Progressive Multifocal Leukoencephalopathy (PML)

A rare demyelinating CNS disorder

Caused by the reactivation of two polyoma viruses, the JC virus (John Cunningham virus or JCV) and, less commonly, the BK virus (associated with nephropathy)

JCV

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• Efalizumab (withdrawn from the US market in April 2009)

• Azathioprine with corticosteroids

• Mycophenolate mofetil

Smoking is reportedly associated with an increased risk of PML

Altered mental status

Aphasia

Ataxia

Hemiparesis

Hemiplegia and visual field disturbances

Seizures

Involvement of cranial nerves and cervical spine (rare)

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 patients living with HIV

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 patients living with HIV, a syndrome of cerebellar degeneration is described

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

• In patients living with HIV, 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

Pembrolizumab, a down-regulator of PD-1

• Entails inhibition of the programmed cell death protein (PD-1), a negative regulator of immune clearance

• Reduces JC viral load

• Increases CD4+ and CD8+ activity against the virus in a preliminary set of eight patients with PML with different predisposing conditions

In addition, allogeneic BK virus–specific T cells are useful in lowering JC viral load