SURVEY OF OPHTHALMOLOGY

MAJOR

VOLUME 34. NUMBER 5 - MARCH-APRIL 1990

REVIEW

Graft Failure After Penetrating Keratoplasty STEVEN

E. WILSON,

LoGiuna

M.D., AND HERBERT

E. KAUFMAN,

M.D.

State LJnizlersity Eye Center, Louisiam State Univentity Medical Center Srhool New Orlrnns, Lokianct

qf Medicine.

Abstract. Despite

the improving results that have been noted with penetrating keratoplasty, graft failure remains a significant problem. The causes of graft failure are quite varied. Primary donor failure, surgical complications, intraocular lens complications, persistent epithelial defects, allograft rejection, infection, glaucoma, trauma, and recurrences of primary cornea1 dystrophies are common etiologies. In this article, a critical review of the available literature concerned with the factors influencing the many causes of graft failure and their management is provided. (Surv Ophthalmol 34:325-356, 1990)

Key words. acanthamoeba allograft rejection cornea1 dystrophies cornea1 failure cornea1 transplantation glaucoma herpes simplex HI-4 matching intraocular lenses primary donor failure penetrating keratoplasty persistent epithelial defi:cts trauma l

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Every ophthalmic surgeon who performs penetrating keratoplasty has experienced the disappointmenl felt by patient and physician alike when a technically successful cornea1 graft fails. Despite the advances that have been made in cornea1 preservation and surgical technique, a significant proportion of grafts eventually fail. The causes of graft failure after penetrating keratoplasty are numerous. In this article, we review current understanding of the factors influencing graft failure after penetrating keratoplasty and examine potential strategies for decreasing the incidence and improving the treatment of this problem.

I. Donor Tissue Factors related to donor tissue selection and corneal preservation that influence graft failure following penetrating keratoplasty were the subject of a recent review in this journal.“’ ’ These factors will be discussed in this article only as they relate to primary donor failure, which is covered in detail in this review. Primarv donor failure is defined as irreversible

edema of the graft occurring in the immediate postoperative period. Despite the possibility of multiple etiologies, all cases of primary donor failure appear to have in common damage to the donor cornea with marked attenuation or absence of the endothelium noted on pathologic examination.‘7.‘H.” The most commonly cited factors are selection of donor tissue, inadequate cornea1 preservation, and surgical trauma. Although the responsibility for selection of donol tissue ultimately rests with the surgeon, there has been a trend toward increased reliance on the eye bank. The Eye Bank Association of America has established criteria for selection of donor tissue. [The medical standards are available from the Eye Bank Association of America, 15 11 K Street, N.W., D.C., 20005-14011 OptiSuite 830, Washington, mally, each donor cornea should be examined for abnormalities with the slit-lamp and the specular microscope. The specular microscope allows the donor endothelium to be examined before surgery. Tissue with inadequate endothelial cell counts or excessive polymorphism and polymegathism is re-

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jetted. ‘7~24~‘08~“3 in many cases of primary donor failure, the pathologic examination of the donor tissue reveals a diffuse thickening of Descemet’s membrane with cornea guttata suggestive of Fuchs’ dystrophy.42 Rarely, cornea guttata may be absent in a donor with Fuchs’ dystrophy, but the disorder can usually be detected on the basis of excessive thickening of Descemet’s membrane on histopathologic examination.‘77.267 Morphologic abnormalities of the endothelium would, however, usually be detected preoperatively in such cases by specular microscopy. Donor tissue may be damaged during excision of the corneoscleral rim. Improper technique in removing the corneoscleral rim from the donor globe can result in trauma to the endothelium because of distortion of the cornea or contact between the endothelium and other ocular structures.4z*g0 If such damage is localized, it could escape detection by specular microscopy since this technique tends to sample only a few areas of the endothelium of each cornea. Preservation of tissue may also result in endothelial cell loss and an increased incidence of primary donor failure. Bourne2* reported a statistically significant increase in cell loss in tissue preserved in KSol for more than seven days or in M-K medium for more than 36 hours. This finding does not apply to each individual donor cornea; many of the corneas stored for more than seven days in K-Sol or 36 hours in M-K medium had little or no cell loss. More of the corneas with high endothelial cell loss, however, had been stored for prolonged periods. Primary donor failure rates in large studies have been reported to vary from 0 to 5%, and do not appear to be significantly different for organ culture, K-Sol medium, M-K medium, or other preservation methods.27~‘s~64~‘03*‘57~‘68 Preliminary findings of Burris and Iwata3g have demonstrated that focal endothelial cell loss may be associated with stromal swelling and resulting Descemet’s striae during corneal preservation. This study suggests that severe Descemet’s striae may be associated with high endothelial cell loss during preservation in storage media. Further study is needed to ascertain whether advanced Descemet’s folding is associated with primary donor failure. A surgeon experiencing a clustering of cases of primary donor failure should suspect improper removal of the donor tissue, improper formulation of preservation medium, or defective intraocular fluids. Irrigating fluids, viscoelastic agents, and intraocular medications should all be suspected. Surgical trauma and resulting excessive intraocular inflammation may also result in primary donor failure. Care must be taken to ensure that there is no contact between surgical instruments and the

WILSON

AND KAUFMAN

donor cornea1 endothelium. Viscoelastic agents protect the endothelium from contact with intraocular lenses and other structures during penetrating keratoplasty.20s~224~*2’ Lowered intraocular pressure caused by hyposecretion of aqueous humor following penetrating keratoplasty may mimic primary donor failure.15” In such cases, the cornea commonly remains thickened until a more normal rate of aqueous humor production is restored and the cornea1 endotheliurn is provided an adequate supply of metabolites necessary for normal regulation of cornea1 hydration. After the normalization of aqueous humor production, detectable through an increase in intraocular pressure, it is important to allow a period of time for the cornea to resume normal function prior to making the diagnosis of primary donor failure. In cases of primary donor failure, we prefer to reoperate within the first few weeks following the initial surgery. This allows the patient to undergo a more rapid visual rehabilitation. Since primary donor failure is relatively rare, each case should be carefully investigated. The donor button should be submitted for pathologic evaluation and the eye bank should be notified.

II. Surgical

Factors

Surgical variables are major determinants of graft survival and the visual outcome of penetrating keratoplasty. Factors such as surgical technique, intraocular surgery following successful penetrating keratoplasty, combined procedures, viscoelastic agents, vitreous humor, anterior synechiae, and wound dehiscence will be discussed in this section. A. SURGICAL

TECHNIQUE

Many specifics regarding surgical technique will be addressed in later sections. It is important at this point, however, to make some general observations regarding endothelial cell protection and wound apposition. One objective of penetrating keratoplasty is to maintain as high a postoperative endothelial cell count as possible to increase the probability that the graft will survive the attrition of endothelial cells which occurs with time after the transplant,26~“7~60199 following secondary intraocular procedures,‘8*‘53.26’ and secondary to immunologic graft rejections.26,15g It is generally accepted that, regardless of the method of cornea1 preservation, the donor cornea should have a minimum cell count of approximately 2000 cells/mm’ to increase the chances of obtaining a successful graft with good longterm survival. The donor cornea should be punched from the endothelial side since this results in less endothelial cell loss than trephining from the epithelial sur-

GRAFT FAILURE AFTER PENETRATING

KERATOPLASTY

face.” In a prospective study of transplantation in phakic patients, Bourne demonstrated that preoperative hypotony through digital massage resulted in decreased endothelial cell loss.‘” The same principles likely apply to all subgroups of penetrating keratoplasty in which the vitreous humor is intact. Vitreous pressure increases the likelihood of contact between the endothelium and other intraocular structures, including intraocular lenses, during surgery. Hypotony can also be obtained through the use of devices such as the Honan balloon and intravenous mannitol.“‘““‘.““” Viscoelastics should be used to protect the endothelium and help maintain the anterior chamber. Contact between the endothelium and surgical instruments or intraocular structures should be avoided. Improper wound apposition is a common factor leading to graft failure.“‘,‘44 After removal of the recipient button, care should be taken to trim any areas of excess Descemct’s membrane that might interfere with good donor-recipient apposition during suturing. Many methods of suturing have been described. 17x.?w!.!27:\.L’xx These techniques consist of variations of interrupted, running, or a combination of running and interrupted sutures. Regardless of which of the many suturing techniques is favored by the surgeon, it is important to obtain optimal apposition of donor and recipient tissue. During placement of the cardinal sutures care should be taken to ensure proper distribution ofthr donor tissue. Distortion of the donor button during suturing should be minimized to prevent endothelial disruption. Sutures should pass deep into the stroma and at equivalent depth in the donor ancl recipient tissue so that there is good anterior-toposterior donor-recipient apposition. It is especially important to align the donor and recipient epithelial surfaces propel-Iv so that neither an override nor an underride is created that will interfere with reepithelialization of the donor tissue and, in man); cases, lead to severe postoperative astigmatism. The formation ofa smooth transition between the donor and recipient epithelittm can be complicated by wide variations in donor tissue thickness produced using the currently available cornea1 preservation methods. Although excellent results have been obtained using full-thickness sutures,‘xx and controlled studies are not available, our experiencrb suggests that they should be avoided, since wounds that perforate the full-thickness of the cornea are more likely to leak. In thin corneas such leaks call be severe. Also, we believe that there is likely to be increased endothelial cell loss because of direct trauma to the endothelium at the donor-recipient junction when full thickness sutures are utilized. If a double-running or a combined interrupted-running suture technique is used, the first running su-

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ture or the interrupted sutures, respectively, is placed deep into the stroma. The accompanying running suture in each of these techniques may be placed at a shallower depth since anterior-to-posterior wound apposition has been assured by the previously placed sutures. Fluorescein may be applied to the cornea when suturing has been completed and manual pressure applied to the globe to ensure that there is no leak. If necessary, additional sutures should be placed. Even with good technique endothelial cells are lost during transplantation. One study reported that an average of approximately 25% of endothelial cells on the donor cornea were lost during penetrating keratoplasty.“’ B. SECONDARY INTRAOCULAR PROCEDURES FOLLOWING PENETRATING KERATOPLASTY Cornea1 surgeons frequently must decide whether to perform a secondary intraocular surgical procedure, such as cataract surgery, intraocular lens repositioning, insertion, or exchange, or pupillary membrane dissection in a patient with a clear graft following penetrating keratoplasty. I’he primary factor that must be evaluated is the status of the central endothelium of the graft. Although studies on the amount of endothelial cell loss that can be expected following secondary intraocular procedures are lacking, the higher the central endothelial cell count the greater the chance that the graft will survive the planned procedure. J‘ransplants may remain clear with endothelial cell counts as low as 300-500 cells/mm,” ““.“.“,but it is desirable to have substantially higher counts to allow for slow decreases which may occur with time or decreases precipitated by stresses such as rejection episodes or glaucoma. Since studies of routine extracapsular cataract surgery with intraocular lens implantation in patients without grafts have demonstrated mean cell losses from 6 to 12% ,.i’.‘i” it is probable that cell losses of‘at least this magnitude or greater could be expected when similar surgery is performed in patients with grafts. Taking this into account, an endothelial cell density of at least 1000 cells/mm” could be expected to give a reasonable chance of graft survival after routine extracapsular cataract surgery with intraocular lens implantation. ‘l‘he decision to proceed with surgery should not be based on the cornea1 thickness alone, since it is not uncommon to identify a graft with what is considered to be a relatively normal thickness associated with a low endothelial cell density.‘“‘,“!‘,‘!” Available studies regarding secondary cataract surger?’ in patients with clear grafts for the most part report the rate of graft failure after secondary intracapsular cataract surgery without intraocular lens implantation and do not include measurements 01‘ endothelial cell loss. In representative

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WILSON AND KAUFMAN

1990

studies, rates of graft failure following surgery varied from 0 to 20%. 159~26’ The rate of graft failure, however, would be heavily biased by the selection of cases. In a more recent study reported by Binder,‘* 33 eyes with previous cornea1 transplants underwent either extracapsular cataract extraction with posterior chamber intraocular lens implantation (22 eyes), secondary intraocular lens implantation of an anterior chamber intraocular lens, iris-fixed intraocular lens, or posterior chamber intraocular lens (ten eyes), or intraocular lens exchange (one eye). Seven of these grafts failed l-8 months following the secondary procedure, with a mean followup of 24 months. Further studies should be performed and should include measurements of endothelial cell loss so that cornea1 surgeons can anticipate the degree of endothelial cell damage that might be expected following extracapsular cataract surgery with intraocular lens implantation or secondary intraocular lens implantation utilizing viscoelastic agents to protect the graft endothelium.

There are no large studies on the use of trabeculectomy in eyes with cornea1 grafts. We and other surgeons have successfully combined trabeculectomy and penetrating keratoplasty in rare patients. Follow-up data are, however, limited. The incidence of graft failure would be expected to be higher if there is shallowing of the anterior chamber, hemorrhage, or other complications that may be noted following trabeculectomy.

