Progressive multifocal leukoencephalopathy revisited: Has the disease outgrown its name?

Abstract

Nothing is more disappointing for patients than when a promising new treatment hits a roadblock because of unexpected side effects. This is what happened when natalizumab (Tysabri) was associated with a few cases of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis and Crohn's disease patients, caused by the reactivation of the polyomavirus JC. These dramatic events drew PML squarely into the spotlight and generated considerable interest from the medical community, the pharmaceutical industry, financial markets, and regulatory agencies alike. This scrutiny, in turn, helped crystallize areas of consensus and expose gaps in our understanding of PML pathogenesis. Indeed, since its initial description, there has been a considerable evolution in both the epidemiology and clinical presentations of this disease, and new manifestations of central nervous system infection by polyomavirus JC have been characterized. To keep pace with this opportunistic pathogen, we are therefore forced to reexamine the foundations of our knowledge of virus-host interactions, reappraise our investigational approaches, and in short, rethink PML down to its very name. Hopefully, this crisis will be instrumental in helping us define novel avenues of research, develop predictive tests for PML in populations at risk, and challenge us to find a treatment for this deadly disease.

β 1 integrins differentially control extravasation of inflammatory cell subsets into the CNS during autoimmunity

“…Furthermore, they also show that an efficient and selective inhibition of T cell accumulation in the brain of MS patients is likely sufficient to retard or halt the disease course, and thus underscore the notion that autoreactive CD4 ϩ T cells within the CNS represent the trigger of the disease (1). We did not directly investigate the reason for the development of PML as a rare side effect of natalizumab treatment, but it has been shown that that the cellular immune response by CD4 ϩ and CD8 ϩ T cells is critically required to contain JC virus infection (29). Therefore, we speculate based on our results that inefficient immune surveillance of the CNS by T cells facilitates the replication of JC virus.…”

Effective use of JC virus PCR for diagnosis of progressive multifocal leukoencephalopathy

“…However, surprisingly, JCV PCR was positive in only 24 % of patients with radiology findings suggestive of PML (Table 1). This low detection rate may be due to non-specificity of radiological findings (Antinori et al, 1997) or insensitivity of PCR, or perhaps due to highly active antiretroviral therapy (HAART) re-establishing host immune function and reducing JCV below detectable levels (Koralnik, 2006). These possibilities are supported by the findings that PML is often difficult to distinguish radiographically from lesions caused by HIV encephalopathy (Olsen et al, 1988;Koralnik et al, 1999) and that the sensitivity of JCV PCR dropped from 89.5 % in the pre-HAART era (1992)(1993)(1994)(1995) to 57.5 % in the HAART era (1996)(1997)(1998)(1999)(2000)(2001)(2002) (Marzocchetti et al, 2005).…”

Interferon β1-a and selective anti-5HT2a receptor antagonists inhibit infection of human glial cells by JC virus

“…The introduction of highly active antiretroviral therapies (HAART) has increased the mean survival time of AIDS patients with PML from 2 months to one year but has had no effect at reducing the overall incidence of PML in the HIV infected population (Koralnik, 2006). Recently, PML emerged in two multiple sclerosis patients undergoing treatment with IFNβ-1a (Avonex) and Natalizumab (Tysabri) and one Crohn's disease patient undergoing treatment with Natalizumab (Tysabri) (Berger and Koralnik, 2005;Kleinschmidt-DeMasters and Tyler, 2005;Langer-Gould et al, 2005;Van Assche et al, 2005).…”