Publications by authors named "Kazuo Nakamichi"

72 Publications

Therapeutic Experience of Progressive Multifocal Leukoencephalopathy Development during Ofatumumab Therapy for Chronic Lymphocytic Leukemia.

Intern Med 2021 Jun 26. Epub 2021 Jun 26.

Department of Neurology, Japan Community Health Care Organization Kyushu Hospital, Japan.

A 79-year-old man experienced cognitive impairment and visual field defects during ofatumumab therapy for chronic lymphocytic leukemia refractory to combination chemotherapy. Magnetic resonance imaging revealed T1-weighted low-intensity and T2-weighted high-intensity lesions with patchy gadolinium enhancement in the subcortical white matter. A diagnosis of progressive multifocal leukoencephalopathy was made after the detection of John Cunningham virus (JCV) DNA in his cerebrospinal fluid (CSF). Following plasma exchange and the administration of mirtazapine and mefloquine, the JCV DNA levels in the CSF decreased. However, the patient died 55 days after treatment was initiated. Ofatumumab treatment appears to be associated with the development of PML.
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http://dx.doi.org/10.2169/internalmedicine.6723-20DOI Listing
June 2021

Infratentorial onset of progressive multifocal leukoencephalopathy in a patient with systematic lupus erythematosus complicated with lymphoma: a case report.

Mod Rheumatol Case Rep 2021 07 6;5(2):272-277. Epub 2021 Apr 6.

Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan.

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system caused by reactivation of JC virus (JCV). Typical PML shows confluent, bilateral but asymmetric, subcortical lesions in the supratentorial white matter on magnetic resonance imaging (MRI). We report here a 50-year-old woman with systemic lupus erythematosus complicated with lymphoma who developed PML with atypical brain MRI findings limited to the infratentorial area at presentation. She presented with numbness on the right side of the face, including her tongue, clumsiness of the right hand, and gait disturbance, after completion of remission induction therapy for lymphoma, including rituximab. Brain MRI demonstrated a solitary lesion limited to the cerebellum and brainstem, but a definitive diagnosis could not be made from cerebrospinal fluid study or tentative histologic evaluation of brain biopsy specimens. Despite methylprednisolone pulse therapy, her neurological deficits progressively worsened. One month later, in-depth analysis of her cerebrospinal fluid and brain biopsy specimens confirmed the presence of JCV. Eventually, the localised unilateral crescent-shaped cerebellar lesions on MRI expanded to the contralateral cerebellum, middle cerebellar hemisphere, pons, and midbrain and finally developed multifocal invasion into the white matter of the cerebral hemispheres. Our case suggests that PML could first present with a solitary infratentorial lesion in immunocompromised patients.
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http://dx.doi.org/10.1080/24725625.2021.1899763DOI Listing
July 2021

JC virus granule cell neuronopathy associated with Ruxolitinib: A case report and review of the literature.

eNeurologicalSci 2020 Dec 2;21:100269. Epub 2020 Sep 2.

Department of Neurology, Kansai Medical University, 2-5-1, Shinmachi, Hirakata, Osaka 5731010, Japan.

•We report here a case of JC virus granule cell neuronopathy associated with Ruxolitinib•It is worthwhile considering the possibility of JCV-GCN in myelofibrosis patients receiving ruxiolitinib, who present with progressive cerebellar symptoms and cerebellar atrophy.•Combination therapy using mefloquine and mirtazapine may be an effective treatment.
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http://dx.doi.org/10.1016/j.ensci.2020.100269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486434PMC
December 2020

Characterization of JC Polyomavirus Derived from COS-IMRb Cells.

Jpn J Infect Dis 2021 Jan 1;74(1):48-53. Epub 2020 Aug 1.

Division of Molecular Oncology and Virology, Medical Research Institute, Kanazawa Medical University, Japan.

JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the central nervous system affecting immunocompromised patients. The study of PML-type JCPyV in vitro has been limited owing to the inefficient propagation of the virus in cultured cells. In this study, we carried out long-term culture of COS-7 cells (designated as COS-IMRb cells) transfected with PML-type M1-IMRb, an adapted viral DNA with a rearranged non-coding control region (NCCR). The JCPyV derived from COS-IMRb cells were characterized by analyzing the viral replication, amount of virus by hemagglutination (HA), production of viral protein 1 (VP1), and structure of the NCCR. HA assays indicated the presence of high amounts of PML-type JCPyV in COS-IMRb cells. Immunostaining showed only a small population of JCPyV carrying COS-IMRb cells to be VP1-positive. Sequencing analysis of the NCCR of JCPyV after long-term culture revealed that the NCCR of M1-IMRb was conserved in COS-IMRb cells without any point mutation. The JCPyV genomic DNA derived from a clone of COS-IMRb-3 cells was detected, via Southern blotting, as a single band of approximately 5.1 kbp without deletion. These findings suggest the potential of using COS-IMRb-3 cells as a useful tool for screening anti-JCPyV drugs.
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http://dx.doi.org/10.7883/yoken.JJID.2020.325DOI Listing
January 2021

Progressive multifocal leukoencephalopathy during treatment with lenalidomide and elotuzumab for multiple myeloma.

