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Progressive multifocal leukoencephalopathy in a lung transplant recipient
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Progressive Multifocal Leukoencephalopathy in a Lung Transplant Recipient David Shitrit, MD,a Lev Nirit, MD,b Sheely I. Shiran, MD,c Gabriel Izbicki, MD,a Dov Sofer, MD,d Melamed Eldad, MD,b and Mordechai R. Kramer, MDa Progressive multifocal leukoencephalopathy (PML) is a sub-acute, demyelinating disease of the brain caused by a human polyomavirus. We describe a patient with the onset of PML 7 months after lung transplantation. The patient was treated with immunosuppressive modulation and cidofovir, a new anti-viral therapy for PML, with stabilization of the symptoms. We also review the 4 additional reports in the literature of PML after heart and lung transplantation. Progressive multifocal leukoencephalopathy may become more prevalent as the population of heart and lung transplantation recipients increases. J Heart Lung Transplant 2003;22:946 –950.
I
n 1958, Astrom et al1 first described progressive multifocal leukoencephalopathy (PML) in patients with lymphoma and leukemia. Progressive multifocal leukoencephalopathy is associated with immunosuppressive states such as those involving human immunodeficiency virus type 1 (HIV-1),2 and organ transplantation. Progressive multifocal leukoencephalopathy has been described in recipients of renal, liver, and heart allografts, and in allogenic bone marrow transplant recipients.3– 6 We describe a lung transplant recipient with neurologic symptoms caused by the onset of PML 7 months after transplantation. From the aPulmonary Institute, bNeurology Department, cRadiology Department, Rabin Medical Center, Belinson Campus, Petach Tikva and Sackler School of Medicine, Tel-Aviv; and d Pathological Department, Hadassah Medical Center, Jerusalem, Israel. Submitted August 1, 2002; revised September 5, 2002; accepted October 3, 2002. Reprint requests: M. R. Kramer, MD, Pulmonary Institute, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel 49100. Telephone: 972-3-9377221. Fax: 972-3-9242091. E-mail: [email protected] Copyright © 2003 by the International Society for Heart and Lung Transplantation. 1053-2498/03/$–see front matter doi:10.1016/S1053-2498(02)00804-5
946
CASE REPORT In the course of 3 years, a 55-year-old man was diagnosed with idiopathic pulmonary fibrosis and received treatment with steroids and azathioprine, until his condition deteriorated and on May 2001 he underwent right lung transplantation. His surgery and immediate post-operative course were uneventful. The patient has been maintained on triple-drug immunosuppression therapy including 7.5 mg prednisone daily and 0.5 g mycophenolate mofetil twice daily, and 4 mg tacrolimus daily. In July 2001, he was admitted with dyspnea and was diagnoses with pulmonary embolism. The patient received anti-coagulation therapy. Seven months after transplantation, he was admitted to our hospital because of left hemiparesis. He underwent transesophageal echocardiography, which showed duplex of the carotid arteries without a source of embolism. Computerized tomography of the brain showed bilateral hypodense lesions in the left frontal and right frontoparietal and occipital white matter that did not involve the cortex (Figure 1 A). During the following weeks, the left hemiparesis progressed to hemiplegia, and the patient experienced behavioral changes and became lethargic. Neurologic examination revealed a lethargic patient with frontal release
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FIGURE 1 (A) Computed tomographic of the brain showed bilateral hypodense lesions in the left frontal and right frontoparietal and occipital white matter. (B) Computed tomographic of the brain showed marked improvement in the left frontal lesions.