C. COMBINED

PROCEDURES

3. Penetrating

1. Penetrating Extraction

Keratoplasty

and Cataract

During the past 20 years there has been a trend toward increasing combined penetrating keratoplasty and cataract extraction in patients with significant cataract associated with a cornea1 opacity. Since Hughes”* reported a 69% rate of graft failure in 13 cases of combined penetrating keratoplasty and intracapsular cataract extraction in 1960, there has been a steady improvement in results and an evolution of the surgery to favor the combined penetrating keratoplasty, extracapsular cataract extraction, and intraocular lens implantation procedure 36.40.113,127.1.5~.182 Success rates from (triple procedure). 82 to 100% have been reported with variable followIn one study, endothelial cell loss in UP. 36~1’3.‘58,‘82 the triple procedure with extracapsular cataract extraction in which Healon@ was used averaged 14%, 20%, and 23% after one, two, and three years, respectively.“’ Bourne”’ found no statistically signilicant difference in endothelial cell loss two months after penetrating keratoplasty between phakic patients (22%), aphakic patients (23%), and patients undergoing combined penetrating keratoplasty and extracapsular cataract surgery (20%). Although the available data are limited, in the hands of experienced surgeons it would appear that the risk of failure for the triple procedure is not substantially greater than that of penetrating keratoplasty alone. Brightbills in a retrospective study, found comparable results for the combined procedure with either intracapsular or extracapsular cataract extraction. A higher incidence of secondary procedures in the extracapsular cataract group was ac-

counted for by posterior capsule opacification treated with Neodymium:YAG laser posterior capsulotomy. In the intracapsular group, there was a higher incidence of glaucoma and three grafts failed after vitreoendothelial touch. Most surgeons favor extracapsular cataract extraction in the triple procedure because the intraocular lens can be secured within the capsular bag behind the iris and there is better control of the vitreous without the need for vitrectomy. 2. Penetrating

Keratoplasty

Keratoplasty

and Trabeculectomy

and Vitrectomy

With the development of the Landers-Foulks’46 and Eckardt” temporary keratoprostheses, combined penetrating keratoplasty and vitrectomy, as well as other posterior segment manipulations, have become possible in patients with opacified corneas and posterior segment disorders. Success has been reported in obtaining clear grafts following this procedureg5v1”“; however, a proportion of grafts have failed postoperatively as a result of allograft rejection, phthisis bulbi, or other causes. There is a high incidence of cornea1 graft failure, approaching 100% if there is silicone oil-cornea1 endothelial touch, which may occur if it is necessary to use silicone oil for a complicated retinal detachment during this procedure. Graft failure associated with silicone oil is usually caused by the development of severe band keratopathy.77 A high risk of graft failure can also be expected in any aphakic eye with a previously successful penetrating keratoplasty in which silicone oil was used to repair a complicated retinal detachment.77 D. RELAXING RESECTIONS

INCISIONS

AND WEDGE

Many series of patients who have had cornea1 relaxing incisions or cornea1 wedge resections for high astigmatism following penetrating keratoplasty have been reported,’ 1R,139,140.1~0.166.174.274.289. While several authors have described perforations associated with relaxing incisions,‘3g*‘50~‘Hg none have reported graft failures as a result of either relaxing incisions or wedge resection. It seems likely, however, that in a patient with borderline endothelial cell density, a perforation with collapse

2go~2g7

GRAFT

FAILURE

AFTER

PENETRATING

KERATOPLASTY

of the anterior chamber could result in endothelial decompensation and graft failure. Based on the published series, this would appear to be a rare occurrence. One case of endothelial allograft rejection that occurred shortly after a relaxing incision has been reported.‘“” It is probably judicious to administer topical corticosteroids fin- a short time following a relaxing incision or any other procedure that is likely to stimulate a significant inflammatory reaction. For patients who are already being treated with corticosteroids the frequency may be increased for a period of a few weeks. Some clinicians advocate the use of topical corticosteroids for a brief interval following suture removal after penetrating keratoplasty. E. VISCOELASTIC

AGENTS

The availability of viscoelastic agents has revolutionized anterior segment surgery. Immediately after their introduction, cornea1 surgeons realized the advantages these agents provided in simplifying penetrating keratoplasty by maintaining the anterior chamber and protecting the donor endothelibenefits are so marked um.- ““‘z”‘.“:‘~ The technical that f&w studies have been reported that compare procedures performed with and without viscoelastic agents IO ascertain the effect on endothelial cell survival. In vitro studies in animals and humans have demonstrated that the endothelium is protected from damage secondary to contact with intraocular lenses by a coating of viscoelastic material.“.‘“’ Alpar’ performed a stratified, randomized, prospective study of different groups of patients requiring penetrating keratoplasty. Healon@ was utilized during surgery for l/2 of the patients in each of’ four groups. Mean percent endothelial cell loss was fimnd to be statistically significantly less at four weeks and six months in the Healon@ group (14.34 and 12.2%, respectively) than in the control group (24.3’3 and 20.6%, respectively).,’ The risk of elevated intraocular pressure after penetrating keratoplasty is increased by the use of viscoelastic agents.‘)“.‘” Increases are temporary in most cases and usually easily controlled with medicatioll. F. VITREOUS

HUMOR

Vitreo-endothelial contact is a common cause of graft failure after penetrating keratoplasty in aphakit patients.:“‘,“:’ Vitreous touch results in loss of endothelial cells. Bourne” reported endothelial cell losses of 83% and 75%’ in two eyes with vitreoendothelial touch one year after penetrating keratoplasty. The specific mechanism by which the vitreous damages lhe endothelium is unknown. In some pa-

329

tients, the vitreous appears to be tolerated indefinitely without clinically observable efrects on corneal hydration. In other eyes, localized areas of edema develop over the area of vitreo-endothelial touch and in some cases, progress to complete cornea1 decompensation. Removal of the vitreous with elimination of vitreo-endothelial contact may result in clinical reversal of cornea1 edema in some patients.“’ During penetrating keratoplasty in aphakic patients and in pseudophakic patients with intraocular lens exchange, or in combined procedures with extracapsular cataract extraction in which there is rupture of the posterior capsule with a ioss of vitreous, a generous anterior vitrectomy should be performed. We prefer to use a hand-held vitrectomy unit which is passed via the pupil into the central vitreous. Vitrectomy is continued until there is no further vitreous aspirated into the port. Other freestanding vitrectomy units may also be used. After completion of the vitrectomy, fluid is removed from the anterior chamber and the surface of the iris in each quadrant is gently touched with a cellulose sponge to search for residual vitreous. If vitreous is detected, it is removed by retracting the sponge and cutting the adherent vitreous at the surface of the iris with Vannas scissors. Since the presence of vitreous in the anterior chamber is commonly associated with graft failure,“‘,“” vitrectomy should be performed despite the documented increased risk of cystoid macular edema. ‘-I’? G. ANTERIOR

SYNECHIAE

The presence of anterior synechiae following penetrating keratoplasty increases the risk of graft failure.‘)i.~“,?~~~,~~~ In one study, 13 of 15 patients with anterior synechiae and seven of 45 patients without synechiae had episodes of graft edema.“’ Both immunologic and nonimmunologic failures were included. In addition, patients with anterior synechiae had a higher incidence of multiple episodes of graft edema. There are several mechanisms by which anterior synechiae may increase the risk of graft failure. First, anterior synechiae expose the donor endothelium to blood vessels that may increase the risk ofallograft rejection. “‘z”? Mechanical traction at the site of attachment of the anterior synechiae to the cornea1 endothelium may result in progressive loss of endothelial cells either directly or because of increased anterior segment inflammation.“’ Eventually. the number of endothelial cells may decrease to a level which is insufficient to maintain cornea1 deturgescence. Finally, there is an increased incidence of glaucoma in eyes with anterior synechiae after penetrating keratoplasty.“’ Elevated intraocular pressure may directly damage endothelial cells

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and damage to the optic nerve may result in a poor visual result. If possible, existing peripheral anterior synechiae should be released and the formation of new anterior synechiae during transplantation should be prevented. A combination of traction, blunt dissection, and even sharp dissection should be utilized to perareas of trabecuform synechiolysis.““s~285 Although lar meshwork that are uncovered may or may not resume a functional status,‘57 lysing the anterior synechiae appears to help retard progression of anterior synechiae to include areas of meshwork that are filtering. A dental mirror may be used as an aid in the visualization of the angle.308 Viscoelastic agents are helpful in preventing the formation of anterior synechiae.4’” After dissection of any existing synechiae, a small amount of viscoelastic agent should be injected into the angle for 360 degrees. If defects are present in the iris, iridoplasty should be performed to reestablish a rigid iris diaphragm as an aid to preventing formation or progression of anterior synechiae.“” H. WOUND

WILSON

1990

DEHISCENCE

Wound dehiscence is a common and, in many cases, preventable risk factor for graft failure. In one large series, 5.7% of 369 consecutive patients had wound gape, override, or separation.20 In our experience, this complication can be nearly eliminated with a combined 10-O and 1 I-O nylon doublerunning suture technique. In this technique, the 10-O nylon suture is usually removed 2-3 months after penetrating keratoplasty. If the 11-O nylon suture is inadvertently cut during removal of the 10-O nylon suture, it must be repaired because the rate of dehiscence in such cases is very high. The 11-O nylon suture is left in place for a period of at least one year, unless the suture breaks or vascularization occurs. When dehiscences do occur in grafts that have been performed using this technique they are most commonly associated with the removal of the 10-O nylon suture. They may occur, however, even if the IO-O nylon suture is retained for over a year and corticosteroids are discontinued after suppression of inflammation in the early postoperative period. In patients with interrupted sutures, we remove sutures when deep blood vessels cross the donor-recipientjunction, the sutures become loose, or a visible scar is present. In the case of a scar, the interrupted sutures are normally left in place for a period of at least 4 to 6 months. Wound separations can be divided into three groups.” In the first group, separations occur prior to suture removal and can be attributed to technical problems or increased intraocular pressure. Most separations fall into the second group, which occur

AND KAUFMAN

immediately or a short time after suture removal. The third group consists of wound dehiscences that occur long after suture removal. These cases may or may not be related to trauma. In cases where a full-thickness wound dehiscence occurs the incidence of graft failure may be very high, with one study reporting a rate approaching 50%.20 III.

Intraocular Lenses

The role of intraocular lenses in cornea1 graft failure is controversial. The available data are in many cases difftcult to correlate because of the retrospective nature of most studies, the variety of lens styles available, and small numbers of patients included, with high variability. Many conclusions regarding the effects of lenses on grafts are drawn from studies on cornea1 decompensation following cataract surgery in eyes that have not had cornea1 transplants. Although these conclusions may be valid, care must be taken in making such generalizations. In addition, studies have demonstrated that the mean time to cornea1 decompensation following anterior chamber and iris-supported intraocular lens implantation in cataract surgery is from 13 to 34 months.52,‘x”,27x,s*.5 Assuming that the mean time to failure in most grafted patients is similarly measured in years, it is obvious that prolonged follow-up is necessary for meaningful study. Nevertheless, an attempt will be made to draw some conclusions from the available information and to point out uncertainties where they exist. A. INFLUENCE FAILURE

OF IOL STYLE ON GRAFT

As was previously discussed, studies on the effect of specific intraocular lens styles on graft failure are hampered by the variety available within even a single class of lenses. Anterior chamber lenses are commonly inserted into eyes that have complications that may influence the prognosis, including loss of vitreous. The effect of these complications on graft survival may exceed any effects of the lens itself. Also, the quality of similar styles of lenses may vary considerably among manufacturers.234 Evidence appears to be overwhelming that semiflexible, closed loop anterior chamber intraocular lenses are associated with a higher incidence of corneal decompensation and other complications.7*“‘5’* ‘02~22y~234~p50~260~?75 These include, among others, the Surgidev style 10 Leiske lenses,7J”0 the IOLAB Azar 9 1Z lens,7~‘02*z50the Optical Radiation Corporation Model 11 Stableflex lens,7 and the Pharmacia Intermedics Ophthalmics Hessburg model 024.“’ Many of these lenses have been withdrawn from the market, but are still commonly encountered in eyes

GRAFT FAILURE AFTER PENETRATING

KERATOPLASTY

with pseudophakic bullous keratopathy. There are several mechanisms that may account for the increased incidence of cornea1 endothelial damage associated with this style of lens. When compressed under experimental conditions, these lenses may have pronounced anterior displacement of the optic.“” Resulting intermittent endothelial touch may result in endothelial decompensation.‘” In addition, the loops of these lenses are relatively resistant to compression and may cause damage by exerting excessive pressure on the angle. This may result in uveitis-glaucoma-hyphema (UGH) syndrome, erosion into uveal tissue, iris neovascularization, and angle fibrosis.“,1n’,‘2”,994 Miyake et al”’ demonstrated increased breakdown of the blood-aqueous barrier in eyes with these lenses compared with other types of anterior and posterior chamber intraocular lenses.“’ The Kelman tripod, Choyce, and other rigid style anterior chamber lenses appear to be well tolerated if sized and positioned properly.‘xx.‘sg We and others, however, have noted major problems with sizing. Damage to the angle and pain may result if the lenses are too large and pseudophakodonesis commonly occurs, with resulting complications, if the lenses are too small.‘Xy~““”Apple et al” have pointed out that some unauthorized and poorly manufactured lenses of Choyce design have been marketed. These lenses should always be removed if they are identified in eyes with pseudophakic bullous keratopathy. Increasing numbers of flexible, anterior chamber intraocular lenses are being utilized. Cases of pseudophakic bullous keratopathy are frequently seen in eyes with these lenses in place. Such lenses tend, however, LO be used in cases where there have been surgical complications such as vitreous loss, which may predispose to cornea1 decompensation. Thus far, no conclusive evidence indicates that these lenses themselves are associated with an increased incidence of cornea1 decompensation after cataract surgery or penetrating keratoplasty. A large, prospective, randomized study is indicated to determine the incidence of graft failure associated with these lenses compared with posterior chamber intraocular lenses in eyes with similar risk factors. Studies have suggested that iris-supported intraocular lenses have an increased incidence of endothelial cell loss,~~.l”l.‘:“.97’ pseudophakic bullous keratopathy,- “_(R.L’li’?,L’7X.2X0.:ol(igraft failure,““” glaucoma,” and chronic inflammation.‘““,“‘:‘,““‘Taylor et al”” reported a 4.3%~ incidence of pseudophakic bullous keratopathy in a consecutive series of 800 intracapsular cataract surgeries with implantation of irissupported intraocular lenses, compared with an 0.%X incidence of aphakic bullous keratopathy in a

