分期实施异体角膜缘干细胞移植与穿透性角膜移植术治疗严重化学伤 - 国内文献区干细胞之家



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发表于 2009-3-3 11:38 |只看该作者 |倒序浏览 |打印

作者：Ali Hassan Alashwal, Raja Azmi Mohd Noor, Mohtar Ibrahim作者单位：马来西亚理科大学医学院眼科
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      【摘要】  　　有1位于1996年实施右眼穿透性角膜移植术失败的双眼严重眼表化学伤的患者，62岁，右眼视力手动，左眼视力光感。于20060916/20070207分别对右眼实施了异体角膜缘干细胞移植术和穿透性角膜移植术，经过术后5mo的药物治疗观察，最终获得了右眼最佳矫正视力为6/30，角膜移植片透明，眼表得以重建，并未发现明显排斥迹象的良好效果。   V& ?# j7 W9 x& w8 a# [
      【关键词】角膜缘干细胞移植术；化学伤；穿透性角膜移植术
   　　Correspondence to: Ali Hassan Alashwal. Department of Ophthalmology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia. alashwalmed@yahoo.com
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　　Abstract　A 62yearold man presented with severe bilateral ocular surface chemical injury and history of failed penetrating keratoplasty of right eye in 1996. Visual acuity was hand movement in right eye and light perception in left eye. Staged procedures of limbal stem cells allograft followed by penetrating keratoplasty have been done and resulted in good ocular surface restoration and rehabilitation of vision in right eye.& @9 ~* U& d. i0 Q' F5 ^- x0 C

　　KEYWORDS: limbal stem cells transplantation; chemical injury; penetrating keratoplasty

　　INTRODUCTION
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　　The normal ocular surface is covered by corneal, limbal, and conjunctival epithelia, each of which has a distinct cellular phenotype. These three epithelia maintain the ocular surface integrity[1]. Limbal stem cells can be considered as the ultimate source of corneal epithelial regeneration. They support and maintain the corneal epithelial turnover since they have unlimited capacity for cells regeneration[2]. When these cells are in dysfunctional state due to any disorders or injuries, a unique pathologic state will invariably ensue and severe ocular surface insufficiency occurs characterized by persistent epithelial defects, vascularization, and conjunctivalization of the cornea with eventual loss of vision[1,3].8 J- b/ l) m0 f; P6 p6 q
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　　Severe chemical injury results in limbal stem cells deficiency which was manifested clinicallyby conjunctivalization, scarring of the cornea secondary to destruction of the basement membrane,corneal neovascularization, chronic inflammation and fibrous ingrowth[4]. In such case, restoration of the corneal clarity and improving vision can be achieved only by considering reconstruction of the ocular surface by limbal stem cells allograft accompanied with or followed by penetrating keratoplasty (PK). In our patient the corneal epithelium as well as conjunctival surface were severely injured, which resulted in a complete corneal conjunctivalization on both eyes. In order to repair the ocular surface and regain the functional vision in this patient, a twostep procedure of limbal stem cells allograft followed by PK was considered.8 H: D/ b4 {" p
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　　CASE REPORT
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　　A 62yearold man, a known case of hypertension and diabetes mellitus on regular medication, presented with remarkably reduced vision following severe chemical injury in both eyes in 1993. He had severe ocular surface damage and eventually developed deep corneal stromal opacity and vascularization. He underwent PK in right eye in 1996. In 2003 extracapsular cataract extraction with posterior chamber intraocular lens (IOL) implantation had been performed in right eye. However, the visual acuity did not improve because the transplantation had failed and perhaps was attributable to the poor corneal reepithelialization in view of severe limbal stem cell damage.  h# Y$ e# @; y+ g; V8 A$ ^
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　　Ocular examination revealed that the visual acuity was hand movement in right eye with good light projection in all gazes and light perception in left eye. He had deep corneal opacification in the left eye (Figure 1). There was upper fornix symblepharon in the right eye and generalized diffuse corneal opacity with deep stromal vascularization 360°as shown in Figure 2,3. Right eye intraocular pressure (IOP) was 15mmHg and anterior chamber was formed but the details of the iris can not be visualized. Baseline hematological investigations, hepatic and renal parameters were obtained and repeated every 24 weeks.5 o4 s$ r, J$ f* Y2 J
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　　An attempt to achieve normal ocular surface was considered first by releasing symblepharon and buccal mucosa grafting done in 2005. Right limbal stem cells allograft was performed on 16 September 2006. The limbal stem cells were obtained from a live donor who had severe proptosis blind eye due to neurofibromatosis type I and underwent enucleation. First the recipient bed was prepared. A lamellar dissection of the limbus and fibrovascular tissue was done. Then the limbal conjunctival graft was dissected 360° and advanced to the recipient bed. The donor tissue was sutured to the limbal side as well as to the surrounding conjunctival edge by interrupted 100 nylon sutures. At the end of surgery a bandage contact lens was placed.
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　　Postoperatively topical prednisolone acetate 10g/L was given every two hours, and then the dosage was tapered gradually. Topical ciprofloxacin every six hours and free preserved lubricants every two hours were given." Z1 ]* Y. v' T$ L

