Review
Progressive multifocal leukoencephalopathy in HIV-1 infection

https://doi.org/10.1016/S1473-3099(09)70226-9Get rights and content

Summary

Progressive multifocal leukoencephalopathy is caused by the JC polyomavirus (JCV) and is one of the most feared complications of HIV-1 infection. Unlike other opportunistic infections, this disease can present when CD4 counts are higher than those associated with AIDS and when patients are receiving combined antiretroviral therapy, either shortly after starting or, more rarely, during long term successful treatment. Clinical suspicion of the disease is typically when MRI shows focal neurological deficits and associated demyelinating lesions; however, the identification of JCV in cerebrospinal fluid or brain tissue is needed for a definitive diagnosis. Although no specific treatment exists, the reversal of immunosuppression by combined antiretroviral therapy leads to clinical and MRI stabilisation in 50–60% of patients with the disease, and JCV clearance from cerebrospinal fluid. A substantial proportion of patients treated with combined antiretroviral therapy develop inflammatory lesions, which can be associated with either a favourable outcome or clinical worsening. The reasons for variability in the natural history of progressive multifocal leukoencephalopathy and treatment responses are largely undefined, and more specific and rational approaches to management are needed.

Introduction

Progressive multifocal leukoencephalopathy causes an infection of the CNS by JC virus (JCV), a polyomavirus that destroys oligodendrocytes and their myelin processes. On the rare occasions that this disease is not associated with HIV-1 infection it develops as a complication of conditions that compromise immunity, such as haematological malignant diseases and treatments that suppress the immune system.1, 2 Interest in progressive multifocal leukoencephalopathy has increased since its detection in patients receiving humanised antibody-based immunomodulatory drugs, such as natalizumab,3, 4 efalizumab,5 and, possibly, rituximab.6 However, this disease is most commonly found in patients infected with HIV-1, and its biology, diagnosis, and treatment have been studied most extensively in these patients.

In this Review we summarise the epidemiology, biology, and clinical presentation of HIV-1-related progressive multifocal leukoencephalopathy, and discuss views on management, emphasising areas in need of better information and understanding.

Section snippets

Epidemiology

Antiretroviral treatment has reduced the incidence of and mortality due to progressive multifocal leukoencephalopathy in patients infected with HIV-1. Before the use of combined antiretroviral therapy, progressive multifocal leukoencephalopathy affected 3–7% of patients infected with HIV-17, 8 and was the cause of up to 18% of fatal CNS diseases.9 The incidence has decreased substantially with combined antiretroviral therapy, although not to the same extent as that of other opportunistic

Pathogenesis

JCV is a small, ubiquitous DNA virus belonging to the family of human polyomaviruses (figure 1). JCV infection is common worldwide, and both inhalation and ingestion of contaminated water or food have been suggested as major modes of transmission between people.20, 21, 22 The seroprevalence of JCV in healthy people varies between studies, this variability likely depends on the technique used. In a large British survey,23 the overall seroprevalence was 35% by haemagglutination inhibition assay

Neuropathology

Patients with progressive multifocal leukoencephalopathy have multiple areas of demyelination in their brains, varying in size and stage of development. Initial foci of demyelination expand and might coalesce into larger areas that, in advanced cases, can evolve into cavitary necrosis. All CNS regions can be involved, although spinal cord lesions are rare.44

Oligodendrocytes sustain productive lytic infection accompanied by characteristic histopathology (figure 2). Their nuclei become enlarged

Clinical features

The classic presentation of progressive multifocal leukoencephalopathy begins with focal neurological deficits that vary depending on the location of the lesion. The deficit might result in hemisensory defects or hemiparesis (following involvement of parietal or frontal lobes), visual field loss and hemianopsia (occipital lobes or optic radiations), aphasia (language-dominant hemisphere), or ataxia and dysmetria (cerebellar hemispheres and peduncles). These symptoms often begin as partial

Diagnosis

The definitive diagnosis of progressive multifocal leukoencephalopathy is not only useful for clinical studies, but also important for individualised management of patients. A definitive diagnosis is needed in atypical cases, and, in the more typical cases prevents the need to revisit the diagnosis as the disease progresses, helps physicians to quickly and confidently treat patients, and guides prognosis for patient and family decisions. Diagnosis can be divided into three stages: clinical

