- Email: [email protected]
Prospective Comparison of Two Suturing Techniques of Amniotic Membrane Transplantation for Symptomatic Bullous Keratopathy
Prospective Comparison of Two Suturing Techniques of Amniotic Membrane Transplantation for Symptomatic Bullous Keratopathy UGUR E. ALTIPARMAK, YUSUF OFLU, ELVIN H. YILDIZ, KORAY BUDAK, BEKIR SITKI ASLAN, AYSE NUROZLER, MUSTAFA ONAT, REMZI KASIM, AND SUNAY DUMAN ● PURPOSE:
To determine the outcomes of a modified amniotic membrane transplantation (AMT) suturing technique for pain and discomfort relief in patients with symptomatic bullous keratopathy (BK). ● DESIGN: Randomized, double-blind controlled clinical trial. ● METHODS: SETTING: Ankara Research and Training Hospital 1st and 2nd Eye Clinics, Ankara, Turkey. STUDY POPULATION: This prospective study included 39 eyes (39 patients) with BK presenting with intractable pain or discomfort and poor visual potential. INTERVENTION: Patients were randomly assigned into two groups: in group 1 (21 patients), patients underwent a modified AMT suturing technique; a groove was prepared by vacuum trephine on the recipient cornea and the edges of the punch-shaped amniotic membrane (AM) were sutured to this groove with the basement membrane side up. In group 2 (18 patients), patients underwent the standard AMT suturing to the cornea. MAIN OUTCOME MEASURE: During a mean follow-up of 27.3 ⴞ 8.5 months (standard deviation) (range, 12 to 36 months), epithelial healing, persistence of AM, pain relief, and visual changes were analyzed and were compared between groups. ● RESULTS: The mean age (P ⴝ .15), the mean follow-up (P ⴝ .73), and the mean preoperative visual acuity (P ⴝ .53) were similar in both groups. With the modified suturing technique, the postoperative visual acuity was better (P ⴝ .03), epithelialization time was shorter (P < .001), and the AM remained longer (P < .001). Successful epithelialization was achieved in 20 eyes (95.3%) in group 1, and in 16 eyes (88.9%) in group 2 (P ⴝ .586). The pain scores of patients in group 1 remained stable (P ⴝ .223) over time, however increased from the first week to the third month postoperatively in group 2 (P ⴝ .046). ● CONCLUSIONS: The modified AMT suturing technique has a similar epithelialization rate to standard AMT suturing to cornea. Though technically more Supplemental Video available at AJO.com. Accepted for publication Aug 28, 2008. From the Department of Ophthalmology Ankara Research and Training Hospital, Ankara, Turkey. Inquiries to Ugur E. Altiparmak, Naci Cakir Mah., 13. sok. 3/21, Dikmen, Ankara, Turkey; e-mail: [email protected]
442
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2009 BY
demanding, shorter epithelialization time, longer persistence of AM, and stable pain scores in the postoperative period makes this a promising method for the treatment of symptomatic BK. (Am J Ophthalmol 2009;147: 442– 446. © 2009 by Elsevier Inc. All rights reserved.)
T
REATMENT OF BULLOUS KERATOPATHY (BK) DE-
pends on the severity of symptoms, underlying etiology, and potential visual acuity (VA) in the affected eyes. Though penetrating keratoplasty (PK) is the mainstay treatment for eyes with potential VA, lack of donor corneas necessitated the development of alternative treatments. Ocular pain, prolonged corneal edema, and secondary ulcerative keratitis, deep and superficial epithelial vascular ingrowth that may complicate future surgical treatments also stimulated the development of alternative treatments until PK is performed.1 Some of the alternative treatment options are bandage contact lenses,2 stromal micropuncture,3,4 conjunctival flaps,5 and phototerapeutic keratotomy.6,7 Yet, there is a subpopulation of patients who can not tolerate these treatments nor can achieve them attributable to financial reasons. Amniotic membrane (AM) was first used by Pires and associates for the treatment of symptomatic BK.8 The advantages of AM in BK are its low cost and easy availability, its intraoperative ease of manipulation, and postoperative success in rapid decline in pain and discomfort.8 –14 Most studies regarding amniotic membrane transplantation (AMT) described direct suturing of the AM onto the corneal surface 8 –11,13,14 and rare studies described suturing of the AM underneath the conjunctiva.12 In an attempt to achieve better surgical and clinical outcomes with longer resolution of symptoms, a modified AMT suturing technique was used. In this technique, we modified the intrastromal suturing technique described by Espana and associates10 by creating more regular contours of the stromal pockets, using a corneal trephine and cutting the AM with a punch trephine to fit into this pocket. To our knowledge, there is no report in the literature comparing this modified AMT suturing technique with the standard AMT suturing technique. Therefore, the current study was conducted to compare the
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0002-9394/09/$36.00 doi:10.1016/j.ajo.2008.08.036
results of AMT using the modified AMT suturing technique and the standard AMT suturing technique.
