OCULAR COMPLICATIONS ASSOCIATED WITH CARDIAC TRANSPLANTATION* BY Francis j Wapner, MD (BY INVITATION), Martin L. Leib, MD (BY INVITATION), Ronald Drusin, MD (BY INVITATION), Eric Rose, MD (BY INVITATION), AND B. Dobli Srinivasan, MD INTRODUCTION

OCULAR

COMPLICATIONS OCCUR IN PATIENTS WITH IATROGENIC OR AC-

quired immunosuppression and result from drug or radiation toxicity, opportunistic infection, and/or graft-versus-host disease. 1-23 These findings have been reported in bone marrow and renal transplantation patients. 1-14 Patients with acquired immunodeficiency syndrome (AIDS) are at risk for similar ocular opportunistic infection. 15-20 Three brief reports of eye findings in four cardiac transplant patients have been made.21-23 Since 1977, over 485 cardiac transplantations have been performed at Columbia-Presbyterian Medical Center in New York. During the past 15 years, 67 of these patients presented to the Edward S. Harkness Eye Institute for ophthalmic evaluation. Ocular findings in these patients were compared with those found in other immunosuppressed patient populations. To our knowledge, this report describes the largest series of ocular complications in heart recipents to date. PATIENTS AND METHODS

From February 1977 to September 1991, 488 cardiac transplantations were performed at Columbia-Presbyterian Medical Center. Sixty-seven (14.3%) transplant patients presented to the Edward S. Harkness Eye Institute for ophthalmic evaluation. Five patients with a significant past ocular history were excluded from the study. All patients had undergone one cardiac transplantation at an average age of 45 years (range, 21 to 63). Cardiac diagnoses were ischemic cardio*From Columbia University College of Physicians and Surgeons, The Edward S. Harkness Eye Institute, Columbia-Presbyterian Medical Center, New York. TR. AM. OPHTH. Soc. vol. LXXXX, 1992

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myopathy (48 patients, 74%), coronary artery disease (17 patients, 23%), and congestive heart disease (4 patients, 3%). Patients were treated with postoperative corticosteroids and a combination of azathioprine and/or cyclosporine. Eight eye patients had transplants prior to the use of cyclosporine. Eye examinations and chart reviews were conducted between 1 week ad 6.5 years postoperatively, with a mean intervening period of 16.4 months. Exams included best corrected Snellen visual acuity, near acuity, slit-lamp biomicroscopy, applanation tonometry, and indirect ophthalmoscopy, with additional testing as warranted. RESULTS

Sixty-two patients (12.8%) with their primary ocular finding were included in this review: 50 male (80%) and 12 female (20%). Fifty were white (82%), 5 African-American (8%), 5 Hispanic (8%), and 2 Asian (2%). The mean age of examined patients was 46.4 years (range, 21 to 63) (Table I). Thirty-two patients (51.6%) had posterior subcapsular cataracts (PSC); 23 patients had bilateral involvement, and 9 patients had unilateral or significantly asymmetric involvement (greater than 3 lines difference on the Snellen chart or near card). The mean age at diagnosis was 49.1 years (range, 22 to 61) in 24 male and 7 females. Four patients between 21 and 30 years of age had PSC diagnosed an average of 4 months posttransplant (range, 1 to 6 months); patients between 31 and 61 years of age had a mean intervening period of 28 months. Visual acuity at time of diagnosis ranged from 20/20 to 20/100, with a mean of 20/40; average near acuity was J2. All patients were on a corticosteroid regimen at the time of diagnosis; use of additional immunosuppressives varied. Six patients had uncomplicated unilateral extracapsular cataract extraction with posterior chamber intraocular lens placement. The mean age at the time of surgery TABLE I: OCULAR COMPLICATIONS IN CARDIAC TRANSPLANT PATIENTS

