Iatrogenic Limbal Stem Cell Deficiency

Introduction

A stable ocular surface depends upon the proper functioning of the limbal stem cells (SC). A limited number of disorders have been described that lead to ocular surface instability from abnormal stem cell function. Aniridia is a primary disorder in which improper development of the anterior segment results in a decreased number of SC. In all likelihood, the remaining cells, in addition to being decreased in number, are also dysfunctional. Aniridic patients are not born with abnormal ocular surfaces. As they become older, epitheliopathy develops in the peripheral cornea and slowly extends centrally. This advancement of surface disease indicates a progression of limbal SC dysfunction or loss.

Another cause of SC dysfunction is severe conjunctival deficiency. Examples of this category include patients with Stevens–Johnson syndrome (SJS) and ocular cicatricial pemphigoid (OCP), diseases resulting in inflammation of the conjunctiva and limbus. In these patients, the primary disease affects the conjunctiva, and the SC are involved secondarily. The corneal surface is almost always normal throughout the early stages of these disease processes. Only later, when the stem cell population is diminished from the constant conjunctival inflammation, does the corneal epithelium become abnormal. Eventually, if stem cell loss continues, conjunctivalization of the cornea will occur and the patient will show clinical signs of stem cell deficiency.

Other patients develop SC deficiency due to loss of stem cells from chemical or thermal injury. In this category are those patients with ocular surface disease secondary to alkali, acid, or thermal injury. These patients sustain loss of the majority of their SC populations at the time of the injury. In all likelihood, they sustain further, gradual SC loss in the period following injury, due to inflammation. The injury to the conjunctival tissue is another important factor that leads to the worsening of the stem cell function seen in these patients.

Yet another cause of ocular surface disease due to SC deficiency is contact-lens-induced keratopathy.1 Contact-lens-induced keratopathy can lead to severe conjunctivalization of the cornea. Kenyon and co-work- ers evaluated one case of severe contact-lens-induced keratopathy and found migration of conjunctival epithelium and goblet cells into the corneal surface. The ocular surface disease here is most likely due to chronic injury to the limbal SC. The injury to the SC is probably due to chronic ischemia in these patients, since it is worst in the superior quadrants compared with all other quadrants.

Corneal intraepithelial neoplasia (CIN) is a less commonly described cause of ocular surface disease from limbal SC deficiency.2 CIN thought to cause SC deficiency from replacement of normal SC with neoplastic ones. Typically, the ocular surface disease starts sectorally at the location of the limbal CIN. This abnormal corneal tissue then spreads circumferentially, and, if enough of the limbus is eventually involved, total ocular surface failure may result.

Etiology of Iatrogenic Limbal

Stem Cell Deficiency

The above mentioned categories account for the vast majority of cases of limbal stem cell deficiency reported in the literature. However, another group of patients exists that have stem cell deficiency but yet do not fit into any of these categories. It is likely that many of these patients go undiagnosed with stem cell deficiency because they do not have a classically described cause for their stem cell dysfunction.

Tseng categorized stem cell deficiency etiologies according to whether they represented hypofunction or aplasia of stem cells.3 Those etiologies resulting from stem cell hypofunction included aniridia, multiple endocrine deficiency, neurotrophic keratopathy, chronic lim-

bitis, pterygium, and pseudoterygium. Etiologies listed as stem cell aplasia included chemical/thermal injury, SJS, and multiple surgeries or cryotherapies to the limbal region. Although the latter category was named in Tseng’s study, details of patients with this condition were not described.

In 1998, the authors described a group of patients with iatrogenic limbal stem cell deficiency.4 These patients had stem cell disease not secondary to a known diagnosis. These patients were similar to the above patients in Tseng’s “multiple surgeries or cryotherapies to the limbal region” group. Although these eyes do not have a known specific cause for stem cell deficiency, they do share similarities in past ocular history, clinical findings, and clinical course. All eyes demonstrated a chronic, progressive epitheliopathy that began in the peripheral cornea and progressed centrally (Figure 10.1). In some cases, the epitheliopathy was accompanied by fine neovascularization (Table 10.1). The clinical findings were not consistent with other causes of epitheliopathy such as keratoconjunctivitis sicca, blepharopkeratoconjunctivitis, or toxic epitheliopathy. In addition, the epitheliopathy neither responded to standard therapies for dry eye management, nor resolved after reduction or cessation of topical medications.

