SINCE THE FIRST REPORT OF KELLY AND WENDEL1 OF

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1 Anatomic and Visual Outcomes After Indocyanine Green-assisted Peeling of the Retinal Internal Limiting Membrane in Idiopathic Macular Hole Surgery FUMITAKA ANDO, MD, KUMIKO SASANO, MD, NORIO OHBA, MD, HIROSHI HIROSE, MD, AND OSAMU YASUI, MD PURPOSE: To report anatomic and visual outcomes after vitrectomy and adjunctive retinal internal limiting membrane (ILM) peeling with and without intravitreal indocyanine green for idiopathic macular hole repair. DESIGN: Retrospective comparative study of consecutive case series. METHODS: Three consecutive groups of idiopathic macular hole cases underwent modifications of surgical technique. Group I (48 eyes of 47 patients) underwent a standard vitrectomy, fluid/gas exchange, and 1 week s face-down positioning, group II (21 eyes of 21 patients) an adjunctive ILM peeling without use of indocyanine green, and group III (28 eyes of 28 patients) an adjunctive peeling of ILM stained with intravitreal application of 0.1 to 0.2 ml of 0.5% indocyanine green dye. RESULTS: Three groups of patients had comparable clinical characteristics as to age, gender, estimated duration of macular hole, preoperative visual acuity, and follow-up time. The rate of macular hole closure after a single surgery, as determined by optical coherence topography was 85.4% in group I, 85.7% in group II, and 100% in group III. Groups I and II showed a statistically significant visual improvement, but group III did not show significant visual acuity improvement as the mean logarithm of the minimal angle of resolution visual acuity was from (20/120) preoperatively to (20/ 100) postoperatively (P.342). Eight cases in group III developed within a few postoperative months of optic disk pallor and irreversible peripheral visual field loss, predominately affecting the nasal field. Biosketch and/or additional material at Accepted for publication Aug 20, From Eye Care Nagoya, Nagoya, Japan (F.A., K.S., N.O.); and Nagoya National Hospital, Nagoya, Japan (H.H., O.Y.). Inquiries to Fumitaka Ando, MD, Eye Care Nagoya, Nagoya Diabuil 3-1, Meieki , Nakamura-key, Nagoya-shi , Japan; fax: ( 81) ; f.andou@eyecare-nagoya.com CONCLUSIONS: Intravitreal indocyanine green-assisted ILM peeling improves anatomic success in macular hole surgery, but it may potentially lead to unfavorable visual acuity outcome and peripheral visual field loss. (Am J Ophthalmol 2004;137: by Elsevier Inc. All rights reserved.) SINCE THE FIRST REPORT OF KELLY AND WENDEL1 OF successful closure of idiopathic macular hole by pars plana vitrectomy, several modifications of the surgical technique have been advocated. In recent years, adjunctive removal of the retinal internal limiting membrane (ILM) has been shown to improve anatomic results. 2 4 Thorough removal of the ILM is, however, unavailable to many surgeons because of poor visibility of the transparent retinal tissue. To overcome the problem, intravitreal application of indocyanine green (ICG) dye has been employed to stain the ILM and enhance its visibility, 5,6 and ICG-assisted peeling of the ILM during vitrectomy surgery has become the surgical treatment of choice for macular hole repair However, whether intravitreal application of ICG dye affects the retinal anatomy and physiology remains unclear. Recently, Engelbrecht and associates 12 reported poor visual acuity after vitrectomy with ICG-assisted ILM peeling for macular hole treatment, and Haritoglou and associates 13 reported in a noncomparative analysis of case series that intravitreal application of ICG may alter the cleavage plane to the innermost retinal layers and result in unfavorable visual outcomes. Furthermore, intravitreally applied ICG in macular hole surgery may persist in the retina or optic disk for 3 months or longer. 14,15 We report, herein, long-term anatomic and visual results in consecutive groups of macular hole patients undergoing vitrectomy with adjunctive peeling of the ILM with and without intravitreal application of ICG and discuss a potential negative effect of intravitreal ICG dye /04/$ BY ELSEVIER INC. ALL RIGHTS RESERVED. 609 doi: /j.ajo