METHODS
TABLE 1. Characteristics of Patients Treated With the Modified Amniotic Membrane Suturing Technique (Group 1) and the Standard Amniotic Membrane Suturing to Cornea (Group 2) at the Beginning and During the Follow-up Period of the Study
FIFTY EYES OF 50 PATIENTS WITH A CLINICAL DIAGNOSIS OF
symptomatic BK with intractable pain, photophobia, tearing, and foreign-body sensation were enrolled from our outpatient clinic from May 1, 2004 to July 31, 2006. Inclusion criteria were failure of conservative methods such as hyperosmolar agents, artificial tears, lubricants, bandage contact lens, and anterior stromal puncture to control the symptoms. The inclusion criteria also included a minimum follow-up of 12 months. Clinical data on age, gender, VA changes, etiology, pain relief, epithelialization, time to disappearance of AMT, and complications were recorded. Time to disappearance of AMT and epithelial defects were taken as primary outcome measures and change in VA and ocular pain were taken as secondary outcome measures. The AM was harvested and preserved using the method described by Kim and Tseng.15 After signed consent was obtained from all patients, they were randomly assigned into two groups, using stratified randomization method (UEA). This method was preferred for equal distribution of patients with poor visual potential. For patients in group 1, a modified AMT suturing technique was applied, described by (Gomes JAP, Dua HS, personal communication) (see Supplemental Video available at AJO.com): After retrobulbar block administration, an 8.5 mm trephine was used to mark the area to be de-epithelized. Loose corneal epithelium was scraped using microsurgical sponge, fine forceps, and crescent blade. Using the blade, a 360 C subepithelial/ superficial stromal pocket was made within the 8.5 mm mark. A 9 mm trephine was used to punch a disc of AM and the AM disc was placed on the bed of the deepithelized corneal area, and its edges were placed within the stromal pockets. The edges of the disc and the cornea were tied together using a 10/0 nylon running suture. Each suture bite was advanced by putting the edge of the AM into the lamellar pockets so that the AM was flattened and sandwiched within the lamellar pocket with the running suture. In group 2, the preferred technique was standard AMT suturing technique with the epithelial side up, as described by Letko and associates.16 At the end of surgery, a bandage contact lens was used, until epithelialization was complete. After AMT, topical antibiotics (Ciloxan; Alcon Laboratories, Fort Worth, Texas, USA; four times a day), topical steroids (Predforte; Allergan, Irvine, California, USA; four times a day), and intensive lubrication with artificial tear drops (Tears Naturale Free; Alcon; hourly) were administered to all patients. Topical antibiotic was used for one week, steroid VOL. 147, NO. 3
Patient Characteristics
Age Follow-up (mos) Preoperative VA (logMAR) Postoperative VA (logMAR) Epithelialization time postoperatively (wks) Disappearance of AM (mos)
Group 1a (mean ⫾ SD)
Group 2b (mean ⫾ SD)
P value
74.3 ⫾ 7.3 26.9 ⫾ 7.9 1.4 ⫾ 0.1 1.4 ⫾ 0.1
70.6 ⫾ 8.7 27.8 ⫾ 9.6 1.4 ⫾ 0.1 1.3 ⫾ 0.1
.15 .73 .53 .03
2.4 ⫾ 0.9 3.2 ⫾ 1.1
3.8 ⫾ 1.1 1.9 ⫾ 0.7
⬍.001 ⬍.001
AM ⫽ amniotic membrane; logMAR ⫽ logarithm of the minimum angle of resolution; mos ⫽ months; SD ⫽ standard deviation; VA ⫽ visual acuity; wks ⫽ weeks. a Patients who underwent modified inlay AM technique. b Patients who underwent overlay AM technique.
was used for two weeks, and artifical tear drops were continued for four to six weeks with a slow taper. Patients were followed up daily after the AMT procedure (Y.O.) for the first week, weekly for the first three months, and monthly thereafter. Surgical success was defined as complete re-epithelialization of the cornea. At each follow-up visit, VA, epithelialization, and persistence of pain were checked carefully. Corneal epithelialization was monitored using fluorescein dye staining. Pain relief was graded subjectively by the patients as ‘total’ or ‘none.’ For analysis of data, Statistical Package for Social Sciences, version 13.0 (SPSS Inc, Chicago, Illinois, USA) software program was used. Continuous variables were expressed as mean ⫾ standard deviation and categorical variables were expressed as percentages. Independent samples t test was used for comparison of age, follow-up, preoperative and postoperative vision, and time to complete epithelialization. The change in pain score over time was evaluated using the Friedman test; for significant results, the Wilcoxon signed-rank test was performed to determine which results were significantly different. P values less than .05 were considered significant.
RESULTS TWO PATIENTS IN GROUP 1 AND FOUR PATIENTS IN GROUP
2 were lost to follow-up during the course of the study. Two patients in group 1 and three patients from group 3 were excluded from the analysis attributable to insufficient follow-up period. Finally, 39 eyes of 39 patients were included for analysis. Sixteen patients were male and 23 were female with a mean age of 72.6 ⫾ 8.1 years (range, 50 to 84 years). The mean age of patients in group 1 was 74.3 ⫾
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TABLE 2. Comparison of Various Studies With Amniotic Membrane Transplantation for Bullous Keratopathy is Demonstrated
Author (yr)
Pires and associates (1999)8 Mejia and associates (2002)9 Espana and associates (2003)10 Georgiadis and associates (2008)12 Saw and associates (2007)13 Sonmez and associatesa (2007)11 Srinivas and associates (2007)14 Current study Current study
No. of Eyes
50 9 18 81 18 5 7 21 18
Follow-up (mean)
Complete Epithelization (%)
Pain Relief (%)
Mean Time to Epithelization
Overlay
33.8 wks
90
90
—
Nonpreserved AM
40 wks
88
88
11.2 days
Cryopreserved AM sutured into lamellar pockets Cryopreserved AM sutured underneath conjunctival peritomy Cryopreserved AM used with various techniques Cryopreserved AM sutured to peripheral cornea Preserved (frozen) AM sutured to peripheral cornea Modified Suturing into corneal pockets Overlay technique with epithelial side up
25.1 mos
94.4
88
2.2 wks
21 mos
87.6
87.6
15.3 days
3 mos
55.5
22.2
—
Technique
21 mos
100
—
—
26.6 wks
100
100
—
26.9 mos 27.8 mos
95.3 88.9
100 61.1
2.4 wks 3.8 wks
AM ⫽ amniotic membrane; mos ⫽ months; wks ⫽ weeks; yrs ⫽ years. a In this article, AM transplantation is combined with anterior stromal micropuncture for treatment of bullous keratopathy.
