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Factors Predictive of Corneal Graft Survival
Factors Predictive of Corneal Graft Survival Report from the Australian Corneal Graft Registry
Keryn A. Williams, PhD, l David Roder, DDSc, MPH, 2 Adrian Esterman, MSC, 2 Sylvia M. Muehlberg,l Douglas]. Coster, FRCS,l on behalf of all contributing surgeons
R
isk factors for graft failure after penetrating keratoplasty were investigated in 961 patients from records collected prospectively by the Australian Corneal Graft Registry. The most common cause of graft failure was irreversible rejection. A multivariate proportional hazards regression analysis indicated that the key predictors of graft failure were: an indication for graft other than keratoconus or corneal dystrophy; a failed previous graft (ipsilateral eye); aphakia; inflammation at the time of graft; presence of an anterior chamber or iris-clip intraocular lens; graft size outside the range of 7.0 to 7.9 mm diameter; and corneal vascularization occurring in the postoperative period. Ophthalmology 1992; 99:403-414
Multicenter registries exist for most forms of transplantation, to provide information on graft outcome. A major advantage of such registries is that a large body of data can be accumulated rapidly. However, the establishment of registries for corneal transplantation has been relatively slow, perhaps in part because the procedure is frequently performed by ophthalmologists working under a variety of conditions, including solo practice, rather than in a small number of designated transplant centers. The Australian Corneal Graft Registry began operating in May 1985, to overcome a deficiency in the data available on corneal transplantation in this country. Voluntary contributions of information were solicited from all registered specialists performing corneal grafts in Australia.
Originally received: April 9, 1991 . Revision accepted: November 8, 199 1. 1 Department of Ophthalmology, Flinders University of South Australia, Bedford Park. Epidemiology Branch, South Australian Health Commission, Adelaide, Australia. Supported by the NH & MRC (grant no. 890858), the Pank Ophthalmic Trust, and the FMC Research Foundation. Reprint requests to Keryn A. Williams, PhD, Department of Ophthalmology, Flinders Medical Centre, Bedford Park SA 5042, Australia.
2
We estimate that information is now being collected on approximately 75 % of all corneal grafts performed in the country. Somewhat similar registries are in operation elsewhere: The Eurotransplant Foundation (Leiden, The Netherlands) has collected data on corneal transplantation for some years, and prospective data on corneal grafts are being collected by United Kingdom Transplant (Bristol, United Kingdom) and by the Canadian Registry. However, most published reports on corneal graft outcome to date have originated from individual centers or surgeons l - 3 or have described data limited to specific aspects of corneal transplantation, including studies of penetrating keratoplasty in children 4 and of the outcome of corneal transplantation for bullous keratopathy,5-7 corneal ulcers,8.9 herpetic keratitis,IO-14 and keratoconus. 10.1 5,16 Recent reports have described the outcome after triple procedures,I7,18 the incidence and treatment of glaucoma after corneal transplantation,19.20 and the assessment of visual outcome after the graft procedure. 5.21 The purposes of the Australian Registry are fourfold. 22,23 First, data are collected on the practice of corneal transplantation for surgical audit. For this purpose, the assessment of graft survival and visual outcome is important. Second, the Registry aims to disclose risk factors for graft failure so that aspects warranting further research may be identified. Third, the data collected are made available for promotional purposes and for the strength-
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ening of donor procurement services. Finally, the information provided by the Registry allows ophthalmologists to counsel their patients as to likely risks and outcomes. In this report, we have identified risk factors for graft failure that have emerged in the initial years of the Registry's operation.
Materials and Methods Entry and Follow-up The study period for the present analyses extended from May 5, 1985, to July 4, 1989. Data were entered into the Registry by the contributing surgeon as soon as possible after the graft, and follow-up information was requested at 12-month intervals. Information was obtained by mail, using well-validated proformas; missing data were routinely sought by follow-up letter. Each graft was followed until graft failure or until the death or loss to follow-up of the patient. By July 4, 1989, information had been contributed on 1485 grafts (both penetrating and lamellar), of which follow-up had been acquired for 1064 at least once. The 220 contributing ophthalmologists and other practitioners were from all Australian states and territories. Approval for the establishment and continuation of the Registry was obtained from the institutional Clinical Investigations Committee. Statistical Analyses On July 5, 1989, follow-up data had been collected for 1035 penetrating corneal grafts. However, some patients with bilateral grafts and/or repeat grafts were represented within the Registry. To ensure statistical independence in these analyses, one penetrating graft per patient was selected at random in cases where a patient had had more than one graft entered into the Registry. This left 961 penetrating corneal grafts for analysis. Initially, various risk factors were studied separately and Kaplan-Meier survival functions were constructed to provide a graphical record of graft survival at 1, 2, and 3 years after graft. 24 - 26 For surviving grafts, trial time was calculated as the number of days between the date of graft and the date on which the patient was last seen. For failed grafts, trial time was calculated as the number of days between the date of graft and the date of failure. Cox proportional hazards regression was used to investigate associations between potential risk factors and the risk of graft failure 27 ; 95% confidence limits about the relative risk were obtained using the formula: exp {[b ± 1.96x s.e. (b)]}. Multivariate analysis was performed using a manual backward elimination procedure to identify the subset of risk factors most predictive of graft failure. For the sake of parsimony, variable categories were combined when they presented similar levels of risk in the univariate analysis. Proportionality was tested using stratified analyses. The absence of multicollinearity was checked to ensure the stability of the underlying model. The risk of graft failure for each value of the factor was compared with the risk for a specified reference value.
404
The category with the largest number of subjects was chosen as the reference category for the computation of risk ratios to minimize the standard error of the relative risk. In the case of the quantitative variables of graft size, recipient age at graft, donor age, and death to enucleation time, categories were chosen as follows. For graft size, divisions of 0.5 mm (reflecting the size increments actually used by contributing surgeons) were selected within the range of 7 to 9 mm diameter and the category with the largest number of subjects was then chosen for reference. Recipient age at graft ranged from 8 months to older than 90 years; a histogram plot (not shown) indicated a bimodal distribution with peaks at approximately 35 to 75 years. Two categories (~50 and >50 years), each containing approximately half of the total subjects, were selected for analysis, the reference category being the larger of the two. Donor age (range, 2 to 93 years) was analyzed in quartiles. As the recommended maximum death to enucleation time is 12 hours, two strata (0 to <6 and 6 to 12 hours) were initially constructed, but a third stratum (> 12 hours) was found to be necessary to accommodate the 25 subjects outside the stratum of 0 to 12 hours.
Definition of Risk Factors A history of past inflammation was recorded if the individual was specifically reported to have had such an episode, if the patient had had one or more previous grafts in the ipsilateral eye, if any intraocular surgery had ever been performed on that eye, or if there was a history of the use of topical corticosteroids in that eye within the 4 weeks preceding the graft. Vessel ingrowth into the cornea at the time of graft was scored on a scale of 0 to 4, with 0 representing no growth in any quadrant extending to the graft-host junction, 1 representing growth of vessels extending to the graft-host junction in 1 quadrant only, 2 representing such growth in 2 quadrants, 3 representing growth in 3 quadrants, and 4 being vessel ingrowth in 4 quadrants. No distinction was made between superficial or deep vessels, patent or ghost vessels, or single or multiple vessel leashes. For the purposes of this analysis, vascularization was considered to exist if the score was equal to or greater than 1. After corneal transplantation, the presence of even one vessel leash extending into the graft was considered enough to classify that graft as vascularized. The intraocular pressure (lOP) was considered to be raised if a reading of 25 mm of mercury or greater was made by applanation tonometry. Presenting diseases, indications for graft, postoperative complications, and reasons for graft failure were coded using the ICD.9.CM system (United States Department of Health and Human Services). Corneal dystrophies included cases of Fuchs, anterior, macular, lattice, granular, and Reis-Buckler's dystrophies, as well as some unspecified dystrophies. The category of corneal scars was heterogeneous and included cases of trachomatous scarring, herpetic scarring in the absence of active disease, and corneal opacities resulting from old interstitial keratitis, abscesses, trauma and burns, as well as some of unknown
Williams et al . Australian Corneal Graft Survival Table 1. Synopsis of the Data Base at Last Follow-up Total number of grafts entered· Number of grafts with completed third follow-up Number of grafts with completed second follow-up Number of grafts with completed first follow-up Number of grafts with no follow-up as yet Number of surviving grafts t Number of failed graftst
1485 186 219 659 421 925 139
• As of July 4, 1989.
t Excludes those not yet followed.
pathogenesis. Patients with active herpetic disease at the time of graft were classified separately, irrespective of whether or not they also had corneal scarring. Information was collected on both recipient bed size and donor button size; for the purpose of examining the influence of graft size, the former was used. Because not all geographic areas within Australia are served by eye banks, only a proportion of corneas used for transplantation are collected, assessed, and distributed by the five existing banks. Surgeons in other areas (including some major cities and population centers) must organize the harvesting and assessment of donor corneas themselves, without the benefit of any structured organization. Corneas harvested through the efforts of individual ophthalmologists, rather than having been processed by an eye bank, have been classified as having been privately procured. The standard contraindications to corneal donation are widely accepted; apart from the requirements that
corneal donors be seronegative for the human immunodeficiency virus and for hepatitis B virus, any other assessment procedures undertaken on privately procured corneas are at the discretion of the ophthalmologist concerned.