Leuk Lymphoma 2020 09 18;61(9):2234-2237. Epub 2020 May 18.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.

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http://dx.doi.org/10.1080/10428194.2020.1765237DOI Listing
September 2020

Pomalidomide-associated progressive multifocal leukoencephalopathy in multiple myeloma: cortical susceptibility-weighted imaging hypointense findings prior to clinical deterioration.

J Neurovirol 2020 06 11;26(3):452-455. Epub 2020 May 11.

Department of Clinical Neuroscience and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.

Although there are several case reports of progressive multifocal leukoencephalopathy (PML) in multiple myeloma (MM), there are few reports of cases associated with pomalidomide. Here, we report the case of a 69-year-old female who had received 41 cycles of pomalidomide and dexamethasone treatment for relapsed/refractory IgG-κ MM presented with right-hand weakness; she was diagnosed as pomalidomide-associated PML. Fluid-attenuated inversion recovery (FLAIR) on admission showed high signals in the bilateral front-parietal lobe white matter, with multiple punctate lesions in the vicinity of the main lesions. These punctate pattern findings on FLAIR were similar to that of natalizumab-associated PML. Susceptibility weighted imaging (SWI) showed hypointense rims within the cortex at unaffected sites, in the initial stages. Subsequently, the clinical manifestations deteriorated, and the FLAIR images showed new hyperintense white matter lesions at the sites where cortical SWI hypointense rims were detected on the initial MRI examination. Our patient's serial MRI findings suggest that cortical SWI hypointense rims appear prior to the visible demyelinating white matter lesions in patients with PML.
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http://dx.doi.org/10.1007/s13365-020-00845-0DOI Listing
June 2020

[Progressive Multifocal Leukoencephalopathy Associated with HIV Infection Diagnosed by Brain Biopsy with Repeated Negative PCR Testing of CSF JC Virus DNA].

Brain Nerve 2020 May;72(5):541-546

Department of Neurology, University of Fukui Hospital.

A 36-year-old man with human immunodeficiency virus (HIV) infection was admitted to our hospital due to progressive ataxia. Brain MRI demonstrated high-signal intensity in the white matter of the right parietal lobe and left cerebellar hemisphere on T2-weighted images. Despite antiretroviral therapy, as his clinical symptoms worsened and MRI lesions gradually increased with the appearance of gadolinium-enhanced lesions, immune reconstitution inflammatory syndrome by progressive multifocal leukoencephalopathy (PML) associated with HIV infection was suspected. However, JC virus (JCV) in the cerebrospinal fluid (CSF) was undetectable by DNA PCR twice. Therefore, biopsy of the right parietal lobe was performed. JCV DNA was detected by PCR using the biopsy sample. JC viral protein was also identified by immunohistochemistry. Brain biopsy should be considered for the clinical diagnosis of PML when CSF JCV is negative on repeated DNA PCR. (Received September 20, 2019; Accepted January 14, 2020; Published May 1, 2020).
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http://dx.doi.org/10.11477/mf.1416201559DOI Listing
May 2020

Progressive multifocal leukoencephalopathy in a patient with primary amyloid light-chain amyloidosis.

Clin Neurol Neurosurg 2020 05 3;192:105709. Epub 2020 Feb 3.

Department of Neurology, Japanese Red Cross Medical Center, 4-1-22 Hiroo, Shibuya-ku, Tokyo, 150-8935, Japan.

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http://dx.doi.org/10.1016/j.clineuro.2020.105709DOI Listing
May 2020

Successful treatment of non-HIV progressive multifocal leukoencephalopathy: case report and literature review.

J Neurol 2020 Mar 14;267(3):731-738. Epub 2019 Nov 14.

Department of Neurology, Dokkyo Medical University, Shimotsuga, 321-0293, Tochigi, Japan.

Background: Progressive multifocal leukoencephalopathy (PML) is a subacute onset demyelinating disease caused by JC virus and characterized by multifocal involvement of the subcortical white matter and cerebellar hemispheres or peduncles on magnetic resonance imaging (MRI). However, non-HIV PML patients with brain lesions limited to the cerebellum and brainstem have not been well characterized.

Methods: We report a 68-year-old man with systemic lupus erythematosus under treatment with immunosuppressants who developed non-HIV PML with brain lesions limited to the cerebellum and brainstem and successfully treated with a combination of mefloquine and mirtazapine. We performed a literature review to characterize patients with non-HIV PML with brain lesions limited to the cerebellum and brainstem.

Results: Eight cases with non-HIV brainstem/cerebellar form PML were identified including our case. All cases had compromised status related underlying diseases. Four (50%) had a good prognosis. Five cases were treated, including 3 with favourable outcomes. Between the good prognosis group (n = 4) and the poor prognosis group (n = 4), treatment status for PML and the interval between the initial manifestation and diagnosis did not differ. Among those who performed contrast-enhanced brain imaging, lesion enhancement was related to good prognosis (good prognosis group vs. poor prognosis group; 100% vs. 0%).