　　Immunosuppressive therapy have been startedpostoperatively in the form of oral predinsolone 60mg once daily which tapered off weekly by 10mg. Oral cyclosporine 300mg once daily was started and its blood level was monitored regularly. A gap of four months after limbal stem cells transplantationwas considered before proceeding to PK to allow the ocular surface to stabilize.$ H# C5 M# \* f9 S3 y  M! Z

　　He underwent PK on 7th February 2007 with a standard surgical procedure for penetrating keratoplasty. A fullthickness corneal button with a diameter of 7.5mm was grafted by 100 nylon interrupted sutures. There was iatrogenic trauma to iris at around 45 oclock intraoperatively. Visual acuity was 1/60 on the first day postoperatively and there was a small central epithelial defect in otherwise clear graft. This epithelial defect healed within the first week. Table 1 showed the events and operations that our patient had undergone since 1993.

　　Immunosuppressive therapy (cyclosporine 300mg once daily) was given with the postoperative medications in the form of topical prednisolone acetate 10g/L every two hours, topical chloramphenicol every four hours and free preservative lubricant every two hours. After five months the best corrected visual acuity has improved to 6/30, and cornea was clear with no signs of rejection noted (Figure 4).

　　Cyclosporine blood level as well as renal and liver function parameters were within normal limit.

　　DISCUSSION+ G" u# U4 M8 v% n" o
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　　Severe chemical injury is a challenging disorder. It can cause destruction of limbal stem cells which represent the ultimate source of corneal epithelial cells replacement[5]. Also it can damage corneal tissue and lead to persistent epithelial defect and corneal scarring. In severe limbal stem cell deficiency, the ideal procedure will entail replacing the lost limbal stem cells through limbal stem cells transplantation (LST). However, the aim of surgery is not to restore vision but to replenish limbal stem cells and replace conjunctival phenotypic epithelium by corneal phenotypic epithelium, consequently maintaining a stable ocular surface. In 1989 Kenyon and Tseng were the first who appied LST clinically Figure 2, 3Right eye after limbal stem cells transplantation; cornea has deep stromal vascularized scar

