JC virus persistence following progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab

Abstract

JC virus DNA in the cerebrospinal fluid provides the laboratory confirmatory diagnosis of progressive multifocal leukoencephalopathy in patients whose clinical symptoms and MRI findings are consistent with PML. The LMMN, NIH made the confirmatory laboratory diagnosis in 35 MS patients treated with natalizumab. Thirteen patients had 3 or more CSF samples taken from weeks to months following PML diagnosis. Seven of the 13 patients demonstrated persistence of JCV DNA in the CSF even though all patients experienced IRIS, immune reconstitution inflammatory syndrome and 11 patients had plasma exchange and 2 had immunoabsorption. Specific anti-JCV antibody was measured in plasma/sera samples from 25 of the 35 patients. Most of the samples showed moderate to high or rising antibody levels from the time of PML diagnosis. However, plasma from 1 patient at or near the time of PML diagnosis had a titer considered seronegative and 2 other plasma samples from patients had titers considered at baseline for seropositivity. In several PML cases, viral persistence and neurological deficits have continued for several years indicating that once initiated, JCV infection may not entirely clear even with IRIS.

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

“…In patients with untreated HIV infection, the viral copy numbers are usually quite high and easily detectable, but in patients with multiple sclerosis where the immune system is relatively intact, the copy numbers of the virus can be quite low and more difficult to detect (430). In the era of HAART, HIV patients with PML and low or undetectable JCV copy number have been described with increased frequency (319,320), and HAART treatment is correlated with a reduction in the viral load of JCV in the CSF (108,166).…”

“…Other changes in the CSF are nonspecific, with a mild increase in protein but a normal cell count and glucose. Interestingly, despite immune reconstitution, some patients may not clear the virus completely, and it may persist in the CSF (430). While the significance of this persistent virus is not clear, it indicates that JCV can remain in the brain for long periods despite reconstitution of the immune system or frank IRIS.…”

Immunogenicity and other problems associated with the use of biopharmaceuticals

“…The detection of some 85 cases of PML in patients with RRMS treated with natalizumab as of January 2011 [Gryta, 2011], equivalent to an incidence of approximately 1 case per 1000, necessitates particular vigilance especially in patients treated for 2 years or more [Ryschkewitsch et al 2010]. Furthermore, the observation that JC virus DNA can persist in the cerebrospinal fluid (CSF) for years, even in the presence of high levels of anti-JC virus antibody, may warrant periodic testing for the presence of viral DNA in the CSF as well as in serum [Ryschkewitsch et al 2010].…”

“…Furthermore, the observation that JC virus DNA can persist in the cerebrospinal fluid (CSF) for years, even in the presence of high levels of anti-JC virus antibody, may warrant periodic testing for the presence of viral DNA in the CSF as well as in serum [Ryschkewitsch et al 2010]. Three cases of PML were also reported in patients with psoriasis treated with the monoclonal antibody, efalizumab [Lysandropoulos and Du Pasquier, 2010], which targets the integrin, LFA-1 (CD11a).…”

Immunology of progressive multifocal leukoencephalopathy

“…The occurrence of IRIS in the CNS can be dangerous since it may cause additional damage in the brain and even lead to death of the patient by tissue swelling if not at least temporarily attenuated by immunosuppression (Tan et al, 2009). However, a substantial proportion (20-47%) of natalizumabassociated PML patients do not clear JCV DNA from cerebrospinal fluid (CSF) despite IRIS (Dahlhaus et al, 2013;Ryschkewitsch et al, 2010). The significance of JCV persistence in the CSF despite clinically stably disease course after IRIS is unclear.…”