Conclusion: PML should be considered in the differential diagnosis of brain lesions limited to the cerebellum and brainstem in immunocompromised patients. The presence of immune response against JC virus and inflammatory reactions may indicate good prognosis in non-HIV brainstem/cerebellar form PML.
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http://dx.doi.org/10.1007/s00415-019-09629-xDOI Listing
March 2020

Probable progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome with immunosuppressant dose reduction following lung transplantation: a case report and literature review.

BMC Neurol 2019 Oct 31;19(1):263. Epub 2019 Oct 31.

Department of Neurology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Ten'noudai, Tsukuba, Ibaraki, 305-8575, Japan.

Background: Progressive multifocal leukoencephalopathy (PML) is a rapidly developing demyelinating disease in the cerebral white matter and is often caused by JC polyomavirus (JCV). PML after lung transplantation is rare and has a poor prognosis, with no established therapies. Reducing the patient's immunosuppressant doses, thereby restoring immunity, could be used to treat PML. However, some patients develop immune reconstitution inflammatory syndrome (IRIS) with this treatment, an immune-induced inflammatory response to JCV that results in serious neuronal damage. We herein report a case of a 60-year-old female who suffered from PML 5 years after lung transplantation, had worsened brain lesions thought to be related to PML-IRIS at the time of immunosuppressant reduction, and missed treatment opportunities.

Case Presentation: A 60-year-old female developed PML 5 years after lung transplantation. Fluid-attenuated inversion recovery and diffusion-weighted brain magnetic resonance imaging (MRI) revealed multiple high-signal lesions, mainly in the cerebral white matter. Polymerase chain reaction found 0.32 million copies/mL of JCV in the cerebrospinal fluid. Thus, she was given a diagnosis of PML. Mycophenolate mofetil and tacrolimus dosages were reduced, and CD4-positive cell counts and the blood concentration of each immunosuppressant were monitored. Mefloquine was also orally administered at a daily dose of 275 mg for 3 days and was then administered at a dose of 275 mg per week. Although the patient's CD4-positive cell counts increased and her immune system recovered, her symptoms and brain MRI findings worsened. We suspected PML progression or a transition to PML-IRIS. Steroid pulse therapy to suppress the inflammatory lesions was not possible but was retrospectively indicated. The patient rapidly began to exhibit akinetic mutism and died 4 months after the onset of neurologic symptoms.

Conclusions: When neurologic symptoms and abnormal brain MRI findings are noted during immune recovery, it is often difficult to distinguish between progressed PML and PML-IRIS. However, the pathogenesis of brain lesions usually involves inflammation and immune-reactive mechanisms for JCV. Steroid pulse therapy, which can reduce inflammation, should thus be administered in organ transplantation cases with differential diagnoses including PML-IRIS.
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http://dx.doi.org/10.1186/s12883-019-1493-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822459PMC
October 2019

Improving detection of JC virus by ultrafiltration of cerebrospinal fluid before polymerase chain reaction for the diagnosis of progressive multifocal leukoencephalopathy.

BMC Neurol 2019 Oct 25;19(1):252. Epub 2019 Oct 25.

Department of Virology 1, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo, 162-8640, Japan.

Background: Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder caused by JC virus (JCV). Although detecting JCV DNA in the cerebrospinal fluid (CSF) by real-time polymerase chain reaction (PCR) is useful, diagnosis is difficult when JCV concentrations are low. We therefore aimed to lower the detection limit of real-time PCR testing by enriching JCV in the CSF via ultrafiltration.

Methods: Virus suspensions and CSF specimens from 20 untreated patients with suspected PML were collected and total DNAs were extracted. The JCV large T gene was detected by quantitative real-time PCR under condition with and without prior centrifugal ultrafiltration.

Results: The JCV DNA was reliably detected to a lower limit of 10 copies/mL of virus suspension by real-time PCR with ultrafiltration. When using this method, the quantity of JCV DNA per PCR reaction increased 3.2- to 8.7-fold compared with the standard procedure. Seven patients were positive for JCV when using the standard procedure, and an additional patient was positive when using ultrafiltration. All JCV-positive patients had neurological features and magnetic resonance imaging findings compatible with PML.

Conclusions: The detection limit of JCV DNA by real-time PCR can be lowered by viral enrichment using ultrafiltration. Our simple protocol offers a valuable tool for PML diagnosis when extremely low copy numbers of JCV are released into the CSF or when brain biopsy is not feasible.
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http://dx.doi.org/10.1186/s12883-019-1476-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815041PMC
October 2019

Simultaneous Development of Progressive Multifocal Leukoencephalopathy and Cryptococcal Meningitis during Methotrexate and Infliximab Treatment.

Intern Med 2019 15;58(18):2703-2709. Epub 2019 Sep 15.

