Penetrating Keratoplasty for Herpes Simplex Keratitis and Keratoconus

Penetrating Keratoplasty for Herpes Simplex Keratitis and l(eratoconU5 Allograft Rejection and Survival RANDY J. EPSTEIN, MD, JOHN A. SEEDOR, MD, NEIL G. DREIZEN, MD, R. DOYLE STULTING, MD, PhD, GEORGE O. WARING III, MD, LOUIS A. WILSON, MD, H. DWIGHT CAVANAGH, MD, PhD Abstract: To determine the relationship between corneal allograft rejection and failure, we studied patients who underwent penetrating keratoplasty for herpes simplex keratitis (n = 82) and keratoconus (n = 345), two frequent indications for keratoplasty in young patients, using survival analysis. For first grafts for herpes, the probability of survival was significantly less than it was for keratoconus (P < 0.0001). For second grafts, this difference was less pronounced, and for three or more grafts, the difference in survival was not significant. The incidence of rejection episodes was similar in first grafts for herpes (16.6%) and keratoconus (18.5%) (P > 0.05). However, the incidence of rejection episodes in reg rafts for herpes was significantly greater than in keratoconus (23.7 versus 17%, P < 0.01). The incidence of failure after rejection episodes (first grafts and reg rafts combined) was significantly greater in grafts for herpes (52.4 versus 16.2%, P < 0.001). Because survival after multiple reg rafts in both groups is poor, additional measures, such as tissue matching, may be necessary to improve the likelihood of success in these high-risk cases. [Key words: allograft rejection, corneal allografts, herpes simplex keratitis, keratoconus, penetrating keratoplasty, survival analysis.] Ophthalmology 94:935-944, 1987

Allograft rejection is the leading cause of corneal graft failure. 1- 3 Numerous studies have reported the incidence of rejection after penetrating keratoplasty for herpes simplex keratitis4,5 and keratoconus. 6- 10 Only recently have modern actuarial techniques of survival analysis been applied to the study of penetrating keratoplastyY-15 We use them here to assess the relationship From the Department of Ophthalmology, Emory University, Atlanta. Dr. Epstein is currently affiliated with the Department of Ophthalmology, Rush·Presbyterian·St. Luke's Medical Center, Chicago, Dr. Seedor is cur· rently affiliated with New York Eye and Ear Infirmary, New York, and Drs. Dreizen and Cavanagh are currently affiliated with the Department of Ophthalmology, Georgetown University, Washington, DC. Supported by an unrestricted grant to the Emory University Department of Ophthalmology from Research to Prevent Blindness, Inc., the Heed Oph· thalmic Foundation (Drs. Epstein and Dreizen), Fight for Sight, Inc., New York City (Dr. Seedor), and the Comeal Research Fund, Department of Ophthalmology, Rush·Presbyterian-St. Luke's Medical Center (Dr. Ep· stein). Reprint requests to Randy J. Epstein, MD, Comea Service, Department of Ophthalmology, Rush·Presbyterian·St. Luke's Medical Center, 1725 W. Harrison St, Chicago, IL 60612.

between allograft rejection and graft failure, and to determine the outcome of regrafting, which has been associated with a poor prognosis. 16-18 We have studied the relationship between allograft rejection and survival in these two diagnostic groups, which include relatively young patients who would be expected to have substantial long-term follow-up data and the highest incidence of rejection. 19 These diagnoses were selected beca.use they represent patients who are in both good and bad prognostic categories with regard to their prognosis for successful penetrating keratoplasty. 13 Using survival analysis, we compared the results of corneal transplantation in patients with corneal scarring from herpes simplex keratitis to those with keratoconus to define which associated conditions or surgical procedures were predictors of decreased graft survival.

PATIENTS AND METHODS We reviewed four corneal surgeons' clinical records of all patients who underwent penetrating keratoplasty for 935

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visual acuity as our measure of success. The diagnosis of herpes simplex keratitis was made on the basis of positive cultures or a prior history of typical dendritic keratitis or, more commonly, because of an appearance and clinical course which was consistent with this diagnosis. 11 • 12 Although a small number of patients with active inflammation and acute perforation were included, the majority of eyes were not inflamed and had vascular or, less commonly, avascular stromal scars. The diagnosis of keratoconus was based on its previously described clinical characteristics,6 and indications for surgery included scarring in the visual axis and contact lens intolerance or unacceptable distortion from irregular astigmatism corrected by spectacles. Fig 1. Corneal graft in patient with herpes simplex keratitis is vascularized and exhibits edema in association with acute inflammation. Lack of well-defined endothelial line makes diagnosis of rejection difficult.

