AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Although described for more than 100 years, corneal transplantation has become increasingly common since the 1960s. Over 40,000 transplants were performed in 1990 in the United States and Canada. The 5-year failure rate for corneal grafts is approximately 35%; corneal graft rejection is the most common cause of graft failure in the late postoperative period.

Pathophysiology

The term graft rejection refers to the specific immunologic response of the host to the donor corneal tissue. As it is a specific process, it should be distinguished from other causes of graft failure that are not immune mediated. A corneal graft that has suffered this immunologic response may or may not ultimately fail. Some physicians distinguish between graft reaction, which is reversible with medical therapy, and graft rejection, in which the immunologic end stage has been reached and the process is irreversible. Other physicians simply use graft rejection to refer to this immunologic process at any stage of its development, noting that some cases will progress to graft failure because of rejection. This second terminology is used in this article since it is in line with terminology used in other types of organ transplantation. Furthermore, at the time of presentation, it is not possible to know with certainty whether an immune process is reversible.

Frequency

United States

Over 40,000 transplants were performed in 1990 in the United States and Canada. The 5-year failure rate for corneal grafts is approximately 35%.

Mortality/Morbidity

Corneal graft rejection is the most common cause of graft failure in the late postoperative period.

Race

No known difference in corneal graft rejection between different races exists.

Sex

No known sex predilection for corneal graft rejection exists.

Age

Host age may influence the risk of corneal graft rejection. Although it is not certain, some investigators have concluded that a lower risk of corneal graft rejection exists for hosts who are older than 60 years. It is generally believed that infants have higher rates of graft rejection than adults.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Diagnosis of corneal graft rejection should be made only in grafts that have remained clear for at least 2 weeks following keratoplasty. By observing this guideline, graft rejection can be distinguished easily from other causes of graft failure that are more common in the early postoperative period (eg, primary donor failure). It is possible, but quite rare, for a sensitized host to exhibit immunologic graft rejection before this 2-week period. Graft rejection has been observed to occur as late as 20 years after transplantation. Incidence of graft rejection is greatest in the first year following transplantation.

• No symptoms are related universally to corneal graft rejection. Although, astute patients may complain of the following:
• • Decrease in visual acuity
  • Redness
  • Pain
  • Irritation
  • Photophobia
• Depending on the severity of the graft rejection, patients may be asymptomatic. Any patient with a corneal graft should be instructed to seek ophthalmologic care if these symptoms occur for more than a few hours.

Physical

• Animal models of graft rejection reveal that the 3 corneal layers, epithelium, stroma, and endothelium, can be rejected separately. Although these separate rejection processes have been observed in humans, it is important to realize that many patients will manifest combinations of epithelial, stromal, and endothelial rejection.
• Epithelial rejection presents in 1 of 2 manners, as follows:
• • The first type is characterized by an irregular, elevated epithelial rejection line that stains with fluorescein or rose bengal. The rejection line progresses rapidly across the cornea over several days to 2 weeks. A variant of this presentation may occur in which the epithelial rejection line takes the form of a ring, concentric with the limbus, which begins peripherally at the graft-host junction and progresses by shrinking centrally to a point. The rejection line represents a region of destruction of donor epithelium; the resulting epithelial defect is covered by host epithelium that grows inward from the remaining host cornea and limbus to cover the graft.
  • The second type of epithelial rejection is characterized by the presence of subepithelial infiltrates. These infiltrates consist of leukocytes and frequently have an appearance similar to the subepithelial infiltrates seen in adenoviral keratoconjunctivitis. These lesions may change location and shape over time, and they generally disappear on their own after several weeks.
  • Both types of epithelial rejection are steroid responsive, but, in many cases, the patient is either asymptomatic or has symptoms only of minimal irritation. As a result, the patient may not present to the ophthalmologist during these episodes. Although epithelial rejection generally is self-limited and tends not to cause visual disturbance on its own, it should be treated when found on examination as it may herald a more severe endothelial rejection.
• Stromal rejection: Generally, stromal rejection in humans accompanies endothelial rejection and is difficult to demonstrate alone. It is characterized by peripheral full-thickness haze with limbal injection in a previously clear graft. An arc-shaped infiltrate may be noted peripherally at the graft-host junction that progresses centrally.
• Endothelial rejections
• • Classic endothelial rejection presents with an endothelial rejection line (Khodadoust line) that usually begins at a vascularized portion of the peripheral graft-host junction and progresses, if untreated, across the endothelial surface over several days. The rejection line consists of mononuclear white cells that damage endothelial cells as the line sweeps across the endothelium.
  • Generally, a mild-to-moderate anterior chamber reaction is present. The damaged endothelium is unable to properly dehydrate the corneal graft; as a result, the donor cornea is clear ahead of the rejection line and is cloudy and edematous behind it.
  • A second variant of endothelial rejection is more diffuse in character, with scattered keratic precipitates and an anterior chamber reaction indicative of endothelial rejection and damage. In this type of endothelial rejection, stromal edema typically is not localized, but rather generalized throughout the graft, consistent with the generalized endothelial damage. The combination of keratic precipitates, an anterior chamber reaction, circumcorneal injection, and regions of corneal edema should be diagnosed as corneal graft rejection. In some cases, it may be difficult to distinguish graft edema from rejection and graft edema from endothelial insufficiency. Since rejection may be reversible, it is best in these situations to treat patients as if they have graft rejection.

