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.
ReviewProgressive multifocal leukoencephalopathy in HIV-1 infection
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
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