Autologous Transplantation of the Internal Limiting Membrane for Refractory Macular Holes YUKI MORIZANE, FUMIO SHIRAGA, SHUHEI KIMURA, MIO HOSOKAWA, YUSUKE SHIODE, TETSUHIRO KAWATA, MIKA HOSOGI, YUKARI SHIRAKATA, AND TOSHIO OKANOUCHI PURPOSE:
To determine the effectiveness of autologous transplantation of the internal limiting membrane (ILM) for refractory macular holes. DESIGN: Prospective, interventional case series. PATIENT AND METHODS: Ten eyes of 10 consecutive patients who underwent autologous transplantation of the ILM for the treatment of refractory macular holes were studied. The primary diseases in these patients were large idiopathic macular holes that had existed for more than 1 year (4 eyes), a traumatic macular hole (1 eye), myopic foveoschisis (2 eyes), foveoschisis resulting from pit-macular syndrome (2 eyes), and proliferative diabetic retinopathy (1 eye). Apart from the 5 eyes with idiopathic or traumatic macular holes, macular holes developed in the other 5 eyes after initial vitrectomies with ILM removal. In all eyes, regular macular hole surgery failed to achieve closure. The main outcome measures used in this study were macular hole closure and best-corrected visual acuity (BCVA). RESULTS: Macular holes were closed successfully in 9 eyes (90%) after autologous transplantation of the ILM. The postoperative BCVAs were significantly better than the preoperative BCVAs (P [ .007, paired t test). Postoperative BCVAs improved by more than 0.2 logarithm of the minimal angle of resolution units in 8 eyes (80%) and were unchanged in 2 eyes (20%). CONCLUSIONS: Although this is a pilot study, the results suggest that autologous transplantation of the ILM may contribute to improved anatomic and visual outcomes in the treatment of refractory macular holes and may warrant further investigation. (Am J Ophthalmol 2014;157:861–869. Ó 2014 by Elsevier Inc. All rights reserved.)
Supplemental Material available at AJO.com. Accepted for publication Dec 31, 2013. From the Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan (Y.M., F.S., S.K., M.H., Y.Shiode., T.K., M.H.); the Department of Ophthalmology, Kagawa University Faculty of Medicine, Kagawa, Japan (Y.Shirakata); and the Department of Ophthalmology, Kurashiki Medical Center, Okayama, Japan (T.O.). Inquiries to Yuki Morizane, Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama City, 7008558 Japan; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2013.12.028
Ó
2014 BY
I
NTERNAL LIMITING MEMBRANE (ILM) PEELING HAS
become an important element in the surgical treatment of a variety of retinal disorders, including macular holes, epiretinal membranes, vitreomacular traction, retinoschisis, and macular edema.1 ILM peeling is thought to provide good anatomic and functional results in these diseases by releasing the tractional forces on the macula completely and reducing the risk of postoperative epiretinal membrane formation. However, removal of the ILM recently was suggested to be ineffective for refractory macular holes and to be detrimental in macular diseases such as foveoschisis by causing the development of secondary macular holes.2–6 To address this problem, Michalewska and associates reported the efficacy of a modified surgical procedure, called the inverted ILM flap technique, for large macular holes.2 Kuriyama and associates also reported the efficacy of this procedure for myopic macular holes.3 To avoid the postoperative development of macular holes in myopic foveoschisis, Ho and associates and Shimada and associates reported an ILM peeling technique that left the epifoveal ILM in situ.4,5 Although these procedures can be an option for an initial vitrectomy, to avoid the failure of macular hole closure or the development of secondary macular holes, they cannot be applied to eyes with idiopathic macular holes, in which the initial vitrectomies with ILM peeling fail to achieve closure, or to eyes with secondary macular holes, in which the ILM already has been removed in previous vitrectomies. To try to solve this problem, we developed a new surgical technique, called autologous transplantation of the ILM, that transplants a flap of the ILM to the inside of the macular hole. This study was carried out to evaluate the functional and anatomic efficacy of autologous transplantation of the ILM for the treatment of refractory macular holes.
METHODS PATIENTS AND STUDY DESIGN:
This study was a prospective, interventional case series. All investigations adhered to the tenets of the Declaration of Helsinki. Each patient was informed about the risks and benefits of the surgery and their written, informed consent was obtained. The study was approved by the Institutional Review Boards of Okayama University Graduate School
ELSEVIER INC. ALL
RIGHTS RESERVED.
861
FIGURE 1. Schematic drawings showing the autologous transplantation of the internal limiting membrane (ILM) surgical technique for repairing macular holes. (Top left) Visualization of the residual ILM using 0.25 mg/mL brilliant blue G solution to identify the area where the ILM already had been peeled off during the initial surgery. White arrow indicates the area of residual ILM. Open arrowhead indicates macular hole. (Top right) A small piece of the ILM was peeled off to make a free flap, and this was transplanted and placed inside the macular hole. (Middle left) Surgical photograph of autologous transplantation of the ILM showing a free flap of ILM (black arrow), looking pale blue because of brilliant blue G staining, placed inside the macular hole. (Middle right) The free flap of ILM was stabilized by placing low molecular weight viscoelastic material (black arrowhead) over it. (Bottom left) Drawing of a cross-section of the transplanted ILM (black arrow), the low molecular weight viscoelastic material (black arrowhead), and the retina (asterisk).
of Medicine, Dentistry and Pharmaceutical Sciences and Kagawa University Faculty of Medicine. Ten eyes of 10 consecutive patients who had refractory macular holes and who underwent pars plana vitrectomy with autologous transplantation of the ILM between May 1, 2012, and June 30, 2013, were enrolled in the study. The inclusion criteria were as follows: (1) clinical presentation with macular hole after the initial vitrectomy with ILM removal; (2) treatment with 25-gauge, 3-port pars plana vitrectomy with autologous transplantation of the ILM and 10% sulfur hexafluoride gas tamponade; and (3) a follow-up period of more than 3 months since the last vitrectomy. The primary diseases in these patients were large idiopathic macular holes with diameters of more than 400 mm that had existed for more than 1 year (4 eyes), a 862
traumatic macular hole (1 eye), myopic foveoschisis (2 eyes), foveoschisis resulting from pit-macular syndrome (2 eyes), and proliferative diabetic retinopathy (1 eye). Apart from the 5 eyes with idiopathic or traumatic macular holes, macular holes developed in the remaining 5 eyes after initial vitrectomies. In all 10 eyes, the initial regular macular hole surgery with ILM removal or enlargement of the ILM-peeled area failed to close the macular holes. We measured the size of the macular holes parallel to the retinal pigment epithelium at the nearest point of retinal apposition. Macular hole closure was defined as the absence of a neurosensory defect over the fovea.7 All patients underwent comprehensive ophthalmologic examinations, including measurement of best-corrected visual acuity (BCVA) with refraction using the 5-m
AMERICAN JOURNAL OF OPHTHALMOLOGY
APRIL 2014
VOL. 157, NO. 4
Pseudophakic Pseudophakic Pseudophakic Pseudophakic Pseudophakic Phakic Phakic 1.00 0.15 0.22 0.22 1.05 0.40 0.52 1.10 1.00 0.52 0.70 1.05 0.82 1.00 Open Closed Closed Closed Closed Closed Closed — — — — 640 — 281 789 592 516 474 — 442 —
Pseudophakic Pseudophakic Pseudophakic 0.40 0.70 1.05 1.30 1.15 1.30 Closed Closed Closed 450 479 430 — — —
AUTOLOGOUS TRANSPLANTATION FOR MACULAR HOLE CLOSURE
— ¼ the data (value) is not provided.
