Dr. Greenlee of the University of Utah School of Medicine received an honorarium from Merck for authorship and compensation as an expert witness from Wheeler Trigg O'Donnell LLP.)
Progressive multifocal leukoencephalopathy is an opportunistic demyelinating infection of the central nervous system caused by JC virus, 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 contract and 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 may be suspected in immunocompromised individuals presenting with multifocal neurologic signs and/or with 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, HAART 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. 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 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 from whom it had been recovered (Padgett et al 1971). In that year, a second human polyomavirus, BK virus, was recovered from human urine (Gardner et al 1971). 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). BK virus, although associated with rare cases of encephalitis, has never been isolated from a case of progressive multifocal leukoencephalopathy (Vallbracht et al 1993; Voltz et al 1996).
Until 1980, progressive multifocal leukoencephalopathy remained an extraordinarily rare condition; 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 PCR analysis of CSF. Regression of the disease has been observed in some, but not all, patients treated with highly active antiretroviral therapy (HAART). Nonetheless, the pathogenesis of progressive multifocal leukoencephalopathy is incompletely understood, and although the greater number of progressive multifocal leukoencephalopathy cases associated with AIDS has permitted therapeutic trials, specific antiviral therapy does not yet exist.
The past few years have brought new findings regarding this disorder. The first of these has been the association of progressive multifocal leukoencephalopathy 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; Martin et al 2006; Neff et al 2008; Rahmlow et al 2008; Graff-Radford et al 2012; Schwab et al 2012; Greenlee and Hirsch 2017). Along with this has come the realization that progressive multifocal leukoencephalopathy has become more common in transplant recipients treated with newer, more aggressive immunosuppressive strategies to prevent transplant rejection (Mateen et al 2011). The second has been the recognition that JCV attaches the 5HT2AR serotonin receptor, which has been found to be present on oligodendrocytes. This observation has led to attempts to use serotonin receptor antagonists for the treatment of progressive multifocal leukoencephalopathy (Elphick et al 2004; Focosi et al 2007; Verma et al 2007). The third has been the finding that, in rare instances, JCV is also capable of infecting cerebellar granule cells (Koralnik et al 2005; Wuthrich et al 2009; Brew et al 2010; Tan et al 2011; Henry et al 2015) as well as cortical neurons (Brew et al 2010; Wuthrich and Koralnik 2012). 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 (Travis et al 2008; Tan et al 2009; Clifford et al 2010; Sidhu and McCutchan 2010; Bauer et al 2015; Greenlee and Hirsch 2017).
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