2 TABLE 1. Clinical Characteristics of Three Groups of Patients With Idiopathic Macular Hole Group I Group II Group III Number of patients Age, years mean (range) 63.9 (29 81) 65.3 (44 82) 64.5 (38 82) Sex (male/female) 19/28 7/14 8/20 Number of eyes treated Estimated duration of macular hole, months (range) 3.5 (1 5.5) 3.3 (0.8 6) 3.2 (1 6) Macular hole state, stage stage stage Surgical intervention Standard vitrectomy ILM Peeling Without ICG ILM Peeling With ICG Follow-up, months mean (range) 16.8 (13 30) 15.6 (12 22) 17.5 (13 32) State of lens phakia pseudophakia Macular hole closure 41 (85.4%) 18 (85.7%) 28 (100%) Corrected visual acuity Preoperative Snellen 20/ (54.1%) 14 (66.7%) 12 (42.9%) 20/200 20/50 13 (27.1%) 6 (28.5%) 9 (32.1%) 20/50 9 (18.8%) 1 (4.8%) 7 (25.0%) logmar, mean (SD) (0.368) (0.433) (0.352) Postoperative Snellen 20/ (29.2%) 6 (28.6%) 11 (39.3%) 20/200 20/50 9 (18.7%) 5 (33.3%) 10 (35.7%) 20/50 25 (52.1%) 10 (38.1%) 7 (25.0%) logmar, mean (SD) (0.414) (0.401) (0.467) Postoperative visual field degrees 0 0 8/12 (*) ICG indocyanine green; logmar logarithm of the minimal angle of resolution; SD standard deviation METHODS WE REVIEWED THE RECORDS OF 97 EYES OF 96 PATIENTS who had undergone surgical treatment for idiopathic macular hole in a 4-year period between 1998 and 2001 at Nagoya National Hospital and Eye Care Nagoya. Exclusion criteria were macular holes associated with high myopia, peripheral rhegmatogenous retinal detachment, epimacular membrane, and trauma. All patients underwent ocular surgery for the first time, performed by a single experienced surgeon (F.A.). During the 4-year period of the study, three consecutive groups of eyes received sequential modifications of surgical technique. First, group I underwent a standard vitrectomy procedure that consisted of a three-port pars plana approach, removal of the posterior cortical vitreous, creation of posterior vitreous detachment when necessary, fluid gas exchange, and face-down positioning for 1 week after surgery. Second, group II underwent a peeling of the ILM in addition to the standard vitrectomy, wherein, after removing the vitreous, ILM was severed from the inner surface of the sensory retina by sucking with a back-flush needle and peeled off using a vitreous forceps at an area of approximately 1 2 disk diameter surrounding the macular hole. Third, group III received an ICG-assisted peeling of the ILM in addition to the standard vitrectomy. Indocyanine green dye was prepared and applied as follows: 25 mg of commercially available sterile ICG powder (Dai-ichi Pharmacy Co., Tokyo, Japan) was dissolved in 2 ml of sterile distilled water and diluted with 3 ml of balanced salt solution to yield 0.5% in concentration. Indocyanine green dye ( ml) was injected around the macular hole, and, immediately after application, the dye was washed out using a vitreous cutter. The ILM was then peeled off as in group II. Preoperative and postoperative routine examination included determination of corrected visual acuity, applanation tonometry, biomicroscopy with a 90-diopter preset lens or three-mirror contact lens, binocular indirect ophthalmoscopy, and optical coherence tomography. Fundus photography, fluorescein angiography, and a perimetric test using a Goldmann perimeter were done in selected cases. Anatomic results were determined in all cases for the foveal configuration by optical coherence tomography as 610 AMERICAN JOURNAL OF OPHTHALMOLOGY APRIL 2004

3 FIGURE 1. Snellen visual acuity, postoperative vs preoperative. Open squares, group I (n 48) undergoing a standard vitrectomy; closed circles, group II (n 21) undergoing a standard vitrectomy with peeling of the retinal internal limiting membrane; closed circles, group III (n 28) undergoing a standard vitrectomy with indocyanine green-assisted peeling of the retinal internal limiting membrane. The straight line of a 45-degree slope represents equality of the postoperative and preoperative Snellen visual acuity. Note that more data points in group III are below the straight line. well as by biomicroscopy. Data were reviewed for eye history, age, gender, estimated duration of macular hole, evolutionary