83 65 66 72 68 17 41 4 5 6 7 8 9 10
Female Female Female Male Male Male Female
15 15 12 11 9 5 3
Myopic foveoschisis Myopic foveoschisis Foveoschisis resulting from pit-macular syndrome Large macular hole Large macular hole Large macular hole Large macular hole Proliferative diabetic retinopathy Traumatic macular hole Foveoschisis resulting from pit-macular syndrome
Final Primary Disease
Visual Acuity
Before Surgery (after Internal Limiting Membrane Transplantation)
Macular Hole Status Size of Macular Hole
after Initial Surgical Repair (mm) Follow-up (m)
18 16 16 Male Female Female 51 65 78
enrolled in this study are shown in the Table. The mean age of the 6 female and 4 male patients was 60.6 6 19.5 years (range, 17 to 83 years). The mean follow-up period was 12 6 5 months (range, 3 to 18 months). The mean diameter of the macular holes before autologous transplantation of the ILM was 509.3 6 137.8 mm (range, 281 to 789 mm). The lens status of the eyes was unchanged after autologous transplantation of the ILM. Intraocular
1 2 3
THE CHARACTERISTICS OF THE 10 PATIENTS WHO WERE
Sex
RESULTS
Age (y)
BCVA was recorded as decimal values and converted to the logarithm of the minimal angle of resolution units for statistical analysis. All visual acuity results are presented in logarithm of the minimal angle of resolution units. To evaluate the surgical outcomes, the preoperative and postoperative BCVA were compared using the paired t test. A P value of less than .05 was considered significant. All statistical analyses were performed using SPSS for Windows version 17.0 (SPSS, Inc., Chicago, Illinois, USA). Data are presented as mean 6 standard deviation.
Patient No.
DATA ANALYSIS:
Initial Size of Macular Hole (mm)
All patients underwent 25gauge, transconjunctival, sutureless microincision vitrectomy. All surgeries were performed by the same surgeon (F.S.). The residual ILM first was stained with 0.25 mg/ mL brilliant blue G solution (Coomassie BBG 250; Sigma-Aldrich, St. Louis, Missouri, USA) to identify the area where the ILM had been peeled off in previous surgery (Figure 1). We then peeled off a small piece of the ILM to create a free flap, so that its diameter was almost the same in diameter as the macular hole to be repaired. To avoid losing sight of the free flap of ILM, we turned off the infusion line and placed the free flap inside the macular hole. We then placed a low molecular weight viscoelastic material (Opegan; Santen Pharmaceutical Co, Ltd, Osaka, Japan) over the free flap of ILM to stabilize it, and this was left in the eye. Immediately after reopening the infusion line, we performed fluid–air exchange, keeping the extrusion needle away from the macula. At the end of the operation, the air was replaced with 10% sulfur hexafluoride gas. Patients were asked to remain face down for 3 days after surgery (Supplemental Video available at AJO.com).
TABLE. Characteristics of Patients Undergoing Autologous Transplantation of the Internal Limiting Membrane for Refractory Macular Holes
SURGICAL TECHNIQUES:
Lens Status
Landolt C acuity chart and indirect and contact lens slitlamp biomicroscopy. Spectral-domain optical coherence tomography (SD OCT) examinations were performed before and after surgery and at follow-up in all eyes using commercially available instruments (Cirrus [Carl Zeiss Meditec, Inc., Dublin, California, USA] or Spectralis [Heidelberg Engineering GmbH, Heidelberg, Germany]).
863
results of autologous transplantation of the ILM for 1 of the 2 patients with foveoschisis resulting from pit-macular syndrome are shown in Figure 6. Again, the SD OCT images show a successful outcome after autologous transplantation of the ILM.
DISCUSSION RECENTLY, SEVERAL SURGICAL PROCEDURES THAT INTEN-
FIGURE 2. Scatterplot showing a comparison of preoperative and postoperative best-corrected visual acuities (BCVAs) of 10 eyes undergoing autologous transplantation of the internal limiting membrane for macular holes. logMAR [ logarithm of the minimal angle of resolution.
lenses had been inserted in 8 eyes (80%), and the other 2 eyes (20%) were phakic. Macular hole closure was achieved after autologous trans- plantation of the ILM in 9 eyes (90%). In only 1 eye (10%; Patient 4), in which a large macular hole had existed for more than 3 years, was the procedure unsuccessful. In the 9 eyes (90%) in which the macular holes closed after autologous transplantation of the ILM, the transplanted ILM flaps were visible as highly reflective areas on SD OCT within 7 days of autologous transplantation of the ILM. These highly reflective areas disappeared within 3 months. The mean BCVA was 0.99 6 0.25 (range, 0.52 to 1.30) before surgery and 0.57 6 0.36 (range, 0.15 to 1.05) at the final visit. This showed a significant difference in BCVA before and after autologous transplantation of the ILM (P ¼ .007). The postoperative BCVA improved by more than 0.2 logMAR in 8 eyes (80%), but was unchanged in 2 eyes (20%; Figure 2). No complications occurred during surgery or after surgery in any cases. Figures 3 and 4 show the clinical results for 2 patients who underwent autologous transplantation of the ILM for large macular holes. SD OCT images show the macular hole closure achieved after autologous transplantation of the ILM. Figure 5 shows similar results for the patient who sought treatment with a traumatic macular hole, choroidal rupture, and subretinal fibrosis. Similarly, the initial regular macular hole surgery, in which the ILM was removed, did not result in any success. However, after we performed autologous transplantation of the ILM at the second surgery, the macular hole was closed successfully, resulting in an improvement in visual acuity. The clinical 864
tionally spare the foveal ILM have been reported to be effective in conditions such as large macular holes, myopic macular holes, and myopic foveoschisis.2–5 Although these procedures can be options for the initial vitrectomy, to avoid the failure of macular hole closure and the development of secondary macular holes, they cannot be the solution for eyes with macular holes from which the ILMs already have been removed in previous vitrectomies. To solve this problem, we developed this new surgical procedure, autologous transplantation of the ILM, and assessed its efficacy as a new option for the treatment of refractory macular holes. Large and traumatic macular holes may be conditions in which removing the ILM is sometimes ineffective. After vitrectomy with ILM removal, up to 44% of large macular holes have been reported to remain open.2 Repeated surgeries for failed closures of macular holes also have been reported to have a lower success rate than primary surgery.8 Furthermore, the visual outcomes for large macular holes usually are limited even after hole closure because, although large macular holes frequently close with flat borders with the retina, the retinal pigment epithelium may be bare (flat-open macular holes).2,9 To improve the closure rate, Alpatov and associates presented a method for bringing the borders of full-thickness macular holes together mechanically.10 Although this method does indeed improve closure rate and can be a solution in eyes in which the ILM already has been removed, the visual outcomes were limited, because the surgical manipulation could damage the retina.2 In this study, we performed autologous transplantation of the ILM on 4 eyes with large macular holes and obtained successful hole closures, without bare retinal pigment epithelium and with improved visual outcomes, in 3 eyes (75%; Figures 3 and 4). These results indicate that autologous transplantation of the ILM may be a solution for large macular holes when the ILM already has been removed. For traumatic macular holes, 10% to 67% of cases have been reported to close spontaneously.11–14 However, these cases sometimes are associated with choroidal rupture and subsequent subretinal hemorrhage and fibrosis.15,16 In such cases, traumatic macular holes do not close spontaneously and furthermore are difficult to close, even if the vitreous and ILM are removed, because the retina adheres to the choroid and sclera and lacks extensibility and flexibility. This study included 1 such
AMERICAN JOURNAL OF OPHTHALMOLOGY
APRIL 2014
FIGURE 3. Results of autologous transplantation of the internal limiting membrane (ILM) in Patient 5, a 65-year-old woman with a large macular hole. (Top left) Fundus photograph obtained before the initial vitrectomy showing a macular hole. (Top right) Spectraldomain optical coherence tomography (SD OCT) images obtained before the initial vitrectomy (upper panel) and after the initial vitrectomy (lower panel) showing an open macular hole. (Bottom left) Fundus photograph obtained 3 months after autologous transplantation of the ILM showing the closure of the macular hole. (Bottom right) SD OCT images obtained 5 days after autologous transplantation of the ILM (upper panel) and 3 months after autologous transplantation of the ILM (lower panel). The transplanted ILM flap (arrow) is visible inside of the macular hole at 5 days and there is a defect in the line between the inner segment and outer segment (IS/OS) junction of the photoreceptor. After 3 months, the macular hole closed and the IS/OS line was restored. Best-corrected visual acuity (logarithm of the minimal angle of resolution) improved from 1.0 before surgery to 0.15 at the final visit.
