Progressive Multifocal Leukoencephalopathy (PML)

Overview

Progressive multifocal leukoencephalopathy (PML) is an important potential consequence of immunosuppression, especially from the MS drug natalizumab.

Clinical presentation

Patients can present with a myriad of potential neurological symptoms (given the diffuse nature of the disease): including, but not limited to, ataxia, visual disturbance, encephalopathy, given its predilection for the parieto-occipital regions.

JC Virus

In PML, JC virus (John Cunningham virus, a strain of human polyoma virus) infects oligodendrocytes.
Much of the population eventually is infected with JC virus but they remain asymptomatic, if immunocompetent.

When people become immune suppressed, such as with immune-modulating agents (eg, natalizumab), the JC virus can enter the CNS and attack oligodendrocytes (hence PML is an oligodendropathy: a white matter disease at onset).

PML Histopathology

On histopathology, intranuclear inclusions are observed within the oligodendrocytes, along with enlarged astrocytes and a sparse inflammatory response.

PML Gross Pathology & Radiography

On gross pathology and radiographic imaging, the PML lesions are characteristically large, confluent, necrotic and typically localize to the brain, itself (rather than the spinal cord).
There is destruction of myelin out of proportion to the axon damage, at least initially. Eventually, however, axon degeneration ultimately occurs; as discussed previously, the myelin sheath has important metabolic effects on the maintenance and health of axons and when it is destroyed, the axons eventually fail.
There are typically large, confluent subcortical white matter PML lesion; these lesions commonly affect the cortical U-fibers.
Importantly, although the lesions are large, they lack any mass effect (helping to distinguish it from a structural lesion, such as a tumor).
As another distinguishing factor, the gray matter border is typically well-defined while its white matter border is poorly defined.

Prognosis/Treatment

The disease is rapidly fatal, if untreated (thus time is of the essence in making a diagnosis).
Plasmapharesis and immune reconstitution are the current mainstays of treatment.

Risks of PML with various MS medications

We categorize both dimethyl fumarate and fingolimod as having a low but real risk of PML.

The risk of PML with fingolimod is ~ 1/10,000 but other opportunistic infections (note that other opportunistic infections can also occur with fingolimod, including herpes zoster and cryptococcal infections).
At present time, DMF appears to confer less of a risk of PML than fingolimod but there is a concern that prolonged CD8+ T-cell suppression could lead to more PML over time.

We categorize natalizumab as having a high risk of PML: 1/90 (in anti-JC virus positive patients) and 4/1,000, overall.

Anti-JC antibody testing helps risk stratify patients for the possibility of getting PML from treatment with natalizumab.

References

See the Non-MS White Matter Disorders tutorial.