 |
|
Effect on Visual Outcome After Macular Hole Surgery When Staining the Internal Limiting Membrane With Indocyanine Green Dye
Naoichi Horio, MD;
Masayuki Horiguchi, MD
Arch Ophthalmol. 2004;122:992-996.
ABSTRACT
| |
Objectives To determine the effect on the visual outcome after macular hole surgery when staining the internal limiting membrane (ILM) with indocyanine green (ICG) dye and to study the mechanism of the adverse effects.
Patients and Methods We studied 40 eyes of 38 patients with an idiopathic macular hole (size, <0.5 disc diameter; duration, <12 months). The concentration, exposure time, and amount of the ICG solution that was minimally required to make the ILM visible were determined. The patients were randomly divided into group 1 (20 eyes of 19 patients) who underwent ILM peeling without ICG staining, and group 2 (20 eyes of 19 patients) who underwent ILM peeling with ICG staining. Routine examinations were conducted during the 12-month follow-up period. Multifocal electroretinogram, optical coherence tomography, and fluorescein angiography were performed on 31 eyes of 30 patients.
Results The macular hole was closed in all patients. Visual acuity was improved in both groups, but it was significantly better in group 1 (median, 0.85) than in group 2 (median, 0.60; P = .02) after 12 months. The improvement of visual acuity in group 1 (logarithm of the minimum angle of resolution [logMAR] units [SD], 0.82 [0.19]) was significantly better than that in group 2 (logMAR units, 0.67 [0.21]; P = .30). The multifocal electroretinogram and optical coherence tomographic findings were not significantly different in the 2 groups. Fluorescein angiogram showed only weak hyperfluorescence at the macula in some patients of both groups.
Conclusions The results suggest that ICG staining should not be used as long as the visibility of the retinal surface is good. However, ICG staining may be acceptable at a low concentration when a clear view of the retinal surface is unattainable. The results of the multifocal electroretinogram, optical coherence tomography, and fluorescein angiography suggest that the differences in visual recovery were caused not only by pigment epithelial cell damage or retinal toxic effect but also probably by the effect of ICG staining on ganglion cells and their axons.
INTRODUCTION
In 1998, we described a new surgical technique of staining the capsule of the crystalline lens with indocyanine green (ICG) dye during mature cataract surgery (ICG with continuous circular capsulorhexis [ICG-CCC]).1 Later, ICG staining was applied to the internal limiting membrane (ILM) to make it more visible during macular hole surgery (ICG-ILMrhexis).2-3 Although our report on ICG-CCC was a randomized control study, to our knowledge, ICG-ILMrhexis has not been studied in such a manner. In addition, the concentration of ICG solution in ICG-CCC was determined from the results of animal experiments; however, to our knowledge, the optimal concentration for human ICG-ILMrhexis has not been determined.
Recently, we reported that the ICG dye remained in the eye for a long period after ICG-ILMrhexis.4 This is important because there have been reports that ICG dye is a toxic substance,5-7 and other groups have described the efficacy and safety of ICG-ILMrhexis.8-10 Furthermore, in vitro studies using human retinal pigment epithelial (RPE) cells have demonstrated the toxic effect of ICG dye and illumination, an osmotic effect of the vehicle of ICG solution, and an ICG-induced decrease of mitochondrial enzyme activity.11-14 We have performed a randomized control study to determine the effect of ICG-ILMrhexis on the visual outcome after macular hole surgery and to study the mechanism of the adverse effects.
METHODS
PATIENTS
Forty eyes of 38 patients with an idiopathic macular hole and no other eye disease were studied prospectively. Eyes with an old macular hole (>12 months), eyes with a large macular hole (>0.5 disc diameter), or eyes with atrophic RPE changes at the macular hole were excluded from the study. After obtaining informed consent, the study eyes were randomly divided before surgery into 2 groups using a coin-tossing method.
There were 20 eyes of 19 patients that underwent ILM peeling without ICG staining in group 1, and 20 eyes of 19 patients that underwent ILM peeling with ICG staining in group 2. Preoperatively, there was no significant difference in the visual acuity (range, group 1: 0.03-0.3, median, 0.125; group 2: 0.03-0.3, median, 0.15), the size and stage of the macular hole, the duration of the symptoms, and age of the patient (mean [SD] age, group 1: 63.5 [6.9] years; group 2: 64.7 [6.9] years; Table 1). The stage of the macular hole was determined during surgery.