COMPLICATION

% OF TOTAL

Posterior subcapsular cataract

51.6

Conjunctival chemosis/

17.7

cysts Opportunistic chorioretinitis Herpes simplex keratitis Keratitis sicca

Miscellaneous

8.0 6.4 4.8 11.5

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was 53.2 years and average preoperative visual acuity was 20/80, J10; mean postoperative visual acuity was 20/30, J1-2. One patient required postoperative Nd:YAG capsulotomy for posterior capsule opacification. Eleven patients (17.7%) had chemosis and/or cysts of the bulbar conjunctiva an average of 11 months posttransplantatian. Local irritation was the chief complaint. All were being treated with cyclosporine at the time of the diagnosis in combination with prednisone and/or azathioprine. Past ocular history was negative. The conjunctival lesions appeared to wax and wane over a period of 2 to 8 months, and several resolved without topical treatment. Biopsy specimen from one patient revealed an atypical lymphangiectasis without evidence of inflammation (Fig 1). Herpes simplex keratitis (dendritic) was diagnosed in four patients (6.4%) 1 to 10 months posttransplant. Two patients who had transplantation prior to the use of cyclosporine had peripheral dendrites (culturepositive for herpes simplex) and one recurrence each. The other two patients had centrally located dendritic lesions. All were treated with topical antiviral agents (Idoxiuridine, Trifluridine). Two patients died

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FIGURE 1

Spectrum of conjunctival abnormalities seen in association with cardiac transplantation, including chemosis, cysts, and expanded cysts with dilated lymphatic channels (a, b, and c). Histopathology reveals lymphangiectasia of subepithelial conjunctiva (d) (hematoxylin-eosin, x 100).

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within 2 months of diagnosis and a third within 10 months. Causes of death were endocarditis (patient not taking cyclosporine), pancreatitis (patient not taking cyclosporine), and cardiac rejection, respectively. Five cases (8%) of retinochoroiditis were diagnosed. Three patients had unilateral cytomegalovirus (CMV) retinitis; heart donors were CMVnegative. One patient, transplanted before cyclosporine was in use, died within 10 months of ocular diagnosis of an unspecified carcinoma; a second died within 8 months of rejection. Both contracted retinal CMV prior to ganciclovir (DHPG) use. The third patient had unilateral peripapillary CMV retinitis sparing the macula 2 months after transplant and was treated with DHPG (5 mg intravenously every 12 hours) for 21 days. Visual acuity decreased to 20/80 before disease activity was considered arrested. A fourth patient (not taking cyclosporine) had presumptive Candida chorioretinitis 1 month posttranplant, which progressed to endophthalmitis. Blood cultures grew C albicans. Amphotericin B (total dose, 1.2 g intravenously) was administered, with resolution (negative blood cultures, no active vitritis) after 14 days. Final visual acuity was 20/20 with no recurrence in 9 years of follow-up (Fig 2).

FIGURE

2

Patient with Candida albicans septicemia and presumptive Candida chorioretinitis 1 month

posttransplantation, which progressed

to

endophthalmitis.

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A fifth patient (taking cyclosporine) had a unilateral Toxoplasma retinochoroiditis 1.5 years posttransplantation. This was considered to be an acquired primary ocular infection or a reactivation from a latent extraocular site based on fundus appearance and positive immunoglobulin assay for IgM. The patient was treated with pyrimethamine, 25 mg twice daily; sulfadiazine, 1 g four times daily; and folinic acid, 5 mg four times daily. Vitritis regressed; however, a tractional retinal detachment developed by day 10, necessitating surgical intervention. Final visual acuity was count fingers at 2 feet (Fig 3). Three cases of "dry eyes," in addition to isolated cases of branch retinal vein occlusion, canalicular obstruction, angular blepharitis (culture-negative), chalazion, orbital myositis, and top of the basilar syndrome, were evaluated. Twelve of the 62 eye patients (19.3%) died during the course of this review, compared with 30.4% (128 of 421) in the nonophthalmology group. Of the eye patients who died, the average age at transplant was 42.8 years and mean survival was 25 months. For the nonophthalmology patients who died, the average age at transplant was 4.4 years and mean survival of 8 months; many of the early patients died in the immediate

FIGURE 3

Serous retinal elevation and mild vitritis overlying active toxoplasmic retinitis 11/2 years after

cardiac transplantation.

