Dr. Greenlee of the University of Utah School of Medicine has no relevant financial relationships to disclose.)
Progressive multifocal leukoencephalopathy is an opportunistic demyelinating infection of the central nervous system caused by JC virus (JCV, JCPyV), a human polyomavirus. It is characterized pathologically by multifocal areas of myelin loss and microscopically by lytic infection of oligodendrocytes. The disorder is rare outside the setting of HIV infection, but 4% of untreated AIDS patients may succumb to the disease. The condition has also 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. In this article, the author reviews the pathogenesis, clinical features, diagnosis, and treatment of this disorder.
• 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.
• 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 indicate that progressive multifocal leukoencephalopathy may be arrested through use of immune checkpoint inhibitors 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 (Hallervorden 1930). Additional, similar cases were described by Winkelman and Moore, Bateman, Squires and Thannhauser, and Christensen and Fog (Winkelman and Moore 1941; Bateman et al 1945; Christensen and Fog 1955). 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 (Astrom et al 1958). 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 (Richardson 1961). The presence of inclusions within oligodendrocytes led first Cavanagh and then Richardson to suggest that the disease might represent an unusual sort of infection (Cavanagh et al 1959; Richardson 1961). 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 (Silverman and Rubinstein 1965; Zu Rhein and Chou 1965). 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 the virus 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 (Padgett et al 1971). In that year, a second human polyomavirus, BK virus (BKV, BKPyV), was recovered from human urine (Gardner et al 1971). 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 (Greenlee and Hirsch 2017). Of these, only JC virus has been consistently associated with progressive multifocal leukoencephalopathy. BK virus has been associated with rare cases of encephalitis (Voltz et al 1996; Antoniolli et al 2017) and in 2 cases BK virus has been reported to be associated with progressive multifocal leukoencephalopathy lesions (Brew et al 2013; Daveson et al 2013; Melis et al 2018). 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 (Shah and Nathanson 1976; Greenlee and Hirsch 2017). 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 (Stoner and Ryschkewitch 1998).
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 (Kleinschmidt-DeMasters and Tyler 2005; Langer-Gould 2005; Van Assche et al 2005; Neff et al 2008; Rahmlow et al 2008; Graff-Radford et al 2012; Schwab et al 2012; Carson et al 2014; Greenlee and Hirsch 2017; Iacobaeus et al 2018).
To date, no successful antiviral treatment has been developed for progressive multifocal leukoencephalopathy. A second approach, 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 treat progressive multifocal leukoencephalopathy using 5-HT2Rs antagonists such as mirtazapine (Mayberry et al 2017); however, these have not proven definitively successful. The third and most promising approach stems from recognition that progressive multifocal leukoencephalopathy can stabilize if there is restoration of effective T lymphocyte response. This has led to promising treatment using checkpoint inhibitors or modification of host T cells (Muftuoglu et al 2018; Cortese et al 2019; Walter et al 2019). Increasingly, it has been recognized that institution of HAART 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 (Bauer et al 2015; Clifford 2015a; Clifford 2015b; Fournier et al 2017; Greenlee and Hirsch 2017).
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