signs, pseudo-bulbar signs, left central facialis, and left hemiplegia, with pyramidal signs. His condition deteriorated progressively, and focal motor seizures developed in the left side of his face and left arm. Magnetic resonance imaging of the brain demonstrated multiple lesions in the hemispheral white matter, involving the right frontal white matter, the right internal capsule, the cingulate gyrus, and the left frontal and temporal white matter (Figure 2). Follow-up computerized tomography showed progression of the damage in the left frontal white matter. The patient underwent multiple lumbar punctures that demonstrated normal cerebrospinal fluid content, with no malignant cells or evidence of infection. Serologic tests for toxoplasmosis, cryptococcosis, and human immunodeficiently virus were negative. Polymerase chain reaction results were negative for polyoma viruses in the cerebral spinal fluid
and blood. Polymerase chain reaction of the urine demonstrated BK virus. Because of progressive deterioration and suspicion of PML, a stereotactic brain biopsy was performed. Hematoxylin and eosin stain demonstrated multifocal areas of demyelination in the white matter with variable axonal sparing, perivascular lymphocytic infiltrations, sheets of reactive gemistocytic astrocytes with bizarre nuclei, and nuclear inclusions within oligodendrocytes typical of PML. On the basis of clinical, radiologic, and pathologic evidence including immunofluorescent stain with antibodies to polyomaviruses, we diagnosed PML. Steroid therapy was decreased, mycophenolate mofetil was discontinued, and the tacrolimus levels were decreased to obtain a blood level of 4 to 5 ng/ml (1 mg daily). However, despite modifying the immunosuppressive regimen, the patient’s neurologic condition continued to deteriorate. Treat-
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FIGURE 2 Magnetic resonance imaging of the brain demonstrated multiple lesions in the hemispheral white matter, involving the right frontal white matter. ment with cidofovir was started (5 mg/kg IV once weekly, concomitant with probenecid for 2 weeks, followed by the same dosage once every other week) with stabilization of his disease and improvement in alertness. He was discharged from our hospital and is observed in our outpatient clinics. Cidofovir therapy was continued for 4 months with stable renal function throughout treatment. It is now 7 months since the start of the patient’s disease, and he continues to have neurologic deficits including left hemiparesis and involuntary crying. However, deterioration has stopped and brain computerized tomography (Figure 1 B) demonstrates improvement.
DISCUSSION The differential diagnosis of neurologic manifestations after heart and lung transplantation includes bacterial, viral, and fungal infections; vasculitis; lymphoma; immunosuppressive-associated
The Journal of Heart and Lung Transplantation August 2003
leukoencephalopathy; and PML. However, only PML and immunosuppressive-associated leukoencephalopathy involve the white matter as seen with neuroimaging.7,8 Immunosuppressive-associated leukoencephalopathy affects sub-cortical white matter, preferentially in the posterior cerebral hemispheres. Frontal lobe involvement was reported in 16% of the cases. One percent to 6% of treated patients are affected, with a median time to onset of 28 days (in lung transplant recipients, it was 60 days). In 61% of the cases, cyclosporine levels were increased, and levels were increased in 9 of 11 cases of tacrolimusinduced leukoencephalopathy. The clinical course is sub-acute or has abrupt onset, manifested by seizures (74%), altered mental status (50%), visual abnormalities (28%), focal motor signs (24%), and fever (10%). Results of cerebral spinal fluid testing is usually normal. This leukoencephalopathy is reversible by ceasing or decreasing the