Seminars in Ophthalmology, Early Online, 1–7, 2014 ! Informa Healthcare USA, Inc. ISSN: 0882-0538 print / 1744-5205 online DOI: 10.3109/08820538.2013.874468
ORIGINAL ARTICLE
Comparison of Two Techniques for the Treatment of Recurrent Pterygium: Amniotic Membrane vs Conjunctival Autograft Combined with Mitomycin C
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Yasemin Arslan Katircioglu, Ugur Altiparmak, Seniz Engur Goktas, Burcin Cakir, Evin Singar, and Firdevs Ornek Ministry of Health, Ankara Training and Research Hospital, Ankara, Turkey
ABSTRACT Purpose: To compare the results of amniotic membrane transplantation (AMT) combined with mitomycin C (MMC) to the results of free conjunctival autograft (CA) combined with MMC for the treatment of patients with recurrent pterygium. Methods: In this prospective study, 60 eyes of 55 patients with recurrent pterygium were included and randomly assigned into group I (n = 30) who underwent AMT combined with MMC (AMT-MMC) and group II (n = 30) who underwent CA combined with MMC (CA-MMC). During a mean follow-up of 27.2 ± 20.8 months, recurrence of pterygium, change in uncorrected visual acuity and complications (including pain, corneal, conjunctival or scleral changes) were analyzed and were compared between groups. Results: Five eyes of 5 patients were lost to follow-up and were removed from analysis. The mean age (p = 0.274), the mean follow-up (p = 0.063), the number of prior pterygium excision surgeries (p = 0.641) and the mean preoperative visual acuity (p = 0.959) were similar in both groups. Recurrence was seen in 2 eyes (8%) in AMT-MMC group and 4 patients (13.3%) in CA-MMC group (p = 0.531). Postoperative visual acuity (p = 0.237), change in visual acuity (p = 0.525), severe pain (p = 0.531) and epithelial defect lasting more than 5 days (p = 0.510) were similar in both groups. Conclusions: Amniotic membrane combined with MMC has similar recurrence rate to CA combined with MMC, in patients with recurrent pterygium. Similar outcomes and complication rates make AMT-MMC a promising method for the treatment of recurrent pterygium cases. Keywords: Amniotic membrance, conjunctival autograft, mitomycin C, pterygium, recurrent pterygium
INTRODUCTION
transplantation (AMT), penetrating keratoplasty, or sclerokeratoplasty), or those dealing with adjunctive therapy (including beta irradiation, thiotepa, or mitomycin C (MMC).1 Many studies have reported increased recurrence rates for the removal of already recurrent pterygia.2 Occasionally, recurrences are far more aggressive and are larger than the original pterygium, and can be considered a serious complication of the surgery. Removal of recurrent pterygium tissue is more difficult due to the abundant subconjunctival fibrous tissue and its tight attachment to underlying sclera.3
Pterygium is the excessive fibrovascular proliferation of the degenerated bulbar conjunctival tissue on the exposed ocular surface. Surgery is the mainstay treatment for pterygium; however, the recurrence rate is high, unless accompanied by an adjacent procedure dealing with closure of the defect (including primary closure, pedicle flap, transposition of the pterygium head, conjunctival autograft (CA) with or without limbus, buccal mucous membrane grafts, lamellar keratoplasty, amniotic membrane
Received 15 May 2013; revised 17 June 2013; accepted 8 December 2013; published online 31 January 2014 Correspondence: Seniz Engur Goktas, Ministry of Health Ankara Training and Research Hospital, Ankara, TR06340 Turkey. E-mail: [email protected]
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Conjunctival autograft surgery is generally regarded as the procedure of choice for the treatment of primary and recurrent pterygium because of its efficacy and long-term safety.4–10 On the other hand, a combination of CA with low-dose (0.2 mg/ml) MMC was shown to have a significantly lower recurrence rate compared with conjunctival graft alone.11 It has been documented that use of AMT alone has a higher recurrence rate than use of CA alone, both for primary and recurrent pterygium.12 Nevertheless, AMT bears the advantage of removing the need for harvesting large autografts, thereby minimizing iatrogenic injury to the rest of the conjunctival surface. Therefore, an adjacent procedure that may increase the success rate of AMT may be a useful surgical alternative for the treatment of recurrent pterygia. In an attempt to increase surgical success, AMT was combined with intraoperative MMC and its surgical and clinical outcomes were compared with CA with intraoperative MMC for the treatment of recurrent pterygium.
MATERIALS AND METHODS Patients This study was conducted in accordance with the Declaration of Helsinki. The operative procedure and the use of human amniotic membrane for this surgery were approved by the Ethics Committee of Ankara Research and Training Hospital. Patients with recurrent pterygium were included in this study. Exclusion criteria were the presence of major eye diseases such as dry eye, cicatricial pemphigoid, glaucoma, and vitreoretinal disease and intercurrent severe systemic disease, or any condition affecting follow-up or documentation. The inclusion criteria also included a minimum follow-up of 12 months. From May 2004 to July 2006, 60 eyes of 55 patients with the clinical diagnosis of recurrent pterygium were recruited from our outpatient clinic. Complete ophthalmic examinations, including best spectaclecorrected visual acuity (BSCVA), intraocular pressure (IOP), slit-lamp biomicroscopy, and funduscopy, were performed on all patients. After all the patients provided signed consent, they were randomly assigned (by UEA) using an adaptive randomization procedure to receive CA combined with intraoperative MMC or AMT combined with intraoperative MMC treatment. For ethical reasons, a control group that did not receive any adjunctive treatment was not created because of the unacceptably high recurrence rates, as previously demonstrated.1,13 Amniotic membrane was harvested and preserved using the method described by Kim and Tseng.14 All operations were performed by one surgeon, experienced in pterygium excision, including CA and AMT surgery (by YAK).