FIGURE 4. Results of autologous transplantation of the internal limiting membrane in Patient 7, a 72-year-old man with a large macular hole. (Top left) Spectral-domain optical coherence tomography (SD OCT) image obtained before initial vitrectomy showing a macular hole. (Top right) SD OCT image obtained after initial vitrectomy showing a residual macular hole. (Bottom left) SD OCT image obtained 7 days after autologous transplantation of the ILM showing the closure of the macular hole. The transplanted ILM flap is visible as a highly reflective area (arrow), and there is a defect in the inner segment/outer segment (IS/OS) junction of the photoreceptor line. (Bottom right) SD OCT image obtained 14 days after autologous transplantation of the ILM showing the closure of the macular hole. The IS/OS line is restored. Best-corrected visual acuity (logarithm of the minimal angle of resolution) improved from 0.70 before surgery to 0.22 at the final visit.
VOL. 157, NO. 4
AUTOLOGOUS TRANSPLANTATION FOR MACULAR HOLE CLOSURE
865
FIGURE 5. Results of autologous transplantation of the internal limiting membrane (ILM) in Patient 9, a 17-year-old boy with a traumatic macular hole. (Top left) Fundus photograph obtained on the day of injury. (Top right) Spectral-domain optical coherence tomography (SD OCT) image obtained on the day of injury showing dense subfoveal hemorrhage. (Second row left) Fundus photograph obtained 4 months after injury when the patient was referred to our hospital by an ophthalmologist in general practice. Arrow indicates a choroidal rupture. (Second row right) SD OCT image obtained 4 months after the injury showing the spontaneous absorption of subfoveal hemorrhage and a full-thickness macular hole. Best-corrected visual acuity (BCVA; logarithm of the minimal angle of resolution) was 1.52 on the day of injury and 0.70 after 4 months. (Third row left) Fundus photograph and (Third row right) SD OCT image obtained after the initial vitrectomy with ILM peeling showing an unclosed macular hole and a choroidal rupture. The macular hole showed no improvement compared with the images before surgery. (Bottom left) Fundus photograph and (Bottom right) SD OCT image obtained 14 days after autologous transplantation of the ILM showing closure of the macular hole. The white arrow indicates the transplanted ILM flap. BCVA improved from 0.82 before the second surgery to 0.40 at the final visit.
866
AMERICAN JOURNAL OF OPHTHALMOLOGY
APRIL 2014
FIGURE 6. Results of autologous transplantation of the internal limiting membrane (ILM) in Patient 3, a 78-year-old woman with foveoschisis resulting from pit-macular syndrome. (Top left) Spectral-domain optical coherence tomography (SD OCT) image obtained before surgery for foveoschisis showing foveoschisis and macular detachment. Best-corrected visual acuity (BCVA; logarithm of the minimal angle of resolution) was 1.0. (Top right) SD OCT image obtained after the initial vitrectomy with ILM peeling for foveoschisis showing the macular hole that developed after surgery, macular detachment, and foveoschisis. (Middle row left) SD OCT image obtained after the second vitrectomy that enlarged the area of ILM peeled and used 10% sulfur hexafluoride gas tamponade; the macular hole had not closed and was still large and retinoschisis was present. (Middle row right) SD OCT image of the gasfilled eye obtained 1 day after the third surgery using autologous transplantation of the ILM showing the closure of the macular hole. The highly reflective area represents the transplanted ILM flap (arrow). (Bottom left) SD OCT image obtained 5 days after autologous transplantation of the ILM showing the closure of the macular hole. The arrow indicates the transplanted ILM flap. BCVA improved from 1.30 before the third surgery to 1.05 at the final visit.
eye, accompanied by choroidal rupture and subretinal fibrosis, in which we had tried to close the traumatic macular hole using ILM removal and 10% sulfur hexafluoride gas tamponade. However, as shown in Figure 5, the macular hole failed to close after this initial surgery. We performed autologous transplantation of the ILM at the second surgery and the macular hole then closed successfully, resulting in an improvement in visual acuity. Although this is a single case, we consider that traumatic macular holes accompanied by retinal fibrosis, in which the retina lacks extensibility, are good candidates for autologous transplantation of the ILM. In foveoschisis, which often is associated with high myopia or pit-macular syndrome, vitrectomy with ILM removal has been reported to lead to significantly better visual outcomes and to prevent recurrent tractional macular detachments compared with vitrectomy without ILM removal.17 However, there is a dilemma for surgeons when the ILM is removed for foveoschisis, because its removal also has been reported sometimes to worsen the situation by causing the development of macular holes after surgery. For example, in myopic foveoschisis, the prevaVOL. 157, NO. 4
lence of secondary macular holes after ILM removal was found to be 19% to 27%, which is much higher than that reported for rhegmatogenous retinal detachment repair after vitrectomy.4,6,18–20 The secondary macular holes usually are refractory, because the ILM already has been removed at vitrectomy. In this study, we performed autologous transplantation of the ILM for 4 eyes with secondary macular holes that had developed after the initial vitrectomy with ILM removal for foveoschisis. In all 4 cases, we finally achieved successful hole closures after autologous transplantation of the ILM (Table), demonstrating that autologous transplantation of the ILM may resolve our dilemma during initial surgery and enable surgeons to remove ILMs without hesitation. With one exception (Patient 4), transplanted ILM flaps were visible in the eyes on SD OCT images for some time after autologous transplantation of the ILM. This suggests that our surgical technique was able to transplant ILM flaps stably inside macular holes with a high success rate. In Patient 4, the transplanted ILM flap probably moved away from the inside of the macular hole. In this case, with long-established pathologic characteristics, the retinal
AUTOLOGOUS TRANSPLANTATION FOR MACULAR HOLE CLOSURE
867
pigment epithelium inside the macular hole was atrophic, as was the retinal fluid cuff surrounding it, so the glial proliferation, which is integral to hole closure, may have been insufficient. The results of this study imply that the flap of ILM placed inside a macular hole has the ability to repair the foveal contour. Recent in vivo studies using OCT to detect glial tissue reflectivity suggested that Mu¨ller cell gliosis is essential for macular hole healing.21–27 Mu¨ller cell proliferation is thought to play an important role in filling macular holes and in producing an environment conducive to the repositioning of photoreceptors by moving photoreceptors to new locations.2 Furthermore, in animal models, Mu¨ller cells have been reported to have the potential to proliferate, dedifferentiate, and produce photoreceptors under cytotoxic conditions.28,29 Based on the results of inverted ILM surgery for large macular holes, Michalewska and associates hypothesized that the ILM flap functions as both a source of Mu¨ller cells, which locate to the surface
of the ILM flap, and as a scaffold for Mu¨ller cell proliferation.2 Although the exact mechanism by which the ILM flap restores the fovea remains unknown, our OCT results after autologous transplantation of the ILM, which indicate that filling macular holes with new tissue occurs around the ILM flap (Figures 3–6), support their hypothesis. To confirm this, further studies, including experiments with animal models, are needed. The study described here was limited by a small sample size and a relatively short follow-up period. Our results show that this new surgical technique has the potential to improve visual function in patients with refractory macular holes in the short term. However in the longer term, this technique has the potential to induce adverse events after ILM transplantation, such as retinal fibrosis, that require further monitoring. Further randomized controlled clinical studies involving a larger number of patients are needed to determine the impact that this technique could have in the management of refractory macular holes.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and none were reported. Involved in Design and conduct of study (Y.M., F.S., S.K.); Data collection (S.K., M.H., Y.Shiode., T.K., M.H., Y.Shirakata., T.O.); Management, analysis, and interpretation of data (Y.M., F.S.); Writing article (Y.M.); and Critical revision and final approval of article (Y.M., F.S., S.K., M.H., Y.Shiode., T.K., M.H., Y.Shirakata., T.O.).