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postoperative period. Five of the eight eye patients who had transplantation prior to the use of cyclosporine (62.5%) died within 14.5 months. Causes of death for the eye patients included rejection (4), prostate cancer (1), unspecified carcinoma (1), lymphoma (1), multiple system failure (1), pneumonia (1), endocarditis (1), pancreatitis (1), and one nonspecified. DISCUSSION

Posterior subcapsular cataract is the most common ophthalmic complication in immunosuppressed cardiac transplantation patients, a finding reported in renal transplant patients receiving immunosuppressive therapy.9-14 PSC and ocular manifestations of chronic graft-versus-host disease are the most common ophthalmic findings in bone marrow recipients. 1-8 Clinically apparent PSC developed in 52% of cardiac transplant patients compared with 12% to 60% of renal transplant patients and 9% to 80% in bone marrow recipients. The wide range of incidence in the former may be attributed to variations in steroid dosages, duration of steroid usage, age at transplantation, and other factors.9-12 PSC incidence in bone marrow recipients appears to be altered most significantly by single-shot (ssTBI) versus fractionated total-body irradiation (ffBI), with ssTBI appearing more cataractogenic.6-8 Three of the four patients with herpes simplex keratoconjunctivitis died within 10 months of diagnosis, indicating a poor prognosis. Two of these three patients underwent transplantation prior to the use of cyclosporine, and both had peripheral dendrites similar to those seen in AIDS patients.15,16 A recent report of epithelial keratitis in a cardiac transplant patient attributed to CMV (on the basis of viral cytopathology) was remarkably similar to these four cases.23 Perilimbal chemosis and/or cysts of the bulbar conjunctiva seen in 11 patients could not be linked to any known etiologic factor. To our knowledge, this has not been reported in the transplant literature, because it pertains to ocular complications. This presentation did not mimic the conjunctival inflammations or neoplasia seen in AIDS patients. 15-20 Patients with this finding were all taking cyclosporine; a mild conjunctivitis has been attributed to a topical cyclosporine-castor oil suspension.24 Its frequency in this series warrants investigation into whether it is a finding specific to this patient population or is a drug-induced (ie, cyclosporine)

phenomenon. Opportunistic retinal infections were similar to those seen in other transplant groups and in the AIDS population. 1-20 The incidence of reti-

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nochoroiditis in our series (5%) was lower than that reported in AIDS patients (6% to 38%), although etiology (eg, CMV, Candida, Toxoplasma) was similar. 5,13, 15-21 Two patients contracted CMV retinitis prior to use of DHPG, and one patient was successfully treated with it. This regimen was not complicated by a secondary neutropenia (nor by incompatibility with azathioprine), which complicates its use in the AIDS population.'6 AIDS patients with CMV retinitis have a guarded prognosis for survival; two of three cardiac transplant patients in our series died within 10 months of its diagnosis, indicating a similar poor prognosis. 15-20 No idiopathic serous retinal detachments were noted in our series. Three cases in two cardiac and one renal transplant patient were reported at an institution that has performed over 250 cardiac transplants. No definitive etiology was identified.22 Cotton-wool spots and intraretinal hemorrhages frequently noted in AIDS patients (28% to 92%) were not seen in our patients and have not been reported in renal transplant patients.9-22 Intraretinal hemorrhages have been reported in some bone marrow recipients; they may be a sequela of irradiation, graft-versus-host disease, or some other factor(s). 6,8 The absence of cotton-wool spots in the majority of transplant patients may support the theory that "AIDS retinopathy" is a vasculitis secondary to circulating immune complexes or the result of direct HIV infection of the retina and/or retinal vascular endothelium and not a retinal toxic effect of an opportunistic infection. 15-20 This retrospective review indicates that immunosuppressed cardiac transplant patients are at risk for similar ocular complications (eg, cataracts) reported in renal and bone marrow transplant patients. Cataract surgery was uneventful in this patient population. Cases of retinochoroiditis similar to those found in AIDS patients were also seen, but the frequency was lower. Conjunctival chemosis and/or cysts appears to be a unique finding, with the cause remaining to be determined. ACKNOWLEDGMENT

We gratefully acknowledge the cooperation of Drs Anthony Donn, Michael Weiss, and Daniel Casper who provided several patients for this study. Dr Hermann Schubert kindly reviewed the histopathology of several conjunctival biopsies. REFERENCES 1. Jack MK, Hicks JD: Ocular complications in high-dose chemoradiotherapy and marrow transplantation. Ann Ophthalmol 1981; 13:709.

