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