ICG SOLUTION
We use a 0.125% solution of ICG dye. The solution was made by injecting 2.0 mL of sterile distilled water into a bottle of 25 mg of ICG dye (Daiichi Pharmaceutical Co Ltd, Tokyo, Japan, identical to Acorn product), and the bottle was shaken until the powdered ICG was completely dissolved. Then, 1.5 mL of the dissolved ICG was aspirated and 4.5 mL of an irrigating solution (BBS Plus; Alcon Inc, Forth Worth, Tex) was injected into the remaining 0.5 mL of ICG in the bottle to make a final concentration of 0.125%. The osmolarity of the ICG solution in the bottle was 270 mOsm that is identical to that reported in our original article.1
SURGICAL TECHNIQUES
A posterior vitreous detachment was formed with a cutter unless it was already present, and as much of the vitreous was removed as possible. The infusion of fluid was stopped, and 0.2 mL of the 0.125% ICG solution was flushed onto the surface of the retina. The ICG dye in the vitreous cavity was removed immediately by aspiration with the cutter.
With an excellent view of the ILM, the ILM was successfully peeled in all patients. Fluid-gas exchange was performed, and the vitreous was replaced by 12% perfluoropropane. The light source of endoillumination was a 150-W halogen lamp; no filter was used.
CONCENTRATION, EXPOSURE TIME, AND AMOUNT OF ICG SOLUTION
Before beginning this study, we determined the concentration, exposure time, and amount of ICG solution that was minimally needed to make the ILM visible during surgery (minimal staining). We found that 0.2 mL of a 0.125% ICG solution placed on the retina for 10 to 30 seconds was effective. The 0.125% ICG solution was diluted immediately after injection by the residual vitreous; the volume in the vitreous cavity varied among the patients. Therefore, the concentration of ICG solution in the vitreous cavity was not constant and was estimated to be 0.05 to 0.06 mg/mL (0.005%-0.006% with an assumed volume of the vitreous cavity of 4-5 mL). This concentration is much lower than the original report using ICG mixed with a viscomaterial.2 However, the concentration of the dye in the vitreous may differ from the concentration achieved at the vitreoretinal interface. The injected 0.125% ICG solution was aspirated immediately, but the exposure time of the ICG solution on the retina, the time from the start of the injection to the end of aspiration, was not constant, and was estimated to be 10 to 30 seconds from a review of the videotape taken during the surgery.
VISUAL ACUITY
The visual acuity was measured preoperatively and postoperatively. We have reported that the preoperative visual acuity in patients with a macular hole is greatly affected by the patient's fixation and the use of a multiple letter chart can solve the problem.15 Unfortunately, the multiple letter chart was unavailable at the start of this study; therefore, we used a standard visual acuity chart (EA-117D; Takada Co Ltd, Tokyo Japan) that is widely used in Japan.
MULTIFOCAL ELECTRORETINOGRAMS
Multifocal stimulation and analyses were performed using the VERIS Science 4.1 system (Electro-Diagnostic Imaging, San Mateo, Calif, and Meiyo, Aichi, Japan). Multifocal electroretinograms (mfERGs) were recorded from 16 eyes of 15 patients in group 1 and 15 eyes of 15 patients in group 2 from whom informed consent was obtained.
A stimulus array of 61 densely packed hexagons covered the central 50°. Within each frame of the cathode ray tube, each stimulus hexagon was either flashed on at an intensity of 2.67 candela (cd)//s per square meter or remained dark (<0.01 cd · s · m2) and modulated at an m-sequence (215 – 1 steps).
