Progressive multifocal leukoencephalopathy (PML) is an uncommon and often fatal subacute demyelinating disease of the white matter, caused by reactivation of the JC virus (JCV) infection, which has tropism for oligodendrocytes, in an immunocompromised individual. PML originally was described half a century ago by Astrom et al in patients with chronic lymphoid leukemia and Hodgkin lymphoma. JCV was isolated in 1971 and is named for the initials of the first patient from whose brain it was isolated.
- Seroepidemiologic studies have shown that asymptomatic primary infection with JCV occurs at an early age, and by adult life 30% to 90% of the population is seropositive. It becomes dormant in tissues such as kidney, bone marrow, tonsils, and lymphoreticular tissue.
- The PML era can be broadly divided into four epochs: Pre-HIV, HIV (pre-ART), HIV (post-ART), and modern era.
- Prior to the HIV epidemic in the early 1980s, PML was rare and seen almost exclusively in patients with lymphoproliferative and myeloproliferative disorders.
- HIV: A fiftyfold increase in PML cases was reported with HIV epidemic. During the HIV precombined antiretroviral therapy (cART) era, 3% to 5% of patients with HIV developed PML. PML is an AIDS-defining illness. cART has led to some decline in PML cases.
- Modern era: HIV still accounts for a large percentage of PML incidence but needs to be considered in anyone whose cellular immunity is compromised with an underlying disorder or secondary to iatrogenic immunosuppression or immunomodulation. Bone marrow transplant, lupus, rheumatoid arthritis, multiple sclerosis, as well as solid or hematologic malignancies are all at risk.
- Natalizumab is the medication associated with the highest incidence of PML and is dependent on JCV antibody status, history of prior immunosuppression, and length of treatment.
Typically seen in patients with profound immunosuppression and impaired cell-mediated immunity. These include patients with AIDS, lymphoproliferative disorders, chronic infections such as tuberculosis, and, more recently, patients on immunosuppressive or immunomodulating medications such as corticosteroids, natalizumab, rituximab, ocrelizumab, alemtuzumab, efalizumab, brentuximab vedotin, cyclophosphamide, mycophenolate mofetil, anti-TNF-alpha agents, and oral agents used in the treatment of multiple sclerosis (dimethyl fumarate and fingolimod). In rare instances, it may be seen in the absence of apparent immunologic abnormality.
- Subacute neurologic deficits are common; can also present acutely as a stroke mimic.
- The clinical course spans weeks to months leading to severe disability and death.
- PML lesions usually involve cerebral hemispheres; cerebellar and brain stem involvement may be seen in AIDS. Multifocal asymmetric white matter involvement is common; rarely there can be gray matter involvement. Usually the optic nerve and spinal cord are not involved.
- Non-AIDS-associated PML: Early lesions involve occipital subcortical white matter and cause visual-field deficits (homonymous hemianopia) or cortical blindness. Motor weakness and altered mentation may be seen, while headache, seizures, and extrapyramidal syndromes are rare.
- AIDS-related PML: Motor weakness is more common. Abnormalities of speech, cognition, gait, sensation, and visual impairment are also seen.
- Natalizumab-associated PML: Frontal lobe is commonly involved, leading to cognitive impairment, neurobehavioral changes, motor disorders, language disorders, and visual defects.
- Immune reconstitution inflammatory syndrome (IRIS): A paradoxical clinical deterioration that occurs during immunologic recovery in previously immunocompromised patients, such as antiretroviral therapy-treated HIV-seropositive patients or cessation of immunomodulating treatment, such as natalizumab. An increase in the number or size of lesions on neuroimaging with contrast enhancement of brain lesions and brain edema may be seen.
- JCV infection may be acquired through respiratory tissue or oropharyngeal route; seroconversion usually occurs in childhood.
- A cytotoxic-specific response against JCV acts as a containing mechanism for PML. Immunosuppression leads to development of PML either as primary infection of the CNS following immunosuppression or reactivation of a dormant infection. The virus produces lytic infection of the oligodendrocytes and causes oligodendrocyte death and demyelination. Neuronal infection does not usually occur except in granule cell neurons of the cerebellum. Infection of the astrocytes is abortive, leading to characteristic bizarre, enlarged cells.