Department of Neurology, Toyohashi Municipal Hospital, Japan.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of the JC virus under an immunosuppressed state. This condition carries a high risk of cryptococcal meningitis. We herein report a 65-year-old woman who simultaneously developed PML and cryptococcal meningitis and presented with bilateral sixth nerve palsy. She had been treated with methotrexate and infliximab for rheumatoid arthritis. Her symptoms improved with antifungal drug treatment and discontinuation of immunosuppression therapy. Although concurrent PML and cryptococcal meningitis is rare, it should be considered in immunosuppressed patients.
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http://dx.doi.org/10.2169/internalmedicine.2570-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794173PMC
December 2019

Inflammatory Cerebellar PML with a CD4/CD8 Ratio of 2.9 Showed a Favorable Prognosis in a Patient with Rheumatoid Arthritis.

Intern Med 2019 Nov 31;58(22):3323-3329. Epub 2019 Jul 31.

Department of Neurology, Tokyo Metropolitan Neurological Hospital, Japan.

The patient was a 74-year-old woman with rheumatoid arthritis who developed ataxia. MRI revealed T2-hyperintense lesions predominantly in the left middle cerebellar peduncle. Punctate or linear Gd enhancement was also observed on T1-weighted images. A brain biopsy was conducted and the pathology revealed a mild demyelinated lesion. Polymerase chain reaction (PCR) of biopsied brain tissues revealed the presence of JC virus (JCV) DNA, but JCV-infected oligodendroglia-like cells were not apparent on immunohistochemistry. Sensitive in-situ hybridization, however, detected three JCV-positive cells and the infiltration of CD4 and CD8 T cells and plasma cells was also observed. Immunosuppressants were tapered off and mirtazapine and mefloquine administered, resulting in a favorable outcome.
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http://dx.doi.org/10.2169/internalmedicine.3038-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911754PMC
November 2019

[A Patient with Progressive Multifocal Leukoencephalopathy Who Developed Bálint Syndrome Improved by Combination Therapy Using Mefloquine and Mirtazapine].

Brain Nerve 2019 Mar;71(3):281-286

Department of Neurology and Geriatrics, Gifu University Graduate School of Medicine.

We describe a 62-year-old man who developed subacute visual loss after cord blood stem cell transplantation for malignant lymphoma. Brain magnetic resonance imaging (MRI) showed bilateral hyperintense lesions in the occipital and parietal lobes. A diagnosis of progressive multifocal encephalopathy (PML) was established following brain biopsy and detection of JC virus (JCV) deoxyribonucleic acid (DNA) in the cerebrospinal fluid (CSF). He developed optic ataxia and visual inattention, and was then diagnosed as having Bálint syndrome. After he was treated with mefloquine and mirtazapine, his Bálint syndrome and, MRI findings improved and the copy number of JCV DNA in the CSF decreased. In summary, we demonstrate that patient with PML may develop Bálint syndrome and that combination therapy using mefloquine and mirtazapine may be an effective treatment. (Received August 23, 2018; Accepted November 29, 2018; Published March 1, 2019).
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http://dx.doi.org/10.11477/mf.1416201256DOI Listing
March 2019

[Idiopathic CD4-positive lymphocytopenia-associated progressive multifocal leukoencephalopathy confirmed by brain biopsy following negative results of repeated CSF-JC-virus tests: a case report].

Rinsho Shinkeigaku 2018 Dec 29;58(12):750-755. Epub 2018 Nov 29.

Department of Neurology, Tosei General Hospital.

A 75-year-old man presented with dysarthria and left facial paralysis. Brain diffusion-weighted MRI revealed a high-signal intensity in the right precentral gyrus, and he was hospitalized under the diagnosis of cerebral infarction. His symptoms worsened and brain MRI findings were consistent with progressive multifocal leukoencephalopathy (PML). Cerebrospinal fluid (CSF) JC virus (JCV) was undetectable in the DNA polymerase chain reaction (PCR) test four times, but brain biopsy revealed typical PML histopathology. He had no human immunodeficiency virus infection and history of immunosuppressive treatment, but he was found to have CD4+ lymphocytopenia. He was treated with mefloquine and mirtazapine, and died 29 months after symptoms onset. In cases whose repeated DNA PCR results are negative for CSF JCV, brain biopsy may be useful for the diagnosis of PML.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001227DOI Listing
December 2018

Correction to: A loop-mediated isothermal amplification assay for the detection and quantification of JC polyomavirus in cerebrospinal fluid: a diagnostic and clinical management tool and technique for progressive multifocal leukoencephalopathy.

Virol J 2018 10 8;15(1):154. Epub 2018 Oct 8.

Department of Virology 1, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, 162-8640, Japan.

In the original publication of article [1], '20 × 10 copies', which is in the sentence 'As seen in Fig. 4, the sensitivity of the specimens containing equal to or more than 20 × 10 copies in 2 μL of extracted DNA (equivalent to ≥3.0 × 103 copies/mL CSF) was 100% (29/29)' changes to '2.0 × 10 copies' in results section. The publisher apologizes to the readers and authors for the inconvenience.
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http://dx.doi.org/10.1186/s12985-018-1057-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176501PMC
October 2018

A loop-mediated isothermal amplification assay for the detection and quantification of JC polyomavirus in cerebrospinal fluid: a diagnostic and clinical management tool and technique for progressive multifocal leukoencephalopathy.

Virol J 2018 08 31;15(1):136. Epub 2018 Aug 31.