The mfERGs were recorded with a Burian-Allen bipolar contact lens electrode, amplified (x50 000), and bandpass filtered between 10 and 300 Hz. K1 and K2 were extracted using the fast m-transform algorithm, and we measured the implicit times and the amplitudes of the largest peaks of the first-order kernel (b wave) of the central hexagon that fell on the fovea. Because the amplitudes of the mfERG are highly variable, the ratio of the amplitudes, affected eye to fellow eye (A/F) ratio, was used to compare the 2 groups.16
OPTICAL COHERENCE TOMOGRAPHY
Cross-sectional images of the retina were obtained by optical coherence tomography (OCT) (Humphrey Instruments, San Leandro, Calif). The measurement of the foveal thickness was made manually using the longitudinal reflectivity profile in a scan profile program of the OCT.17-18 For the measurement, cursors were placed at the steepest part of each rising slope produced at the ILM and RPE. The retinal thickness used for analysis was the average of 4 measurements at the fovea. Optical coherence tomography was performed on 16 eyes of 15 patients in group 1 and 15 eyes of 15 patients in group 2.
OTHER MEASUREMENTS
Fluoresein angiography (FA), ophthalmoscopy, and Goldmann perimetry were performed during the follow-up period.
STATISTICAL ANALYSIS
Data are shown as the mean (SD). Statistical analysis software (SigmaStat; Jandel Scientific, San Rafael, Calif) was used for statistical comparisons. Comparisons for the 2 groups were performed using unpaired t test, and the Mann-Whitney test was performed for comparisons of visual acuity. Values of P<.05 were considered to be statistically significant.
RESULTS
VISUAL ACUITY
The median visual acuity in both groups was the same at 0.60 at 6 months after surgery, but at 12 months, the median visual acuity in group 1 was significantly better at 0.85 than in group 2 at 0.60 (P = .02; Figure 1). The improvements of visual acuity in logMAR (logarithm of the minimum angle of resolution) units are shown in Figure 2 for both groups. At 12 months, the improvements were significantly better in group 1 (0.82 [0.19]) than in group 2 (0.67 [0.21], P = .03).
|
|
|
|
Figure 1. Distribution of the visual acuities of the 2 groups during the 12-month follow-up period. The visual acuity was not significantly different between the 2 groups at 6 months after surgery, but at 12 months, the visual acuity was significantly better in group 1 ( those who underwent internal limiting membrane peeling [ILMrhexis] without indocyanine green [ICG] dye staining; 20 eyes of 19 patients) than in group 2 (those who underwent ILMrhexis with ICG staining; 20 eyes of 19 patients). The median value is represented by the line in the box with the 25th and the 75th percentiles being the boundaries of the box and the whiskers representing the 10th and 90th percentiles. Asterisk indicates P<.05.
|
|
|
|
|
|
|
Figure 2. Improvements of visual acuity in logMAR (logarithm of the minimum angle of resolution) units. Although there is no significant difference in the improvement of the visual acuity at 6 months, the improvement was significantly better in group 1 (those who underwent internal limiting membrane peeling [ILMrhexis] without indocyanine green [ICG] dye staining; 20 eyes of 19 patients) than in group 2 (those who underwent ILMrhexis with ICG staining; 20 eyes of 19 patients) at 12 months. Data are expressed as mean (SD). Box-and-whiskers represent the mean (SD) of change in visual acuity from the preoperative to the 12-month examination. Asterisk indicates P<.05.
|
|
|
A comparison of the preoperative and postoperative visual acuities at 12 months in all eyes is shown in Figure 3. All eyes had an improvement of visual acuity of more than 2 lines on the letter chart. The results of visual acuity in the 31 eyes of 30 patients who had mfERGs, OCT, and FA tests were consistent. Although group 2 included 5 more patients with a stage 4 macular hole (Table 1), their postoperative visual acuity ranged from 0.3 to 1.0 (median, 0.6) and so was not the cause of the difference in postoperative visual acuity.
|
|
|
|
Figure 3. Preoperative and postoperative visual acuities of all eyes. All eyes in both groups had an improvement of visual acuity of more than 2 lines on the letter chart.
|
|
|
MULTIFOCAL ELECTRORETINOGRAMS
There was no significant difference in the implicit time or the A/F ratio of the b-wave amplitudes preoperatively. The ratio of the amplitudes and peak time of the b wave of the mfERGs from the central hexagon were not significantly different for the 2 groups postoperatively (Table 2).
|
|
|
|
Table 2. Multifocal Electroretinogram and Foveal Thickness*
|
|
|
OPTICAL COHERENCE TOMOGRAPHY
In all cases, OCT showed a complete closure of the macular hole, and the thickness of the retina in the center of the fovea was not significantly different in the 2 groups (mean [SD], group 1: 147.9 [29.7] µm; group 2: 169.6 [58.2] µm; Table 2).