stage of macular hole formation according to Gass classification 16 and follow-up period after surgery. Anatomic and visual data were evaluated by authors unmasked as to the surgical technique. Snellen visual acuity was converted to the logarithm of the minimal angle of resolution (logmar) for statistical analysis by taking the logarithm of the reciprocal of the Snellen fraction. The visual acuity outcome was calculated by subtracting the preoperative logmar from the postoperative logmar at the final follow-up examination, in which minus, zero, and plus value indicated visual acuity improvement, no change, and deterioration, respectively. Statistical analysis of the data were performed using StatView (SAS Institute Inc., Cary, North Carolina, USA). Preoperative and final visual acuity in each group and between the groups were compared using paired or unpaired t test, and categorical data such as anatomic hole closure rate were analyzed using the Fisher exact test; P values less than.05 were considered significant. FIGURE 2. Differences between postoperative and preoperative logarithm of the minimal angle of resolution (logmar) visual acuity in three groups undergoing surgeries of minimum modifications. Positive data points indicate postoperative visual acuity worsening, and negative data points postoperative visual acuity improvement. The symbols with bars points represent mean ( in group I, in group II, in group III) and 95% confidence interval of the mean. RESULTS TABLE 1 SHOWS CHARACTERISTICS OF PATIENTS AND SUMmary of data. A total of 96 patients (97 eyes) satisfying the above inclusion/exclusion criteria were included in the study, consisting of 48 eyes of 47 patients in group I, 21 eyes of 21 patients in group II, and 28 eyes of 28 patients in group III; one patient was bilateral. There was no difference in age or gender distribution among the groups. The majority of cases in each group presented with Stage 3 or Stage 4 full-thickness macular hole. The estimated duration of symptoms was comparable among the groups, and all cases were operated on within 6 months of the development of the disorder. The mean length of follow-up time from surgery to final examination was comparable among the three groups (16.8 months in group I, 15.6 months in group II, and 17.5 months in group III). The rate of macular hole closure after a single surgery as evaluated by optical coherence topography was 85.4% in VOL. 137, NO. 4 ICG IN MACULAR HOLE SURGERY 611

4 FIGURE 3. Goldmann visual fields of four cases in group III. group I, 85.7% in group II, and 100% in group III (Table 1); a second operation was performed on failed cases in group I and II, by which the success rate increased to 100%. Intravitreal ICG stained the ILM selectively, facilitated peeling of the ILM, and resulted in a higher, although not significant, anatomic success rate, with normal-appearing macular configuration, as revealed by optical coherence tomography images. Preoperative, baseline visual acuity did not differ among the three groups (Table 1). Postoperatively, corrected visual acuity at the final examination of at least 12 months follow-up varied considerably among cases and groups, as illustrated in Figure 1 for postoperative vs preoperative Snellen visual acuity and in Figure 2 for the difference between postoperative and preoperative logmar visual acuity. Statistically, group I and group II achieved significant visual improvement in such a fashion that the mean postoperative logmar visual acuity was (approximately 20 of 60) in group I and (approximately 20/55) in group II, and the difference in logmar visual acuity between the postoperative and preoperative examination was in group I (P.0001) and in group II (P.0001). There was no significant difference in visual acuity improvement between group I and group II (P.08), as demonstrated in Figure 2. Conversely, group III did not exhibit statistically significant improvement in visual acuity. At the final examination, 11 (39.3%) of 28 cases in group III showed visual acuity of 20/200 or worse, 10 cases (35.7%) between 20/200 and 20/50, and 7 cases (25.0%) 20/50 or better. The mean logmar visual acuity was.767 (approximately 