7.3 years, and the mean age of patients in group 2 was 70.6 ⫾ 8.7 years (P ⫽ .15). The patients were followed for 27.3 ⫾ 8.6 months (range, 12 to 49 months). The mean follow-up period was 26.9 ⫾ 7.9 months in group 1 and was 27.8 ⫾ 9.6 months in group 2 (P ⫽ .73). Twenty-one patients in group 1 underwent the modified AMT suturing technique and 18 patients in group 2 underwent the standard AMT suturing technique. One patient in group 1 (4.8%) and three patients in group 2 (18%) were aphakic and the rest of the patients were pseudophakic. Among the pseudophakic eyes, nine had anterior chamber intraocular lenses (AC IOLs) and 11 had posterior chamber (PC) IOLs in group 1. Similarly, seven patients had AC IOLs and 10 had PC IOLs in group 2. The mean age and mean follow-up periods were similar in both groups (P ⫽ .15 and P ⫽ .73, respectively) (Table 1). The mean preoperative VA was 1.4 7 ⫾ 0.1 on logarithm of the minimum angle of resolution scales. Though the preoperative VAs were similar in the two groups (P ⫽ .53), patients in group 1 had better VA than group 2 at the end of the follow-up period (P ⫽ .03) (Table 1). One patient in group 1 had age-related macular degeneration. Two patients in group 1 and one patient in group 2 had glaucomatous optic atrophy. The VA did not change in these patients throughout the follow-up period. The mean epithelialization time was 3.0 ⫾ 1.2 weeks. Patients in group 1 had a shorter epithelialization time than patients in group 2, with a high significance (P ⬍ .001) (Table 1). One patient in group 1 (4.7%) and two patients in group two (11.1%) had incomplete epithelialization (P ⫽ .586). These patients underwent a second AMT procedure. The patient in group 1 with incomplete 444
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epithelialization developed desmetocele formation and corneal perforation, and PK was performed. The patients in group 2 developed complete epithelialization after the second AMT procedure and remained asymptomatic until the end of the follow-up period. The pain scores of patients in group 1 did not change significantly over time; the number of pain-free patients were 19 (90.5%) after one week, 20 (95.2%) after one month, and 21 (100%) after three months (P ⫽ .223). In group 2, the number of pain-free patients were 15 (83.3%) after one week, 14 (77.7%) after one month, and 11 (61.1%) after three months. Since the pain scores of patients in group 2 increased over time, the Wilcoxon signed-rank test was performed. The pain scores were similar between one week-one month (P ⫽ .317) and one month-three month (P ⫽ .083) but increased between one week-three months (P ⫽ .046). During the follow-up period, the AM thinned progressively from a thick, whitish membrane to a very thin almost transparent membrane. The AM dissolved completely after a mean period of 2.6 ⫾ 1.1 months (range, one to six months). The membrane remained significantly longer in patients from group 1 (P ⬍ .001; Table 1). The suture was removed in all patients after four to six weeks of follow-up period.
DISCUSSION BULLOUS KERATOPATHY IN APHAKIC OR PSEUDOPHAKIC
eyes is characterized by decompensation of corneal endothelium with resultant stromal edema and epithelial/ OF
OPHTHALMOLOGY
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subepithelial bullae formation.17–20 Despite modern surgical techniques like the use of viscoelastic substances and PC IOLs, this complication is still inevitable, especially attributable to the presence of preoperative endothelial dysfunction.21 Though PK is the most effective treatment for reducing symptoms and restoring vision, lack of donor corneas is a common problem and alternative interventions are applied in cases with BK.22 Amniotic membrane transplantation to the corneal surface has been reported as effective in reducing the formation of epithelial bullae and associated ocular discomfort in patients with painful aphakic bullous keratopathy (ABK) and pseudophakic bullous keratopathy (PBK). However, regression of epithelial bullae and recurrence of pain and discomfort have been reported after treatment with each procedure.8 –10 One reason might be the use of different modifications of the AMT technique (inlay or overlay) or different side of AMT coming above. Another reason is the recurrence of symptoms after dissolution of the AMT.23 The AMT is performed as inlay (or graft) or overlay (or patch) technique in most cases with BK. When the AMT is tailored to the size of the bullous defect and is meant to act as a scaffold for the epithelial cells, which then merges with the host tissue, it is referred to as a graft.24 Inlay technique allows the migrating epithelial cells to grow over the membrane, hence the membrane acts as a basement membrane for the newly growing cells. When the AM is used akin to biological contact lens in order to protect the healing surface defect beneath, it is referred to as a patch. A patch also bears the advantages of a barrier, by avoiding the chemical mediators in the tear film and reducing inflammation.16,25 The AMT suturing technique as modified or standard suturing to cornea for the treatment of BK is debatable. The modified technique may be more advantageous by providing a new basal membrane more resistant to bullae formation but it is recommended to leave the limbus out, so that re-epithelialization must be over and not under the AMT.9 Yet, there is a wide variation in the results that may originate from the surgical technique used (modified or standard AMT suturing technique) or the side of AM coming above. The reports where AMT was used for the treatment of BK are summarized in Table 2.8 –14 We studied a modified AMT suturing technique and compared its effectiveness with the standard AM suturing to the cornea. The modified AMT suturing technique was first described by (Gomes JAP, Dua HS, personal communication). This method bears the theoretical advantage of epithelialization on top of the AMT. Though a similar technique has been used by Espana and associates,10 the modified technique can create stromal pockets with predictable depths and more regular contours. AM inserted into a lamellar pocket, tailored to its size, is theoretically more advantageous by ensuring epithelialization will take VOL. 147, NO. 3
place on the top of AM. This is in contrast to direct suturing of AM on the cornea, which may allow some epithelialization to take place under AM if the suturing method does not ensure tight approximation. With the use of modified AM suturing technique, we determined similar epithelialization rates (95.3% vs 94.4%), pain relief (100% vs 88%), and mean time to epithelization (2.4 weeks vs 2.2 weeks) with Espana and associates.8 (Table 2). Other studies in literature with the use of different AMT techniques determined epithelialization rates between 55.5% and 100% and pain relief between 22.2% and 90% (Table 2).8 –14 The modified AMT suturing technique is relatively new and clinical data on its use is rare. This method seems advantageous over the standard AMT suturing over the cornea, by shortening the epithelialization time and extending the survival of the AM. Shortening of epithelialization time may reside in the ability of this technique to avoid limbal stem cells. Though, a healthy corneal epithelium can be created with AMT for BK, even in longstanding BK with limbal stem cell deficiency,10,12,26 preserving the remaining functional limbal stem cells may further help epithelialization compared with other AMT techniques, as seen in our results. This technique may also provide a better scaffold for the growth of new epithelial cells over the AMT. This approach benefits both from the contact lens and scaffold effect of AMT for epithelialization. Mejia and associates9 determined lack of symptoms with the bullae that grew under the AMT, both during its presence as when they ruptured, possibly because of a contact lens effect. We observed the same findings in our patients. However, nonpreserved AM was used by Mejia and associates,9 in contrast to preserved AM used in our study. Furthermore, our results revealed that the percentage of pain-free patients treated with the modified AM suturing technique was higher than patients that underwent standard suturing of AM to the cornea. Additionally, in group 1, the number of pain-free patients increased with time (19 [90.5%] of the patients at first week, 21 [100%] of the patients at third month), whereas it gradually decreased in group 2 (15 [83.3%] of the patients at first week, 11 [61.1%] of the patients at third month). We believe the results of the pain scores should be approached with caution and be further validated with future studies, especially with more detailed pain scoring systems. As a summary, the modified AMT suturing technique seems a safe and effective method for the treatment of symptomatic BK and may shorten epithelialization time and prolong time to disappearance of AM compared with the standard AMT suturing to cornea. Though this technique is more involved than simple suturing, our results on this pilot study warrant use of this technique in future studies with larger series and the possibility of adding it to the armamentarium of ophthalmologists for the treatment of painful BK.