Definition of Graft Failure, Rejection, and Complications Primary graft non functions were defined as grafts that did not thin and clear in the postoperative period. The trial time for such grafts was arbitrarily adjusted to 1 day. Any existing graft that was replaced by another in the same eye, irrespective of graft clarity and for whatever reason, was classified as a failed graft. An example in this category would be a clear graft with an unacceptably high degree of irregular astigmatism, not improved by refractive surgery, which was then replaced. In all other cases, graft failure was defined as edema and irremediable loss of clarity in a previously thin, clear graft. The day of failure was the first day the patient was seen with an edematous, opaque graft that subsequently failed to thin and clear. Rejection was defined as the development of a rejection line (epithelial or endothelial) or a unilateral anterior chamber reaction with corneal infiltrates and spreading corneal edema in a previously thin, clear graft. The reasons for graft failure were left to the clinical judgment of the ophthalmologist. In a number of cases, the cause of graft failure was listed as corneal edema or bullous keratopathy. Some of these cases were found to be patients who presented late to their ophthalmologist, at a time when no definite decision could be made as to the likely pathogenesis underlying the graft failure: the cause of graft failure was then listed as unknown.
Table 2. Demographic Data on Corneal Graft Recipients All grafts
Male Female Indication for Penetrating Keratoplasty Keratoconus· 475 (33%) Bullous keratopathyt 330 (23%) Failed previous graftt 193 (13%) Corneal scars§ 175 (12%) Corneal dystrophies II 81 (6%) Herpetic keratitis§ 46 (3%) Corneal ulcers·· 40 (3%) Miscellaneous 98 (7%)
Recipient sex
Total
1438
726 (49%) 759 (51%)
All patients
669 (49%) 701 (51%)
Male Female Indication for Lamellar Graft Recurrent pterygium Marginal/ scleral ulcers Failed previous graft Familial dermoid Scleral degeneration Miscellaneous
17 (36%) 11 (23%) 4(9%) 4(9%) 4(9%) 7 (15%)
Total
47
• 13 with acute hydrops.
t193 with pseudophakic, 59 with aphakic bullous keratopathy.
t 33 graft rejections,
4 primary graft failures.
§ 42 with history of herpes simplex virus infection, 16 with history of trachoma, 12 with history of trauma, 7 with history of bums; 4 with adherent leukoma.
II 64 with Fuchs dystrophy, 5 unspecified, 3 anterior, 3 macular, 3 lattice, 2 granular, 1 Reis-Buckler's dystrophy. 11 3 with Herpes zoster ophthalmic us . •• 30 with perforation.
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Any development with the potential to compromise graft outcome was considered to be a complication. Postoperative complications were collected in two ways. First, a number of specified complications (development/occurrence of exposed suture; stitch abscess; breakage/premature loosening of graft suture; retained suture material; wound dehiscence; neovascularization of the graft; synechiae; uveitis; rise in lOP; fixed, dilated pupil; cataract; rejection episode; herpetic recurrence; early changes of bullous keratopathy), refractive and related errors (anisometropia; greater than 5 diopters astigmatism; refraction: sphere, cyl, axis), and factors potentially affecting vis~al outcome but unrelated to the graft (cataract; aphakia; amblyopia; retinal detachment; cystoid macular edema or senile macular degeneration) were listed, requiring a yes/no answer. Second, contributors were asked to specify any other relevant complications, information, or departures from their preferred treatment.
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Figure 1. Recipient and donor age range (in decades) at the time of graft.
Descriptive Features of the Data Base Descriptive features of the data base are presented in Table I. At the end of the study period, 1485 grafts in 1370 patients had been entered into the Registry. Of the 115 patients who had been entered into the Registry on more than 1 occasion, 57 had had 1 graft in each eye, 48 had had 2 grafts in the same eye, 7 had had 3 grafts in the same eye, 1 had had 2 grafts in 1 eye and 1 in the other, and 2 patients had had 4 grafts in the same eye. Graft losses through patient death or loss to follow-up were low (31 and 41 , respectively). Demographic features of recipient and donor populations are presented in Tables 2 and 3 respectively; recipient and donor ages are shown in Figure 1. The recipient population was unexceptional with respect to sex distribution (approximately equal numbers of males and females were grafted) and age at graft. Recipient age showed a bimodal distribution, with peaks at
Table 3. Demographic Data on Corneal Graft Donors Donor sex
Male Female Unknown
Total Cause of donor death Heart/coronary artery disease CVA/hemorrhage Cancer T rauma/accident Pulmonary disease Miscellaneous Total eVA = cerebrovascular accident.
406
896 (60%) 525 (35%) 64(4%) 1485 620 (42%) 238 (16%) 197 (13%) 176 (12%) 133 (9%) 121 (8%) 1485
around 35 and 75 years corresponding to grafts performed predominantly for keratoconus and bullous keratopathy, respectively. Sixty percent of corneal donors were male, with heart and coronary artery disease, cerebrovascular accidents, hemorrhage, cancer, and trauma accounting for 83% of donor deaths. Forty-seven percent of donor corneas were processed through an eye bank and came from a variety of sources, including public hospitals, coroners' mortuaries, private hospitals, and funeral directors' rooms, whereas 50% were procured privately by individual ophthalmologists, largely (88%) from public hospitals. The source of the donor cornea was not recorded in the remaining 3% of cases. Approximately 3% of grafts registered were lamellar, slightly fewer than recorded elsewhere. 28 The leading indication for lamellar keratoplasty was recurrent pterygium.
Graft Failures and Complications after Graft Placement The primary reasons given for graft failure are presented in Table 4; in cases where the cause offailure was believed to be multifactorial, the precipitating event that eventually led to graft failure was chosen. Irreversible immunologic rejection was the most common cause of graft failure. In a number of cases, graft rejection and herpes simplex virus recurrences were recorded as joint causes of failure, a not unexpected combination. Early signs of impending graft failure were reported in a further 15 grafts. Complications after graft placement, which affected the corneal graft, are shown in Table 5; problems relating t? graft sutures were the most commonly reported comphcations. Retained suture material was considered as a complication because of the propensity of such material to induce vessel ingrowth. Astigmatism and rejection episodes also were frequently noted complications. The
Williams et al . Australian Corneal Graft Survival Table
4.
Precipitating Cause of Corneal Graft Failure
Precipitating Cause of Failure
No.
Irreversible rejection Sequelae of raised lOP Herpes simplex virus recurrence Primary graft nonfunction Suppurative keratitis Corneal ulceration Wound dehiscence, trauma, leak Pseudophakic bullous keratopathy Endophthalmitis Miscellaneous Unknown
59* 18t 9'1' 8 7§ 711
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Total lOP
Percent
42 13 6 6 5 5 4 4 2 3 9 100
intraocular pressure.
• With herpes simplex virus recurrence (5), glaucoma (4), suppurative keratitis (3), ulcer (2), iritis (1), herpes simplex virus recurrence and glaucoma (1).
t With uveitis (1), abscess (1), perforated ulcer (1). t With perforation (3), uveitis (1). § With Mycobacterium fortuitum, Moraxella sp, Staphylococcus epidermidis (1 case each).
II With iris prolapse (2). 11 With perforation (2). •• With rheumatoid arthritis (1).
tt Sequelae of retinal detachment (2), ectasia with peripheral synechiae (1), herpes zoster ophthalmicus with iritis (1).
number of rejection episodes (reversible and irreversible) that occurred within 1, 2, and 3 months of suture removal was 13, 6, and 4, respectively (14% of all episodes of rejection).
Graft Survival: Overall and by Risk Factor Overall, for the 1035 penetrating corneal grafts registered (no exclusions), the penetrating corneal graft survival rate at 1 year and 3 years after grafting was 91 % and 79%, respectively. These grafts comprised 70% of those entered into the Registry at the time of analysis. The remainder were excluded, either because the first follow-up had not yet been requested (n = 421) or because the grafts, although followed, were lamellar (n = 29). When repeat or bilateral penetrating grafts in the one patient were excluded, graft survival (±standard error) at 1 and 3 years was 91.6% ± 1.0% and 80.9% ± 1.9%, respectively (n = 961). The center effect, in which survival functions were constructed for the 8 individual surgeons contributing 25 or more patients with follow-up (n varied from 25 to 265) to the Registry, indicated that graft survival varied by approximately 25% at 1 year among individual centers (P < 0.0001). The relative risk of graft failure for different values of each factor and the overall statistical significance of each
factor as a single predictor of graft outcome are shown in Table 6. Penetrating corneal graft survival functions for individual factors are presented in Figures 2 to 7. The absence of keratoconus or a corneal dystrophy as the indication for graft and a history of a previous failed graft in the ipsilateral eye were predictors of graft failure (Figs 2A and B). Anterior segment inflammation in the grafted eye before or at the time of graft, corneal vascularization at the time of graft, and a history of raised lOP all were associated with subsequent corneal graft failure (Figs 3A-C). Aphakic grafts and pseudophakic grafts performed less well than phakic grafts (Fig 4A). The type of intraocular lens also was associated with graft outcome; the presence of an iris-clip or an anterior chamber lens was associated with an increased risk of graft failure (Fig 4B); the presence of a posterior chamber intraocular lens was not in itself a risk factor for failure. Another significant influence on outcome was graft size, with sizes larger than 7.9 mm in diameter and very small sizes (less than 7.0 mm in diameter) associated with poorer outcomes (Fig 5A). Eye bank corneas showed poorer survival than did privately procured corneas (Fig 5B). In general, recipients older than 50 years of age at the time of graft had a poorer outcome than younger recipients (Fig 6A), and graft survival decreased as the donor death to enucleation time was prolonged (Fig 6B). In the postoperative period, neovascularization of the graft and herpetic recurrences were both significant risk factors for graft failure (Figs 7A and B) . Factors that did not appear to influence corneal graft survival to a statistically significant extent (P> 0.05) included recipient sex (male, n = 462; female, n = 499); donor sex (male, n = 592; female, n = 333; unknown, n = 36); sex match (male/male, n = 297; female/female, n = 178) or mismatch (male to female, n = 295; female Table 5. Postoperative Complications Specified Complication Suture-related Complication Exposed suture Stitch abscess Breakage/premature loosening Retained suture material Wound dehiscence More than 5 Diopters Irregular Astigmatism One or more Rejection Episodes Neovascularization of the Graft Rise in Intraocular Pressure Synechiae Cataract Herpes Simplex Virus Recurrence Fixed Pupil Uveitis
No.
