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Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system (CNS) caused by reactivation of the John Cunningham virus (JC virus) in immunocompromised individuals, leading to multifocal, asymmetric white matter destruction.

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https://www.youtube.com/watch?v=001xTEa10Ak

Scientific history:

![Timeline of PML disease eras: From an epidemiological perspective, three distinct eras of progressive multifocal leukoencephalopathy (PML) have been identified. In the early years, following its first description, PML was rare and almost uniformly fatal, seen most commonly in patients with haematological malignancy. During the AIDS pandemic, the incidence of PML increased dramatically — up to 5% of patients with AIDS developed the disease. With the introduction of combined antiretroviral therapies (cART) in 1996, this proportion declined substantially, and immune reconstitution was established as a way to prevent PML and to increase the chance of survival. Although the majority of PML cases worldwide are still associated with AIDS, iatrogenic PML is linked to a growing number of therapies that target immune function. Most notable of these are natalizumab for the treatment of relapsing–remitting multiple sclerosis (MS), rituximab for the treatment of haematological cancers and rheumatological disorders, and efalizumab for the treatment of psoriasis (efalizumab was withdrawn from the market in 2009 after reports of association with PML). JCV, JC virus; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.

Cortese, I., Reich, D.S. & Nath, A. Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease. Nat Rev Neurol 17, 37–51 (2021). https://doi.org/10.1038/s41582-020-00427-y](attachment:de4a7d40-9cda-4a04-be8d-be9cfa472e9d:image.png)

Timeline of PML disease eras: From an epidemiological perspective, three distinct eras of progressive multifocal leukoencephalopathy (PML) have been identified. In the early years, following its first description, PML was rare and almost uniformly fatal, seen most commonly in patients with haematological malignancy. During the AIDS pandemic, the incidence of PML increased dramatically — up to 5% of patients with AIDS developed the disease. With the introduction of combined antiretroviral therapies (cART) in 1996, this proportion declined substantially, and immune reconstitution was established as a way to prevent PML and to increase the chance of survival. Although the majority of PML cases worldwide are still associated with AIDS, iatrogenic PML is linked to a growing number of therapies that target immune function. Most notable of these are natalizumab for the treatment of relapsing–remitting multiple sclerosis (MS), rituximab for the treatment of haematological cancers and rheumatological disorders, and efalizumab for the treatment of psoriasis (efalizumab was withdrawn from the market in 2009 after reports of association with PML). JCV, JC virus; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.

Cortese, I., Reich, D.S. & Nath, A. Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease. Nat Rev Neurol 17, 37–51 (2021). https://doi.org/10.1038/s41582-020-00427-y

Etipathology

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~80% of adults have latent JC virus; PML occurs only in immunosuppression.

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Pathophysiology

• Reactivated JC virus infects and destroys oligodendrocytes

• Leads to multifocal demyelination of CNS white matter without inflammation (initially)

• Involves subcortical white matter, progressing rapidly

  ![Proposed disease course of PML: Initial JCV infection is thought to occur in tonsillar tissue after inhalation. Lymphocytes infected with JCV carry virions to the kidney and bone marrow, which are thought to be the primary sites of viral latency. Following reactivation of JCV, the virus is thought to cross the blood–brain barrier within B cells and infect oligodendroglia. The change in JCV color from red to green indicates genetic rearrangement. Abbreviations: JCV, JC virus; PML, progressive multifocal leukoencephalopathy.

  Brew, B., Davies, N., Cinque, P. et al. Progressive multifocal leukoencephalopathy and other forms of JC virus disease. Nat Rev Neurol 6, 667–679 (2010). https://doi.org/10.1038/nrneurol.2010.164](attachment:94608e6d-64db-4ad9-a153-dd4223d84c63:image.png)

  Proposed disease course of PML: Initial JCV infection is thought to occur in tonsillar tissue after inhalation. Lymphocytes infected with JCV carry virions to the kidney and bone marrow, which are thought to be the primary sites of viral latency. Following reactivation of JCV, the virus is thought to cross the blood–brain barrier within B cells and infect oligodendroglia. The change in JCV color from red to green indicates genetic rearrangement. Abbreviations: JCV, JC virus; PML, progressive multifocal leukoencephalopathy.

  Brew, B., Davies, N., Cinque, P. et al. Progressive multifocal leukoencephalopathy and other forms of JC virus disease. Nat Rev Neurol 6, 667–679 (2010). https://doi.org/10.1038/nrneurol.2010.164

Clinical Features

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PML has an insidious onset and steady subacute progression and manifests as focal neurological deficits. Since demyelinating lesions can involve any region in the brain, neurological disabilities vary from patient to patient.

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Special Consideration

Immune reconstitution inflammatory syndrome (IRIS): PML-IRIS

• Occurs after immune recovery (e.g., HAART initiation or stopping natalizumab)