CORNEAL DONOR MATERIAL S E L E C T I O N Z. N I C H O L A S ZAKOV, M.D., C L A E S H. D O H L M A N , M.D., H E N R Y D. P E R R Y , M.D., AND D A N I E L M. A L B E R T , M.D. Boston,
An important responsibility of the corneal surgeon is to evaluate corneal donor material. The chief concern has been with extending the viability and assessing the health of the endothelium. Little has been said about exclusion of donor material because of cause of death, with the excep tion of Creutzfeldt-Jakob disease. This neurologic disorder, which has been transferred by keratoplasty, emphasizes the importance of the cause of death. No uniform code of exclusion of donor mate rial by disease entity exists. Ophthalmic pathologists contribute to the solution of this problem by making histopathologic observations not obvious to the corneal surgeon. Ophthalmic pa thologists must examine the globes used for corneal donor material. In reviewing such material after the fact and in a differ ent context from the surgeon, concern regarding the possible hazards involved with certain donor material is evident. We report herein three cases in which donor eyes illustrate the need for a reevaluation of the criteria used in selecting donor corneal material, and a standardization of those criteria. CASE REPORTS Case 1—The donor cornea was obtained from a 49-year-old patient who died of acute leukemia. Histopathologic examination of the donor eye after the removal of the corneal button revealed the following positive findings: thickening and poster ior migration of the lens epithelium; gliotic and From the Howe Laboratory of Ophthalmology, Massachusetts Eye and Ear Infirmary (Drs. Zakov, Dohlman, and Albert), Boston, Massachusetts, and the Walson Army Hospital, Department of Ophthal mology (Dr. Perry), Fort Dix, New Jersey. Reprint requests to Daniel M. Albert, M.D., Howe Laboratory of Ophthalmology, Massachusetts Eye and Ear Infirmary, 243 Charles St., Boston, MA 02114.
Massachusetts thickened retina, especially in the macular area, with microcystoid degeneration peripherally. The choroid was diffusely infiltrated by a large number of immature white cells, which were variable in size and had large basophilic nuclei with prominent nucleoli and irregular chromatin clumping. These were evident within blood vessels and extravascularly. The optic nerve showed thickened septa with mild gliosis. Examination of the fellow eye showed a similar histopathologic picture, and additionally, showed leukemic keratitic precipitates on the corne al endothelium. T h e eye that was used for the donor cornea was chosen arbitrarily and the keratitic pre cipitates in the fellow eye were not noted on preoperative screening of the donor material. Other eye bank eyes with massive leukemic infiltrates (Fig. 1) have subsequently been observed by us. Case 2—The donor cornea was obtained from a patient who died of glioblastoma multiforme and had had mitral valve disease. There was also a history of rash and fever. The right fundus examina tion showed two brown, granular-appearing lesions along the inferior nasal vessels. The left fundus had flame-shaped hemorrhages. The diagnosis of subacute bacterial endocarditis in addition to the brain tumor had been considered before death, but not verified. At autopsy, heart valve cultures grew the following organisms: Staphylococcus aureus, S. enterococci, Klebsiella pneumoniae, and K. lactoba-
cilli
Histopathologic examination of the donor eye revealed inflammatory nodules in the ciliary body and the choroid with some central necrosis (Fig. 2, left). These microabscesses were localized and were composed of acute and chronic inflammatory cells, predominantly lymphocytes and macrophages (Fig. 2, right). Clusters of gram-positive bacteria were also present. In the midperipheral area, an abscess had focally destroyed and disrupted the ret inal elements through a break in Bruch's membrane, and there were inflammatory cells in the overlying vitreous. Case 3—The donor cornea was obtained from a patient with known metastatic breast carcinoma. Examination of the donor eyes showed that the left eye was entirely normal except for missing cornea, iris, and part of the ciliary body. In the right eye the cornea, iris, and part of the ciliary body were miss ing. The choroid contained a focus of invasion by metastatic breast tumor in an "Indian file" fashion. The cells were anaplastic with large vesicular and variable in size nuclei. Some tumor cells contained PAS-positive material. The cell columns extended to the ciliary body (Fig. 3) and adjacent to the wound area where the anterior segment structures were removed for transplant. In all cases no adverse ocular effects or systemic
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® ML Fig. 1 (Zakov and associates). Left, Example of an eye bank eye showing massive infiltration of iris with leukemic cells (hematoxylin and eosin, x50). Right, Higher power showing leukemic cells (heratoxylin and eosin, x 1040).