Surgical Technique Pterygium was excised using the same technique in all patients. In brief, after topical and subconjunctival anesthesia (Benoxinate, 2% lidocaine containing 1:10,000 epinephrine), the apex of the pterygium was dissected from the cornea and limbus with a No. 15 Beard-Parker blade; then, the body of pterygium was excised with spring scissors. Episcleral and tenon tissues were removed as much as possible with consideration given to potential damage to the underlying muscle sheath. Cautery was avoided to preserve vascularity in the recipient bed, unless there was extensive hemorrhage that could cause clot formation under the graft. The bare scleral bed was created and measured in the position in which the eye deviated away from the side of the lesion in which a maximum area of defect could be obtained. After pterygium excision, a microsponge was soaked in a 0.2 mg/ml (0.02%) solution of MMC (KyowaÕ Onko) for one minute and placed over the exposed sclera. After three minutes, the sponge was removed and the ocular tissues were irrigated with 100 cc balanced salt solution (Isolyte SÕ Eczacibasi Baxter, Turkey). For patients in group 1, the preserved amniotic membrane was cut to a slightly larger size than the conjunctival defect. The bare sclera area was then covered with amniotic membrane graft with the basement-membrane-side up. The membrane was sutured continuously to the episcleral bed at the limbus and conjunctival edge with 7-0 polyglactin sutures (VicrylÕ ; Ethicon, Edinburgh, UK). For patients in group 2, a tenon-free conjunctival graft was harvested from the temporal and superior bulbar conjunctiva and was sutured in place over the bare scleral defect. The graft was cut to a size similar to the conjunctival defect and was oriented with the limbal side of the graft to the limbal side of the defect. The graft was secured and approximated with the recipient conjunctival edge by interrupted 7-0 polyglactin sutures. The conjunctiva at the harvest site was approximated using 7-0 polyglactin sutures. At the end of the surgery, Tobramycin 0.3% ointment (TobrexÕ Alcon) was applied and the eye was patched for at least one day. Also, patients were asked to grade the intraoperative pain subjectively as ‘‘mild,’’ ‘‘moderate,’’ or ‘‘severe.’’ Postoperatively, all eyes were treated with Ciprofloxacin 0.3% (CiloxanÕ Alcon) and tear substitute (Tears Naturale IIÕ Alcon) four times a day for one week, and Prednisolon-acetate 1% (PredForteÕ Abdi-Ibrahim, Allergan) for one month. After one month, steroid drops were changed to fluorometholone 0.1% four times to twice daily and then tapered. All sutures were removed (if not naturally resorbed) within two weeks. Patients were examined one day after surgery and followed up after one week; Seminars in Ophthalmology
Treatment of Recurrent Pterygium one, three, and six months; and every 12 months thereafter.
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We certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during this research.
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Outcome Measures Clinical data were recorded for age, gender, visual acuity changes, time and frequency of previous operations, postoperative follow-up duration, recurrence of pterygium, and complications (including corneal, conjunctival, or scleral changes) (by BK). True recurrence was defined as fibrovascular tissue growth onto the cornea, as described by Prabhasawat et al.1 In brief, a grade 1 result denoted the operated eye indistinguishable from normal; grade 2, presence of some fine episcleral vessels in the excised area extending up to the limbus but not beyond, in the absence of any fibrous tissue; grade 3, presence of additional fibrous tissues in the excised area without invasion into the cornea; and grade 4, true recurrence of pterygium with fibrovascular tissue invading a clear cornea.1 Recurrence was the main outcome measure and postoperative BSCVA and change in BSCVA, epithelial defect lasting more than five days, and the presence of intraoperative severe pain were taken as secondary outcome measures.
Statistical Analysis For analysis of data, the Statistical Package for Social Sciences, version 13.0 (SPSS Inc., Chicago, IL) software program was used. Eyes rather than persons were used as the unit for statistical analysis. Continuous variables were expressed as mean ± standard deviation and categorical variables were expressed as percentages. Independent sample t-tests were used for comparison of age. A Mann-Whitney u-test was used for comparison of gender, follow-up, preoperative and postoperative vision, change in BSCVA, and recurrence rate. The same test was also used for the comparison of complications among the two groups. p Values less than 0.05 were considered significant.
