Progressive multifocal leukoencephalopathy (PML) is a central nervous system infection of oligodendrocytes by a human papovavirus resulting in large lesions and demyelination.
The virus has been named as JC virus after John Cunningham, from whom it was first isolated.
Causes of Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy is almost exclusive in immunosuppressed persons with
- Acquired immunodeficiency syndrome [HIV 1 & 2]
- Hematological and lymphoreticular malignancies
- Autoimmune rheumatological diseases
- Organ transplantation patients
- Patients on immune therapy with monoclonal antibodies (eg, natalizumab, rituximab)
- Immunosuppressant drugs
HIV infection accounts for almost 85% of the total cases.
It is currently one of the AIDS-defining illnesses in HIV-infected patients.
Progressive multifocal leukoencephalopathy is also found during immune recovery following the initiation of highly active antiretroviral therapy.
This type is characterized by an inflammatory reaction in brain lesions and contrast enhancement on neuroimaging studies.
Typical CD4 cell count in HIV related progressive multifocal leukoencephalopathy is < 200/µL.
Pathophysiology of Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy is caused by reactivation of the endemic JC virus, a type of papovavirus.
Initially, the virus enters the body through the respiratory or oral route. The virus replicates in the body without producing any symptoms and can be detected in the urine. After initial episode, it stays latent in kidneys, lymphoreticular tissues, and brain.
In the case of immune suppression, the virus replicates and dissemination to the brain may occur via B-lymphocytes. This is when it causes progressive multifocal leukoencephalopathy.
Latent reactivation of the virus itself can also occur in the brain.
HIV gene products, such as Tat, may be able to transactivate the JC viral promoter directly and provide additional pathogenic mechanism beyond general immunosuppression.
The virus infects oligodendrocytes and causes lysis. It undergoes DNA replication and synthesis of viral capsid proteins inside the cell. The infection expands circumferentially and astrocytes that are infected by the virus enlarge and resemble the tumor cells in giant cell astrocytomas.
Its presentation is typically unifocal. Progressive multifocal leukoencephalopathy evolves over several weeks but has a rapid progression than AIDS dementia complex.
Involvement of the brainstem is more commonly seen in progressive multifocal leukoencephalopathy associated with AIDS than with other entities.
Clinical Presentation of Progressive Multifocal Leukoencephalopathy
- Insidious onset and steady progression of focal symptoms that include behavioral, speech, cognitive, motor, and visual impairment.
- As individual lesions expand, manifestations may worsen and involve a larger territory. For example, initial weakness of one leg may progress to hemiparesis.
- Seizures have been reported to occur in up to 18%
In progressive multifocal leukoencephalopathy related to immune reconstitution, onset may occur weeks to months after the initiation of antiretroviral therapy.
- Focal neurologic signs [Mostly related to occipital lobes]
- Cortical blindness
- Limb apraxia
- Brainstem symptoms
- Head tremor
- Gait abnormalities occur in up to 65% patients
- Cognitive dysfunction
- Conjugate gaze abnormalities are common
- Occasionally, neurologic signs are diffuse rather than focal.
With clinical suspicion of progressive multifocal leukoencephalopathy, neuroimaging is indicated.
CT or MRI of the brain reveals single or multiple confluent lesions without mass effects, most frequently in the parieto-occipital white matter.
Progressive multifocal leukoencephalopathy can rarely also present as a mass lesion, especially in inflammatory progressive multifocal leukoencephalopathy.
CT scan may show hypodense lesions.
On MRI, lesions are hypointense on T1-weighted images. On T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, PML lesions are hyperintense.
Cerebrospinal fluid (CSF) is usually normal, but protein levels may be elevated slightly. Normal CSF findings serve to rule out other causes.
Polymerase chain reaction of the CSF has been shown to be highly specific and sensitive for the detection of JC virus in patients with PML.
Detection of JC virus in CSF may be less likely in patients with inflammatory progressive multifocal leukoencephalopathy.
Mild cortical atrophy may be seen on biopsy. Immunohistochemistry or in situ hybridization is the best method to confirm JC virus in the biopsy specimen.
Read more about Types of Biopsies and Their Applications
Multiple demyelinative foci may be seen in the cerebral, cerebellar, and brainstem white matter and at the gray-white matter junction and in severe cases, cortical gray matter. Foci may become confluent.
Perivascular inflammatory infiltrates are observed. Necrotic and cystic lesions may be present but are rare.
Nuclear inclusions may be seen in large ballooned oligodendrocytes and rarely in astrocytes, both of which show bizarre-looking nuclei. The inclusions contain viruses as identified by electron microscopy and immunohistochemistry.
Treatment & Management
All treatments are experimental.
The principal approach is antiretroviral therapy.
The general guidelines are
- Starting antiretroviral therapy immediately in patients who are not on therapy
- Optimization of the antiretroviral regimen in patients who are on antiretroviral therapy but remain HIV-viremic because of antiretroviral resistance.
Apart from antiretroviral drugs, use of 5HT2a receptor blockers like olanzapine, ziprasidone, mirtazapine, cyproheptadine, risperidone has been suggested
Results for cidofovir, topotecan, and interferon-alfa have been inconclusive.
Further studies are underway.
Prognosis of Progressive Multifocal Leukoencephalopathy
Before highly active retroviral therapy, the prognosis in patients with progressive multifocal leukoencephalopathy was poor, with death occurring in approximately 95% of patients within 4-6 months.
With the widespread adoption of highly active antiretroviral therapy, the incidence of progressive multifocal leukoencephalopathy has decreased.
CD4+ T-cell counts less than 100/μL at baseline are associated with a higher mortality rate.
Death usually results from end-stage immune deficiency.
A recent study on patients with >5 years survival
- 33% of patients had no significant disability
- 25% had a slight disability and were living independently
- 21% were moderately disabled, requiring some help during activities of daily living
- 21% had a moderately severe disability, requiring constant help or institutionalization.