Progressive multifocal leukoencephalopathy

The JC virus (JCV).

Sites of Infection:
JCV infects oligodendrocytes, the cells in the brain that produce myelin. PML is a rare neurological disease believed to be caused by reactivation of latent JCV infection, resulting in demyefination of the central nervous system. Initial brain lesions occur around blood vessels, suggesting dissemination via the blood. PML occurs at a much higher frequency in people with AIDS than it does in patients with other immunosuppressive disorders, developing in 3 to 4% of AIDS patients. Approximately 70% of adults in the U.S. have antibodies to JCV. PML does not appear to be contagious, and the primary infection probably occurs in childhood. SYMPTOMS:

Mental status changes followed by speech or language deficits, visual deficits, and generalized or focal weakness. Neurologic signs include lack of coordination (weakness of one limb or one side of the body), cranial nerve palsies, loss of vision on one side, sensory loss in one limb or one side of the body, language disturbance, and unsteadiness.

JCV has been isolated from the brain and urine. Definitive diagnosis of PML requires brain biopsy although sensitivity ranges from 40% to 96%. Clinically, diagnosis is made by detecting focal lesions and abnormalities of the white matter on neuroimaging studies (CT or MRI). Recently, polymerase chain reaction (PCR) of DNA of JCV from cerebrospinal fluid (CSF) has been used in diagnosis.

Treatment Results:
No effective treatment for PML has been identified. The disorder is usually rapidly progressive and fatal, although rare prolonged survival and occasional remissions have been documented.

Britton et al. treated 13 PML patients (mean CD4 count 106) with intrathecal cytosine arabinoside (ara-C, cytarabine). 8/13 subjects stabilized and improved after treatment. Other investigators (de Truchis et al., Nicoli et al., Urtizberea et al., Fong et al., and Antinori et al.) have reported that ara-C offered no prolonged clinical improvement to patients with PML. A trial of IV versus intrathecal ara-C is currently underway by the AIDS Clinical Trials Group (ACTG).

It has been reported by Allegre et al. that no improvement was observed when intrathecal AZT was given for 3 months to 2 PML patients.

Topotecan, a topoisomerase 1 inhibitor, has been shown in vitro to be active against the JC virus. Trials of topotecan for PML are in development.

Allegre T et al. Intrathecal zidovudine (IT-AZT) treatment of patients with HIV associated progressive multifocal leukoencephalopathy (PML). Abstract PO-B16-1727, IX Intl Conf AIDS, Berlin, 1993.

Antinori et al. Failure of cytarabine and increased JC virus-DNA in the cerebrospinal fluid of patients with AIDS-related progressive multifocal leukoencephalopathy. AIDS 8: 1022-1024, 1994.

Britton CB et al. Progressive multifocal leukoencephalopathy: disease progression, stabilization and response to intrathecal ARA-C in 26 patients. Abstract ThB 3886, VIII Intl Conf AIDS, Amsterdam, 1992.

DeTruchis P et al. Inefficiency of cytarabine in progressive multifocal leukoencephalopathy in AIDS. Lancet 342:622,1993.

Fong IW et al. The natural history of progressive multifocal leukoencephalopathy (PML). Abstract PO-B01 -0864, IX Intl Conf AIDS, Berlin, 1993.

Nicoli F. et al. Efficacy of cytarabine in progressive multifocal leukoencephalopathy in AIDS. Lancet 339: 306, 1992.

Urtizebera JA et al. Cytarabine for progressive multifocal leukoencephalopathy (PML) in AIDS patients. Abstract PO-B16-1717, IX Intl Conf AIDS, Berlin, 1993.

Berger J et al. Progressive multifocal leukoencephalc)pathy in IRV-1-inf@ted child=. ALDS 6: 837-941, 1992,

Guadno M et al. Progressive multifocal leukoencephalopathy in AIDS: treatment with cytosine arobinoside. AIDS 9: 815-816, 1995.