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consecutive series of 3000 intracapsular cataract extractions without lens implantation. Sugar et alT7’ found a statistically significantly higher endothelial cell loss one year after penetrating keratoplasty when iris-supported intraocular lenses were retained (39.2%) than when they were removed (21.3%). Another study reported a two-year graft survival of 48.5% after penetrating keratoplasty when an iris-supported intraocular lens was retained, compared with 72.5% survival in a group without intraocular lenses.““” Eight of the transplants in eyes with iris-supported intraocular lenses failed secondary to intraocular lens-endothelial touch. Conclusions from these investigations are limited by retrospective study designs. In the study by Sugar et aLT7’ for example, intraocular lens removal was not randomized and the differences between the two groups could he due to bias in the selection of eyes for intraocular lens removal. In general, however, the data appear to suggest a higher rate of complications that may contribute to graft failure in eyes with iris-supported intraocular lenses. Although further studies with longer follow-up are needed, available data appear to indicate that posterior chamber lenses are associated with a low incidence of endothelial decompensation. For example, Taylor et al “7xfound only a 0.3% incidence of pseudophakic bullous keratopathy after extracapsular cataract surgery in 300 cases with posterior chamber lenses. Two studies have noted that Fuchs’ dystrophy is common in eyes that have pseudophakic bullous keratopathy associated with posterior chamber intraocular lenses and the authors suggested that endothelial decompensation may be due to the dystrophy rather than the intraocular lenS~l:~“.l”l Lug0 et all”l reported pathologic evidence of primary endothelial dystrophy in 67%) of 27 patients with posterior chamber lenses compared with 12% of 51 patients with anterior chamber lenses. Studies of graft survival after penetrating keratoplasty have noted good results with retention of posterior chamber intraocular lenses.5L’~‘J6.“‘7.2RX Sugar et al”’ found a mean 28.1% cornea1 endothelial cell loss at one year after penetrating keratoplasty for nine patients with retained posterior chamber intraocular lenses, compared with mean cell losses of 37.2%1 and 39.2% for eyes with retained anterior chamber and iris-supported intraocular lenses, respectively. Although there were too few retained posterior chamber lenses to reach statistical significance, the trend is suggestive. Therefore, although the presently available data are limited and further studies are needed, results with posterior chamber intraocular lenses appear encouraging.

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WILSON AND KAUFMAN

B. DECISION TO REMOVE THE INTRAOCULAR LENS IN PSEUDOPHAKIC BULLOUS KERATOPATHY Since pseudophakic bullous keratopathy has become the most common indication for penetrating keratoplasty, 237 the ophthalmologist is frequently confronted with decisions regarding retention, removal, or exchange of intraocular lenses. Controversy exists regarding the management of intraocular lenses, to some extent because of a lack of reliable data. We will discuss our current approach based on information detailed in the previous section, although in some cases the approach of other cornea1 specialists might be different. Semiflexible, closed-loop anterior chamber and iris-supported intraocular lenses are removed by us at the time of penetrating keratoplasty in all cases. We consider the following to be absolute indications for the removal of flexible anterior chamber and Choyce style anterior chamber intraocular lenses: intraocular lens-endothelial touch; one or more of the components of the uveitis-glaucoma-hyphema syndrome; progressive anterior synechiae, an unstable or displaced intraocular lens; or the presence of vitreous in the anterior chamber. Although the ideal course of action has not been conclusively established, in most cases we remove flexible anterior chamber and Choyce style intraocular lenses that are present in eyes with cornea1 decompensation even if none of these indications is noted. Two studies have suggested that patients with retained Choyce anterior chamber, iris-supported, and other styles of intraocular lenses have better visual outcomesg’243 and a lower incidence of vitreous loss, glaucoma, and cystoid macular edema.24” These studies, however, were retrospective and may have been biased by the selection of cases. Serious consideration should be given to removal of posterior chamber lenses in eyes with persistent inflammation, uncontrolled glaucoma, and intraocular lens instability or displacement. Most posterior chamber lenses are retained, however, since there is no evidence that they increase the risk of graft failure in the absence of these factors.*a,258 Whether to reinsert an intraocular lens must be decided on a case by case basis with due consideration given to the visual potential and the medical status of the eye. The status of the contralateral eye should also be considered. In cases where we believe intraocular lens exchange is indicated, we currently utilize a C-loop posterior chamber intraocular lens with transscleral fixation. There is no evidence, however, that this method is superior to the insertion of a flexible anterior chamber intraocular lens. Recently,

several

methods

have been

described

Fig. 1. A persistent epithelial defect that was caused by a poorly fit rigid contact lens. The defect closed after treatment for two weeks with a bandage contact lens.

for inserting posterior chamber lenses in the absence of capsular and zonular support. These methods have been developed based on the apparent superiority of posterior chamber lenses when they are inserted without sutures using capsular support. Each of these methods involves suturing the lens to the iris’g’,“55 or using transscleral fixation.5s,‘1’,‘s5 We no longer use iris fixation methods because we find the technique awkward and we are concerned about the longterm effects of suturing the lens to a mobile iris. We must reiterate that there is no evidence that either of these techniques is superior to the insertion of a flexible anterior chamber intraocular lens. A large prospective study should be performed to answer this important question. Longterm experience will demonstrate whether there is an increased incidence of complications such as hemorrhage, retinal detachment, and lens displacement with retro-iris fixation. Pathogenic organisms and epithelial or fibrous tissue could gain entrance to the eye along suture tracks when transscleral fixation is utilized.

IV. Persistent Epithelial Defects and Ocular Surface Disorders Persistent epithelial defects following penetrating keratoplasty are a common cause of graft failure in patients with dry eye syndromes, infectious disorders such as herpes keratitis, ocular pemphigoid, Stevens-Johnson syndrome, alkali burns, and other ocular surface disorders.‘,“7,44.2’8 They are also common in grafts with poor wound apposition, with graft overrides that interfere with epithelial migra-

GRAFT FAILURE AFTER PENETRATING

KERATOPLASTY

tion, and in patients with exposure due to lagophthalmos or lid abnormalities.‘“4” Periodically, contact lens wear precipitates a persistent epithelial defect (Fig. 1). In some cases, an epithelial defect will persist without apparent precipitating factors. Mechanisms of graft failure that have been associated with epithelial defects include stromal opacification, vascularization, ulceration, infection, and poor stromal wound healing.‘~“‘*““.“’ Ultimately, these complications may lead not only to the failure of the graft, but also, in some cases, to loss of the eye. Treatment of persistent epithelial defects after penetrating keratoplasty begins with anticipation of surface healing problems prior to grafting. Lid and lash abnormalities such as trichiasis, entropion, ectropion, and lagophthalmos must be addressed prior to transplantation. Donor tissue should be as fresh as possible in patients with disorders associated with poor epithelial healing, since the donor epithelium becomes less adherent with longer preservation times.‘“4” It has been demonstrated that postoperative healing may be prolonged when epithelial defects are present at the end of surgery.“’ Desiccation or excessive irrigation damages the epithelium. Viscoelastic agents are useful for protecting the epithelium during suturing of the graft. In patients with dry eye syndromes, permanent punctal occlusion can be considered prior to or at the time of surgery if the condition is severe and previous medical treatments have failed.‘““” In cases of severe alkali or other toxic damage, we have transplanted autologous conjunctiva from the contralateral eye.“’ If tissue from the contralateral eye is unavailable, keratoepithelioplasty can be performed at the time of transplantation.‘X’~“X’ We have not, however, been encouraged by our recent results with this technique and are not convinced of its value. We routinely place a collagen shield over the cornea and pressure patch the eye for 24 hours at the end of surgery, although there are as yet no data indicating that this is beneficial. Since Sugar et al”’ have demonstrated that there is no significant difference in the rate of healing in patched and unpatched eyes after penetrating keratoplasty, we do not routinely patch patients after the initial 24 hour period following surgery. Nonhealing epithelial defects must be aggressively treated. Hydrophilic bandage lenses are of benehowever, the patients must be fit in many cases’.“‘; carefully followed, since there is an increased risk of microbial ulcers associated with the use of these lenses in patients following penetrating kerato“‘I.” Kecently, we have had some success in plasty.utilizing collagen shields to promote healing of persistent epithelial defects. Microbial ulcers have not as yet been associated with the use of collagen

333

shields, possibly because the shield disintegrates prior to colonization with potential pathogens. Liberal use should be made of ointments, nonpreserved lubricants, and tear substitutes. Corticosteroids, necessary to prevent allograft rejection, may also be of benefit by suppressing inflammation. Inflammation has been shown to inhibit healing of cornea1 epithelial defects in vitro.““4 Toxicity of topical medications such as gentamicin and antivirals should also be considered in the absence of other identifiable factors. In some cases, lowering the dose or changing to less toxic medications may facilitate epithelial healing.““~‘“” The possibility of herpes simplex virus infection should always be considered when a defect does not respond to treatment, since patients with no previous history of clinical herpes may shed virus in the tears and develop herpetic keratitis.‘4’ Topical mediators that promote epithelial proliferation and adherence would theoretically be useful in the treatment of persistent epithelial defects. Fibronectin may promote healing of epithelial defects by facilitating cellular adhesion.‘gx.‘2”Although there have been studies suggesting that fibronectin may be of benefit in some cases,““.‘“” there has not been a randomized masked study demonstrating efficacy in humans. A controlled, prospective, randomized study failed to demonstrate a beneficial effect of topical epidermal growth factor on epithelial healing after penetrating keratoplasty in humans.“’ Research should continue, however, since it is possible that other mediators or other methods of delivery could be developed that would prove beneficial.

V. Immunologic

Rejection

Prior to discussing immunologic rejection it is necessary to clarify the terms used in this review. The use of the term rejection (allograft rejection, endothelial rejection, immunologic rejection, etc.) refers to the immunologic response to the donor tissue without regard to the effect of the response on the survival of the graft. To avoid ambiguity, actual failure of the graft due to immunologic processes is described by the phrase “graft failure due to rejection.” Immunologic graft rejection is the most common cause of late graft failure.“7.“” The first description of cornea1 allograft rejection was published by Paufique, Sourdille, and Offret in 1948.“” These authors proposed an allergic response to the transplanted tissue as the cause of late clouding of the cornea1 graft and suggested the term graft sickness (“maladie du greffon”). Maumenee and coworksubsequently demonstrated in the rabbit ers ‘fi9.‘7”.‘Hn that the donor cornea could stimulate an immune reaction. These experiments clearly established the

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1990

immunologic nature of the reaction by demonstrating that the simultaneous or subsequent transplantation of skin from the same donor accelerated rejection of the donor cornea. By transplanting individual layers of the cornea in rabbits, Khodadoust and Silverstein’3’.‘32 demonstrated that the epithelium, stroma, and endothelium could separately undergo immunologic rejection. An understanding of the origin of the pathognomonic epithelial and endothelial (Khodadoust) rejection lines, frequently associated with cornea1 allograft rejections, also resulted from these experiments. These investigations were instrumental in stimulating the rapid progress made during the past two decades in our understanding of the factors influencing cornea1 allograft rejection. The relative immune privilege of the cornea has commonly been attributed to a large extent to its avascularity. Experiments in the rabbit have suggested that an absence of vascularization in the transplanted cornea may interfere with both the recognition of the nonself antigens in the graft and their destruction by the immune system in the senthese authors suggested sitized host.‘33 Conversely, that when an allogeneic cornea is transplanted into a vascularized bed, there is an increased probability that the afferent arm of the immune system will recognize the foreign antigens of the donor cornea and mount an immune response, and that the effector cells of the efferent arm of the immune system will have access to and destroy the donor tissue. There are, however, factors other than avascularity that may contribute to the immune privilege of the cornea. Several studies have suggested that immunologically specific tolerance through the suppression of delayed-type hypersensitivity is elicited by the intracameral inoculation of allogenic antigen. ‘05~‘23~124~‘g7~268 This response occurs despite the stimulation of cytotoxic T lymphocytes and antibody production. It may be mediated by direct exposure of the antigen to the venous compartment via the canal of Schlemm and occur only in the presence of a functional spleen. Presumably, antigen processing by this route also avoids exposure of the antigen to lymphoid tissue, such as lymph nodes, that could generate a destructive response. Allogeneic antigen from a cornea1 graft is probably released into the anterior chamber and, if so, could theoretically produce tolerance by a similar mechanism. Further investigation of the potential role of these mechanisms in human allograft survival is needed. A. CLINICAL

SIGNS AND SYMPTOMS

It has been widely accepted that the diagnosis of allograft rejection should be made only in a technically successful graft that has remained clear for at

WILSON AND KAUFMAN

Fig. 2. An epithelial rejection line (arrow) in a cornea1 graft. There was no involvement of the cornea1 endothelium.

least lo-14 days following penetrating keratoplasty. It is theoretically possible for an immunologic rejection to occur prior to this arbitrarily defined period if the recipient has been previously sensitized to the donor antigens stimulating the allograft however, these guidelines response. “” In general, should be followed so that these rare early immunologic reactions can be differentiated from other causes of early graft failure such as primary donor failure. Conversely, although the incidence of allograft rejection is greatest in the first year after transplantation,8.*“~~7~‘80classic endothelial rejection with a rejection line has been observed in grafts more than 20 years after penetrating keratoplasty.4 Depending on the type and severity of the reaction and the awareness of the patient, the allograft rejection may or may not be symptomatic. Symptoms may include a decrease in visual acuity, irritation, redness, photophobia, and tearing. Four types of cornea1 graft rejection have been recognized: epithelial rejection, subepithelial infiltrates, stromal rejection, and endothelial rejection.4,‘7’*25g Epithelial rejection is characterized by the appearance of an elevated epithelial rejection line (Fig. 2) that stains with fluorescein or rose bengal. If untreated, the line may progress across the graft in a period of several days to two weeks. The line represents a zone of destruction of donor epithelial cells. The resulting defect is filled by recipient epithelium. In a retrospective study, the average time of onset of epithelial rejection was three months after surgery and the frequency was 10% in patients followed for a minimum of one year.4 As the authors have noted, however, this is likely to be an underestimate since many of the patients are asymptomatic at the time of diagnosis.