and reported a favorable result. They transplanted a conjunctivolimbal tissue from a normal patients healthy eye[6]. When both eyes are affected, allograft LST obtained from living relative or cadaveric donor must be used, which may be combined with or followed by PK. Once the limbal stem cells are successfully transplanted, they become the new source of epithelium in which they support the corneal graft and cover it by epithelial cells, resulting in a good ocular surface reconstruction and favorable visual outcome. Unfortunately there is a high rate of immune reaction that may be expected due to the immunogenic stimulus of the transplanted limbal cells, which makes the judgment to use aggressive immunosuppressant agents necessary. Topical corticosteroid accompanied with oral cyclosporine has traditionally been the mainstay for preventing graft rejection. Recently a new immunosuppressive agent, FK506, is used for at least 18 months after surgery. This agent shows similar activities and is more potent than cyclosporine.Table 1Events in which patients had gone through since 1993（略）' `, P1 F1 ~0 r; v  E% f
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　　The timing of the surgical procedures perhaps has a role in graft success. A period of at least three months between LST and PK allowing the inflammation to be diminished is preferred by many doctors[710]. Several studies nowencourage staged operations rather than one stage operation. The first stage involves ocular surface reconstruction bytransplantation of limbal stem cells and the second aims at restoration of vision by PK. Shimazaki et al[10] reported that they found that the eyes receiving PK several months after LST showed fewer complications than those with simultaneous PK and more than half of the cases in onestep operation developed immunologic rejection in the central graft, whereas the complication was not observed in the twostep procedure. 3 ~) @# o4 r/ j# C+ \

　　

　　Satisfactory visual rehabilitation is possible after PK following LST without compromising ocular surface stability[11]. However, Yao et al in his study demonstrated that a combination of autologous LST with deep lamellarkeratoplastyas a onestage surgical procedure simultaneously reconstructed the ocular surface and recovered corneal clarity in eyes with severe ocular surface disorders caused by latestage chemical or thermal burns[12].
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　　In our patient the failure of the first corneal graft was most likely attributable to the poor cornealreepithelialization due to severe limbal stem cells deficiency occurring after injury. To minimize the risk of rejection and reduce postoperative complications, we consider the staged operation with 4month gap between allograft LST and PK which was advocated recently by a lot of authors. Besides, the treatment of symblepharon before reconstruction of the ocular surface was performed. By using the immunosuppressive agents in high dose and long duration, staged procedures of LST followed by PK showed a remarkable progress in terms of ocular surface reconstruction and success of cornealepithelialization and clarity as well as improvement and rehabilitation of the vision.3 l) f5 h9 {$ |  O. a1 j
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　　In conclusion, we believe that allograft LST is useful in stabilizing ocular surface in bilateral limbal stem cell deficiency, which renders PK success high and effective. This procedure has now become a widely accepted management for severe chemical ocular surface injury. It has showed good result for ocular surface reconstruction and visual rehabilitation as well. Based on our experience in this case, the ocular surface reconstruction prior to PK and the timing of the surgical procedures has a significant role in graft success, minimizing immunologic rejection and improving the eventual visual outcome.
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　　7 Solomon A, Ellies P, Anderson DF, Touhami A, Grueterich M, Espana EM, Ti SE, Goto E, Feuer WJ, Tseng SC. Longterm outcome of keratolimbal allograft with or without penetrating keratoplasty for total limbal stem cell deficiency. Ophthalmology2002;109:11591166
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　　8 Sangwan VS, Fernandes M, Bansal AK, Vemuganti GK, Rao GN. Early Results of penetrating keratoplasty following limbal stem cell transplantation. Indian J Ophthalmol2005;53:31357 }! I+ \' j/ j5 O' q  f4 l  X
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　　9 Sangwan VS, Matalia HP, Vemuganti GK, Fatima A, Ifthekar G, Singh S, Nutheti R, Rao GN. Clinical outcome of autologous cultivated limbal epithelium transplantation.  Indian J Ophthalmol2006;54:2934
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　　11Shimazaki J, Shimmura S, Tsubota K. Donor source affects the outcome of ocular surface reconstruction in chemical or thermal burns of the cornea. Ophthalmology2004;111:3844
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　　12 Yao YF, Zhang B, Zhou P, Jiang JK. Autologous limbal grafting combined with deep lamellar keratoplasty inunilateral eye with severe chemical or thermal burn at late stage. Ophthalmology2002;109: 20112017

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