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THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FINANCIAL CONFLICT OF INTEREST. INVOLVED IN DESIGN OF STUDY (U.E.A., Y.O., E.H.Y., K.B., B.S.A., A.N., M.O., R.K., S.D.); conduct of study (U.E.A.,Y.O., E.H.Y.); collection of data (U.E.A., E.H.Y., Y.O., K.B., B.S.A., A.N., M.O.); management (U.E.A., Y.O., E.H.Y.); analysis and interpretation of data (U.E.A., E.H.Y.); preparation of the manuscript (U.E.A., Y.O., E.H.Y.); review of the manuscript (U.E.A., E.H.Y., K.B.); and approval of the manuscript (U.E.A., Y.O., E.H.Y., K.B., B.S.A., A.N., M.O., R.K., S.D.). This prospective study was approved by the Institutional Review Board (IRB) of Ankara Research and Training Hospital (on March 1, 2004, by the decision number of 1054) and patient recruitment began. With informed consent and approval by the IRB, human placenta was obtained shortly after cesarean delivery. The authors adhered to the Declaration of Helsinki and all federal or state laws in our country. The authors were in compliance with the IRB decision in all stages of the study. Patients were asked to give consent form before being enrolled in the study. The authors thank Dr Yilmaz Aslan, Numune Research and Training Hospital, Ankara, Turkey for his valuable assistance during the statistical analysis of the data of this study.
REFERENCES 1. Luchs JI, Cohen EJ, Rapuano CJ, Laibson PR. Ulcerative keratitis in bullous keratopathy. Ophthalmology 1997;104: 816 – 822. 2. Gasset AR, Kaufman HE. Bandage lenses in the treatment of bullous keratopathy. Am J Ophthalmol 1971;72:376 –380. 3. Cormier G, Brunette I, Boisjoly HM, LeFrançois M, Shi ZH, Guertin MC. Anterior stromal punctures for bullous keratopathy. Arch Ophthalmol 1996;114:654 – 658. 4. Sridhar MS, Vemuganti GK, Bansal AK, Rao GN. Anterior stromal puncture in bullous keratopathy: a clinicopathologic study. Cornea 2001;20:573–579. 5. Alino AM, Perry HD, Kanellopoulos AJ, Donnenfeld ED, Rahn EK. Conjunctival flaps. Ophthalmology 1998;105: 1120 –1123. 6. Maini R, Sullivan L, Snibson GR, Taylor HR, Loughnan MS. A comparison of different depth ablations in the treatment of painful bullous keratopathy with phototherapeutic keratectomy. Br J Ophthalmol 2001;85:912–915. 7. Lin PY, Wu CC, Lee SM. Combined phototherapeutic keratectomy and therapeutic contact lens for recurrent erosions in bullous keratopathy. Br J Ophthalmol 2001;85:908 – 911. 8. Pires RT, Tseng SC, Prabhasawat P, et al. Amniotic membrane transplantation for symptomatic bullous keratopathy. Arch Ophthalmol 1999;117:1291–1297. 9. Mejia LF, Santamaría JP, Acosta C. Symptomatic management of postoperative bullous keratopathy with nonpreserved human amniotic membrane. Cornea 2002;21:342– 345. 10. Espana EM, Grueterich M, Sandoval H, et al. Amniotic membrane transplantation for bullous keratopathy in eyes with poor visual potential. J Cataract Refract Surg 2003;29: 279 –284. 11. Sonmez B, Kim BT, Aldave AJ. Amniotic membrane transplantation with anterior stromal micropuncture for treatment of painful bullous keratopathy in eyes with poor visual potential. Cornea 2007;26:227–229. 12. Georgiadis NS, Ziakas NG, Boboridis KG, Terzidou C, Mikropoulos DG. Cryopreserved amniotic membrane transplantation for the management of symptomatic bullous keratopathy. Clin Experiment Ophthalmol 2008;36:130 – 135. 13. Saw VP, Minassian D, Dart JK, et al. Amniotic Membrane Tissue User Group (AMTUG). Amniotic membrane trans-
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14.
15.
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18.
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21.
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24. 25.
26.
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plantation for ocular disease: a review of the first 233 cases from the UK user group. Br J Ophthalmol 2007;91: 1042–1047. Srinivas S, Mavrikakis E, Jenkins C. Amniotic membrane transplantation for painful bullous keratopathy. Eur J Ophthalmol 2007;17:7–10. Kim JC, Tseng SC. The effects of inhibition of corneal neovascularization after human amniotic membrane transplantation in severely damaged rabbit corneas. Korean J Ophthalmol 1995;9:32– 46. Letko E, Stechschulte SU, Kenyon KR, et al. Amniotic membrane inlay and overlay grafting for corneal epithelial defects and stromal ulcers. Arch Ophthalmol 2001;119:659 – 663. Liu GJ, Okisaka S, Mizukawa A, Momose A. Histopathological study of pseudophakic bullous keratopathy devoloping after anterior chamber of iris-supported intraocular lens implantation. Jpn J Ophthalmol 1993;37:414 – 425. Kenyon KR. The synthesis of basement membrane by the corneal epithelium in bullous keratopathy. Invest Ophthalmol 1969;8:156 –168. Kenney MC, Chwa M. Abnormal extracellular matrix in corneas with pseudophakic bullous keratopathy. Cornea 1990;9:115–121. Ljubimov AV, Burgeson RE, Butkowski RJ, et al. Extracellular matrix alterations in human corneas with bullous keratopathy. Invest Ophthalmol Vis Sci 1996;37:997–1007. Koenig SB, Schultz RO. Penetrating keratoplasty for pseudophakic bullous keratopathy after extracapsular cataract extraction. Am J Ophthalmol 1988;105:348 –353. Sangwan VS, Burman S, Tejwani S, Mahesh SP, Murthy R. Amniotic membrane transplantation: a review of current indications in the management of ophthalmic disorders. Indian J Ophthalmol 2007;55:251–260. López Ferrando N, Celis Sánchez J, González Del Valle F, López Mondéjar E. Monolayered amniotic membrane transplantation as a palliative treatment for bullous keratopathy. Arch Soc Esp Oftalmol 2004;79:27–31. Sippel KC, Ma JJ, Foster CS. Amniotic membrane surgery. Curr Opin Ophthalmol 2001;12:269 –281. Azuara-Blanco A, Pillai CT, Dua HS. Amniotic membrane transplantation for ocular surface reconstruction. Br J Ophthalmol 1999;83:399 – 402. Uchino Y, Goto E, Takano Y, et al. Long-standing bullous keratopathy is associated with peripheral conjunctivalization and limbal deficiency. Ophthalmology 2006;113:1098 –1101.