GRAFT FAILURE AFTER PENETRATING

KERATOPLASTY

Subepithelial infiltrates as a sign of allograft rejection were first described by Krachmer and Alldredge.‘“’ The white infiltrates, which range from 0.2 to 0.5 mm in diameter, are randomly distributed immediately below Bowman’s layer and are seen only in the donor tissue. An associated mild anterior chamber reaction may be noted. The lesions rapidly disappear upon treatment with corticosteroids, but residual scarring may remain. The average time of onset in a retrospective study was 10 months after penetrating keratoplasty and the frequency was 15%. When the subepithelial infiltrates occur as the only manifestation of rejection, however, the patient is commonly asymptomatic.‘“’ Stromal rejections have been described by Stark2”” to consist of a sudden onset of peripheral full-thickness haze in a previously clear graft, associated with circumcorneal injection, and often appearing as an immunologic arc which progresses centrally. Since stromal rejection commonly occurs simultaneously with endothelial rejection it may be difficult to detect. Stromal rejection has been demonstrated in rabbits,“” but there is little information regarding its occurrence in humans. Endothelial cornea1 graft rejection presents in one of two ways. An endothelial rejection line is present in many patients. This line, referred to as the Khodadoust line (Fig. 3), usually originates at a vascularized area of the peripheral donor cornea.““? Rejection lines have, however, been noted to begin at a point ofjunction of an anterior synechiae with the cornea1 endothelium.““’ The rejection line, if untreated. usually proceeds across the donor endothelium from the point of origin over a period of several days, like an advancing forest fire, leaving damaged endothelium and pigmented keratic precipitates in its wake. Histopathologic investigations have confirmed that the rejection line and keratic precipitates are composed of lymphoid cells.‘“‘,“’ A mild to moderate anterior chamber cellular and flare reaction is associated with the process. Damage to the endothelium results in compromised regulation of cornea1 hydration and, therefore, stromal edema in the area of the graft through which the rejection line has passed. In the more diffuse type of‘ endothelial rejection (Fig. 4), diffuse keratic precipitates are scattered across the donor endothelium, but frequently may not be visible. Diffuse endothelial damage eventually results in a generalized disruption of the regulation of cornea1 hydration and, subsequently, diffuse stromal edema.‘,““,“” Little is known regarding possible differences in pathophysiology between diffuse endothelial rejection and endothelial rejection accompanied by a rejection line. It is interesting to speculate, however, that the vascularization commonly associated with the site of origin of an endothelial rejection line may act

355

Fig. 3. An endothelial rejection line in a cornea1 transplant. Top: The slit beam demonstrates the thickening of the inferior cornea. The superior region of the graft rcmains thin. Bottom: A retroillumination view of the same cornea better demonstrates the interface between the inferior rejected endothelium and the normal superior endothelium. The irregular rejection line can be seen coursing across the central cornea.

as a route

of exposure of the donor tissue to the immune system and that the dif‘fuse type of rejection may result from an immunologic process that is initiated via the anterior chamber. Thus, differing routes of antigenic detection and response could account for the two different clinical presentations. It is frequently impossible to differentiate graft edema caused by endothelial insufficiency from that due to rejection. Since re_jection is treatable, any questionable edema in a graft should be treated with corticosteroids as rejection. Similarly, patients should be warned of the need for prompt treatment if- symptoms develop that might suggest allograft rejection.

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WILSON

Many patients with cornea1 graft rejection cannot be classified neatly into one of these four categories of allograft rejection, but present with various combinations of epithelial, subepithelial, stromal, and endothelial rejection. In addition, epithelial rejection and subepithelial infiltrates may precede a more severe endothelial rejection.4 Isolated keratic precipitates, without other signs of anterior segment reaction, have also been found to precede endothelial rejection in some patients.8 Signs such as these should be specifically excluded at each postoperative examination and if they are noted treatment should begin immediately. With aggressive and early treatment many grafts recover endothelial function sufficient to return to a normal state of hydration despite being severely swollen at diagnosis. Although the human cornea1 endothelium may be to a limited extent capable of repair through mitosis,‘45 specular microscopy studies have demonstrated decreases in endothelial cell counts following rejection episodes exceeding those found in controls.‘6~27~32~‘5g If the endothelial destruction is severe, the graft becomes irreversibly edematous and may become vascularized. The incidence of endothelial rejection reported in the literature varies widely depending on the study. Rates ranging from 0%“’ to greater than 60%1‘&‘29have been reported, depending on the patient population, associated risk factors, and length of follow-up. Specific rates will be discussed in the following sections. Rarely, an allograft rejection will precipitate an

AND KAUFMAN

Fig. 4. A diffuse endothelial rejection. The entire graft is thickened and there is no evidence of a rejection line.

elevation in intraocular pressure.225 Since further damage to an already compromised endothelium may result, the patient should be treated with appropriate antiglaucoma medications in addition to corticosteroids. These medications can often be discontinued as the inflammatory process associated with the allograft rejection responds to treatment. In a few patients, however, the glaucoma may become chronic and require continued treatment.225

TABLE

1

HLA Matching Studies

Design of HLA Match

Actuarial Analysis

Patient Characteristics

HLA A,B Matched Patients

HLA DR Matched Patients

Batchelor, 197614

Retrospective

Yes

Vascularized

100

no

Stark, 1983’“4

Retrospective

no

Vascularized

86

no

Foulks, 198387

Prospective HLA match retrospective control

Yes

48

no

Boisjoly, 1986’”

Prospective

Yes

Vascularized or previous immune graft failure Mixed, subgroup with vascularization or previous rejection

185

165

Sanfilippo, 1986245

Prospective

Yes

97

no

Prospective HLA A,B retrospective HLA DR

Yes

497

123

Study

Vblker-Dieben, 19872gH

Vascularized or previous immune failure Mixed, subgroup with vascularization

GRAFT FAILURE AFTER PENETRATING B. HLA A,B, AND DR MATCHING

337

KERATOPLASTY

STUDIES

The specific role of the major histocompatability complex and the human leukocyte antigens (HLA) in cornea1 allograft reaction remains poorly defined. A previous article in Su.ruey of O~h~h~l~ology reviewed the major histocompatibility complex and the immunopathophysiology of cornea1 allograft rejection.“” This information, except for pertinent new findings related to the localization of HLA antigens in human corneas, will not be covered in this article. Our emphasis will be on the clinical significance of HLA matching in cornea1 transplantation. HLA antigens have been detected in all layers of the human cornea. While most studies have found either no evidence for Class I (A,B,C) HLA antigens on normal human cornea1 endothelium’“,“” or the presence of Class I antigens only on the endotheliurn of individuals less than two years of age,““’ a recent study used a sensitive immunoperoxidase technique to demonstrate these antigens on the endothelium of individuals of all ages.“” Although these studies did not detect Class II (HLA-DR) antigens on normal human er~dothelium,x!‘~‘7’~~x~‘~~1’J Class II antigens have been detected on the endothelium of rejected human corneas”” or on cultured human cornea1 endothelium exposed to human gamma interferon.‘“’ Class 1 antigens have also been detected on human cornea1 stroma ce,ls.““,i 7L’.“XB.:iIO The largest quantities of both HLA Class I and Class II antigens are found in the corneal epithelium.X”,“‘.~~l~.:~l’l Most Class II antigens in

TABLE

the epithelium localize to dendritic cells that are found at higher density eral cornea.x9.1'j?."xG.:il~

L.angerhans in the periph-

Many studies on the effect of HLA antigen matching on cornea1 allograft rejection have been published. Most of these studies necessarily include patients considered to be in high risk groups because of extensive cornea1 vascularization or a history of previous cornea1 graft failures secondary to allograft rejection. Smaller numbers of high-risk patients are required to study the effects of HLA matching since the rate of allograft rejection is higher. Some studies have found no evidence for a decrease in the rate of allogrdft re_jection or graft failure when HLA matching is perforrned.“,“.“‘~,~“~ Other studies have reported HLA tnatching to be of benefit, including some investigations that have found a correlation between the degree of HLA match and the incidence of allograft rejection or graft fdilure. I~.'1".7'?.xI~.xi.lol.ll)!),'?0~i.i' The conclusions of the majority of these investigations are limited by small numbers of patients, retrospective designs with poor degrees of HLA match, lack of adequate controls, limited or unspecified follow-up, and invalid statistical methods. Since studies of HLA matching will unavoidably have variable follow-up from patient to patient, it is important that appropriate statistical methods be utilized in analyzing graft rejection or failure due to rejection. As Siegel”” has observed, there are two convenient methods for presenting such data in a meaningful manner. One method is to group data

1

HL.A Matching Studies (Continued) D Lymphocyte/ R Serum

Crossmatch no

yes yes

not

a criterion for matching

Unmatched Controls no

no

72 --retrospective

199 -retrospective

YCS

no

no

721

Conclusions No correlation

between

HLA A,B match and incidence

of rejection.

Lower rate of graft failure in cases of rejection with higher degree of HLA A,B match. No consistent correlation between degree of HLA A,B match and incidence of graft failure. Graft survival: 47% controls vs 75%, HLA A,B matched, p = 0.041, Trend in matched vascularized cases for better survival with more HLA A,B matches, not statistically significant. No difference between matched vs control in rejection-free survival for high risk (p = 0.32) or all patients (p = 0.38). Well matched study pts (22 A,B match, DR2 1) vs poorly matched study pts (2 1 A,B match, 0 DR match) significantly fewer rejections tar all pts (p < 0.02) and high risk pts (p < 0.01). 2-3 HLA A,B match greater rate rejection-free survival than O-l HLA A,B match, p < 0.012. HLAA,B match group significantly better survival for all patients (p = 0.0008) and vascularized subgroup (p = 0.0001). No significant difference in survival 2 HLA A.B match vs 4 HLA A,B match. No significant effect of HLA DR match.

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34 (5) March-April

WILSON AND KAUFMAN

1990

according to specific durations of follow-up and to specify the number at risk and the number with a rejection episode or graft failure due to rejection during each specific period of follow-up. Another method is actuarial analysis. 59,I2Z,Ifi?.PI5,PI6In this method a life-table is used to report rates for events of interest within a designated period of follow-up. Estimates can be also obtained of the cumulative probability that the event will occur during a specified time period. Unfortunately, many of the reported studies on the effect of HLA matching on allograft rejection were not analyzed with methods that take into account variable follow-up. Comparisons with retrospective controls are questionable because even if all variables appear comparable between the control and experimental groups, the act itself of beginning a study tends to improve the diligence of the investigator in educating and following the patient. This, in turn, is likely to have an effect on patient outcome. Table 1 compares study designs and conclusions for several representative HLA matching studies. The majority of these and other available studies have suggested that the degree of HLA A and B antigen match correlates with the incidence of allograft rejection and failure due to allograft rejection. Information is limited regarding the role of the HLA DR antigen in allograft rejection after penetrating keratoplasty. In the study by Boisjoly et al,‘” priority was given to the HLA DR match before HLA A and B in matching donors and recipients. Although the overall HLA A,B, and DR match of the patient correlated with rejection-free graft survival, no specific conclusions can be made regarding the DR locus alone. Three patients who were perfectly matched at all HLA A,B, and DR loci did not have allograft rejection. One patient with perfect matching of all HLA A and B loci but mismatches at the DR loci, and four patients with perfect matches at both HLA DR loci but mismatches at HLA A,B loci had rejection episodes. These results suggest that HLA A,B and HLA DR antigens are factors in allograft rejection. The patient numbers are small, however, and any conclusions should await larger studies. It is possible that other unknown antigens influence rejection and are confounding these results. Several studies on the effect of HLA matching on cornea1 allograft rejection have included a crossmatch test between the serum of the recipient and lymphocytes of potential donors.X7*945*8~ This test is designed to detect the presence of preformed antibodies in the recipient directed against antigens in the donor. The investigators in these trials suggested that a negative cross-match between recipient and donor improved graft survival. Since retrospective and historical controls were used and

grafts with positive cross-match tests were not included, however, definitive conclusions cannot be made. Further studies with prospective controls are indicated. Vannas and coworkers493~2g9.2’6 have suggested that patients with the B 27, and possibly the B 12, HLA alleles are at increased risk for cornea1 allograft rejection even if the cornea is not vascularized. The etiology of this increased susceptibility is unknown. It is possible that the increased incidence of uveitis, at least for recipients with HLA B 27, increases immune detection of foreign HLA antigens and leads to allograft rejection. There is as yet no conclusive evidence that HLA matching is of benefit to these patients. Our knowledge of the role of the HLA system in cornea1 allograft rejection has been limited by the high variability of the antigens in the human population and the resulting difficulty in obtaining high level matches. Large groups of patients with perfect matches at all HLA A,B, and DR loci need to be compared with groups that are mismatched at only one loci so that the relative roles of the HLA A,B, DR, and possibly other as yet unidentified antigens, can be determined. This information can only be obtained in a large, well-designed study. The Collaborative Cornea1 Transplantation Studies are prospective, randomized, masked, multicenter trials of HLA matching and cross-match testing that are in progress and may answer many of these questions. C. POTENTIAL RISK FACTORS FOR ALLOGRAFT REJECTION Several potential clinical risk factors for cornea1 allograft rejection have been described. Many of these factors may be clinically modified. Each of these factors will be discussed individually in the following sections. 1. Vascularization The factor most commonly associated with an increased risk of allograft rejection is cornea1 vascularization. Many studies, including several in which actuarial analysis was performedI4.‘2.“‘,I8O,~Y~,Zgg,~O3 have demonstrated either an increased incidence of allograft rejection or decreased graft survival in eyes with cornea1 vascularization. Although the degree of vascularization is difftcult to quantitate in a meaningful way, these studies have also reported a correlation between the incidence of allograft rejection or graft survival and the extent of vascularization. Immune-related graft failure rates of approximately 25-50% in severely vascularized corneas compared with rates from O-10% in avascular corneas were noted within the first year after penetrating keratoplasty. 14.29X.P99.YO:’

