Abstract
Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection associated with the reactivation of the JC virus, causing a severe demyelination within the central nervous system in patients with immunosuppression caused by disease or secondary to use of drugs. Several therapies used in the treatment of MS have reported cases of associated PML, most cases being related to Natalizumab treatment. In this article we review specific MS medication with a reported risk for PML, and also revise PML epidemiology, pathogenesis, treatment and available approaches on therapy in patients at high risk for developing this infection.
Highlights
Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection associated with the reactivation of the John Cunningham Virus (JCV), causing a severe demyelination within the central nervous system. [1].The JC is a ubiquitous non-enveloped double-stranded DNA-virus of the Polyomaviridae genus, 50-86% of general population having positive antibodies. [1,4,16,37]The infection was initially described in 3 patients with lymphoproliferative disorders in the 1960s, afterwards reported in patients with severe immunosuppression caused by malignancies, granulomatous inflammatory diseases, solid organ transplant recipients or secondary to the use of certain immunosuppressing drugs
In contrast to the classic PML, the form associated to Natalizumab treatment and highly aggressive antiretroviral therapy (HAART) has an important inflammatory component described as the immune reconstitution inflammatory syndrome (IRIS) demonstrated by contrast enhancement of PML lesions on brain MRI; even if this form is considered to have a better prognosis, high mortality is still a concern with a reported rate of 23% among these patients. [4,9,10,37]
After reviewing the available literature we focus on multiple sclerosis disease modifying therapies with reported cases of PML, PML pathology, diagnosis and available treatment
Summary
PML is an opportunistic infection associated with the reactivation of the John Cunningham Virus (JCV), causing a severe demyelination within the central nervous system. [1].The JC is a ubiquitous non-enveloped double-stranded DNA-virus of the Polyomaviridae genus, 50-86% of general population having positive antibodies. [1,4,16,37]. Interest in JC infections and especially PML has increased considerably since 2005, when first cases were described in patients with Crohn and multiple sclerosis treated with Natalizumab. In contrast to the classic PML, the form associated to Natalizumab treatment and HAART has an important inflammatory component described as the immune reconstitution inflammatory syndrome (IRIS) demonstrated by contrast enhancement of PML lesions on brain MRI; even if this form is considered to have a better prognosis, high mortality is still a concern with a reported rate of 23% among these patients. New treatments for multiple sclerosis were introduced, with good control on disease clinical and imagistic activity, but emerging evidence report cases of PML associated with these drugs. After reviewing the available literature we focus on multiple sclerosis disease modifying therapies with reported cases of PML, PML pathology, diagnosis and available treatment. Rotropic strain, providing the way for the virus to enter the brain, a theory supported by the high prevalence of PML in B-cell disorders and by Natalizumab’s mechanism of action. [1,4,11,16]
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