RESULTS Most patients in group 2 were followed throughout the follow-up period, but five eyes of five patients in group 1 were lost to follow-up. Finally, 25 eyes of 25 patients in group 1 and 30 eyes of 30 patients in group 2 were included for analysis. The mean age of the patients was 57.1 ± 12.6 (32–81). The mean age of the patients in group 1 was 59.1 ± 12.1, and the mean age of the patients in group 2 was 55.4 ± 12.9 (p = 0.228, confidence interval(CI) = 3.1–+10.6). There were nine female patients in group 1 (56.25%) and 12 female patients in group 2 (66.7%, p = 0.763, CI = 0.23– +0.31). The mean number of prior surgeries was 1.31 ± 0.57. The number of prior surgeries was similar in the two groups (p = 0.641, CI = 0.22–+0.40, Table 1). The patients were followed for 27.2 ± 20.8 (12–94) months. The mean follow-up period was 28.8 ± 15.7 (13–80) in group 1 and was 25.9 ± 24.4 (12–94) in group 2 (p = 0.063, CI = 8.5–+14.3). The mean preoperative BSCVA was 0.2 ± 0.5 on logMAR scales. The preoperative BSCVAs were similar in the two groups (p = 0.959, CI = 0.15–+0.12, Table 1). The mean postoperative BSCVA was 0.1 ± 0.7 on LogMAR scales. The postoperative BSCVA was found to be similar in the two groups (p = 0.237, CI = 0.07–+0.16, Table 1). The mean percentage change in BSCVA was 36.5 ± 0.9 and was also similar in both groups (p = 0.525, CI = 0.35–+1.05, Table 1). Most patients in both groups enjoyed a successful outcome without recurrence (Figures 1–4). On the other hand, true recurrence was seen in two patients (8%) in group 1 and four patients (13.3%) in group 2 (p = 0.531, CI = 0.12–+0.22). Severe intraoperative pain was seen in two patients (8%) in group 1
TABLE 1. Patient characteristics of each group at the beginning and during the follow-up period of the study. Patient Characteristics Age Gender (Female/Male) Number of prior surgeries (range) Follow-up (months) Preoperative visual acuity (log MAR) Postoperative visual acuity (log MAR) Change in visual acuity (%) Recurrence (%) Severe Pain (%) Epithelial Defect (more than 5 days) (%)
Group 1a (mean ± SD)
Group 2b (mean ± SD)
Total (mean ± SD)
Confidence Interval
p Value
59.1 ± 12.1 9/16 1.36 ± 0.12 (1–3) 28.8 ± 15.7 0.2 ± 1.0 0.1 ± 1.2 53.1 ± 1.2 2 (8%) 2 (8%) 5 (20%)
55.4 ± 12.9 12/18 1.26 ± 0.1 (1–3) 25.9 ± 24.4 0.2 ± 1.4 0.1 ± 1.3 21.8 ± 0.4 4 (13.4%) 4 (13.4%) 4 (13.4%)
57.1 ± 12.6 21/34 1.31 ± 0.57 27.2 ± 20.8 0.2 ± 0.5 0.1 ± 0.7 36.5 ± 0.9 6 (10.9%) 6 (10.9%) 9 (16.4%)
3.1–+10.6 0.23–+0.31 0.22–+0.40 8.5–+14.3 0.15–+0.12 0.07–+0.16 0.35–+1.05 0.12–+0.22 0.22–+0.11 0.13–+27
0.274 y 0.763yy 0.641yy 0.063yy 0.959yy 0.237yy 0.525yy 0.531yy 0.531yy 0.510yy
(SD: Standard deviation; aPatients who underwent modified inlay amniotic membrane technique; bpatients who underwent overlay conjunctival autograft technique; y independent samples t-test; yy Mann-Whitney U-test). !
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FIGURE 1. Recurrent pterygium; 90 62 mm (300 300 DPI).
FIGURE 3. Recurrent pterygium 2; 89 62 mm (300 300 DPI).
FIGURE 2. Clear cornea and no residue pteryqium; 89 62 mm (300 300 DPI).
FIGURE 4. Good result with clear cornea and conjunctiva; 90 62 mm (300 300 DPI).
and four patients (%13.4) in group 2 (p = 0.531, CI = 0.22–+0.11). Epithelial defect lasting more than five days was seen in five patients in group 1 (20%) and four patients in group 2 (13.3%) (p = 0.510, CI = 0.13–+27). Among the five patients in group 1, none of them had persistant epithelial defects lasting more than 10 days. In the second group, epithelial defect persisted more than 10 days in one patient, despite intensive lubricant and bandage contact lens application. Amniotic membrane was transplanted to the defective area and was healed after the AMT dissolved after six weeks.
pterygium recurrence.15 Therefore, the commonly used adjunctive therapies have been radiation, chemotherapy, or grafting procedures such as CA to reduce the hyperproliferation of fibrovascular tissue and thereby reduce the recurrence rate. Intraoperative mitomycin is a method of adjunctive therapy that has been commonly reported for the treatment of recurrent pterygium.16–18 It aims at inhibiting proliferating cells, thereby reducing recurrence. Earlier reports were about the use of MMC in bare scleral closure and the reported rate of recurrence was 7% to 38%.16–18 The variable description of complications, which include severe pain, scleral necrosis, and even scleral perforation, created doubt about the use of MMC. Since some of these complications occur later in the follow-up period, long-term evaluation after surgery seems necessary, especially after the the use of bare sclera technique. Some authors recommend the use of MMC for active and aggressive recurrent pterygium2 or in combination with a grafting procedure, as used in this study. This is due to the fact that it is not theoretically possible to remove subconjunctival fibrous tissue completely, especially in recurrent pterygia, because inflamed tissue extends deep into the fornix.