GRAFT FAILURE AFTER PENETRATING

JCERATOPLASTY

The type of vascularization may also be a factor in determining the risk of allograft rejection. The clinical impression of many investigators is that deep stromal vascularization is more likely to be associated with rejection than superficial vascularization (Fig. 5).” It is not clear that the presence of vascularization itself, rather than associated factors, leads to an increased risk of allograft rejection. In animal models, there is evidence that lymphatic vessels are present in vascularized cornea1 beds.5”.57*253If such lymphatics can be demonstrated in the vascularized human corneas, they could provide a route for allogeneic antigens to lymphatic tissue, such as the regional lymph nodes, that could stimulate an allograft rejection. Vascularization of the transplanted cornea is commonly associated with previous graft failures, persistent epithelial defects, infections, chemical burns, and other disorders associated with inflammation. In some cases, vascularization may be stimulated by cornea1 sutures.“” There appears to be an association with the composition of the suture: silk is more of a stimulus than nylon and larger diameter sutures are more angiogenic than smaller diameter sutures. When sutures appear to be stimulating the ingrowth of vessels the ophthalmologist must decide whether healing of the wound has progressed to the point that they can be removed. Normally, healing is sufficient when vessels have entered the donor-recipient junction. Loose sutures should always be removed. In patients who develop vascularization after penetrating keratoplasty with a running suture the decision can be more difficult. Although vascularization may have occurred in one quadrant, healing may not be sufficient in another quadrant to remove the sutures without risking a dehiscence. If the vessels progress, it may be necessary to remove the running suture and place interrupted sutures in the non-vascularized quadrant if a dehiscence occurs. Interrupted sutures should be used in all patients who have significant cornea1 vascularization prior to penetrating keratoplasty so that sutures may be removed selectively if vascularization progresses postoperatively.‘4x” In addition, we believe that buried knots may provide less stimulus for vascularization than knots that remain on the surface. The use of contact lenses after penetrating keratoplasty is also associated with vascularization and most commonly occurs in aphakic patients using extended-wear lenses.4J,‘5’.‘63,307 All types of contact lenses, however, may induce vascularization. The mechanism of contact lens-induced vascularization is uncertain. The most likely possibilities include mechanical trauma and hypoxia. When contact lenses appear to he stimulating the ingrowth of ves-

339

Fig. 5. A cornea1 graft that remained rejection free for a period of several years despite prominent superficial vascularization.

sels, lenses with a higher oxygen transmissibility that are used on a daily wear basis may stabilize the vascularization.“4” In some cases, however, contact lenses may have to be abandoned. The argon laser has been proposed as a method to close intracorneal vessels prior to penetrating keratoplasty or to treat neovascularization that develops postoperatively.4H.‘“4 While it is possible to close intracorneal vessels with the argon laser, in our experience vessels rapidly reappear at the same location if the stimulus to vascularization is still present. It is unknown whether this occurs by recanalization of the previously closed vessels or by the growth of new vessels. 2. Previous Graft Failure Patients with previous graft failure have long been considered to have a greater risk of allograft rejection than patients undergoing penetrating keratoplasty for the first time. For example, one study reported a statistically significant difference in graft survival one year after transplantation for the first graft (83.4%) compared with second and subsequent grafts (74.6%).‘“” Although it may be true that repeat grafts have a higher risk of rejection, there are relatively few controlled studies to support this contention.“.‘)“.5.?~X,:{‘)~ Even less is known regarding the factors that lead to a higher rate of failure in repeat grafts. While it is possible that the patient may have become sensitized to nonself HLA antigens present on previous grafts, the diversity of the major histocompatibility complex is such that it is common for a repeat graft to have no HLA A,B, or DR antigens in common with the previous graft.“.“j4 Certainly, the higher

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the number of repeat grafts the patient has had, the more likely that his immune system has previously encountered a particular antigen. However, Khodadoust and Silverstein’ have shown in rabbits that even when the host is highly sensitized to the donor antigens, the donor cornea may be protected from rejection. The fact that previous grafts have been performed in the same eye, therefore, may not be as important as other factors commonly associated with previous graft failures such as vascularization and infection. Studies by Gebhardtg’ in the rat have demonstrated that both the dose and the route of allogeneic antigen exposure may affect the recipient’s response to cornea1 tissue. In this model, a single orthotopic allogeneic graft was rejected in a localized immune response without stimulating systemic immune effector mechanisms such as antibody production and lymphocyte activation. If a similar localized mechanism of rejection is active in the human, then a graft rejection in and of itself may have no effect on the rate of rejection in subsequent grafts. 3. Bilateral

Penetrating

Keratoplasty

There is controversy regarding the possibility of an increased risk of allograft rejection following penetrating keratoplasty in the second eye. All of the available studies are retrospective and, therefore, have the limitations of such studies. In addition, in only two studies were the data analyzed using actuarial or other methods appropriate for a series of patients with variable follow-up.‘xo~‘g2 The conclusion that there is an increased risk of allograft rejection after bilateral penetrating keratoplasty is based primarily on three studies. Ruedemannz4’ published a small series that included 15 patients with bilateral transplants for keratoconus. He suggested that there was an increased risk of cornea1 allograft rejection after keratoplasty in the second eye. Donshik et a16’ described 24 bilateral and 76 unilateral transplants in patients with keratoconus with avascular recipient beds. In the patients with unilateral transplants, 10 eyes ( 13%) had homograft rejections. In the 24 patients with bilateral transplants, 13 out of 48 eyes (27%) had ailograft rejection. Mean follow-up for all patients in the study was 18 months. The difference was found to be statistically significant (p < 0.01); however, it is not possible to ascertain whether the follow-up was similar for the two groups. Of the 76 patients with unilateral transplants, 13% and 0% developed allograft rejection in the first and second postoperative year, respectively. Interestingly, none of the first eyes in the 24 patients that would eventually have bilateral transplants had allograft rejections in the first year after the first transplant. Four of these first eyes eventually developed allograft rejection in the

WILSON AND KAUFMAN year following penetrating keratoplasty in the second eye. Second eyes were noted to have a 38% incidence of allograft rejection in the first year after transplantation. The authors did not specify whether the difference in allograft rejection noted for the first and second years after transplantation for unilateral cases and for the first and second eye in bilateral cases were statistically significant. Khodadoust and Karnema’“” found no evidence of an increased risk of allograft rejection after penetrating keratoplasty in the second eye in patients with avascular grafts compared with historical controls. In 18 patients with vascularized grafts, a twofold increase in the incidence of allograft rejection was seen in both the first and second eye compared with the incidence of graft rejections in unilaterally grafted historical controls with mild to moderate vascularization. These conclusions are of questionable significance since no statistical analysis was performed, controls were historical, and the degree of vascularization may have been different in the study and control groups. Other studies have suggested that penetrating keratoplasty in the second eye does not increase the risk of allograft rejection. One study described a series with 45 unilateral and 30 bilateral keratoconus grafts in which the second graft did not increase the risk of allograft rejection.‘64 Again, however, the data were not analyzed using methods that would allow comparisons to be made between groups that had variable follow-up. Buxton et a14’ reported that the incidence of allograft rejection for avascular keratoconus patients during the first year after penetrating keratoplasty was not statistically significantly different in cases of unilateral grafts (16%), the first eye of bilateral grafts (16%), or the second eye of bilateral grafts (25%). Meyer”’ reported the largest study of the incidence of allograft rejection in unilateral and bilateral grafts. Results were analyzed using actuarial methods. The study included 726 patients with mixed diagnoses; 546 patients had unilateral grafts and 180 patients had bilateral grafts. There was no significant difference in rejection-free survival between unilateral cases, first eyes in bilateral cases, and second eyes in bilateral cases. Interestingly, unilateral grafts had significantly worse survival after endothelial rejection than bilateral grafts (p = 0.0173). This may have been due to the higher proportion of patients with preoperative stromal vascularization in the unilateral group. When the subgroup of patients with either Fuchs’ dystrophy or keratoconus was evaluated there was no significant difference in rejectionfree survival or graft survival after rejection in unilateral or bilateral grafts. Recently, Musch and Meyer’“” reported another study using actuarial analysis in which penetrating keratoplasty in the

GRAFT FAILURE AFTER PENETRATING

second eye of patients who had previously undergone surgery in the other eye did not increase the risk of endothelial rejection in either eye. In that study, there was no difference in endothelial rejection-free survival between either the first or second eyes of patients with bilateral transplants and the eyes of a concurrent control group that had unilateral penetrating keratoplasty. When the results and methods used in data analysis for all of the available studies are examined. there appears to be no convincing evidence that a graft in the second eye of bilateral cases increases the risk of allograft rejection in either eye. Since the risk of allograft rejection is greatest in the first yea] after a transplant is perf’ormed,H,“~,X’,‘XOit is probably .judicious to wait at least 12 months after transplantation in the first eye before grafting the second eye. Many reports of bilateral simultaneous allograft Al_ rejection have been published. ti~79,1:~0,IxII,Ixt~.l9” .’ though in some cases the two grafts may have HLA antigens in common,“’ It is not clear that this is true ofall bilateral simultaneous rejections. Conceivably, a generalized systemic stimulation of the immune system could result in a simultaneous rejection of grafts that have no HLA antigens in common. The requirement for sensitization to specific antigens, however, is emphasized by two cases reported by Kozenman et al.““’ In each case, allograft rejection occurred in a grafted eye that also had a full-thickness patch graft. In one case, the original graft had an allograft rejection while the patch graft remained clear without rejection. In the second case, the patch graft had an allograft rejection, while the original graft was unaffected. 4. Donor

331

KERATOPLASTY

Epithelium

Class I (A,B,C) HLA antigens are expressed in large amounts on cornea1 epithelium.XY~‘77~‘X6~‘3”’ Class I HLA antigen donor-recipient matching has been demonstrated to have an effect on the inci’101’206. dence of cornea1 allograft rejection. 14v2:~.7”.X6,xi “~‘,.L’li:~.“!~~.?RX.“R!~.:~o, .:+,)L’ Class II (DR) HLA antigens have been identified on Langerhans cells found in the X1l.I 72363I0 cornea1 epithelium. The Langerhans cells are thought to play a role in the processing of antigen and the sensitization of the host to non-self antigens.Ox The presence of HLA Class 1 and II antigens and Langerhans cells in the epithelium has suggested that the removal of donor epithelium at the time of penetrating keratoplasty might decrease the incidence of allograft rejection. Tuberville et al”“’ published a combined retrospective-prospective study on the effect of donor epithelium removal at penetrating keratoplasty. In a retrospective study of 152 patients, they reported a significant (p = 0.008) decrease in the incidence ofallograft rejection in patients with donor epitheli-

urn removal (7.2%) compared to patients without donor epithelium removal (24.7%). Patients in the two groups were not operated on concurrently. Therefore, differences in surgeon experience and other uncontrolled factors could have influenced the results. In the prospective portion of the study there was an incidence of including 55 patients, rejection of 30% when the donor epithelium was retained and X.O’;/ctwhen it was removed (p = 0.04). A shorter follow-up period for the group with epithelium removal may have accounted for some of‘ the difference noted in this study. Sundmacher’s retrospective studyY7” of 16X patients found no difference in the rate of allograft rejection when the donor epithelium was removed or retained. The results of this stlldy must be seriously questioned, however, since the authors used a different postoperative corticosteroid regimen ti)r the two groups. Recently, Stulting et al”‘” have published a prospective randomized study of’ 232 ryes analyzed using actuarial analysis and found no difference in reversible allograft rejection, irreversible &graft rejection, or graft f’dilure between patients with or without removal of the donor epithelium at the time of’ penetrating keratoplasty. I’herefore, conclusive evidence that removal of’ donor epithelium decreases the rate ofallograft rejection is lacking. Since epithelial defects are associated with graft failure, the donor epithelium should be protected at the time of transplant. This is especially important in patients with keratocon_junctivitis sicca, chemical burns, and other ocular surtace disorders where persistent epithelial defects are a common complication. 5. Graft Size and Eccentric