complications have occurred to the recipients to date (postoperative duration, seven months to two years). DISCUSSION
There are few commonly accepted stan dards for selection of corneal donor mate rial among surgeons. The criteria for ex clusion of donor material are variable. A survey of eye bank procedures carried out by Rabb and Brose 1 showed a wide range of conditions mentioned, rendering the donor material unacceptable for trans plantation purposes by the various eye banks. However, there was no uniformity in adhering to this exclusion code by the eye banks surveyed.
Case 1 of our series shows that the use of leukemic donor material may lead to the transplantation of viable leukemic cells to the recipient's anterior chamber. It may be argued that the recipient's im mune mechanisms will be able to handle the leukemic cell load. However, the eti ology of leukemia, and especially its rela tion to a viral pathogenesis, is not clear. C-type and virus-like particles have been described in human leukemic cells. 2 - 4 C-type particles have been observed in a variety of other human cancers. 5 - 9 The Epstein-Barr virus is associated with two human malignancies, Burkitt's lymphoma and human nasopharyngeal carcino-
Fig. 2 (Zakov and associates). Left, Retinal and choroidal abcess (PAS, x30). Right, Primarily mononuclear cells in choroidal abscess (hematoxylin and eosin, x750).
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Fig. 3 (Zakov and associates). Ciliary body stroma and muscles infiltrated by metastatic breast carcino ma cells (arrow) in characteristic "Indian file" pat tern (hematoxylin and eosin, x94).
ma. Patients with these tumors always have increased serum titers against Epstein-Barr virus associated antigens, and tumor biopsy specimens from these malignancies grown in athymic nude mice contain Epstein-Barr virus DNA in a covalently closed circular form. Dohlman and Boruchoff 10 noted that donor material from leukemic patients should be rejected, and they cited a case in which a gliomatous growth occurred in a grafted eye with the donor eye having retinoblastoma. Even though no convinc ing demonstration of the infectivity of human associated C-type particles in vivo has been shown, no long-range studies on the effect of transplanting tumor cells have been done. No long-range study of corneal transplantation has been done to demonstrate possible negative effects on the recipient who has received material from patients dying with malignancies and various neurologic disorders. This is particularly important since many re cipients are young and presumably would have a long period to express any longterm effects of transplantation. In our three cases, all recipients were under age 34 years. Case 2 emphasizes that sufficient histo ry of the donor material is not always
607
available. Terminal septicemia indicates that the donor material is not suitable for transplant purposes. Pollack 11 noted that donor corneas obtained from debilitated donors or cancer patients treated with immunosuppressive drugs do not survive cryopreservation and do not function as well as healthy donor tissue. Chronically ill patients on long-term corticosteroids, immunosuppressive or multiple antibiot ic regimens may harbor occult infection, not apparent on a cursory perusal of the donors' terminal diagnoses. Additionally, a recent study by Keates, Mishler, and Riedinger 12 showed that it is not possible to render donor eyes sterile from patients with systemic infections by using current techniques. Of corneas stored in the McCarey-Kaufman medium, 30% in their study, and 40% of corneas stored in moist chambers had positive cultures. They also were able to isolate organisms from the aqueous of three donor eyes and suggest ed that this may be a source of contamina tion to the cornea. In our Case 2 the vitreous abscess present was not noted on screening of the donor eye. Conversely, the risk of postoperative infection in the transplanted eye is small. Recently, cryptococcal endophthalmitis developing after corneal transplantation was report ed. 13 The donor material was obtained from a patient with a history of polymyositis who had been treated with cortico steroids and intermittent cyclophosphamide. Additionally, the patient had evidence of Pneumocystis carinii and cytomegalovirus infection, and the blood cultures confirmed the presence of Cryptococcus neoformans after death. Before keratoplasty, the corneal graft was bathed with a solution of polymyxin B sulfate, neomycin, and gramicidin and stored for 48 hours at 4° C. Routine bacteriologic studies of the aqueous were negative, but the eye was not examined patho logically. Case 3 emphasizes the concept that
