Update on Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the central nervous system that occurs in 2-7% of individuals with AIDS. PML is caused by JC virus, a polyomavirus that belongs to the papovavirus family of viruses. A small number of cases have been caused by papovaviruses that were more similar to SV-40 virus. About 70% of HIV seronegative individuals [Taguchi F et al, Microbiol Immunol 26:1057, 1982] and nearly 65% of patients with AIDS [Gillespie S et al, Ann Neurol 30:597,1991] produce antibodies against JC virus, indicating prior infection. Among healthy individuals primary infection with JC virus causes no known disease, with the virus assuming a latent state in the kidney. However, in the setting of chronic immunosuppression the infection may become reactivated, and JC virus may subsequently reach the nervous system by transport within infected B cells [Tornatore C, et al Ann Neurol 31:454, 1992].

The clinical manifestations of PML result from involvement of the brain white matter by lesions associated with the disease. Patients may present with focal weakness, dizziness, abnormal coordination or unsteady gait, or impairment of vision, speech, or superficial sensation. In most patients the clinical course is progressive, with death frequently occurring within 3-7 months. In a very small percentage of individuals the infection may spontaneously stabilize or partially remit [Berger J, et al Neurology 38:1060, 1988], either without specific therapeutic intervention or in the setting of treatment with antiretroviral drugs. In some biopsied cases, improvement has been associated with the presence of a prominent inflammation within the lesion, suggesting the presence of an effective JC virus-directed immune response in such individuals.

Magnetic resonance imaging (MRI) of patients with PML demonstrates dense high signal areas on T2-weighted images that may appear low density on T1 sequences. In general, no enchancement of the lesion is seen on MRI following administration of gadolinium although occasionally a faint blush may be seen at the border of the lesion or at the center of large lesions, representing areas of impaired blood-brain barrier and, in the latter case, associated tissue necrosis. Brain computerized tomography (CT) is less sensitive than MRI and may show hypointense regions that correspond to the PML lesions.

Definitive diagnosis of PML rests on the demonstration of virus within the brain lesion. For this purpose tissue can be obtained by stereotactic needle biopsy, open biopsy, or post-mortem examination. Using histologic stains, JC virus infection is suggested by the presence of oligodendrocytes bearing eosinophilic inclusions representing virus structures at the periphery of demyelinated areas that contain enlarged astrocytes which may be multinucleated and tumor-like in appearance. Viral antigens can be identified in the tissue specimen by immunoperoxidase staining for a SV-40 virus-related antigen, virus isolation by tissue culture, or electronmicroscopic identification of virus particles. JC virus DNA in lesions can be demonstrated using conventional or in situ polymerase chain reaction assay (PCR) techniques. PCR can also be used to detect JC virus in CSF with high sensitivity and specificity [McGuire D, Ann Neurol 37:395, 1995].

Treatment involves optimizing antiretroviral therapy, which may lead to clinical stabilization or remission in some cases. Cytosine arabinoside (Ara-C) has not been demonstrated to be effective in treating PML, and interferon-alpha treatment may or may not be of benefit [Berger JR et al, Neurology 42(Suppl 3):257,1992; Huang S et al, 4th Conf. on Retroviruses and Opportunistic In-fections 4:127,1997]. A clinical trial is in progress using the topoisomerase inhibitor, topotecan hydrochloride, which has been demonstrated to inhibit the replication of JC virus in infected glial cells in culture [Kerr DA, et al Virology 196:612, 1993] and to suppress replication of HIV [Li C, et al PNAS, USA 90:1839, 1993]. This study is being sponsored by Smith Kline Beecham Pharmaceuticals and involves the administration of topotecan to patients with PML who do not have a history of prior treatment for the infection. Patients are currently being enrolled at the Johns Hopkins Hospital with other U.S. sites in Los Angeles, San Francisco/Berkeley, Miami, and New York and a European site in Paris, France.