Grafts

The avascularity of the central cornea is thought to be an important factor in the success of cornea1 transplants. It follows that larger graft sizes and eccentric grafts might be expected to increase the risk of allograft rejection by increasing the proximity of the donor tissue to the limbal vasculature. Several studies have addressed the relationship between graft size and immunologic rejection%“‘, L’1,.L’!I I or graft survival.“‘“.‘““’ Analysis of graft size data in each of these studies was retrospective. ~The validity of the conclusions is uncertain because the majority of patients in each study tended to have graft sizes that fell within a small range and the graft sizes were not randomizecl. Significantly larger grafts tend to be used in cases with infections and other disorders commonly considered to have a worse prognosis. In the stuhies that have examined the relationship of graft size to overall graft survival, failures due to rejection, glaucoma, and other cause4 were not separated. (:onclusions have var-

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ied, with studies reporting no association between graft size and the incidence of allograft rejection g7,zg’lower allograft rejection rates with larger graft sizes,245 lower allograft rejection rates with smaller graft sizes,‘* and lower graft survival with larger graft sizes.2g8,303 Similarly, little has been published regarding eccentric cornea1 grafts and allograft rejection in humans. 74,“g Conclusions are limited because eccentric grafts also tend to be placed in patients considered to have a worse prognosis due to the primary disorder. Evidence is available from animal models of an increase in allograft rejection with increased graft diameter and eccentric grafts. Griinemeyer,‘oo using inbred strains of rats, reported an increased frequency of graft rejections when the graft apand Silverproached the limbus. Khodadoust stein’33 noted that an effective means for stimulating allograft rejection of lamellar grafts in rabbits was to place the graft adjacent to the limbus. Despite the lack of reliable data and the varied conclusions, we prefer to use well centered recipient trephine sizes less than or equal to 8.0 mm in diameter. At times, however, larger trephines and eccentric grafts are indicated by the cornea1 pathology and must be used. 6. Comeal Preservation Method Two studies have reported a loss of Class II (HLA-DR) positive epithelial Langerhans cells after cornea1 preservation in organ culture for l-3 weeks.“0~2’2 A prelininary study in rats found that the levels of Class I antigens were diminished in the epithelium and stroma after storage for 5-7 days at 4°C in intermediate term storage media such as CSM and K-Sol, compared with levels in fresh tissue, tissue preserved for three days at 4” C in MK short-term storage medium, or tissue preserved for 17 days at 37” C in organ culture medium.“’ Since Class II antigen-bearing Langerhans cells are thought to play a role in the processing of antigen and the sensitization of the host to nonself antigens,gE and Class I antigens elicit strong cellular and humoral responses during allograft rejection,34 these studies suggest that the method of cornea1 preservation might influence allograft rejection after penetrating keratoplasty. A species-specific prolongation of xenograft survival after organ culture has been reported in rabbits,‘j5 but there are no data to suggest that this applies to allografts. While these studies are suggestive, there is no evidence that the incidence of cornea1 allograft rejection in humans is influenced by the use of fresh tissue, tissue preserved using any of the currently available cornea1 storage media, or tissue preserved in organ culture.

WILSON AND KAUFMAN 7. Age: Donor and Recipient A few reports of an association between donor or recipient age and the incidence of allograft rejection or graft failure due to allograft rejection have appeared in the literature. Alldredge and Krachmer,4 in a retrospective study, reported a significantly higher incidence of epithelial rejection (p < 0.005), subepithelial infiltrates (p < 0.05), and endothelial rejections (p < 0.005) in patients younger than 50, compared to patients 50 years of age and older. There was no difference in vascularization between the two groups to account for the difference. Boisjoly et al” found a significantly higher rejection-free transplant survival for recipients who were 60 years or older compared with recipients less than 60 years old (p = 0.006). Arentsen and Laibson’ also reported a trend toward a higher incidence of allograft rejection in patients less than 60 years of age. The difference, however, did not reach statistical signiflcance. The incidence of irreversible allograft rejection in the latter study was similar in all age groups. If the incidence of allograft rejection does decrease with increased age, one could hypothesize that the decrease is the result of a diminution in the ability of the aged immune system either to recognize the foreign tissue or to destroy the tissue once it is recognized as non-self. With respect to cornea1 grafts, there is at present no evidence that this is true. There is one report of an association between donor age and the incidence of allograft reactions. Sanfilippo et a1245reported an increased risk of allograft rejection (p = 0.004) and irreversible allograft rejection (p = 0.004) when the donor age was 50 years of age or older. There is currently no explanation for this finding and there have been no other studies with similar findings. 8. Sex and Racial Donor-Recipient Disparity There is one report of significantly (p < 0.05) better survival of female donor corneas at one year in female recipients (85%), compared with male recipients (76%). 3’S No difference in survival was seen with male donor corneas in either male or female recipients. Whether the difference noted with female donor corneas was due to immunologic graft rejection or other causes of graft failure was not specified. A more recent and larger study by the same investigators, however, found no difference in graft survival based on donor and recipient sex.2g8 Thus, donor-recipient sex matches are considered unlikely to be a factor in the rate of allograft rejection. Sanfilippo et a1245reported a trend toward a lower rejection rate in white patients compared with nonwhite patients, but the difference was not statis-

GRAFT

FAILURE

AFTER

PENETRATING

KERATOPLASTY

ticatly significant (p = 0.09). Recently, Musch et at’!“’ reported a study of 998 patients in which actuarial methods were used to analyze the data for all patients in the study, as well as a subgroup of patients with stromal vascularity or previous graft failure. There was no difference in the cumulative risk of endothelial rejection in cases with donor-recipient racial match or mismatch. There was also no difference between the two groups in the incidence of graft failure following altograft rejection. Therefore, there is no evidence that race is a factor in altograft rejection. 9. Blood Transfusion,

Pregnancy,

and

Immunization

In the past, there has been speculation that corneat transplant recipients who have had blood transfusions or have been pregnant might be at greater risk for allograft rejection.‘7”.‘YX.“n” Presumably. this would be due to a previous sensitization to HLA antigens shared by the donor cornea and the transfused blood cells or fetus. There is one report of’ altograft rejection occurring in a gravid woman one year following transplantation.“” However, there is no HLA antigen or other evidence that the rejection was more than coincidental with the pregnancy. Viilker-Dieben et al’“H,“O”found no evidence of an association between blood transfusions or pregnancy and an increase in the incident of allograft rejection. This was also true for the subgroup of patients whose corneas were highly vascularized.‘{“” There is, therefore, no conclusive evidence that prior transfusion or pregnancy increases the risk of cornea1 allograft rejection. Steinemann et al”‘.’ have described five patients who suffered cornea1 allograft rejections from 24 hours to eight weeks following immunization fol influenza or hepatitis K. It is conceivable that allograti rejection could be precipitated by nonspecific stimulation of the immune system, immune complex deposition in the uvea, or some other mechanism. This study, however, is small and uncontrolled. The possibility that immunization increases the risk of allograft rejection should be addressed with a controlled prospective study. D. TREATMENT

OF ALLOGRAFT

REJECTION

The treatment of allograft rejection varies with the type and severity of the reaction. In this section, we will discuss our approach to treatment. With minor differences, our method is similar to that published by other clinicians.t,“” Undoubtedly, any treatment is more likely to be effective if the condition is diagnosed early. We, therefore, carefully discuss the signs and symptoms of cornea1 graft rejection with each patient and reinforce the importance of immediate treatment.

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Epithelial, subepithelial, or stromal rqjections are not associated with permanent allograft failure in the absence of endothelial involvement.‘l They do, however, indicate that recipient sensitization to donor histocompatibility antigens has occurred and, in some cases, may be an indicator of impending endothelial altograft rejection. These nonendothelial rejection episodes should, therefore, be treated fairly aggressively. We treat these patients with topical 1% prednisolone acetate or 0.1% dexamethasone sodium phosphate six times a day for approximately one week and then taper the medication slowly over a 3-5-week period. There are no studies which prove that one particular treatment regimen for endothelial graft rejection is superior to others. Our approach to treatment is similar to that of other clinicians.‘,~“,‘“9.’ We begin treatment for all patients with a subconjunctivat injection of 2 mg of dexamethasone phosphate, topical 1%’prednisolone acetate or 0.1% dexamethasone sodium phosphate drops every hour while the patient is awake. and 0.05% dexamethasone sodium phosphate ointment at bedtime. The corticosteroid drops are administered every hour while the patient is awake for approximately three days, then reduced to every two hours while awake for several days, then reduced to six times a day for several days, and then reduced to four times a day for several days. At this point, the corticosteroid drops are tapered slowly over a period of several weeks to a few months. In aphakic patients without glaucoma, we commonly continue topical corticosteroids at a drop a day indefinitely if vascularization or other significant risk factors for a recurrence of rejection are present. In alkali burn and other high ;isk patients even higher maintenance frequencies may be necessary to prevent rejectioIl.‘“.“g.’ The corticosteroid ointment is usually discontinued after the first 2-3 weeks. If there ark no contraindications,h”,’ severe endothelial rejections may also be treated with oral prednisone. Oral prednisone is begun at 60 mg per day for three days and then tapered over a 1-2-week period. In selected cases, the corticosteroid subconjunctival injection may be repeated after several days if the clinical response is deemed inadequate.‘“‘.’ Since subcon.junctival injections can be painfLtl and a proportion of the medication may be lost through the conjunctival perforation, studles are indicated to test the efficacy of‘corticosteroids used in conjunction with bandage collagen shields as an alternative form of treatment in the acute stages of altograft rejection. .4 recent study in rabbits found that bandage collagen shields with hourly drops of dexamethasone alcohol substantially increased the penetration of the steroid into the it-is and vitreous, comcornea, aqueous humor, pared with hourly drops alone.“’ (Xnical studies

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have found the rate of successful reversal of cornea1 allograft rejections with treatment to vary from 50-91%, depending on the severity of the rejection, the presence of vascularization and other risk factors, and the length of the delay before treatment is initiated. 4,46,79,86,1'2 Several studies have investigated the effects of systemic antimetabolites, such as azathioprine, in the treatment and prevention of cornea1 allograft rejections in high risk patients.‘3~‘62~‘75*2” Their usefulness in the treatment of cornea1 allograft rejection remains uncertain. Since the complications from these agents are frequently life threatening, we do not advocate their use for cornea1 rejection. The use of cyclosporines for the treatment of corneal allograft rejection in high risk patients is in its infancy. Although uncertainty remains regarding the mechanism by which cyclosporines exert their effects, they are known to be powerful immunosuppressants that have T-cell specificity.‘06 Oral cyclosporine A could possibly have a role in the treatment of allograft rejection in selected patients. In a recent randomized prospective study by Hil1,‘07 patients with a high risk of cornea1 allograft rejection due to severe cornea1 vascularization had much greater graft survival when treated prophylactically with oral cyclosporine A and oral and topical corticosteroids (88.9%) compared with patients treated with oral and topical corticosteroids alone (5%) with approximately one year of follow-up. No permanent complications from the use of cyclosporine A were noted. Many of the potential side effects of systemic cyclosporine A might be avoided through topical administration. Animal studies of topical cyclosporine A have noted various results.“4*‘P0~24g The variation among these studies in the efftcacy of topical cyclosporine A may be related to differences in cornea1 penetration depending on the vehicle and the frequency of administration. In a study of rabbits, cyclosporine A was administered in conjunction with the cornea1 penetration enhancer Azone.“‘j In this study, clinically significant levels of cyclosporine A were detected in the cornea and there was a decrease in the incidence and severity of allograft rejection in the treated group. Recently, an uncontrolled trial of 2% cyclosporine A in olive oil following penetrating keratoplasty in high risk patients has been reported.15 Ten of eleven corneas remained clear with a mean follow-up of 16 months. These studies suggest that topical cyclosporine A may be useful in the treatment of cornea1 allograft rejection. In the future, more hydrophilic derivatives of cyclosporine may be developed that better penetrate the cornea1 epithelium and stroma allowing reliable topical treatment without the need for special vehicles.

AND KAUFMAN

Cyclosporines appear to be promising agents for the treatment of high risk cornea1 transplant patients. There are, however, significant risks associated with the use of cyclosporine including hypertensionzo7 renal toxicity,“’ and neurotoxicity.207,3” Importantly, one study detected cyclosporine A in the blood after topical administration in olive oil,” suggesting that systemic toxicity could be a problem with topical routes of administration.

