Full text of DOI:10.1007/s12009-001-0058-1

A B S T R A C T
Cytomegalovirus (CMV) retinitis after heart transplantation is well
documented, but few cases of central retinal vein occlusion (CRVO)
have been described in these patients. A man seropositive to CMV
antigen after heart transplantation received prophylactic ganci-
clovir therapy. Nevertheless, cytomegalovirus retinitis developed
and CRVO was diagnosed in his other eye. Common risk factors for
retinal vein occlusion were excluded. Cytomegalovirus infection may
have played a role in the pathogenesis of CRVO.
C A S E R E P O R T
Simultaneous Cytomegalovirus Retinitis
and Central Retinal Vein Occlusion of a
Heart Transplant Recipient
Juan A. Aviñó, MD, Enrique España, MD, PhD,
Luis Almenar, MD, Marino Blanes, MD, Manuel
Díaz-Llopis, MD, PhD, & José L. Menezo, MD, PhD
ytomegalovirus (CMV) retinitis after organ trans-
C
plantation has been well documented,1-4 and usu-
ally responds adequately to a short course of
ganciclovir therapy. In contrast, when retinits affects
patients with acquired immunodeficiency syndrome
(AIDS), suppressive therapy for prolonged periods
may be required.5 Cytomegalovirus retinitis in heart
transplant recipients is similar to that described for
other organ transplantations.3
On the other hand, central retinal vein occlusion
(CRVO) after cardiac transplant has been scarcely
described in the literature.6,7 We herein present the
simultaneous presentation of CMV retinitis and CRVO
in the fellow eye of a heart transplant recipient. The
occurrence of CMV infection may have contributed to
the development of CRVO in our patient.
Case Report
A 51-year-old man underwent successful orthotopic
heart transplantation, performed because of refracto-
ry advanced idiopathic myocardiopathy. The patient
had no peripheral vascular disease, hypertension, or
diabetes mellitus before the transplant. Preoperative-
ly, serologic testing for human immunodeficiency
virus (HIV) was negative, and the IgG anti-CMV titer
Reprints:
Juan A. Aviñó Martínez, MD, c/ Stma. Trinidad, 24 Bajo, 46290 Alcacer, Valencia,
Spain.
Drs. Aviñó, España, Díaz-Llopis, and Menezo are from the Department of Ophthalmol-
ogy, University Hospital “La Fe,” Valencia, Spain. Dr. España also is from the Depart-
ment of Optics, University of Valencia, Valencia, Spain. Dr. Almenar is from the
Department of Cardiology and Dr. Blanes is from the Department of Internal Medicine,
University Hospital “La Fe.” Dr. Díaz-Llopis is from the University of the Basque Coun-
try, Basque Country, Spain. Dr. Menezo is from the Department of Surgery, University
of Valencia, Valencia, Spain.
60
ANN OPHTHALMOL. 2001;33(1):60–63

was 1/10,000. The donor organ came from a 34-year-old
man, who was CMV seronegative. Cardiopulmonary
bypass time was 60 minutes. The patient received
fresh-frozen plasma during the intervention.
The immunosuppressive regimen included induc-
tion therapy with OKT3 (5 mg/day for 7 days). The
patient also received concomitant administration of
signs of ischemia (Fig 3). A diagnosis of CMV retinitis
in the right eye and CRVO in the left eye was made.
At diagnosis, his blood pressure was 110/70 mm Hg.
Laboratory evaluation showed normal cholesterol and
triglyceride levels. Glucose level was 89 mg/dL (nor-
mal range, 65 to 110 mg/dL). Hemoglobin level was
12.8 g/dL (normal range, 12 to 16 g/dL), with a hemat-
ocrit of 33.1% (normal range, 37% to 55%). The leuko-
cyte count was 7.1 × 109/L with a CD4+ lymphocyte
count of 366 cells/mm3. The CD4/CD8 ratio at this time,
5 months after transplant, was 5.08, changing from
2.43, 2.21, and 3.64 at 1, 2, and 3 weeks, respectively,
and 2.34 and 8.31 at 1 and 3 months, respectively.