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slit-lamp evaluation of the donor material is inadequate in establishing the presence of metastatic disease to the ciliary body in the donor eye. Gross examination of the globe in the eye pathology laboratory failed to raise suspicion of metastatic dis ease to the globe, and only the histopathologic sections showed tumor in close proximity to the line of resection of the donor corneal button. Although 89% of eye banks queried by Rabb and Brose 1 stated that anterior segment tumors make donor corneas unacceptable for trans plant purposes, our Case 3 clearly illus trates that there is no sure method of ruling out this diagnosis short of histopathologic sectioning of the globe. Transmission of Creutzfeldt-Jakob dis ease through a corneal transplant has been documented. 1 4 - 1 7 However, recent evidence presented by Gajdusek and as sociates 18,19 suggests that donor material from aged patients, and particularly pa tients with any dementia, should not be used for corneal grafting. Accidental transmission of Creutzfeldt-Jakob disease has occurred in two neurosurgic cases through the use of contaminated stereotactic electrodes, 20 and there is suspicion that a neurosurgeon may have contracted the disease from one of his patients. 1 9 Experimentally, corneas from guinea pigs with Creutzfeldt-Jakob disease, when placed in the anterior chambers of healthy guinea pigs, produced clinical and histologic evidence of CreutzfeldtJakob disease in all of the animals after approximately a two-year incubation peri od. 21 Another feature of CreutzfeldtJakob disease, not clearly understood at the present time, is that patients develop ing it have a higher frequency of having had brain or eye surgery within two years before the onset of the disease. 19 Since the virus responsible for this fatal condition is extremely hardy and resists inactivation even by 10% formalin and 70% alcohol
NOVEMBER, 1978
solutions, 19 certain precautions in han dling patients with Creutzfeldt-Jakob dis ease and their tissues become mandatory. Gajdusek and associates 19 recommended that tonometers and surgical instruments used on patients with this disease be properly sterilized. This can be achieved by autoclaving for one hour at 121° C and 20 psi or by the use of 5% hypochlorite, 0.03% permanganate, phenolics and io dine solutions. 19 The following conditions should ren der donor material absolutely unac ceptable for transplant purposes: Creutz feldt-Jakob disease, any dementia, and probably any chronic neurologic disorder unless clearly secondary to a traumatic etiology. This includes subacute sclerosing panencephalitis, progressive congen ital rubella, progressive multifocal leukoencephalopathy, cytomegalovirus brain infection, Crohn's disease, and subacute encephalitis. 1 8 Ophthalmologists should also be aware of the many other condi tions in which slow virus etiology is suspected, but so far not proven. This includes multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, some of the collagen vascular diseases, and others. 18 Other conditions include: septicemia; hepatitis, jaundice, and evi dence of any active viral infection; syphi lis and positive serology (in certain cases of treated tertiary syphilis, the cornea is probably noninfectious and safe to use). Many other conditions require extreme caution with regard to selection as donor material, although currently no state ments can be made regarding absolute contraindication to use. These conditions include: (1) ocular or systemic malignan cy of any kind; (2) long terminal dis ease, particularly if immunosuppressive agents, large doses of corticosteroids, and multiple antibiotic regimens were used terminally and particularly if there is evi dence of systemic or focal infection; (3)
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history of eye diseases, including external eye diseases, corneal disease or dystro phy, iritis, absolute glaucoma, and acute glaucoma attack; and (4) history of previ ous intraocular surgical procedure of any kind. The above criteria for selection of donor corneal material are practical and are currently implemented at the New England Eyebank in Boston, Massachu setts. The majority of corneal grafting proce dures are elective by nature. A thorough evaluation of donor material should be undertaken by the corneal surgeon and the eyebanks. In emergencies, use of ma terial from donor eyes with the previously mentioned relative contraindications may be justified. The tightening up of guide lines on the use of donor material should serve as a further impetus for research to achieve more satisfactory ways of pre serving donor tissue. From our study, we believe it would be advisable to initiate a long-term prospective study on the effects of keratoplasty in which the clinical and pathologic findings of the donor as well as any ocular or systemic changes of the recipient are recorded. SUMMARY