VI. Graft Infections Infection is a common cause of graft failure. Patients with cornea1 transplants are especially prone to infection because of the frequent use of contact lenses and corticosteroid medications. Viral, bacterial, fungal, and protozoan cornea1 infections may lead to loss of the graft and, in some cases, loss of the eye. A. HERPES VIRUS 1. Herpes Simplex

Herpes keratitis is a common indication for penetrating keratoplasty. Although many papers have been written on this subject, the literature is confusing and conclusions controversial because of the retrospective nature of most studies, varied statistical methods, the wide range of cornea1 involvement and disease activity, differences in diagnostic criteria, difficulties in distinguishing recurrent herpes simplex from allograft rejection, and variation in treatment regimens. Graft survival is better if patients with herpetic keratitis undergo penetrating keratoplasty when the disease is inactive.“‘~54~H~~s3~‘47.“‘“‘22s If possible, the patient should be treated with topical antivirals and corticosteroids until there is no epithelial involvement and ocular inflammation is reduced to a minimum.‘47”~2n* There is no evidence that a prolonged period of disease inactivity is beneficial. Although controlled studies are not available, oral acyclovir may also be helpful.‘47 A conjunctival flap prior to penetrating keratoplasty is also ofbenefit in some cases.‘“‘a Penetrating keratoplasty may become necessary while the disease is active, however, because of impending or actual perforation. The reported incidence of recurrent herpetic keratitis after penetrating keratoplasty has varied depending on diagnostic criteria, antiviral treatment, and length of follow-up (Fig. 6). Other variables may also be important. For example, the rate of recurrence may be decreased if the stromal scar is completely excised, since virus may persist in the stroma for an extended period of time following necrotizing keratitis. Representative reported recurrence rates include 9.4% after one year,“’ 17% after one year,“28 18% after two years,“’ 15% after two years,14’ and 12% after three years.7x Recur-

GRAFT FAILURE AFTER PENETRATING

KERATOPLASTY

Fig. 6. Recurrence of a herpetic epithelial dendrite in a graft performed for herpes simplex keratitis.

rence rates for herpetic keratitis in the graft would be more meaningful if the data were presented as recurrence-free survival using an actuarial method to allow for varied follow-up. It is clear, however, that recurrent herpetic keratitis is noted in a higher proportion of patients as the length of follow-up increases. Rates close to 50% have been reported with follow-up periods of up to 15 years.jn Allograft rejection has been cited as the most common cause of graft failure for transplants performed for herpetic keratitis.‘“,*“.“‘” It is, however, frequently impossible to distinguish recurrent herpetit keratouveitis from allograft rejection. The actual proportions of graft failures attributable to these disorders are, therefore, uncertain. In addition, allograft rejection may trigger the reactivation of herpes keratitis, or the inflammation accompanying a reactivation of herpes keratitis may precipitate The incidence of allo_ an allograft rejection. ‘I’.7X,L’:‘(i graft rejection in grafts performed for herpes keratitis may also be influenced by the presence of vascularization.;‘,“‘!’ Other causes of graft failure in these patients include persistent epithelial defects”’ and bacterial or fungal infections.“‘.x’ Representative rates of overall graft survival that have been reported are 60% at three years,2”” 69% at five to seven years,‘” and 80%’ at three years.“” Although there are no controlled studies that suggest that one particular treatment regimen is superior to another, we use the following approach. ‘L‘opical corticosteroids are routinely covered with trifluridine on a drop-for-drop basis preoperatively

345

and postoperatively. We expect greater inflammation after penetrating keratoplasty for herpes keratitis and, therefore, oral prednisone (60 mg per day) is begun on the day prior to surgery if there are no systemic contraindications. The prednisone is usually continued at this dose for at least one week after surgery and then discontinued by tapering over the second week. We also give 400 mg of oral acyclovir five times a day for two weeks after surgery. Since the role of oral immunosuppression has not been established by controlled studies, many surgeons choose not to use oral corticosteroids or acyclovir. A proportion of patients will have a reactivation of the herpes simplex in the graft regardless of which preoperative treatment regimen is prescribed. It should also be noted that prophylactic topical antiviral treatment does not appear to prevent reactivation of the herpes simplex virus. Although a recent retrospective, uncontrolled clinical trial has suggested that prophylactic oral acyclovir may reduce the rate of recurrence of herpes simplex keratitis,“’ a prophvlact’ lc role for oral acyclovir following penetratini keratoplasty in these patients has not been established. Epithelial herpes simplex virus activation may also occur following penetrating keratoplasty for cornea1 disorders other than herpes.‘4’ This possibility should be considered in patients with dendritic lesions and in patients with persistent non-dendritic epithelial defects. Rapid sensitive clinical tests are helpful for confirming the diagnosis so that appropriate treatment can be provided.“” 2. Herpes Zoster Cornea1 involvement is frequent in herpes zoster ophthalmicus.“‘~“” Patients with resulting cornea1 opacification have traditionally been considered to be poor candidates for penetrating keratoplasty because of the associated hypesthesia, lid abnormalities, dryness, vascularization, uveitis, and glaucoma~~ll.2:~lRecently, however, two series of patients receiving cornea1 transplants for herpes zoster keratopathy have been published. Reed et al’“’ reported a retrospective study of 12 patients. With a mean follow-up time of 36 months, ten of the twelve grafts remained clear. Soong et alsAtihave published a retrospective series of nine patients with zoster keratopathy who underwent penetrating keratoplasty. Seven of the grafts remained clear with a mean follow-up of 18 months. The results of this study suggest that there is a better prognosis with a longer quiescent period between the initial episodes of herpes zoster ophthalmicus and transplantation. Although the numbers are small, these studies indicate that graft survival may be acceptable if patients are selected properly, but further investigation is indicated.

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WILSON

AND KAUFMAN

B. BACTERIA AND FUNGUS Bacterial or fungal keratitis following penetrating keratoplasty may result in graft failure by producing cornea1 scarring (Fig. 7), wound dehiscence, endothelial decompensation secondary to accompanying inflammation, and allograft rejection attributable to cornea1 vascularization and immune cell invasion. There are three common sources for bacterial and fungal keratitis following penetrating keratoplasty. Contamination of the donor tissue with microorganisms will not be discussed, since it has been covered extensively in a recent review on cornea1 preservation. 3” The other two sources of microbial keratitis following penetrating keratoplasty, which will be discussed in this article, are incomplete excision of infected recipient tissue and infection from organisms that are acquired from the environment. Penetrating keratoplasty may become necessary as a treatment for severe bacterial or fungal keratitis when there is pending or actual cornea1 perforation or medical treatment has failed. At the time of surgery, the surgeon should attempt to excise all infected recipient cornea by using a trephine size that encompasses the clinically involved area. Despite careful attention to the apparent boundaries of the infection, in some cases there will be a recurrence of keratitis caused by the same organism indicating that the excision of infected tissue was incomplete.“4824” The recurrence is usually noted soon after penetrating keratoplasty. Recurrent infection is especially common in grafts performed for fungal keratitis, 84,244but it can also be associated with bacterial keratitis. Since the bulk of the infected tissue has been removed, the recurrent infection may respond to appropriate antimicrobials. A partial conjunctival flap can be utilized successfully in some is cases of fungal keratitis, “Ia since the recurrence usually in the periphery. Despite the transfer of superficial vessels into the vicinity of the donor tissue, this technique rarely precipitates allograft rejection. The environment is the most common source of bacterial and fungal infections after penetrating 67~‘04*2g2 These infections are almost alkeratoplasty. ways noted in the late postoperative period. Several recent publications have been devoted to this topic.2,67.81,104.292 Factors associated with the development of late bacterial and fungal infections include topical antibiotic and corticosteroid usage, loose or broken sutures, contact lenses, persistent epithelial defects, keratoconjunctivitis sicca, and previous herpes simplex infection. 2,67s81.104.292 Corticosteroid usage impairs the host defense mechanisms and may result in more advanced disease at presentation by suppressing symptom-evoking inflammation. The other factors predispose to microbial colo-

Fig. 7. Streptococcus pneumoniae cornea1 ulcer that occurred in a cornea transplant 2 months after penetrating keratoplasty. The infection was successfully treated with topical antibiotics, but it was necessary because of axial cornea1 scarring.

to repeat

the graft

nization and epithelial defects that provide a route for the microbes to enter the stroma. The incidence of fungal infection appears to vary with the geographic location; reported incidences in transplant patients vary from 0.1%’ to 36%” ofall cornea1 infections. Where the proportion of fungal infections is high, Candida a&cans is a common Both gram-positive and gram-negapathogen.“* tive organisms are frequently isolated in cases of bacterial keratitis.‘~67*“‘.‘04,2g2 A high incidence of graft failure may be associated with fungal or bacterial infections.67~104~2g2 Harris that only 40% of previously clear et allo reported grafts retained clarity after an episode of microbial keratitis. Our experience has been similar. Resistance of microbes to commonly used antimicrobials is an ever increasing problem. The use of prophylactic antibiotics is commonly associated with the isolation of resistant organisms.‘7,81~‘04 In the Harris et al series described above,lo4 only 38% of isolated organisms were sensitive to gentamicin. We have also noted an increasing proportion of gram-positive cocci that are resistant to cephalosporins such as cefazolin. These findings are of major concern, since these antibiotics are frequently used as part of broad-spectrum coverage prior to identification of the infecting organism. One specific infectious disorder in cornea1 transplant patients that is related to long term topical corticosteroid usage is infectious crystalline keratopathy~17".2"" This disorder is usually associated with Streptococcus viridans infection with relatively little inflammatory reaction and intrastromal opacities that appear crystalline. ‘7y,235The diagnosis is commonly not made until pathologic analysis of the tissue is performed.

GRAFT FAILURE

AFTER PENETRATING

RERATOPLASTY

Specific recommendations can be made to help reduce the incidence of microbial infections in grafts and to improve treatment when they occur. Loose or broken sutures should be removed immediately. Patients with persistent epithelial defects must be treated aggressively to promote epithelial healing and should be followed carefully. Instructions should be provided regarding lens care to patients wearing contact lenses. Although most ophthalmologists administer a topical antibiotic when an epithelial defect is present, infections by resistant organisms commonly occur. Antibiotics should not be administered for longterm prophylaxis in patients without epithelial defects. In patients without vascularization of the cornea or previous rejection episodes in the existing graft, we taper topical corticosteroids and discontinue their use when there are no signs of anterior segment inflammation. Finally, when a patient presents with a cornea1 infection, aggressive diagnostic steps are indicated. We routinely perform Gram, periodic acid-&hill (PAS), and calcofluor white stains on smears of cornea1 scrapings in all cases. Blood agar, chocolate agar, Sabaroud’s agar, and thioglycolate broth cultures, with sensitivities to antibiotics, are routinely performed. Cultures for Acanthamoeba, acid-fast bacteria, and other more unusual organisms are also frequently performed, depending on the clinical situation. Topical antibiotics for initial treatment are selected on the basis of the results of smears and previous antibiotic administration. Broad-spectrum antibiotics are given when no indication of the infecting organism is obtained from smears. Vigorous debridement is used to remove devitalized tissue. If the infection does not respond to the selected antibiotics and the initial cultures are unrewarding, we do not hesitate to perform a corneal biopsy to obtain a definitive diagnosis. Biopsy specimens are examined with gram, PAS, and calcofluor white stains and cultured for the full range of potential pathogens. In addition, transmission electron microscopy is performed on most specimens. Antibiotic choices are adjusted based on the results of these tests. In some cases, despite aggressive treatment, surgical intervention is required. If possible, regrafting is avoided until all signs of ocular inflammation are gone. We frequently use conjunctival llaps in the interim. C. ACANTHAMOEBA Primary Acanthamoeba infection of a cornea1 graft is not a commonly reported problem, although patients who wear contact lenses after penetrating keratoplasty should be instructed in the proper care of lenses to decrease the risk of infection. Since early diagnosis provides the best opportunity for a medical cure, Acanthamoeba must be

considered in cases where an infection in a graft is unresponsive to conventional antimicrobial therapy. Frequently, a cornea1 biopsy must be performed to make the diagnosis. Although better drugs are needed, treatment with propamidine isethionate and neomycin-polymyxin-gramicidin can be effective if the diagnosis is made early in the course of the disease.lR7 Topical clotrimazone has also been reported to be efftcacious.“* Unfortunately, Acanthamoeba is frequently encountered as a recurrence following therapeutic penetrating keratoplasty. As with fungal and some bacterial infections, it is often difficult based on the clinical examination to determine the lateral extent of the spread of the Acanthamoeba within the infected recipient cornea.“‘.i5 Consequently, it is common for infectious microorganisms to recur after therapeutic penetrating keratoplasty. Results in recurrent cases have been poor.i5.‘x7 Complications have included progressive sclerokeratitis, wound dehiscence, persistent epithelial defects, stromal melting, and loss of the eye:“.” Moore’x7 has suggested that the chances of obtaining a clear graft are improved if medical treatment is successful in arresting the progression of the infection and the treatment can be continued for a period of up to one year prior to transplantation. There is no conclusive evidence, however, that this is efftcacious. Unfortunately, many cases progress despite aggressive medical treatment and surgical intervention during an active stage becomes necessary. With continued medical treatment after the transplant, however, some of these grafts survive.