Each of the eyes described had prior surgery involving the corneoscleral limbus, and the mean number of prior surgeries per eye was 2.6. We hypothesize that direct trauma to the limbus at the time of surgery results in loss of stem cells. Ocular surgery involving the corneoscleral limbus is, of course, quite common, yet limbal stem cell deficiency from prior surgery is quite rare. We believe that surgery to the limbus does not typically

Figure 10.1. Patient 1. Slit-lamp photograph demonstrating a superior sectoral area of thickened, irregular epithelium with neovascularization and lipid keratopathy. Stem cell deficiency resulted from multiple surgeries for pterygium and the use of topical Mitomycin C.

cause loss of enough of the stem cell population to result in ocular surface disease. However, surgical manipulation of the limbus does initiate a localized loss of SC that predisposes patients to develop the clinical findings of limbal deficiency when exposed to further stem cell trauma.

In support of this argument, all of our patients were affected in the superior quadrant corresponding to the site of prior limbal surgery. It is well known that the superior limbus is richer in limbal stem cells than any other part of the ocular surface.5 It is likely that both the length and location of the surgical incisions were influential in the development of stem cell deficiency. Two eyes of two patients had extracapsular cataract extraction (ECCE) utilizing an eleven millimeter limbal wound. Four eyes of three patients had previous intracapsular

Table 10.1. Sequelae of limbal stem cell deficiency.

R.E., right eye; L.E., left eye

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cataract extraction (ICCE) with wounds typically involving 180 degrees of the corneal perimeter (Figure 10.2). The anterior nature of ICCE and older ECCE wounds likely caused direct trauma to the limbal SC at the time of the surgery. It is interesting to note that none of the patients reported in this series had cataract surgery via phacoemulsification. It is very likely that phacoemulsification incisions, by nature of their being shorter than both the ECCE and ICCE incisions, result in significantly less trauma to the limbal SC population.

G.S. Schwartz and E.J. Holland

Another possible factor for the superior location of the stem cell damage is the contribution of the upper eyelids. Although difficult to evaluate, it is possible that mechanical forces elicited by the upper eyelids may cause localized ischemia and further stem cell damage.

The chronic use of topical medications including pilocarpine, beta blockers, antibiotics, and corticosteroids appeared to play a significant role in six eyes (Table 10.2). These topical medications are known to be toxic to the corneal epithelium. It is possible that chronic use

is also toxic to the limbal SC. One eye was exposed to topical mitomycin C for 30 days. Mitomycin C is an antimetabolite that specifically targets dividing cells. The entire ocular surface was exposed to MMC, but the only site of stem cell decompensation was at the site of the previous conjunctival autograft. It is probable that the surgical trauma in combination with the antimetabolic toxicity led to irreversible stem cell damage and resulting ocular surface disease.

Other diagnoses that may have contributed to stem cell failure, and which were present in some of these patients, include keratoconjunctivitis sicca, rosacea, and HSV keratitis. It is possible that these disease entities led to stem cell dysfunction through chronic inflammation or increased epithelial turnover. It is interesting to note that, although penetrating keratoplasty (PK) does not cause specific surgical trauma to the limbal stem cells, 5 eyes in this study had a total of 8 prior PK’s. The increased demand on the host epithelium to repopulate the donor graft was probably a factor for the development of limbal SC deficiency in these patients.

The patients with iatrogenic limbal stem cell deficiency are different from those with limbal stem deficiency from other causes, since there is not a single disease entity that leads to their limbal deficiency. Multiple factors, including surgery, topical medications, and external disease probably all contribute to limbal stem cell deficiency in these patients. It is likely that prior surgery, with its traumatic insult to the limbal stem cells,

the most important etiologic factor, since each patient within this study had undergone extensive surgery involving the corneoscleral limbus, and the area of stem cell deficiency always corresponded to the area of prior limbal surgery.

The clinical course of this disorder is a slowly progressive epitheliopathy beginning at the peripheral cornea and progressing centrally. It may be sectoral in an area corresponding to an area of previous limbal surgery. This sectoral nature can lead to the appearance of a wedge-shaped area of abnormal epithelium immediately adjacent to normal epithelium (Figure 10.3). By and large, the sectoral nature separates this form of limbal stem deficiency from those described previously, which tend to involve the entire limbus.

Medical Management

A certain percentage of iatrogenic limbal stem cell deficiency patients will require no therapy. These patients are either asymptomatic or mildly symptomatic, and the visual axis is not threatened. Therefore, the initial decision is whether to initiate treatment in a patient with iatrogenic limbal stem cell deficiency.