offending drug.7 This is in contrast with PML, which most commonly has a progressive and fatal course. Diagnosis is made by demonstrating JC virus in the cerebrospinal fluid, or by brain biopsy tissue that shows the characteristic gigantic astrocytes with large irregular hyperchromatic nuclei.8 Differentiating between PML and immunosuppressive-induced leukoencephalopathy can be difficult, because the neurologic symptoms and the neuroradiologic findings in computerized tomography scan and magnetic resonance imaging do not necessarily differentiate, and in both, white matter lesions often are found.7,8 The human polyomaviruses are members of the papovavirus family. The most common species in his genus are the BK virus, JC virus, and the simian virus SV40. BK virus is involved in hemorrhagic cystitis after bone marrow transplantation. In renal transplantation, BK virus and JC virus are now recognized as possible causes of transplant interstitial nephritis, mimicking rejection or drug toxicity.9 A MEDLINE search of the English literature revealed only 4 reports of PML after heart and lung transplantation.10 –13 Three case reports describe PML after heart transplantation, and 1 report describes PML after lung transplantation. Table I summarizes the pertinent clinical data. Patient ages ranged from 43 to 59 years (median, 55 years); all were men. Progressive multifocal leukoencephalopathy occurred from 7 to 57 months after transplantation (median 15 months). The neurologic manifestations included confusion, dizziness, ataxia, memory loss, and cognitive
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TABLE I Progressive multifocal leukoencephalopathy after lung and heart transplantation: review of the literature
Case Hall et al. (10) Flomenbaum et al. (11) Lewis et al. (6) Ouwens et al. (12) Present report
Time Sex/age from Tx (years) Organ (months) M/59
Heart
24
M/49
Heart
57
M/59
Heart
12
M/43
Lung
15
M/55
Lung
7
Neurologic symptoms Confusion, lethargy coma Dizziness, ataxia Hemiparesis cognitive impairment Visual loss, convulsion, paresis, ataxia memory loss Hemiparesis, visual disturbances apathy, convulsion
Follow-up after beginning of disease (days) Outcome
Diagnosis
Treatment
Autopsy
No
Death
22
Autopsy
No
Death
14
Death
60
Death
450
Live
210
Brain No biopsy PCR- Immunosuppressive CSF modulation Brain Immunosuppressive biopsy modulation, cidofovir
CSF, cerebral spinal fluid; PCR, polymerase chain reaction; Tx, transplantation.
impairment. Three patients had focal neurologic signs (hemiparesis). The diagnosis was made at autopsy and at brain biopsy in 2 patients each, and by using polymerase chain reaction to JC virus in the cerebral spinal fluid in 1 patient. Various reports in recent literature describe therapy for PML after bone marrow transplantation. Therapies included immunosuppressive modulation to limit progression of PML, cytarabine, interleukin-2, and interferon ␣. However, the value of these treatments remains uncertain. Recently, cidofovir, a nucleoside analog, emerged as the most selective anti-polyomavirus agent.14 The major limiting toxicity is nephrotoxicity. Intravenous pre-hydration with normal saline and administration of oral probenecid must be used with each cidofovir infusion. Immunosuppressive modulation was tried unsuccessfully in the 2 lung recipient and included discontinuing steroids and mycophenolate mofetil, and tapering cyclosporine and tacrolimus to minimal blood levels. Our patient also received cidofovir therapy, the new anti-viral therapy for PML, with stabilization. The prognosis of PML is very poor. All 4 four patients described in the literature died. Time from onset until death ranged from 14 to 60 days in the 3 heart recipients and was 450 days in the lung transplant recipient. However, our patient is still alive 7 months after disease onset, and symptoms have been stabilized.