Percent *
65 13 130 31 28
25
207 170 75 72
37 31 28 19 14
19 16 7 7 3 3 3 2 1
• Expressed as a percentage of the total number of grafts with at least one round of follow-up (n = 1064).
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Table 6. Summary of Estimates of Relative Risks for Corneal Graft Failure, for Separate Risk Factors Stratum
No.
Relative Risk *
Indication for Graft No dystrophy Keratoconus Corneal dystrophy First graft (ipsilateral) Second graft Third/subsequent graft
544 360 57 834 99 28
om (0.03, 0.16)
Inflammation, Vascularization, and lOP Never inflamed Inflamed in past Inflamed at graft Inflamed in past, at graft Unknown A vascular at graft Vascularized lOP never high lOP high in past lOP high at graft Unknown
521 222 37 180 1 680 281 796 116 28 21
1.00 4.40 (2.53, 7.67) 9.60 (5.73, 16.09) 9.64 (4.50, 20.66)
Lens Status Phakic Aphakic Pseudophakic Unknown NoIOL Posterior chamber IOL Anterior chamber IOL Iris-clip IOL
529 120 295 17 666 158 108 29
1.00 4.93 (3,00, 8.10) 2.99 (1.93, 4.62)
Other Factors Graft size 7.5-7.9 mm in diameter Graft size <7.0 mm in diameter Graft size 7.0-7.4 mm in diameter Graft size 8.0-8.4 mm in diameter Graft size 8.5-8.9 mm in diameter Graft size 29.0 mm in diameter Unknown Private procurement Eye bank cornea Recipient age at graft ~50 yrs Recipient age at graft >50 yrs Death to enucleation <6 hrs Death to enucleation 6-12 hrs Death to enucleation > 12 hrs Unknown No vascularization after graft Neovascularization of the graft No herpetic disease after graft Herpetic recurrence after graft
510 17 123 283 13 8 7 530 431 485 476 647 252 25 37 894 67 935 26
1.00 5.43 0.59 1.60 3.31 5.34
lOP = intraocular pressure; lOL = intraocular lens . • 95% confidence limits in parentheses.
t
Cox proportional hazards regression model.
408
PValuet
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0.23 (0.07, 0.73) 1.00 3.80 (2.51,5.76) 5.08 (2.69, 9.58)
1.00 2.74 (1.91, 3.95) 1.00 2.81 (1.85, 4.28) 1.95 (0.79, 4.83)
1.00 0.98 (0.57, 1.69) 2.50 (1.55, 4.02) 5.24 (2.88, 9.53)
(2.46, (0.27, (1.07, (1.20, (1.67,
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11.96) 1.28) 2.41) 9.14) 17.09)
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Figure 2. The effect of (A) keratoconus or corneal dystrophy and (B) graft number in the ipsilateral eye on subsequent corneal graft survival. N represents the number initially at risk.
to male, n = 155, unknown for match or mismatch, n = 36); donor age (examined within the strata: <25 years, n = 108; 25 to 49 years, n = 156; 50 to 74 years, n = 552; >74 years, n = 145); method of corneal storage (strata: McCarey-Kaufman medium, n = 796; moist pot, n = 130; organ-culture storage, n = 13; unknown, n = 22); corneal scars or ulcers as the indication for graft (strata: corneal scars, n = 66; corneal ulcers, n = 24; neither scars nor ulcers, n = 871); development of synechiae after graft (strata: with synechiae, n = 36; without synechiae, n = 925); and raised lOP after graft (strata: no rise in rop, n = 895; rise in lOP, n = 66).
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AVASCULAR GRAFT BED, N .. 680
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TRIAL TIME (YEARS) Figure 3. The effect of (A) anterior segment inflammation, (B) corneal neovascularization and (C) raised intraocular pressure in the ipsilateral eye, either prior to graft or at graft, on subsequent corneal graft survival. N represents the number initially at risk.
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inflammation at the time of graft; the presence of an anterior chamber or iris-clip intraocular lens in the grafted eye; a graft diameter outside the 7.0 to 7.9 mm range; or corneal neovascularization occurring subsequent to graft.
Discussion The data presented shed light on the pattern of practice of corneal transplantation across Australia, provide information on outcome, and identify significant risk factors for corneal graft failure. It is important to appreciate that the Registry was designed to obtain information on outcome in a highly heterogeneous group of patients and on the way corneal transplantation is actually practiced, however varied. The cases analyzed represent consecutive cases from those surgeons contributing data, but do not cover every graft performed in the country over the time span considered. Selection bias cannot therefore be excluded, although the prospective nature of the data col-
410
lection (whereby grafts are registered at the time that they are performed) and the relatively low number oflosses to follow-up would mitigate a biased reporting of grafts by contributing surgeons. Seven risk factors were identified in the multivariate analysis to be key predictors of graft outcome. The fit of the model was not improved (P > 0.05) by including additional factors. A noteworthy feature of the final model was the absence of corneal neovascularization (at the time of graft) as an independent predictor of graft failure. Neovascularization at the graft site has been considered to be a risk factor of fundamental biologic significance for corneal graft outcome for at least the past 15 years. 2 ,29-32 It proved to be a risk factor when analyzed separately in this study, as did a history of raised lOP, but neither of these factors were included in the final model. However, both were associated with at least five other risk factors that did feature in the final model. Interestingly, vascularization at the graft site was found not to be a significant
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TRIAL TIME (YEARS) Figure 5. The effect of (A) graft size and (B) donor cornea procurement source on corneal graft survival. N represents the number initially at risk.
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tried to take account of the fact that a given patient might not have been always treated by the contributing surgeon, but might have been referred from, for example, a general practitioner or optometrist. We considered that the answer to a single question, "Has the eye been inflamed in the past?" was quite likely to be "unknown" in the majority of cases, and we therefore sought additional objective measures of a past history of inflammation. However, the definition used took no account of the severity of any past inflammation, so that some trivial inflammatory episodes may have been included and some serious episodes may have been overlooked. The presence of a posterior chamber intraocular lens in situ was not related to graft survival, although both aphakia and the presence of anterior chamber or iris-clip lenses were risk factors for graft failure. Posterior chamber, anterior chamber, and iris-clip lenses have all been used (and continue to be used) since the Registry's inception. More grafts for keratoconus and fewer grafts for bullous keratopathy (especially pseudophakic bullous kerato-
III
1· <6 HOURS, N = 647
•
6·12 HOURS, N = 252
•
>12·18 HOURS, N = 25
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Figure 6. The effect of (A) recipient age at graft and (B) donor death to enucleation time on corneal graft survival. N represents the number initially at risk.
independent predictor of graft outcome in another study in which multivariate analysis was performed. 33 The biologic links underlying the statistical interrelationships are complex, but it appears that factors found to be associated with graft survival in univariate analyses, such as corneal neovascularization at the time of graft and a history of raised lOP, may be reflected in multivariate models indirectly, through the inclusion of other risk factors with which they are associated. Another possibility is that differences in the grading of neovascularization among studies (deep, superficial, patent, ghost vessels, single or multiple leashes, number of quadrants vascularized) may alter the results obtained. Inflammation at the time of graft was a significant risk factor for graft failure in the multivariate analysis, in contrast to a past history of inflammation, which appeared as a risk factor only in univariate analysis. We categorized a patient as having had a past history of inflammation on the basis of objective measures, such as a history of prior surgery to the eye. The rationale for the definition used
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AVASCULAR, N = 894
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NO HSV RECURRENCE, N = 935
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1
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4
TRIAL TIME (YEARS) Figure 7. The effect of the postoperative complications of (A) vascularization of the graft and (B) herpetic recurrence on corneal graft survival. N represents the number initially at risk.