Platelet counts were normal. Rapid plasmin reagin,
anticardiolipin antibody, and lupus anticoagulant were
negative. Serum viscosity, serum complement concen-
trations, and fibrinogen concentrations were normal.
Results of IgM anti-CMV detection were negative.
The patient was then treated with intravenous
ganciclovir sodium (9 mg/kg/day). The dosages of
immunosuppressive therapy were reduced as fol-
lows: deflazacort, 0.2 mg/kg/day; cyclosporine, 3.5
mg/kg/day (levels of 150 to 250 ng/mL); and azathio-
prine, 2 mg/kg/day.
Three weeks later, visual acuity remained the same
in the right eye (20/20) and had decreased to 20/400 in
the left eye. In the right eye, retinitis and hemorrhag-
ic areas had decreased considerably, and opaque
threads corresponding to occluded vessels, with reso-
lution of the periphlebitis, could be seen (Fig 1B). In
the left eye, a substantial decrease was seen in the
amount of hemorrhages. Cytomegalovirus antigen
detection and blood culture for CMV were negative.
Because of the improvement in the ophthalmoscopic
findings, maintenance therapy with oral ganciclovir
(1000 mg 3 times a day) was started.
corticosteroids
(deflazacort,
0.6
mg/kg/day),
cyclosporine (5 mg/kg/day for a level of 200 to 300
ng/mL assessed by radioimmunoassay and started on
postoperative day 4), and azathioprine (3 mg/kg/day to
maintain a total white blood cell count of at least 4000
cells/mm3, started 10 days after surgery).
According to our hospital’s post-transplantation
protocol, the patient underwent periodical assays for
CMV antigen detection and blood cultures for CMV.
By postoperative day 15, these assays and cultures
became persistently positive. Although the patient
remained asymptomatic, he was admitted to the hos-
pital 3 months after the transplant in an attempt to
achieve negative CMV antigen detection. He was
treated with intravenous ganciclovir sodium (6.5
mg/kg/day for 3 weeks), followed by oral ganciclovir
therapy (1000 mg 3 times a day). Nevertheless, CMV
antigen positivity persisted.
Five months after the transplant, the patient noted
decreased vision in his left eye. He was still receiving
oral ganciclovir (1000 mg 3 times a day). Best-correct-
ed visual acuity was 20/20, right eye, and 20/70, left
eye, with a correction of –0.50 –0.50 × 120 and –0.75
–0.50 × 60, respectively. The anterior segment findings
were unremarkable. Intraocular pressures were 15
mm Hg in the right eye and 16 mm Hg in the left eye.
The vitreous was clear bilaterally. Fundus examina-
tion revealed patches of retinitis in the inferior tem-
poral quadrant of the right eye, with minor
hemorrhages and perivenous sheathing (Fig 1A). In
the left eye, widespread areas of retinal hemorrhage,
affecting mainly the inferior retina, were seen (Fig 2).
Fluorescein angiography of the left eye showed no
Seven weeks after diagnosis, visual acuity in the
left eye had increased to 20/100. Visual acuity in the
right eye remained stable, and complete resolution of
retinitis was observed.
Fig 1A.—Fundus photograph of the inferior temporal quadrant of the retina of the
right eye at diagnosis. Small areas of active retinitis are evident.
Fig 1B.—Fundus photograph of the inferior temporal quadrant of the retina of the
right eye after 3 weeks of induction treatment. A substantial improvement can be
observed. Note that the perivascular sheathing has disappeared.
ANN OPHTHALMOL. 2001;33(1)
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Fig 3.—Fluorescein angiogram of the left eye. The retinal capillary bed is well per-
fused, and no signs of ischemia are seen.
Fig 2.—Central retinal vein occlusion is observed in the left eye.
retinal vein. There are several conditions that may
contribute to thrombus formation. These include
altered blood flow, alterations in blood viscosity, clot-
ting factor abnormalities, and abnormalities of the
vessel walls.12 Common risk factors for CRVO (ie, dia-
betes mellitus, systemic arterial hypertension, hyper-
lipidemia, and hyperopia) were exhaustively ruled out
in our patient. Laboratory workup showed no alter-
ations in blood cell count, clotting factors, or blood vis-
cosity. Other factors that may have contributed to the
development of CRVO are related to the surgical pro-
cedure and immunosuppressive therapy.