Fig 2. Probable endothelial rejection in herpes patient manifested by diffuse large keratic precipitates in association with stromal neovascularization.

herpes simplex keratitis (82 patients) or keratoconus (345 patients) between 1974 and 1984. Cases were located by a computerized search which targeted the charts of patients hospitalized for penetrating keratoplasty with these diagnoses. Records were incomplete or unobtainable in 20 cases of keratoconus and 10 cases of herpes. The remaining 372 grafts in 325 eyes with keratoconus and 110 grafts in 72 eyes with herpes are the subject of this report. We classified the procedures as primary grafts or regrafts. Each individual graft was considered separately for purposes of data analysis. Information was gathered on associated preoperative diagnoses, surgical procedures, and postoperative courses. Each rejection episode was studied in detail. We used graft clarity rather than 936

DONOR CORNEAS, SURGICAL TECHNIQUE, AND POSTOPERATIVE CARE

All donor tissue was obtained from the Georgia Lions Eye Bank, Inc. Before 1976, whole eyes were used exclusively, usually within 1 to 2 days of enucleation. Since 1977, donor tissue has consisted of corneal-scleral rims stored in modified McCarey-Kaufman (M-K) medium at 4°C and used within 4 days of preservation. Donor buttons were manually trephined with a disposable blade from the endothelial side, 0.25 to 0.50 mm larger than the recipient bed. Recipient tissue was removed by partial thickness trephination and excision with corneal scissors, diamond knives, or microrazor blades. Peripheral iridectomies were done in all herpes patients and in some keratoconus patients. Cataract extraction and synechialysis were done when indicated. Anterior vitrectomy was done in all aphakic patients using cellulose sponges and scissors or mechanical suction-cutting instruments. Insertion, removal, or exchange of intraocular lenses was done when indicated. The donor button was sewn into place using 10-0 running nylon sutures, a combination of interrupted 10-0 and running 11-0 nylon, or a combination of running 10-0 and running 11-0 nylon. In a majority of cases, the donor epithelium was removed with a cellulose sponge at the conclusion of the case. Sub-Tenon injections of gentamicin (20 mg) and dexamethasone (2 mg) were administered at the conclusion of most cases. Postoperatively, treatment varied, but usually consisted of 1% prednisolone acetate hourly for 24 hours, every 2 hours for 24 hours, and then five times daily. Topical corticosteroids were tapered and generally discontinued by 6 months after surgery. Postoperative antivirals were used only when clinically indicated, generally because of acute dendritic keratitis. DIAGNOSIS AND TREATMENT OF ALLOGRAFT REJECTION

Allograft rejection was categorized using previously published criteria. Possible rejection was defined as the acute onset of ciliary flush, anterior chamber reaction, and/or keratic precipitates with (Fig 1) or without (Fig 2) corneal edema in a previously clear graft. Definite rejection was characterized by an epithelial or endothelial rejection line (Fig 3) or unilateral subepithelial infil-

EPSTEIN et al

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ALLOGRAFT REJECTION AND SURVIVAL

Fig 3. Endothelial line (arrows) indicative of definite allograft rejection.

trates confined to the donor and not associated with an acute conjunctivitis. 19 Endothelial rejection was treated with intensive topical 1% prednisolone acetate and, in some instances, periocular or systemic corticosteroids which were tapered according to the patient's clinical response. Subepithelial infiltrates were treated with lesser doses of topical prednisolone acetate, most commonly four times daily. The patient was considered to have experienced an irreversible rejection if the graft remained edematous after 4 weeks of intensive topical and/or systemic corticosteroid therapy. Recurrent herpes simplex keratitis was characterized by typical dendritic figures, geographic ulcers, or persistent epithelial defects with or without positive viral cultures and/or stromal inflammation. Treatment consisted of topical antivirals and corticosteroids administered with approximately equal frequency. Acute, anterior segment inflammation after penetrating keratoplasty for herpes simplex keratitis was categorized as possible rejection, as suggested previously,I,20,21 unless definite signs of recurrent herpetic disease, such as dendrites, were also present. GRAFT FAILURE AND SURVIVAL ANALYSIS

Graft failure was defined as an irreversible loss of clarity in a graft which had previously been clear after sur-

gery, which precluded a view of fine iris detail, estimated to be compatibile with a visual acuity ofless than 20/60. The date of failure was estimated from available clinical information or, if not documented precisely, it was assumed to have occurred midway between the time of the last examination when the graft was clear and the first examination when the graft was noted to be cloudy. Survival curves were constructed using the KaplanMeier method 22 and compared by the Breslow23 and Mantel-Cox 24 tests. The Breslow test is more sensitive to differences that occur on the steepest portion of the survival curves « 1 year postoperatively), whereas the Mantel-Cox test weighs all of the data points equally and is more sensitive to differences later in the postoperative course. Covariants were studied by stepwise regression analysis of right censored data. 25 Comparison of groups for continuous variables was made by the two-tailed Student's t test. Proportions were compared by the chisquare method.

RESULTS DEMOGRAPHIC DATA

Recipient data are summarized in Table 1. Although first grafts have been separated from regrafts in our analysis, patients are included in both groups. The number (percentage) of clear grafts at the time of the study was as follows: for first grafts, there were 299 (92%) for keratoconus and 54 (75%) for herpes (P < 0.0001); for second grafts, there were 29 (87.8%) for keratoconus and 14 (66.7%) for herpes (P = 0.12); for three or more grafts, there were eight (57.1 %) for keratoconus and eight (47%) for herpes (P = 0.84). There were no significant differences in age between the two diagnostic groups at the time of the first graft (P > 0.05). Keratoconus patients requiring a second graft were significantly older than herpes patients requiring a second graft (P = 0.006), but those requiring three or more grafts were significantly younger than herpes patients in this category (P < 0.001). Differences in sex were not significant. The mean length of follow-up for patients with keratoconus was significantly longer than for herpes simplex keratitis in all three groups (P < 0.05), a function of their increased survival.