REFERENCES 1. Almony A, Nudleman E, Shah GK, et al. Techniques, rationale, and outcomes of internal limiting membrane peeling. Retina 2012;32(5):877–891. 2. Michalewska Z, Michalewski J, Adelman RA, Nawrocki J. Inverted internal limiting membrane flap technique for large macular holes. Ophthalmology 2010;117(10):2018–2025. 3. Kuriyama S, Hayashi H, Jingami Y, Kuramoto N, Akita J, Matsumoto M. Efficacy of inverted internal limiting membrane flap technique for the treatment of macular hole in high myopia. Am J Ophthalmol 2013;156(1):125–131. 4. Shimada N, Sugamoto Y, Ogawa M, Takase H, OhnoMatsui K. Fovea-sparing internal limiting membrane peeling for myopic traction maculopathy. Am J Ophthalmol 2012; 154(4):1–9. 5. Ho T-C, Chen M-S, Huang J-S, Shih Y-F, Ho H, Huang Y-H. Foveola nonpeeling technique in internal limiting membrane peeling of myopic foveoschisis surgery. Retina 2012;32(3): 631–634. 6. Kobayashi H, Kishi S. Vitreous surgery for highly myopic eyes with foveal detachment and retinoschisis. Ophthalmology 2003;110(9):1702–1707. 7. Kang SW, Ahn K, Ham D-I. Types of macular hole closure and their clinical implications. Br J Ophthalmol 2003;87(8): 1015–1019. 8. Hillenkamp J, Kraus J, Framme C, et al. Retreatment of full-thickness macular hole: predictive value of optical coherence tomography. Br J Ophthalmol 2007;91(11):1445–1449. 9. Cho HY, Kim YT, Kang SW. Laser photocoagulation as adjuvant therapy to surgery for large macular holes. Korean J Ophthalmol 2006;20(2):93–98.
868
10. Alpatov S, Shchuko A, Malyshev V. A new method of treating macular holes. Eur J Ophthalmol 2007;17(2): 246–252. 11. Hernandez-Da Mota SE. Posttraumatic giant macular hole. Case Rep Ophthalmol 2011;2(2):283–286. 12. Huang J, Liu X, Wu Z, Sadda S. Comparison of full-thickness traumatic macular holes and idiopathic macular holes by optical coherence tomography. Graefes Arch Clin Exp Ophthalmol 2010;248(8):1071–1075. 13. Arevalo JF, Sanchez JG, Costa RA, et al. Optical coherence tomography characteristics of full-thickness traumatic macular holes. Eye (Lond) 2008;22(11):1436–1441. 14. Yamashita T, Uemara A, Uchino E, Doi N, Ohba N. Spontaneous closure of traumatic macular hole. Am J Ophthalmol 2002;133(2):230–235. 15. Yeung L, Chen T-L, Kuo Y-H, et al. Severe vitreous hemorrhage associated with closed-globe injury. Graefes Arch Clin Exp Ophthalmol 2006;244(1):52–57. 16. Yanagiya N, Akiba J, Takahashi M, et al. Clinical characteristics of traumatic macular holes. Jpn J Ophthalmol 1996; 40(4):544–547. 17. Taniuchi S, Hirakata A, Itoh Y, Hirota K, Inoue M. Vitrectomy with or without internal limiting membrane peeling for each stage of myopic traction maculopathy. Retina 2013; 33(10):2018–2025. 18. Gao X, Ikuno Y, Fujimoto S, Nishida K. Risk factors for development of full-thickness macular holes after pars plana vitrectomy for myopic foveoschisis. Am J Ophthalmol 2013;155(6): 1021–1027. 19. Hwang JU, Joe SG, Lee J-Y, Kim J-G, Yoon YH. Microincision vitrectomy surgery for myopic foveoschisis. Br J Ophthalmol 2013;97(7):879–884.
AMERICAN JOURNAL OF OPHTHALMOLOGY
APRIL 2014
20. Gaucher D, Haouchine B, Tadayoni R, et al. Long-term follow-up of high myopic foveoschisis: natural course and surgical outcome. Am J Ophthalmol 2007;143(3):455–462. 21. Michalewska Z, Michalewski J, Cisiecki S, Adelman R, Nawrocki J. Correlation between foveal structure and visual outcome following macular hole surgery: a spectral optical coherence tomography study. Graefes Arch Clin Exp Ophthalmol 2008;246(6):823–830. 22. Ko TH, Witkin AJ, Fujimoto JG, et al. Ultrahigh-resolution optical coherence tomography of surgically closed macular holes. Arch Ophthalmol 2006;124(6):827–836. 23. Kang SW, Lim JW, Chung SE, Yi C-H. Outer foveolar defect after surgery for idiopathic macular hole. Am J Ophthalmol 2010;150(4):551–557. 24. Michalewska Z, Michalewski J, Nawrocki J. Continuous changes in macular morphology after macular hole closure visualized with spectral optical coherence tomography. Graefes Arch Clin Exp Ophthalmol 2010;248(9):1249–1255.
VOL. 157, NO. 4
25. Funata M, Wendel RT, la Cruz de Z, Green WR. Clinicopathologic study of bilateral macular holes treated with pars plana vitrectomy and gas tamponade. Retina 1992;12(4): 289–298. 26. Madreperla SA, Geiger GL, Funata M, la Cruz de Z, Green WR. Clinicopathologic correlation of a macular hole treated by cortical vitreous peeling and gas tamponade. Ophthalmology 1994;101(4):682–686. 27. Oh J, Yang SM, Choi YM, Kim S-W, Huh K. Glial proliferation after vitrectomy for a macular hole: a spectral domain optical coherence tomography study. Graefes Arch Clin Exp Ophthalmol 2013;251(2):477–484. 28. Ooto S, Akagi T, Kageyama R, et al. Potential for neural regeneration after neurotoxic injury in the adult mammalian retina. Proc Natl Acad Sci U S A 2004;101(37):13654–13659. 29. Osakada F, Ooto S, Akagi T, Mandai M, Akaike A, Takahashi M. Wnt signaling promotes regeneration in the retina of adult mammals. J Neurosci 2007;27(15):4210–4219.
AUTOLOGOUS TRANSPLANTATION FOR MACULAR HOLE CLOSURE
869
Biosketch Yuki Morizane, MD, PhD, is an Assistant Professor (Lecturer), Department of Ophthalmology, Okayama University, Okayama, Japan. After finishing his residency in ophthalmology and retina fellowship at Okayama University Hospital, he completed a retinal research fellowship at Harvard Medical School, Massachusetts Eye and Ear Infirmary from 2008 to 2011. His research interests are metabolic mechanisms of ocular diseases, ocular neovascularization, and vitrectomy.