In summary, PML should be considered in any lung or heart transplant recipient who presents with focal neurologic symptoms. The outcome is usually fatal, although regression can be achieved with cidofovir therapy. REFERENCES 1. Astrom KE, Mancall EL, Richardson EP. Progressive multifocal leukoencephalopathy: a hitherto unrecognized complication of chronic lymphatic leukemia and Hodgkin’s disease. Brain 1958;81:93–111. 2. Berger JR, Kaszovitz B, Post MJ, Dickinson G. Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection: a review of the literature with a report of sixteen cases. Ann Intern Med 1985;107:78 –87. 3. Gardner SD, Mackenzie EFD, Smith C, Porter AA. Prospective study of the human polyomavirus BK and JC and cytomegalovirus in renal transplant recipients. J Clin Pathol 1984;37:578 –86. 4. Aksamit AJ, de Groen PC. Cyclosporine-related leukoencephalopathy and PML in a liver transplant recipient. Transplantation 1995;60:874 –6. 5. Arthur RR, Shah KV, Charache P, Saral R. BK and JC virus infections in recipients of bone marrow transplants. J Infec Dis 1988;158:79 –82. 6. Lewis AR, Kline LB, Pinkard NB. Visual loss due to progressive multifocal leukoencephalopathy in a heart transplant patient. J Clin Neuroophthalmol 1993;13:237–41. 7. Singh N, Bonham A, Fukui M. Immunosuppressive-associated leukoencephalopathy in organ transplant recipients. Transplantation 2000;69:467–71. 8. Whiteman MLH, Donovan MJ, Berger JR, Tate LG, Bell MD, Limonite LP. Progressive multifocal leukoencephalopathy in 47
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HIV-seropositive patients: neuroimaging with clinical and pathologic correlation. Radiology 1993;187:233–40. 9. Boubenider S, Hiesse C, Marchand S, Hafi A, Al kriaa F, Charpentier B. Post-transplantation polyomavirus infections. J Nephrol 1999;12:24–9. 10. Hall WA, Martinez AJ, Dummer JS. Progressive multifocal leukoencephalopathy after cardiac transplantation. Neurology 1988;38:995–6. 11. Flomenbaum MA, Jarcho JA, Schoen FJ. Progressive multifocal leukoencephalopathy fifty-seven months after heart transplantation. J Heart Lung Transplant 1991;10:888–93.
The Journal of Heart and Lung Transplantation August 2003 12. Quwens JP, Haaxma-Reiche H, Verschuuren EAM, et al. Visual symptoms after lung transplantation: a case of progressive multifocal leukoencephalopathy. Transplant Infect Dis 2000;2:29–32. 13. Hall C, Dafni U, Simpson D, et al. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. N Engl J Med 1998;338: 1343–51. 14. Andrei G, Snoeck R, Vandeputte M, De-Clercq E. Activities of various compounds against murine and primate polyomaviruses. Antimicrob Agents Chemother 1997;41:587–93.
Progressive Multifocal Leukoencephalopathy in a Lung Transplant Recipient David Shitrit, MD,a Lev Nirit, MD,b Sheely I. Shiran, MD,c Gabriel Izbicki, MD,a Dov Sofer, MD,d Melamed Eldad, MD,b and Mordechai R. Kramer, MDa Progressive multifocal leukoencephalopathy (PML) is a sub-acute, demyelinating disease of the brain caused by a human polyomavirus. We describe a patient with the onset of PML 7 months after lung transplantation. The patient was treated with immunosuppressive modulation and cidofovir, a new anti-viral therapy for PML, with stabilization of the symptoms. We also review the 4 additional reports in the literature of PML after heart and lung transplantation. Progressive multifocal leukoencephalopathy may become more prevalent as the population of heart and lung transplantation recipients increases. J Heart Lung Transplant 2003;22:946 –950.
