Progressive Multifocal Leukoencephalopathy (PML)

Key Features

• A rare demyelinating CNS disorder

• Caused by the reactivation of the JC virus (John Cunningham virus or JCV)

  • Virus remains latent in the kidneys, lymphoid tissues, epithelial cells, peripheral blood leukocytes, bone marrow, and possibly brain until reactivation occurs and symptoms become evident

  • Reactivation is usually seen in adults with

    • Impaired cell-mediated immunity, especially AIDS patients

    • Idiopathic CD4 lymphopenia syndrome

  • Virus reactivation is also reported among patients who have

    • Lymphoproliferative and myeloproliferative disorders

    • Granulomatous, inflammatory, and rheumatic diseases (systemic lupus erythematosus and rheumatoid arthritis in particular)

    • Undergone solid and hematopoietic cell transplantation

    • Other medical states, including cirrhosis and kidney disease (occasionally)

• Medication-associated PML is described with the use of

  • Natalizumab

  • Rituximab

  • Infliximab

  • Efalizumab (withdrawn from the US market in April 2009)

  • Alemtuzumab

  • Azathioprine with corticosteroids

  • Cyclophosphamide

  • Mycophenolate mofetil

Clinical Findings

• Altered mental status

• Aphasia

• Ataxia

• Hemiparesis

• Hemiplegia and visual field disturbances

• Seizures

• Involvement of cranial nerves and cervical spine (rare)

Diagnosis

• Polymerase chain reaction (PCR) for JCV in cerebrospinal fluid; a quantitative PCR is more sensitive

• Persistent JC viremia and increasing urinary JCV DNA may be predictive of PML

• An anti-JCV immunoglobuin G (IgG) was higher 6 months before diagnosis but was not predictive of PML in a cohort of HIV-infected patients

• MRIs of the brain show multifocal areas of white matter demyelination without mass effect or contrast enhancement; these findings may not be distinguishable from immune reconstitution inflammatory syndrome (IRIS)

• Increased uptake of methionine with concomitant decreased uptake of fluorodeoxyglucose in positron emission tomography may be helpful for diagnosis

• In the HIV-infected a syndrome of cerebellar degeneration is described

Treatment

• Limiting the immunosuppression state without inducing IRIS represents the mainstay of therapy

  • In HIV-infected patients, antiretroviral therapy

  • Reduces the incidence of PML

    • Improves the clinical symptoms

    • Reverses some of the radiographic abnormalities

    • Improves the 1-year mortality rate, regardless of baseline CD4 count

  • In non-AIDS patients (eg, multiple sclerosis or transplant patients)

    • Cidofovir may be beneficial

    • Corticosteroids may be useful with immune reconstitution

    • Because the JCV infects cells through serotonin receptors, risperidone and mirtazapine are recommended by some clinicians

• In natalizumab-associated PML, plasma exchange is used by some experts