Penetrating Keratoplasty in Ocular Stem Cell Disease

Introduction

Reconstruction of the ocular surface is often a sequence of procedures that culminates in optical keratoplasty. The surface reconstruction procedures that precede the corneal transplant are designed to optimize conditions for optical function by ensuring a normal interface between the lids and the globe, normal tear function, and, finally, cellular replacement or reconstruction. Despite the fact that roughly 50% of stem cell transplant procedures are followed ultimately by corneal transplantation, there has been relatively little attention in the literature devoted to the special requirements of the corneal graft in the context of stem cell disease. In this brief chapter, we will attempt to provide a logical approach to corneal grafting in the context of the patient who is being treated for a stem cell deficiency.

The overall therapeutic goals in performing a penetrating or lamellar keratoplasty in any patient are (1) to achieve anatomic integration and surface compatibility of the corneal graft; (2) immunobiologic acceptance of the transplanted tissue; and (3) adequate refractive function. In the ophthalmic literature, a great deal of attention has been paid to the phenomenon of graft rejection and its immunomodulation with corticosteroids and other immunosuppressive agents. Likewise there is also a sizable literature that deals with the refractive function of corneal grafts, ranging from studies of regular and irregular astigmatism after keratoplasty, as well as contact-lens fitting and refractive surgical modification of corneal grafts. However, the issue of surface integration has been less extensively covered in the ophthalmic literature, and it is this component that is perhaps most crucial in the patient who has been previously treated, or is currently receiving treatment, for stem cell dysfunction.

In the context of stem cell disease, there are several highly specific factors that become crucial to the survival of the corneal graft. The first is, of course, the de-

gree of severity of the stem deficiency. The extent of a stem cell deficiency is largely dependent on the etiology. As outlined in Chapter 13, the cause of the stem cell deficiency will likely determine whether it is a partial or total deficiency, whether it is associated with inflammation, and whether other components of the ocular surface aside from the stem cells are involved. Determination of these factors is crucial when a corneal transplant is considered as the ultimate rehabilitative step in the process.

The factors that are critical to the survival of a corneal graft include the adequacy of the stem cell reserve, aqueous- or mucin-deficiency dry eye, and anatomic lid abnormalities. In the absence of optimized conditions, the consequence for the corneal graft is that, even with excellent donor material and meticulous surgical technique, the patient may develop persistent nonhealing epithelial defects, secondary ulceration with stromal melting, vascularization and conjunctivalization, and ultimately immune graft rejection. In the context of a noninflamed eye, which has undergone successful stem cell replacement with a procedure such as a conjunctival limbal autograft or keratolimbal allograft, the subsequent placement of a lamellar or penetrating keratoplasty may stress the limits of the available stem cell reserve to produce recurrent ocular surface disease. Therefore, in any patient in which keratoplasty is a component of the therapeutic plan, there must first be an adequate stem cell supply, adequate tear function, and anatomically functional lids.

Review of the Literature

Unfortunately, the existing clinical series that discuss keratoplasty in the context of ocular stem cell disease are, in general, small and have varying degrees of fol- low-up. This limits our ability to draw any valid conclusions from these studies about which technique is op-

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timal. Nonetheless, there are some general principles of management that can be adduced from these small clinical series. The primary question that has faced ocular surface specialists has been whether stem cell replacement should precede keratoplasty, or whether the best approach is simultaneous surgery. Those who would argue in favor of simultaneous stem cell replacement in penetrating keratoplasty cite the advantages of the need for only a single surgery, the use of a single-donor tissue for both stem cell replacement and keratoplasty, and, therefore, a procedure that presents only a single antigenic challenge. On the other hand, those who advocate sequential procedures suggest that a well-healed, noninflamed eye status post-stem cell transplant is the most favorable condition for a successful corneal graft and will, therefore, be associated with a considerably lower incidence of graft failure.

If one examines the literature over the last decade of the 20th century, there is clearly a division between the advocates of simultaneous combined stem cell transplantation/keratoplasty and those who advocate staged or sequential procedures. In 1989, Kenyon and Tseng1 presented four cases of conjunctival limbal autograft in 26 consecutive cases in patients who had suffered chemical burns. They recommended that penetrating keratoplasty be performed at least one year after limbal transplantation. In 1997, Theng and Tan published a case report2 in which a patient received a simultaneous keratolimbal allograft and penetrating keratoplasty with donor tissue from a single donor. The recipient was managed with perioperative immunosuppression and re-epithelized within 24 days. Follow-up of this patient was 21 weeks only, at which time the central cornea remained clear.