Causes

• Risk factors for rejection
• • A great deal of energy has been expended in trying to determine clinical risk factors for corneal graft rejection. Since corneal graft rejection is the leading cause of graft failure in the late postoperative period, it would be useful to be able to identify and treat those patients at highest risk for graft rejection. Unfortunately, patients undergoing corneal transplantation represent a heterogeneous population, and it is difficult to prove that certain factors uniformly increase the risk of graft rejection. Differences in study designs exacerbate these difficulties.
  • Potential risk factors for corneal graft rejection are outlined below.
    • Host corneal vascularization
    • Larger and eccentric grafts
    • Human leukocyte antigen A (HLA-A) and human leukocyte antigen (HLA-B) and ABO blood type incompatibility
    • Presence of donor epithelium upon transplantation
    • History of previous graft failure of any cause
    • Bilateral penetrating keratoplasty
    • Pretransplantation corneal tissue media and preservation
    • Host age (lower risk with age >60 y, much higher risk in infants)
  • Of these risk factors, the only factor that has been decidedly proven to increase the risk of rejection is host corneal vascularization. Multiple studies have confirmed an increased risk of corneal graft rejection with increasing host vascularization, ranging from rates of 0-10% of graft rejection in avascular host corneas to rates of up to 25-50% in severely vascularized host corneas. The precise cause for this increased risk is unclear, although it is believed to be due to the relative loss of immune privilege that accompanies the usually avascular central cornea.
  • The other risk factors listed above remain in some dispute. In some cases, multiple studies have yielded contradictory results, whereas, in other cases, an insufficient number of clinical studies exist. In all cases, these risk factors will be modified by the particular clinical situation. In particular, studies regarding the role of the major histocompatibility complex and HLAs have yielded contradictory data, although several studies indicate a trend toward a decreased incidence of graft rejection occurring in matched corneal grafts. At the present time, corneal grafts are not HLA typed and matched, unlike other organ transplants. Further evidence is needed to justify the added cost and complexity of performing HLA typing prior to corneal transplantation.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Corneal edema from endothelial insufficiency

TREATMENT

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• Treatment of graft rejection depends upon the type of rejection present; however, in all cases, topical corticosteroids are the mainstay of treatment. Epithelial or stromal rejection without endothelial involvement usually does not progress to graft failure. As previously noted, epithelial rejection may be a self-limited process. Nonetheless, epithelial and stromal rejection should be treated aggressively, because they indicate host immunologic recognition of the graft and may precede a more severe endothelial rejection. Topical corticosteroids (eg, dexamethasone 0.1%, prednisolone acetate 1%) are prescribed 4-6 times/day until the signs of rejection resolve, followed by a slow tapering of the topical medication. These patients should be followed closely to be certain that the signs of rejection are improving and that endothelial rejection has not developed.
• In cases of endothelial rejection, treatment must be more aggressive if the episode is to be reversed. Topical corticosteroids should be used every hour while awake and as frequently as possible at night for 2-3 days, followed by every 2 hours while awake. Steroid ointment may be used at bedtime. Therapy should be continued until signs of rejection resolve. Topical medications should be tapered slowly over several weeks to a few months depending upon the patient's response to treatment. Therapy should be continued for at least 3 weeks in the absence of response before judging that the graft has failed.
• Other routes of administration of corticosteroids can be used in more severe endothelial rejections, in recurrent rejections, or if the patient is at high risk (eg, alkali burns, patients with vascularized corneas). Corticosteroids may be given by subconjunctival injection (eg, dexamethasone phosphate 2 mg, betamethasone 3 mg in 0.5 mL). A less painful alternative is a collagen shield soaked in corticosteroids and applied to the cornea combined with frequent corticosteroid eye drops. The collagen shield results in a higher local concentration of steroid than can be obtained by the use of corticosteroid drops alone. The shield acts as a depot reservoir for the drug that slowly releases its contents during the period between topical applications. Higher steroid concentrations have been noted in the cornea, aqueous humor, iris, and vitreous, compared with hourly drops alone.
• Systemic corticosteroids also can be used in cases of severe endothelial rejection. Oral prednisone generally is started at dosages of 60-80 mg daily and continued for as long as 1-2 weeks before tapering. In line with findings in other fields of medicine, data suggest that pulsed IV steroids may be more effective than oral prednisone in reversing corneal graft rejection. Pulsed steroids (a single IV administration of 500 mg methylprednisolone) have been shown to improve the percentage of graft survival compared with oral steroids in patients who present early (within the first 8 d) in a rejection episode. A nonsignificant trend toward improved survival in all episodes of rejection in favor of pulsed steroids exists. In addition, pulsed steroids reduce the risk of subsequent rejection episodes, which may be a significant benefit in higher risk corneal grafts. Pulsed steroids also avoid prolonged administration of oral steroids.
• In all cases of rejection, intraocular pressure should be monitored closely, especially when frequent corticosteroids are used. If necessary, elevated intraocular pressure should be controlled by topical medications to prevent glaucoma and to improve the chance of graft survival.