I
n 1958, Astrom et al1 first described progressive multifocal leukoencephalopathy (PML) in patients with lymphoma and leukemia. Progressive multifocal leukoencephalopathy is associated with immunosuppressive states such as those involving human immunodeficiency virus type 1 (HIV-1),2 and organ transplantation. Progressive multifocal leukoencephalopathy has been described in recipients of renal, liver, and heart allografts, and in allogenic bone marrow transplant recipients.3– 6 We describe a lung transplant recipient with neurologic symptoms caused by the onset of PML 7 months after transplantation. From the aPulmonary Institute, bNeurology Department, cRadiology Department, Rabin Medical Center, Belinson Campus, Petach Tikva and Sackler School of Medicine, Tel-Aviv; and d Pathological Department, Hadassah Medical Center, Jerusalem, Israel. Submitted August 1, 2002; revised September 5, 2002; accepted October 3, 2002. Reprint requests: M. R. Kramer, MD, Pulmonary Institute, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel 49100. Telephone: 972-3-9377221. Fax: 972-3-9242091. E-mail: [email protected] Copyright © 2003 by the International Society for Heart and Lung Transplantation. 1053-2498/03/$–see front matter doi:10.1016/S1053-2498(02)00804-5
946
CASE REPORT In the course of 3 years, a 55-year-old man was diagnosed with idiopathic pulmonary fibrosis and received treatment with steroids and azathioprine, until his condition deteriorated and on May 2001 he underwent right lung transplantation. His surgery and immediate post-operative course were uneventful. The patient has been maintained on triple-drug immunosuppression therapy including 7.5 mg prednisone daily and 0.5 g mycophenolate mofetil twice daily, and 4 mg tacrolimus daily. In July 2001, he was admitted with dyspnea and was diagnoses with pulmonary embolism. The patient received anti-coagulation therapy. Seven months after transplantation, he was admitted to our hospital because of left hemiparesis. He underwent transesophageal echocardiography, which showed duplex of the carotid arteries without a source of embolism. Computerized tomography of the brain showed bilateral hypodense lesions in the left frontal and right frontoparietal and occipital white matter that did not involve the cortex (Figure 1 A). During the following weeks, the left hemiparesis progressed to hemiplegia, and the patient experienced behavioral changes and became lethargic. Neurologic examination revealed a lethargic patient with frontal release
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FIGURE 1 (A) Computed tomographic of the brain showed bilateral hypodense lesions in the left frontal and right frontoparietal and occipital white matter. (B) Computed tomographic of the brain showed marked improvement in the left frontal lesions.
signs, pseudo-bulbar signs, left central facialis, and left hemiplegia, with pyramidal signs. His condition deteriorated progressively, and focal motor seizures developed in the left side of his face and left arm. Magnetic resonance imaging of the brain demonstrated multiple lesions in the hemispheral white matter, involving the right frontal white matter, the right internal capsule, the cingulate gyrus, and the left frontal and temporal white matter (Figure 2). Follow-up computerized tomography showed progression of the damage in the left frontal white matter. The patient underwent multiple lumbar punctures that demonstrated normal cerebrospinal fluid content, with no malignant cells or evidence of infection. Serologic tests for toxoplasmosis, cryptococcosis, and human immunodeficiently virus were negative. Polymerase chain reaction results were negative for polyoma viruses in the cerebral spinal fluid
and blood. Polymerase chain reaction of the urine demonstrated BK virus. Because of progressive deterioration and suspicion of PML, a stereotactic brain biopsy was performed. Hematoxylin and eosin stain demonstrated multifocal areas of demyelination in the white matter with variable axonal sparing, perivascular lymphocytic infiltrations, sheets of reactive gemistocytic astrocytes with bizarre nuclei, and nuclear inclusions within oligodendrocytes typical of PML. On the basis of clinical, radiologic, and pathologic evidence including immunofluorescent stain with antibodies to polyomaviruses, we diagnosed PML. Steroid therapy was decreased, mycophenolate mofetil was discontinued, and the tacrolimus levels were decreased to obtain a blood level of 4 to 5 ng/ml (1 mg daily). However, despite modifying the immunosuppressive regimen, the patient’s neurologic condition continued to deteriorate. Treat-
948
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FIGURE 2 Magnetic resonance imaging of the brain demonstrated multiple lesions in the hemispheral white matter, involving the right frontal white matter. ment with cidofovir was started (5 mg/kg IV once weekly, concomitant with probenecid for 2 weeks, followed by the same dosage once every other week) with stabilization of his disease and improvement in alertness. He was discharged from our hospital and is observed in our outpatient clinics. Cidofovir therapy was continued for 4 months with stable renal function throughout treatment. It is now 7 months since the start of the patient’s disease, and he continues to have neurologic deficits including left hemiparesis and involuntary crying. However, deterioration has stopped and brain computerized tomography (Figure 1 B) demonstrates improvement.
