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  • Updated 12.03.2023
  • Released 03.08.1996
  • Expires For CME 12.03.2026

Progressive multifocal leukoencephalopathy



Progressive multifocal leukoencephalopathy (PML) 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. PML is characterized clinically by the development of multifocal neurologic signs referable to cerebrum, or, less frequently, cerebellum or brainstem; spinal cord involvement is rare. Pathologically, PML is characterized grossly by multifocal areas of myelin loss. Microscopically, the disease is characterized by lytic infection of oligodendrocytes, and in many cases, the presence of atypical astrocytes. The disorder has been rare outside the setting of HIV infection, but 4% of untreated AIDS patients may succumb to the disease. PML has become of increasing concern in patients receiving aggressive immunosuppression for organ or stem cell transplantation or in patients treated with newer immunomodulatory agents, in particular natalizumab. In this article, the author reviews the pathogenesis, clinical features, diagnosis, and treatment of this disorder.

Key points

• Progressive multifocal leukoencephalopathy (PML) is an opportunistic demyelinating infection of the central nervous system caused by the human polyomavirus, JC virus (JCV). The disorder almost invariably affects immunosuppressed patients, in particular, those with impaired T-cell response.

• The major risk factor for development of PML is untreated AIDS. PML may affect up to 4% of such patients.

• PML also occurs in individuals receiving newer, more aggressive immunosuppressive regimens for organ or stem cell transplantation, as well as in individuals receiving immunomodulatory agents for treatment of multiple sclerosis or other disorders. The agent most frequently associated with PML is natalizumab. Cases of PML may occur in patients receiving drugs, such as dimethyl fumarate, fingolimod, brentuximab vedotin, or other agents.

• The diagnosis of PML should be considered in immunocompromised individuals presenting with multifocal neurologic signs or evidence of multiple white matter lesions on MRI. Specific detection of JCV is typically made by polymerase chain reaction analysis of cerebrospinal fluid.

• In occasional patients, almost always in the setting of HIV, JCV may also cause infection of cerebellar granule cells or cortical or hippocampal neurons.

• There is no proven antiviral therapy for PML. In patients with AIDS-associated PML, antiretroviral therapy may allow sufficient recovery of the immune system to allow stabilization or improvement (Historical note: ART: combined antiretroviral therapy was initially termed “highly active antiretroviral therapy” or “HAART” and subsequently “combined antiretroviral therapy” or “cART”, replaced by “ART”). Remission has also been reported after withdrawal of immunosuppressive drugs and, in patients with PML in the setting of natalizumab treatment, after cessation of therapy. Plasma exchange (PLEX) or immunoadsorption therapy have been used in natalizumab-associated PML, but their efficacy is unproven.

• Stabilization or improvement in PML has been reported in limited numbers of cases following treatment with the recombinant human methionyl granulocyte colony-stimulating actor, 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). Definitive treatment for PML, however, remains unestablished.

• 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 two cases of a previously undescribed, apparently degenerative condition accompanied by central nervous system demyelination (80). Additional, similar cases were described by Winkelman and Moore, Bateman, Squires and Thannhauser, and Christensen and Fog (208; 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” (PML) and noted the close association of this condition with hematological malignancies, subsequently describing the association of the disorder with other immunocompromised states (149). 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; 149). Evidence that PML 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 (167; 218). 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 universally confirmed by other investigators.

Attempts to culture an agent from PML 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 (139). In that year, a second, closely related human polyomavirus, BK virus (BKV, BKPyV), was recovered from human urine (65). It is now known that polyomaviruses are widespread agents in both mammalian and avian species and that four different polyomaviruses have been associated with human disease (77). Of these, JCV has been associated with almost all cases of PML. PML apparently caused by BK virus has been reported in rare patients (25; 24; 47; 125; 135); and BK virus has also been associated with rare cases of encephalitis (193; 04). 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 (165; 77). 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 (172).

Until 1980, PML 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 PML changed dramatically as AIDS became epidemic, and PML became a prominent opportunistic central nervous system infection in HIV-infected patients. Antemortem diagnosis of PML became possible by MRI and polymerase chain (PCR) analysis of CSF. Development of effective ART has led to a decrease in numbers of PML cases, and regression or stabilization of PML may occur in some, but not all, patients treated with antiretroviral therapy (94). In recent years, PML has been associated with monoclonal and other newer immunosuppressive agents, including natalizumab, efalizumab, rituximab, alemtuzumab, mycophenolate mofetil, etanercept, leflunomide, and brentuximab vedotin (98; 109; 186; 131; 146; 73; 162; 27; 77; 90).

To date, no successful antiviral treatment has been developed for PML (150). In recent years, however, three 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 PML using 5-HT2Rs antagonists such as mirtazapine (121); however, these have not proven definitively successful. A second and more promising approach stems from recognition that PML can stabilize if there is restoration of effective T lymphocyte response. This has led to efforts to treat PML using checkpoint inhibitors (pembrolizumab or nivolumab) or using methods, which modify host T cells (128; 43; 195; 71; 106; 105; 41). A third, potentially promising approach has been to treat PML using infusions of BK virus-specific T lymphocytes (128; 44; 88). Institution of ART or reduction in immunosuppressive regimens (eg, natalizumab) in patients with PML 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; 62; 77).

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