20/120) preoperatively and.691 (approximately 20/100) postoperatively, and the difference was not significant (P.274). The degree of postoperative visual acuity improvement was significantly less as compared with that in group I (P.0004) and in group II (P.003), as demonstrated in Figure 2. The poor visual outcomes in group III were not attributed to progression of lens opacities; we did not perform lens extraction at the time of vitreous surgery, but performed cataract extraction with intraocular lens implantation when necessary during at least 12 months follow-up. The ratio of phakia/pseudophakia at the last examination did not differ significantly among the three groups (Table 1). Follow-up examinations with ophthalmoscopy, biomicroscopy, and optical coherence tomography did not reveal gross retinal damages such as retinal pigment epithelial atrophy to account for poor visual acuity in either of the groups; as it was also true in fluorescein angiographic findings performed in a few selected cases. As regards visual 612 AMERICAN JOURNAL OF OPHTHALMOLOGY APRIL 2004

5 field tests in selected cases using a Goldmann perimeter, none of the cases in group I and group II showed visual field abnormality, aside from preexisting central scotomas. Conversely, of 12 cases in group III undergoing follow-up Goldmann perimetric tests, eight (66.7%) developed irreversible peripheral visual field loss within several months after surgery, and its pattern conformed to retinal nerve fiber defect involving predominantly the temporal retina (nasal field defect), as illustrated for representative cases in Figure 3; one of the cases accompanied extensive central scotoma. The cases of postoperative visual field loss showed optic disk pallor. DISCUSSION CORE VITRECTOMY WITH CREATION OF POSTERIOR VITREous detachment and fluid gas exchange and 1 week s face-down positioning had been our standard macular hole surgery until July 1999, which was thereafter modified with adjunctive peeling of the ILM. We confirmed that removal of the ILM improves, although statistically not significant, the anatomic success rate in closure of macular hole, but we felt technical difficulties in meticulous peeling of the ILM because of its poor visibility. Encouraged by reports that intravitreal application of ICG dye stains the ILM and facilitates a safe, complete removal of the ILM, 5,6 we introduced the new procedure in our institution and confirmed its usefulness. However, we have noticed with an increasing experience that visual outcomes after ICGassisted peeling of the ILM are frequently discouraging despite persistent closure of macular hole, which prompted us to review the anatomic and visual outcomes and compare three consecutive groups of patients who had undergone standard vitrectomy alone, peeling of the ILM without use of ICG dye, and peeling of the ILM with help of intravitreal application of ICG dye. In our data, there was no significant visual acuity improvement after adjuvant ICG-assisted ILM removal, and not a few cases had visual deterioration. The findings are distinct from significant visual acuity improvements after ILM peeling without use of ICG dye as well as after standard vitrectomy alone. Although visual outcomes after macular hole surgery are dependent on many variables, our unexpected visual data after ICG-assisted ILM peeling by a single surgeon are unlikely due to patient selection biases as regards age, gender, state of macular hole, preoperative visual acuity, and other factors. Progression of cataract is a well-known complication of pars plana vitrectomy surgery and was not evaluated systematically in this study, because baseline lens opacity grading was not undertaken. In our surgical technique, lensectomy was not combined with vitrectomy as a simultaneous operation, and extracapsular cataract extraction and intraocular lens insertion were performed later when necessary. There was no significant difference in the rate of postvitrectomy cataract surgery among groups undergoing ICG-assisted ILM peeling, standard vitrectomy alone, and adjunctive ILM peeling without ICG dye, which excludes a possibility that the less favorable follow-up