869.e1
AMERICAN JOURNAL OF OPHTHALMOLOGY
APRIL 2014
To determine the effectiveness of autologous transplantation of the internal limiting membrane (ILM) for refractory macular holes. DESIGN: Prospective, interventional case series. PATIENT AND METHODS: Ten eyes of 10 consecutive patients who underwent autologous transplantation of the ILM for the treatment of refractory macular holes were studied. The primary diseases in these patients were large idiopathic macular holes that had existed for more than 1 year (4 eyes), a traumatic macular hole (1 eye), myopic foveoschisis (2 eyes), foveoschisis resulting from pit-macular syndrome (2 eyes), and proliferative diabetic retinopathy (1 eye). Apart from the 5 eyes with idiopathic or traumatic macular holes, macular holes developed in the other 5 eyes after initial vitrectomies with ILM removal. In all eyes, regular macular hole surgery failed to achieve closure. The main outcome measures used in this study were macular hole closure and best-corrected visual acuity (BCVA). RESULTS: Macular holes were closed successfully in 9 eyes (90%) after autologous transplantation of the ILM. The postoperative BCVAs were significantly better than the preoperative BCVAs (P [ .007, paired t test). Postoperative BCVAs improved by more than 0.2 logarithm of the minimal angle of resolution units in 8 eyes (80%) and were unchanged in 2 eyes (20%). CONCLUSIONS: Although this is a pilot study, the results suggest that autologous transplantation of the ILM may contribute to improved anatomic and visual outcomes in the treatment of refractory macular holes and may warrant further investigation. (Am J Ophthalmol 2014;157:861–869. Ó 2014 by Elsevier Inc. All rights reserved.)
Supplemental Material available at AJO.com. Accepted for publication Dec 31, 2013. From the Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan (Y.M., F.S., S.K., M.H., Y.Shiode., T.K., M.H.); the Department of Ophthalmology, Kagawa University Faculty of Medicine, Kagawa, Japan (Y.Shirakata); and the Department of Ophthalmology, Kurashiki Medical Center, Okayama, Japan (T.O.). Inquiries to Yuki Morizane, Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama City, 7008558 Japan; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2013.12.028
Ó
2014 BY
I
NTERNAL LIMITING MEMBRANE (ILM) PEELING HAS
become an important element in the surgical treatment of a variety of retinal disorders, including macular holes, epiretinal membranes, vitreomacular traction, retinoschisis, and macular edema.1 ILM peeling is thought to provide good anatomic and functional results in these diseases by releasing the tractional forces on the macula completely and reducing the risk of postoperative epiretinal membrane formation. However, removal of the ILM recently was suggested to be ineffective for refractory macular holes and to be detrimental in macular diseases such as foveoschisis by causing the development of secondary macular holes.2–6 To address this problem, Michalewska and associates reported the efficacy of a modified surgical procedure, called the inverted ILM flap technique, for large macular holes.2 Kuriyama and associates also reported the efficacy of this procedure for myopic macular holes.3 To avoid the postoperative development of macular holes in myopic foveoschisis, Ho and associates and Shimada and associates reported an ILM peeling technique that left the epifoveal ILM in situ.4,5 Although these procedures can be an option for an initial vitrectomy, to avoid the failure of macular hole closure or the development of secondary macular holes, they cannot be applied to eyes with idiopathic macular holes, in which the initial vitrectomies with ILM peeling fail to achieve closure, or to eyes with secondary macular holes, in which the ILM already has been removed in previous vitrectomies. To try to solve this problem, we developed a new surgical technique, called autologous transplantation of the ILM, that transplants a flap of the ILM to the inside of the macular hole. This study was carried out to evaluate the functional and anatomic efficacy of autologous transplantation of the ILM for the treatment of refractory macular holes.
METHODS PATIENTS AND STUDY DESIGN:
This study was a prospective, interventional case series. All investigations adhered to the tenets of the Declaration of Helsinki. Each patient was informed about the risks and benefits of the surgery and their written, informed consent was obtained. The study was approved by the Institutional Review Boards of Okayama University Graduate School
ELSEVIER INC. ALL
RIGHTS RESERVED.
861
FIGURE 1. Schematic drawings showing the autologous transplantation of the internal limiting membrane (ILM) surgical technique for repairing macular holes. (Top left) Visualization of the residual ILM using 0.25 mg/mL brilliant blue G solution to identify the area where the ILM already had been peeled off during the initial surgery. White arrow indicates the area of residual ILM. Open arrowhead indicates macular hole. (Top right) A small piece of the ILM was peeled off to make a free flap, and this was transplanted and placed inside the macular hole. (Middle left) Surgical photograph of autologous transplantation of the ILM showing a free flap of ILM (black arrow), looking pale blue because of brilliant blue G staining, placed inside the macular hole. (Middle right) The free flap of ILM was stabilized by placing low molecular weight viscoelastic material (black arrowhead) over it. (Bottom left) Drawing of a cross-section of the transplanted ILM (black arrow), the low molecular weight viscoelastic material (black arrowhead), and the retina (asterisk).
of Medicine, Dentistry and Pharmaceutical Sciences and Kagawa University Faculty of Medicine. Ten eyes of 10 consecutive patients who had refractory macular holes and who underwent pars plana vitrectomy with autologous transplantation of the ILM between May 1, 2012, and June 30, 2013, were enrolled in the study. The inclusion criteria were as follows: (1) clinical presentation with macular hole after the initial vitrectomy with ILM removal; (2) treatment with 25-gauge, 3-port pars plana vitrectomy with autologous transplantation of the ILM and 10% sulfur hexafluoride gas tamponade; and (3) a follow-up period of more than 3 months since the last vitrectomy. The primary diseases in these patients were large idiopathic macular holes with diameters of more than 400 mm that had existed for more than 1 year (4 eyes), a 862
traumatic macular hole (1 eye), myopic foveoschisis (2 eyes), foveoschisis resulting from pit-macular syndrome (2 eyes), and proliferative diabetic retinopathy (1 eye). Apart from the 5 eyes with idiopathic or traumatic macular holes, macular holes developed in the remaining 5 eyes after initial vitrectomies. In all 10 eyes, the initial regular macular hole surgery with ILM removal or enlargement of the ILM-peeled area failed to close the macular holes. We measured the size of the macular holes parallel to the retinal pigment epithelium at the nearest point of retinal apposition. Macular hole closure was defined as the absence of a neurosensory defect over the fovea.7 All patients underwent comprehensive ophthalmologic examinations, including measurement of best-corrected visual acuity (BCVA) with refraction using the 5-m
AMERICAN JOURNAL OF OPHTHALMOLOGY
APRIL 2014
VOL. 157, NO. 4
Pseudophakic Pseudophakic Pseudophakic Pseudophakic Pseudophakic Phakic Phakic 1.00 0.15 0.22 0.22 1.05 0.40 0.52 1.10 1.00 0.52 0.70 1.05 0.82 1.00 Open Closed Closed Closed Closed Closed Closed — — — — 640 — 281 789 592 516 474 — 442 —
Pseudophakic Pseudophakic Pseudophakic 0.40 0.70 1.05 1.30 1.15 1.30 Closed Closed Closed 450 479 430 — — —
AUTOLOGOUS TRANSPLANTATION FOR MACULAR HOLE CLOSURE
— ¼ the data (value) is not provided.