Table 1. Profile of Recipients First Grafts Diagnosis No. of grafts Age (yrs) Mean Range Mean follow-up (yrs)t

Second Grafts

~3

Grafts

KC 325

HSK 72

KC 33

HSK 21

KC 14

HSK 17

34.9 ± 11.9 16.1-86.1 4.25

39.9 ± 16.5 15.1-87.3 2.87

37.9 ± 13.8 20.0-83.9 3.06

21.0 ± 16.4* 16.5-69.1 1.81

28.9 ± 3.7 21.6-36.5 2.75

47.3 ± 19.2* 18.5-71.6 0.96

KC = keratoconus; HSK = herpes simplex keratitis. * Age difference significant (P < 0.05, Student's t test), KC versus HSK within each grouping. t For clear grafts (graft failure = endpoint). Data on recipients who had multiple keratoplasties done at Emory will appear in more than one group. Differences in follow-up significant (P < 0.05, chi-square) within each grouping.

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Table 2. Associated Diagnoses and Procedures Regrafts

First Graft HSK KC (n = 325) (n = 72) Diagnoses 12 (3.7) Cataract (%) 20 (6.2) Glaucoma (%) Active inflammation (%) 0 1 (0.3) Anterior synechiae (%) Aphakia (%) 1 (0.3) Pseudophakia (%) 0 Procedures ICCE (%) ECCE (%) Anterior vitrectomy (%) Synechialysis (%) AC IOL (%) PC IOL (%) Iris IOL (%)

14 (19.4) 10 (13.9) 3 (4.2) 2 (2.8) 0 0

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7 (14.9)* 10 (21.3)* 3 (6.4) 1 (2.1) 5 (10.6)* 0

4 (1.2) 12 (16.7)t 4 5 (6.9) 2 9 (2.8) 4 (1.2)* 11 (15.3)t 4 1 1 (0.3) 2 (2.8) 2 1 (0.3) 0 1 7 (2.2) 3 (4.2) 2 (2.8) 0 0

VOLUME 94

3 (7.9) 8 (21.1) 3 (7.9) 6 (15.8)* 3 (7.9) 4 (10.5)*

(8.5)* 0 (4.3) .3 (7.9) (8.5) 6 (15.8) (2.1) 5 (13.2) (4.3) 0 (2.1) 3 (7.9) 0

KC = keratoconus; N= number of grafts; HSK = herpes simplex keratitis; ICCE = intracapsular cataract extraction; ECCE = extracapsular cataract extraction; AC IOL = insertion of anterior chamber intraocular lens; PC IOL = insertion of posterior chamber IOL; Iris IOL = insertion of iris-supported IOL. * P < 0.05, chi-square, primary graft versus reg raft for each diagnostic group. t P < 0.05, chi-square, HSK versus KC for each numerical grouping.

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ASSOCIATED DIAGNOSES AND PROCEDURES

Patients receiving regrafts for keratoconus had a significantly higher incidence of glaucoma, cataract, aphakia, cataract extraction, and vitrectomy than those receiving first grafts for keratoconus (Table 2). Patients receiving regrafts for herpes had a significantly higher incidence of anterior synechiae, cataract, cataract ex938

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The probability of survival of first grafts for keratoconus (Fig 4) was 97.2% at I year, 95 .5% at 2 years, and 91.3% at 4 years. For the second graft, the probability of survival was 92.7% at 1 year, 91.8% at 2 years, and 86.3% at 4 years. The difference between survival of first and second grafts was not significant. The probability of survival of third or subsequent grafts was 76.2% at 1 year, 61.6% at 2 years, and 49.7% at 3 years, which was significantly less than first or second grafts (P < 0.0001). In herpes, the probability of survival for first grafts was 86.1 % at 1 year, 75.6% at 2 years, and 73.2% at 4 and 6 years (Fig 5). For second grafts, the probability of survival was 83.1 % at 1 year, 74.3% at 2 years, and 67.9% at 4 years. The difference between first and second grafts was not significant (P> 0.05). For the third or subsequent grafts, the probability of survival was 78.3% at 1 year and 66.5% at 2 years, which was significantly less than first or second grafts (P = 0.008, Mantel-Cox). The probability of survival of first grafts (Fig 6) for

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Fig 7. Comparison of survival for the second graft in herpes and keratoconus. Survival in herpes is marginally less than keratoconus (P = 0.06, Breslow; 0.019, Mantel-Cox).

Fig 8. Comparison of survival in herpes and keratoconus for three or more g rafts. The difference is not statistically significant (P > 0.05).

herpes was significantly less than first grafts for keratoconus (P < 0.0001) and marginally less when second grafts (Fig 7) were compared (P = 0.06, 0.019). The difference between survival of grafts for keratoconus and herpes was not significant for patients requiring three or more grafts (Fig 8). Risk factors affecting survival. In first grafts for keratoconus, the only preoperative condition associated with decreased survival was glaucoma (P = 0.03, Table 2). In regrafts for keratoconus, both glaucoma (P = 0.002) and cataract (P = 0.02) were risk factors for decreased survival. In first grafts for herpes, both cataract (P = 0.01) and glaucoma (P = 0.003) were risk factors, whereas in regrafts for herpes, only glaucoma (P = 0.01) was asso-

ciated with a significant decrease in survival. Although our review did not categorize the type of glaucomas that were present, the vast majority of these were due to inflammation and/or synechiae. Surgical procedures associated with decreased survival included anterior vitrectomy in first grafts for herpes (P < 0.001) and in regrafts for herpes and keratoconus (P < 0.001). In regrafts for keratoconus, synechialysis was also associated with decreased survival (P < 0.01). Cataract extraction and lens implantation did not have a significant impact on survival (P > 0.05), nor was there any difference in survival after intracapsular versus extracapsular cataract extraction. The causes of failure are listed in Table 3. The most common category in keratoconus was "un-