411
Ophthalmology Table
Volume 99, Number 3, March 1992
7. Multivariate Cox Model Showing Key Predictors of Graft Failure and Relative Risks of Graft Failure * Value
No.
keratoconus/corneal dystrophy presence of other condition first graft second graft third/subsequent graft not aphakic aphakic not inflamed at graft inflamed at graft absence of AC or iris-clip IOL AC IOL present iris-clip IOL present 7.0-7.9 mm diameter any other diameter avascular vascularized
414 522 817 91 28 817 119 730 206 802 106 28 622 314 871 65
Characteristic Presence of keratoconus/corneal dystrophy History of previous ipsilateral failed corneal graft
Lens status Inflammation at time of graft Presence/absence of AC or iris-clip IOL
Graft size Corneal vascularization occurring after graft
Relative Riskt 1.00 4.38 (2.04, 7.18) 1.00 1.43 (1.07, 1.91) 2.05 (1.15, 3.66) 1.00 1.98 (1.24, 3.18) 1.00 2.05 (1.38, 3.03) 1.00 1.74 (1.03,2.94) 3.59 (1.90, 6.79) 1.00 1.89 (1.28, 2.80) 1.00 5.03 (3.33, 7.56)
AC = anterior chamber; IOL = intraocular lens . • Cox proportional hazards regression model based on the 936 patients with penetrating corneal grafts for whom information was complete for all variables. Study period: May 5, 1985 to July 4, 1989. t 95% confidence limits in brackets.
pathy) were reported in this series than have been reported elsewhere.31.34.35 Australian ophthalmologists have possibly been less inclined than their counterparts in other developed countries to insert posterior chamber intraocular lenses, although it may be that the number of patients presenting with pseudophakic bullous keratopathy will slowly increase with time, as the time-in-eye of these lenses increases in the cohort at risk. Another possibility is that, with the relative shortage of donor corneas in Australia in recent years, patients with keratoconus have received grafts preferentially. Management of keratoconus in this country is currently based primarily on contact lens wear followed by penetrating keratoplasty, rather than on epikeratophakia. The positive association of corneal dystrophies (not including keratoconus) with survival in the univariate analysis was of interest considering the mixed nature of the indications grouped together in the category of dystrophies. Presence of a dystrophy as the indication for graft yielded a relative risk for failure of 0.23 (95% confidence limits 0.07,0.73) compared with 1.00 in the absence of keratoconus or a dystrophy. Approximately 13% of all penetrating grafts with at least one follow-up had failed at the time of analysis, with the major causes of graft loss being irreversible rejection (42%) and the sequelae of glaucoma (13%). The latter finding was somewhat surprising, although evidence that both acute and prolonged elevations in lOP can damage corneal endothelium has previously been adduced. 2o ,36,37 In some cases, graft failure may have resulted from procedures used to control glaucoma, as has been reported
412
by Foulks. 19 The most commonly recorded postoperative complication was the breakage or premature loosening of graft sutures. Only 14% of rejection episodes occurred within 3 months of suture removal. Herpetic recurrences, although relatively uncommon, were associated with a greatly increased risk of graft failure in the univariate analysis. Penetrating corneal graft survival (considering one graft per patient) was 75% at 3 years, a figure comparable with cadaver renal allograft survival in the postcyclosporine era. 38 Of interest was the relatively slow rate of attrition of corneal grafts. The so-called "center effect," in which survival rates vary among centers of practice, is well established for other forms oftransplantation39 and is presumed to reflect differences in local patient populations and possibly in factors such as patterns of management. Graft survival at 1 year in this study varied among surgeons by approximately 25%, and it is clear that the center effect must be considered in corneal transplantation as in renal transplantation. Initial investigation of this effect within the Registry has indicated that differences in indications for graft in different centers account for at least some of the variation observed. Published data on the influence of graft size on corneal graft survival are at variance. V6lker-Dieben et al,2 in a study of 1218 consecutive grafts, reported a significant influence of graft size (P < 0.00001), with smaller grafts (s7.1 mm in diameter) showing better survival than intermediate (7.2 to 7.9 mm) or larger grafts (~8.0 mm). The difference remained after stratification for the degree of vascularization. Sanfilippo and Foulks,32 however, have
Williams et al . Australian Corneal Graft Survival reported on a series of 97 grafts in which a graft size of <8.0 mm was associated with a poorer survival (by both univariate and multivariate analysis) than that observed for larger grafts. Our data agree more with those of the Dutch group, with larger grafts showing poorer survival. However, it is noteworthy that, in our series, the very small grafts of <7.0 mm also did poorly, although the sample size was small (n = 17). The influence of procurement source in the univariate analysis, with donor corneas procured by individual surgeons showing better survival after transplantation than corneas processed through an eye bank, confirms recent findings from the Canadian Registry.40 However, patients receiving eye bank corneas were found to show an excess of other risk factors, including indications for graft other than keratoconus or corneal dystrophy, and procurement source was not found to be significant in the multivariate analysis. No significant influence of donor age was apparent within the univariate analysis, which was in agreement with some 28 ,41,42 but not all other reports. 2,32 In our data, there was little difference in graft outcome among donors aged younger than 25 years, 50 to 74 years, or older than 74 years; however, there was a suggestion that corneas from donors aged 25 to 49 years may have a lower risk of graft failure than those from other age groups (relative risk of 0.57, 95% confidence limits 0.33, 1.00). The recommendations arising from the results of our analyses may be summarized in terms of (1) the importance of achieving a functional graft at the first attempt, (2) a preference for the pseudophakic state with a posterior chamber intraocular lens in place rather than aphakia or pseudophakia with an anterior chamber or iris-clip lens (although the options available to the surgeon are limited by the presence or absence of the posterior capsule), (3) the use of small rather than large grafts (although very small grafts may need to be avoided) (4) avoiding transplantation in inflamed eyes, where possible, and (5) attempting to reduce the incidence of corneal neovascularization in the postoperative period.
References 1. V61ker-Dieben HJ, D'Amaro J, Kruit PJ, de Lange P. Interaction between prognostic factors for corneal allograft survival. Transplant Proc 1989; 21 :3135-8, 2, V61ker-Dieben HJ, D'Amaro J, Kok-van Alphen Cc. Hierarchy of prognostic factors for corneal allograft survival. Aust NZ J Ophthalmol 1987; 15:11-8. 3. Bishop VLM, Robinson LP, Wechsler A, Billson FA. Corneal graft survival: a retrospective Australian study. Aust NZ J Ophthalmol 1986; 14:133-8. 4. Stulting RD, Sumers KD, Cavanagh HD, et al. Penetrating keratoplasty in children, Ophthalmology 1984; 91: 122230. 5. Samples JR, Binder PS. Visual acuity, refractive error, and astigmatism following corneal transplantation for pseudophakic bullous keratopathy, Ophthalmology 1985; 92: 155460. 6. Kozarsky AM, Stopak S, Waring GO III, et al. Results of penetrating keratoplasty for pseudophakic corneal edema
with retention of intraocular lens. Ophthalmology 1984; 91: 1141-6. 7. Sugar A, Meyer RF, Heidemann D, et al. Specular microscopic follow-up of corneal grafts for pseudophakic bullous keratopathy. Ophthalmology 1985; 92:325-30. 8. Ehlers N, Andersen J, Treatment of central corneal ulcers by achaud transplantation of organ culture preserved donor tissue. Acta Ophthalmol 1987; 65:516-20. 9. Du NZ, Chen JQ, Gong XM, et al. Therapeutic keratoplasty in the management of purulent corneal ulceration-report of 100 cases. Jpn J Ophthalmol 1979; 23:412-20. 10. Epstein RJ, Seedor JA, Dreizen NG, et al. Penetrating keratoplasty for herpes simplex keratitis and keratoconus. Allograft rejection and survival. Ophthalmology 1987; 94:93544. 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. Foster CS, Duncan J. Penetrating keratoplasty for herpes simplex keratitis. Am J Ophthalmol 1981; 92:336-43. 13. Cohen EJ, Laibson PR, Arentsen JJ. Corneal transplantation for herpes simplex keratitis. Am J Ophthalmol 1983; 95: 645-50, 14. Ficker LA, Kirkness CM, Rice NSC, Steele ADMcG. Longterm prognosis for corneal grafting in herpes simplex keratitis. Eye 1988; 2:400-8. 15. Keates RH, Falkenstein S, Keratoplasty in keratoconus, Am J Ophthalmol 1972; 74:442-4. 16. Young SR, Olson RJ. Results of a double running suture in penetrating keratoplasty performed on keratoconus patients. Ophthalmic Surg 1985; 16:779-86. 17. Binder PS. Secondary intraocular lens implantation during or after corneal transplantation. Am J Ophthalmol 1985; 99:515-20. 18, Meyer RF, Musch DC. Assessment of success and complications of triple procedure surgery. Am J Ophthalmol1987; 104:233-40, 19. Foulks GN. Glaucoma associated with penetrating keratoplasty. Ophthalmology 1987; 94:871-4. 20. Beebe WE, Starita RJ, Fellman RL, et al. The use of Molteno implant and anterior chamber tube shunt to encircling band for the treatment of glaucoma in keratoplasty patients. Ophthalmology 1990; 97:1414-22. 21. Jager MJ, Hermans LJA, Kok JHC. Visual results after corneal transplantation. Doc Ophthalmol 1989; 72:265-71. 22. Williams KA, Sawyer M, Alfrich SJ, et al. First report of the Australian Corneal Graft Registry. Aust NZ J Ophthalmol 1987; 15:291-302. 23. Williams KA, Sawyer MA, White MA, et al. Report from the Australian Corneal Graft Registry. Transplant Proc 1989; 21:3142-4. 24. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:475-81. 25. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br J Cancer 1976; 34:585-612. 26. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 1977; 35:1-39. 27. Cox DR. Regression models and life-tables. J Roy Stat Soc [Ser B] 1972; 34: 187-220, 28. Council on Scientific Affairs. Report of the organ transplant panel. Corneal transplantation. JAMA 1988; 259:719-22.