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Biosketch Dr Ugur E. Altiparmak graduated from Hacettepe Medical School, Ankara, Turkey in 1997. He completed Ophthalmology residency in Ankara Research and Training Hospital Ankara, Turkey in 2001. Dr Altiparmak trained at Meir Hospital, Tel-Aviv University between October 1999 and January 2001 with focus on anterior segment surgery and corneal diseases, trained at Michigan State University, Departments of Ophthalmology and Neurology between 2002 and 2003, and completed Neuro-ophthalmology fellowship. Dr Altiparmak’s currently works at 1st Department of Ophthalmology, Ankara Research and Training Hospital Ankara, Turkey. His main areas of interest are neuro-ophthalmology, anterior segment surgery, and corneal diseases.
VOL. 147, NO. 3
MODIFIED AMNIOTIC MEMBRANE TECHNIQUE
446.e1
To determine the outcomes of a modified amniotic membrane transplantation (AMT) suturing technique for pain and discomfort relief in patients with symptomatic bullous keratopathy (BK). ● DESIGN: Randomized, double-blind controlled clinical trial. ● METHODS: SETTING: Ankara Research and Training Hospital 1st and 2nd Eye Clinics, Ankara, Turkey. STUDY POPULATION: This prospective study included 39 eyes (39 patients) with BK presenting with intractable pain or discomfort and poor visual potential. INTERVENTION: Patients were randomly assigned into two groups: in group 1 (21 patients), patients underwent a modified AMT suturing technique; a groove was prepared by vacuum trephine on the recipient cornea and the edges of the punch-shaped amniotic membrane (AM) were sutured to this groove with the basement membrane side up. In group 2 (18 patients), patients underwent the standard AMT suturing to the cornea. MAIN OUTCOME MEASURE: During a mean follow-up of 27.3 ⴞ 8.5 months (standard deviation) (range, 12 to 36 months), epithelial healing, persistence of AM, pain relief, and visual changes were analyzed and were compared between groups. ● RESULTS: The mean age (P ⴝ .15), the mean follow-up (P ⴝ .73), and the mean preoperative visual acuity (P ⴝ .53) were similar in both groups. With the modified suturing technique, the postoperative visual acuity was better (P ⴝ .03), epithelialization time was shorter (P < .001), and the AM remained longer (P < .001). Successful epithelialization was achieved in 20 eyes (95.3%) in group 1, and in 16 eyes (88.9%) in group 2 (P ⴝ .586). The pain scores of patients in group 1 remained stable (P ⴝ .223) over time, however increased from the first week to the third month postoperatively in group 2 (P ⴝ .046). ● CONCLUSIONS: The modified AMT suturing technique has a similar epithelialization rate to standard AMT suturing to cornea. Though technically more Supplemental Video available at AJO.com. Accepted for publication Aug 28, 2008. From the Department of Ophthalmology Ankara Research and Training Hospital, Ankara, Turkey. Inquiries to Ugur E. Altiparmak, Naci Cakir Mah., 13. sok. 3/21, Dikmen, Ankara, Turkey; e-mail: [email protected]
442
©
2009 BY
demanding, shorter epithelialization time, longer persistence of AM, and stable pain scores in the postoperative period makes this a promising method for the treatment of symptomatic BK. (Am J Ophthalmol 2009;147: 442– 446. © 2009 by Elsevier Inc. All rights reserved.)
T
REATMENT OF BULLOUS KERATOPATHY (BK) DE-
pends on the severity of symptoms, underlying etiology, and potential visual acuity (VA) in the affected eyes. Though penetrating keratoplasty (PK) is the mainstay treatment for eyes with potential VA, lack of donor corneas necessitated the development of alternative treatments. Ocular pain, prolonged corneal edema, and secondary ulcerative keratitis, deep and superficial epithelial vascular ingrowth that may complicate future surgical treatments also stimulated the development of alternative treatments until PK is performed.1 Some of the alternative treatment options are bandage contact lenses,2 stromal micropuncture,3,4 conjunctival flaps,5 and phototerapeutic keratotomy.6,7 Yet, there is a subpopulation of patients who can not tolerate these treatments nor can achieve them attributable to financial reasons. Amniotic membrane (AM) was first used by Pires and associates for the treatment of symptomatic BK.8 The advantages of AM in BK are its low cost and easy availability, its intraoperative ease of manipulation, and postoperative success in rapid decline in pain and discomfort.8 –14 Most studies regarding amniotic membrane transplantation (AMT) described direct suturing of the AM onto the corneal surface 8 –11,13,14 and rare studies described suturing of the AM underneath the conjunctiva.12 In an attempt to achieve better surgical and clinical outcomes with longer resolution of symptoms, a modified AMT suturing technique was used. In this technique, we modified the intrastromal suturing technique described by Espana and associates10 by creating more regular contours of the stromal pockets, using a corneal trephine and cutting the AM with a punch trephine to fit into this pocket. To our knowledge, there is no report in the literature comparing this modified AMT suturing technique with the standard AMT suturing technique. Therefore, the current study was conducted to compare the
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/09/$36.00 doi:10.1016/j.ajo.2008.08.036
results of AMT using the modified AMT suturing technique and the standard AMT suturing technique.