Table 3. Allograft Rejection and Failure: Primary Grafts and Regrafts Combined-Comparison in Cases with and without Rejection Rejections

No Rejections

All Grafts Combined (total)

68 (18.3) 11 (16.2)

304 (81.7) 20 (6.6)

372 36 (8.3)

9 (81 .8) 0 2 (1 8.2) 0 0 0

0 12 (60.0) 1 (5.0) 2 (10.0) 1 (5.0) 4 (20..0)

9 (29.0) 12 (38.7) 3 (9.7) 2 (6.5) 1 (3.2) 4 (12.9)

21 (19.1) 11 (52.4)

89 (80.9) 23 (25.8)

110 34 (30.9)

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Keratoconus Total no. of grafts (%) No. of failures (%)* Primary cause of failure Rejection (%)t Unknown, late (%) Herpes simplex keratitis (%) Primary failure (%) Microbial ulcer (%) Other (%) Herpes simplex keratitis Total no. of grafts (%) No. of failures (%)* Primary cause of failure Rejection (%)t Unknown, late (%) Herpes simplex keratitis (%) Primary failure (%) Microbial ulcer (%) Other (%)

5 (45.5) 1 (9.1) 2 (18.2) 1 (9.1) 0 2 (18.2)

0 5 (21.7) 7 (30.4)t 0 4 (17.4) 7 (30.4)

5 (14.7) 6 (17.6) 9 (265) 1 (2.9) 4 (11 .8) 9 (26.5)

* Percentage of total number of grafts in category. t Percentage of failed grafts in category. t P < 0.05, chi-square (grafts with versus graft without rejection).

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Table 4. Incidence of Allograft Rejection Episodes Regrafts

Diagnosis Total no. of grafts Grafts with ~ 1 episodes of probable or definite rejection (%) 2 rejection episodes (%) ~ 3 episodes (%)

HSK 72

KC 325

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HSK

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12 (16.6) 5 (6.9) 1 (1.4)

21 (65)

3 (09)

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Fig 9. Allograft rejection and survival in keratoconus. A single rejection episode was not associated with a significant decrease in survival. However, two or more rejection episodes were associated with significantly decreased survival (P = 0.03, Breslow; P = 0.008, Mantel-Cox).

known late failure," whereas the most common identifiable cause of failure in keratoconus was allograft rejection. In herpes simplex keratitis, the most common cause of failure was recurrent herpetic disease, followed by unknown late failure and rejection. Causes of failure in herpes were not significantly different from keratoconus, with the exception of recurrent herpetic disease (P < 0.05). ALLOGRAFT REJECfION

Incidence of rejection episodes. There was an 18.5% incidence of rejection episodes in first grafts for keratoconus, including all episodes of possible and definite rejection combined (Table 4). Of the first grafts, 6.5% had two episodes of rejection and 0.9% had three or more. For regrafts, 17% had one or more episodes, 6.4% had two episodes, and 4.2% had three or more episodes. Of the first grafts for herpes, 16.6% had one or more episodes of rejection, 6.9% had two episodes, and 1.4% had three. 23.7% of regrafts for herpes had a single episode, and, possibly because of the high incidence of failure in this subgroup, none of them had documented multiple rejection episodes. The incidence of rejection episodes in first grafts for herpes was not significantly different from first grafts for 940

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keratoconus (P = 0.85). The incidence of rejection in regrafts for herpes (23.7%) was greater than keratoconus (17.0%), but this difference was not statistically significant (P = 0.62). Only one patient with a first graft for herpes had three documented rejection episodes, whereas three patients with keratoconus had three episodes, one had four, and one had five. In first grafts for keratoconus, the mean length of time until the occurrence of the first rejection episode was 508 days. For second grafts, the interval was decreased to 155 days, and for three or more grafts (14 cases) it was 418 days. In first grafts for herpes, the intervals were 753, 234, and 138 days, respectively. The only interval that was significantly different was for first grafts (P = 0.02). Impact of rejection on survival. Figures 9 and 10 illustrate the influence of allograft rejection on survival. A single rejection episode did not significantly affect the survival of grafts for keratoconus or herpes. Multiple rejection episodes were associated with decreased survival in both keratoconus and herpes (P < 0.05). Grafts for herpes that experienced one or more rejection episodes had significantly decreased survival when compared with similar grafts for keratoconus (P = 0.001). Causes of graft failure in grafts with rejection episodes. The causes of failure in grafts experiencing rejection episodes are shown in Table 3. In both keratoconus and herpes, rejection itself was the leading cause of failure. In grafts for keratoconus that had rejection episodes, herpetic disease was the second most common cause of failure (18.2% offailures). In grafts for herpes, recurrent herpetic disease was a more frequent cause of failure in grafts that did not experience rejection. Aside from rejection, differences in the identifiable causes of failure between grafts with and without rejection were not statistically significant. Since these data were collected in a retrospective manner, postoperative management, and quantitation of corneal neovascularization were not controlled. Corticosteroid therapy was too variable to enable us to determine its impact on the incidence or timing of rejection episodes or to comment on differences between the various groups and subgroups.