Because chronic use of topical medications is a probable etiologic agent, the first step in medical management is discontinuation of any unnecessary topical medications. These agents typically include antiglaucoma

medications and antibiotics. Preserved artificial tear preparations should be either discontinued, or replaced by nonpreserved lubricants.

Topical corticosteroids appear to relieve discomfort and may cause some regression of clinical findings in select patients with mild disease. The mechanism for this is uncertain, but these patients do have chronic, lowgrade inflammation, and the topical corticosteroids not

only improve comfort, but also reduce inflammation and encourage regression of neovascularization.

Another possible beneficial medical therapy, although unproven, is topical retinoic acid. It has been our experience that this medication can prevent progression and, in some cases, even lead to regression of abnormal epithelial cells in patients with mild to moderate disease.

Surgical Management

If medical therapy fails, the first surgical technique to consider is sequential conjunctival epitheliectomy.6 In this procedure, described by Dua, abnormal epithelium is scraped repeatedly, allowing normal epithelium to repopulate the corneal surface. This technique is described in detail in Chapter 14.

Amniotic membrane transplantation may also be used to manage iatrogenic limbal stem cell deficiency. Placement of this membrane at the time of superficial keratectomy provides scaffolding for the growth of new healthy epithelial cells.7 It also may promote transdifferentiation of conjunctiva-like epithelium to corneal epithelium. Innate anti-inflammatory properties of the human amniotic membrane also likely work to improve the overall health of the ocular surface.

For severe disease resulting in visual loss, a stem cell transplant procedure may be required for visual rehabilitation.8 If the fellow eye is unaffected, the procedure of choice is conjunctival limbal autograft (CLAU) and, in the future, possibly ex vivo expanded limbal autograft (EVELAU). Although the fellow eye may not manifest clinical findings of iatrogenic limbal stem cell deficiency, it often has had exposure to similar surgical trauma, chronic medications, and external disease factors, and may harbor a subclinical stem cell deficiency. These eyes should be approached cautiously, since using this otherwise asymptomatic eye as a donor for a CLAU may deplete it of necessary stem cells and cause symptomatic iatrogenic limbal stem cell deficiency in that eye as well. For these reasons, EVELAU may prove a superb option for these patients in the future.

For severe bilateral disease, one of the limbal allograft procedures is required for visual rehabilitation. These include living-related conjunctival limbal allograft, keratolimbal allograft, and living-related ex vivo expanded limbal allograft. Because iatrogenic limbal stem cell deficiency often manifests in a sectoral nature, it has been our experience that a partial keratolimbal allograft placed over the affected area of limbus will usually restore a healthy ocular surface.

Conclusions

Although little has been written about iatrogenic limbal stem cell deficiency, patients with this disorder are probably more common than the literature might suggest. It is important to recognize this disorder as a limbal deficiency, since standard medical therapies will not address its etiology. The sequelae of this condition include stromal scarring and significant loss of vision. Fortunately, phacoemulsification has replaced ECCE and ICCE as the procedure of choice for cataract extraction in many parts of the world. Because of its shorter, and often temporally placed, incision, phacoemulsification is probably less likely to lead to iatrogenic limbal stem cell deficiency. Hopefully we will be witnessing less iatrogenic limbal stem cell deficiency in the future.

References

1.Jenkins C, Tuft S, Liu C, et al. Limbal transplantation in the management of chronic contact-lens-associated epitheliopathy. Eye 1993; 7:629–33.

2.Erie JC, Campbell RJ, Liesegang TJ. Conjunctival and corneal intraepithelial and invasive neoplasia. Ophthalmol 1986; 93:176–83.

3.Tseng SCG, Chen JJY, Huang AJW, et al. Classification of conjunctival surgeries for corneal disease based on stem cell concept. Ophthalmology Clinics of North America 1990; 3:595– 610.

4.Schwartz GS, Holland EJ. Iatrogenic limbal stem cell deficiency. Cornea 1998; 17(1):31–7.

5.Wiley L, SunderRaj N, Sun TT, et al. Regional heterogeneity in human corneal and limbal epithelia: An immunohistochemical evaluation. Invest Ophthalmol Vis Sci 1991; 32: 594–602.

6.Dua HS, Azuara-Blanco A. Limbal stem cells of the corneal epithelium. Surv Ophthalmol 2000; 44(5):415–25.

7.Schwab IR. Cultured corneal epithelia for ocular surface disease. Tr Am Ophth Soc 1999; XCVII:891–986.

8.Holland EJ, Schwartz GS. The evolution of epithelial transplantation for severe ocular surface disease and a proposed classification system. Cornea 1996; 15(6):549–556.