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2. Hirst LW, Jabs DA, Tutschka PJ, et al: The eye in bone marraw transplantation: I. Clinical study. Arch Ophthalmol 1983; 101:580. 3. Jabs DA, Hirst LW, Green WR, et al: The eye in bone marrow transplantation: II. Histopathology. Arch Ophthalmol 1983; 101:585. 4. Jabs DA, Wingard J, Green WR, et al: The eye in bone marrow transplantation: II. Conjunctival graft-vs-host disease. Arch Ophthalmol 1989; 107:1343. 5. Pauleikoff D, Messmer E, Beelen DW, et al: Bone marrow transplantation and toxoplasmic retinochoroiditis. Albrecht von Graefes Arch Klin Exp Ophthalmol 1987; 225:239. 6. Livesy SJ, Holmes JA, Whittaker JA: Ocular complications of bone marrow transplantation. Eye 1989; 3:271. 7. Sanders J: Long-term effects of bone-marrow transplantation. Pediatrician 1991; 18:76. 8. Bray LC, Carey PJ, Proctor SJ, et al: Ocular complications of bone marrow transplantation. Br J Ophthalmol 1991; 75:611. 9. Hovland KR, Ellis PP: Ocular changes in renal transplant patients. Am J Ophthalmol 1967; 63:283. 10. Kern R, Zaruba K, Scheitlin W: Ocular side-effects of long-term immunosuppressive therapy in recipients of cadaver kidney transplants. Ophthalmol Res 1970; 1:21. 11. Sutherland DE, Fryd DS, Strand M, et al: Results of renal transplantation in diabetics at the University of Minnesota since 1979. Transplant Proc 1984; 16:629. 12. Denath SC, Abomehla MS, Jawdat M, et al: Ocular side effects of systemic steroid therapy in renal transplant patients. Ann Ophthalmol 1987; 19:435. 13. Algan M, Jonon B, George JL, et al: Listeria monocytogenes endophthalmitis in a renal transplant patient receiving Ciclosporine. Ophthalmologica 1990; 201:23. 14. Mansour AM: Renal allograft tuberculosis. Tubercle 1990; 71:147. 15. Schuman JS, Orellana J, Friedman AH, et al: Acquired immunodeficiency syndrome. Surv Ophthalmol 1987; 31:384. 16. Culbertson WW: Infections of the retina in AIDS. Int Ophthalmol Clin 1989; 29:108. 17. O'Donnell JJ, Jacobson MA: Cotton-wool spots and cytomegalovirus retinitis in AIDS. Int Ophthalmol Clin 1989; 29:105. 18. Shuler JD, Engstrom RE Jr, Holland GN: External ocular disease and anterior segment disorders associated with AIDS. Int Ophthalmol Clin 1989; 29:98. 19. Holland GN, Pepose JS, Petis TH, et al: Acquired immunodeficiency syndrome: Ocular manifestations. Ophthalmology 1982; 90:859. 20. O'Donnell JJ, Goodner EK, Shiba AH: A prospective study of eye disease in AlDS. Invest Ophthalmol Vis Sci (Suppl) 1986; 2:122. 21. Mammalis M, Daily MJ, Ross D: Presumed intraocular nocardiosis in a cardiac transplant patient. Ann Ophthalmol 1988; 20:271. 22. Friberg TR, Eller AW: Serous retinal detachment resembling central serous chorioretinopathy following organ transplantation. Albrecht von Graefes Arch Klin Exp Ophthalmol 1990; 228:305. 23. Yee RW, Sigler SC, Lawton AW, et al: Apparent cytomegalovirus epithelial keratitis in a cardiac transplant recipient. Transplantation 1991; 51:104. 24. Nussenblatt RB, Palestine AG: Cyclosporine: Immunology, pharmacology and therapeutic uses. Surv Ophthalmol 1986; 31:159.