DISCUSSION The differential diagnosis of neurologic manifestations after heart and lung transplantation includes bacterial, viral, and fungal infections; vasculitis; lymphoma; immunosuppressive-associated
The Journal of Heart and Lung Transplantation August 2003
leukoencephalopathy; and PML. However, only PML and immunosuppressive-associated leukoencephalopathy involve the white matter as seen with neuroimaging.7,8 Immunosuppressive-associated leukoencephalopathy affects sub-cortical white matter, preferentially in the posterior cerebral hemispheres. Frontal lobe involvement was reported in 16% of the cases. One percent to 6% of treated patients are affected, with a median time to onset of 28 days (in lung transplant recipients, it was 60 days). In 61% of the cases, cyclosporine levels were increased, and levels were increased in 9 of 11 cases of tacrolimusinduced leukoencephalopathy. The clinical course is sub-acute or has abrupt onset, manifested by seizures (74%), altered mental status (50%), visual abnormalities (28%), focal motor signs (24%), and fever (10%). Results of cerebral spinal fluid testing is usually normal. This leukoencephalopathy is reversible by ceasing or decreasing the offending drug.7 This is in contrast with PML, which most commonly has a progressive and fatal course. Diagnosis is made by demonstrating JC virus in the cerebrospinal fluid, or by brain biopsy tissue that shows the characteristic gigantic astrocytes with large irregular hyperchromatic nuclei.8 Differentiating between PML and immunosuppressive-induced leukoencephalopathy can be difficult, because the neurologic symptoms and the neuroradiologic findings in computerized tomography scan and magnetic resonance imaging do not necessarily differentiate, and in both, white matter lesions often are found.7,8 The human polyomaviruses are members of the papovavirus family. The most common species in his genus are the BK virus, JC virus, and the simian virus SV40. BK virus is involved in hemorrhagic cystitis after bone marrow transplantation. In renal transplantation, BK virus and JC virus are now recognized as possible causes of transplant interstitial nephritis, mimicking rejection or drug toxicity.9 A MEDLINE search of the English literature revealed only 4 reports of PML after heart and lung transplantation.10 –13 Three case reports describe PML after heart transplantation, and 1 report describes PML after lung transplantation. Table I summarizes the pertinent clinical data. Patient ages ranged from 43 to 59 years (median, 55 years); all were men. Progressive multifocal leukoencephalopathy occurred from 7 to 57 months after transplantation (median 15 months). The neurologic manifestations included confusion, dizziness, ataxia, memory loss, and cognitive
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TABLE I Progressive multifocal leukoencephalopathy after lung and heart transplantation: review of the literature
Case Hall et al. (10) Flomenbaum et al. (11) Lewis et al. (6) Ouwens et al. (12) Present report
Time Sex/age from Tx (years) Organ (months) M/59
Heart
24
M/49
Heart
57
M/59
Heart
12
M/43
Lung
15
M/55
Lung
7
Neurologic symptoms Confusion, lethargy coma Dizziness, ataxia Hemiparesis cognitive impairment Visual loss, convulsion, paresis, ataxia memory loss Hemiparesis, visual disturbances apathy, convulsion
Follow-up after beginning of disease (days) Outcome
Diagnosis
Treatment
Autopsy
No
Death
22
Autopsy
No
Death
14
Death
60
Death
450
Live
210
Brain No biopsy PCR- Immunosuppressive CSF modulation Brain Immunosuppressive biopsy modulation, cidofovir
CSF, cerebral spinal fluid; PCR, polymerase chain reaction; Tx, transplantation.