Tsubota et al.3 published a series of 9 patients who underwent combined keratolimbal allograft with penetrating keratoplasty, once again with the donor tissue for the stem cell transplant and the keratoplasty from the same donor tissue. Five of these 9 grafts remained clear after 12.3 months. Although there were 2 episodes of graft rejection and 2 patients required a second limbal graft, visual acuity was improved in all 9 patients. In 1998, Tseng et al.4 presented a series of 14 eyes that underwent staged procedures, the first stage of which was amniotic membrane transplantation, followed by a combined keratolimbal allograft and penetrating keratoplasty from the same donor. Although staged in a sense, in one group of the patients studied, the penetrating keratoplasties and keratolimbal allografts were performed at the same time, but subsequent to amniotic membrane transplantation. Nine of 14 eyes experienced a penetrating keratoplasty rejection, and 5 of 14 had recurrent surface breakdowns. Three of 14 experienced early keratolimbal allograft rejection. Frucht-Pery et al.5 presented a small series of three patients with chemical trauma who underwent staged conjunctival limbal au-

M.J. Mannis

tograft, followed by penetrating keratoplasty 3 to 6 months later. Graft epithelialization was complete within 7 to 12 days, and there were no recurrent epithelial defects or graft rejections. In 1999, Tsubota et al.6 presented a series of 28 eyes with simultaneous penetrating keratoplasty and keratolimbal allograft. The keratolimbal allograft and donor cornea tissue were from the same donor, and cyclosporin A was used systemically, beginning preoperatively and for one month in the postoperative period. Fifteen of 28 (54%) of the penetrating keratoplasties survived, while 13 of 28 rejected. Nine of the 13 had regrafts, and of these, 7 had a second episode of rejection. Four patients underwent a third penetrating keratoplasty.

Croasdale, Schwartz et al.7 presented a series of 36 cases using staged stem cell transplantation followed by penetrating keratoplasty approximately 3 months later. They employed 2 eyes from the same donor for the keratolimbal tissue and a third donor for the corneal transplant. The patients were treated with topical corticosteroids as well as systemic cyclosporin A for 12 to 18 months. In a subsequent expansion of this series to 54 patients with keratolimbal allograft (personal communication), 35 patients underwent lamellar or penetrating keratoplasty 3 to 4 months post-stem cell graft and were followed for at least one year. Forty of these patients (74%) were stable, and 60% (21 of 35) had successful corneal grafts. Of the 14 failed grafts, 3 succumbed to endothelial graft rejection and 11 to recurrent ocular surface disease.

Rao et al.8 reported 2 eyes with staged conjunctival limbal allografts, followed by corneal transplantation using limbal tissue from living, related donors. Patients were treated with topical and oral prednisone, and corneal transplantation was performed at 7 and 16 months, respectively, post-stem cell transplant. Both patients developed recurrent epithelial breakdown, although the vision improved to 20/40 in one of these cases.

An alternative approach that has been discussed in greater detail in Chapter 18 is the technique of Sundmacher et al. They employed a single-stage homologous penetrating central limbal keratoplasty using a corneal button harvested eccentrically from the donor eye, so that roughly 40% of the limbus from the donor was transplanted centrally into the recipient.9 These patients were treated with cyclosporin A, and in 25 eyes of 24 patients, 18 of the transplants failed, either due to recurrent surface breakdown, graft rejection, or a combination of both.

As one can see from this brief summary of several of the major series from the literature that specifically relate to penetrating keratoplasty after stem cell transplant (either keratolimbal allograft or conjunctival limbal autograft), there are three basic approaches. These include

(1) simultaneous stem cell graft and penetrating ker-

atoplasty using the same donor tissue, (2) the staged approach, which consists of the appropriate stem cell surgery followed by penetrating or lamellar keratoplasty at a later date (Figure 23.1), and (3) a large eccentric donor graft supplying both limbal stem cells and the optimal keratoplasty. Both the simultaneous as well as the sequential approaches have theoretical advantages and disadvantages. The advantage of combined limbal stem cell transplant and penetrating keratoplasty using tissue from the same donor is that this technique (1) uses only a single donor cornea; (2) avoids two separate surgical procedures; and (3) avoids the introduction of additional antigens, thereby potentially diminishing the risk of graft rejection. On the other hand, the simultaneous stem cell/keratoplasty technique is associated with significantly greater technical difficulty. In addition, it is often associated with both increased inflammation at the time of corneal transplant as well as the placement of the graft in a destabilized ocular surface that has not yet had the advantage of stem cell replenishment.