Surgical Care

No surgical care has proven beneficial during an episode of acute graft rejection. Some transplant surgeons scrape the donor corneal epithelium to reduce the antigen load. No solid evidence exists that removing the donor epithelium is beneficial in reducing the risk of subsequent graft rejection.

Diet

No dietary restrictions

Activity

No activity restrictions

MEDICATION

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Corticosteroids are the mainstay of treatment of acute graft rejection. They can be given topically, via subconjunctival injection, or systemically.

Drug Category: Corticosteroids

Provide anti-inflammatory activity to suppress the natural immune response that leads to acute graft rejection.

FOLLOW-UP

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Patients should receive follow-up care as needed.

Complications

• Depending upon the degree of injury sustained by the graft, graft rejection episodes can progress to graft failure due to rejection.

Prognosis

• The sooner an episode of graft rejection is detected clinically and therapy is begun, the better the prognosis for graft survival. The rate of reversal of corneal endothelial graft rejection has been reported from 50-91%, depending upon the clinical setting. In general, the prognosis is good if therapy is instituted immediately.
• Depending upon the degree of irreversible damage to the graft endothelium, even markedly edematous grafts may clear again. Once endothelial destruction has progressed to the point where the remaining endothelial function is inadequate to maintain deturgescence, the graft fails and becomes irreversibly edematous. Unfortunately, the endothelium has no or at best a very limited capacity for repair through mitosis.

Patient Education

• No symptoms are related universally to graft rejection. Astute patients may complain of a decrease in visual acuity, redness, pain, irritation, and photophobia. Patients also may be asymptomatic. Any patient with a corneal graft should be instructed to seek ophthalmologic care urgently if these symptoms persist for more than a few hours.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Since a patient with a corneal transplant may present to any ophthalmologist with an episode of acute graft rejection, all ophthalmologists need to be aware of signs, symptoms, and treatment of acute graft rejection. This disease process is not limited to those ophthalmologists who perform corneal transplants.

Special Concerns

• Frontiers in corneal graft rejection therapy
• • Early results of the use of cyclosporin A in high-risk corneal transplantation have been promising. Cyclosporin A is a potent immunosuppressive agent that has revolutionized transplant therapy by reducing rejection in heart, kidney, liver, and other organ transplants. Cyclosporine is a fungal protein that has a high degree of specificity for T-cell lymphocytes and inhibits T-cell–mediated immune responses. Systemic cyclosporin A (blood levels 130-170 mcg/L) has been shown to greatly increase the rate of graft survival in high-risk corneal transplantation when used prophylactically for 12 months following transplantation. Cyclosporin A therapy carries known significant risks, including hypertension, renal toxicity, hepatotoxicity, and neurotoxicity; it should be used only after a thorough medical evaluation. Careful postoperative monitoring is essential and is generally best completed in conjunction with other physicians.
  • Topical administration of cyclosporin A also has been examined, and it has yielded conflicting results for both prophylaxis and treatment of graft rejection episodes. Cyclosporin A is not readily able to penetrate the corneal epithelium. Differences in drug vehicle and corneal penetration may account for the different outcomes seen in the use of topical cyclosporin A. Interestingly, collagen shields impregnated with cyclosporin A increase the corneal penetration of cyclosporine and can successfully reverse graft rejection in rabbits. Although methods that improve corneal penetration of cyclosporin A may improve its efficacy, they also may increase its potential systemic adverse effects. Note that blood levels of cyclosporin A have been recorded after topical administration of cyclosporin A in olive oil.
  • Other potential agents in the treatment of corneal graft rejection include antimetabolites (eg, azathioprine, 6-mercaptopurine) and immunosuppressives (eg, tacrolimus [FK-506], rapamycin). Relatively few studies have been performed using these agents in corneal transplantation, and their role in corneal transplantation therapy has yet to be determined. Each of these medications is associated with significant systemic adverse effects.
  • • Tacrolimus has received more study than the other agents. One group in England reported significant success in preventing and reversing corneal and limbal allograft rejection in high-risk eyes.¹ They found that no patient with therapeutic levels of tacrolimus suffered irreversible graft rejection. Several patients suffered from systemic adverse effects, including irreversible renal failure. In the United States, tacrolimus has only rarely been used in the setting of corneal transplantation.
    • Charles McMahon, MD, a surgeon in Colorado Springs, Colorado, has had success with tacrolimus in a series of approximately 20 patients (written communication, January 2005). McMahon has been successful in reversing rejection episodes in 3 corneas and in preventing rejection in 15 high-risk eyes. Two patients suffered from adverse effects, including agitation, nervousness, and skin paresthesias, that caused them to discontinue the medication. Both corneas in these patients failed within 2 weeks of discontinuing tacrolimus, suggesting the potency of this medicine in preventing rejection. No patients suffered serious or irreversible adverse effects in this series. McMahon generally used tacrolimus for a 3-month period following transplantation, although patients with particularly high-risk eyes continued the medication for 1 year. Patients have been successfully weaned off tacrolimus after this period without suffering rejection.
    • One significant issue is that the cost of tacrolimus for this indication is not always covered.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  This severely vascularized cornea would be at high risk for graft rejection following a penetrating keratoplasty. This patient experienced Stevens-Johnson syndrome.
	View Full Size Image
Media type:  Photo