Classification of HIV-1-associated progressive multifocal leukoencephalopathy

To provide a subject designation for planning and investigating treatment interventions, we have developed a classification system for HIV-1-associated progressive multifocal leukoencephalopathy that uses two principal components: combined antiretroviral therapy and immunovirological response and inflammatory features (table 1). Inflammation characterises immune reconstitution inflammatory syndrome (IRIS) associated with combined antiretroviral therapy, and the presence of inflammation in

Treatment

At present, the main approach to treatment of HIV-1-related progressive multifocal leukoencephalopathy involves combined antiretroviral therapy with the objective of reversing the immunological defect that interferes with the normal host response to JCV. This is therefore an indirect approach to treatment, but it is the only one that has proven effective. Although several antiviral or immunomodulant drug types have been proposed or used as more specific treatments, none has proven effective

Conclusions

Progressive multifocal leukoencephalopathy remains an important complication of HIV-1 infection. It should be promptly considered in any patients infected with HIV-1 presenting with insidious onset of focal neurological symptoms, with or without combined antiretroviral therapy, but particularly in those patients recently starting this treatment. If progressive multifocal leukoencephalopathy is diagnosed, combined antiretroviral therapy needs be started immediately or continued. More generally,

Search strategy and selection criteria

Data for this review were identified by searches of PubMed, and references from relevant articles. No date restrictions were set in the search. We also reviewed abstracts from major meetings on HIV-1 infection and neurology during the past 3 years. Search terms were “progressive multifocal leukoencephalopathy” and “JC virus”. English language papers only were reviewed.

References (112)

  • W Lang et al.

    Neuropathology of the acquired immune deficiency syndrome (AIDS): a report of 135 consecutive autopsy cases from Switzerland

    Acta Neuropathol

    (1989)
  • P Cinque et al.

    Polymerase chain reaction on cerebrospinal fluid for diagnosis of virus-associated opportunistic diseases of the central nervous system in HIV-infected patients

    AIDS

    (1996)
  • A d'Arminio Monforte et al.

    Changing incidence of central nervous system diseases in the EuroSIDA cohort

    Ann Neurol

    (2004)
  • S Grabar et al.

    Causes of the first AIDS-defining illness and subsequent survival before and after the advent of combined antiretroviral therapy

    HIV Med

    (2008)
  • P Cinque et al.

    The effect of highly active antiretroviral therapy-induced immune reconstitution on development and outcome of progressive multifocal leukoencephalopathy: study of 43 cases with review of the literature

    J Neurovirol

    (2003)
  • V Falco et al.

    Influence of HAART on the clinical course of HIV-1-infected patients with progressive multifocal leukoencephalopathy: results of an observational multicenter study

    J Acquir Immune Defic Syndr

    (2008)
  • DB Clifford et al.

    HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy

    Neurology

    (1999)
  • J Berenguer et al.

    Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy

    Clin Infect Dis

    (2003)
  • N Khanna et al.

    Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study

    Clin Infect Dis

    (2009)
  • A Mocroft et al.

    Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal

    Clin Infect Dis

    (2009)
  • C Lewden et al.

    Changes in causes of death among adults infected by HIV between 2000 and 2005: the “Mortalite 2000 and 2005” surveys (ANRS EN19 and Mortavic)

    J Acquir Immune Defic Syndr

    (2008)
  • RJ Frisque et al.

    Human polyomavirus JC virus genome

    J Virol

    (1984)
  • S Bofill-Mas et al.

    Potential transmission of human polyomaviruses through the gastrointestinal tract after exposure to virions or viral DNA

    J Virol

    (2001)
  • MC Monaco et al.

    Detection of JC virus DNA in human tonsil tissue: evidence for site of initial viral infection

    J Virol

    (1998)
  • BF Sabath et al.

    Traffic of JC virus from sites of initial infection to the brain: the path to progressive multifocal leukoencephalopathy

    J Infect Dis

    (2002)
  • WA Knowles et al.

    Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40

    J Med Virol

    (2003)
  • JM Kean et al.

    Seroepidemiology of human polyomaviruses

    PLoS Pathog

    (2009)
  • RS Hamilton et al.

    Comparison of antibody titers determined by hemagglutination inhibition and enzyme immunoassay for JC virus and BK virus

    J Clin Microbiol

    (2000)
  • A Egli et al.

    Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors

    J Infect Dis

    (2009)
  • RB Markowitz et al.

    Incidence of BK virus and JC virus viruria in human immunodeficiency virus-infected and -uninfected subjects

    J Infect Dis

    (1993)
  • JA Lednicky et al.

