case series of patients effectively treated with LASIK to correct post-keratoplasty astigmatism and myopia [7]. Holland et al. have described the use of post-keratoplasty LASIK to reduce astigmatism and myopia too [8]. Surgical planning for this procedure should not be done until all sutures are removed and most authors advocate waiting at least a year to ensure wound stability. One of the fears in this procedure is that of wound dehiscence during ßap creation. For this reason, PRK may be considered the preferred refractive procedure.

4.1.10.4Photorefractive Keratectomy with Mitomycin C

PRK over a cornea transplant has traditionally been thought of as less predictable than PRK for naturally occurring astigmatism and myopia [1]. Also, it has been associated with cornea haze and regression. Mitomycin C (MMC) is an antibiotic alkylating agent produced by the bacteria Streptomyces caespitious. Its mechanism of action involves the inhibition of DNA synthesis thus affecting rapidly dividing cells and inhibiting the proliferation of Þbroblasts and keratocytes [2]. MMC 0.02% has been shown to be effective in the prevention of subepithelial haze following PRK [2].

We have demonstrated that the application of MMC to the cornea for 10 s following the refractive procedure eliminates cornea haze and we have not experienced a signiÞcant regression amongst our patients we have treated with PRK. A cohort of our patients with post-keratoplasty astigmatism experienced a 42.6% reduction in their spherical equivalent, a 38.8% reduction in manifest cylinder, and a 45.2% reduction in topographic cylinder (Table 4.1). Forty percent of our patients had an improvement in the UCVA and 33.3% had an improvement in the BCVA. All grafts have remained clear postoperatively.

For post-keratoplasty astigmatism, we prefer PRK with MMC as the procedure of choice.

4.1.11 Corneal Allograft Rejection

Corneal allograft rejection is the leading cause of graft failure [3]. A review of the literature shows a decline in the incidence of cornea graft rejection over the years, but the fact that it is still a relatively common occurrence demonstrates that we do not understand it completely [9]. Prompt recognition and treatment are essential in preventing graft failure.

Corneal graft rejection is deÞned as a complex immune-mediated process that results in decompensation of the transplanted cornea [9]. Billingham and Medawar coined the term Òimmune privilegeÓ to convey the concept that the anterior segment was exempt from some forms of immune-mediated inßammation [9]. The idea that cornea transplants enjoy immune privilege is supported by the observation that keratoplasty is normally performed without HLA-matching and in the absence of systemically administered immunosuppressive drugs. As a result of these things, there is a common misconception that the immune privilege of the cornea is unconditional. This is very misleading. The immune privilege of corneal allografts is abolished in any condition in which inßammation, neovascularization, or trauma is elicited in the cornea [9]. Most keratoplasty patients, with the exception of those with KCN, have corneal graft beds that have lost their immune privilege due to preceding corneal inßammation, neovascularization, trauma, or infections [9]. Corneal immune privilege in these situations has been revoked and immunologic rejection becomes a major threat to the survival of the cornea transplant. As mentioned, immune rejection is the leading cause of graft failure [9].

Maumenee was the Þrst to establish the immunological basis for corneal allograft rejection [10]. He demonstrated that the application of donor-speciÞc skin grafts to rabbits 2 weeks prior to cornea transplantation resulted in accelerated corneal allograft rejection [10]. He also demonstrated that application of

Table 4.1 PRK with mitomycin C for postkeratoplasty astigmatism: results

donor-speciÞc skin grafts to rabbits bearing successful cornea allografts induced a rejection in the previously clear grafts [10]. Khodadoust and Silverstein completed a series of studies in the late 1960s and mid1970s that demonstrated that all three layers of the cornea transplant were independently able to undergo immunologic attack [11].

Since all three layers of the cornea allograft can undergo rejection independent of each other, cornea graft rejection can be classiÞed. Panda et al. classiÞed cornea graft rejection based on a review of the literature [3]. Cornea graft rejection was classiÞed as epithelial rejection, chronic stromal rejection and hyperacute stromal rejection, endothelial rejection, combined stromal and endothelial rejection, and rejection in a repeat graft [3]. As such, corneal graft rejection is characterized by either the development of epithelial and or endothelial rejection lines, unilateral anterior chamber reaction with keratic precipitates, or an increase in cornea thickness in a previously clear graft with aqueous cells [3]. The process occurs at 10 days or more following a successful clear graft [3]. Prior to 10 days the process is termed primary graft failure.

4.1.11.1 Host Risk Factors

A number of factors have been found to increase the risk of immunologic rejection in PK. These include corneal stromal vascularization, prior graft loss, anterior synechiae, previous intraocular surgery, herpes simplex keratitis, ocular surface disease, young age, and a history of anterior segment inßammatory disease [1]. Large diameter grafts have traditionally been associated with an increased risk of graft failure secondary to proximity to the limbal vasculature, but we did not note this complication in our study of large diameter grafts.

4.1.11.2 Vascularized Corneas

The Collaborative Corneal Transplantation Studies (CCTS) deÞned Òhigh riskÓ as a cornea with two or more quadrants of deep stromal vascularization [12]. In the CCTS, the risk of rejection was doubled in patients with stromal vascularization in all four quadrants [12]. The degree and depth of preoperative corneal vascularization determines the onset and severity of rejection [12]. The average time of onset to rejection

from time of surgery in one study was 10 months in avascular corneas, 4 months in mildly vascularized corneas, and 2 months in corneas that were heavily vascularized [1]. Polack observed that allograft rejections were more commonly observed in patients with deep stromal vascularization than those with superÞcial neovascularization [1]. Fine and Stein reported that rejection was reversible in only 50% of patients with vascularized corneas, compared to 66% of patients with avascular corneas [1].