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29. Khodadoust AA. The allograft rejection reaction: the leading cause of late failure of clinical corneal grafts. In: Corneal Graft Failure. Amsterdam: Elsevier, 1973; 151-67. (Ciba Foundation Symposium 15 (new series». 30. Batchelor JR, Casey T A, Werb A, et al. HLA matching and corneal grafting. Lancet 1976; 1:551-4. 31. V6lker-Dieben HJM. The Effect of Immunological and Non-Immunological Factors on Corneal Graft Survival. A Single Centre Study. Dordrecht: Dr W Junk, (Monogr Ophthalmol; 8). 32. Sanfilippo F, Foulks GN. The role of histocompatibility in human corneal transplantation. Transplant Proc 1989; 21 : 3127-9. 33. Sanfilippo F, MacQueen JM, Vaughn WK, Foulks GN. Reduced graft rejection with good HLA-A and B matching in high-risk corneal transplantation. New Engl J Med 1986; 315:29-35. 34. Smith RE, McDonald R, Nesburn AB, Minckler DS. Penetrating keratoplasty: changing indications, 1947 to 1978. Arch Ophthalmol 1980; 98: 1226-9. 35. Robin JB, Gindi 11, Koh K, et al. An update of the indications for penetrating keratoplasty: 1979 through 1983. Arch Ophthalmol 1986; 104:87-9.
414
36. Bigar F, Witmer R. Corneal endothelial changes in primary acute angle-closure glaucoma. Ophthalmology 1982; 89: 596-9. 37. Thoft RA, Gordon JM, Dohlman CH. Glaucoma following keratoplasty. Trans Am Acad Ophthalmol Otolaryngol 1974; 78:0P352-64. 38. Jeffery JR, Arbus GS, Hutchinson T, Posen GA. Renal transplantation in Canada from 1981-86: report of the Canadian Renal Failure Register. Transplant Proc 1989; 21 (no. 1, pt. 2):2171-3 . 39. Opelz G, Mickey MR, Terasaki PI. HLA matching and cadaver kidney transplant survival in North America: influence of center variation and presensitization. Transplantation 1977; 23:490-7. 40. Chipman ML, Willett P, Basu PK, Wolf A. Donor eyes: a comparison of characteristics and outcomes for eye bank and local tissue. Cornea 1989; 8:62-6. 41. Forster RK, Fine M. Relation of donor age to success in penetrating keratoplasty. Arch Ophthalmol1971; 85:42-7. 42. Matsuda M, Yee RW, Glasser DB, et al. Specular microscopic evaluation of donor corneal endothelium. Arch Ophthalmol 1986; 104:259-62.
Keryn A. Williams, PhD, l David Roder, DDSc, MPH, 2 Adrian Esterman, MSC, 2 Sylvia M. Muehlberg,l Douglas]. Coster, FRCS,l on behalf of all contributing surgeons
R
isk factors for graft failure after penetrating keratoplasty were investigated in 961 patients from records collected prospectively by the Australian Corneal Graft Registry. The most common cause of graft failure was irreversible rejection. A multivariate proportional hazards regression analysis indicated that the key predictors of graft failure were: an indication for graft other than keratoconus or corneal dystrophy; a failed previous graft (ipsilateral eye); aphakia; inflammation at the time of graft; presence of an anterior chamber or iris-clip intraocular lens; graft size outside the range of 7.0 to 7.9 mm diameter; and corneal vascularization occurring in the postoperative period. Ophthalmology 1992; 99:403-414
Multicenter registries exist for most forms of transplantation, to provide information on graft outcome. A major advantage of such registries is that a large body of data can be accumulated rapidly. However, the establishment of registries for corneal transplantation has been relatively slow, perhaps in part because the procedure is frequently performed by ophthalmologists working under a variety of conditions, including solo practice, rather than in a small number of designated transplant centers. The Australian Corneal Graft Registry began operating in May 1985, to overcome a deficiency in the data available on corneal transplantation in this country. Voluntary contributions of information were solicited from all registered specialists performing corneal grafts in Australia.
Originally received: April 9, 1991 . Revision accepted: November 8, 199 1. 1 Department of Ophthalmology, Flinders University of South Australia, Bedford Park. Epidemiology Branch, South Australian Health Commission, Adelaide, Australia. Supported by the NH & MRC (grant no. 890858), the Pank Ophthalmic Trust, and the FMC Research Foundation. Reprint requests to Keryn A. Williams, PhD, Department of Ophthalmology, Flinders Medical Centre, Bedford Park SA 5042, Australia.
2
We estimate that information is now being collected on approximately 75 % of all corneal grafts performed in the country. Somewhat similar registries are in operation elsewhere: The Eurotransplant Foundation (Leiden, The Netherlands) has collected data on corneal transplantation for some years, and prospective data on corneal grafts are being collected by United Kingdom Transplant (Bristol, United Kingdom) and by the Canadian Registry. However, most published reports on corneal graft outcome to date have originated from individual centers or surgeons l - 3 or have described data limited to specific aspects of corneal transplantation, including studies of penetrating keratoplasty in children 4 and of the outcome of corneal transplantation for bullous keratopathy,5-7 corneal ulcers,8.9 herpetic keratitis,IO-14 and keratoconus. 10.1 5,16 Recent reports have described the outcome after triple procedures,I7,18 the incidence and treatment of glaucoma after corneal transplantation,19.20 and the assessment of visual outcome after the graft procedure. 5.21 The purposes of the Australian Registry are fourfold. 22,23 First, data are collected on the practice of corneal transplantation for surgical audit. For this purpose, the assessment of graft survival and visual outcome is important. Second, the Registry aims to disclose risk factors for graft failure so that aspects warranting further research may be identified. Third, the data collected are made available for promotional purposes and for the strength-
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ening of donor procurement services. Finally, the information provided by the Registry allows ophthalmologists to counsel their patients as to likely risks and outcomes. In this report, we have identified risk factors for graft failure that have emerged in the initial years of the Registry's operation.
Materials and Methods Entry and Follow-up The study period for the present analyses extended from May 5, 1985, to July 4, 1989. Data were entered into the Registry by the contributing surgeon as soon as possible after the graft, and follow-up information was requested at 12-month intervals. Information was obtained by mail, using well-validated proformas; missing data were routinely sought by follow-up letter. Each graft was followed until graft failure or until the death or loss to follow-up of the patient. By July 4, 1989, information had been contributed on 1485 grafts (both penetrating and lamellar), of which follow-up had been acquired for 1064 at least once. The 220 contributing ophthalmologists and other practitioners were from all Australian states and territories. Approval for the establishment and continuation of the Registry was obtained from the institutional Clinical Investigations Committee. Statistical Analyses On July 5, 1989, follow-up data had been collected for 1035 penetrating corneal grafts. However, some patients with bilateral grafts and/or repeat grafts were represented within the Registry. To ensure statistical independence in these analyses, one penetrating graft per patient was selected at random in cases where a patient had had more than one graft entered into the Registry. This left 961 penetrating corneal grafts for analysis. Initially, various risk factors were studied separately and Kaplan-Meier survival functions were constructed to provide a graphical record of graft survival at 1, 2, and 3 years after graft. 24 - 26 For surviving grafts, trial time was calculated as the number of days between the date of graft and the date on which the patient was last seen. For failed grafts, trial time was calculated as the number of days between the date of graft and the date of failure. Cox proportional hazards regression was used to investigate associations between potential risk factors and the risk of graft failure 27 ; 95% confidence limits about the relative risk were obtained using the formula: exp {[b ± 1.96x s.e. (b)]}. Multivariate analysis was performed using a manual backward elimination procedure to identify the subset of risk factors most predictive of graft failure. For the sake of parsimony, variable categories were combined when they presented similar levels of risk in the univariate analysis. Proportionality was tested using stratified analyses. The absence of multicollinearity was checked to ensure the stability of the underlying model. The risk of graft failure for each value of the factor was compared with the risk for a specified reference value.
404
The category with the largest number of subjects was chosen as the reference category for the computation of risk ratios to minimize the standard error of the relative risk. In the case of the quantitative variables of graft size, recipient age at graft, donor age, and death to enucleation time, categories were chosen as follows. For graft size, divisions of 0.5 mm (reflecting the size increments actually used by contributing surgeons) were selected within the range of 7 to 9 mm diameter and the category with the largest number of subjects was then chosen for reference. Recipient age at graft ranged from 8 months to older than 90 years; a histogram plot (not shown) indicated a bimodal distribution with peaks at approximately 35 to 75 years. Two categories (~50 and >50 years), each containing approximately half of the total subjects, were selected for analysis, the reference category being the larger of the two. Donor age (range, 2 to 93 years) was analyzed in quartiles. As the recommended maximum death to enucleation time is 12 hours, two strata (0 to <6 and 6 to 12 hours) were initially constructed, but a third stratum (> 12 hours) was found to be necessary to accommodate the 25 subjects outside the stratum of 0 to 12 hours.