83 65 66 72 68 17 41 4 5 6 7 8 9 10
Female Female Female Male Male Male Female
15 15 12 11 9 5 3
Myopic foveoschisis Myopic foveoschisis Foveoschisis resulting from pit-macular syndrome Large macular hole Large macular hole Large macular hole Large macular hole Proliferative diabetic retinopathy Traumatic macular hole Foveoschisis resulting from pit-macular syndrome
Final Primary Disease
Visual Acuity
Before Surgery (after Internal Limiting Membrane Transplantation)
Macular Hole Status Size of Macular Hole
after Initial Surgical Repair (mm) Follow-up (m)
18 16 16 Male Female Female 51 65 78
enrolled in this study are shown in the Table. The mean age of the 6 female and 4 male patients was 60.6 6 19.5 years (range, 17 to 83 years). The mean follow-up period was 12 6 5 months (range, 3 to 18 months). The mean diameter of the macular holes before autologous transplantation of the ILM was 509.3 6 137.8 mm (range, 281 to 789 mm). The lens status of the eyes was unchanged after autologous transplantation of the ILM. Intraocular
1 2 3
THE CHARACTERISTICS OF THE 10 PATIENTS WHO WERE
Sex
RESULTS
Age (y)
BCVA was recorded as decimal values and converted to the logarithm of the minimal angle of resolution units for statistical analysis. All visual acuity results are presented in logarithm of the minimal angle of resolution units. To evaluate the surgical outcomes, the preoperative and postoperative BCVA were compared using the paired t test. A P value of less than .05 was considered significant. All statistical analyses were performed using SPSS for Windows version 17.0 (SPSS, Inc., Chicago, Illinois, USA). Data are presented as mean 6 standard deviation.
Patient No.
DATA ANALYSIS:
Initial Size of Macular Hole (mm)
All patients underwent 25gauge, transconjunctival, sutureless microincision vitrectomy. All surgeries were performed by the same surgeon (F.S.). The residual ILM first was stained with 0.25 mg/ mL brilliant blue G solution (Coomassie BBG 250; Sigma-Aldrich, St. Louis, Missouri, USA) to identify the area where the ILM had been peeled off in previous surgery (Figure 1). We then peeled off a small piece of the ILM to create a free flap, so that its diameter was almost the same in diameter as the macular hole to be repaired. To avoid losing sight of the free flap of ILM, we turned off the infusion line and placed the free flap inside the macular hole. We then placed a low molecular weight viscoelastic material (Opegan; Santen Pharmaceutical Co, Ltd, Osaka, Japan) over the free flap of ILM to stabilize it, and this was left in the eye. Immediately after reopening the infusion line, we performed fluid–air exchange, keeping the extrusion needle away from the macula. At the end of the operation, the air was replaced with 10% sulfur hexafluoride gas. Patients were asked to remain face down for 3 days after surgery (Supplemental Video available at AJO.com).
TABLE. Characteristics of Patients Undergoing Autologous Transplantation of the Internal Limiting Membrane for Refractory Macular Holes
SURGICAL TECHNIQUES:
Lens Status
Landolt C acuity chart and indirect and contact lens slitlamp biomicroscopy. Spectral-domain optical coherence tomography (SD OCT) examinations were performed before and after surgery and at follow-up in all eyes using commercially available instruments (Cirrus [Carl Zeiss Meditec, Inc., Dublin, California, USA] or Spectralis [Heidelberg Engineering GmbH, Heidelberg, Germany]).
863
results of autologous transplantation of the ILM for 1 of the 2 patients with foveoschisis resulting from pit-macular syndrome are shown in Figure 6. Again, the SD OCT images show a successful outcome after autologous transplantation of the ILM.
DISCUSSION RECENTLY, SEVERAL SURGICAL PROCEDURES THAT INTEN-
FIGURE 2. Scatterplot showing a comparison of preoperative and postoperative best-corrected visual acuities (BCVAs) of 10 eyes undergoing autologous transplantation of the internal limiting membrane for macular holes. logMAR [ logarithm of the minimal angle of resolution.
lenses had been inserted in 8 eyes (80%), and the other 2 eyes (20%) were phakic. Macular hole closure was achieved after autologous trans- plantation of the ILM in 9 eyes (90%). In only 1 eye (10%; Patient 4), in which a large macular hole had existed for more than 3 years, was the procedure unsuccessful. In the 9 eyes (90%) in which the macular holes closed after autologous transplantation of the ILM, the transplanted ILM flaps were visible as highly reflective areas on SD OCT within 7 days of autologous transplantation of the ILM. These highly reflective areas disappeared within 3 months. The mean BCVA was 0.99 6 0.25 (range, 0.52 to 1.30) before surgery and 0.57 6 0.36 (range, 0.15 to 1.05) at the final visit. This showed a significant difference in BCVA before and after autologous transplantation of the ILM (P ¼ .007). The postoperative BCVA improved by more than 0.2 logMAR in 8 eyes (80%), but was unchanged in 2 eyes (20%; Figure 2). No complications occurred during surgery or after surgery in any cases. Figures 3 and 4 show the clinical results for 2 patients who underwent autologous transplantation of the ILM for large macular holes. SD OCT images show the macular hole closure achieved after autologous transplantation of the ILM. Figure 5 shows similar results for the patient who sought treatment with a traumatic macular hole, choroidal rupture, and subretinal fibrosis. Similarly, the initial regular macular hole surgery, in which the ILM was removed, did not result in any success. However, after we performed autologous transplantation of the ILM at the second surgery, the macular hole was closed successfully, resulting in an improvement in visual acuity. The clinical 864
tionally spare the foveal ILM have been reported to be effective in conditions such as large macular holes, myopic macular holes, and myopic foveoschisis.2–5 Although these procedures can be options for the initial vitrectomy, to avoid the failure of macular hole closure and the development of secondary macular holes, they cannot be the solution for eyes with macular holes from which the ILMs already have been removed in previous vitrectomies. To solve this problem, we developed this new surgical procedure, autologous transplantation of the ILM, and assessed its efficacy as a new option for the treatment of refractory macular holes. Large and traumatic macular holes may be conditions in which removing the ILM is sometimes ineffective. After vitrectomy with ILM removal, up to 44% of large macular holes have been reported to remain open.2 Repeated surgeries for failed closures of macular holes also have been reported to have a lower success rate than primary surgery.8 Furthermore, the visual outcomes for large macular holes usually are limited even after hole closure because, although large macular holes frequently close with flat borders with the retina, the retinal pigment epithelium may be bare (flat-open macular holes).2,9 To improve the closure rate, Alpatov and associates presented a method for bringing the borders of full-thickness macular holes together mechanically.10 Although this method does indeed improve closure rate and can be a solution in eyes in which the ILM already has been removed, the visual outcomes were limited, because the surgical manipulation could damage the retina.2 In this study, we performed autologous transplantation of the ILM on 4 eyes with large macular holes and obtained successful hole closures, without bare retinal pigment epithelium and with improved visual outcomes, in 3 eyes (75%; Figures 3 and 4). These results indicate that autologous transplantation of the ILM may be a solution for large macular holes when the ILM already has been removed. For traumatic macular holes, 10% to 67% of cases have been reported to close spontaneously.11–14 However, these cases sometimes are associated with choroidal rupture and subsequent subretinal hemorrhage and fibrosis.15,16 In such cases, traumatic macular holes do not close spontaneously and furthermore are difficult to close, even if the vitreous and ILM are removed, because the retina adheres to the choroid and sclera and lacks extensibility and flexibility. This study included 1 such
AMERICAN JOURNAL OF OPHTHALMOLOGY
APRIL 2014
FIGURE 3. Results of autologous transplantation of the internal limiting membrane (ILM) in Patient 5, a 65-year-old woman with a large macular hole. (Top left) Fundus photograph obtained before the initial vitrectomy showing a macular hole. (Top right) Spectraldomain optical coherence tomography (SD OCT) images obtained before the initial vitrectomy (upper panel) and after the initial vitrectomy (lower panel) showing an open macular hole. (Bottom left) Fundus photograph obtained 3 months after autologous transplantation of the ILM showing the closure of the macular hole. (Bottom right) SD OCT images obtained 5 days after autologous transplantation of the ILM (upper panel) and 3 months after autologous transplantation of the ILM (lower panel). The transplanted ILM flap (arrow) is visible inside of the macular hole at 5 days and there is a defect in the line between the inner segment and outer segment (IS/OS) junction of the photoreceptor. After 3 months, the macular hole closed and the IS/OS line was restored. Best-corrected visual acuity (logarithm of the minimal angle of resolution) improved from 1.0 before surgery to 0.15 at the final visit.
