VOLUME
32
䡠
NUMBER
9
䡠
MARCH
20
2014
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
O N C O L O G Y
lesion was hyperintense, with sparing of the adjacent cortex (Fig 1B, arrowhead) and without mass effect or edema. A T1-weighted postgadolinium image showed no lesion enhancement, reflecting an intact blood-brain barrier (Fig 1C, arrowhead). The lack of mass effect and contrast enhancement made the diagnosis of metastases from the breast cancer or myeloid sarcoma unlikely, and the distribution of the hyperintense areas on T2 with involvement of the subcortical U fibers is not typical for hemorrhagic or ischemic lesions. In contrast, confinement within subcortical U-fiber regions is a characteristic finding of progressive multifocal leukoencephalopathy (PML).1 In line with this diagnosis, a spinal tap was positive for the John Cunningham (JC) virus without evidence of inflammation or malignant cells. An EEG demonstrated severely altered baseline activity in the right hemisphere with epilepsy-specific potentials such as polymorphic Theta-Delta-waves, thus antiepileptic prophylaxis with valproic acid was started. HIV-serology and HIV– polymerase chain reaction in the CSF and the blood were negative. An immunoglobin G (IgG) subclass deficiency and cerebral autoantibodies were excluded. The patient’s CD4 and CD8 count in the peripheral blood was 284 cells/L (normal limits, 300 to 1,140 cells/L) and 2,570 cells/L (normal limits, 140 to 830 cells/L), respectively. Owing to the lack of therapeutic options, no specific treatment was started. The patient’s neurologic condition continued to deteriorate with progressive motoric weakness and dementia. Currently, the patient is alive 20 months after the diagnosis of PML and is living at home in need of care. Neurologic examination reveals a lack of temporal orientation and dysarthria; standing is only possible with assistance on both sides.
Unusual Case of Progressive Multifocal Leukoencephalopathy After Allogeneic Hematopoietic Stem-Cell Transplantation Case Report A 42-year-old female patient presented with rapidly progressive gait instability and short-term memory impairment after allogeneic hematopoietic stem-cell transplantation. Her medical history was remarkable for invasive ductal breast cancer in 2005 that was treated with mastectomy, adjuvant chemotherapy, and consecutive radiotherapy. In 2009, she developed a therapy-related acute myeloid leukemia and was treated with two cycles of chemotherapy followed by allogeneic-unrelated, human leukocyte antigen (HLA) –identical, peripheral blood stem-cell transplantation with myeloablative conditioning. Her post-transplant course was unremarkable with no evidence of acute or chronic graft-versus-host disease, and the immunosuppression was tapered off 6 months after the transplantation and 12 months before the onset of neurologic deterioration. At the time of neurologic deterioration, the patient was in continuous remission of her leukemia. Clinical examination revealed diminished muscular strength and reduced sensibility in the patient’s left arm and leg, consistent with left sensomotoric hemiplegia. Furthermore, she had a left-sided hemineglect. Coordination was normal on the right side, but some ataxia was recorded on the left. Differential diagnosis included cerebral ischemia or bleeding, metastases from the breast carcinoma, or extramedullary leukemia. The T1-weighted axial magnetic resonance imaging without contrast revealed a hypointense area in the white matter involving the right lobulus parietalis with a connection to the gyrus cinguli and parahippocampalis (Fig 1A, inset with overview). The hypointense lesion was sharply bordered and involved the subcortical U fibers (Fig 1A, detail with arrowhead). On T2-weighted spin-echo imaging, the
A
I N
Discussion Progressive multifocal leukoencephalopathy is a rapidly progressive demyelinating disorder of the CNS almost exclusively encountered in immunocompromised patients.2 It is caused by reactivation of the JC
C
B
Fig 1. Journal of Clinical Oncology, Vol 32, No 9 (March 20), 2014: pp e33-e34
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
e33
Berger et al
virus under conditions of cellular immunosuppression, such as those acquired in patients with AIDS, patients with hematologic and solid malignancies undergoing chemotherapy, and transplantation recipients undergoingimmunosuppressivetherapy.3 Mostrecently,interestinPML has been revived because of its association with monoclonal antibody therapy.4 Although stereotactic brain biopsy is the gold standard for diagnosis of PML, polymerase chain reaction for the JC virus in the CSF is the method of first choice with high specificity from 96% to 100% and sensitivity from 74% to 82%.5,6 A combination of characteristic imaging features with appropriate laboratory tests can be confidently used to diagnose PML.1 JC viral infections in the setting of allogeneic stem-cell transplantations are exceedingly rare. Kharfan-Dabaja et al7 described two cases of PML after allogeneic hematopoietic stem-cell transplantation. At the time of onset, these patients were under immunosuppressive therapy because of acute graft-versus-host disease.7 In this case report, we describe an unusual presentation of PML in a patient 18 months after allogeneic stem-cell transplantation without immunosuppressive therapy for at least 12 months. In a recent report,8 the median onset of viral encephalitis as a result of JC virus after allogeneic stem-cell transplantation was 334 days, but this report did not specify the immunosuppression at the time of onset. Our case report illustrates that patients after allogeneic hematopoietic stem-cell transplantation remain severely immunocompromised even in the absence of immunosuppression.
