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the major part of a cerebral or cerebellar hemisphere (Fig 33-4) The abnormalities of the glial cells are distinctive Many of the reactive astrocytes in the lesions are gigantic and contain deformed and bizarre-shaped nuclei and mitotic gures, changes that are seen otherwise only in malignant glial tumors Also, at the periphery of the lesions, the nuclei of oligodendrocytes are greatly enlarged and contain abnormal inclusions Many of these cells are destroyed, accounting for the demyelination Vascular changes are lacking, and in ammatory changes are present but usually insigni cant Clinical Features An uncommon disease of late adult life, PML usually develops in a patient with a neoplasm or chronic immunode ciency state The large majority of cases are now observed in patients with AIDS in whom the incidence of PML approaches 5 percent Viewed from another perspective, over three-quarters of cases of PML in the current era are associated with AIDS Indeed, the incidence is so much higher than in any other form of immunosuppression that an interaction between HIV and the causative virus of PML has been suggested Other important associations are with chronic neoplastic disease (mainly chronic lymphocytic leukemia, Hodgkin disease, lymphosarcoma, myeloproliferative disease) and, less often, with nonneoplastic granulomatosis, such as tuberculosis or sarcoidosis A number of cases occur in patients receiving immunosuppressive drugs for renal transplantation or for other reasons Personality changes and intellectual impairment may introduce the neurologic syndrome which evolves over a period of several days to weeks Any one or some combination of hemiparesis progressing to quadriparesis, visual eld defects, cortical blindness, aphasia, ataxia, dysarthria, dementia, confusional states, and coma are the typical manifestations (see Gillespie et al) Some of the cases under our observation had a predominantly cerebellar syndrome Seizures are infrequent, occurring in 11 percent of cases

03-20-2005

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collected by Gillespie and colleagues In most cases death occurs in 3 to 6 months from the onset of neurologic symptoms and even more rapidly in patients with AIDS unless aggressive antiretroviral treatment is undertaken The CSF is usually normal CT and MRI localize the lesions with striking clarity (Fig 33-4) Pathogenesis Waksman s original suggestion (quoted by Richardson) that PML could be due to viral infection of the CNS in patients with impaired immunologic responses proved to be correct ZuRhein and Chou, in an electron microscopic study of cerebral lesions from a patient with PML, demonstrated crystalline arrays of particles resembling papovaviruses in the inclusion-bearing oligodendrocytes Since then, a human polyomavirus, designated JC virus or JCV (initials of the patient from whom the virus was originally isolated), has de nitively been shown to be the causative agent JCV is ubiquitous, as judged by the presence of antibodies to the virus in approximately 70 percent of the normal adult population It is thought to be dormant until an immunosuppressed state permits its active replication The virus has been isolated from the urine, blood lymphocytes, and kidney, but there is no clinical evidence of damage to extraneural structures Treatment The disease is generally believed to be untreatable in the non-AIDS patient Several anecdotal reports of the ef cacy of cytosine arabinoside have appeared, but a controlled trial has failed to demonstrate an increased survival in AIDS patients with this disease Interferon alpha has been thought to be bene cial in a few cases and the antiviral agent cidofovir is being tested in a large trial based on anectodal bene t In treated AIDS patients, aggressive treatment using antiretroviral drug combinations, including protease inhibitors, greatly slows the progression of PML and has even led to apparent remission A review of these issues, particularly relating to AIDS and PML, is included in the report by Mangi and Miller.

Figure 33-4 Progressive multifocal leukoencephalitis MRI in the axial plane demonstrates multiple nonenhancing white matter lesions in a 31-year-old male with AIDS

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03-25-2005