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ALLOGRAFT REJECTION AND SURVIVAL

DISCUSSION Using survival analysis to assess the results of penetrating keratoplasty for herpes simplex keratitis and keratoconus, we have determined that, although the incidence of rejection episodes in these two conditions was similar, the incidence of failure from rejection was markedly different. The importance of using survival analysis for the measurement of success in penetrating keratoplasty has been emphasized previously. I 1,13-15 This technique minimizes the bias related to differing lengths offollow-up and graphically indicates the probability of graft survival. The prognosis for success in penetrating keratoplasty is related to the preoperative diagnosis. 21 ,26 Although patients with herpes simplex keratitis are a somewhat heterogeneous group in comparison to those with keratoconus, we believed that it would be useful to compare and contrast them because both are frequent indications for penetrating keratoplasty in young patients l2 ,27 in whom long-term follow-up data are readily available, and who would be expected to have the highest incidence ofrejection. 19 In our series, the probability of graft survival at 2 years (75.6%) compares favorably with the previously reported figure of 69% II when a similar analysis of survival was done. Survival analysis has not yet been used in the study of penetrating keratoplasty for keratoconus. Allograft rejection is the leading cause of corneal graft failure, 1,2 but its precise relationship to graft survival has not been determined. Studies of rejection episodes in keratoconus have noted an incidence ranging from 6.3 7 to 39%,10 but more frequently, it has been reported to range from 13 to 27%.2,8,28 The incidence of allograft rejection episodes in herpes simplex keratitis has ranged from a low of 0% in a small series4 to as high as 58% when liberal criteria such as ours, were used to make the diagnosis. 2o More commonly, the reported incidence of rejection episodes has ranged from 20 to 35%.12,29 Figures derived from studies done before the recognition that subepithelial infiltrates are an important sign of allograft rejection may have underestimated its true incidence. In our patients, as in a previous study,19 subepithelial infiltrates were a much more common manifestation of rejection in keratoconus than in herpes simplex keratitis (data not shown). The similar incidence of rejection episodes in first grafts for keratoconus and herpes simplex keratitis may be related to a variety of factors. Since some herpes simplex keratitis patients remained on topical corticosteroids for prolonged periods of time because of their underlying disease, it is possible that this may have actually suppressed some of the manifestations of rejection, such as subepithelial infiltrates. The impact of individual rejection episodes in herpes simplex keratitis tended to be more severe than in keratoconus, as evidenced by the decreased survival of grafts for herpes simplex keratitis with rejection when compared with keratoconus. This has been noted previously by others. II Further-

more, multiple rejection episodes were far more common in keratoconus, possibly because of the longer survival of these grafts and the higher incidence of graft failure in herpes simplex keratitis after a single episode of rejection. We categorized as rejection those episodes of acute anterior segment inflammation that were not associated with a rejection line. Some of these cases may have actually represented herpetic keratouveitis, a diagnostic problem which has been recognized previously.4,20,21,30 Because allograft rejection is the most significant risk factor for survival, we agree that such questionable episodes are best classified and treated as presumed rejection. II ,20 In studying the preoperative diagnoses related to decreased survival in penetrating keratoplasty for herpes simplex keratitis and keratoconus, only cataract and glaucoma were found to be significant risk factors, presumably because of the more complicated nature of these cases. Similarly, of the associated surgical procedures, only vitrectomy was associated significantly with decreased survival in grafts for both groups. Others have noted this association,21 which is also probably related to the more complicated nature of patients requiring this procedure at the time of grafting. Allograft rejection was the single leading identifiable cause of failure in keratoconus. However, failures definitely due to rejection accounted for only 9 of 372 grafts (2.42%). Therefore, although rejection is a significant problem associated with penetrating keratoplasty for keratoconus, the fact that it so infrequently results in graft failure argues in favor of the continued use of penetrating keratoplasty as the procedure of choice in the surgical management of this condition. In grafts for herpes simplex keratitis with rejection episodes, rejection was also the leading identifiable cause of failure. These grafts had significantly decreased survival when compared with grafts for keratoconus which had rejection episodes. Although recurrent herpes simplex keratitis was a frequent cause offailure in grafts for herpes, as noted previously, 11,30 it was also a frequent cause of failure in grafts for keratoconus which were treated for rejection. It has been suggested that steroid therapy for rejection episodes in grafts for herpes simplex keratitis increases their susceptibility to recurrent herpes simplex keratitis. I A similar mechanism may also be operative in keratoconus. Nonimmunologic factors are also important determinants of graft survival in herpes simplex keratitis because the high failure rate we noted in these grafts cannot be explained on the basis of an increased incidence of allograft rejection. Many of these grafts succumbed to sequelae of herpetic disease, including persistent epithelial defects and stromal keratitis. The decreased length of follow-up in grafts for herpes simplex keratitis when compared with keratoconus is undoubtedly owing to their decreased survival. In addition, most of the "unknown late" failures probably represent failures from occult or undiagnosed episodes of allograft rejection. Unknown late failures and failures resulting from documented rejection episodes combined represented the leading cause of failure in all groups studied. 941