visual acuity data in the group with ICG-assisted ILM peeling was due to a higher rate of cataractous complication. Because peeling of the ILM with or without intravitreal application of ICG dye was the only step of procedure that was altered from the standard vitrectomy, it is suggested that intravitreal ICG dye has potentially adverse effects on visual functional outcomes. During the same period, we also experienced frequent deterioration of visual acuity after ICG-assisted peeling of the ILM in patients with diabetic macular edema (unpublished observations). Therefore, we have now stopped use of intravitreal application of ICG dye in vitreoretinal surgeries. Limited published information is available about visual outcomes after vitrectomy and adjunctive ICG-assisted ILM removal for macular hole repair. Some authors reported that ICG-assisted ILM peeling does not compromise visual result, or it does not impose negative effect on the retinal function Conversely, Engelbrecht and associates 12 reviewed 21 cases of macular hole undergoing ICG-assisted ILM removal and found that the median visual acuity was 20/200 preoperatively and 20/400 postoperatively. 12 Haritoglou and associates 13 reported on a retrospective, noncomparative analysis of 20 eyes of 20 patients undergoing ICG-assisted ILM removal for macular hole removal that there was no statistically significant improvement of postoperative visual acuity, with postoperative development of visual field defects in seven eyes. Thus, our current data conform to these recent reports. The visual field defect in our patients suggests predominant involvement of the retinal nerve fiber layer. The cause of poor visual acuity and visual field loss after ICG-assisted removal of the ILM remains unknown. Histopathologic studies of ICG-stained specimens revealed cellular elements resembling the plasma membrane of Müller cells and other undetermined retinal structures, adherent to the retinal side of the ILM, suggesting intravitreal application of ICG may cause retinal damage by altering the cleavage plane to the innermost retinal layers. 13,17 Engelbrecht and associates 12 reported that 10 (47.6%) of 21 cases undergoing intravitreal application of ICG for macular hole repair had unusual atrophic changes in the retinal pigment epithelium at the site of the previous macular hole or in the area where the ICG solution would have had direct access to the bare retinal pigment epithelial cells, and Sakamoto and associates 18 described two cases of retinal pigment epithelial changes after ICG-assisted vitrectomy. Intravitreally applied ICG for macular hole surgery has been shown to be retained in the retina and optic disk 3 months or longer after application, 14,15 and injection of ICG into rat vitreous results in long-term staining of the visual pathway. 19 Thus, potentially adverse effects of intravitreal application of ICG may VOL. 137, NO. 4 ICG IN MACULAR HOLE SURGERY 613

6 be attributed to either mechanical or toxic influence, or both, to the retina. As regards the ICG concentration, we used 0.1 to 0.2 ml of 0.5% ICG concentration recommended in the previous literature. 7 However, recent reports suggest that this concentration level may damage the retina. 20,21 In conclusion, further studies are justified to determine whether there exist optimal conditions for a safe clinical application, including concentration, osmolarity ph, and time of tissue contact, and to explore to what extent the adjunctive procedure is visually beneficial in vitreoretinal surgeries. REFERENCES 1. Kelly NE, Wendel RT. Vitreous surgery for idiopathic macular holes: Results of a pilot study. Arch Ophthalmol 1991;109: Park DW, Sipperley JO, Sneed SR, Dugel PU, Jacobsen J. Macular hole surgery with internal-limiting membrane peeling and intravitreous air. Ophthalmology 1999;106: Brooks HL, Jr. Macular hole surgery with and without internal limiting membrane peeling. Ophthalmology 2000; 107: Haritoglou C, Gass CA, Schaumberger M, Ehrt O, Gandorfer A, Kampik A. Macular changes after peeling of the internal limiting membrane in macular hole surgery. Am J Ophthalmol 2001;132: Kadonosono K, Itoh N, Uchio E, Nakamura S, Ohno