CONCLUSION Although many studies have compared their results for the treatment of primary and recurrent pterygium, the differences between the growth and morphological characteristics of recurrent pterygium versus primary pterygium have been given scant attention. The general consensus is that surgical trauma and subsequent postoperative inflammation activate subconjunctival fibroblasts, inducing the proliferation of fibroblasts and vascular cells; the deposition of extracellular matrix proteins, in turn, contribute to
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Treatment of Recurrent Pterygium The concentration of intraoperative mitomycin C used in most of the studies ranges from 0.01 to 0.04%, with 0.02% applied for 3 min being the most common dosage used.10,19,22 Since increasing the duration and concentration of mitomycin C may potentially lead to a higher risk of complications, it was avoided in our study. The conjunctival autograft gained popularity in the 1980s and is generally regarded as the procedure of choice for the treatment of primary and recurrent pterygium because of its efficacy and long-term safety.4–6,8,9,10,24 A free conjunctival graft is harvested from the superior bulbar conjunctiva and is sutured in place over the bare scleral defect.25 It aims at wound healing and restoration of the limbal barrier.26 Variations in conjunctival autograft surgery include the use of narrow-strip conjunctival autograft, limbalconjunctival autografts, limbal epithelial autografts, conjunctival flaps, or conjunctival rotation autografts.27–33 The use of CA for the treatment of recurrent pterygium resulted in recurrence rates of 9.2% to 14%.5,34,35 This method appears to reconstruct a more normal limbal anatomy with a better cosmetic result with respect to vascularization and bunching of conjunctiva. On the other hand, it requires more disruption of the healthy conjunctiva that may become necessary in a future filtering procedure. To date, there has been no conclusive evidence regarding the superiority of limbal–conjunctival autografts over conventional conjunctival autografts, and the added risk of limbal damage at the donor site. Furthermore, rejection is a major concern of limbal autograft transplantation. Hence, the authors of this study avoided this technique and performed CA rather than limbal-CA in their study.27 For the treatment of primary pterygium, a combination of conjunctival autograft with low-dose (0.2 mg/ ml) MMC was shown, in a prospective randomized comparative study by Frucht-Pery et al.,11 to have a significantly lower recurrence rate compared with conjunctival graft alone. The recurrence rate of combined conjunctival autograft with MMC for the treatment of recurrent pterygium is in the range of 0 to 14.2% in various studies.36–39 The recurrence rate was 13.3% in the CA-MMC group in our study, and the results were comparable to other studies in literature. The first ophthalmic use of AMT was for replacement of lost conjunctival tissue40 and as a biologic bandage in the treatment of caustic burn to the eye.41,42 The presence of anti-angiogenic and antiinflammatory factors in AMT helps decrease inflammation, neovascularization, and pain.43 In this way, it suppresses extracellular matrix protein production and scar formation by pterygial fibroblasts.44,45 Delayed vascularization of the amniotic membrane demonstrated with anterior segment indocyanine green angiography is thought to be responsible for !
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the delayed recurrence after pterygium surgery.46 On the other hand, the promotion of growth and differentiation of conjunctival47 as well as adjacent limbal epithelial cells48 by AMT may, in turn, promote wound healing, reduce inflammation, and eventually help to restore the limbal barrier function. Although CA to cover the bare sclera remains the mainstay of treatment for recurrent pterygium, it is extremely difficult to fashion a large enough CG in some recurrent pterygium eyes, due to the shortage of healthy tissue available. Besides, in eyes that have had multiple failed surgeries, previous conjunctival harvesting often renders the donor site scarred and reduces the availability of healthy conjunctiva. Especially in the presence of symblepharon, amniotic membrane (AM) may serve as an ideal cover, facilitate fornix reconstruction, and thus represent an alternative surgical method. Solomon et al. reported a recurrence rate of 9.5% for the treatment of recurrent pterygium with the use of AMT.49 In order to achieve this result, they used an intraoperative long-acting steroid injection and double layers of AM, in addition to extensive removal of the conjunctiva, which presumably increased the effectiveness.49 Luanratanakorn et al. compared CA with AMT for the treatment of recurrent pterygium and the recurrent rates were 21.4% and 52.6%, respectively.12 They used single-layer preserved AM and concluded that AM alone is associated with an unacceptably high recurrence rate compared with conjunctival autograft. Their findings were supported by Tananuvat et al., who used single-layered AM with the basement-membrane-side up.50 Ma et al. compared the excision of recurrent pterygia followed by amniotic membrane and amniotic membrane graft combined with intraoperative mitomycin C(0.025%), and found no significant difference in the recurrence rates between the two groups (12.5% vs 12.8%).51 They also sutured the AM with the basement-membrane-side up. The technique used in our study was also single-layer AM with the basement-membraneside up and our results (recurrence rate of 8%) were comparable to those of Ma et al.51 The weaknesses of our study are the small number of patients and resultant high range of CI in selected parameters. Also, the scoring system for intraoperative pain was relatively simple and subjective; therefore, its results should be approached more cautiously. To the best of our knowledge, this is the first report on the comparison of these two techniques for the treatment of recurrent pterygium cases. Though AM cannot surpass normal conjunctiva due to the lack of host epithelium and fibroblasts, the results of this pilot study encourage the use of AM in combination with MMC for the treatment of recurrent pterygium with similar success to CA combined with MMC.