Media file 2:  This is an example of an acute graft rejection episode. Note the graft edema, Descemet folds, and keratic precipitates.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

1. Sloper CM, Powell RJ, Dua HS. Tacrolimus (FK506) in the management of high-risk corneal and limbal grafts. Ophthalmology. Oct 2001;108(10):1838-44. [Medline].
2. Bertelmann E, Pleyer U. Immunomodulatory therapy in ophthalmology - is there a place for topical application?. Ophthalmologica. Nov-Dec 2004;218(6):359-67. [Medline].
3. Boisjoly HM, Tourigny R, Bazin R, Laughrea PA, Dube I, Chamberland G, et al. Risk factors of corneal graft failure. Ophthalmology. Nov 1993;100(11):1728-35. [Medline].
4. Chen YF, Gebhardt BM, Reidy JJ, Kaufman HE. Cyclosporine-containing collagen shields suppress corneal allograft rejection. Am J Ophthalmol. Feb 15 1990;109(2):132-7. [Medline].
5. Hegde S, Beauregard C, Mayhew E. CD4(+) T-cell-mediated mechanisms of corneal allograft rejection: role of Fas-induced apoptosis. Transplantation. Jan 15 2005;79(1):23-31. [Medline].
6. Hill JC. Systemic cyclosporine in high-risk keratoplasty. Short- versus long-term therapy. Ophthalmology. Jan 1994;101(1):128-33. [Medline].
7. Hill JC. The use of cyclosporine in high-risk keratoplasty. Am J Ophthalmol. May 15 1989;107(5):506-10. [Medline].
8. Hill JC, Maske R, Watson P. Corticosteroids in corneal graft rejection. Oral versus single pulse therapy. Ophthalmology. Mar 1991;98(3):329-33. [Medline].
9. Hwang DG, Stern WH, Hwang PH, MacGowan-Smith LA. Collagen shield enhancement of topical dexamethasone penetration. Arch Ophthalmol. Sep 1989;107(9):1375-80. [Medline].
10. Khodadoust AA, Silverstein AM. Transplantation and rejection of individual layers of the cornea. In: Investigative Ophthalmologic and Visual Sciences. Vol 8. 180-195.
11. Reidy JJ, Gebhardt BM, Kaufman HE. The collagen shield. A new vehicle for delivery of cyclosporin A to the eye. Cornea. Jul 1990;9(3):196-9. [Medline].
12. Smolin G, Thoft RA. The cornea. In: Scientific Foundations and Clinical Practice. 3^rd ed. Lippincott William & Wilkins; 1994.
13. Wang M, Lin Y, Chen J, Liu Y, Xie H, Ye C. Studies on the effects of the immunosuppressant FK-506 on the high-risk corneal graft rejection. Yan Ke Xue Bao. Sep 2002;18(3):160-4. [Medline].
14. Wilson SE, Kaufman HE. Graft failure after penetrating keratoplasty. Surv Ophthalmol. Mar-Apr 1990;34(5):325-56. [Medline].

Article Last Updated: Sep 25, 2007