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For both the low- (keratoconus) and high-risk (herpes simplex keratitis) diagnoses, a single regraft was not associated with a statistically significant decrease in survival, but additional regrafts carried a poor prognosis in both groups. Other investigators have noted an increased incidence of rejection as well as a high-failure rate in regrafts. 2,16,17,18 The propensity toward rejection and failure in regrafts may be related to the chronic anterior chamber inflammation associated with rejection episodes. The release of immunologic mediators by stimulated sensitized lymphocytes may result in enhanced expression ofHLA-DR antigens by the endothelium. 31 ,32 Therefore, strategies which attempt to decrease the antigenicity of donor tissue 3 may be useful in high-risk cases. Additional measures, possibly including histocompatibility matching,13,14,33,34 local 35 or systemic 36 immunologic modulation with cyclosporine may be required to improve the success rate in patients requiring multiple regrafts.

ACKNOWLEDGMENTS The authors thank John Haugaard, MS, Emory University Computing Center, for his help with statistical analysis.

REFERENCES 1. Khodadoust AA. The allograft rejection reaction: the leading cause of late failure of clinical corneal grafts. In: CIBA Foundation Symposium. 15 (newseries) Corneal Graft Failure. Amsterdam: Elsevier, 1973; 151-67. 2. Arentsen JJ. Corneal transplant allograft reaction: possible predisposing factors. Trans Arn Ophthalrnol Soc 1983; 81:361-402. 3. Braude LS, Chandler JW. Corneal allograft rejection: the role of the major histocompatibility complex. Surv Ophthalmol 1983; 27:290305. 4. Polack FM, Kaufman HE. Penetrating keratoplasty in herpetic keratitis. Am J Ophthalmol 1972; 73:908-13. 5. Cohen EJ, Laibson PR, Arentsen JJ. Corneal transplantation for herpes sirnplex keratitis. Am J Ophthalmol1983; 95:645-50. 6. Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammatory corneal thinning disorders. Surv Ophthalmol 1984; 28:293-322. 7. Moore TE Jr., Aronson SB. Results of penetrating keratoplasty in keratoconus. Adv Ophthalmol1978; 37:106-8. 8. Buxton IN, Schuman M, Pecego J. Graft reactions after unilateral and bilateral keratoplasty for keratoconus. Ophthalmology 1981; 88: 771-

3. 9. Paglen PG, Fine M, Abbott RL, Webster RG. The prognosis for keratoplasty in keratoconus. Ophthalmology 1982; 89:651-4. 10. Chandler JW, Kaufman HE. Graft reactions after keratoplasty for keratoconus. Am J Ophthalmol 1974; 77:543-7. 11. Cobo LM, Coster DJ, Rice NSC, Jones BR. Prognosis and management of corneal transplantation for herpetic keratitis. Arch Ophthalmol 1980; 98:1755-9. 12. Wilhelmus KR, Coster DJ, Donovan HC, et al. Prognosis indicators of herpetic keratitis. Analysis of a five-year observation period after corneal ulceration. Arch Ophthalrnol 1981; 99:1578-82.

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13. Foulks GN, Sanfilippo FP, Locascio JA III, et al. Histocompatibility testing for keratoplasty in high-risk patients. Ophthalrnology 1983; 90:239-44. 14. Volker-Dieben HJ, Kok-van Alphen CC, D'Amaro J, de Lange P. The effect of prospective HLA-A and -B matching in 288 penetrating keratoplasties for herpes simplex keratitis. Acta Ophthalmol 1984; 62:513-23. 15. Stulting RD, Sumers KD, Cavanagh HD, et al. Penetrating keratoplasty in children. Ophthalmology 1984; 91:1222-30. 16. Khodadoust AA, Abizadeh A. The fate of corneal regrafts after previous rejection reactions. In: Silverstein AM, O'Connor GR, eds. Imrnunology and Immunopathology of the Eye. New York: Masson, 1979; 167-73. 17. Khodadoust AA, Karnema Y. Corneal grafts in the second eye. Cornea 1984; 3:17-20. 18. Insler MS, Pechous B. Visual results in repeat penetrating keratoplasty. Arn J Ophthalmol1986; 102:371-5. 19. Alldredge ~C, Krachmer JH. Clinical types of corneal transplant rejection. Their rnanifestations, frequency, preoperative correlates, and treatment. Arch Ophthalmol1981; 99:599-604. 20. Rice NSC, Jones BR. Problems of corneal grafting in herpetic keratitis. In: Jones BR, ed. CIBA Foundation Symposium 15 (newseries). Corneal Graft Failure. Amsterdam: Elsevier, 1973; 221-39. 21. Foster CS, Duncan J. Penetrating keratoplasty for herpes simplex keratitis. Am J Ophthalmol 1981; 92:336-43. 22. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457-81. 23. Breslow N. A generalized Kruskal-Wallis test for comparing K samples subject to unequal pattern of censorship. Biometrika 1970; 57:579-94. 24. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50:163-70. 25. Krall JM, Uthoff VA, Harley JB. A step-up procedure for selecting variables associated with survival. Biometrics 1975; 31:49-57. 26. Volker-Dieben HJM. Different influences on corneal graft survival in 539 transplants. Doc Ophthalmol1984; 57:43-56. 27. Robin JB, Gindi JJ, Koh K, et al. An update of the indications for penetrating keratoplasty: 1979 through 1983. Arch Ophthalmol 1986; 104:87-9. 28. Donshik PC, Cavanagh HD, Boruchoff SA, Dohlman CH. Effect of bilateral and unilateral grafts on the incidence of rejections on keratoconus. Am J Ophthalmol1979; 87:823-6. 29. Knobel H, Hinzpeter EN, Naumann GOH. Keratoplasty in herpetic corneal disease. Doc Ophthalmol Proc Ser 1985; 44:311-17. 30. Pfister RR, Richards JSF, Dohlman CH. Recurrence of herpetic keratitis in corneal grafts. Am J Ophthalmol 1972; 73:192-6. 31. Young E, Stark WJ, Prendergast RA. Immunology of corneal allograft rejection: HLA-DR antigens on human corneal cells. Invest Ophthalmol Vis Sci 1985; 26:571-4. 32. Dreizen NG, Whitsett CF, Stulting RD. Modulation of histocompatibility antigen expression on cultured corneal epithelial cells and stromal fibroblasts. ARVO Abstracts. Invest Ophthalmol Vis Sci 1986; 27 (Suppl):133. 33. Stark WJ, Taylor HR, Bias WB, Maumenee AE. Histocompatibility (HLA) antigens and keratoplasty. Am J Ophthalmol 1978; 86:595604. 34. Stark WJ, Taylor HR, Datiles M, et al. Transplantation antigens and keratoplasty. Aust J Ophthalmol 1983; 11 :333-9. 35. Hunter PA, Garner A, Wilhelm us KR. Corneal graft rejection: a new rabbit model and cyclosporin-A. Br J Ophthalmol 1982; 66:292-302. 36. Bell TAG, Easty DL, McCullagh KG. A placebo-controlled blind trial of cyclosporin-A in prevention of corneal graft rejection in rabbits. Br J Ophthalmol 1982; 66:303-8.