Alexander Meisel, Martin Andres, Urs Schanz, and Urs Schwarz
Martin D. Berger
DOI: 10.1200/JCO.2012.47.5194; published online ahead of print at www.jco.org on January 13, 2014
University Hospital of Berne, Berne, Switzerland
University Hospital of Zurich, Zurich, Switzerland
Georg Stussi Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Bag AK, Cure´ JK, Chapman PR, et al: JC virus infection of the brain. Am J Neuroradiol 31:1564-1576, 2010 2. Koralnik IJ: New insights into progressive multifocal leukoencephalopathy. Curr Opin Neurol 17:365-370, 2004 3. Koralnik IJ: Progressive multifocal leukoencephalopathy revisited: Has the disease outgrown its name? Ann Neurol 60:162-173, 2006 4. Kleinschmidt-DeMasters BK, Tyler KL: Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 353:369-374, 2005 5. Fong IW, Britton CB, Luinstra KE, et al: Diagnostic value of detecting JC virus DNA in cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy. J Clin Microbiol 33:484-486, 1995 6. Weber T, Turner RW, Frye S, et al: Specific diagnosis of progressive multifocal leukoencephalopathy by polymerase chain reaction. J Infect Dis 169:1138-1141, 1994 7. Kharfan-Dabaja MA, Ayala E, Greene J, et al: Two cases of progressive multifocal leukoencephalopathy after allogeneic hematopoietic cell transplantation and a review of the literature. Bone Marrow Transplant 39:101-107, 2007 8. Schmidt-Hieber M, Schwender J, Heinz WJ, et al: Viral encephalitis after allogeneic stem cell transplantation: A rare complication with distinct characteristics of different causative agents. Haematologica 96:142-149, 2011
■ ■ ■
e34
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
32
䡠
NUMBER
9
䡠
MARCH
20
2014
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
O N C O L O G Y
lesion was hyperintense, with sparing of the adjacent cortex (Fig 1B, arrowhead) and without mass effect or edema. A T1-weighted postgadolinium image showed no lesion enhancement, reflecting an intact blood-brain barrier (Fig 1C, arrowhead). The lack of mass effect and contrast enhancement made the diagnosis of metastases from the breast cancer or myeloid sarcoma unlikely, and the distribution of the hyperintense areas on T2 with involvement of the subcortical U fibers is not typical for hemorrhagic or ischemic lesions. In contrast, confinement within subcortical U-fiber regions is a characteristic finding of progressive multifocal leukoencephalopathy (PML).1 In line with this diagnosis, a spinal tap was positive for the John Cunningham (JC) virus without evidence of inflammation or malignant cells. An EEG demonstrated severely altered baseline activity in the right hemisphere with epilepsy-specific potentials such as polymorphic Theta-Delta-waves, thus antiepileptic prophylaxis with valproic acid was started. HIV-serology and HIV– polymerase chain reaction in the CSF and the blood were negative. An immunoglobin G (IgG) subclass deficiency and cerebral autoantibodies were excluded. The patient’s CD4 and CD8 count in the peripheral blood was 284 cells/L (normal limits, 300 to 1,140 cells/L) and 2,570 cells/L (normal limits, 140 to 830 cells/L), respectively. Owing to the lack of therapeutic options, no specific treatment was started. The patient’s neurologic condition continued to deteriorate with progressive motoric weakness and dementia. Currently, the patient is alive 20 months after the diagnosis of PML and is living at home in need of care. Neurologic examination reveals a lack of temporal orientation and dysarthria; standing is only possible with assistance on both sides.
