Etiology of Limbal Stem Cell Transplantation Failure

Abstract

Only a short time ago, patients with severe ocular surface disease (OSD) from limbal stem cell deficiency had a dismal prognosis. The development of limbal stem cell transplantation procedures has dramatically improved our ability to rehabilitate the ocular surface of these patients. Despite these recent advances, there is a significant failure rate both in ocular surface transplantation and subsequent keratoplasty. This chapter will delineate the various causes of limbal stem cell transplantation failure and will discuss potential strategies to improve the success rate. When evaluating whether a patient has had a successful result, it is imperative to consider the length of follow-up. Evaluation of short-term results (i.e., less than one year) reveals a high success rate with most techniques studied. It must be remembered that penetrating or lamellar keratoplasty in a patient with a total absence of stem cells will do well for the short term. An example of this is the practice of penetrating keratoplasty for patients with aniridia.1 The aniridic patient with conjunctivalization of the cornea and stromal scarring achieves dramatic improvement in visual acuity immediately after penetrating keratoplasty. However, because aniridic patients have a limbal stem cell deficiency, when the inevitable sloughing of the donor epithelium occurs, it will be replaced by conjunctiva-like tissue. As a result, the ocular surface will fail. We know from studies of epithelial rejection following keratoplasty that the donor epithelium can survive up to 13 months.2 Therefore, when stem cell transplantation studies have follow-up of less than a year, it may very well be that the surface appears healthy because of the survival of donor corneal epithelium, rather than from repopulation by the transplanted stem cells. Other factors important in evaluating success or failure of a particular stem cell transplantation technique is the preoperative diagnosis and severity of disease of the patients enrolled in the study. Patients with total limbal stem cell deficiency will be more difficult to rehabilitate than those with partial limbal stem cell deficiency, and patients with active conjunctival inflammation will have a higher failure rate than those with normal conjunctiva. This concept is discussed in detail in Chapter 13. Also important are the various factors that one can evaluate in determining success versus failure. Stability of the ocular surface is the fundamental anatomic criterion with which to evaluate stem cell transplantation success. A stable ocular surface has the clinical features of a healthy transparent epithelium and is devoid of neovascularization and inflammation. A stable ocular surface results not only in improvement in visual acuity, but also in resolution of the pain that typically occurs in these patients because of conjunctivalization or persistent epithelial defects. Another important factor in evaluating success of a limbal stem cell transplantation procedure is visual acuity. This factor is, of course, most important to the patient, and must not be forgotten by the clinician. Unfortunately, many patients with severe OSD have decreased visual acuity secondary to other ocular pathology, such as the aniridic patient with foveal hypoplasia. For this reason, visual acuity cannot be the only measure to evaluate the success of a particular technique. In the authors’ experience, approximately 50% of patients with OSD will require a subsequent penetrating or lamellar keratoplasty for visual rehabilitation. Many of these patients will develop with chronic endothelial rejection with a healthy ocular surface, and therefore graft clarity serves as another determinant of overall success. The success of ocular surface transplantation has been reported to be between 0–75%.1,3–5 Rao and coworkers in 1999 reported on their results with livingrelated conjunctival limbal allograft (lr-CLAL).3 Donors were HLA-matched, and patients were not given systemic immunosuppression. In all patients, ocular surface went on to fail.