DISCUSSION DR DENNIS M. ROBERTSON. The authors report the postoperative complications among 62 patients who had undergone cardiac transplantation at ColumbiaPresbyterian Medical Center and who were subsequently examined at the Edward S. Harkness Eye Institute. Since cardiac transplant patients are treated with systemic corticosteroids and immunosuppressive agents postoperatively, it is not

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surprising that recognized ocular complications in these patients include cataract and opportunistic infection in the form of a retinochoroiditis or keratitis. An unusual, unexpected complication was the postoperative appearance of chemosis and conjunctival cyst formation in about one fifth of the patients. The authors do not state whether the patients with conjunctival chemosis were in congestive heart failure, had renal failure, had generalized edema, or were on ventilators, all of which can be associated with conjunctival edema. The authors also fail to explain what they mean by the term "conjunctival cyst." It is known that systemic corticosteroids can cause angioneurotic edema and chemosis, and that cyclosporine can cause allergic reactions, conjunctivitis, and conjunctival edema, but these drug complications are uncommon and ordinarily do not approach the 18% incidence of conjunctival reactions reported in these cardiac transplant patients. The appearance of the chemosis may be related to the graft-versus-host disease reaction that was described by Jabs and associates in 1989 (Arch Ophthalmol 1989; 107:1343-1348). Those investigators identified four stages of conjunctival-corneal reaction in patients in whom a graft-versus-host disease developed following bone marrow transplantation. The stage II reaction was a mild reaction characterized by chemosis as well as mild hyperemia. The histologic features of the conjunctival biopsies recorded by Jabs and colleagues included expressions of graft-versus-host disease characterized by mononuclear inflammatory infiltrates in the substantia propria of the conjunctiva and loss of the conjunctival epithelium (Arch Ophthalmol 1989; 107:1343-1348). The investigators also observed conjunctival bullae (are these analagous to the "conjunctival cysts" reported by Wapner and associates?), pseudomembranous conjunctivitis, and frequently keratinization of the conjunctival and corneal epithelium (Arch Ophthalmol 1983; 101:585-590). In the patients who had bone marrow transplants, donor lymphocytes reacting with the host tissues may cause, in some instances, a severe graft-versus-host disease reaction, resulting in stasis ofboth liver and lacrimal gland secretions; the latter is related to the development of the conjunctival and corneal changes reported by Jabs and associates (Arch Ophthalmol 1989; 107:1343-1348). Jabs and associates also described a peculiar, unique histiocytic focal reaction in the choroid among patients receiving marrow transplantation. The conjunctival biopsy reported by Wapner and associates did not show any of these expressions. Regarding the development of cataracts, the authors do not offer an explanation why the average interval between cardiac transplantation and the development of cataracts was only 4 months in those patients under the age of 30, but was almost 21/2 years in those patients over 30 years of age. The authors compare the ocular findings following cardiac transplantation with those findings following renal and bone marrow transplantation and contrast them with what has been recognized in patients with AIDS retinopathy. They specifically note the interesting observation that cotton-wool spots are generally and peculiarly absent in patients undergoing transplantation. The authors noted, further, that retinal hemorrhages were uncommonly observed in patients undergoing either cardiac transplantation or renal transplantation. Retinal hemorrhages, however, are common in patients undergoing bone marrow transplanta-