METHODS
TABLE 1. Characteristics of Patients Treated With the Modified Amniotic Membrane Suturing Technique (Group 1) and the Standard Amniotic Membrane Suturing to Cornea (Group 2) at the Beginning and During the Follow-up Period of the Study
FIFTY EYES OF 50 PATIENTS WITH A CLINICAL DIAGNOSIS OF
symptomatic BK with intractable pain, photophobia, tearing, and foreign-body sensation were enrolled from our outpatient clinic from May 1, 2004 to July 31, 2006. Inclusion criteria were failure of conservative methods such as hyperosmolar agents, artificial tears, lubricants, bandage contact lens, and anterior stromal puncture to control the symptoms. The inclusion criteria also included a minimum follow-up of 12 months. Clinical data on age, gender, VA changes, etiology, pain relief, epithelialization, time to disappearance of AMT, and complications were recorded. Time to disappearance of AMT and epithelial defects were taken as primary outcome measures and change in VA and ocular pain were taken as secondary outcome measures. The AM was harvested and preserved using the method described by Kim and Tseng.15 After signed consent was obtained from all patients, they were randomly assigned into two groups, using stratified randomization method (UEA). This method was preferred for equal distribution of patients with poor visual potential. For patients in group 1, a modified AMT suturing technique was applied, described by (Gomes JAP, Dua HS, personal communication) (see Supplemental Video available at AJO.com): After retrobulbar block administration, an 8.5 mm trephine was used to mark the area to be de-epithelized. Loose corneal epithelium was scraped using microsurgical sponge, fine forceps, and crescent blade. Using the blade, a 360 C subepithelial/ superficial stromal pocket was made within the 8.5 mm mark. A 9 mm trephine was used to punch a disc of AM and the AM disc was placed on the bed of the deepithelized corneal area, and its edges were placed within the stromal pockets. The edges of the disc and the cornea were tied together using a 10/0 nylon running suture. Each suture bite was advanced by putting the edge of the AM into the lamellar pockets so that the AM was flattened and sandwiched within the lamellar pocket with the running suture. In group 2, the preferred technique was standard AMT suturing technique with the epithelial side up, as described by Letko and associates.16 At the end of surgery, a bandage contact lens was used, until epithelialization was complete. After AMT, topical antibiotics (Ciloxan; Alcon Laboratories, Fort Worth, Texas, USA; four times a day), topical steroids (Predforte; Allergan, Irvine, California, USA; four times a day), and intensive lubrication with artificial tear drops (Tears Naturale Free; Alcon; hourly) were administered to all patients. Topical antibiotic was used for one week, steroid VOL. 147, NO. 3
Patient Characteristics
Age Follow-up (mos) Preoperative VA (logMAR) Postoperative VA (logMAR) Epithelialization time postoperatively (wks) Disappearance of AM (mos)
Group 1a (mean ⫾ SD)
Group 2b (mean ⫾ SD)
P value
74.3 ⫾ 7.3 26.9 ⫾ 7.9 1.4 ⫾ 0.1 1.4 ⫾ 0.1
70.6 ⫾ 8.7 27.8 ⫾ 9.6 1.4 ⫾ 0.1 1.3 ⫾ 0.1
.15 .73 .53 .03
2.4 ⫾ 0.9 3.2 ⫾ 1.1
3.8 ⫾ 1.1 1.9 ⫾ 0.7
⬍.001 ⬍.001
AM ⫽ amniotic membrane; logMAR ⫽ logarithm of the minimum angle of resolution; mos ⫽ months; SD ⫽ standard deviation; VA ⫽ visual acuity; wks ⫽ weeks. a Patients who underwent modified inlay AM technique. b Patients who underwent overlay AM technique.
was used for two weeks, and artifical tear drops were continued for four to six weeks with a slow taper. Patients were followed up daily after the AMT procedure (Y.O.) for the first week, weekly for the first three months, and monthly thereafter. Surgical success was defined as complete re-epithelialization of the cornea. At each follow-up visit, VA, epithelialization, and persistence of pain were checked carefully. Corneal epithelialization was monitored using fluorescein dye staining. Pain relief was graded subjectively by the patients as ‘total’ or ‘none.’ For analysis of data, Statistical Package for Social Sciences, version 13.0 (SPSS Inc, Chicago, Illinois, USA) software program was used. Continuous variables were expressed as mean ⫾ standard deviation and categorical variables were expressed as percentages. Independent samples t test was used for comparison of age, follow-up, preoperative and postoperative vision, and time to complete epithelialization. The change in pain score over time was evaluated using the Friedman test; for significant results, the Wilcoxon signed-rank test was performed to determine which results were significantly different. P values less than .05 were considered significant.
RESULTS TWO PATIENTS IN GROUP 1 AND FOUR PATIENTS IN GROUP
2 were lost to follow-up during the course of the study. Two patients in group 1 and three patients from group 3 were excluded from the analysis attributable to insufficient follow-up period. Finally, 39 eyes of 39 patients were included for analysis. Sixteen patients were male and 23 were female with a mean age of 72.6 ⫾ 8.1 years (range, 50 to 84 years). The mean age of patients in group 1 was 74.3 ⫾
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TABLE 2. Comparison of Various Studies With Amniotic Membrane Transplantation for Bullous Keratopathy is Demonstrated
Author (yr)
Pires and associates (1999)8 Mejia and associates (2002)9 Espana and associates (2003)10 Georgiadis and associates (2008)12 Saw and associates (2007)13 Sonmez and associatesa (2007)11 Srinivas and associates (2007)14 Current study Current study
No. of Eyes
50 9 18 81 18 5 7 21 18
Follow-up (mean)
Complete Epithelization (%)
Pain Relief (%)
Mean Time to Epithelization
Overlay
33.8 wks
90
90
—
Nonpreserved AM
40 wks
88
88
11.2 days
Cryopreserved AM sutured into lamellar pockets Cryopreserved AM sutured underneath conjunctival peritomy Cryopreserved AM used with various techniques Cryopreserved AM sutured to peripheral cornea Preserved (frozen) AM sutured to peripheral cornea Modified Suturing into corneal pockets Overlay technique with epithelial side up
25.1 mos
94.4
88
2.2 wks
21 mos
87.6
87.6
15.3 days
3 mos
55.5
22.2
—
Technique
21 mos
100
—
—
26.6 wks
100
100
—
26.9 mos 27.8 mos
95.3 88.9
100 61.1
2.4 wks 3.8 wks
AM ⫽ amniotic membrane; mos ⫽ months; wks ⫽ weeks; yrs ⫽ years. a In this article, AM transplantation is combined with anterior stromal micropuncture for treatment of bullous keratopathy.
