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

      case-report

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          Abstract

          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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          Immune restoration disease after antiretroviral therapy.

          Shelley F. Stone, Patricia Price, Jeffrey French (2004)
          Suppression of HIV replication by highly active antiretroviral therapy (HAART) often restores protective pathogen-specific immune responses, but in some patients the restored immune response is immunopathological and causes disease [immune restoration disease (IRD)]. Infections by mycobacteria, cryptococci, herpesviruses, hepatitis B and C virus, and JC virus are the most common pathogens associated with infectious IRD. Sarcoid IRD and autoimmune IRD occur less commonly. Infectious IRD presenting during the first 3 months of therapy appears to reflect an immune response against an active (often quiescent) infection by opportunistic pathogens whereas late IRD may result from an immune response against the antigens of non-viable pathogens. Data on the immunopathogenesis of IRD is limited but it suggests that immunopathogenic mechanisms are determined by the pathogen. For example, mycobacterial IRD is associated with delayed-type hypersensitivity responses to mycobacterial antigens whereas there is evidence of a CD8 T-cell response in herpesvirus IRD. Furthermore, the association of different cytokine gene polymorphisms with mycobacterial or herpesvirus IRD provides evidence of different pathogenic mechanisms as well as indicating a genetic susceptibility to IRD. Differentiation of IRD from an opportunistic infection is important because IRD indicates a successful, albeit undesirable, effect of HAART. It is also important to differentiate IRD from drug toxicity to avoid unnecessary cessation of HAART. The management of IRD often requires the use of anti-microbial and/or anti-inflammatory therapy. Investigation of strategies to prevent IRD is a priority, particularly in developing countries, and requires the development of risk assessment methods and diagnostic criteria.
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            A study of mefloquine treatment for progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes

            David Clifford, Avindra Nath, Paola Cinque … (2013)
            Immune reconstitution has improved outcomes for progressive multifocal leukoencephalopathy (PML), a potentially lethal brain disease caused by JC virus (JCV). However, an antiviral treatment to control JCV is needed when immune reconstitution is delayed or not possible. On the basis of in vitro efficacy, this study evaluated the effect of mefloquine on PML and factors that may predict PML outcomes. This 38-week, open-label, randomized, parallel-group, proof-of-concept study compared patients with PML who received standard of care (SOC) with those who received SOC plus mefloquine (250 mg for 3 days, then 250 mg weekly). Patients randomized to SOC could add mefloquine treatment at week 4. The primary endpoint was change from baseline to weeks 4 and 8 in JCV DNA copy number (load) in cerebrospinal fluid (CSF). Exploratory analyses evaluated factors that might correlate with clinical outcome. The majority of enrolled patients were HIV positive. Preplanned interim data analyses suggested that the study was unlikely to successfully demonstrate a significant difference between groups; therefore, the study was terminated prematurely. There was no significant difference between groups in CSF JCV DNA loads or clinical/MRI findings. Decrease in CSF JCV DNA load from baseline to week 4 was associated with a better clinical outcome at 16 weeks, as measured by Karnofsky scores. This study found no evidence of anti-JCV activity by mefloquine. An early decrease of CSF JCV DNA load appears to be associated with a better clinical outcome. Electronic supplementary material The online version of this article (doi:10.1007/s13365-013-0173-y) contains supplementary material, which is available to authorized users.
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              Progressive multifocal leukoencephalopathy.

              Robert Weissert (2011)
              Progressive multifocal leukoencephalopathy (PML) is a disease of the central nervous system (CNS) with destructive infection of oligodendrocytes by JC virus. PML belongs to the opportunistic infections. It is observed in patients with HIV infection, lymphoid malignancies, after organ- and stem cell transplantations and more recently in the context of modern immune-therapies with monoclonal antibodies (mAb) like natalizumab, rituximab, infliximab and efalizumab. The natural course of PML is fatal within months. More recently, the Immune Reconstitution Inflammatory Syndrome (IRIS) has been observed in patients with HIV infection treated with combination antiretroviral therapy (cART) as well as patients in whom the PML-inducing immune therapy has been terminated. In PML-IRIS the immune system contributes to the elimination of JC virus from the CNS and if PML-IRIS emerges, PML can be survived but can lead as well to catastrophic outcomes with brain herniation and death. Therefore the management of IRIS requires special knowledge in JC virus biology and patient care. JC virus infection is possibly involved in a variety of additional neurological conditions and cancer. Much will be learned within the next years that could change our view on the understanding of JC virus and human disease. Copyright © 2010 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Intern Med
                Journal ID (iso-abbrev): Intern. Med
                Title: Internal Medicine
                Publisher: The Japanese Society of Internal Medicine
                ISSN (Print): 0918-2918
                ISSN (Electronic): 1349-7235
                Publication date (Print): 15 May 2017
                Volume: 56
                Issue: 10
                Pages: 1231-1234
                Affiliations
                [1 ]Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan
                [2 ]Department of Neurosurgery, Shinshu University School of Medicine, Japan
                [3 ]Department of Pathology, National Institute of Infectious Diseases, Japan
                [4 ]Division of Virology 1, National Institute of Infectious Diseases, Japan
                Author notes

                Correspondence to Dr.　Shu-ichi Ikeda, ikedasi@ 123456shinshu-u.ac.jp

                Article
                DOI: 10.2169/internalmedicine.56.7689
                PMC ID: 5491822
                PubMed ID: 28502942
                SO-VID: 3d7ed5d4-b004-462d-9c93-4049a65641f2
                Copyright © Copyright © 2017 by The Japanese Society of Internal Medicine
                License:

                The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit ( https://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 7 May 2016
                Date accepted : 19 September 2016
                Categories
                Subject: Case Report

                Keywords: progressive multifocal leukoencephalopathy,jc virus,dna test,brain biopsy,demyelination,slow virus infection
                Data availability:
                Keywords: progressive multifocal leukoencephalopathy, jc virus, dna test, brain biopsy, demyelination, slow virus infection

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