Definition of Risk Factors A history of past inflammation was recorded if the individual was specifically reported to have had such an episode, if the patient had had one or more previous grafts in the ipsilateral eye, if any intraocular surgery had ever been performed on that eye, or if there was a history of the use of topical corticosteroids in that eye within the 4 weeks preceding the graft. Vessel ingrowth into the cornea at the time of graft was scored on a scale of 0 to 4, with 0 representing no growth in any quadrant extending to the graft-host junction, 1 representing growth of vessels extending to the graft-host junction in 1 quadrant only, 2 representing such growth in 2 quadrants, 3 representing growth in 3 quadrants, and 4 being vessel ingrowth in 4 quadrants. No distinction was made between superficial or deep vessels, patent or ghost vessels, or single or multiple vessel leashes. For the purposes of this analysis, vascularization was considered to exist if the score was equal to or greater than 1. After corneal transplantation, the presence of even one vessel leash extending into the graft was considered enough to classify that graft as vascularized. The intraocular pressure (lOP) was considered to be raised if a reading of 25 mm of mercury or greater was made by applanation tonometry. Presenting diseases, indications for graft, postoperative complications, and reasons for graft failure were coded using the ICD.9.CM system (United States Department of Health and Human Services). Corneal dystrophies included cases of Fuchs, anterior, macular, lattice, granular, and Reis-Buckler's dystrophies, as well as some unspecified dystrophies. The category of corneal scars was heterogeneous and included cases of trachomatous scarring, herpetic scarring in the absence of active disease, and corneal opacities resulting from old interstitial keratitis, abscesses, trauma and burns, as well as some of unknown
Williams et al . Australian Corneal Graft Survival Table 1. Synopsis of the Data Base at Last Follow-up Total number of grafts entered· Number of grafts with completed third follow-up Number of grafts with completed second follow-up Number of grafts with completed first follow-up Number of grafts with no follow-up as yet Number of surviving grafts t Number of failed graftst
1485 186 219 659 421 925 139
• As of July 4, 1989.
t Excludes those not yet followed.
pathogenesis. Patients with active herpetic disease at the time of graft were classified separately, irrespective of whether or not they also had corneal scarring. Information was collected on both recipient bed size and donor button size; for the purpose of examining the influence of graft size, the former was used. Because not all geographic areas within Australia are served by eye banks, only a proportion of corneas used for transplantation are collected, assessed, and distributed by the five existing banks. Surgeons in other areas (including some major cities and population centers) must organize the harvesting and assessment of donor corneas themselves, without the benefit of any structured organization. Corneas harvested through the efforts of individual ophthalmologists, rather than having been processed by an eye bank, have been classified as having been privately procured. The standard contraindications to corneal donation are widely accepted; apart from the requirements that
corneal donors be seronegative for the human immunodeficiency virus and for hepatitis B virus, any other assessment procedures undertaken on privately procured corneas are at the discretion of the ophthalmologist concerned.
Definition of Graft Failure, Rejection, and Complications Primary graft non functions were defined as grafts that did not thin and clear in the postoperative period. The trial time for such grafts was arbitrarily adjusted to 1 day. Any existing graft that was replaced by another in the same eye, irrespective of graft clarity and for whatever reason, was classified as a failed graft. An example in this category would be a clear graft with an unacceptably high degree of irregular astigmatism, not improved by refractive surgery, which was then replaced. In all other cases, graft failure was defined as edema and irremediable loss of clarity in a previously thin, clear graft. The day of failure was the first day the patient was seen with an edematous, opaque graft that subsequently failed to thin and clear. Rejection was defined as the development of a rejection line (epithelial or endothelial) or a unilateral anterior chamber reaction with corneal infiltrates and spreading corneal edema in a previously thin, clear graft. The reasons for graft failure were left to the clinical judgment of the ophthalmologist. In a number of cases, the cause of graft failure was listed as corneal edema or bullous keratopathy. Some of these cases were found to be patients who presented late to their ophthalmologist, at a time when no definite decision could be made as to the likely pathogenesis underlying the graft failure: the cause of graft failure was then listed as unknown.
Table 2. Demographic Data on Corneal Graft Recipients All grafts
Male Female Indication for Penetrating Keratoplasty Keratoconus· 475 (33%) Bullous keratopathyt 330 (23%) Failed previous graftt 193 (13%) Corneal scars§ 175 (12%) Corneal dystrophies II 81 (6%) Herpetic keratitis§ 46 (3%) Corneal ulcers·· 40 (3%) Miscellaneous 98 (7%)
Recipient sex
Total
1438
726 (49%) 759 (51%)
All patients
669 (49%) 701 (51%)
Male Female Indication for Lamellar Graft Recurrent pterygium Marginal/ scleral ulcers Failed previous graft Familial dermoid Scleral degeneration Miscellaneous
17 (36%) 11 (23%) 4(9%) 4(9%) 4(9%) 7 (15%)
Total
47
• 13 with acute hydrops.
t193 with pseudophakic, 59 with aphakic bullous keratopathy.
t 33 graft rejections,
4 primary graft failures.
§ 42 with history of herpes simplex virus infection, 16 with history of trachoma, 12 with history of trauma, 7 with history of bums; 4 with adherent leukoma.
II 64 with Fuchs dystrophy, 5 unspecified, 3 anterior, 3 macular, 3 lattice, 2 granular, 1 Reis-Buckler's dystrophy. 11 3 with Herpes zoster ophthalmic us . •• 30 with perforation.
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Any development with the potential to compromise graft outcome was considered to be a complication. Postoperative complications were collected in two ways. First, a number of specified complications (development/occurrence of exposed suture; stitch abscess; breakage/premature loosening of graft suture; retained suture material; wound dehiscence; neovascularization of the graft; synechiae; uveitis; rise in lOP; fixed, dilated pupil; cataract; rejection episode; herpetic recurrence; early changes of bullous keratopathy), refractive and related errors (anisometropia; greater than 5 diopters astigmatism; refraction: sphere, cyl, axis), and factors potentially affecting vis~al outcome but unrelated to the graft (cataract; aphakia; amblyopia; retinal detachment; cystoid macular edema or senile macular degeneration) were listed, requiring a yes/no answer. Second, contributors were asked to specify any other relevant complications, information, or departures from their preferred treatment.
400
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AGE RANGE (DECADES)
Results
Figure 1. Recipient and donor age range (in decades) at the time of graft.
Descriptive Features of the Data Base Descriptive features of the data base are presented in Table I. At the end of the study period, 1485 grafts in 1370 patients had been entered into the Registry. Of the 115 patients who had been entered into the Registry on more than 1 occasion, 57 had had 1 graft in each eye, 48 had had 2 grafts in the same eye, 7 had had 3 grafts in the same eye, 1 had had 2 grafts in 1 eye and 1 in the other, and 2 patients had had 4 grafts in the same eye. Graft losses through patient death or loss to follow-up were low (31 and 41 , respectively). Demographic features of recipient and donor populations are presented in Tables 2 and 3 respectively; recipient and donor ages are shown in Figure 1. The recipient population was unexceptional with respect to sex distribution (approximately equal numbers of males and females were grafted) and age at graft. Recipient age showed a bimodal distribution, with peaks at
Table 3. Demographic Data on Corneal Graft Donors Donor sex
Male Female Unknown
Total Cause of donor death Heart/coronary artery disease CVA/hemorrhage Cancer T rauma/accident Pulmonary disease Miscellaneous Total eVA = cerebrovascular accident.
406
896 (60%) 525 (35%) 64(4%) 1485 620 (42%) 238 (16%) 197 (13%) 176 (12%) 133 (9%) 121 (8%) 1485
around 35 and 75 years corresponding to grafts performed predominantly for keratoconus and bullous keratopathy, respectively. Sixty percent of corneal donors were male, with heart and coronary artery disease, cerebrovascular accidents, hemorrhage, cancer, and trauma accounting for 83% of donor deaths. Forty-seven percent of donor corneas were processed through an eye bank and came from a variety of sources, including public hospitals, coroners' mortuaries, private hospitals, and funeral directors' rooms, whereas 50% were procured privately by individual ophthalmologists, largely (88%) from public hospitals. The source of the donor cornea was not recorded in the remaining 3% of cases. Approximately 3% of grafts registered were lamellar, slightly fewer than recorded elsewhere. 28 The leading indication for lamellar keratoplasty was recurrent pterygium.
Graft Failures and Complications after Graft Placement The primary reasons given for graft failure are presented in Table 4; in cases where the cause offailure was believed to be multifactorial, the precipitating event that eventually led to graft failure was chosen. Irreversible immunologic rejection was the most common cause of graft failure. In a number of cases, graft rejection and herpes simplex virus recurrences were recorded as joint causes of failure, a not unexpected combination. Early signs of impending graft failure were reported in a further 15 grafts. Complications after graft placement, which affected the corneal graft, are shown in Table 5; problems relating t? graft sutures were the most commonly reported comphcations. Retained suture material was considered as a complication because of the propensity of such material to induce vessel ingrowth. Astigmatism and rejection episodes also were frequently noted complications. The
Williams et al . Australian Corneal Graft Survival Table
4.
Precipitating Cause of Corneal Graft Failure
Precipitating Cause of Failure
No.
Irreversible rejection Sequelae of raised lOP Herpes simplex virus recurrence Primary graft nonfunction Suppurative keratitis Corneal ulceration Wound dehiscence, trauma, leak Pseudophakic bullous keratopathy Endophthalmitis Miscellaneous Unknown
59* 18t 9'1' 8 7§ 711
=
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Total lOP
Percent
42 13 6 6 5 5 4 4 2 3 9 100
intraocular pressure.
• With herpes simplex virus recurrence (5), glaucoma (4), suppurative keratitis (3), ulcer (2), iritis (1), herpes simplex virus recurrence and glaucoma (1).
t With uveitis (1), abscess (1), perforated ulcer (1). t With perforation (3), uveitis (1). § With Mycobacterium fortuitum, Moraxella sp, Staphylococcus epidermidis (1 case each).
II With iris prolapse (2). 11 With perforation (2). •• With rheumatoid arthritis (1).
tt Sequelae of retinal detachment (2), ectasia with peripheral synechiae (1), herpes zoster ophthalmicus with iritis (1).
number of rejection episodes (reversible and irreversible) that occurred within 1, 2, and 3 months of suture removal was 13, 6, and 4, respectively (14% of all episodes of rejection).