Histologic study of eyes used as donor material for corneal transplant revealed one instance of massive leukemic infiltra tion with leukemic keratic precipitates on the fellow eye. In another eye, microabscesses composed of acute and chronic inflammatory cells containing Cryptococcus neoformans were present. In a third patient metastatic anaplastic cells were present in the choroid. We think donor eyes are absolutely unacceptable if death was caused by any chronic neurologic disorder, unless clearly secondary to trau ma. Eyes from patients with septecimia, hepatitis, jaundice and any evidence of
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any active viral infection, syphilis, and positive serology are also unacceptable. Extreme caution should be used in select ing eyes of patients with ocular or system ic malignancy, long-term diseases, partic ularly if immunosuppressive agents were used, where a history of eye disease ex ists, including corneal disease or dystro phy, iritis, absolute glaucoma or acute glaucoma, and eyes with a history of previous intraocular surgery. REFERENCES 1. Rabb, M. F., and Brose, B.: Survey of eye bank procedures. In Capella, J. A., Edelhauser, H. F., and Van Horn, D. L. (eds.): Corneal Preservation. Clini cal and Laboratory Evaluation of Current Methods. Springfield, Charles C Thomas, 1971, pp. 3-17. 2. Dmochowski, L., Taylor, H. G., Grey, C. E., Dreyer, D. A., Sykes, J. A., Langford, P. L., Roger, T., Shullenberger, C. C , and Howe, C. D.: Virus and mycoplasma (PPLO) in human leukemia. Can cer 18:1345, 1965. 3. Dmochowski, L., Rumoto, T., Grey, C. E., Deisgner, E., Hales, R. L., Langford, P. L., Taylor, H. G., Freireich, E. J., Shullenberger, C. C , Shir ley, J. A., and Howe, C. D.: Electronmicroscopic studies of human leukemia and lymphoma. Cancer 20:760, 1967. 4. Newell, G. R., Harris, W. W., Bowmann, K. D., Boone, C. W., and Anderson, N. G.: Evaluation of "virus-like" particles in the plasma of 225 patients with leukemia and related diseases. N. Engl. J. Med. 278:1185, 1968. 5. Morton, D. L., Malingren, R. A., Hall, W. T., and Schildovsky, G.: Immunological and virus stud ies with human sarcomas. Surgery 66:152, 1969. 6. Chopra, M. C., and Feller, W. F.: Virus-like particles in human breast cancer. Tex. Rep. Biol. Med. 27:945, 1969. 7. Todaro, G. J., Zeve, V., and Aaronson, S.: A virus in cell culture derived from human tumor patients. Nature 226:1047, 1970. 8. Seman, G., Gallager, H. S., Lukeman, J. M., and Dmochowski, L.: Studies on the presence of particles resembling RNA virus particles in human breast tumors, pleural effusions, their tissue cul tures, and milk. Cancer 28:1431, 1971. 9. Birkmayer, G. D., Galda, B. R., and Miller, F.: Oncoma-viral information in human melanoma. Eur. J. Cancer 10:419, 1974. 10. Dohlman, C. H., and Boruchoff, S. A.: Pene trating keratoplasty, Int. Ophthalmol. Clin. 8:3:655, 1968. 11. Pollack, F . M.: Corneal Transplantation. New York, Grune and Stratton, 1977, pp. 98-99. 12. Keates, R. H., Mishler, K. E., and Riedinger,
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D.: Bacterial contamination of donor eyes. Am. J. Ophthalmol. 84:617, 1977. 13. Beyt, B. E., and Waltman, S. R.: Cryptococcal endophthalmitis after corneal transplantation. N. Engl. J. Med. 298:825, 1978. 14. Duffy, P., Wolf, J., Collins, G., DeVoe, A. G., Streeten, B., and Cowen, D.: Possible person-toperson transmission of Creutzfeldt-Jakob disease. N. Engl. J. Med. 290:692, 1974. 15. DeVoe, A. G.: Complications of keratoplasty. The Gifford Lecture. Am. J. Ophthalmol. 79:907, 1975. 16. Kaufman, H. E.: Contamination of donor eyes. Am. J. Ophthalmol. 84:746, 1977. 17. Bellows, J., and Bellows, R.: Slow viruses. New concern for ophthalmologists. Ann. Ophthal mol. 7:857, 1975. 18. Gajdusek, D. C : Unconventional viruses and
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the origin and disappearance of kuru. Science 197: 943, 1977. 19. Gajdusek, D. C , Gibbs, C. J., Asher, D. M., Brown, P., Diwan, A., Hoffman, P., Nemo, G., Rohwer, R., and White, L.: Precautions in medical care of, and in handling materials from, patients with transmissible virus dementia (CreutzfeldtJakob disease). N. Engl. J. Med. 297:1253, 1977. 20. Bernoulli, C , Siegfried, J., Baumgartner, G., Regli, F., Rabinowicz, T., Gajdusek, D. C , and Gibbs, C. J.: Danger of accidental person-to-person transmission of Creutzfeldt-Jakob disease by sur gery. Lancet 1:478, 1977. 21. Manuelidis, E. E., Angelo, J. N., Gorgacz, E. J., Kim, J. H., and Manuelidis, L.: Experimental Creutzfeldt-Jakob disease transmitted via the eye with infected cornea. N. Engl. J. Med. 296:1344, 1977.