Regarding the surgical procedure, a cardiopul-
monary bypass is required in patients undergoing
heart transplantation. Cardiopulmonary bypass has
been shown to cause systemic hypotension and loss of
the pulsatile component of blood flow.13 In addition,
platelets are frequently damaged, and complement
activation with platelet aggregates may develop dur-
ing the procedure.14 Thus, cardiopulmonary bypass
causes both blood flow and viscosity alterations. Nev-
ertheless, this mechanism is an unlikely cause since
venous occlusion ocurred a long time after surgery.
Concerning factors related to immunosuppressive
therapy, OKT3 (ie, monoclonal antibody used in
induction therapy) has been associated with a high
occurrence of vascular thrombosis.15 Furthermore,
cyclosporine has been reported to cause damage to
small vessels.16
Discussion
Ocular complications after heart transplantation
have been described in very few reports.4,6-8 Quinlan
and Salmon7 found that lens changes related to pro-
longed oral corticosteroid therapy (in 43% of patients)
and retinal vascular changes (37.3 %) were the 2
major complications. They described a 3.4% inci-
dence of CMV retinitis during the first 6 months after
heart transplant.7
Possible sources of CMV infection in transplant
recipients are: (1) reactivation of a latent infection pre-
sent before transplantation due to the immunosup-
pressive therapy and (2) primary infection transmitted
through blood transfusion or via transplanted organs,
particularly when seropositive organs are implanted
in seronegatives recipients.3 Since our patient was
CMV seropositive before transplant, CMV infection
was problably the result of immunosuppression sec-
ondary to drug therapy. However, blood transfusion or
organ donor transmission cannot be completely ruled
out in our patient, since it has been suggested that
transmission of CMV from an organ donor can occur
even in seropositive recipients.9 Cytomegalovirus
infections in recipients of a solid organ transplant,
globally evidenced in two-thirds of these patients,
have not been as severe as in bone marrow transplan-
tation and in patients with AIDS.
Regarding the immunologic parameters, inverted
CD4/CD8 ratios have been described as occurring
about the same time as symptomatic CMV infection,
and these ratios remain suppressed for the course of
the infection.10 However, this did not occur in our
patient, as can be observed in the evolution of the
CD4/CD8 ratio, mentioned in the Results. Evidence of
the formation of IgM antibody to CMV has been
detected in patients with both primary infection and
in those with reactivation.11 However, in our patient,
IgM antibody CMV detection proved negative at the
time of active infection.
It is known that endothelial cells play an active role
in the control of the procoagulant-anticoagulant bal-
ance in blood. A displacement of this equilibrium
leads to hemorrhage or thrombotic complications. It
has been shown that CMV can proliferate in human
endothelial cells.17 Bruggeman et al18 demonstrated
that CMV infection induces a decrease in the cellular
content of von Willebrand factor in infected cells.
This factor, synthesized and released by endothelial
cells, plays a role in the adhesion of platelets to the
vessel wall. In addition, Hendrix et al19 reported the
presence of CMV nuclear acids in the arterial walls of
patients with atherosclerosis; they suggested that the
human arterial wall may be a site of latency for this
Central retinal vein occlusion is thought to be sec-
ondary to the formation of a thrombus in the central
62
ANN OPHTHALMOL. 2001;33(1)

3. Pollard RB. Cytomegalovirus infections in renal, heart, heart-lung
and liver transplantation. Pediatr Infect Dis J. 1988;7:S97–S102.
4. Cortina P, Díaz M, España E, et al. Acute frosted retinal
periphlebitis associated with cytomegalovirus retinitis in a heart
transplant patient. Retina. 1994;14:463–464.
5. Erice A, Jordan MC, Chace BA, et al. Ganciclovir treatment of
cytomegalovirus disease in transplant recipients and other
immunocompromised hosts. JAMA. 1987;257:3082–3087.
6. Keller JC, Linn JE. Central retinal vein occlusion in a heart
trasplant patient: a case report. J Tenn Med Assoc. 1990;83:347.