Graft Survival: Overall and by Risk Factor Overall, for the 1035 penetrating corneal grafts registered (no exclusions), the penetrating corneal graft survival rate at 1 year and 3 years after grafting was 91 % and 79%, respectively. These grafts comprised 70% of those entered into the Registry at the time of analysis. The remainder were excluded, either because the first follow-up had not yet been requested (n = 421) or because the grafts, although followed, were lamellar (n = 29). When repeat or bilateral penetrating grafts in the one patient were excluded, graft survival (±standard error) at 1 and 3 years was 91.6% ± 1.0% and 80.9% ± 1.9%, respectively (n = 961). The center effect, in which survival functions were constructed for the 8 individual surgeons contributing 25 or more patients with follow-up (n varied from 25 to 265) to the Registry, indicated that graft survival varied by approximately 25% at 1 year among individual centers (P < 0.0001). The relative risk of graft failure for different values of each factor and the overall statistical significance of each
factor as a single predictor of graft outcome are shown in Table 6. Penetrating corneal graft survival functions for individual factors are presented in Figures 2 to 7. The absence of keratoconus or a corneal dystrophy as the indication for graft and a history of a previous failed graft in the ipsilateral eye were predictors of graft failure (Figs 2A and B). Anterior segment inflammation in the grafted eye before or at the time of graft, corneal vascularization at the time of graft, and a history of raised lOP all were associated with subsequent corneal graft failure (Figs 3A-C). Aphakic grafts and pseudophakic grafts performed less well than phakic grafts (Fig 4A). The type of intraocular lens also was associated with graft outcome; the presence of an iris-clip or an anterior chamber lens was associated with an increased risk of graft failure (Fig 4B); the presence of a posterior chamber intraocular lens was not in itself a risk factor for failure. Another significant influence on outcome was graft size, with sizes larger than 7.9 mm in diameter and very small sizes (less than 7.0 mm in diameter) associated with poorer outcomes (Fig 5A). Eye bank corneas showed poorer survival than did privately procured corneas (Fig 5B). In general, recipients older than 50 years of age at the time of graft had a poorer outcome than younger recipients (Fig 6A), and graft survival decreased as the donor death to enucleation time was prolonged (Fig 6B). In the postoperative period, neovascularization of the graft and herpetic recurrences were both significant risk factors for graft failure (Figs 7A and B) . Factors that did not appear to influence corneal graft survival to a statistically significant extent (P> 0.05) included recipient sex (male, n = 462; female, n = 499); donor sex (male, n = 592; female, n = 333; unknown, n = 36); sex match (male/male, n = 297; female/female, n = 178) or mismatch (male to female, n = 295; female Table 5. Postoperative Complications Specified Complication Suture-related Complication Exposed suture Stitch abscess Breakage/premature loosening Retained suture material Wound dehiscence More than 5 Diopters Irregular Astigmatism One or more Rejection Episodes Neovascularization of the Graft Rise in Intraocular Pressure Synechiae Cataract Herpes Simplex Virus Recurrence Fixed Pupil Uveitis
No.
Percent *
65 13 130 31 28
25
207 170 75 72
37 31 28 19 14
19 16 7 7 3 3 3 2 1
• Expressed as a percentage of the total number of grafts with at least one round of follow-up (n = 1064).
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Ophthalmology
Volume 99, Number 3, March 1992
Table 6. Summary of Estimates of Relative Risks for Corneal Graft Failure, for Separate Risk Factors Stratum
No.
Relative Risk *
Indication for Graft No dystrophy Keratoconus Corneal dystrophy First graft (ipsilateral) Second graft Third/subsequent graft
544 360 57 834 99 28
om (0.03, 0.16)
Inflammation, Vascularization, and lOP Never inflamed Inflamed in past Inflamed at graft Inflamed in past, at graft Unknown A vascular at graft Vascularized lOP never high lOP high in past lOP high at graft Unknown
521 222 37 180 1 680 281 796 116 28 21
1.00 4.40 (2.53, 7.67) 9.60 (5.73, 16.09) 9.64 (4.50, 20.66)
Lens Status Phakic Aphakic Pseudophakic Unknown NoIOL Posterior chamber IOL Anterior chamber IOL Iris-clip IOL
529 120 295 17 666 158 108 29
1.00 4.93 (3,00, 8.10) 2.99 (1.93, 4.62)
Other Factors Graft size 7.5-7.9 mm in diameter Graft size <7.0 mm in diameter Graft size 7.0-7.4 mm in diameter Graft size 8.0-8.4 mm in diameter Graft size 8.5-8.9 mm in diameter Graft size 29.0 mm in diameter Unknown Private procurement Eye bank cornea Recipient age at graft ~50 yrs Recipient age at graft >50 yrs Death to enucleation <6 hrs Death to enucleation 6-12 hrs Death to enucleation > 12 hrs Unknown No vascularization after graft Neovascularization of the graft No herpetic disease after graft Herpetic recurrence after graft
510 17 123 283 13 8 7 530 431 485 476 647 252 25 37 894 67 935 26
1.00 5.43 0.59 1.60 3.31 5.34
lOP = intraocular pressure; lOL = intraocular lens . • 95% confidence limits in parentheses.
t
Cox proportional hazards regression model.
408
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1.00 2.74 (1.91, 3.95) 1.00 2.81 (1.85, 4.28) 1.95 (0.79, 4.83)
1.00 0.98 (0.57, 1.69) 2.50 (1.55, 4.02) 5.24 (2.88, 9.53)
(2.46, (0.27, (1.07, (1.20, (1.67,
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11.96) 1.28) 2.41) 9.14) 17.09)
P < 0.0001 P < 0.0001
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Williams et al . Australian Corneal Graft Survival included in the model, an elevated risk of graft failure was evident where there was an indication for graft that was neither keratoconus nor a corneal dystrophy; a history of a previous failed graft in the ipsilateral eye; aphakia;
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Figure 2. The effect of (A) keratoconus or corneal dystrophy and (B) graft number in the ipsilateral eye on subsequent corneal graft survival. N represents the number initially at risk.
to male, n = 155, unknown for match or mismatch, n = 36); donor age (examined within the strata: <25 years, n = 108; 25 to 49 years, n = 156; 50 to 74 years, n = 552; >74 years, n = 145); method of corneal storage (strata: McCarey-Kaufman medium, n = 796; moist pot, n = 130; organ-culture storage, n = 13; unknown, n = 22); corneal scars or ulcers as the indication for graft (strata: corneal scars, n = 66; corneal ulcers, n = 24; neither scars nor ulcers, n = 871); development of synechiae after graft (strata: with synechiae, n = 36; without synechiae, n = 925); and raised lOP after graft (strata: no rise in rop, n = 895; rise in lOP, n = 66).
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AVASCULAR GRAFT BED, N .. 680
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1
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409
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inflammation at the time of graft; the presence of an anterior chamber or iris-clip intraocular lens in the grafted eye; a graft diameter outside the 7.0 to 7.9 mm range; or corneal neovascularization occurring subsequent to graft.
Discussion The data presented shed light on the pattern of practice of corneal transplantation across Australia, provide information on outcome, and identify significant risk factors for corneal graft failure. It is important to appreciate that the Registry was designed to obtain information on outcome in a highly heterogeneous group of patients and on the way corneal transplantation is actually practiced, however varied. The cases analyzed represent consecutive cases from those surgeons contributing data, but do not cover every graft performed in the country over the time span considered. Selection bias cannot therefore be excluded, although the prospective nature of the data col-
410
lection (whereby grafts are registered at the time that they are performed) and the relatively low number oflosses to follow-up would mitigate a biased reporting of grafts by contributing surgeons. Seven risk factors were identified in the multivariate analysis to be key predictors of graft outcome. The fit of the model was not improved (P > 0.05) by including additional factors. A noteworthy feature of the final model was the absence of corneal neovascularization (at the time of graft) as an independent predictor of graft failure. Neovascularization at the graft site has been considered to be a risk factor of fundamental biologic significance for corneal graft outcome for at least the past 15 years. 2 ,29-32 It proved to be a risk factor when analyzed separately in this study, as did a history of raised lOP, but neither of these factors were included in the final model. However, both were associated with at least five other risk factors that did feature in the final model. Interestingly, vascularization at the graft site was found not to be a significant
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TRIAL TIME (YEARS) Figure 5. The effect of (A) graft size and (B) donor cornea procurement source on corneal graft survival. N represents the number initially at risk.