An important responsibility of the corneal surgeon is to evaluate corneal donor material. The chief concern has been with extending the viability and assessing the health of the endothelium. Little has been said about exclusion of donor material because of cause of death, with the excep tion of Creutzfeldt-Jakob disease. This neurologic disorder, which has been transferred by keratoplasty, emphasizes the importance of the cause of death. No uniform code of exclusion of donor mate rial by disease entity exists. Ophthalmic pathologists contribute to the solution of this problem by making histopathologic observations not obvious to the corneal surgeon. Ophthalmic pa thologists must examine the globes used for corneal donor material. In reviewing such material after the fact and in a differ ent context from the surgeon, concern regarding the possible hazards involved with certain donor material is evident. We report herein three cases in which donor eyes illustrate the need for a reevaluation of the criteria used in selecting donor corneal material, and a standardization of those criteria. CASE REPORTS Case 1—The donor cornea was obtained from a 49-year-old patient who died of acute leukemia. Histopathologic examination of the donor eye after the removal of the corneal button revealed the following positive findings: thickening and poster ior migration of the lens epithelium; gliotic and From the Howe Laboratory of Ophthalmology, Massachusetts Eye and Ear Infirmary (Drs. Zakov, Dohlman, and Albert), Boston, Massachusetts, and the Walson Army Hospital, Department of Ophthal mology (Dr. Perry), Fort Dix, New Jersey. Reprint requests to Daniel M. Albert, M.D., Howe Laboratory of Ophthalmology, Massachusetts Eye and Ear Infirmary, 243 Charles St., Boston, MA 02114.
Massachusetts thickened retina, especially in the macular area, with microcystoid degeneration peripherally. The choroid was diffusely infiltrated by a large number of immature white cells, which were variable in size and had large basophilic nuclei with prominent nucleoli and irregular chromatin clumping. These were evident within blood vessels and extravascularly. The optic nerve showed thickened septa with mild gliosis. Examination of the fellow eye showed a similar histopathologic picture, and additionally, showed leukemic keratitic precipitates on the corne al endothelium. T h e eye that was used for the donor cornea was chosen arbitrarily and the keratitic pre cipitates in the fellow eye were not noted on preoperative screening of the donor material. Other eye bank eyes with massive leukemic infiltrates (Fig. 1) have subsequently been observed by us. Case 2—The donor cornea was obtained from a patient who died of glioblastoma multiforme and had had mitral valve disease. There was also a history of rash and fever. The right fundus examina tion showed two brown, granular-appearing lesions along the inferior nasal vessels. The left fundus had flame-shaped hemorrhages. The diagnosis of subacute bacterial endocarditis in addition to the brain tumor had been considered before death, but not verified. At autopsy, heart valve cultures grew the following organisms: Staphylococcus aureus, S. enterococci, Klebsiella pneumoniae, and K. lactoba-
cilli
Histopathologic examination of the donor eye revealed inflammatory nodules in the ciliary body and the choroid with some central necrosis (Fig. 2, left). These microabscesses were localized and were composed of acute and chronic inflammatory cells, predominantly lymphocytes and macrophages (Fig. 2, right). Clusters of gram-positive bacteria were also present. In the midperipheral area, an abscess had focally destroyed and disrupted the ret inal elements through a break in Bruch's membrane, and there were inflammatory cells in the overlying vitreous. Case 3—The donor cornea was obtained from a patient with known metastatic breast carcinoma. Examination of the donor eyes showed that the left eye was entirely normal except for missing cornea, iris, and part of the ciliary body. In the right eye the cornea, iris, and part of the ciliary body were miss ing. The choroid contained a focus of invasion by metastatic breast tumor in an "Indian file" fashion. The cells were anaplastic with large vesicular and variable in size nuclei. Some tumor cells contained PAS-positive material. The cell columns extended to the ciliary body (Fig. 3) and adjacent to the wound area where the anterior segment structures were removed for transplant. In all cases no adverse ocular effects or systemic
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® ML Fig. 1 (Zakov and associates). Left, Example of an eye bank eye showing massive infiltration of iris with leukemic cells (hematoxylin and eosin, x50). Right, Higher power showing leukemic cells (heratoxylin and eosin, x 1040).