OTHER EXAMINATIONS
Fluorescein angiography showed only a faint hyperfluorescence in the macula in 7 of 16 eyes in group 1 and 8 of 15 eyes in group 2. Dilated fundus examination revealed no obvious atrophy of the RPE. Goldmann perimetry revealed no scotoma or constriction of the peripheral field.
COMMENT
MILD DEPRESSED RECOVERY OF VISUAL ACUITY BY ICG-ILMrhexis
Our data showed that the visual acuity and the improvement of visual acuity in the 2 groups were not significantly different 6 months after surgery. However at 12 months, the recovery of the visual acuity was significantly better in eyes that were not stained with ICG than in eyes with ICG-ILMrhexis. This long-term effect is probably due to the delayed clearance of the dye after surgery because we have found that the dye remained in the eye for a mean (SD) of 2.7 (1.4) months after macular surgery in contrast to the rapid clearance after ICG-CCC (6.0 [2.2] days).4 Both groups achieved good recovery of visual acuity. This suggests that ICG toxicity did exist but is limited in this study.
Our results indicated that ICG staining might be acceptable at a low concentration in selected cases. For example, in an eye with media opacity that prevents a clear view of the retinal surface, ICG staining may be used to identify the ILM, but ICG staining should be avoided when the retinal surface is clearly visible.
MECHANISM OF THE DELAY IN RECOVERY OF VISUAL ACUITY
The mechanism of the effect of ICG staining on the visual acuity at 12 months has not been determined. The mfERGs were not significantly different in the 2 groups suggesting that the retinal cells giving rise to the mfERGs (photoreceptors, bipolar cells, and Müller cells) were minimally affected by ICG staining. The OCT-determined foveal thicknesses were also not significantly different in the 2 groups suggesting that there was no retinal edema or atrophy at the fovea. Fluorescein angioagraphy showed only faint hyperfluorescence in some cases in both groups suggesting that RPE atrophy and retinal damage were not obvious as described previously6 in both groups.
Thus, these data suggest that the possible mechanism of the depressed visual acuity in the eyes exposed to ICG dye is damage to the axons of the ganglion cells or the nerve fibers at the optic nerve head. Recent reports4, 19-20 stated that ICG dye remains at the optic nerve head for a long time after ICG-ILMrhexis. The findings from an experimental report21 demonstrating ICG dye in retinal ganglion cells after intravitreal injection support this possibility. Furthermore, photodynamic effects may account for the nerve fiber layer and ganglion cell damage.22 However, there may have been subclinical changes at the center of the fovea that could not be detected by mfERG, OCT, or FA. Several in vitro experiments11-14 have shown the toxic effect of ICG dye on the human RPE. We do not have a clinical test for measuring the function of RPE in the fovea. Therefore, we cannot exclude the possibility that dysfunction of foveal RPE affected visual acuity. To make a more definitive conclusion, further examinations of the visual fields and the RPE with longer follow-up periods are needed.
CONCENTRATION, EXPOSURE TIME, AND AMOUNT OF ICG SOLUTION
The use of ICG-ILMrhexis has been controversial. While some investigators reported poor results, other investigators reported good results. One of the reasons for this confusion is that the optimal concentration, exposure time, and quantity of ICG solution have not been determined. In our study, we determined a combination of the concentration, exposure time, and amount of ICG solution for minimal staining, which may be different among the hospitals because of the difference in instruments, source of the ICG dye, and color of the fundus in different races/ethnicities. Our results indicated that even a minimal staining procedure affects the visual acuity slowly and slightly; thus, we recommend that ICG dye might be used only when the retinal surface is not clearly visible.
CONCLUSIONS
Visual recovery after macular hole surgery was affected by ICG-ILMrhexis, even when it was performed using a minimal staining technique. However, because the effect was slight, ICG staining may be acceptable at a low concentration for a short time in eyes with media opacity that prevents a clear view of the retinal surface.