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tried to take account of the fact that a given patient might not have been always treated by the contributing surgeon, but might have been referred from, for example, a general practitioner or optometrist. We considered that the answer to a single question, "Has the eye been inflamed in the past?" was quite likely to be "unknown" in the majority of cases, and we therefore sought additional objective measures of a past history of inflammation. However, the definition used took no account of the severity of any past inflammation, so that some trivial inflammatory episodes may have been included and some serious episodes may have been overlooked. The presence of a posterior chamber intraocular lens in situ was not related to graft survival, although both aphakia and the presence of anterior chamber or iris-clip lenses were risk factors for graft failure. Posterior chamber, anterior chamber, and iris-clip lenses have all been used (and continue to be used) since the Registry's inception. More grafts for keratoconus and fewer grafts for bullous keratopathy (especially pseudophakic bullous kerato-
III
1· <6 HOURS, N = 647
•
6·12 HOURS, N = 252
•
>12·18 HOURS, N = 25
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Figure 6. The effect of (A) recipient age at graft and (B) donor death to enucleation time on corneal graft survival. N represents the number initially at risk.
independent predictor of graft outcome in another study in which multivariate analysis was performed. 33 The biologic links underlying the statistical interrelationships are complex, but it appears that factors found to be associated with graft survival in univariate analyses, such as corneal neovascularization at the time of graft and a history of raised lOP, may be reflected in multivariate models indirectly, through the inclusion of other risk factors with which they are associated. Another possibility is that differences in the grading of neovascularization among studies (deep, superficial, patent, ghost vessels, single or multiple leashes, number of quadrants vascularized) may alter the results obtained. Inflammation at the time of graft was a significant risk factor for graft failure in the multivariate analysis, in contrast to a past history of inflammation, which appeared as a risk factor only in univariate analysis. We categorized a patient as having had a past history of inflammation on the basis of objective measures, such as a history of prior surgery to the eye. The rationale for the definition used
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NO HSV RECURRENCE, N = 935
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HSV RECURRENCE, N = 26
1
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4
TRIAL TIME (YEARS) Figure 7. The effect of the postoperative complications of (A) vascularization of the graft and (B) herpetic recurrence on corneal graft survival. N represents the number initially at risk.
411
Ophthalmology Table
Volume 99, Number 3, March 1992
7. Multivariate Cox Model Showing Key Predictors of Graft Failure and Relative Risks of Graft Failure * Value
No.
keratoconus/corneal dystrophy presence of other condition first graft second graft third/subsequent graft not aphakic aphakic not inflamed at graft inflamed at graft absence of AC or iris-clip IOL AC IOL present iris-clip IOL present 7.0-7.9 mm diameter any other diameter avascular vascularized
414 522 817 91 28 817 119 730 206 802 106 28 622 314 871 65
Characteristic Presence of keratoconus/corneal dystrophy History of previous ipsilateral failed corneal graft
Lens status Inflammation at time of graft Presence/absence of AC or iris-clip IOL
Graft size Corneal vascularization occurring after graft
Relative Riskt 1.00 4.38 (2.04, 7.18) 1.00 1.43 (1.07, 1.91) 2.05 (1.15, 3.66) 1.00 1.98 (1.24, 3.18) 1.00 2.05 (1.38, 3.03) 1.00 1.74 (1.03,2.94) 3.59 (1.90, 6.79) 1.00 1.89 (1.28, 2.80) 1.00 5.03 (3.33, 7.56)
AC = anterior chamber; IOL = intraocular lens . • Cox proportional hazards regression model based on the 936 patients with penetrating corneal grafts for whom information was complete for all variables. Study period: May 5, 1985 to July 4, 1989. t 95% confidence limits in brackets.
pathy) were reported in this series than have been reported elsewhere.31.34.35 Australian ophthalmologists have possibly been less inclined than their counterparts in other developed countries to insert posterior chamber intraocular lenses, although it may be that the number of patients presenting with pseudophakic bullous keratopathy will slowly increase with time, as the time-in-eye of these lenses increases in the cohort at risk. Another possibility is that, with the relative shortage of donor corneas in Australia in recent years, patients with keratoconus have received grafts preferentially. Management of keratoconus in this country is currently based primarily on contact lens wear followed by penetrating keratoplasty, rather than on epikeratophakia. The positive association of corneal dystrophies (not including keratoconus) with survival in the univariate analysis was of interest considering the mixed nature of the indications grouped together in the category of dystrophies. Presence of a dystrophy as the indication for graft yielded a relative risk for failure of 0.23 (95% confidence limits 0.07,0.73) compared with 1.00 in the absence of keratoconus or a dystrophy. Approximately 13% of all penetrating grafts with at least one follow-up had failed at the time of analysis, with the major causes of graft loss being irreversible rejection (42%) and the sequelae of glaucoma (13%). The latter finding was somewhat surprising, although evidence that both acute and prolonged elevations in lOP can damage corneal endothelium has previously been adduced. 2o ,36,37 In some cases, graft failure may have resulted from procedures used to control glaucoma, as has been reported
412
by Foulks. 19 The most commonly recorded postoperative complication was the breakage or premature loosening of graft sutures. Only 14% of rejection episodes occurred within 3 months of suture removal. Herpetic recurrences, although relatively uncommon, were associated with a greatly increased risk of graft failure in the univariate analysis. Penetrating corneal graft survival (considering one graft per patient) was 75% at 3 years, a figure comparable with cadaver renal allograft survival in the postcyclosporine era. 38 Of interest was the relatively slow rate of attrition of corneal grafts. The so-called "center effect," in which survival rates vary among centers of practice, is well established for other forms oftransplantation39 and is presumed to reflect differences in local patient populations and possibly in factors such as patterns of management. Graft survival at 1 year in this study varied among surgeons by approximately 25%, and it is clear that the center effect must be considered in corneal transplantation as in renal transplantation. Initial investigation of this effect within the Registry has indicated that differences in indications for graft in different centers account for at least some of the variation observed. Published data on the influence of graft size on corneal graft survival are at variance. V6lker-Dieben et al,2 in a study of 1218 consecutive grafts, reported a significant influence of graft size (P < 0.00001), with smaller grafts (s7.1 mm in diameter) showing better survival than intermediate (7.2 to 7.9 mm) or larger grafts (~8.0 mm). The difference remained after stratification for the degree of vascularization. Sanfilippo and Foulks,32 however, have
Williams et al . Australian Corneal Graft Survival reported on a series of 97 grafts in which a graft size of <8.0 mm was associated with a poorer survival (by both univariate and multivariate analysis) than that observed for larger grafts. Our data agree more with those of the Dutch group, with larger grafts showing poorer survival. However, it is noteworthy that, in our series, the very small grafts of <7.0 mm also did poorly, although the sample size was small (n = 17). The influence of procurement source in the univariate analysis, with donor corneas procured by individual surgeons showing better survival after transplantation than corneas processed through an eye bank, confirms recent findings from the Canadian Registry.40 However, patients receiving eye bank corneas were found to show an excess of other risk factors, including indications for graft other than keratoconus or corneal dystrophy, and procurement source was not found to be significant in the multivariate analysis. No significant influence of donor age was apparent within the univariate analysis, which was in agreement with some 28 ,41,42 but not all other reports. 2,32 In our data, there was little difference in graft outcome among donors aged younger than 25 years, 50 to 74 years, or older than 74 years; however, there was a suggestion that corneas from donors aged 25 to 49 years may have a lower risk of graft failure than those from other age groups (relative risk of 0.57, 95% confidence limits 0.33, 1.00). The recommendations arising from the results of our analyses may be summarized in terms of (1) the importance of achieving a functional graft at the first attempt, (2) a preference for the pseudophakic state with a posterior chamber intraocular lens in place rather than aphakia or pseudophakia with an anterior chamber or iris-clip lens (although the options available to the surgeon are limited by the presence or absence of the posterior capsule), (3) the use of small rather than large grafts (although very small grafts may need to be avoided) (4) avoiding transplantation in inflamed eyes, where possible, and (5) attempting to reduce the incidence of corneal neovascularization in the postoperative period.
References 1. V61ker-Dieben HJ, D'Amaro J, Kruit PJ, de Lange P. Interaction between prognostic factors for corneal allograft survival. Transplant Proc 1989; 21 :3135-8, 2, V61ker-Dieben HJ, D'Amaro J, Kok-van Alphen Cc. Hierarchy of prognostic factors for corneal allograft survival. Aust NZ J Ophthalmol 1987; 15:11-8. 3. Bishop VLM, Robinson LP, Wechsler A, Billson FA. Corneal graft survival: a retrospective Australian study. Aust NZ J Ophthalmol 1986; 14:133-8. 4. Stulting RD, Sumers KD, Cavanagh HD, et al. Penetrating keratoplasty in children, Ophthalmology 1984; 91: 122230. 5. Samples JR, Binder PS. Visual acuity, refractive error, and astigmatism following corneal transplantation for pseudophakic bullous keratopathy, Ophthalmology 1985; 92: 155460. 6. Kozarsky AM, Stopak S, Waring GO III, et al. Results of penetrating keratoplasty for pseudophakic corneal edema
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29. Khodadoust AA. The allograft rejection reaction: the leading cause of late failure of clinical corneal grafts. In: Corneal Graft Failure. Amsterdam: Elsevier, 1973; 151-67. (Ciba Foundation Symposium 15 (new series». 30. Batchelor JR, Casey T A, Werb A, et al. HLA matching and corneal grafting. Lancet 1976; 1:551-4. 31. V6lker-Dieben HJM. The Effect of Immunological and Non-Immunological Factors on Corneal Graft Survival. A Single Centre Study. Dordrecht: Dr W Junk, (Monogr Ophthalmol; 8). 32. Sanfilippo F, Foulks GN. The role of histocompatibility in human corneal transplantation. Transplant Proc 1989; 21 : 3127-9. 33. Sanfilippo F, MacQueen JM, Vaughn WK, Foulks GN. Reduced graft rejection with good HLA-A and B matching in high-risk corneal transplantation. New Engl J Med 1986; 315:29-35. 34. Smith RE, McDonald R, Nesburn AB, Minckler DS. Penetrating keratoplasty: changing indications, 1947 to 1978. Arch Ophthalmol 1980; 98: 1226-9. 35. Robin JB, Gindi 11, Koh K, et al. An update of the indications for penetrating keratoplasty: 1979 through 1983. Arch Ophthalmol 1986; 104:87-9.
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