Unusual Case of Progressive Multifocal Leukoencephalopathy After Allogeneic Hematopoietic Stem-Cell Transplantation Case Report A 42-year-old female patient presented with rapidly progressive gait instability and short-term memory impairment after allogeneic hematopoietic stem-cell transplantation. Her medical history was remarkable for invasive ductal breast cancer in 2005 that was treated with mastectomy, adjuvant chemotherapy, and consecutive radiotherapy. In 2009, she developed a therapy-related acute myeloid leukemia and was treated with two cycles of chemotherapy followed by allogeneic-unrelated, human leukocyte antigen (HLA) –identical, peripheral blood stem-cell transplantation with myeloablative conditioning. Her post-transplant course was unremarkable with no evidence of acute or chronic graft-versus-host disease, and the immunosuppression was tapered off 6 months after the transplantation and 12 months before the onset of neurologic deterioration. At the time of neurologic deterioration, the patient was in continuous remission of her leukemia. Clinical examination revealed diminished muscular strength and reduced sensibility in the patient’s left arm and leg, consistent with left sensomotoric hemiplegia. Furthermore, she had a left-sided hemineglect. Coordination was normal on the right side, but some ataxia was recorded on the left. Differential diagnosis included cerebral ischemia or bleeding, metastases from the breast carcinoma, or extramedullary leukemia. The T1-weighted axial magnetic resonance imaging without contrast revealed a hypointense area in the white matter involving the right lobulus parietalis with a connection to the gyrus cinguli and parahippocampalis (Fig 1A, inset with overview). The hypointense lesion was sharply bordered and involved the subcortical U fibers (Fig 1A, detail with arrowhead). On T2-weighted spin-echo imaging, the
A
I N
Discussion Progressive multifocal leukoencephalopathy is a rapidly progressive demyelinating disorder of the CNS almost exclusively encountered in immunocompromised patients.2 It is caused by reactivation of the JC
C
B
Fig 1. Journal of Clinical Oncology, Vol 32, No 9 (March 20), 2014: pp e33-e34
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
e33
Berger et al
virus under conditions of cellular immunosuppression, such as those acquired in patients with AIDS, patients with hematologic and solid malignancies undergoing chemotherapy, and transplantation recipients undergoingimmunosuppressivetherapy.3 Mostrecently,interestinPML has been revived because of its association with monoclonal antibody therapy.4 Although stereotactic brain biopsy is the gold standard for diagnosis of PML, polymerase chain reaction for the JC virus in the CSF is the method of first choice with high specificity from 96% to 100% and sensitivity from 74% to 82%.5,6 A combination of characteristic imaging features with appropriate laboratory tests can be confidently used to diagnose PML.1 JC viral infections in the setting of allogeneic stem-cell transplantations are exceedingly rare. Kharfan-Dabaja et al7 described two cases of PML after allogeneic hematopoietic stem-cell transplantation. At the time of onset, these patients were under immunosuppressive therapy because of acute graft-versus-host disease.7 In this case report, we describe an unusual presentation of PML in a patient 18 months after allogeneic stem-cell transplantation without immunosuppressive therapy for at least 12 months. In a recent report,8 the median onset of viral encephalitis as a result of JC virus after allogeneic stem-cell transplantation was 334 days, but this report did not specify the immunosuppression at the time of onset. Our case report illustrates that patients after allogeneic hematopoietic stem-cell transplantation remain severely immunocompromised even in the absence of immunosuppression.
Alexander Meisel, Martin Andres, Urs Schanz, and Urs Schwarz
Martin D. Berger
DOI: 10.1200/JCO.2012.47.5194; published online ahead of print at www.jco.org on January 13, 2014
University Hospital of Berne, Berne, Switzerland
University Hospital of Zurich, Zurich, Switzerland
Georg Stussi Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Bag AK, Cure´ JK, Chapman PR, et al: JC virus infection of the brain. Am J Neuroradiol 31:1564-1576, 2010 2. Koralnik IJ: New insights into progressive multifocal leukoencephalopathy. Curr Opin Neurol 17:365-370, 2004 3. Koralnik IJ: Progressive multifocal leukoencephalopathy revisited: Has the disease outgrown its name? Ann Neurol 60:162-173, 2006 4. Kleinschmidt-DeMasters BK, Tyler KL: Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 353:369-374, 2005 5. Fong IW, Britton CB, Luinstra KE, et al: Diagnostic value of detecting JC virus DNA in cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy. J Clin Microbiol 33:484-486, 1995 6. Weber T, Turner RW, Frye S, et al: Specific diagnosis of progressive multifocal leukoencephalopathy by polymerase chain reaction. J Infect Dis 169:1138-1141, 1994 7. Kharfan-Dabaja MA, Ayala E, Greene J, et al: Two cases of progressive multifocal leukoencephalopathy after allogeneic hematopoietic cell transplantation and a review of the literature. Bone Marrow Transplant 39:101-107, 2007 8. Schmidt-Hieber M, Schwender J, Heinz WJ, et al: Viral encephalitis after allogeneic stem cell transplantation: A rare complication with distinct characteristics of different causative agents. Haematologica 96:142-149, 2011
■ ■ ■
e34
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
