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  • Updated 10.17.2021
  • Released 03.08.1996
  • Expires For CME 10.17.2024

Progressive multifocal leukoencephalopathy



Progressive multifocal leukoencephalopathy is an opportunistic demyelinating infection of the central nervous system caused by JC virus (JCV, JCPyV), a polyomavirus that is widely distributed in human populations. Progressive multifocal leukoencephalopathy is characterized clinically by the development of multifocal neurologic signs referable to cerebrum, or, less frequently, cerebellum or brainstem. Pathologically, progressive multifocal leukoencephalopathy is characterized grossly by multifocal areas of myelin loss and microscopically by lytic infection of oligodendrocytes, and in many cases, the presence of atypical astrocytes. Historically, the disorder has been rare outside the setting of HIV infection, but 4% of untreated AIDS patients may succumb to the disease. Progressive multifocal leukoencephalopathy has become of increasing concern in patients receiving aggressive immunosuppression for organ or stem cell transplantation or in patients treated with newer immunosuppressive agents, in particular natalizumab and brentuximab vedotin. In this article, the author reviews the pathogenesis, clinical features, diagnosis, and treatment of this disorder.

Key points

• Progressive multifocal leukoencephalopathy is an opportunistic demyelinating infection of the central nervous system. The disorder almost invariably affects immunosuppressed patients, in particular, those with impaired T-cell response.

• Progressive multifocal leukoencephalopathy may affect up to 4% of patients with AIDS. An increased incidence of progressive multifocal leukoencephalopathy has also been described in individuals receiving newer, more aggressive immunosuppressive regimens for organ or stem cell transplantation, as well as in individuals receiving newer biological agents, in particular natalizumab and brentuximab vedotin.

• Progressive multifocal leukoencephalopathy should be considered in immunocompromised individuals presenting with multifocal neurologic signs and/or evidence of multiple white matter lesions on MRI. Specific detection of JC virus can often be made by polymerase chain reaction analysis of cerebrospinal fluid.

• There is no proven therapy for progressive multifocal leukoencephalopathy. In patients with AIDS-progressive multifocal leukoencephalopathy, antiretroviral therapy (ART: combined antiretroviral therapy was initially termed highly active antiretroviral therapy or HAART and subsequently combined antiretroviral therapy or cART, replaced by ART) may produce stabilization or improvement. Remission has also been reported after withdrawal of immunosuppressive drugs and, in patients with progressive multifocal leukoencephalopathy in the setting of natalizumab treatment, after removal of the monoclonal by plasma exchange, with or without accompanying immunoabsorption therapy. Reports suggest that progressive multifocal leukoencephalopathy may be arrested through use of filgrastim, immune checkpoint inhibitors with or without concomitant treatment with interleukin 2, or T cells sensitized to a second human polyomavirus, BK virus (BKV, BKPyV). In both HIV-infected and iatrogenically immunosuppressed patients, restoration of immune function may result in immune reconstitution inflammatory syndrome (IRIS).

Historical note and terminology

Hallervorden, in 1930, reported 2 cases of a previously undescribed, apparently degenerative condition accompanied by central nervous system demyelination (77). Additional, similar cases were described by Winkelman and Moore, Bateman, Squires and Thannhauser, and Christensen and Fog (187; 10; 34). It was not until 1958, however, that Richardson, Astrom, and Mancall published the first case series of this disorder, describing its clinical features and its neuropathological findings of multifocal demyelination, nuclear enlargement or inclusions in oligodendrocytes, and bizarre alteration of individual astrocytes (07). These authors termed the condition progressive multifocal leukoencephalopathy and noted the close association of this condition with hematological malignancies, subsequently recognizing the association of the disorder with other immunosuppressed states (135). The presence of inclusions within oligodendrocytes led first Cavanagh and then Richardson to suggest that the disease might represent an unusual sort of infection (29; 135). Support that progressive multifocal leukoencephalopathy was caused by a virus came in 1965, when Zu Rhein and Chou and Silverman and Rubinstein independently identified crystalline arrays of virions in progressive multifocal leukoencephalopathy oligodendrocytes (148; 198). The arrays most closely resembled those seen in cells infected with the mouse agent, polyoma virus, an agent not known at that time to have any human counterpart. Despite intense initial skepticism, this observation was confirmed by other investigators.