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tion in which circumstance they usually are associated with episodes of thrombocytopenia (Arch Ophthalmol 1983; 101:585-590). The authors fail to explain precisely why they excluded five patients from the statistics in this series. Sixty-seven patients were originally seen at their eye institute, and because five patients had "significant past ocular history" they were excluded from this review. The authors also fail to identify who conducted the ocular examinations. Presumably, this study was a retrospective review of the medical records. It is uncertain whether the examinations were performed by residents, postgraduate fellows, or full-time consultants on the staff of the Edward Harkness Eye Institute, and this may significantly affect the observed incidences of the posttransplant complications. Nevertheless, the large numbers of cases studied and reported here make this paper deserving of considerable respect. DR W JACKSON ILIFF. I wanted to comment briefly about the possible canalicular obstruction. I can think of several possible scenarios for that. We certainly see people on a variety of chemotherapeutic agents who develop canalicular obstruction. I have seen three or four different viral causes that can produce obstruction. Herpes Simplex certainly is one. Doctor Robertson mentioned the pseudomembranous conjunctivitis of graft-versus-host disease which also may produce a canalicular problem. Although I don't know about systemic application of cyclosporine, the veterinary ophthalmologists have found that topical cyclosporine is helpful in treating dogs with keratoconjunctivitis sicca. Is it possible that some of the tearing aspects may be associated with that? DR NARSING A. RAo. I congratulate the authors for such a detailed study and for collecting such a large number of patients. There are some similarities between ocular complications observed in AIDS and cardiac transplant patient. It will be interesting to know what the CD4 lymphocyte count was in cardiac transplant patients when they developed ocular complications? DR JOHN D. BULLOCK. Thank you. That was an excellent paper and discussions. I have a patient in Dayton, OH, who has been written up in the New England Journal of Medicine and in JAMA; he has had more hearts than anybody who has ever lived. He had his own heart, then he had a transplant that he rejected, then he had a Jarvic heart, and then he had a second transplant. He was placed on cyclosporine and prednisone and developed bilateral posterior subcapsular cataracts. I removed both cataracts. Interestingly, after his first cataract, he had a pressure rise. In your paper you mentioned that there were no complications from cataract surgery. My patient had a pressure rise to the mid 30s for 1 week. We just waited it out because I was afraid to give him Diamox because cyclosporine is nephrotoxic and I wasn't sure what effect the Timoptic might have on his transplanted heart. He now has 20/25 vision in each eye.

DR J. DONALD M. GASS. I enjoyed the paper by Doctor Wapner and co-workers very much. I wanted to mention a complication that they did not find that we have

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seen in five patients after organ transplantation, four after renal transplantation and one after a heart-lung transplantation. This consists of loss of vision in both eyes caused by an exudative retinal detachment that is associated with multiple leopard spot changes in the pigment epithelium occurring around the optic disc and in the macula area. We do not know its cause. All of the patients were receiving azathioprine, cyclosporine, and predisone. Only one patient had a transplant reaction shortly before the onset of visual symptoms. Nevertheless, we suspect that it may be caused by a subclinical reaction to the transplanted organ. The fundus changes suggest a localized intravascular coagulopathy affecting the choriocapillaris.

DR MARTIN L. LEIB. I appreciate the astute comments made by all of these reviewers. By way of introduction, there is always a thematic problem in a series such as this that looks in retrospect upon patients such as the ones that we have seen. We had a grand opportunity having an extremely large compliment of patients, namely, 544 cardiac transplant patients to date. But, in reality, we only examined those that were symptomatic. So, those patients with asymptomatic early PSCs or small conjunctival cysts may have been more worried about life and death issues than, perhaps, mild diminution of vision. In spite of the breadth of this patient population, we only saw those that were symptomatic and thus, the absolute incidence of these ocular complications could be much larger and shall be studied in greater depth. The issue of chemosis raised by Doctor Robertson is an excellent one. However, the chemosis seen most commonly in the bone marrow transplant population was diffuse. It was not sectoral as that which we have seen here. We have now addressed this issue and expanded our investigation by asking our renal transplant service to have us review all of their renal transplant patients as well. Excellent reviews by Doctors Green, Jab, and others at Wilmer did study histopathologically the graft vs host reaction seen in bone marrow transplant patients. The conjunctival disease in that clinical disease spectrum is very different from the one we have seen here. The issue raised by Doctor Rao of the cotton-wool spots that we failed to see in our patients I think highlights the fact that, perhaps, the AIDS population represents a very distinct entity of vasculitis secondary to either circulating immune complex or the result of direct HIV infection of the retina or retinal vascular endothelium and is not the result of opportunistic infection as is seen in renal patients and patients with cardiac transplantation. Doctor Iliff raised an interesting point about nasolacrimal side-effects seen in patients on various topical medications. Our patient with epiphora, however, was never on any topical medication nor did he have a history of viral keratitis. Thematically again, this is a review in retrospect and now armed with our eyes open and your thoughtful comments, hopefully in the future we shall be able to produce a more meaningful paper. Thank you.

Ocular complications associated with cardiac transplantation.

OCULAR COMPLICATIONS ASSOCIATED WITH CARDIAC TRANSPLANTATION* BY Francis j Wapner, MD (BY INVITATION), Martin L. Leib, MD (BY INVITATION), Ronald Drus...
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