impairment. Three patients had focal neurologic signs (hemiparesis). The diagnosis was made at autopsy and at brain biopsy in 2 patients each, and by using polymerase chain reaction to JC virus in the cerebral spinal fluid in 1 patient. Various reports in recent literature describe therapy for PML after bone marrow transplantation. Therapies included immunosuppressive modulation to limit progression of PML, cytarabine, interleukin-2, and interferon ␣. However, the value of these treatments remains uncertain. Recently, cidofovir, a nucleoside analog, emerged as the most selective anti-polyomavirus agent.14 The major limiting toxicity is nephrotoxicity. Intravenous pre-hydration with normal saline and administration of oral probenecid must be used with each cidofovir infusion. Immunosuppressive modulation was tried unsuccessfully in the 2 lung recipient and included discontinuing steroids and mycophenolate mofetil, and tapering cyclosporine and tacrolimus to minimal blood levels. Our patient also received cidofovir therapy, the new anti-viral therapy for PML, with stabilization. The prognosis of PML is very poor. All 4 four patients described in the literature died. Time from onset until death ranged from 14 to 60 days in the 3 heart recipients and was 450 days in the lung transplant recipient. However, our patient is still alive 7 months after disease onset, and symptoms have been stabilized.
In summary, PML should be considered in any lung or heart transplant recipient who presents with focal neurologic symptoms. The outcome is usually fatal, although regression can be achieved with cidofovir therapy. REFERENCES 1. Astrom KE, Mancall EL, Richardson EP. Progressive multifocal leukoencephalopathy: a hitherto unrecognized complication of chronic lymphatic leukemia and Hodgkin’s disease. Brain 1958;81:93–111. 2. Berger JR, Kaszovitz B, Post MJ, Dickinson G. Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection: a review of the literature with a report of sixteen cases. Ann Intern Med 1985;107:78 –87. 3. Gardner SD, Mackenzie EFD, Smith C, Porter AA. Prospective study of the human polyomavirus BK and JC and cytomegalovirus in renal transplant recipients. J Clin Pathol 1984;37:578 –86. 4. Aksamit AJ, de Groen PC. Cyclosporine-related leukoencephalopathy and PML in a liver transplant recipient. Transplantation 1995;60:874 –6. 5. Arthur RR, Shah KV, Charache P, Saral R. BK and JC virus infections in recipients of bone marrow transplants. J Infec Dis 1988;158:79 –82. 6. Lewis AR, Kline LB, Pinkard NB. Visual loss due to progressive multifocal leukoencephalopathy in a heart transplant patient. J Clin Neuroophthalmol 1993;13:237–41. 7. Singh N, Bonham A, Fukui M. Immunosuppressive-associated leukoencephalopathy in organ transplant recipients. Transplantation 2000;69:467–71. 8. Whiteman MLH, Donovan MJ, Berger JR, Tate LG, Bell MD, Limonite LP. Progressive multifocal leukoencephalopathy in 47
950
Shitrit et al.
HIV-seropositive patients: neuroimaging with clinical and pathologic correlation. Radiology 1993;187:233–40. 9. Boubenider S, Hiesse C, Marchand S, Hafi A, Al kriaa F, Charpentier B. Post-transplantation polyomavirus infections. J Nephrol 1999;12:24–9. 10. Hall WA, Martinez AJ, Dummer JS. Progressive multifocal leukoencephalopathy after cardiac transplantation. Neurology 1988;38:995–6. 11. Flomenbaum MA, Jarcho JA, Schoen FJ. Progressive multifocal leukoencephalopathy fifty-seven months after heart transplantation. J Heart Lung Transplant 1991;10:888–93.
The Journal of Heart and Lung Transplantation August 2003 12. Quwens JP, Haaxma-Reiche H, Verschuuren EAM, et al. Visual symptoms after lung transplantation: a case of progressive multifocal leukoencephalopathy. Transplant Infect Dis 2000;2:29–32. 13. Hall C, Dafni U, Simpson D, et al. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. N Engl J Med 1998;338: 1343–51. 14. Andrei G, Snoeck R, Vandeputte M, De-Clercq E. Activities of various compounds against murine and primate polyomaviruses. Antimicrob Agents Chemother 1997;41:587–93.