Progressive Multifocal Leukoencephalopathy: What’s New?

Abstract

Progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease that is caused by human JC polyomavirus, was first described as a complication of immune suppression 50 years ago and emerged as a major complication of HIV infection in the 1980s. The prognosis has remained dismal since then, with discouraging results from clinical trials of various therapeutic approaches, including immunomodulation and/or inhibition of viral replication. PML is caused by reactivation of latent JC virus, and serotonergic 5-HT(2a) receptors have been identified as being critical for viral infection of glial cells. In recent years, immunosuppressive therapeutic antibodies have been associated with an increased incidence rate of PML. Here, the authors review findings on the pathogenesis of PML and the encouraging case reports of novel treatments.

Progressive Multifocal Leukoencephalopathy in an HIV Patient

“…Cidofovir is a deoxycytidine monophosphate analogue that inhibits viral DNA synthesis by interfering with viral DNA polymerase. There have been some positive reports concerning the use of cidofovir in HIV patients with PML in the past [1]. However, a recent paper concludes that cidofovir does not influence mortality or morbidity related to PML in HIV infected patients [17].…”

“…A polyomavirus was identified as the etiological agent in 1967, named in 1971 as JC Virus (JCV), after the initials of the patient where the virus was first isolated (John Cunningham) [1,2]. It occurs in immunocompromised patients, nowadays mainly in HIV infected ones.…”

“…It occurs in immunocompromised patients, nowadays mainly in HIV infected ones. HIV infection accounts for 85% of all cases of PML, with a prevalence estimated of 4-5% in this population [1,3]. The probability of an HIV patient developing neurological symptoms and PML lesions is higher amongst the ones with a lower immunological status, expressed by a CD4 T cell count lower than 200/mm 3 [4,5].…”

Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children

“…30 With the advent of multiple modalities to support PML diagnosis, diagnostic criteria can be stratified according to the following terminology and levels of certainty of diagnosis:

Biopsy-confirmed PML: JCV antigens detected by immunohistochemistry, JCV DNA detected by in situ nucleic acid hybridization, or JC virions detected by electron microscopy in brain tissue obtained by cerebral biopsy, associated with typical histology, in patients with typical clinical and radiological findings

Laboratory-confirmed PML: JCV DNA detected by PCR of CSF in patients with typical, clinical, and radiological findings (detection of intrathecal antibody production may also support the diagnosis)

Possible PML: Patients with typical clinical and radiological findings, without virologic or histologic confirmation in brain tissue or CSF. 31,32

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Infection with polyomavirus JC

“…1 It was first described as a complication of immune suppression 50 years ago and emerged as a major complication of HIV infection in the 1980s. 6 PML has recently become topical because it is a side effect of some newly developed immunomodulatory drugs for autoimmune diseases, including natalizumab for multiple sclerosis and Crohn's disease, rituximab for systemic lupus erythematosus, and efalizumab for psoriasis. 1 4 6 PML has had a dramatic effect on the use of these drugs-efalizumab was withdrawn from the market in April 2009 and natalizumab was transiently withdrawn in February 2005 after three confirmed cases of PML.…”