7. Quinlan MF, Salmon JF. Ophthalmic complications after heart
transplantation. J Heart Lung Transplant. 1993;12:252–255.
8. Klaver CCW, Hoyng CB, de Jong PTVM. Pigmentary irregularities
and optic disc edema after heart transplantation. Arch Ophthal-
mol. 1995;113:1281–1285.
virus and that CMV might play a role in the patho-
genesis of atherosclerosis. Moreover, some authors
have also implicated CMV infection in the production
of vasculitis with pathologic involvement of both
small and large veins. Thus, CMV infection has been
linked to portal vein thrombosis.20 Likewise, Muldoon
et al21 associated it to colic vein thrombosis. In view of
all the above-mentioned aspects, it now seems clear
that CMV infection could play a role in the pathogen-
esis of certain thromboses.
In our patient, CMV antigen assay became positive
by day 15 after surgery and remained positive there-
after. A failed attempt to obtain negative readings was
made 3 months after surgery, when the patient was
treated with prophylactic intravenous ganciclovir
sodium for 3 weeks. He subsequently received oral
ganciclovir. Nevertheless, CMV retinitis developed in
his right eye. The patient presented to us for evalua-
tion of diminished vision in the left eye, in which we
detected the CRVO, and CMV retinitis in the right eye
was a casual finding. Therefore, we believe that the
CRVO was posterior to CMV retinitis and that CMV
infection may have triggered the occurrence of CRVO.
To summarize, factors related to surgical procedure
(cardiopulmonary bypass) and immunosuppressive
therapy (OKT3 and cyclosporine) might have played a
role in the pathogenesis of CRVO in our patient. How-
ever, the fact that CRVO is infrequent after heart
transplantation, and the concurrence with active CMV
retinitis, leads us to believe that CMV infection may
have played a major role in the pathogenesis of the
CRVO. The presence of positive CMV antigen tests in
heart transplant recipients should alert the ophthal-
mologist and attending physicians to the possibility of
this development, and specific attempts to prevent
these results should be made.
9. Chou S. Acquisition of donor strains of cytomegalovirus by renal
transplant recipients. N Engl J Med. 1986;314:1418–1423.
10. Schooley RT, Hirsch MS, Colvin RB, et al. Association of her-
pesvirus infections with T-lymphocyte-subset alterations,
glomerulopathy, and opportunistic infections after renal trans-
plantation. N Engl J Med. 1983;308:307–313.
11. Rasmussen L, Kelsall D, Nelson R, et al. Virus-specific IgG and
IgM antibodies in normal and immunocompromised subjects
infected with cytomegalovirus. J Infect Dis. 1982;145:191–199.
12. Gutman FA. Evaluation of a patient with central retinal vein
occlusion. Ophthalmology. 1983;90:481–483.
13. Allison RW, Limstrom SA, Sethi GK, Copeland JG. Central retinal
vein occlusion after heart-lung transplantation. Ann Ophthalmol.
1993;25:58–63.
14. Solis RT, Kennedy PS, Beall AC Jr, et al. Cardiopulmonary bypass:
microembolization and platelet aggregation. Circulation. 1975;52:
103–108.
15. Bartosh SM, Aronson AJ, Swanson-Pewitt EE, Thistlethwaite JR
Jr. OKT3 induction in pediatric renal transplantation. Pediatr
Nephrol. 1993;7:45–49.
16. Myers BD, Newton L, Boshkos C, et al. Chronic injury of human
renal microvessels with low-dose cyclosporine therapy. Trans-
plantation. 1988;46:694–703.
17. Ho DD, Rota TR, Andrews CA, Hirsch MS. Replication of human
cytomegalovirus in endothelial cells. J Infect Dis. 1984;150:956–
957.
18. Bruggeman CA, Debie WHM, Muller AD, et al. Cytomegalovirus
alters the von Willebrand factor content in human endothelial
cells. Thromb Haemost. 1988;59:264–268.
19. Hendrix MGR, Salimans MMM, van Boven CPA, Bruggeman CA.
High prevalence of latently present cytomegalovirus in arterial
walls of patients suffering from grade III atherosclerosis. Am J
Pathol. 1990;136:23–28.
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