Progressive multifocal leukoencephalpathy (PML) is a severe, often fatal, opportunistic infection of the CNS. First reported in 1958 as a white matter disorder in 3 patients with lymphoproliferative disorders, subsequent studies revealed a polyomavirus, named John Cunningham (JC) virus from the initials of the patient from whose brain it was initially isolated, as the causative agent.
The pathogen is a ubiquitous DNA virus that infects only humans. Subclinical infection often takes place within the first decade of life.
PML became strikingly prevalent, observed in 4%–5% of all patients with HIV prior to the availability of highly active anti-retroviral therapy (HAART).
The era of monoclonal antibodies for immune-mediated conditions such as natalizumab (Tysabri) for MS and Crohns disease and efalizumab (Raptiva) for psoriasis heralded another context for PML.
As of November 30, 2016, there have been 698 reported cases of PML under natalizumab.
While HAART has a significant beneficial impact on the prognosis of PML in patients with HIV, it remains one of the 4 most common CNS opportunistic infections affecting patients with AIDS.
The institution of screening patients with MS for seropositivity for JC virus has decreased the prevalence of PML in natalizumab-treated patients with MS. The termination of this therapy and using plasma exchange to remove the monoclonal antibody from the circulation when PML is diagnosed has a beneficial effect on prognosis.
However, the introduction of HAART and the discontinuation of natalizumab led to the recognition of the immune reconstitution inflammatory syndrome (IRIS), an entity that is not unique to PML and has been observed also with mycobacterial diseases, leprosy, fungal infections, and herpes viruses.
IRIS is the consequence of rapid entry of immune cells into the brain at the time of immune restoration. IRIS has occurred in the majority of patients with natalizumab-associated PML following withdrawal of natalizumab and plasma exchange. The diagnosis of CNS-IRIS in patients with MS with natalizumab-associated PML can be challenging because the deterioration might be attributed to PML, MS, or some other opportunistic infection.
Thus, diagnosis of PML in an immune-compromised patient is associated with a 2-edge challenge and risk: clearing the JC virus from the brain, which requires normalisation of the immune state, and reconstitution of immune surveillance while minimising infiltration of the brain with activated T cells that attempt to control an underlying CNS opportunistic infection.