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DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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46. Kucukerdonmez C, Akova YA, Altinors DD. Vascularization is more delayed in amniotic membrane graft than conjunctival autograft after pterygium surgery. Am J Ophthalmol Feb 2007;143:245–249. 47. Meller D, Tseng SCG. Conjunctival epithelial cell differentiation on amniotic membrane. Invest Ophthalmol Vis Sci 1999;40:878–886. 48. Koizumi N, Fullwood NJ, Bairaktaris G, et al. Cultivation of corneal epithelial cells on intact and denuded human amniotic membrane. Invest Ophthalmol Vis Sci 2000;41: 2506–2513. 49. Solomon A, Pires RTF, Tseng SCG. Amniotic membrane transplantation after extensive removal of primary and recurrent pterygia. Ophthalmology 2001;108:449–460. 50. Tananuvat N, Martin T. The results of amniotic membrane transplantation for primary pterygium compared with conjunctival autograft. Cornea 2004;23: 458–463. 51. Ma DHK, See LC, Wang SF. Comparison of amniotic membrane graft alone or combined with intraoperative mitomycin c to prevent recurrence after excision of recurrent pterygia. Cornea 2005;24:141–150.
ORIGINAL ARTICLE
Comparison of Two Techniques for the Treatment of Recurrent Pterygium: Amniotic Membrane vs Conjunctival Autograft Combined with Mitomycin C
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Yasemin Arslan Katircioglu, Ugur Altiparmak, Seniz Engur Goktas, Burcin Cakir, Evin Singar, and Firdevs Ornek Ministry of Health, Ankara Training and Research Hospital, Ankara, Turkey
ABSTRACT Purpose: To compare the results of amniotic membrane transplantation (AMT) combined with mitomycin C (MMC) to the results of free conjunctival autograft (CA) combined with MMC for the treatment of patients with recurrent pterygium. Methods: In this prospective study, 60 eyes of 55 patients with recurrent pterygium were included and randomly assigned into group I (n = 30) who underwent AMT combined with MMC (AMT-MMC) and group II (n = 30) who underwent CA combined with MMC (CA-MMC). During a mean follow-up of 27.2 ± 20.8 months, recurrence of pterygium, change in uncorrected visual acuity and complications (including pain, corneal, conjunctival or scleral changes) were analyzed and were compared between groups. Results: Five eyes of 5 patients were lost to follow-up and were removed from analysis. The mean age (p = 0.274), the mean follow-up (p = 0.063), the number of prior pterygium excision surgeries (p = 0.641) and the mean preoperative visual acuity (p = 0.959) were similar in both groups. Recurrence was seen in 2 eyes (8%) in AMT-MMC group and 4 patients (13.3%) in CA-MMC group (p = 0.531). Postoperative visual acuity (p = 0.237), change in visual acuity (p = 0.525), severe pain (p = 0.531) and epithelial defect lasting more than 5 days (p = 0.510) were similar in both groups. Conclusions: Amniotic membrane combined with MMC has similar recurrence rate to CA combined with MMC, in patients with recurrent pterygium. Similar outcomes and complication rates make AMT-MMC a promising method for the treatment of recurrent pterygium cases. Keywords: Amniotic membrance, conjunctival autograft, mitomycin C, pterygium, recurrent pterygium
INTRODUCTION
transplantation (AMT), penetrating keratoplasty, or sclerokeratoplasty), or those dealing with adjunctive therapy (including beta irradiation, thiotepa, or mitomycin C (MMC).1 Many studies have reported increased recurrence rates for the removal of already recurrent pterygia.2 Occasionally, recurrences are far more aggressive and are larger than the original pterygium, and can be considered a serious complication of the surgery. Removal of recurrent pterygium tissue is more difficult due to the abundant subconjunctival fibrous tissue and its tight attachment to underlying sclera.3
Pterygium is the excessive fibrovascular proliferation of the degenerated bulbar conjunctival tissue on the exposed ocular surface. Surgery is the mainstay treatment for pterygium; however, the recurrence rate is high, unless accompanied by an adjacent procedure dealing with closure of the defect (including primary closure, pedicle flap, transposition of the pterygium head, conjunctival autograft (CA) with or without limbus, buccal mucous membrane grafts, lamellar keratoplasty, amniotic membrane
Received 15 May 2013; revised 17 June 2013; accepted 8 December 2013; published online 31 January 2014 Correspondence: Seniz Engur Goktas, Ministry of Health Ankara Training and Research Hospital, Ankara, TR06340 Turkey. E-mail: [email protected]
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Conjunctival autograft surgery is generally regarded as the procedure of choice for the treatment of primary and recurrent pterygium because of its efficacy and long-term safety.4–10 On the other hand, a combination of CA with low-dose (0.2 mg/ml) MMC was shown to have a significantly lower recurrence rate compared with conjunctival graft alone.11 It has been documented that use of AMT alone has a higher recurrence rate than use of CA alone, both for primary and recurrent pterygium.12 Nevertheless, AMT bears the advantage of removing the need for harvesting large autografts, thereby minimizing iatrogenic injury to the rest of the conjunctival surface. Therefore, an adjacent procedure that may increase the success rate of AMT may be a useful surgical alternative for the treatment of recurrent pterygia. In an attempt to increase surgical success, AMT was combined with intraoperative MMC and its surgical and clinical outcomes were compared with CA with intraoperative MMC for the treatment of recurrent pterygium.