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Discussion by

Kirk R. Wilhelmus, MD Allograft rejection is one of the most important causes of graft failure after penetrating keratoplasty. Although improvements in surgical technique and donor storage have decreased the occurrence of corneal graft failure, an immunologic reaction limits the success and scope of corneal transplantation. Dr. Epstein and his associates at Emory University School of Medicine have reviewed their experience with graft survival after corneal surgery performed for two specific indications: keratoconus (KC) or herpes simplex keratitis (HSK). In reviewing their results, I would like to raise some issues that tend to occur in large retrospective studies; by responding to these concerns, it may be easier to appreciate the importance of this article. The first issue is the patient population reported: the two patient groups initially appear very disparate. One group includes patients with a bilateral corneal dystrophy who have little if any active corneal inflammation or vascularization and generally do not need to undergo regrafting, 13% of this series.

From the Cullen Eye Institute, Baylor College of Medicine, Houston. Reprint requests to Kirk R. Wilhelm us, MD, Cullen Eye Institute, 6501 Fannin Street, Houston, TX 77030.

The second group includes a variety of patients with uniocular disease resulting from presumed HSK whose preoperative status ranged from an inactive corneal opacity to active stromal inflammation to acute corneal perforation; one third of this group had had a prior transplant. Despite these differences, the authors state that they chose to compare these two groups because both diagnoses are "frequent indications for penetrating keratoplasty in young adults." Information regarding the entire transplant population from which these subsets were taken was not provided, but this supposition is probably true even though only 5 to 6% of grafts are done for these two reasons. The second stated reason for selecting these particular corneal conditions was that they "represent two extremes with regard to prognosis." Perhaps the authors were anticipating that HSK represents a relatively poor prognosis and chose KC patients to highlight the differences in expected outcome. Let us look into these two patient populations. For KC, this study provides data on the largest series yet reported, made even more remarkable as coming from a single center where patients were followed for at least 1 year. Previous reports of keratoplasty for KC have shown a wide range of the risk of graft rejection (Table 1), and the authors' rate of 18% corresponds very closely with the overall average. Using currently available technology, this incidence should prove

Table 1. Selected Series of Penetrating Keratoplasties Done for Keratoconus

References

Total

Rejection (%)*

Anseth, 1967 Keates and Falkenstein, 1972 Chandler and Kaufman, 1974 Gibbs and associates, 1974 Pouliquen and Rocher, 1975 Cherry and associates, 1975 Vannas and associates, 1977 Moore and Aronson, 1978 Donshik and associates, 1979 Troutman and Gaster, 1980 Buxton and associates, 1981 Alldridge and Krachmer, 1981 Linn and associates, 1981 Malbran and Fernandez-Meijide, 1982 Paglen and aSSOCiates, 1982 Payne, 1982 Ehlers and Olsen, 1983 Arentsen, 1983 Lagoutte and Comte, 1984 Shivitz and associates, 1984 Young and Olson, 1985 Annonier and associates, 1986 Wood and Tuberville, 1986 McDonald and associates, 1987 Epstein and associates

50 27 53 47 105 103 56 64 124 82 134 33 55 105 326 322 54 178 31 151 76 32 161 17 372

3 (6) 2 (7) 20 (38) 19 (40) 59 (56) 20 (19) 7 (12) 4 (6) 23 (19) 6 (7) 28 (21) 6 (18) 10 (18) 16 (15) 30 (9) 32 (10) 5 (9) 28 (16) 8 (26) 12 (8) 16 (21) 8 (25) 38 (24) 8 (47) 57 (15)t