    Polyomavirus JCV excretion and genotype analysis in HIV-infected patients receiving highly active antiretroviral therapy

    AIDS

    (2003)
  • CS Tan et al.

    Detection of JC virus DNA and proteins in the bone marrow of HIV-positive and HIV-negative patients: implications for viral latency and neurotropic transformation

    J Infect Dis

    (2009)
  • FA White et al.

    JC virus DNA is present in many human brain samples from patients without progressive multifocal leukoencephalopathy

    J Virol

    (1992)
  • G Perez-Liz et al.

    Detection of JC virus DNA fragments but not proteins in normal brain tissue

    Ann Neurol

    (2008)
  • L Vago et al.

    JCV-DNA and BKV-DNA in the CNS tissue and CSF of AIDS patients and normal subjects: study of 41 cases and review of the literature

    J Acquir Immune Defic Syndr

    (1996)
  • GW Procop et al.

    JC virus chromogenic in situ hybridization in brain biopsies from patients with and without PML

    Diagn Mol Pathol

    (2006)
  • S Ciappi et al.

    Archetypal and rearranged sequences of human polyomavirus JC transcription control region in peripheral blood leukocytes and in cerebrospinal fluid

    J Gen Virol

    (1999)
  • CG Fedele et al.

    Identical rearranged forms of JC polyomavirus transcriptional control region in plasma and cerebrospinal fluid of acquired immunodeficiency syndrome patients with progressive multifocal leukoencephalopathy

    J Neurovirol

    (2003)
  • LA Pfister et al.

    JC virus regulatory region tandem repeats in plasma and central nervous system isolates correlate with poor clinical outcome in patients with progressive multifocal leukoencephalopathy

    J Virol

    (2001)
  • J Gasnault et al.

    Critical role of JC virus-specific CD4 T-cell responses in preventing progressive multifocal leukoencephalopathy

    AIDS

    (2003)
  • RA Du Pasquier et al.

    Detection of JC virus-specific cytotoxic T lymphocytes in healthy individuals

    J Virol

    (2004)
  • RW Price et al.

    Progressive multifocal leukoencephalopathy: a burnt-out case

    Ann Neurol

    (1983)
  • RA Du Pasquier et al.

    A prospective study demonstrates an association between JC virus-specific cytotoxic T lymphocytes and the early control of progressive multifocal leukoencephalopathy

    Brain

    (2004)
  • N Khanna et al.

    JC virus-specific immune responses in human immunodeficiency virus type 1 patients with progressive multifocal leukoencephalopathy

    J Virol

    (2009)
  • B Giudici et al.

    Highly active antiretroviral therapy and progressive multifocal leukoencephalopathy: effects on cerebrospinal fluid markers of JC virus replication and immune response

    Clin Infect Dis

    (2000)
  • RA Du Pasquier et al.

    Presence of JC virus-specific CTL in the cerebrospinal fluid of PML patients: rationale for immune-based therapeutic strategies

    AIDS

    (2005)
  • F Bernal-Cano et al.

    Spinal cord lesions of progressive multifocal leukoencephalopathy in an AIDS patient

    J Neurovirol

    (2007)
  • C Wuthrich et al.

    Frequent infection of cerebellar granule cell neurons by polyomavirus JC in progressive multifocal leukoencephalopathy

    J Neuropathol Exp Neurol

    (2009)
  • D Huang et al.

    Inflammatory progressive multifocal leukoencephalopathy in human immunodeficiency virus-negative patients

    Ann Neurol

    (2007)
  • P Miralles et al.

    Inflammatory reactions in progressive multifocal leukoencephalopathy after highly active antiretroviral therapy

    AIDS

    (2001)
  • Cited by (169)

    • Human Immunodeficiency Virus: Opportunistic Infections and Beyond

      2023, Neuroimaging Clinics of North America
      Citation Excerpt :

      PML, caused by reactivation of the JC virus and characterized by lytic infection of the oligodendrocytes, astrocytes, and neurons, leading to demyelination and neuronal damage.43 ART has reduced the incidence and mortality due to PML in patients with HIV-1 infection, although not to the same extent as that of other CNS OIs.44 Unlike other OIs, PML can develop in patients with CD4 counts greater than 200, in patients starting ART and rarely, in patients on long-term ART with full viral suppression.45

    • MRI signs of CNS demyelinating diseases

      2021, Multiple Sclerosis and Related Disorders
    View all citing articles on Scopus
    View full text