Department of Virology 1, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, 162-8640, Japan.

Background: JC polyomavirus (JCV) is the causative agent of progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the central nervous system in immunosuppressed patients. PML usually has a poor prognosis. Detection and quantification of the JCV genome in cerebrospinal fluid (CSF) is an efficacious tool for the diagnosis and management of PML, for which proper therapeutic interventions are required.

Methods: A loop-mediated isothermal amplification (LAMP) assay was applied for the quantitative detection of JCV. The LAMP assay was evaluated for the efficacy in diagnosis of PML in comparison with the TaqMan-based quantitative real-time PCR (qPCR) assay using 153 CSF specimens collected from patients with suspected PML.

Results: The LAMP assay showed no cross-reactivity against other polyomavirus plasmids, viral DNA, and viral RNA, which causes encephalitis, and detected 1 copy of the standard DNA per reaction. Among 50 qPCR-positives, 42 specimens (containing JCV genome ranged from 3.2 × 10 to 3.2 × 10 copies/reaction) showed positive reactions and 8 specimens (containing 0.9 to 19.9 copies/reaction) showed negative in the LAMP assay. Furthermore, 3 of 103 qPCR-negative specimens showed positive reactions in the LAMP assay. The sensitivity, specificity, positive predictive value, and negative predictive values of the LAMP assay were 84% (42/50), 97% (100/103), 93% (42/45), and 93% (100/108), respectively. The kappa statistic was 0.83. The JCV loads determined by the LAMP assay showed a strong positive correlation with those determined by the qPCR assay for 33 specimens with copy numbers of ≥1 copies/reaction (r = 0.89). Additionally, the LAMP assay could monitor the JCV genome copy number in CSF for sequential samples equivalently to qPCR assay.

Conclusions: The newly developed LAMP assay is highly specific against JCV and detect the JCV genome in the sample DNA containing 20 or more copies of JCV genome per reaction with 100% sensitivity (n = 29), which corresponds to ≥3 × 10 copies/mL of CSF. The LAMP assay is useful for the diagnosis and offers valuable information for the evaluation and management of PML in the clinical setting.
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http://dx.doi.org/10.1186/s12985-018-1046-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119251PMC
August 2018

Establishment of COS-JC cells persistently producing archetype JC polyomavirus.

Microbiol Immunol 2018 Aug 25;62(8):524-530. Epub 2018 Jul 25.

Division of Molecular Oncology and Virology, Medical Research Institute, Kanazawa Medical University, Ishikawa 920-0293, Japan.

JC polyomavirus (JCPyV) is the causative agent of progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the central nervous system in immunocompromised patients. Archetype JCPyV circulates in the human population. There have been several reports of archetype JCPyV replication in cultured cells, in which propagation was not enough to produce high titers of archetype JCPyV. In this study, we carried out cultivation of the transfected cells with archetype JCPyV DNA MY for more than 2 months to establish COS-7 cells (designated COS-JC cells) persistently producing archetype JCPyV. Moreover, JCPyV derived from COS-JC cells was characterized by analyzing the viral propagation, size of the viral genome, amount of viral DNA, production of viral protein, and structure of the non-coding control region (NCCR). Southern blotting using a digoxigenin-labeled JCPyV probe showed two different sizes of the JCPyV genome in COS-JC cells. For molecular cloning, four of five clones showed a decrease in the size of complete JCPyV genome. Especially, clone No. 10 was generated the large deletion within the Large T antigen. On the other hand, the archetype structure of the NCCR was maintained in COS-JC cells, although a few point mutations occurred. Quantitative PCR analysis of viral DNA in COS-JC cells indicated that a high copy number of archetype JCPyV DNA was replicated in COS-JC cells. These findings suggest that COS-JC cells could efficiently propagate archetype JCPyV MY and offer a useful tool to study persistent infection of archetype JCPyV in a kidney-derived system.
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http://dx.doi.org/10.1111/1348-0421.12632DOI Listing
August 2018

Fingolimod-associated PML with mild IRIS in MS: A clinicopathologic study.

Neurol Neuroimmunol Neuroinflamm 2018 Jan 10;5(1):e415. Epub 2017 Nov 10.

Department of Neurology (S.N., T.M., Y.T., K.T., N.Y., H.K., M.A.), Department of Multiple Sclerosis Therapeutics (T.M.), Department of Neurosurgery (R.S., T.T.), and Department of Pathology (M.W.), Tohoku University Graduate School of Medicine, Sendai; Department of Anatomic Pathology (Y.S.-H.), Tokyo Medical University; Department of Virology 1 (K.N., M.S.), Laboratory of Neurovirology, National Institute of Infectious Diseases; Department of Neurology (I.N.), Tohoku Medical and Pharmaceutical University, Sendai; and Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine and Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Japan.

Objective: To clarify the clinical, neuropathologic, and virologic characteristics of progressive multifocal leukoencephalopathy (PML) and its immune reconstitution inflammatory syndrome (IRIS) in a patient with fingolimod-treated MS.

Methods: A case study.