7.3 years, and the mean age of patients in group 2 was 70.6 ⫾ 8.7 years (P ⫽ .15). The patients were followed for 27.3 ⫾ 8.6 months (range, 12 to 49 months). The mean follow-up period was 26.9 ⫾ 7.9 months in group 1 and was 27.8 ⫾ 9.6 months in group 2 (P ⫽ .73). Twenty-one patients in group 1 underwent the modified AMT suturing technique and 18 patients in group 2 underwent the standard AMT suturing technique. One patient in group 1 (4.8%) and three patients in group 2 (18%) were aphakic and the rest of the patients were pseudophakic. Among the pseudophakic eyes, nine had anterior chamber intraocular lenses (AC IOLs) and 11 had posterior chamber (PC) IOLs in group 1. Similarly, seven patients had AC IOLs and 10 had PC IOLs in group 2. The mean age and mean follow-up periods were similar in both groups (P ⫽ .15 and P ⫽ .73, respectively) (Table 1). The mean preoperative VA was 1.4 7 ⫾ 0.1 on logarithm of the minimum angle of resolution scales. Though the preoperative VAs were similar in the two groups (P ⫽ .53), patients in group 1 had better VA than group 2 at the end of the follow-up period (P ⫽ .03) (Table 1). One patient in group 1 had age-related macular degeneration. Two patients in group 1 and one patient in group 2 had glaucomatous optic atrophy. The VA did not change in these patients throughout the follow-up period. The mean epithelialization time was 3.0 ⫾ 1.2 weeks. Patients in group 1 had a shorter epithelialization time than patients in group 2, with a high significance (P ⬍ .001) (Table 1). One patient in group 1 (4.7%) and two patients in group two (11.1%) had incomplete epithelialization (P ⫽ .586). These patients underwent a second AMT procedure. The patient in group 1 with incomplete 444
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epithelialization developed desmetocele formation and corneal perforation, and PK was performed. The patients in group 2 developed complete epithelialization after the second AMT procedure and remained asymptomatic until the end of the follow-up period. The pain scores of patients in group 1 did not change significantly over time; the number of pain-free patients were 19 (90.5%) after one week, 20 (95.2%) after one month, and 21 (100%) after three months (P ⫽ .223). In group 2, the number of pain-free patients were 15 (83.3%) after one week, 14 (77.7%) after one month, and 11 (61.1%) after three months. Since the pain scores of patients in group 2 increased over time, the Wilcoxon signed-rank test was performed. The pain scores were similar between one week-one month (P ⫽ .317) and one month-three month (P ⫽ .083) but increased between one week-three months (P ⫽ .046). During the follow-up period, the AM thinned progressively from a thick, whitish membrane to a very thin almost transparent membrane. The AM dissolved completely after a mean period of 2.6 ⫾ 1.1 months (range, one to six months). The membrane remained significantly longer in patients from group 1 (P ⬍ .001; Table 1). The suture was removed in all patients after four to six weeks of follow-up period.
DISCUSSION BULLOUS KERATOPATHY IN APHAKIC OR PSEUDOPHAKIC
eyes is characterized by decompensation of corneal endothelium with resultant stromal edema and epithelial/ OF
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subepithelial bullae formation.17–20 Despite modern surgical techniques like the use of viscoelastic substances and PC IOLs, this complication is still inevitable, especially attributable to the presence of preoperative endothelial dysfunction.21 Though PK is the most effective treatment for reducing symptoms and restoring vision, lack of donor corneas is a common problem and alternative interventions are applied in cases with BK.22 Amniotic membrane transplantation to the corneal surface has been reported as effective in reducing the formation of epithelial bullae and associated ocular discomfort in patients with painful aphakic bullous keratopathy (ABK) and pseudophakic bullous keratopathy (PBK). However, regression of epithelial bullae and recurrence of pain and discomfort have been reported after treatment with each procedure.8 –10 One reason might be the use of different modifications of the AMT technique (inlay or overlay) or different side of AMT coming above. Another reason is the recurrence of symptoms after dissolution of the AMT.23 The AMT is performed as inlay (or graft) or overlay (or patch) technique in most cases with BK. When the AMT is tailored to the size of the bullous defect and is meant to act as a scaffold for the epithelial cells, which then merges with the host tissue, it is referred to as a graft.24 Inlay technique allows the migrating epithelial cells to grow over the membrane, hence the membrane acts as a basement membrane for the newly growing cells. When the AM is used akin to biological contact lens in order to protect the healing surface defect beneath, it is referred to as a patch. A patch also bears the advantages of a barrier, by avoiding the chemical mediators in the tear film and reducing inflammation.16,25 The AMT suturing technique as modified or standard suturing to cornea for the treatment of BK is debatable. The modified technique may be more advantageous by providing a new basal membrane more resistant to bullae formation but it is recommended to leave the limbus out, so that re-epithelialization must be over and not under the AMT.9 Yet, there is a wide variation in the results that may originate from the surgical technique used (modified or standard AMT suturing technique) or the side of AM coming above. The reports where AMT was used for the treatment of BK are summarized in Table 2.8 –14 We studied a modified AMT suturing technique and compared its effectiveness with the standard AM suturing to the cornea. The modified AMT suturing technique was first described by (Gomes JAP, Dua HS, personal communication). This method bears the theoretical advantage of epithelialization on top of the AMT. Though a similar technique has been used by Espana and associates,10 the modified technique can create stromal pockets with predictable depths and more regular contours. AM inserted into a lamellar pocket, tailored to its size, is theoretically more advantageous by ensuring epithelialization will take VOL. 147, NO. 3
place on the top of AM. This is in contrast to direct suturing of AM on the cornea, which may allow some epithelialization to take place under AM if the suturing method does not ensure tight approximation. With the use of modified AM suturing technique, we determined similar epithelialization rates (95.3% vs 94.4%), pain relief (100% vs 88%), and mean time to epithelization (2.4 weeks vs 2.2 weeks) with Espana and associates.8 (Table 2). Other studies in literature with the use of different AMT techniques determined epithelialization rates between 55.5% and 100% and pain relief between 22.2% and 90% (Table 2).8 –14 The modified AMT suturing technique is relatively new and clinical data on its use is rare. This method seems advantageous over the standard AMT suturing over the cornea, by shortening the epithelialization time and extending the survival of the AM. Shortening of epithelialization time may reside in the ability of this technique to avoid limbal stem cells. Though, a healthy corneal epithelium can be created with AMT for BK, even in longstanding BK with limbal stem cell deficiency,10,12,26 preserving the remaining functional limbal stem cells may further help epithelialization compared with other AMT techniques, as seen in our results. This technique may also provide a better scaffold for the growth of new epithelial cells over the AMT. This approach benefits both from the contact lens and scaffold effect of AMT for epithelialization. Mejia and associates9 determined lack of symptoms with the bullae that grew under the AMT, both during its presence as when they ruptured, possibly because of a contact lens effect. We observed the same findings in our patients. However, nonpreserved AM was used by Mejia and associates,9 in contrast to preserved AM used in our study. Furthermore, our results revealed that the percentage of pain-free patients treated with the modified AM suturing technique was higher than patients that underwent standard suturing of AM to the cornea. Additionally, in group 1, the number of pain-free patients increased with time (19 [90.5%] of the patients at first week, 21 [100%] of the patients at third month), whereas it gradually decreased in group 2 (15 [83.3%] of the patients at first week, 11 [61.1%] of the patients at third month). We believe the results of the pain scores should be approached with caution and be further validated with future studies, especially with more detailed pain scoring systems. As a summary, the modified AMT suturing technique seems a safe and effective method for the treatment of symptomatic BK and may shorten epithelialization time and prolong time to disappearance of AM compared with the standard AMT suturing to cornea. Though this technique is more involved than simple suturing, our results on this pilot study warrant use of this technique in future studies with larger series and the possibility of adding it to the armamentarium of ophthalmologists for the treatment of painful BK.