AUTHOR INFORMATION
Correspondence: Masayuki Horiguchi, MD, Department of Ophthalmology, Fujita Health University School of Medicine, 1-98 Toyoake, Aichi 470-1192, Japan (masayuki{at}fujita-hu.ac.jp).
Submitted for publication July 1, 2003; final revision received November 17, 2003; accepted December 2, 2003.
Both authors contributed equally to the work and therefore should be regarded as equivalent senior authors.
From the Department of Ophthalmology, Fujita Health University School of Medicine, Aichi, Japan. The authors have no relevant financial interest in this article.
REFERENCES
1. Horiguchi M, Miyake K, Ohta I, Ito Y. Staining of the lens capsule for circular continuous capsulorrhexis in eyes with white cataract. Arch Ophthalmol. 1998;116:535-537.
FREE FULL TEXT
2. Kadonosono K, Itoh N, Uchio E, Nakamura S, Ohno S. Staining of internal limiting membrane in macular hole surgery. Arch Ophthalmol. 2000;118:1116-1118.
FREE FULL TEXT
3. Burk SE, Da Mata AP, Snyder ME, Rosa RH Jr, Foster RE. Indocyanine green-assisted peeling of the retinal internal limiting membrane. Ophthalmology. 2000;107:2010-2014.
FULL TEXT
|
ISI
| PUBMED
4. Horiguchi M, Nagata S, Yamamoto N, Kojima Y, Shimada Y. Kinetics of indocyanine green dye after intraocular surgeries using indocyanine green staining. Arch Ophthalmol. 2003;121:327-331.
FREE FULL TEXT
5. Gandorfer A, Haritoglou C, Gass CA, Ulbig MW, Kampik A. Indocyanine green-assisted peeling of the internal limiting membrane may cause retinal damage. Am J Ophthalmol. 2001;132:431-433.
FULL TEXT
|
ISI
| PUBMED
6. Engelbrecht NE, Freeman J, Sternberg P Jr, et al. Retinal pigment epithelial changes after macular hole surgery with indocyanine green-assisted internal limiting membrane peeling. Am J Ophthalmol. 2002;133:89-94.
FULL TEXT
|
ISI
| PUBMED
7. Haritoglou C, Gandorfer A, Gass CA, Schaumberger M, Ulbig MW, Kampik A. Indocyanine green-assisted peeling of the internal limiting membrane in macular hole surgery affects visual outcome: a clinicopathologic correlation. Am J Ophthalmol. 2002;134:836-841.
FULL TEXT
|
ISI
| PUBMED
8. Kwok AK, Li WW, Pang CP, et al. Indocyanine green staining and removal of internal limiting membrane in macular hole surgery: histology and outcome. Am J Ophthalmol. 2001;132:178-183.
FULL TEXT
|
ISI
| PUBMED
9. Weinberger AW, Schlossmacher B, Dahlke C, Hermel M, Kirchhof B, Schrage NF. Indocyanine green–assisted internal limiting membrane peeling in macular hole surgery: a follow-up study. Graefes Arch Clin Exp Ophthalmol. 2002;240:913-917.
ISI
| PUBMED
10. Kwok AK, Lai TY, Man-Chan W, Woo DC. Indocyanine green–assisted retinal internal limiting membrane removal in stage 3 or 4 macular hole surgery. Br J Ophthalmol. 2003;87:71-74.
FREE FULL TEXT
11. Sippy BD, Engelbrecht NE, Hubbard GB, et al. Indocyanine green effect on cultured human retinal pigment epithelial cells: implication for macular hole surgery. Am J Ophthalmol. 2001;132:433-435.
FULL TEXT
|
ISI
| PUBMED
12. Yam HF, Kwok AK, Chan KP, et al. Effect of indocyanine green and illumination on gene expression in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2003;44:370-377.
FREE FULL TEXT
13. Stalmans P, Van Aken EH, Veckeneer M, Feron EJ, Stalmans I. Toxic effect of indocyanine green on retinal pigment epithelium related to osmotic effects of the solvent. Am J Ophthalmol. 2002;134:282-285.
FULL TEXT
|
ISI
| PUBMED
14. Ho JD, Tsai RJ, Chen SN, Chen HC. Toxic effect of indocyanine green on retinal pigment epithelium related to osmotic effects of the solvent. Am J Ophthalmol. 2003;135:258.