FIGURE 4. Results of autologous transplantation of the internal limiting membrane in Patient 7, a 72-year-old man with a large macular hole. (Top left) Spectral-domain optical coherence tomography (SD OCT) image obtained before initial vitrectomy showing a macular hole. (Top right) SD OCT image obtained after initial vitrectomy showing a residual macular hole. (Bottom left) SD OCT image obtained 7 days after autologous transplantation of the ILM showing the closure of the macular hole. The transplanted ILM flap is visible as a highly reflective area (arrow), and there is a defect in the inner segment/outer segment (IS/OS) junction of the photoreceptor line. (Bottom right) SD OCT image obtained 14 days after autologous transplantation of the ILM showing the closure of the macular hole. The IS/OS line is restored. Best-corrected visual acuity (logarithm of the minimal angle of resolution) improved from 0.70 before surgery to 0.22 at the final visit.
VOL. 157, NO. 4
AUTOLOGOUS TRANSPLANTATION FOR MACULAR HOLE CLOSURE
865
FIGURE 5. Results of autologous transplantation of the internal limiting membrane (ILM) in Patient 9, a 17-year-old boy with a traumatic macular hole. (Top left) Fundus photograph obtained on the day of injury. (Top right) Spectral-domain optical coherence tomography (SD OCT) image obtained on the day of injury showing dense subfoveal hemorrhage. (Second row left) Fundus photograph obtained 4 months after injury when the patient was referred to our hospital by an ophthalmologist in general practice. Arrow indicates a choroidal rupture. (Second row right) SD OCT image obtained 4 months after the injury showing the spontaneous absorption of subfoveal hemorrhage and a full-thickness macular hole. Best-corrected visual acuity (BCVA; logarithm of the minimal angle of resolution) was 1.52 on the day of injury and 0.70 after 4 months. (Third row left) Fundus photograph and (Third row right) SD OCT image obtained after the initial vitrectomy with ILM peeling showing an unclosed macular hole and a choroidal rupture. The macular hole showed no improvement compared with the images before surgery. (Bottom left) Fundus photograph and (Bottom right) SD OCT image obtained 14 days after autologous transplantation of the ILM showing closure of the macular hole. The white arrow indicates the transplanted ILM flap. BCVA improved from 0.82 before the second surgery to 0.40 at the final visit.
866
AMERICAN JOURNAL OF OPHTHALMOLOGY
APRIL 2014
FIGURE 6. Results of autologous transplantation of the internal limiting membrane (ILM) in Patient 3, a 78-year-old woman with foveoschisis resulting from pit-macular syndrome. (Top left) Spectral-domain optical coherence tomography (SD OCT) image obtained before surgery for foveoschisis showing foveoschisis and macular detachment. Best-corrected visual acuity (BCVA; logarithm of the minimal angle of resolution) was 1.0. (Top right) SD OCT image obtained after the initial vitrectomy with ILM peeling for foveoschisis showing the macular hole that developed after surgery, macular detachment, and foveoschisis. (Middle row left) SD OCT image obtained after the second vitrectomy that enlarged the area of ILM peeled and used 10% sulfur hexafluoride gas tamponade; the macular hole had not closed and was still large and retinoschisis was present. (Middle row right) SD OCT image of the gasfilled eye obtained 1 day after the third surgery using autologous transplantation of the ILM showing the closure of the macular hole. The highly reflective area represents the transplanted ILM flap (arrow). (Bottom left) SD OCT image obtained 5 days after autologous transplantation of the ILM showing the closure of the macular hole. The arrow indicates the transplanted ILM flap. BCVA improved from 1.30 before the third surgery to 1.05 at the final visit.
eye, accompanied by choroidal rupture and subretinal fibrosis, in which we had tried to close the traumatic macular hole using ILM removal and 10% sulfur hexafluoride gas tamponade. However, as shown in Figure 5, the macular hole failed to close after this initial surgery. We performed autologous transplantation of the ILM at the second surgery and the macular hole then closed successfully, resulting in an improvement in visual acuity. Although this is a single case, we consider that traumatic macular holes accompanied by retinal fibrosis, in which the retina lacks extensibility, are good candidates for autologous transplantation of the ILM. In foveoschisis, which often is associated with high myopia or pit-macular syndrome, vitrectomy with ILM removal has been reported to lead to significantly better visual outcomes and to prevent recurrent tractional macular detachments compared with vitrectomy without ILM removal.17 However, there is a dilemma for surgeons when the ILM is removed for foveoschisis, because its removal also has been reported sometimes to worsen the situation by causing the development of macular holes after surgery. For example, in myopic foveoschisis, the prevaVOL. 157, NO. 4
lence of secondary macular holes after ILM removal was found to be 19% to 27%, which is much higher than that reported for rhegmatogenous retinal detachment repair after vitrectomy.4,6,18–20 The secondary macular holes usually are refractory, because the ILM already has been removed at vitrectomy. In this study, we performed autologous transplantation of the ILM for 4 eyes with secondary macular holes that had developed after the initial vitrectomy with ILM removal for foveoschisis. In all 4 cases, we finally achieved successful hole closures after autologous transplantation of the ILM (Table), demonstrating that autologous transplantation of the ILM may resolve our dilemma during initial surgery and enable surgeons to remove ILMs without hesitation. With one exception (Patient 4), transplanted ILM flaps were visible in the eyes on SD OCT images for some time after autologous transplantation of the ILM. This suggests that our surgical technique was able to transplant ILM flaps stably inside macular holes with a high success rate. In Patient 4, the transplanted ILM flap probably moved away from the inside of the macular hole. In this case, with long-established pathologic characteristics, the retinal
AUTOLOGOUS TRANSPLANTATION FOR MACULAR HOLE CLOSURE
867
pigment epithelium inside the macular hole was atrophic, as was the retinal fluid cuff surrounding it, so the glial proliferation, which is integral to hole closure, may have been insufficient. The results of this study imply that the flap of ILM placed inside a macular hole has the ability to repair the foveal contour. Recent in vivo studies using OCT to detect glial tissue reflectivity suggested that Mu¨ller cell gliosis is essential for macular hole healing.21–27 Mu¨ller cell proliferation is thought to play an important role in filling macular holes and in producing an environment conducive to the repositioning of photoreceptors by moving photoreceptors to new locations.2 Furthermore, in animal models, Mu¨ller cells have been reported to have the potential to proliferate, dedifferentiate, and produce photoreceptors under cytotoxic conditions.28,29 Based on the results of inverted ILM surgery for large macular holes, Michalewska and associates hypothesized that the ILM flap functions as both a source of Mu¨ller cells, which locate to the surface
of the ILM flap, and as a scaffold for Mu¨ller cell proliferation.2 Although the exact mechanism by which the ILM flap restores the fovea remains unknown, our OCT results after autologous transplantation of the ILM, which indicate that filling macular holes with new tissue occurs around the ILM flap (Figures 3–6), support their hypothesis. To confirm this, further studies, including experiments with animal models, are needed. The study described here was limited by a small sample size and a relatively short follow-up period. Our results show that this new surgical technique has the potential to improve visual function in patients with refractory macular holes in the short term. However in the longer term, this technique has the potential to induce adverse events after ILM transplantation, such as retinal fibrosis, that require further monitoring. Further randomized controlled clinical studies involving a larger number of patients are needed to determine the impact that this technique could have in the management of refractory macular holes.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and none were reported. Involved in Design and conduct of study (Y.M., F.S., S.K.); Data collection (S.K., M.H., Y.Shiode., T.K., M.H., Y.Shirakata., T.O.); Management, analysis, and interpretation of data (Y.M., F.S.); Writing article (Y.M.); and Critical revision and final approval of article (Y.M., F.S., S.K., M.H., Y.Shiode., T.K., M.H., Y.Shirakata., T.O.).
