Progressive multifocal leukoencephalopathy (PML)

This document aims to provide healthcare professionals with the information necessary to assist in the assessment and management of patients at risk of developing or suspected of having progressive multifocal leukoencephalopathy (PML).

Definition

Progressive multifocal leukoencephalopathy (PML) is a rare but potentially fatal demyelinating disease of the central nervous system (CNS) caused by reactivation of the JC polyomavirus (JCV),^r usually in immunocompromised individuals with long-lasting and profound impairment of cellular immunity.^r

Pathophysiology

In immunocompromised patients, the JCV can reactivate from latency or persistent asymptomatic infection and undergo intra-individually acquired viral genomic rearrangements leading to neuroinvasion and lytic infection of oligodendrocytes and astrocytes within the CNS.^rr This results in demyelination of multiple areas within the CNS.^r 

Incidence/prevalence

PML is most likely to occur in patients with lymphoproliferative and myeloproliferative diseases, solid organ malignancies, HIV infection, autoimmune diseases, and in patients on anti-rejection immunosuppressive drugs after organ transplantation or patients treated with immunomodulatory therapies^rr

Onset/duration

PML should be considered in the differential diagnosis in immunosuppressed patients with new onset or worsening neurological symptoms. It may be asymptomatic in the earliest stages, and its onset may be delayed for up to months in some patients.^r

Risk factors

Asymptomatic primary infection with JCV occurs in childhood, and antibodies can be found in up to 86% of adults.^r In most individuals, JCV remains latent in kidneys and lymphoid organs, but in cases of profound immunosuppression, JCV can be reactivated.^r

Anti-cancer therapies associated with development of PML

Approximately 50% of cases of PML over the last 40 years have been associated with HIV infection. The following classes of therapies have also been associated with the onset of PML.^r Note that this is not a definitive list and should be used as a guide only:

• Anti-CD20 monoclonal antibodies
• BTK inhibitors
• Anti-CD30 monoclonal antibody-drug conjugates 
• Anti-CD52 monoclonal antibodies
• Proteosome inhibitors
• Immunomodulatory drugs
• JAK inhibitors

Symptoms and signs

Symptoms may progress over weeks to months and can include:^r

• altered mental status
• motor deficits (hemiparesis or monoparesis)
• limb ataxia
• gait ataxia
• visual symptoms such as hemianopia and diplopia

Investigations and diagnosis^rr

If PML is suspected, immediate neurological referral and assessment are required, as well as a brain MRI and lumbar puncture to support the diagnosis. Confirmation of diagnosis is obtained by the detection of JCV DNA by polymerase chain reaction in the cerebrospinal fluid (CSF) or in brain biopsy tissue.

Prevention

There are no known interventions that can reliably prevent or adequately treat PML.^r Health professionals should maintain a high degree of suspicion for PML in any patient treated with therapies associated with the development of PML presenting with new-onset neurological symptoms.

Treatment

• If symptoms suggestive of PML occur, the primary approach to management of PML is to reverse immunosuppression, including cessation of any possible causative therapies immediately until a diagnosis of PML has been excluded.
• Recent case reports suggest potential benefits of agents that may restore immunocompetence (although currently, no treatment recommendations can be made), such as:^r
  • Immune checkpoint inhibitors
  • JC/BK virus-specific cytotoxic T-cells
  • Interleukins

Inform the patient and their carer:

• about the signs and symptoms of PML
• to report any issues to their treating team immediately

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