Progressive multifocal leukoencephalopathy

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Abstract

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.

Introduction

Progressive multifocal leukoencephalopathy (PML) is a disease of the central nervous system (CNS) that is characterized by destructive infection of oligodendrocytes by JC virus (Berger and Major, 1999). PML belongs to the opportunistic infections (Berger and Houff, 2009).

PML was first described as a disease in patients with lymphoid malignancies in 1958 (Astrom et al., 1958). There are earlier reports that mention individuals presenting with a similar clinical picture (Berger and Major, 1999). PML is seen in patients with malignancies, mainly lymphomas (Major et al., 1992, Richardson, 1988). It has emerged as a major complication in HIV infected patients. 5–10% of all AIDS patients develop PML (Berger and Major, 1999, Koralnik, 2006). Also PML can be seen after organ- and stem cell transplantations. More recently, PML has been observed in patients under treatment with immunomodulatory compounds, mainly a number of monoclonal antibodies (mAb) (Tan and Koralnik, 2010, Major, 2010).

Patients affected by PML present with neurological symptoms that develop over weeks. Most common are neuropsychological deficits with progressive subcortical dementia, apraxia, retrochiasmal visual deficits and motor problems (Berger and Major, 1999, Krupp et al., 1985). The natural disease course is progressive and leads to death within months if the patients remain immunocompromised.

Typically the pathology of PML comprises enlarged oligodendrocytes and widespread destruction of those. In addition, in lesions, astrocytes with large and multiple nuclei are observed (Richardson and Webster, 1983, Schmidbauer et al., 1990). Initially, there are multiple foci of demyelination sparsely distributed in subcortical white matter. With disease progression each focus grows as virus spreads from cell to cell. Microscopic areas of necrosis can become macroscopic plaque lesions (Richardson and Webster, 1983).

In nuclear magnetic resonance (NMR) imaging of PML, widespread asymmetrical hypointense lesions on T1 sequences and hyperintense lesions on T2 and FLAIR sequences with ill-defined borders without contrast enhancement are seen (Shah et al., 2010). The lesions do no show mass effects and no edema. The quite typical imaging findings allow the reasonable suspicion of diagnosis of PML. Diagnosis of infection by JC virus can be done by biopsy and demonstration of inclusion bodies in nuclei of injured oligodendrocytes. Electron microscopy reveals viral like particles in nucleoli of abnormal oligodendrocytes. Most important in the diagnosis is the amplification by PCR of JC virus from CNS tissue or/and cerebro-spinal fluid (CSF) (Tan and Koralnik, 2010).

Beside PML, there are a number of additional disease entities that are caused by JC virus (Tan and Koralnik, 2010). These are JC virus granule cell neuronopathy (Koralnik et al., 2005), JC virus encephalopathy (Sandyk, 1983) and JC virus meningitis (Blake et al., 1992).

Section snippets

JC virus

JC virus was first isolated from patient J.C. through inoculation of primary fetal glial cells with extracts from PML disease brain (Padgett et al., 1971). It belongs to the group of polyomaviruses. BK virus and simian vacuolating virus (SV40) also belong to this group (Osborn et al., 1974). SV40 virus entered the human population through contaminated polio vaccines (Rizzo et al., 1999). New members of the polyomavirus family are KI virus, WU virus and Merkel cell virus (Johnson, 2010).

JC virus

PML Immune Reconstitution Inflammatory Syndrome (IRIS)

Under treatment with combination antiretroviral therapy (cART) in HIV-positive patients with PML, the PML Immune Reconstitution Inflammatory Syndrome (IRIS) is commonly observed (French et al., 2004). This disease condition is due to an immune reconstitution which leads to infiltration of lymphocytes into the PML lesions. Unlike in PML, in this disease condition an inflammatory response can be seen in NMR with presence of gadolinium (Gd) enhancing lesions. An elevation of the CD8+ and CD4+ T

PML and immunotherapy

Cases of PML have been observed after application with mAbs and pharmaceutical small molecules (Major, 2010). Recently, PML has received most attention in the context of modern multiple sclerosis (MS) therapy. How did this happen? Two patients with MS treated in pivotal phase III studies with natalizumab, a mAb directed against CD49a (alpha-4 integrin, very late antigen 4 [VLA-4]), were diagnosed with PML in 2005 after the drug had been introduced on the market (Kleinschmidt-DeMasters and

Treatment of PML

PML is treated as follows. cART is given to HIV-positive patients. Treatment of PML precipitating compounds is discontinued in HIV-negative patients. Plasma exchange is being done for natalizumab-treated patients to rapidly reduce levels of natalizumab in blood and thus shorten the time for restoration of immune function (Kappos et al., 2007, Linda et al., 2009, Wenning et al., 2009, Khatri et al., 2009).

PML-IRIS has been observed in almost all patients in which the treatment with natalizumab

JC virus and multiple sclerosis

Due to the demyelinating nature of PML, investigations have been conducted early on in regard to the possible connection of JC virus infection and MS. In most studies using a variety of methods, no viral JC virus DNA was present in patients with MS (Bogdanovic et al., 1998, Buckle et al., 1992, Chesters et al., 1983, Meinke et al., 1977, Stoner et al., 1986). It has been reported that a low copy number of JCV DNA may occasionally be observed both in CSF of patients with MS and other

Future directions

In order to better assess the risk of individual patients to develop PML under the treatment with certain pharmaceuticals such as natalizumab, the combined efforts of neurologists and industry are necessary. Long term follow up of patients with novel therapeutics is of major importance. Assessment of emergence of PML in regard to duration of monotherapy, combination approaches and sequential treatment approaches with certain therapeutics should be conducted in a more systematic fashion. In

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