VII. Glaucoma Glaucoma is frequently cited as a cause of graft failure following penetrating keratoplasty.“,“g,‘4’J”i In the series published by Arentsen and Laibson,” postoperative permanent cornea1 edema was attributed to uncontrolled glaucoma in 19 of 869 grafts (2%). The incidence of glaucoma following penetrating keratoplasty varies from study to study, depending on the patient population. Factors that have been associated with glaucoma following corneal transplantation include preexisting glaucoma,YY“)XS aphakia or pseudophakia,‘“~““,““~“” anteri_ or synechiae,N”.‘8” semiflexible closed loop anterior chamber intraocular lenses, 1!l,lll'L."'?li.5"9~2~~and visco_ elastic agents.“” There also tends to be a high incidence of glaucoma in some diagnostic groups such as alkali burn and trauma patients. Foulks”” reported intraocular pressures greater than or equal to 25 mm Hg following penetrating keratoplasty in 34% of aphakic or pseudophakic eyes and in 4%) of phakic eyes. The incidence of increased intraocular pressure following penetrat-

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ing keratoplasty in aphakic or pseudophakic patients can be decreased by using oversize donor buttons.2Q*20’~9’5 In the prospective randomized study by Zimmerman et al,‘15 the incidence of intraocular pressures greater than 50 mm Hg was dramatically reduced by the use of 0.5 mm oversize donor buttons. One of 35 patients with 0.5 mm oversize donor buttons and 19 of 35 patients with same-size donor buttons had intraocular pressures greater than 50 mm Hg. The use of oversize grafts in aphakic or pseudophakic eyes is thought to decrease the incidence of glaucoma by reducing distortion of the angle and collapse of the filtering meshwork.203 Some studies have found no difference in intraocular pressure in aphakic transplants with oversize or same-size grafts.““z”4 To some extent, therefore, this effect may be dependent on surgical technique. Although increased intraocular pressure has been associated with graft failure,8~4g*‘4g~223there is little direct evidence of cornea1 endothelial cell damage produced by increased intraocular pressure in the human eye. Bigar” reported a reduction in the endothelial cell count in 5 of 13 eyes following an attack of acute angle closure glaucoma. Evidence is better in animal models. Svedbergh”’ reported that increased intraocular pressure could produce irreversible damage to cornea1 endotheliurn in the monkey in vitro. Charlin and Polack4’ found that intraocular pressures of 35 mm Hg in transplanted rabbit eyes caused graft edema, distention of cell junctions, and cell destruction. Thus, it is likely that elevations in intraocular pressure can produce irreversible endothelial cell damage. We do not know the degree of elevation or the duration necessary to produce irreversible changes in grafts in human eyes. It is likely, however, that these parameters vary from patient to patient depending on the status of the endothelium. It is, of course, also desirable to control the intraocular pressure to avoid other complications of increased intraocular pressure, such as glaucomatous nerve damage and retinal vein occlusion. If possible, intraocular pressure should be well controlled prior to penetrating keratoplasty. In many cases, medical treatment with beta-blockers, pilocarpine, and carbonic anhydrase inhibitors is effective. Cyclocryotherapy may be used in eyes that are unresponsive to medical treatment.“‘” At the time of transplantation, flexible anterior chamber intraocular lenses and other lenses thought to be associated with the increase in intraocular pressure should be removed. Anterior synechiolysis should be performed, as was discussed in a previous section. Healon is necessary to protect the donor endothelium, but excessive amounts should be avoided.

WILSON AND KAUFMAN When persistent elevated intraocular pressure is noted after penetrating keratoplasty, the first step is to initiate or increase medical treatment. If there are no contraindications, beta-blockers are a good first choice.‘4q Other medications may be added if intraocular pressure remains elevated. If intraocular pressure remains uncontrolled despite maximum medical treatment, cyclocryotherapy remains the treatment of choice despite associated complications.‘q,30q Reported complications after cyclocryotherapy have included persistent uveitis, hypotony, retinal detachment, vitreous hemorrhage, cystoid macular edema, and graft failure 19.285*509 Little has been written regarding the use of hltration surgery after penetrating keratoplasty. In our experience, there is a significant incidence of complications such as shallowing of the anterior chamber with formation of anterior synechiae and endothelial damage and a low rate of successful pressure control. Further study, however, is needed. Recently, there have been reports of success YAG using Molten0 implants I’?.‘84 and transscleral laser photocoagulation’54*3’4 to control intraocular pressure after penetrating keratoplasty. Clinical experience with these modalities is limited. In one study, four grafts decompensated after implantation of the Molten0 implant.‘a4 We have also seen In the study by McDonnell et this complication. al,“’ 7 of 17 patients with Molten0 implants had It is not known whether the allograft rejections. allograft rejections were directly associated with the implant. Investigations should continue to find better means for controlling glaucoma after penetrating keratoplasty.

VIII. Trauma After penetrating keratoplasty the donor-recipient wound may remain susceptible to traumatic 76*88x230,284 It is not certain rupture indefinitely. whether this risk factor applies to all cornea1 grafts or only to those with poorly healed wounds. In many cases, despite a prominent scar, the wound never appears to attain the strength of the unoperated cornea. 76*284Even years after transplantation, seemingly trivial blows may result in a dehiscence in some corneas.76.2”0’““4 The rupture almost always occurs at the donor-recipient junction.76.230*284 This may to some extent correlate with the alignment of the surgical wound. Depending on the extent of injury, the graft may sustain damage that results in irreversible graft failure. 76*284 In other cases, however, the cornea deturgesces after repair of the dehiscence.76,2n4 Farley and Pettit”j reported on 14 patients who had traumatic wound dehiscences three days to 13 years after penetrating keratoplasty. All of the rup-

GRAFT FAILURE AFTER PENETRATING

Fig. 8. Recurrence graft.

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KERATOPLASTY

of granular cornea1 dystrophy

in a

tures occurred at the donor-recipient junction. In eleven cases, the sutures were still in place at the time ofthe injury. Raber et al’s”published a series of 12 cases of traumatic wound dehiscence occurring in 10 patients after penetrating keratoplasty. Ten eyes had sutures in place at the time of trauma. Failure occurred in 4 of the 11 grafts. Retinal injury, posterior segment damage, and glaucoma are the primary causes of limited vision following traumatic dehiscence after penetrating keratoplasty.7”.‘“” Many patients have a loss of vitreous humor with extrusion of the crystalline or intraocular ~ens,?ar:~o.ex~ Patients with cornea1 transplants should be cautioned regarding participation in activities that could result in trauma to the eye. They should be encouraged to wear protective eyewear, although a severe blow may result in wound dehiscence despite protectiotl.7”

IX. Recurrence of Primary Cornea1 Dystrophies in the Graft Penetrating keratoplasty is necessary for treatment of many of the primary Bowman’s layer and stromal cornea1 dystrophies when opacification progresses to an extent that limits vision. Recurrences have been noted for Reis-Biicklers’ cornea1 dystrophy,““’ granular dystrophy (Fig. 8),‘x.46s.L’xi macular cornea1 dystrolattice dystrophy,““,‘“” crystalline dystrophy.“’ If a PhY, K”” and central recurrence progresses to the point that vision is sufficiently affected, the graft must be repeated. The effect of Fuchs’ dystrophy on the graft is controversial. Although cornea guttata may be noted in donor tissue transplanted into patients with Fuchs’ dystrophy after several years, this is also true in grafts fi)r aphakic or pseudophakic bullous keratopathy and other cornea1 disorders. Olsen et al”“”

reported on 25 patients with 33 penetrating keratoplasties for Fuchs’ dystrophy. Twelve percent of the grafts failed after a mean follow-up of 50 months. In the failed grafts, edema was noted to develop as a “quiet, slowly progressive edema without any obvious etiology.” The authors suggested that failure in these cases might be associated with the primary disease. Fine and West” published a retrospective study of 193 penetrating keratoplasties performed for Fuchs’ dystrophy and followed for six months to 15 years. The incidence of clear grafts for the entire series was 85% Twenty of these grafts were followed for 8-15 years. In this subgroup with Iongel follow-up, the incidence of clear grafts was also 850/c,.Their data suggest a good prognosis with long follow-up in patients with Fuchs’ dystrophy. Based on currently available data, however, no firm conclusions can be made regarding the eff‘ect ofthe primary disease on grafts performed for Fuchs’ dystrophy.

X. Late Graft Failures of Unknown Etiology Occasionally, a grant that has remained clear for many years will fail without an identifiable cause. In many cases, late decompensation such as this is likely secondary to a decrease in the endothelial cell density below that necessary to maintain cornea1 deturgescence. Central endothelial cell counts as low as 300-550 cells/mm” have been noted in clear grafts.“” Wi t h t h e continued cell loss that occurs with age or due to stresses, such as increased intraocular pressure, many of these grafts will eventually fail. It is, however, frequently impossible to separate endothelial decompensation from failure due to graft rejection. When in doubt, the edema should be treated as a possible graft rejection.

XI. Summary Despite the large number of factors associated with cornea1 graft failure after penetrating keratoplasty, the reported incidence of failure has decreased steadily with improvements in surgical technique and postoperative therapy. Furthe gains are anticipated as advances in basic and clinical research increase our understanding of the pathophysiology of graft injury.

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JH: Clinical types of cornea1 transplant rejection. Their manifestations, frequency, preoperative correlates, and treatment. Arch Ophthalmol 99: 599-604, 1981 5. Alpar JJ: The use of Healon in cornea1 transplant surgery with and without intraocular lenses. Obhthalmic SUW 15: 757-760, 1984 6. Apple DI, Brems RN, Park RB, et al: Anterior chamber lenses. P&t 1: Complications and pathology and a review of designs. 1 Cataract Refract Surf 13:157-174, 1987 7. Apple Dj, Olson RJ: Closed-lo:p anterior chamber lenses. Arch Ophthalmol 105: 19-20, 1987 8. Arentsen JJ: Cornea1 transplant allograft reaction: possible predisposing factors. Trans Am Ophthalmol Sot 81:361-402, 1983 Ba.Arentsen 11, Donoso R, Laibson PR, Cohen E-J: Penetrating keratoplaiiy for the treatment of pseudophakic cornea1 edema associated with posterior chamber lens implantation. Ophthalmic Surg 18:514-517, 1987 9. Arentsen JJ, Laibson PR: Surgical management ofpseudophakic cornea1 edema: Complications and visual results following penetrating keratoplasty. Ophthalmic Surg 13: 371-373, 1982 10. Auran ID, Starr MB, lakobiec FA: Acanthamoeba keratitis. A review of the literature. Cornea 62-26, 1987 11. Bahn CF. Grosserode R. Musch DC. et al: Effect of 1% sodium h;aluronate (Healon) on a nonregenerating (feline) cornea1 endothelium. Invest Ophthalmol Vis Sci 27: 1485-1494, 1986 12. Balin N, Weiss DM: Pigment dispersion and intraocular pressure elevation in pseudophakia. Ann Ophthalmol 14: 627-630, 1982 13. Barraquer J: Immunosuppressive agents in penetrating keratonlastv. Am I Obhthalmol 100:61-64, 1985 14. Batch&or iR, Ca:ey’TA, Gibbs DC, et al: HLA matching and cornea1 grafting. Lancel 1:551-554, 1976 15. Belin MW, Bouchard CS, Frantz S, Chmielinska J: Topical cyclosporine in high-risk corneai transplants. Ophthalmology 96:1144-l 150, 1989 15a.Berkowitz RA, Klyce SD, Kaufman HE: Aqueous hyposecretion after penetrating keratoplasty. Ophthalmic Surg 15:323-324, 1984 in 16. Bigar F: Specular microscopy of the endothelium, Straub W (ed): Developments in Ophthalmology, Vo16. Basel, Karger, 1982, pp l-9 17. Bigar F, Schimmelpfennig B, Gieseler R: Routine evaluation of endothelium in human donor corneas. Albrecht von Graefes Arch Klin Exp Ophthalmol 200:195-200, 1976 18. Binder PS: Intraocular lens implantation after penetrating keratoplasty. Refractive Cornea1 Surg 5:224-230, 1989 19. Binder PS, Abel R, Kaufman HE: Cyclocryotherapy for glaucoma after penetrating keratoplasty. AmJ Ophthalmol 79t489-492, 1975 20. Binder PS, Abel R, Polack FM, Kaufman HE: Keratoplasty wound seoarations. Am I Ofihthalmol 80:109-l 15, 1975 21. Boemer dF, Thrasher ibHi Complications from anterior chamber lenses: report of cases. Ann Ophthalmol 16: 742-744, 1984 22. Boisiolv HM, Bernard PM, Dubt I, et al: Effect of factors unrelated to tissue matching on cornea1 transplant endothelial reiection. Am 1 O~hthulmol 107:647-654. 1989 23. Boisjoly GM, Roy R, bu& 1, et al: HLA-A,B and DR matchin cornea1 transplantation. Ophthalmology 93: ing 1290-1297, 1986 24. Bourne WM: Examination and photography of donor corneal endothelium. Arch Ophthalmol 94:1799-1800, 1976 25. Bourne WM: Reduction ofendothelial cell loss during phakit penetrating keratoplasty. Am J Ophthalmol89:787-790, 1980 26. Bourne WM: One-year observation of transplanted human cornea1 endothelium. Ophthalmology 87:673-679, 1980 27. Bourne WM: Morphologic and functional evaluation ofthe endothelium of transplanted human corneas. Truns Am Ophthalmol Sot 81:403-450, 1983 28. Bourne WM: Endothelial cell survival on transplanted human corneas preserved at 4 C in 2.5% chondroitin sulfate 1

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tis. Arch Ophlhalnwl 98:1755-1759, 1980 52. Cohen EJ, Brady SE, Leavitt K, et al: Pseudophakic bullous keratopathy. Am J Ophthnlmol 106:264-269, 1988 53. (:ohen EJ, Kenyon KR, Dohlman CH: Iridoplasty for prevention of post-keratoplasty angle closure and glaucoma. Obhthalmzr Surg 1?:994-996, 1982 EJ, La&son PR, hrentsen JJ: Cornea1 transplanta54. &hen tion for herpes simplex keratitis. Am J O~hthdmol Y5: 645-650, 1983 5.5. Cohen EJ, Parlato CJ. Arentsen JJ. et al: Medical and surgiLal treatment of Acanthamoebakeratitis. Am .,I Obhthnlmol * 103:615-625, 1987 in alloxan vascularized rab56. (:ollin HB: Cornea1 lymphatics hit eyes. lnvrst Ophthelmol 5:l-13, 1966 drainage of ‘“‘I-albumin from tht 57. (:ollin HB: Lymphatic vascular&d cornea. In?!& Ophthalmol 9: 146-155, 1970 for posteri5x. Cowden JW, Hu BV: A new surgical technique or chamber lens fixation during penetrating keratoplast) in the absence of capsular or zonular support. Cort~acr 7:231-235, 1988 models and life-tables. ,/ K %a& Sot 59.