Progressive multifocal leukoencephalopathy primarily affects immunocomprised adults and is a potentially fatal demyelinating CNS disease caused by JC virus reactivation, characterised by multifocal areas of demyelination with atypical, enlarged oligodendrocytes, and multifocal non-enhancing subcortical T2/FLAIR white matter lesions.
Description
Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating disease of the central nervous system, caused by reactivation of the John Cunningham virus (JCV). This condition typically affects individuals with weakened immune systems, such as those with HIV/AIDS, or those receiving immunosuppressive therapy.
Pathogenesis
PML is caused by the reactivation of JCV, a polyomavirus that typically causes infection in childhood and remains latent in the kidneys and cerebrum. In conditions of immunosuppression or immune modulation, the virus can reactivate and cause lytic infection of oligodendrocytes, leading to progressive demyelination and neurologic damage.
Subtype
There are no established subtypes of PML.
Epidemiology, Risk Factors & Associations
- Commonly associated with immunosuppression (e.g., HIV/AIDS, immunosuppressive therapy)
- It has been reported in patients with haematologic malignancies and organ transplant recipients
- Cases have also been reported in patients treated with monoclonal antibodies such as natalizumab and rituximab
Clinical Features
- Clinical presentation is variable and relates to the location and extent of lesions
- Patients present with speech disturbance (aphasia), cortical blindness, conjugate gaze abnormalities, clumsiness and weakness (hemiparesis).
- Cognitive impairment, and changes in personality or behaviour is also seen.
Complications
- Severe neurological deficits
- Death is often inevitable, usually within 6 months to 2 years after diagnosis
Pathological Features
Histopathology
- Macroscopic: No grossly visible lesions typically seen
- Microscopic: Characterised by demyelination, large bizarre astrocytes, and enlarged oligodendroglial nuclei containing inclusion bodies.
Serology
- ELISA: IgG antibodies against JC virus (non-enveloped double-stranded DNA polyomavirus)
Immunology
- Flow cytometry is used to quantify CD4+ T cells (a type of white blood cell) which is classically low (< 200 cells/μL).
Biochemistry
- Lumbar puncture: Detection of JC virus DNA in cerebrospinal fluid via PCR
Radiological Features
General Features
- Characteristically demonstrates multifocal, asymmetric, subcortical U-fibres areas of demyelination, which typically do not enhance or mass effect
- Lesions often occur at the grey-white matter interface have a scalloped contour secondary to involvement of subcortical U-fibres.
- Parietal lobe is predominantly affected.
- Can also occur in the periventricular white matter, posterior fossa, brainstem, spinal cord and the basal ganglia.
- The findings may be accompanied by encephalopathy (AIDS dementia complex).
CT
- Non-contrast: Asymmetric, focal and usually demarcated zones of hypodensity in the subcortical and periventricular white matter, with no mass effect.
- Contrast-enhanced: Typically, lesions do not enhance
MRI
- Asymmetric, multifocal lesions predominantly involving the subcortical U-fibres and periventricular deep white matter.
- T1: Lesions are hypointense.
- T2: Lesions are hyperintense.
- FLAIR: Suppresses CSF signal to better visualise white matter lesions.
- Hyperintense lesions without significant mass effect.
- T1 C+: Lack of enhancement helps differentiate from other inflammatory or neoplastic conditions.
- Typically no enhancement in PML lesions.
- Thin-rim enhancement may be seen (uncommon).
- DWI/ADC: Thin peripheral rim of diffusion restriction consistent with demyelination
Diagnosis
Diagnosis is typically based on a combination of clinical presentation, radiological findings, and the detection of JC virus DNA in the cerebrospinal fluid via PCR.
Differential Diagnosis
- Multiple sclerosis: Presence of demyelination, but lesions are typically periventricular and show enhancement
- Acute disseminated encephalomyelitis (ADEM): Characterised by large, fluffy white matter lesions that often enhance
- HIV encephalitis: Most common neurological manifestation of HIV infection with similar clinical presentation. Characterised by bilateral atrophy (out of proportion to age) and T2/FLAIR hyperintensity in the periventricular white matter and centrum semiovale, usually symmetric, with no enhancement. There is sparing of the subcortical U-fibres.
Management
Treatment primarily involves reconstitution of the immune system, which can involve antiretroviral therapy in HIV-positive patients or withdrawal of immunosuppressive therapy. There is currently no specific antiviral therapy for JC virus.