Results: A 34-year-old patient with MS using fingolimod for 4 years had a gradual progression of right hemiparesis and aphasia with a new subcortical white matter lesion in the precentral gyrus by initial MRI. Blood tests were normal, except for lymphopenia (160 cells/μL). One month after the cessation of fingolimod, brain MRI depicted a diffusely exacerbated hyperintensity on fluid-attenuated inversion recovery and diffusion-weighed imaging in the white matter with punctate gadolinium enhancement, suggesting PML-IRIS. A very low level of JC virus (JCV)-DNA (15 copies/mL) was detected in the CSF as judged by quantitative PCR. Brain tissues were biopsied from the left frontal lesion, which showed some small demyelinated foci with predominant loss of myelin-associated glycoprotein with infiltrations of lymphocytes and macrophages, but clear viral inclusion was not observed with hematoxylin-eosin staining. JCV-DNA was uniquely detectable in an active inflammatory demyelinating lesion by in situ hybridization, possibly suggesting an early phase of PML. DNA extracted from the brain sample was positive for JCV-DNA (151 copies/cell). It took 3 months to normalize the blood lymphocyte count. The patient was treated with 1 g of IV methylprednisolone for 3 days and a weekly oral dose (375 mg) of mefloquine, and her symptoms gradually improved.

Conclusion: Low CSF JCV-DNA and unfound viral inclusions initially made her diagnosis difficult. The clinical course of fingolimod-associated PML may be associated with mild immune reconstitution.
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http://dx.doi.org/10.1212/NXI.0000000000000415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930970PMC
January 2018

A Punctate Magnetic Resonance Imaging Pattern in a Patient with Systemic Lupus Erythematosus Is an Early Sign of Progressive Multifocal Leukoencephalopathy: A Clinicopathological Study.

Intern Med 2018 Sep 27;57(18):2727-2734. Epub 2018 Apr 27.

Department of Neurology, Kobe City Medical Center General Hospital, Japan.

A 37-year-old woman with systemic lupus erythematosus presented with gait disturbance and cognitive dysfunction. Brain magnetic resonance imaging (MRI) revealed small, punctate, T2-/fluid-attenuated inversion recovery-hyperintense and T1-hypointense lesions without gadolinium enhancement, which is atypical for progressive multifocal leukoencephalopathy (PML). On a pathological examination of biopsied brain tissues, JC virus-infected cells were hardly detected via immunohistochemistry but were certainly detected via in situ hybridization, conclusively verifying the PML diagnosis. After tapering off the immunosuppressant and mefloquine administration, the MRI findings revealed gradual improvement, and she has been stable for over 18 months. A punctate MRI pattern is not specific to natalizumab-associated PML but may be a ubiquitous early sign useful for the early diagnosis of PML.
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http://dx.doi.org/10.2169/internalmedicine.0696-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191581PMC
September 2018

Progressive multifocal leukoencephalopathy associated with thymoma with immunodeficiency: a case report and literature review.

BMC Neurol 2018 Apr 10;18(1):37. Epub 2018 Apr 10.

Department of Neurology, Aomori Prefectural Central Hospital, 2-1-1 Higashi-Tsukurimichi, Aomori, 030-8551, Japan.

Background: The development of progressive multifocal leukoencephalopathy (PML) is associated with severe cellular immunosuppression. Good's syndrome (GS) is a rare immunodeficiency syndrome related to thymoma, with the development of humoral as well as cellular immunosuppression; however, there are few reports of PML due to GS. One report suggested that the neurological symptoms of PML related to thymoma may be improved by a reduction of immunosuppressive therapy for myasthenia gravis (MG). It is therefore necessary to identify the cause of immunodeficiency in patients with PML to enable an appropriate treatment strategy to be adopted.

Case Presentation: A 47-year-old Japanese woman was admitted with aphasia and gait difficulty. She had an invasive thymoma that had been treated with repeated chemotherapy, including cyclophosphamide. She had also previously been diagnosed with MG (Myasthenia Gravis Foundation of America clinical classification IIa), but her ptosis and limb weakness had completely recovered. On admission, neurological examination revealed motor aphasia and central facial weakness on the right side. Laboratory studies showed severe lymphopenia, decreased CD4+ and CD8+ T cell and CD19+ B cell counts, and reduced levels of all subclasses of immunoglobulins, suggesting GS. Serology for human immunodeficiency virus (HIV) infection was negative. Brain magnetic resonance imaging showed asymmetric multifocal white matter lesions without contrast enhancement. Cerebrospinal fluid real-time polymerase chain reaction for JC virus was positive, showing 6,283,000 copies/mL. We made a diagnosis of non-HIV-related PML complicated with GS and probable chemotherapy-induced immunodeficiency. She then received intravenous immunoglobulin therapy, mirtazapine, and mefloquine, but died of sepsis 46 days after admission.

Conclusions: It is necessary to consider the possibility of immunodeficiency due to GS in patients with PML related to thymoma. Neurologists should keep in mind the risk of PML in MG patients with thymoma, even if the MG symptoms are in remission, and should thus evaluate the immunological status of the patient accordingly.
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http://dx.doi.org/10.1186/s12883-018-1041-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891917PMC
April 2018

Brain Biopsy Is More Reliable than the DNA test for JC Virus in Cerebrospinal Fluid for the Diagnosis of Progressive Multifocal Leukoencephalopathy.