complications have occurred to the recipients to date (postoperative duration, seven months to two years). DISCUSSION
There are few commonly accepted stan dards for selection of corneal donor mate rial among surgeons. The criteria for ex clusion of donor material are variable. A survey of eye bank procedures carried out by Rabb and Brose 1 showed a wide range of conditions mentioned, rendering the donor material unacceptable for trans plantation purposes by the various eye banks. However, there was no uniformity in adhering to this exclusion code by the eye banks surveyed.
Case 1 of our series shows that the use of leukemic donor material may lead to the transplantation of viable leukemic cells to the recipient's anterior chamber. It may be argued that the recipient's im mune mechanisms will be able to handle the leukemic cell load. However, the eti ology of leukemia, and especially its rela tion to a viral pathogenesis, is not clear. C-type and virus-like particles have been described in human leukemic cells. 2 - 4 C-type particles have been observed in a variety of other human cancers. 5 - 9 The Epstein-Barr virus is associated with two human malignancies, Burkitt's lymphoma and human nasopharyngeal carcino-
Fig. 2 (Zakov and associates). Left, Retinal and choroidal abcess (PAS, x30). Right, Primarily mononuclear cells in choroidal abscess (hematoxylin and eosin, x750).
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Fig. 3 (Zakov and associates). Ciliary body stroma and muscles infiltrated by metastatic breast carcino ma cells (arrow) in characteristic "Indian file" pat tern (hematoxylin and eosin, x94).
ma. Patients with these tumors always have increased serum titers against Epstein-Barr virus associated antigens, and tumor biopsy specimens from these malignancies grown in athymic nude mice contain Epstein-Barr virus DNA in a covalently closed circular form. Dohlman and Boruchoff 10 noted that donor material from leukemic patients should be rejected, and they cited a case in which a gliomatous growth occurred in a grafted eye with the donor eye having retinoblastoma. Even though no convinc ing demonstration of the infectivity of human associated C-type particles in vivo has been shown, no long-range studies on the effect of transplanting tumor cells have been done. No long-range study of corneal transplantation has been done to demonstrate possible negative effects on the recipient who has received material from patients dying with malignancies and various neurologic disorders. This is particularly important since many re cipients are young and presumably would have a long period to express any longterm effects of transplantation. In our three cases, all recipients were under age 34 years. Case 2 emphasizes that sufficient histo ry of the donor material is not always
607
available. Terminal septicemia indicates that the donor material is not suitable for transplant purposes. Pollack 11 noted that donor corneas obtained from debilitated donors or cancer patients treated with immunosuppressive drugs do not survive cryopreservation and do not function as well as healthy donor tissue. Chronically ill patients on long-term corticosteroids, immunosuppressive or multiple antibiot ic regimens may harbor occult infection, not apparent on a cursory perusal of the donors' terminal diagnoses. Additionally, a recent study by Keates, Mishler, and Riedinger 12 showed that it is not possible to render donor eyes sterile from patients with systemic infections by using current techniques. Of corneas stored in the McCarey-Kaufman medium, 30% in their study, and 40% of corneas stored in moist chambers had positive cultures. They also were able to isolate organisms from the aqueous of three donor eyes and suggest ed that this may be a source of contamina tion to the cornea. In our Case 2 the vitreous abscess present was not noted on screening of the donor eye. Conversely, the risk of postoperative infection in the transplanted eye is small. Recently, cryptococcal endophthalmitis developing after corneal transplantation was report ed. 13 The donor material was obtained from a patient with a history of polymyositis who had been treated with cortico steroids and intermittent cyclophosphamide. Additionally, the patient had evidence of Pneumocystis carinii and cytomegalovirus infection, and the blood cultures confirmed the presence of Cryptococcus neoformans after death. Before keratoplasty, the corneal graft was bathed with a solution of polymyxin B sulfate, neomycin, and gramicidin and stored for 48 hours at 4° C. Routine bacteriologic studies of the aqueous were negative, but the eye was not examined patho logically. Case 3 emphasizes the concept that