MATERIALS AND METHODS Patients This study was conducted in accordance with the Declaration of Helsinki. The operative procedure and the use of human amniotic membrane for this surgery were approved by the Ethics Committee of Ankara Research and Training Hospital. Patients with recurrent pterygium were included in this study. Exclusion criteria were the presence of major eye diseases such as dry eye, cicatricial pemphigoid, glaucoma, and vitreoretinal disease and intercurrent severe systemic disease, or any condition affecting follow-up or documentation. The inclusion criteria also included a minimum follow-up of 12 months. From May 2004 to July 2006, 60 eyes of 55 patients with the clinical diagnosis of recurrent pterygium were recruited from our outpatient clinic. Complete ophthalmic examinations, including best spectaclecorrected visual acuity (BSCVA), intraocular pressure (IOP), slit-lamp biomicroscopy, and funduscopy, were performed on all patients. After all the patients provided signed consent, they were randomly assigned (by UEA) using an adaptive randomization procedure to receive CA combined with intraoperative MMC or AMT combined with intraoperative MMC treatment. For ethical reasons, a control group that did not receive any adjunctive treatment was not created because of the unacceptably high recurrence rates, as previously demonstrated.1,13 Amniotic membrane was harvested and preserved using the method described by Kim and Tseng.14 All operations were performed by one surgeon, experienced in pterygium excision, including CA and AMT surgery (by YAK).
Surgical Technique Pterygium was excised using the same technique in all patients. In brief, after topical and subconjunctival anesthesia (Benoxinate, 2% lidocaine containing 1:10,000 epinephrine), the apex of the pterygium was dissected from the cornea and limbus with a No. 15 Beard-Parker blade; then, the body of pterygium was excised with spring scissors. Episcleral and tenon tissues were removed as much as possible with consideration given to potential damage to the underlying muscle sheath. Cautery was avoided to preserve vascularity in the recipient bed, unless there was extensive hemorrhage that could cause clot formation under the graft. The bare scleral bed was created and measured in the position in which the eye deviated away from the side of the lesion in which a maximum area of defect could be obtained. After pterygium excision, a microsponge was soaked in a 0.2 mg/ml (0.02%) solution of MMC (KyowaÕ Onko) for one minute and placed over the exposed sclera. After three minutes, the sponge was removed and the ocular tissues were irrigated with 100 cc balanced salt solution (Isolyte SÕ Eczacibasi Baxter, Turkey). For patients in group 1, the preserved amniotic membrane was cut to a slightly larger size than the conjunctival defect. The bare sclera area was then covered with amniotic membrane graft with the basement-membrane-side up. The membrane was sutured continuously to the episcleral bed at the limbus and conjunctival edge with 7-0 polyglactin sutures (VicrylÕ ; Ethicon, Edinburgh, UK). For patients in group 2, a tenon-free conjunctival graft was harvested from the temporal and superior bulbar conjunctiva and was sutured in place over the bare scleral defect. The graft was cut to a size similar to the conjunctival defect and was oriented with the limbal side of the graft to the limbal side of the defect. The graft was secured and approximated with the recipient conjunctival edge by interrupted 7-0 polyglactin sutures. The conjunctiva at the harvest site was approximated using 7-0 polyglactin sutures. At the end of the surgery, Tobramycin 0.3% ointment (TobrexÕ Alcon) was applied and the eye was patched for at least one day. Also, patients were asked to grade the intraoperative pain subjectively as ‘‘mild,’’ ‘‘moderate,’’ or ‘‘severe.’’ Postoperatively, all eyes were treated with Ciprofloxacin 0.3% (CiloxanÕ Alcon) and tear substitute (Tears Naturale IIÕ Alcon) four times a day for one week, and Prednisolon-acetate 1% (PredForteÕ Abdi-Ibrahim, Allergan) for one month. After one month, steroid drops were changed to fluorometholone 0.1% four times to twice daily and then tapered. All sutures were removed (if not naturally resorbed) within two weeks. Patients were examined one day after surgery and followed up after one week; Seminars in Ophthalmology
Treatment of Recurrent Pterygium one, three, and six months; and every 12 months thereafter.
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We certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during this research.
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Outcome Measures Clinical data were recorded for age, gender, visual acuity changes, time and frequency of previous operations, postoperative follow-up duration, recurrence of pterygium, and complications (including corneal, conjunctival, or scleral changes) (by BK). True recurrence was defined as fibrovascular tissue growth onto the cornea, as described by Prabhasawat et al.1 In brief, a grade 1 result denoted the operated eye indistinguishable from normal; grade 2, presence of some fine episcleral vessels in the excised area extending up to the limbus but not beyond, in the absence of any fibrous tissue; grade 3, presence of additional fibrous tissues in the excised area without invasion into the cornea; and grade 4, true recurrence of pterygium with fibrovascular tissue invading a clear cornea.1 Recurrence was the main outcome measure and postoperative BSCVA and change in BSCVA, epithelial defect lasting more than five days, and the presence of intraoperative severe pain were taken as secondary outcome measures.
Statistical Analysis For analysis of data, the Statistical Package for Social Sciences, version 13.0 (SPSS Inc., Chicago, IL) software program was used. Eyes rather than persons were used as the unit for statistical analysis. Continuous variables were expressed as mean ± standard deviation and categorical variables were expressed as percentages. Independent sample t-tests were used for comparison of age. A Mann-Whitney u-test was used for comparison of gender, follow-up, preoperative and postoperative vision, change in BSCVA, and recurrence rate. The same test was also used for the comparison of complications among the two groups. p Values less than 0.05 were considered significant.