4.1.11.3 Prior Graft Loss

Previous graft loss was deÞned as an independent risk factor by the CCTS for cornea graft rejection and failure [12]. In the CCTS, the number of previous grafts a patient had was a strong risk factor for graft failure, with each additional graft increasing the risk of graft failure by a factor of 1.2 [12].

4.1.11.4 Graft Diameter

Large-diameter grafts have been avoided by cornea surgeons in the past due to the concern that these grafts have a higher incidence of graft failure. Several studies have commented on an increased risk of graft rejection with large diameter grafts. In the CCTS, the smallest recipient trephine size, 6.5Ð8.0 mm was used [12]. Mader and Stulting reported corneal graft diameter as a risk factor in PK secondary to proximity to the limbal vasculature where there is more antigenic material [13]. Cowden, Copeland, and Schneider reported the use of LDPK as an eye-saving procedure only and stated that almost all would reject due to their large diameter [14]. They also listed LDPK as a predisposing risk factor for graft failure secondary to limbal proximity [14]. Cherry et al. (1979) found a positive correlation between graft size and allograft rejection [15]. Tuberville et al. [16] found no correlation between allograft reaction incidence and graft size ranging 7.0Ð8.0 mm [17].

Six patients of 34 in our study of large-diameter grafts experienced graft rejections, but no patient experienced a graft failure. Four of the 6 patients had documented compliance issues and failure to comply with the postoperative regimen led to a graft rejection episode. This stresses the importance of medication compliance and postoperative care following large diameter PK. When

performing LDPKs for any reason, compliance with the postoperative regimen as outlined by the surgeon should be emphasized preoperatively. Interestingly, no patient with a history of previous graft failure experienced a rejection episode in our study.

More recent studies have shown that graft rejection is statistically independent of the graft size [1].

4.1.11.5 Anterior Synechiae

Anterior synechiae may be present from previous anterior segment surgery or from prior chronic inßammation. In the CCTS, the failure rate from any cause doubled if the eye had three or four quadrants of anterior synechiae [12]. Direct contact of the graft with the host vascular system through the peripheral anterior synechiae is believed to put the host at an increased risk of graft failure [1].

4.1.11.6 Previous Intraocular Surgery

Previous intraocular surgery was associated in the CCTS with an increased risk of graft failure [12]. Anterior synechiae, neovascularization, chronic inßammation, and poorly controlled IOP following a previous surgery may be the mechanisms that make previous surgery a risk factor. SpeciÞcally, lensectomy, vitrectomy, and glaucoma procedures were the procedures identiÞed as risk factors in this study [12].

4.1.11.7 Herpes Simplex

An increased risk of graft failure may be associated with recurrent HSV keratitis following PK [1]. The herpes simplex virus is endemic throughout the world with some studies estimating a prevalence of about 149/100,000 population [1]. Approximately half a million people in the United States have experienced the disease [1]. Primary infection usually occurs in childhood with seroconversion prevalence increasing with age [1]. Studies of human ganglia have found evidence of HSV infection in as many as 94% of specimens in humans older than 60 years of age [1], and the incidence of ocular HSV has been estimated to be six times higher in patients who have undergone corneal transplant for nonherpetic corneal disease [1]. Given the prevalence of the disease, even without a history of

HSV keratitis, a patient may be at risk for HSV corneal disease after a PK [1].

Cornea scarring is the reason a person would require a PK following HSV keratitis. Recurrent episodes of HSV epithelial keratitis and more commonly recurrent stromal keratitis can cause signiÞcant scarring that requires PK for visual rehabilitation [18]. Cornea scarring as a consequence of viral keratitis has declined as an indication for PK over the past Þve decades [19]. During the 1950s viral keratitis was among the most common indications for corneal transplant [19]. In the 1990s referral centers reported a marked decline in the number of PKs being performed for viral keratitis [19]. The main reason for the decline is probably related to improvements in the medical management and early diagnosis of HSV keratitis [19]. Corneal scarring from HSV keratitis accounts for about three percent of PKs performed [20].

Because the majority of the population carries herpes simplex virus in a latent phase, reactivation of HSV after PK can occur [21]. As mentioned, even without a history of HSV keratitis, a person is at risk for HSV corneal disease after a PK. Recurrent HSV keratitis puts the patient at risk for scar formation in the graft, allograft rejection, and graft failure. The innervation density of the corneal epithelium is 300Ð600 times that of skin, and cornea nerve disruption during a PK is believed to be a stimulus for HSV reactivation [20]. Indeed, cornea incisions from radial keratotomy (RK) and PK have been shown to induce the shedding of HSV [20]. Corticosteroids may also increase the incidence of reactivation of HSV [20]. The survival rate of cornea grafts performed for HSV keratitis have been cited to range from 60.4 to 80% with the prophylactic use of acyclovir [20].

Viral reactivation can occur in either the early or late postoperative period following PK. Reactivation of a latent HSV infection is the most likely cause for HSV keratitis in patients who had PK without a previous history of HSV but the possibility of transmission of virus through the donor cornea should also be considered [21]. Sometimes the clinical diagnosis of HSV keratitis after a PK may be difÞcult. The presentation of a HSV epithelial defect may be nondendritic and the HSV keratouveitis and stromal keratitis with edema can be confused with graft rejection. Diagnostic testing for HSV-1 is not very sensitive and a single culture often results in false negatives. The possibility of HSV keratitis must always be considered after PK when an epithelial defect does not respond to standard treatment,