed an average closure rate of 92% using ICG and of 92.4% using TB (Table 3). The hole closure rate of 84% in both of the present treatment groups is markedly lower; however, it is a common observation that results of prospective treatment trials are less favorable. Another explanation is the strict definition of hole closure as complete closure of the inner retinal dehiscence as determined by OCT. Published studies showed a gain of at least 2 VA lines of 60% on average in patients treated with ICG and of 71% in those treated with TB (Table 3). Because of the retrospective design, the lack of any randomization, the short follow-up time, and missing standardized VA tests, the expressiveness and power of explanation is limited. Therefore, the aim of this study was to evaluate in a randomized design whether there is a difference between the most common dyes currently used for ILM removal: ICG and TB. Despite the slightly worse preoperative VA in the TB treatment group, the increase in VA at the 3- and 6-month visits was statistically significant in this group. Furthermore, patients treated with TB achieved more lines of improvement on the ETDRS charts than those treated with ICG (Figure 2). In accordance with other comparative studies,16, 19, 26 the improvement in VA in the ICG group was not statistically significant. Although the comparison of the 2 treatment groups did not show statistical significance, one might speculate that intravitreal ICG application, even in this low concentration and under constant irrigation, has a potentially adverse effect on functional results.
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Table 3. Literature Review of Selected Publications After Macular Hole Surgery Using Indocyanine Green (ICG) or Trypan Blue (TB)*
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A possible negative effect of ICG on visual outcome is discussed controversially and emotionally in recent publications. Several researchers demonstrated the efficacy and safety of ICG,23, 27, 30-33 whereas others note that there was no significant improvement in postoperative VA after ICG application.13, 19, 34 One of these studies31 was also performed in a randomized design comparing ILM peeling with and without ICG staining in 40 eyes, but ETDRS VA was not performed in all of the patients. To evaluate the effect on central visual function and possible differences between both dyes, SLO microperimetry was used to provide another sensitive functional variable. Microperimetry revealed persistent central scotomata in 9 patients (47%) in the ICG group and in 6 patients (32%) in the TB group after 3 months. In only 3 of these patients can the persistent defects be explained by a persistent macular hole. The remaining rates of 5 eyes (26%) in the ICG group and 2 eyes (11%) in the TB group are comparable with those found in previous studies without dye application, which report rates of approximately 17.86%35 and 28.13%36 of persistent central scotomata after ILM peeling despite hole closure. Although the results of both groups are in the range of previous studies without dye application, comparison of the rates reveals a lower incidence in the TB group and, therefore, could provide an indication of better recovery after TB use. However, the difference between treatment groups was not statistically significant. Removal of the ILM around the macular hole in a relatively large area could potentially predispose to more nerve fiber layer damage and paracentral scotomata. Paramacular RPE changes have been observed in macular hole surgery without and with ILM peeling.2, 13, 34, 37 In the present study, 3 patients (16%) in the ICG group and 1 patient (5%) in the TB group developed new paramacular RPE changes. These observations are in the range (3%-33%) commonly found after macular hole surgery.
In several experimental9, 38-39 and clinical3, 16, 28, 40 studies, possible toxic adverse effects and different underlying pathomechanisms of ICG on the retina and RPE were discussed. In vitro studies demonstrated a phototoxic effect of ICG on human RPE cells11, 28 and a decrease in mitochondrial function. Indocyanine green, a tricarbocyanine dye, has infrared absorption properties, with a peak absorption of 800 nm, which leads to formation of singlet oxygen and lipid peroxides after photoactivation.10 In the present study the ICG was dissolved in 5% glucose, which leads to decreased absorption of 600 to 700 nm41 and to decreased osmolarity. Other researchers15, 42 suspect direct toxic effects of ICG on ganglion cells, their axons, and the nerve fibers at the optic nerve head. Persistent ICG fluorescence was first described by Weinberger et al.43 Indocyanine green fluorescence could be detected at the optic nerve head up to 6 months after surgery in 42% of the eyes in the present study. Based on the clinical experience that ILM peeling is less difficult with ICG than with TB, an ICG-induced alteration creating a cleavage plane in the innermost retinal layers was discussed, which may lead to retinal damage.3, 10
But neither is TB an undisputed dye.44-47 The RPE culture studies indicate a potential increase in apoptosis even after application of lower concentrations of 0.05% for 5 minutes.44 In the present study a small volume of TB with a concentration of 0.16% was applied under constant irrigation with Ringer solution, resulting in a lower concentration on the retinal surface. Owing to the higher water solubility, lower postoperative ocular retention of TB and, therefore, an advantage compared with ICG, was suspected.48 In contrast, no direct TB-related toxic effects were observed in a postmortem study,49 in rabbit eyes,17 and in several clinical trials.50-53 The present study could not prove a statistically significant difference comparing TB and ICG at the used concentrations regarding anatomical or functional outcome. However, in the explorative analysis of the study, significant improvement in VA was seen only after the use of TB. Owing to the small sample size of the present study we cannot conclude whether this finding is clinically relevant and outweighs the disadvantage of the less favorable staining capabilities of TB.
The strengths of the present study are the standardized examination of patients under identical conditions by a single examiner and the fact that variability in surgeons' techniques and skills was excluded. Limitations of the study are the small sample size and the effect of cataract on VA during follow-up. There was a high percentage of phakic eyes in both treatment groups, and there was no formal grading of lens opacity changes using the standardized grading system in these patients. Choosing ETDRS VA at the 3-month visit as the primary end point, we tried to minimize the effect of cataract formation on VA outcome. Moreover, there is big individual variance in visual recovery after successful macular hole surgery, which can often be delayed and take up to 1 year or longer.
In conclusion, this small randomized trial could not prove a statistically significant difference between ICG and TB in the used concentrations and application method for the primary end point of ETDRS VA at 3 months. Considering the worse visual recovery after 6 months, the higher rate of persistent central scotomata and postoperative paramacular cystoid changes in the ICG group, this pilot study justifies a multicenter study with a larger number of patients.
AUTHOR INFORMATION
Correspondence: Hans Hoerauf, MD, University Eye Clinic, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany (hanshoerauf{at}yahoo.com).
Submitted for Publication: March 9, 2006; final revision received June 28, 2006; accepted July 8, 2006.
Financial Disclosure: None reported.
Author Affiliations: University Eye Clinic (Drs Beutel and Hoerauf) and Institute for Medical Biometry and Statistics (Drs Dahmen and Ziegler), University Hospital Schleswig-Holstein, Campus Lübeck, University at Lübeck, Lübeck, Germany. Dr Hoerauf is now at the University Eye Clinic, Georg-August-University Göttingen, Göttingen, Germany.
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