REFERENCES 1. Almony A, Nudleman E, Shah GK, et al. Techniques, rationale, and outcomes of internal limiting membrane peeling. Retina 2012;32(5):877–891. 2. Michalewska Z, Michalewski J, Adelman RA, Nawrocki J. Inverted internal limiting membrane flap technique for large macular holes. Ophthalmology 2010;117(10):2018–2025. 3. Kuriyama S, Hayashi H, Jingami Y, Kuramoto N, Akita J, Matsumoto M. Efficacy of inverted internal limiting membrane flap technique for the treatment of macular hole in high myopia. Am J Ophthalmol 2013;156(1):125–131. 4. Shimada N, Sugamoto Y, Ogawa M, Takase H, OhnoMatsui K. Fovea-sparing internal limiting membrane peeling for myopic traction maculopathy. Am J Ophthalmol 2012; 154(4):1–9. 5. Ho T-C, Chen M-S, Huang J-S, Shih Y-F, Ho H, Huang Y-H. Foveola nonpeeling technique in internal limiting membrane peeling of myopic foveoschisis surgery. Retina 2012;32(3): 631–634. 6. Kobayashi H, Kishi S. Vitreous surgery for highly myopic eyes with foveal detachment and retinoschisis. Ophthalmology 2003;110(9):1702–1707. 7. Kang SW, Ahn K, Ham D-I. Types of macular hole closure and their clinical implications. Br J Ophthalmol 2003;87(8): 1015–1019. 8. Hillenkamp J, Kraus J, Framme C, et al. Retreatment of full-thickness macular hole: predictive value of optical coherence tomography. Br J Ophthalmol 2007;91(11):1445–1449. 9. Cho HY, Kim YT, Kang SW. Laser photocoagulation as adjuvant therapy to surgery for large macular holes. Korean J Ophthalmol 2006;20(2):93–98.
868
10. Alpatov S, Shchuko A, Malyshev V. A new method of treating macular holes. Eur J Ophthalmol 2007;17(2): 246–252. 11. Hernandez-Da Mota SE. Posttraumatic giant macular hole. Case Rep Ophthalmol 2011;2(2):283–286. 12. Huang J, Liu X, Wu Z, Sadda S. Comparison of full-thickness traumatic macular holes and idiopathic macular holes by optical coherence tomography. Graefes Arch Clin Exp Ophthalmol 2010;248(8):1071–1075. 13. Arevalo JF, Sanchez JG, Costa RA, et al. Optical coherence tomography characteristics of full-thickness traumatic macular holes. Eye (Lond) 2008;22(11):1436–1441. 14. Yamashita T, Uemara A, Uchino E, Doi N, Ohba N. Spontaneous closure of traumatic macular hole. Am J Ophthalmol 2002;133(2):230–235. 15. Yeung L, Chen T-L, Kuo Y-H, et al. Severe vitreous hemorrhage associated with closed-globe injury. Graefes Arch Clin Exp Ophthalmol 2006;244(1):52–57. 16. Yanagiya N, Akiba J, Takahashi M, et al. Clinical characteristics of traumatic macular holes. Jpn J Ophthalmol 1996; 40(4):544–547. 17. Taniuchi S, Hirakata A, Itoh Y, Hirota K, Inoue M. Vitrectomy with or without internal limiting membrane peeling for each stage of myopic traction maculopathy. Retina 2013; 33(10):2018–2025. 18. Gao X, Ikuno Y, Fujimoto S, Nishida K. Risk factors for development of full-thickness macular holes after pars plana vitrectomy for myopic foveoschisis. Am J Ophthalmol 2013;155(6): 1021–1027. 19. Hwang JU, Joe SG, Lee J-Y, Kim J-G, Yoon YH. Microincision vitrectomy surgery for myopic foveoschisis. Br J Ophthalmol 2013;97(7):879–884.
AMERICAN JOURNAL OF OPHTHALMOLOGY
APRIL 2014
20. Gaucher D, Haouchine B, Tadayoni R, et al. Long-term follow-up of high myopic foveoschisis: natural course and surgical outcome. Am J Ophthalmol 2007;143(3):455–462. 21. Michalewska Z, Michalewski J, Cisiecki S, Adelman R, Nawrocki J. Correlation between foveal structure and visual outcome following macular hole surgery: a spectral optical coherence tomography study. Graefes Arch Clin Exp Ophthalmol 2008;246(6):823–830. 22. Ko TH, Witkin AJ, Fujimoto JG, et al. Ultrahigh-resolution optical coherence tomography of surgically closed macular holes. Arch Ophthalmol 2006;124(6):827–836. 23. Kang SW, Lim JW, Chung SE, Yi C-H. Outer foveolar defect after surgery for idiopathic macular hole. Am J Ophthalmol 2010;150(4):551–557. 24. Michalewska Z, Michalewski J, Nawrocki J. Continuous changes in macular morphology after macular hole closure visualized with spectral optical coherence tomography. Graefes Arch Clin Exp Ophthalmol 2010;248(9):1249–1255.
VOL. 157, NO. 4
25. Funata M, Wendel RT, la Cruz de Z, Green WR. Clinicopathologic study of bilateral macular holes treated with pars plana vitrectomy and gas tamponade. Retina 1992;12(4): 289–298. 26. Madreperla SA, Geiger GL, Funata M, la Cruz de Z, Green WR. Clinicopathologic correlation of a macular hole treated by cortical vitreous peeling and gas tamponade. Ophthalmology 1994;101(4):682–686. 27. Oh J, Yang SM, Choi YM, Kim S-W, Huh K. Glial proliferation after vitrectomy for a macular hole: a spectral domain optical coherence tomography study. Graefes Arch Clin Exp Ophthalmol 2013;251(2):477–484. 28. Ooto S, Akagi T, Kageyama R, et al. Potential for neural regeneration after neurotoxic injury in the adult mammalian retina. Proc Natl Acad Sci U S A 2004;101(37):13654–13659. 29. Osakada F, Ooto S, Akagi T, Mandai M, Akaike A, Takahashi M. Wnt signaling promotes regeneration in the retina of adult mammals. J Neurosci 2007;27(15):4210–4219.
AUTOLOGOUS TRANSPLANTATION FOR MACULAR HOLE CLOSURE
869
Biosketch Yuki Morizane, MD, PhD, is an Assistant Professor (Lecturer), Department of Ophthalmology, Okayama University, Okayama, Japan. After finishing his residency in ophthalmology and retina fellowship at Okayama University Hospital, he completed a retinal research fellowship at Harvard Medical School, Massachusetts Eye and Ear Infirmary from 2008 to 2011. His research interests are metabolic mechanisms of ocular diseases, ocular neovascularization, and vitrectomy.
869.e1
AMERICAN JOURNAL OF OPHTHALMOLOGY
APRIL 2014