Intern Med 2017 15;56(10):1231-1234. Epub 2017 May 15.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan.

The current standard diagnostic approach for progressive multifocal leukoencephalopathy (PML) is to perform a DNA test to identify the presence of the JC virus in cerebrospinal fluid (CSF). A 32-year-old woman with a 5-year history of systemic lupus erythematosus developed right hemiplegia and motor aphasia. MRI revealed a large white matter lesion in the left frontal lobe. JC virus DNA was undetectable in the CSF, but a brain biopsy showed typical histopathology and a high DNA load of the JC virus. The patient was treated with mefloquine and mirtazapine, and is currently alive at 24 months after onset. An early brain biopsy may therefore be important for making a timely diagnosis of PML.
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http://dx.doi.org/10.2169/internalmedicine.56.7689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491822PMC
October 2017

PET Imaging of F-FDG, C-methionine, C-flumazenil, and C-4DST in Progressive Multifocal Leukoencephalopathy.

Intern Med 2017 15;56(10):1219-1223. Epub 2017 May 15.

Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Japan.

The use of positron emission tomography (PET) imaging in progressive multifocal leukoencephalopathy (PML) has rarely been reported. We herein report a set of PET images in a 63-year-old patient with PML. In PML lesions, the uptake of F-fluorodeoxyglucose, C-methionine, C-flumazenil, and [methyl-C]4'-thiothymidine was decreased, increased, decreased, and unchanged, respectively. These results suggest that glucose metabolism decreased, protein synthesis increased, neuronal integrity decreased, and the DNA synthesis and cellular proliferation of host cells were not activated in PML lesions. These results may reflect very little infiltration by inflammatory cells and active infection with JC virus in this case.
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http://dx.doi.org/10.2169/internalmedicine.56.8080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491820PMC
October 2017

CPT11 prevents virus replication in JCI cells persistently infected with JC polyomavirus.

Microbiol Immunol 2017 Jun;61(6):232-238

Division of Molecular Oncology and Virology, Medical Research Institute, Kanazawa Medical University, Ishikawa, 920-0293, Japan.

JC polyomavirus (JCPyV) is the causative agent of the demyelinating disease of the central nervous system known as progressive multifocal leukoencephalopathy (PML), which occurs in immunocompromised patients. Moreover, patients treated with natalizumab for multiple sclerosis or Crohn disease can develop PML, which is then termed natalizumab-related PML. Because few drugs are currently available for treating PML, many antiviral agents are being investigated. It has been demonstrated that the topoisomerase I inhibitors topotecan and β-lapachone have inhibitory effects on JCPyV replication in IMR-32 cells. However, both of these drugs have marginal inhibitory effects on virus propagation in JC1 cells according to RT-PCR analysis. In the present study, the inhibitory effect of another topoisomerase I inhibitor, 7-ethy-10-[4-(1-piperidino)-1-piperidino] carbonyloxy camptothecin (CPT11), was assessed by investigating viral replication, propagation, and viral protein 1 (VP1) production in cultured cells. JCPyV replication was assayed using real-time PCR combined with Dpn I treatment in IMR-32 cells transfected with JCPyV DNA. It was found that JCPyV replicates less in IMR-32 cells treated with CPT11 than in untreated cells. Moreover, CPT11 treatment of JCI cells persistently infected with JCPyV led to a dose-dependent reduction in JCPyV DNA and VP1 production. Additionally, the inhibitory effect of CPT11 was found to be stronger than those of topotecan and β-lapachone. These findings suggest that CPT11 may be a potential anti-JCPyV agent that could be used to treat PML.
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http://dx.doi.org/10.1111/1348-0421.12486DOI Listing
June 2017

Reduction of animal suffering in rabies vaccine potency testing by introduction of humane endpoints.

Biologicals 2017 Mar 28;46:38-45. Epub 2016 Dec 28.

Department of Virology I, National Institute of Infectious Diseases, Japan.

Potency controls of inactivated rabies vaccines for human use are confirmed by the National Institutes of Health challenge test in which lethal infection with severe neurological symptoms should be observed in approximately half of the mice inoculated with the rabies virus. Weight loss, decreased body temperature, and the presence of rabies-associated neurological signs have been proposed as humane endpoints. The potential for reduction of animal suffering by introducing humane endpoints in the potency test for inactivated rabies vaccine for human use was investigated. The clinical signs were scored and body weight was monitored. The average times to death following inoculation were 10.49 and 10.99 days post-inoculation (dpi) by the potency and challenge control tests, respectively, whereas the average times to showing Score-2 signs (paralysis, trembling, and coma) were 6.26 and 6.55 dpi, respectively. Body weight loss of more than 15% appeared at 5.82 and 6.42 dpi. The data provided here support the introduction of obvious neuronal signs combined with a body weight loss of ≥15% as a humane endpoint to reduce the time of animal suffering by approximately 4 days.
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http://dx.doi.org/10.1016/j.biologicals.2016.12.007DOI Listing
March 2017

Deep-Sequence Identification and Role in Virus Replication of a JC Virus Quasispecies in Patients with Progressive Multifocal Leukoencephalopathy.