Attempts to culture an agent from progressive multifocal leukoencephalopathy brains were unsuccessful until 1974 when Padgett and colleagues successfully isolated the agent in primary cultures of human fetal brain cells and named the agent JC virus (JCV), using the initials of the patient (John Cunningham) from whose brain the virus had been recovered (128). In that year, a second human polyomavirus, BK virus (BKV, BKPyV), was recovered from human urine (63). It is now known that polyomaviruses are widespread agents in both mammalian and avian species and that 4 different polyomaviruses have been associated with human disease (75). Of these, only JC virus has been consistently associated with progressive multifocal leukoencephalopathy. BK virus has been associated with rare cases of encephalitis (172; 04) and in 4 cases BK virus has been reported to be associated with progressive multifocal leukoencephalopathy lesions (25; 24; 46; 115). Several early reports described identification of a third polyomavirus, SV40, a simian agent that was a contaminant of early lots of Salk and Sabin polio vaccines (147; 75). Subsequent studies employing molecular methods, however, have demonstrated that in all of these cases in which tissue was still available for study, the causative agent was JCV, and that SV40 had been a laboratory contaminant (152).

Until 1980, progressive multifocal leukoencephalopathy remained an extraordinarily rare condition such that an individual hospital might not see a case for many years. In addition, the diagnosis might be suspected clinically but could only be confirmed by brain biopsy or autopsy. The incidence of progressive multifocal leukoencephalopathy changed dramatically as AIDS became epidemic, and progressive multifocal leukoencephalopathy became a prominent opportunistic central nervous system infection in HIV-infected patients. Antemortem diagnosis of progressive multifocal leukoencephalopathy became possible by MRI and polymerase chain (PCR) analysis of CSF. Regression of the disease was observed in some, but not all, patients treated with antiretroviral therapy. Subsequently, progressive multifocal leukoencephalopathy has been associated with monoclonal and other newer immunosuppressive agents, including natalizumab, efalizumab, rituximab, alemtuzumab, mycophenolate mofetil, etanercept, leflunomide, and brentuximab vedotin (90; 100; 165; 121; 133; 71; 144; 27; 75; 85).

To date, no successful antiviral treatment has been developed for progressive multifocal leukoencephalopathy. In recent years, however, 3 alternative approaches to therapy have been tried. The first of these, based on the recognition that JCV attachment and entry to host cells are mediated by α2,6-linked lactoseries tetrasaccharide c (LSTc) and 5-hydroxytryptamine receptors (5-HT2Rs), has led to attempts to treat progressive multifocal leukoencephalopathy using 5-HT2Rs antagonists such as mirtazapine (111); however, these have not proven definitively successful. A second and more promising approach stems from recognition that progressive multifocal leukoencephalopathy can stabilize if there is restoration of effective T lymphocyte response. This has led to efforts to treat progressive multifocal leukoencephalopathy using checkpoint inhibitors (pembrolizumab or nivolumab) or using methods, which modify host T cells (118; 42; 174; 69; 97; 96). A third, potentially promising approach has been to treat progressive multifocal leukoencephalopathy using infusions of BK virus-specific T lymphocytes (118; 43). Institution of ART or reduction in immunosuppressive regimens (eg, natalizumab) in patients with progressive multifocal leukoencephalopathy may result in a paradoxical inflammatory response (immune reconstitution inflammatory syndrome, or IRIS) which may lead to severe cerebral edema and death (11; 36; 37; 60; 75).

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