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slit-lamp evaluation of the donor material is inadequate in establishing the presence of metastatic disease to the ciliary body in the donor eye. Gross examination of the globe in the eye pathology laboratory failed to raise suspicion of metastatic dis ease to the globe, and only the histopathologic sections showed tumor in close proximity to the line of resection of the donor corneal button. Although 89% of eye banks queried by Rabb and Brose 1 stated that anterior segment tumors make donor corneas unacceptable for trans plant purposes, our Case 3 clearly illus trates that there is no sure method of ruling out this diagnosis short of histopathologic sectioning of the globe. Transmission of Creutzfeldt-Jakob dis ease through a corneal transplant has been documented. 1 4 - 1 7 However, recent evidence presented by Gajdusek and as sociates 18,19 suggests that donor material from aged patients, and particularly pa tients with any dementia, should not be used for corneal grafting. Accidental transmission of Creutzfeldt-Jakob disease has occurred in two neurosurgic cases through the use of contaminated stereotactic electrodes, 20 and there is suspicion that a neurosurgeon may have contracted the disease from one of his patients. 1 9 Experimentally, corneas from guinea pigs with Creutzfeldt-Jakob disease, when placed in the anterior chambers of healthy guinea pigs, produced clinical and histologic evidence of CreutzfeldtJakob disease in all of the animals after approximately a two-year incubation peri od. 21 Another feature of CreutzfeldtJakob disease, not clearly understood at the present time, is that patients develop ing it have a higher frequency of having had brain or eye surgery within two years before the onset of the disease. 19 Since the virus responsible for this fatal condition is extremely hardy and resists inactivation even by 10% formalin and 70% alcohol
NOVEMBER, 1978
solutions, 19 certain precautions in han dling patients with Creutzfeldt-Jakob dis ease and their tissues become mandatory. Gajdusek and associates 19 recommended that tonometers and surgical instruments used on patients with this disease be properly sterilized. This can be achieved by autoclaving for one hour at 121° C and 20 psi or by the use of 5% hypochlorite, 0.03% permanganate, phenolics and io dine solutions. 19 The following conditions should ren der donor material absolutely unac ceptable for transplant purposes: Creutz feldt-Jakob disease, any dementia, and probably any chronic neurologic disorder unless clearly secondary to a traumatic etiology. This includes subacute sclerosing panencephalitis, progressive congen ital rubella, progressive multifocal leukoencephalopathy, cytomegalovirus brain infection, Crohn's disease, and subacute encephalitis. 1 8 Ophthalmologists should also be aware of the many other condi tions in which slow virus etiology is suspected, but so far not proven. This includes multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, some of the collagen vascular diseases, and others. 18 Other conditions include: septicemia; hepatitis, jaundice, and evi dence of any active viral infection; syphi lis and positive serology (in certain cases of treated tertiary syphilis, the cornea is probably noninfectious and safe to use). Many other conditions require extreme caution with regard to selection as donor material, although currently no state ments can be made regarding absolute contraindication to use. These conditions include: (1) ocular or systemic malignan cy of any kind; (2) long terminal dis ease, particularly if immunosuppressive agents, large doses of corticosteroids, and multiple antibiotic regimens were used terminally and particularly if there is evi dence of systemic or focal infection; (3)