J Virol 2017 Jan 16;91(1). Epub 2016 Dec 16.

Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan

JC virus (JCV) is a DNA virus causing progressive multifocal leukoencephalopathy (PML) in immunodeficient patients. In the present study, 22 genetic quasispecies with more than 1.5% variant frequency were detected in JCV genomes from six clinical samples of PML by next-generation sequencing. A mutation from A to C at nucleotide (nt) 3495 in JCV Mad1 resulting in a V-to-G amino acid substitution at amino acid (aa) position 392 of the large T antigen (TAg) was identified in all six cases of PML at 3% to 19% variant frequencies. Transfection of JCV Mad1 DNA possessing the V392G substitution in TAg into IMR-32 and human embryonic kidney 293 (HEK293) cells resulted in dramatically decreased production of JCV-encoded proteins. The virus DNA copy number was also reduced in supernatants of the mutant virus-transfected cells. Transfection of the IMR-32 and HEK293 cells with a virus genome containing a revertant mutation recovered viral production and protein expression. Cotransfection with equal amounts of wild-type genome and mutated JCV genome did not reduce the expression of viral proteins or viral replication, suggesting that the mutation did not have any dominant-negative function. Finally, immunohistochemistry demonstrated that TAg was expressed in all six pathological samples in which the quasispecies were detected. In conclusion, the V392G amino acid substitution in TAg identified frequently in PML lesions has a function in suppressing JCV replication, but the frequency of the mutation was restricted and its role in PML lesions was limited.

Importance: DNA viruses generally have lower mutation frequency than RNA viruses, and the detection of quasispecies in JCV has rarely been reported. In the present study, a next-generation sequencer identified a JCV quasispecies with an amino acid substitution in the T antigen in patients with PML. In vitro studies showed that the mutation strongly repressed the expression of JC viral proteins and reduced the viral replication. However, because the frequency of the mutation was low in each case, the total expression of virus proteins was sustained in vivo. Thus, JC virus replicates in PML lesions in the presence of a mutant virus which is able to repress virus replication.
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http://dx.doi.org/10.1128/JVI.01335-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5165223PMC
January 2017

A case of progressive multifocal leukoencephalopathy with chronic renal failure, whose JC virus in cerebrospinal fluid disappeared after mefloquine-mirtazapine dual therapy.

Rinsho Shinkeigaku 2016 10 16;56(10):705-708. Epub 2016 Oct 16.

Department of Neurology, Saneikai Tsukazaki Hospital.

An 83-year-old man with chronic renal failure was referred to our hospital because of subacute progressive right hemiparesis. A brain MRI showed high-intensity lesions in bilateral middle cerebellar peduncles and white matter of the left frontal lobe on T-weighted images. The lesions increased gradually, so we suspected a brain tumor because H-MRS images showed elevated Cho and decreased NAA, and also pathologic findings of the brain biopsy suggested glioblastoma. However, JC virus (JCV) in cerebrospinal fluid was revealed highly positive by PCR. So we reconsidered pathologically and finally found bizarre astrocytes which were infected with JCV in immunohistochemical studies and we diagnosed progressive multifocal leukoencephalopathy at last. Then we medicated with mefloquine and mirtazapine, and the JCV in cerebrospinal fluid disappeared, without new MRI lesions. This is a rare case in respect of the background of the patient and the clinical course.
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http://dx.doi.org/10.5692/clinicalneurol.cn-000928DOI Listing
October 2016

Progressive multifocal leukoencephalopathy with bilateral middle cerebellar peduncle lesions confirmed by repeated CSF-JC virus tests and coexistence of JC virus granule cell neuronopathy. Report of a case.

Rinsho Shinkeigaku 2016 07 30;56(7):481-5. Epub 2016 Jun 30.

Department of Neurology, Japan Red Cross Nagoya Daini Hospital.

A 65 year-old woman with small lymphocytic leukemia presented with subacute cerebellar ataxia. Six months after rituximab chemotherapy, a cranial MRI revealed lesions in the bilateral middle cerebellar peduncles. Both cerebrospinal fluid (CSF) JC virus (JCV)-DNA PCR test on three occasions and brain biopsy were negative. CSF tests were repeated. The fourth test performed 6 months after the onset showed positive JCV-DNA, and a definite diagnosis of progressive multifocal leukoencephalopathy (PML) was made. Neuroimaging of cerebellar atrophy was considered to be coexistence of granule cell neuronopathy. Medication with mirtazapine and mefloquine was temporarily effective for several months. Little are known solitary bilateral MRI lesions of the middle cerebellar peduncle in PML. JCV-PCR test of CSF may be negative at an earlier stage of PML. Repeated CSF tests should be essential to confirming the diagnosis in such cases.
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http://dx.doi.org/10.5692/clinicalneurol.cn-000873DOI Listing
July 2016
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