The sequential procedure, on the other hand, also has advantages and disadvantages. Performing the stem cell graft and allowing the eye to heal prior to the keratoplasty affords stabilization of the ocular surface prior to the trauma of the corneal graft, and allows the surgeon to place the corneal transplant at a later date in a relatively noninflamed bed. On the negative side, this approach does require two separate operations, substantially prolongs the rehabilitative process, and, from an immunologic standpoint, presents the recipient with two separate antigenic challenges. As previously stated, the series in the literature to date are generally so lim-

Figure 23.1. Successful penetrating keratoplasty after keratolimbal allograft. Photograph 10 years postkeratoplasty.

ited in both numbers of patients as well as length of fol- low-up that no truly definitive conclusions can be drawn as to which procedure is best at this time. Both clearly have theoretical advantages and disadvantages.

Based on the largest series with the longest followup, as well as on our own clinical impressions, the authors favor a staged approach, which is more protracted but allows for surface stabilization and resolution of ocular surface inflammation prior to keratoplasty.

Some investigators advocate the use of lamellar keratoplasty instead of penetrating keratoplasty in order to utilize the healthy endothelium of the recipient. This technique eliminates the risk of endothelial rejection and minimizes the hazards associated with intraocular surgery. It is especially useful in cases such as aniridia, in which the final visual outcome will be predictably limited by macular function. Although it has the advantages outlined above, lamellar keratoplasty remains a technically challenging procedure.

Summary

Certain conclusions appear to be clear regardless of the planned surgical approach. The risk of graft rejection and/or recurrent surface disease is higher whenever penetrating keratoplasty is performed in the context of stem cell dysfunction and after a stem cell transplant. In both approaches, the risk of corneal graft rejection is higher than in the keratoplasty population in general. This mandates special considerations in the management of recipient immunosuppression and management

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of the ocular surface. Finally, larger studies with considerably longer follow-up will be necessary before the ideal surgical and adjunct medical regimens can be determined. It is clear that penetrating keratoplasty plays a significant role in the visual rehabilitative stage of stem cell transplantation. When corneal grafting is necessary after stem cell transplantation, meticulous attention must be paid to nurturing the ocular surface, and to immunosuppression, for the prevention of graft rejection.

References

1.Kenyon KR and Tseng SCG. Limbal autograft transplantation for ocular surface disorders. Ophthalmol 1989; 96:709– 722.

2.Theng JT and Tan DT. Combined penetrating keratoplasty and limbal allograft transplantation for severe corneal burns. Ophthalmol Surg Lasers 1997; 28:765–768.

3.Tsubota K, Toda I, Saito H, Shinozaki N, Shimazaki J. Reconstruction of the corneal epithelium by limbal allograft transplantation for severe ocular surface disorders. Ophthalmol 1995; 102:1486–1496.

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4.Tseng SCG, Prabhasawat P, Barton K, Gray T, Meller D. Amniotic membrane transplantation with or without limbal allografts for corneal surface reconstructions in patients with limbal stem cell deficiency. Arch Ophthalmol 1998; 116:431–441.

5.Frucht-Pery J, Siganos SS. Salomon A, Scheman L, Brautbar C, Zauberman H. Limbal cell autograft transplantation for severe ocular surface disorders. Graefes Arch Clin Exp Ophthalmol 1998; 236:582–587.

6.Tsubota K, Satake Y, Kaido M, Shinozaki N, Shimmura S, Bissen-Miyajima H., Shimazaki J. Treatment of severe ocular surface disorders with corneal epithelial stem cell transplantation. N Engl J Med 1999; 340:1697–1703.

7.Croasdale CR, Schwartz GS, Malling JV, Holland EJ. Keratolimbal allograft: recommendations for tissue procurement and preparation by eye banks, and standard surgical technique. Cornea 1999; 18:52–58.

8.Rao SK, Rajagopal R, Sitalakshmi G, Padmanabhan P. Limbal allografting for related live donors for corneal surface reconstruction. Ophthalmol 1999; 106:822–828.

9.Reinhard T, Sundmacher R, Spelsberg H, Althaus C. Homologous penetrating central limbo-keratoplasty (HPCLK) in bilateral limbal stem cell insufficiency. Arch Ophthalmol Scand 1999; 77:663–667.