Follow-up Period (years)

0.75-8 1-6 NR

6 1-12 NR

0.25-7 >1 0.25-5 NR

0.7 -10 1-6 2.5-35 0.5-11 3-34 0.5 3-12 1.5-6.25 1-4 0.5-11 0.2-2 70.5 NR

0.3-5 1-7

Do Bilateral Grafts Predispose to Rejection? NR NR No NR Yes NR NR NR Yes No No NR NR No NR No Yes No No No No NR No NR NR

NR = not recorded. * For comparison purposes includes mainly endothelial rejection, excludes cases manifested principally as epithelial rejection or subepithelial infiltrates. t All forms of rejection = 68 (18%).

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Table 2. Selected Series of Penetrating Keratoplasties Done for Herpetic Keratitis

Reference

Total

Polack and Kaufman, 1972 Gibbs and associates, 1974 Langston and associates, 1975 Patten and associates, 1976 Fine and Cignetti, 1977 Cobo and associates, 1980 Alldridge and Krachmer, 1981 Witmer, 1981 Pouliquen and associates, 1981 Foster and Duncan, 1981 Cohen and associates, 1983 Arentsen, 1983 Lagoutte and Chahal, 1984 Shivitz and associates, 1984 Epstein and associates

26 168 60 20 49 132 11 60 100 82 107 74 81 34 110

Rejection

(%)*

1 (4) 79 (47) 37 (62) 4 (20) 10 (20) 38 (29) 3 (27) 13 (22) 22 (22) 38 (46) 22 (21) 16 (22) 30 (37) 5 (15) 17 (15)t

Follow-up Period (years) NR

6 2 0.2-5 1-3 2-13 1-6 NR

1-5 2-10 1-12 1.5-6.25 >0.5 0.5-11 1-7

Do Preoperative Vessels Predispose to Rejection? NR Yes Yes NR No Yes Yes NR Yes Yes No NR Yes Yes NR

NR = not recorded. * For comparison purposes includes mainly endothelial rejection, excludes cases manifested principally as epithelial rejection or subepithelial infiltrates. t All forms of rejection = 21 (19%).

useful when informing patients of their chances for postoperative complications. Unfortunately, the authors failed to answer the lingering question whether there is an increased incidence of graft rejection in patients having bilateral keratoplasties. Combining both unilateral and bilateral grafts performed in KC patients could be a possible pitfall, as the paired transplants may be positively correlated. Until further data or other improvements become available, corneal transplantation of each eye with KC should prudently be separated by at least I year. For patients with presumed HSK, literature reports show an even greater range of variability. The authors report that rejection developed in 19% of their patients with prior herpes, a rate in keeping with other recent large series (Table 2). However, differentiating between graft rejection and recurrent HSK may be difficult. Laboratory criteria need to be developed to assist clinicians in making these distinctions. In their analysis, the authors have shown what preoperative and operative factors are associated with the ocurrence of a subsequent allograft reaction. Recipient corneal vascularization is generally understood to be an important prognostic factor; therefore, it was surprising to find that this large series did not report a significant correlation with graft survival. This study does corroborate, however, that the decision to perform keratoplasty in patients with a previously failed graft must be cautiously considered: a substantial proportion of regrafts will fail from a later rejection episode. Some operative variables have also been considered to have a direct impact on later graft survival. Although the authors did not mention the effect of a large graft diameter, they did find that other associated procedures such as anterior vitrectomy and synechiolysis may affect outcome-perhaps by indicating concurrent anterior segment structural changes. Using the extensive database of information accumulated on their patients followed for at least I year after keratoplasty, the study provides an elegant statistical analysis with regard to graft outcome and prognostic factors. Used by insurance ac-

944

tuaries for many years and refined for assessing cancer chemotherapy, I this technique can be generalized to analyze not only patient survival but also graft survival. 2 Calculation of the actuarial survival curve is the most sensible way to present follow-up data for many kinds of ophthalmologic studies and is one of the most important lessons of this article. In using this technique, the authors should probably have included patients who were lost to follow-up in order to avoid a potential source of bias. The survival curves show excellent surgical results after 5 to 7 years of follow-up: 90% of all grafts performed in KC patients were clear, and 69% of corneal transplants in patients with HSK survived. Early recognition of an adverse event such as an allograft reaction with specific, appropriate therapy must be decisive factors for these excellent outcomes. Based on this study and related information, guidelines for advising patients about their chances for success can be clearly stated, and some suggestions for preventing the occurrence of an allograft reaction can be immediately put into practice: appropriate case selection, fastidious surgical technique, periodic postoperative follow-up, and judicious steroid use. The study also provides useful information for the future assessment of innovative maneuvers such as cyclosporine and HLA matching. I would like to thank the authors for providing quantitative information that can provide a basis for informing our patients and in designing protocols to improve the survival of a corneal transplant. References 1. Peto J. The calculation and interpretation of survival curves. In: Buyse ME, Staquet MJ, Slyvester RJ, eds. Cancer Clinical Trials. Methods and Practice. Oxford: Oxford University Press, 1984; 361-80. 2. Coster DJ. Factors affecting the outcome of corneal transplantation. Ann Roy Coli Surg Eng11981; 63:91-7.