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Volume: 16 Issue: 5 October 2018


Sequential Onset of Varicella-Zoster Virus Encephalomeningitis and Progressive Multifocal Leukoencephalopathy in an Allogeneic Hematopoietic Stem Cell Transplant Recipient

Here, we describe a case of sequential varicella-zoster virus encephalomeningitis and progressive multifocal leukoencephalopathy following an allogeneic hema­topoietic stem cell transplant procedure. A 37-year-old male patient presented with fever, incomplete paralysis of bilateral legs, and bullous eruptions 8 months after allogeneic transplant. Polymerase chain reaction assays of cerebrospinal fluid samples for varicella-zoster virus were positive. Bullous eruptions and incomplete paralysis of bilateral legs improved after administration of acyclovir. However, higher brain dysfunction was present and getting worse. We detected no herpes simplex virus, varicella-zoster virus, Cytomegalovirus, human herpes virus 6, Epstein-Barr virus, or JC virus in cerebrospinal fluid samples with polymerase chain reaction assays. Pathologic findings and polymerase chain reaction assays with brain biopsy samples revealed that the patient had progressive multifocal leukoencephalopathy. This is the first report of a case showing dual central nervous system infections due to varicella-zoster virus and JC virus after allogeneic stem cell transplant.

Key words : Allogeneic hematopoietic stem cell transplant, PML, VZV encephalomeningitis


Viral infections in the central nervous system (CNS) critically affect mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients.1,2 Most viral pathogens in allo-HSCT recipients are herpes virus species.3 It is also well known that β- and γ-herpesviruses, such as Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6-8 (HHV6-8), occasionally cause encephalo­meningitis in immunocompromised patients. On the other hand, epidemiologic studies have shown that α-herpesviruses, such as herpes simplex virus type 1 and varicella-zoster virus (VZV), are the most frequent pathogens for encephalomeningitis found in immunocompetent individuals.4

Progressive multifocal leukoencephalopathy (PML) is a fatal, demyelinating disease of the CNS caused by the reactivation of JC virus infection.5,6 Progressive multifocal leukoencephalopathy mostly occurs in immunocompromised patients with acquired immunodeficiency syndrome, collagen diseases, hematologic malignancies, and so on.5,6 So far, the incidence of PML in allo-HSCT patients is significantly less than in patients with acquired immunodeficiency syndrome.7 Despite its relatively lower incidence, when allo-HSCT patients show neurologic symptoms of CNS, PML is one of the important disease entities to differentially diagnose.

Median time from allo-HSCT to symptom onset for encephalitis due to herpesvirus species has been shown to range from 3 to 8 months.3 However, the median time from transplant to symptom onset of PML has been reported to be 11 months, with the duration perhaps notably longer than that of CNS encephalitis due to other herpesviruses species in allo-HSCT recipients.3 Furthermore, no cases of dual CNS infections due to VZV and JC virus have been reported in allo-HSCT recipients.

Here, we are the first to describe an allogeneic hematopoietic transplant recipient who sequentially developed PML during treatment of VZV encep­halo­meningitis. This case also suggests that viral CNS infections due to different pathogens might occur in the setting of allo-HSCT.

Case Report

A 36-year-old man was treated with an allogeneic HLA identical unrelated allo-HSCT for T-lympho­blastic lymphoma in March 2010. On day 24 after treatment, he developed grade 2 acute graft-versus-host disease and was given methylprednisolone (maximum dose 2 mg/kg/day and discontinued on day 164). One month later from the cessation of methylprednisolone, he developed cryptogenic organizing pneumonia, resulting in restart of prednisolone for treatment.

On day 204, he was admitted to our medical center with fever, bullous eruptions on his trunk, and incomplete paralysis of bilateral legs. Brain magnetic resonance imaging findings on day 205 showed patchy high-intensity areas in the left corona radiate and centrum semiovale on T2-weighted images (Figure 1). A lumber puncture yielded colorless cerebrospinal fluid (CSF) with 1932 white cells, which mostly consisted of mononuclear cells, a protein level of 325 mg/dL, and a glucose level of 55 mg/dL. Gram stain showed no bacterial organisms. Polymerase chain reaction assays of CSF samples showed only VZV but no herpes simplex virus, CMV, HHV-6, EBV, or JC virus. These findings revealed that the patient had developed VZV en­cephalomeningitis. He was treated with acyclovir (10 mg/kg × 3/day) for 3 weeks. His bullous eruption, fever, and incomplete paralysis of bilateral legs improved with treatment. Varicella-zoster virus DNA was not detected in CSF samples with PCR on day 224. However, 1 week later, the patient developed higher brain dysfunction and disorientation. No herpes simplex virus, VZV, CMV, HHV-6, EBV, or JC virus was detected in CSF samples on day 231 with PCR assays. Magnetic resonance imaging findings on day 232 revealed that patchy high-intensity areas were getting worse in the left corona radiate and centrum semiovale on T2-weighted images (Figure 1). On day 242, a brain biopsy was performed. Pathologic findings with hematoxylin-eosin staining showed intensive gliosis and ground-glass intra­nuclear inclusions on oligodendrocytes. Immuno­histologic findings showed that the inclusion body had stained positive for anti-JC virus antibody8 (Figure 2). Furthermore, 8 × 10E9 copies/μg DNA (< 4 × 10E1 copies/μg DNA) of JC virus was detected in the brain tissue with PCR assays. This led to our diagnosis of PML during the treatment of VZV encephalomeningitis.