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THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FINANCIAL CONFLICT OF INTEREST. INVOLVED IN DESIGN OF STUDY (U.E.A., Y.O., E.H.Y., K.B., B.S.A., A.N., M.O., R.K., S.D.); conduct of study (U.E.A.,Y.O., E.H.Y.); collection of data (U.E.A., E.H.Y., Y.O., K.B., B.S.A., A.N., M.O.); management (U.E.A., Y.O., E.H.Y.); analysis and interpretation of data (U.E.A., E.H.Y.); preparation of the manuscript (U.E.A., Y.O., E.H.Y.); review of the manuscript (U.E.A., E.H.Y., K.B.); and approval of the manuscript (U.E.A., Y.O., E.H.Y., K.B., B.S.A., A.N., M.O., R.K., S.D.). This prospective study was approved by the Institutional Review Board (IRB) of Ankara Research and Training Hospital (on March 1, 2004, by the decision number of 1054) and patient recruitment began. With informed consent and approval by the IRB, human placenta was obtained shortly after cesarean delivery. The authors adhered to the Declaration of Helsinki and all federal or state laws in our country. The authors were in compliance with the IRB decision in all stages of the study. Patients were asked to give consent form before being enrolled in the study. The authors thank Dr Yilmaz Aslan, Numune Research and Training Hospital, Ankara, Turkey for his valuable assistance during the statistical analysis of the data of this study.
REFERENCES 1. Luchs JI, Cohen EJ, Rapuano CJ, Laibson PR. Ulcerative keratitis in bullous keratopathy. Ophthalmology 1997;104: 816 – 822. 2. Gasset AR, Kaufman HE. Bandage lenses in the treatment of bullous keratopathy. Am J Ophthalmol 1971;72:376 –380. 3. Cormier G, Brunette I, Boisjoly HM, LeFrançois M, Shi ZH, Guertin MC. Anterior stromal punctures for bullous keratopathy. Arch Ophthalmol 1996;114:654 – 658. 4. Sridhar MS, Vemuganti GK, Bansal AK, Rao GN. Anterior stromal puncture in bullous keratopathy: a clinicopathologic study. Cornea 2001;20:573–579. 5. Alino AM, Perry HD, Kanellopoulos AJ, Donnenfeld ED, Rahn EK. Conjunctival flaps. Ophthalmology 1998;105: 1120 –1123. 6. Maini R, Sullivan L, Snibson GR, Taylor HR, Loughnan MS. A comparison of different depth ablations in the treatment of painful bullous keratopathy with phototherapeutic keratectomy. Br J Ophthalmol 2001;85:912–915. 7. Lin PY, Wu CC, Lee SM. Combined phototherapeutic keratectomy and therapeutic contact lens for recurrent erosions in bullous keratopathy. Br J Ophthalmol 2001;85:908 – 911. 8. Pires RT, Tseng SC, Prabhasawat P, et al. Amniotic membrane transplantation for symptomatic bullous keratopathy. Arch Ophthalmol 1999;117:1291–1297. 9. Mejia LF, Santamaría JP, Acosta C. Symptomatic management of postoperative bullous keratopathy with nonpreserved human amniotic membrane. Cornea 2002;21:342– 345. 10. Espana EM, Grueterich M, Sandoval H, et al. Amniotic membrane transplantation for bullous keratopathy in eyes with poor visual potential. J Cataract Refract Surg 2003;29: 279 –284. 11. Sonmez B, Kim BT, Aldave AJ. Amniotic membrane transplantation with anterior stromal micropuncture for treatment of painful bullous keratopathy in eyes with poor visual potential. Cornea 2007;26:227–229. 12. Georgiadis NS, Ziakas NG, Boboridis KG, Terzidou C, Mikropoulos DG. Cryopreserved amniotic membrane transplantation for the management of symptomatic bullous keratopathy. Clin Experiment Ophthalmol 2008;36:130 – 135. 13. Saw VP, Minassian D, Dart JK, et al. Amniotic Membrane Tissue User Group (AMTUG). Amniotic membrane trans-
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Biosketch Dr Ugur E. Altiparmak graduated from Hacettepe Medical School, Ankara, Turkey in 1997. He completed Ophthalmology residency in Ankara Research and Training Hospital Ankara, Turkey in 2001. Dr Altiparmak trained at Meir Hospital, Tel-Aviv University between October 1999 and January 2001 with focus on anterior segment surgery and corneal diseases, trained at Michigan State University, Departments of Ophthalmology and Neurology between 2002 and 2003, and completed Neuro-ophthalmology fellowship. Dr Altiparmak’s currently works at 1st Department of Ophthalmology, Ankara Research and Training Hospital Ankara, Turkey. His main areas of interest are neuro-ophthalmology, anterior segment surgery, and corneal diseases.
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