RESULTS Most patients in group 2 were followed throughout the follow-up period, but five eyes of five patients in group 1 were lost to follow-up. Finally, 25 eyes of 25 patients in group 1 and 30 eyes of 30 patients in group 2 were included for analysis. The mean age of the patients was 57.1 ± 12.6 (32–81). The mean age of the patients in group 1 was 59.1 ± 12.1, and the mean age of the patients in group 2 was 55.4 ± 12.9 (p = 0.228, confidence interval(CI) = 3.1–+10.6). There were nine female patients in group 1 (56.25%) and 12 female patients in group 2 (66.7%, p = 0.763, CI = 0.23– +0.31). The mean number of prior surgeries was 1.31 ± 0.57. The number of prior surgeries was similar in the two groups (p = 0.641, CI = 0.22–+0.40, Table 1). The patients were followed for 27.2 ± 20.8 (12–94) months. The mean follow-up period was 28.8 ± 15.7 (13–80) in group 1 and was 25.9 ± 24.4 (12–94) in group 2 (p = 0.063, CI = 8.5–+14.3). The mean preoperative BSCVA was 0.2 ± 0.5 on logMAR scales. The preoperative BSCVAs were similar in the two groups (p = 0.959, CI = 0.15–+0.12, Table 1). The mean postoperative BSCVA was 0.1 ± 0.7 on LogMAR scales. The postoperative BSCVA was found to be similar in the two groups (p = 0.237, CI = 0.07–+0.16, Table 1). The mean percentage change in BSCVA was 36.5 ± 0.9 and was also similar in both groups (p = 0.525, CI = 0.35–+1.05, Table 1). Most patients in both groups enjoyed a successful outcome without recurrence (Figures 1–4). On the other hand, true recurrence was seen in two patients (8%) in group 1 and four patients (13.3%) in group 2 (p = 0.531, CI = 0.12–+0.22). Severe intraoperative pain was seen in two patients (8%) in group 1
TABLE 1. Patient characteristics of each group at the beginning and during the follow-up period of the study. Patient Characteristics Age Gender (Female/Male) Number of prior surgeries (range) Follow-up (months) Preoperative visual acuity (log MAR) Postoperative visual acuity (log MAR) Change in visual acuity (%) Recurrence (%) Severe Pain (%) Epithelial Defect (more than 5 days) (%)
Group 1a (mean ± SD)
Group 2b (mean ± SD)
Total (mean ± SD)
Confidence Interval
p Value
59.1 ± 12.1 9/16 1.36 ± 0.12 (1–3) 28.8 ± 15.7 0.2 ± 1.0 0.1 ± 1.2 53.1 ± 1.2 2 (8%) 2 (8%) 5 (20%)
55.4 ± 12.9 12/18 1.26 ± 0.1 (1–3) 25.9 ± 24.4 0.2 ± 1.4 0.1 ± 1.3 21.8 ± 0.4 4 (13.4%) 4 (13.4%) 4 (13.4%)
57.1 ± 12.6 21/34 1.31 ± 0.57 27.2 ± 20.8 0.2 ± 0.5 0.1 ± 0.7 36.5 ± 0.9 6 (10.9%) 6 (10.9%) 9 (16.4%)
3.1–+10.6 0.23–+0.31 0.22–+0.40 8.5–+14.3 0.15–+0.12 0.07–+0.16 0.35–+1.05 0.12–+0.22 0.22–+0.11 0.13–+27
0.274 y 0.763yy 0.641yy 0.063yy 0.959yy 0.237yy 0.525yy 0.531yy 0.531yy 0.510yy
(SD: Standard deviation; aPatients who underwent modified inlay amniotic membrane technique; bpatients who underwent overlay conjunctival autograft technique; y independent samples t-test; yy Mann-Whitney U-test). !
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FIGURE 1. Recurrent pterygium; 90 62 mm (300 300 DPI).
FIGURE 3. Recurrent pterygium 2; 89 62 mm (300 300 DPI).
FIGURE 2. Clear cornea and no residue pteryqium; 89 62 mm (300 300 DPI).
FIGURE 4. Good result with clear cornea and conjunctiva; 90 62 mm (300 300 DPI).
and four patients (%13.4) in group 2 (p = 0.531, CI = 0.22–+0.11). Epithelial defect lasting more than five days was seen in five patients in group 1 (20%) and four patients in group 2 (13.3%) (p = 0.510, CI = 0.13–+27). Among the five patients in group 1, none of them had persistant epithelial defects lasting more than 10 days. In the second group, epithelial defect persisted more than 10 days in one patient, despite intensive lubricant and bandage contact lens application. Amniotic membrane was transplanted to the defective area and was healed after the AMT dissolved after six weeks.
pterygium recurrence.15 Therefore, the commonly used adjunctive therapies have been radiation, chemotherapy, or grafting procedures such as CA to reduce the hyperproliferation of fibrovascular tissue and thereby reduce the recurrence rate. Intraoperative mitomycin is a method of adjunctive therapy that has been commonly reported for the treatment of recurrent pterygium.16–18 It aims at inhibiting proliferating cells, thereby reducing recurrence. Earlier reports were about the use of MMC in bare scleral closure and the reported rate of recurrence was 7% to 38%.16–18 The variable description of complications, which include severe pain, scleral necrosis, and even scleral perforation, created doubt about the use of MMC. Since some of these complications occur later in the follow-up period, long-term evaluation after surgery seems necessary, especially after the the use of bare sclera technique. Some authors recommend the use of MMC for active and aggressive recurrent pterygium2 or in combination with a grafting procedure, as used in this study. This is due to the fact that it is not theoretically possible to remove subconjunctival fibrous tissue completely, especially in recurrent pterygia, because inflamed tissue extends deep into the fornix.