Some reports have shown that an antimalarial drug (mefloquine) and a serotonin reuptake inhibitor (mirtazapine) are effective agents for PML.9,10 After obtaining informed consent, we administered meflo­quine and mirtazapine to our patient. However, his condition gradually worsened, and the patient died on day 288 after allo-HSCT.


Progressive multifocal leukoencephalopathy is a progressive demyelinating disease of the CNS exclusively encountered in immunocompromised hosts. Reactivation of JC virus occurs under conditions of cellular immunosuppression, such as in patients with acquired immunodeficiency syn­drome, hematologic and solid-organ malignancies, or transplant recipients.5,6

To diagnose PML, a PCR assay for JC virus in the CSF samples has been reported as the primary method of choice. The sensitivity and negative predictive values for JC virus PCR in the CSF have been reported to be 74% and 88.5%, whereas the specificity and positive predictive values have been reported as 95.8% and 89.5%.11 However, a recent review showed that 8 of 15 PML patients after allo-HSCT had been diagnosed with only a brain biopsy.12 This report and our case reveal that a brain biopsy may be, at least in part, necessary to diagnose PML in patients with PML-suspicious neurologic findings, especially in allo-HSCT recipients.

JC virus infections in recipients of allo-HSCT are relatively rare. The incidence in patients who received stem cell transplants is much less than in patients with acquired immunodeficiency syndrome, with comparative incidence rates of 35.4 versus 130 per 100 person-years.7 In addition, the median time from transplant to onset of symptoms has been reported to be 11 months.3 However, the onset of other viral encephalitis, including HHV-6, herpes simplex virus, EBV, CMV, and VZV, has been reported to be between 3 and 8 months from allo-HSCT.3 In a recent unusual presentation of PML in a patient 18 months after allo-HSCT without administration of immunosuppressive drug for at least 12 months,13 it was shown that the timing of the onset may be dependent on the immuno­compromised conditions of the allo-HSCT patient. In our case report, sequential development of VZV encephalomyelitis and PML occurred in a recipient 8 months after allo-HSCT. The cause of this sequential and early-onset VZV encephalomyelitis-PML is unclear. However, the underlining immuno­compromised conditions are probably due to immunosuppressive therapy before and/or after allo-HSCT, perhaps influencing the sequential onset of VZV encephalomyelitis-PML. Further analyses of cases of viral CNS encephalitis after allo-HSCT are needed to clarify incidence, onset of symptoms, and risk factors of PML and other viral encephalitis.

No specific antiviral drugs are presently admin­istered for JC virus. Recently, it has been reported that mefloquine, an antimalarial drug, inhibits replication of JC virus in the cell culture system.14 Furthermore, it has been reported that mirtazapine, a serotonin inhibitor, could have efficacy for PML patients because of its blocking effect on JC virus infection.15 In fact, we have recently reported a case of PML after allo-HSCT who was successfully treated with mefloquine and mirtazapine.9 However, the combined therapy with these 2 drugs was not effective in the patient described in our present case report. This result shows that it is necessary to establish a treatment strategy for PML, especially in allo-HSCT recipients.

In summary, CNS viral encephalitis due to 2 different viruses could occur in allo-HSCT recipients.


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Volume : 16
Issue : 5
Pages : 628 - 630
DOI : 10.6002/ect.2016.0077

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From the 1Department of Hematology and Oncology and the 2Department of Clinical Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare. We are grateful to Harutaka Katano and Hideki Hasegawa (Department of Pathology National Institute of Infectious Diseases, Tokyo, Japan) for their contribution on JC virus PCR assay and histologic analysis of brain tissue.
Corresponding author: Jun Ishikawa, 1-3-3, Nakamichi, Higashinari-ku, Osaka, Japan 537-8511
Phone: +81 6 6972 1181