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history of eye diseases, including external eye diseases, corneal disease or dystro phy, iritis, absolute glaucoma, and acute glaucoma attack; and (4) history of previ ous intraocular surgical procedure of any kind. The above criteria for selection of donor corneal material are practical and are currently implemented at the New England Eyebank in Boston, Massachu setts. The majority of corneal grafting proce dures are elective by nature. A thorough evaluation of donor material should be undertaken by the corneal surgeon and the eyebanks. In emergencies, use of ma terial from donor eyes with the previously mentioned relative contraindications may be justified. The tightening up of guide lines on the use of donor material should serve as a further impetus for research to achieve more satisfactory ways of pre serving donor tissue. From our study, we believe it would be advisable to initiate a long-term prospective study on the effects of keratoplasty in which the clinical and pathologic findings of the donor as well as any ocular or systemic changes of the recipient are recorded. SUMMARY
Histologic study of eyes used as donor material for corneal transplant revealed one instance of massive leukemic infiltra tion with leukemic keratic precipitates on the fellow eye. In another eye, microabscesses composed of acute and chronic inflammatory cells containing Cryptococcus neoformans were present. In a third patient metastatic anaplastic cells were present in the choroid. We think donor eyes are absolutely unacceptable if death was caused by any chronic neurologic disorder, unless clearly secondary to trau ma. Eyes from patients with septecimia, hepatitis, jaundice and any evidence of
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any active viral infection, syphilis, and positive serology are also unacceptable. Extreme caution should be used in select ing eyes of patients with ocular or system ic malignancy, long-term diseases, partic ularly if immunosuppressive agents were used, where a history of eye disease ex ists, including corneal disease or dystro phy, iritis, absolute glaucoma or acute glaucoma, and eyes with a history of previous intraocular surgery. REFERENCES 1. Rabb, M. F., and Brose, B.: Survey of eye bank procedures. In Capella, J. A., Edelhauser, H. F., and Van Horn, D. L. (eds.): Corneal Preservation. Clini cal and Laboratory Evaluation of Current Methods. Springfield, Charles C Thomas, 1971, pp. 3-17. 2. Dmochowski, L., Taylor, H. G., Grey, C. E., Dreyer, D. A., Sykes, J. A., Langford, P. L., Roger, T., Shullenberger, C. C , and Howe, C. D.: Virus and mycoplasma (PPLO) in human leukemia. Can cer 18:1345, 1965. 3. Dmochowski, L., Rumoto, T., Grey, C. E., Deisgner, E., Hales, R. L., Langford, P. L., Taylor, H. G., Freireich, E. J., Shullenberger, C. C , Shir ley, J. A., and Howe, C. D.: Electronmicroscopic studies of human leukemia and lymphoma. Cancer 20:760, 1967. 4. Newell, G. R., Harris, W. W., Bowmann, K. D., Boone, C. W., and Anderson, N. G.: Evaluation of "virus-like" particles in the plasma of 225 patients with leukemia and related diseases. N. Engl. J. Med. 278:1185, 1968. 5. Morton, D. L., Malingren, R. A., Hall, W. T., and Schildovsky, G.: Immunological and virus stud ies with human sarcomas. Surgery 66:152, 1969. 6. Chopra, M. C., and Feller, W. F.: Virus-like particles in human breast cancer. Tex. Rep. Biol. Med. 27:945, 1969. 7. Todaro, G. J., Zeve, V., and Aaronson, S.: A virus in cell culture derived from human tumor patients. Nature 226:1047, 1970. 8. Seman, G., Gallager, H. S., Lukeman, J. M., and Dmochowski, L.: Studies on the presence of particles resembling RNA virus particles in human breast tumors, pleural effusions, their tissue cul tures, and milk. Cancer 28:1431, 1971. 9. Birkmayer, G. D., Galda, B. R., and Miller, F.: Oncoma-viral information in human melanoma. Eur. J. Cancer 10:419, 1974. 10. Dohlman, C. H., and Boruchoff, S. A.: Pene trating keratoplasty, Int. Ophthalmol. Clin. 8:3:655, 1968. 11. Pollack, F . M.: Corneal Transplantation. New York, Grune and Stratton, 1977, pp. 98-99. 12. Keates, R. H., Mishler, K. E., and Riedinger,
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