S. Staining of internal limiting membrane in macular hole surgery. Arch Ophthalmol 2000;118: 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: Da Mata AP, Burk SE, Riemann CD, et al. Indocyanine green-assisted peeling of the retinal internal limiting membrane during vitrectomy surgery for macular hole repair. Ophthalmology 2001;108: Stalmans P, Parys-Vanginderdeuren R, De Vos R, Feron EJ. ICG staining of the internal limiting membrane facilitates its removal during surgery for macular holes and puckers. Bull Soc Belge Ophtalmol 2001;281: 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: Kumar A, Prakash G, Singh RP. Indocyanine green enhanced maculorhexis in macular hole surgery. Indian J Ophthalmol 2002;50: Kwork AKH, 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: Engelbrecht NE, Freeman J, Sternberg P, et al. Retinal pigment epithelial changes after macular hole surgery with indocyanine green-assisted internal limiting membrane peeling. Am J Ophthalmol 2002;133: Haritoglou C, Gandorfer A, Gass CA, Shaumberger 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: 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: Ciardella AP, Schiff W, Barlie G, et al. Persistent indocyanine green fluorescence after vitrectomy for macular hole. Am J Ophthalmol 2003;136: Gass JDM. Reappraisal of biomicroscopic classification of stages of development of a macular hole. Am J Ophthalmol 1995;119: Gandorfer A, Haritoglou C, Gass CA, Ubig MW, Kampik A. Indocyanine green-assisted peeling of the internal limiting membrane may cause retinal damage. Am J Ophthalmol 2001;132: Sakamoto T, Itaya K, Noda Y, Ishibashi T. Retinal pigment epithelial changes after indocyanine green-assisted vitrectomy. Retina 2002;22: Paques M, Genevois O, Regnier A, et al. Axon-tracing properties of indocyanine green. Arch Ophthalmol 2003; 121: 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: Blem RI, Huynh PD, Thall EH. Altered uptake of infrared diode laser by retina after intravitreal indocyanine green dye and internal limiting membrane. Am J Ophthalmol 2002;134: AMERICAN JOURNAL OF OPHTHALMOLOGY APRIL 2004

7 Biosketch Fumitaka Ando was born in 1935 as the 3rd generation in an Ophthalmology family and graduated from Nagoya University, School of Medicine in After finishing ophthalmology residency program at Nagoya University Hospital, he worked as a faculty member of Department of Ophthalmology, Nagoya University, and then as an ophthalmologist-in-chief of Nagoya National Hospital. He is now working as a founding director of EyeCare Nagoya, Nagoya. His major research interest has been surgical treatment of vitreoretinal diseases and have published over 250 scientific articles that include A plastic tack for the treatment of retinal detachment with giant tear (Am J Ophthalmol 1983; 95: 260), Intraocular hypertension resulting from pupillary block by silicone oil (Am J Ophthalmol 1985;99:87), Surgical techniques for giant retinal tears with retinal tacks (Ophthalmic Surg 1986;17: 408), Usefulness and limit of silicone in management of complicated retinal detachment (Jpn J Ophthalmol 1987; 31: 138), Importance of pupillary diaphragm for vitrectomy with intraocular silicone in hemodialysis patients (Dev Ophthalmol 1989;18:80-5), Factors influencing surgical results in proliferative diabetic retinopathy (Ger J Ophthalmol. 1993;2:155), Treatment of retinal detachment with giant tear by pneumatic retinopexy (Eur J Ophthalmol. 1993;3:201), and Influence of systemic conditions due to diabetes mellitus on visual outcome after vitrectomy (Folia Ophthalmol Jpn 1996; 47: 306). He is a member of Club Jules Gonin and of International Vitreous Society. He served as the President of the following congresses: 30th Japanese Ergohalmological Symposium (1988), 29th Congress of the Vitreoretinal Society of Japan (1990), 37th Ergophthalmological Symposium (1995), and 13th International Ergophthalmological Symposium (1990, Singapore). He is the Chairman of Asian Fund of Ophthalmologist Training, and he has trained many vitreoretinal specialists from Asian countries and trainees are playing a key role in their home countries. VOL. 137, NO. 4 ICG IN MACULAR HOLE SURGERY 614.e1