PUBMED
15. Horiguchi M, Suzuki H, Kojima Y, Shimada Y. New visual acuity chart for patients with macular hole. Invest Ophthalmol Vis Sci. 2001;42:2765-2768.
FREE FULL TEXT
16. Tanikawa A, Horiguchi M, Kondo M, Suzuki S, Terasaki H, Miyake Y. Abnormal focal macular electroretinograms in eyes with idiopathic epimacular membrane. Am J Ophthalmol. 1999;127:559-564.
FULL TEXT
|
ISI
| PUBMED
17. Horio N, Kachi S, Hori K, et al. Progressive change of optical coherence tomography scans in retinal degeneration slow mice. Arch Ophthalmol. 2001;119:1329-1332.
FREE FULL TEXT
18. Baumann M, Gentile RC, Liebmann JM, Ritch R. Reproducibility of retinal thickness measurements in normal eyes using optical coherence tomography. Ophthalmic Surg Lasers. 1998;29:280-285.
ISI
| PUBMED
19. Machida S, Fujiwara T, Gotoh T, Hasegawa Y, Gotoh A, Tazawa Y. Observation of the ocular fundus by an infrared-sensitive video camera after vitreoretinal surgery assisted by indocyanine green. Retina. 2003;23:183-191.
FULL TEXT
|
ISI
| PUBMED
20. Tadayoni R, Paques M, Girmens JF, Massin P, Gaudric A. Persistence of fundus fluorescence after use of indocyanine green for macular surgery. Ophthalmology. 2003;110:604-608.
FULL TEXT
|
ISI
| PUBMED
21. Paques M, Genevois O, Regnier A, et al. Axon-tracing properties of indocyanine green. Arch Ophthalmol. 2003;121:367-370.
FREE FULL TEXT
22. Gandorfer A, Haritoglou C, Kampik A. Retinal damage from indocyanine green in experimental macular surgery. Invest Ophthalmol Vis Sci. 2003;44:316-323.
FREE FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Residual indocyanine green fluorescence pattern after vitrectomy for idiopathic macular hole with internal limiting membrane peeling
Sayanagi et al.
Br. J. Ophthalmol. 2007;91:939-944.
ABSTRACT
| FULL TEXT
Internal Limiting Membrane Peeling With Indocyanine Green or Trypan Blue in Macular Hole Surgery: A Randomized Trial
Beutel et al.
Arch Ophthalmol 2007;125:326-332.
ABSTRACT
| FULL TEXT
Relationship between macular hole size and the potential benefit of internal limiting membrane peeling.
Williams
Br. J. Ophthalmol. 2006;90:1216-1217.
FULL TEXT
Relationship between macular hole size and the potential benefit of internal limiting membrane peeling
Tadayoni et al.
Br. J. Ophthalmol. 2006;90:1239-1241.
ABSTRACT
| FULL TEXT
Selective Amplitude Reduction of the PhNR after Macular Hole Surgery: Ganglion Cell Damage Related to ICG-Assisted ILM Peeling and Gas Tamponade.
Ueno et al.
IOVS 2006;47:3545-3549.
ABSTRACT
| FULL TEXT
Retinal Toxicity of Indocyanine Green in Albino Rabbits
Goldstein et al.
IOVS 2006;47:2100-2107.
ABSTRACT
| FULL TEXT
Retinal ganglion cells toxicity caused by photosensitising effects of intravitreal indocyanine green with illumination in rat eyes
Yip et al.
Br. J. Ophthalmol. 2006;90:99-102.
ABSTRACT
| FULL TEXT
Chemical Toxicity of Indocyanine Green Damages Retinal Pigment Epithelium
Ikagawa et al.
IOVS 2005;46:2531-2539.
ABSTRACT
| FULL TEXT
Indocyanine green accused
Jackson
Br. J. Ophthalmol. 2005;89:395-396.
FULL TEXT
Triamcinolone-Assisted Internal Limiting Membrane Peeling During Idiopathic Macular Hole Surgery
Horio et al.
Arch Ophthalmol 2005;123:96-99.
FULL TEXT
|