CONCLUSION Although many studies have compared their results for the treatment of primary and recurrent pterygium, the differences between the growth and morphological characteristics of recurrent pterygium versus primary pterygium have been given scant attention. The general consensus is that surgical trauma and subsequent postoperative inflammation activate subconjunctival fibroblasts, inducing the proliferation of fibroblasts and vascular cells; the deposition of extracellular matrix proteins, in turn, contribute to
Seminars in Ophthalmology
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Treatment of Recurrent Pterygium The concentration of intraoperative mitomycin C used in most of the studies ranges from 0.01 to 0.04%, with 0.02% applied for 3 min being the most common dosage used.10,19,22 Since increasing the duration and concentration of mitomycin C may potentially lead to a higher risk of complications, it was avoided in our study. The conjunctival autograft gained popularity in the 1980s and is generally regarded as the procedure of choice for the treatment of primary and recurrent pterygium because of its efficacy and long-term safety.4–6,8,9,10,24 A free conjunctival graft is harvested from the superior bulbar conjunctiva and is sutured in place over the bare scleral defect.25 It aims at wound healing and restoration of the limbal barrier.26 Variations in conjunctival autograft surgery include the use of narrow-strip conjunctival autograft, limbalconjunctival autografts, limbal epithelial autografts, conjunctival flaps, or conjunctival rotation autografts.27–33 The use of CA for the treatment of recurrent pterygium resulted in recurrence rates of 9.2% to 14%.5,34,35 This method appears to reconstruct a more normal limbal anatomy with a better cosmetic result with respect to vascularization and bunching of conjunctiva. On the other hand, it requires more disruption of the healthy conjunctiva that may become necessary in a future filtering procedure. To date, there has been no conclusive evidence regarding the superiority of limbal–conjunctival autografts over conventional conjunctival autografts, and the added risk of limbal damage at the donor site. Furthermore, rejection is a major concern of limbal autograft transplantation. Hence, the authors of this study avoided this technique and performed CA rather than limbal-CA in their study.27 For the treatment of primary pterygium, a combination of conjunctival autograft with low-dose (0.2 mg/ ml) MMC was shown, in a prospective randomized comparative study by Frucht-Pery et al.,11 to have a significantly lower recurrence rate compared with conjunctival graft alone. The recurrence rate of combined conjunctival autograft with MMC for the treatment of recurrent pterygium is in the range of 0 to 14.2% in various studies.36–39 The recurrence rate was 13.3% in the CA-MMC group in our study, and the results were comparable to other studies in literature. The first ophthalmic use of AMT was for replacement of lost conjunctival tissue40 and as a biologic bandage in the treatment of caustic burn to the eye.41,42 The presence of anti-angiogenic and antiinflammatory factors in AMT helps decrease inflammation, neovascularization, and pain.43 In this way, it suppresses extracellular matrix protein production and scar formation by pterygial fibroblasts.44,45 Delayed vascularization of the amniotic membrane demonstrated with anterior segment indocyanine green angiography is thought to be responsible for !
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the delayed recurrence after pterygium surgery.46 On the other hand, the promotion of growth and differentiation of conjunctival47 as well as adjacent limbal epithelial cells48 by AMT may, in turn, promote wound healing, reduce inflammation, and eventually help to restore the limbal barrier function. Although CA to cover the bare sclera remains the mainstay of treatment for recurrent pterygium, it is extremely difficult to fashion a large enough CG in some recurrent pterygium eyes, due to the shortage of healthy tissue available. Besides, in eyes that have had multiple failed surgeries, previous conjunctival harvesting often renders the donor site scarred and reduces the availability of healthy conjunctiva. Especially in the presence of symblepharon, amniotic membrane (AM) may serve as an ideal cover, facilitate fornix reconstruction, and thus represent an alternative surgical method. Solomon et al. reported a recurrence rate of 9.5% for the treatment of recurrent pterygium with the use of AMT.49 In order to achieve this result, they used an intraoperative long-acting steroid injection and double layers of AM, in addition to extensive removal of the conjunctiva, which presumably increased the effectiveness.49 Luanratanakorn et al. compared CA with AMT for the treatment of recurrent pterygium and the recurrent rates were 21.4% and 52.6%, respectively.12 They used single-layer preserved AM and concluded that AM alone is associated with an unacceptably high recurrence rate compared with conjunctival autograft. Their findings were supported by Tananuvat et al., who used single-layered AM with the basement-membrane-side up.50 Ma et al. compared the excision of recurrent pterygia followed by amniotic membrane and amniotic membrane graft combined with intraoperative mitomycin C(0.025%), and found no significant difference in the recurrence rates between the two groups (12.5% vs 12.8%).51 They also sutured the AM with the basement-membrane-side up. The technique used in our study was also single-layer AM with the basement-membraneside up and our results (recurrence rate of 8%) were comparable to those of Ma et al.51 The weaknesses of our study are the small number of patients and resultant high range of CI in selected parameters. Also, the scoring system for intraoperative pain was relatively simple and subjective; therefore, its results should be approached more cautiously. To the best of our knowledge, this is the first report on the comparison of these two techniques for the treatment of recurrent pterygium cases. Though AM cannot surpass normal conjunctiva due to the lack of host epithelium and fibroblasts, the results of this pilot study encourage the use of AM in combination with MMC for the treatment of recurrent pterygium with similar success to CA combined with MMC.
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DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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