Epidemiology & Risk Factors
- Reactivation of opportunistic JC virus (polyomavirus) latent in kidneys/lymphoid tissue.
- Severe cell-mediated immunosuppression:
- HIV/AIDS with CD4 < 200/mm³ (most common cause).
- Hematologic malignancies (e.g., CLL, lymphoma) & solid organ transplants.
- Biologic/immunosuppressive therapy:
- Natalizumab (anti-α4 integrin used in MS/Crohn disease).
- Rituximab, efalizumab, dimethyl fumarate.
Clinical Features
- Subacute, rapidly progressive neuro decline without fever or signs of ↑ ICP:
- Focal neuro deficits: Hemiparesis, monoparesis, ataxia, dysarthria. c
- Visual disturbances: Homonymous hemianopsia, cortical blindness (parieto-occipital involvement).
- Cognitive changes: AMS, memory loss, dementia, personality changes.
- Course: Insidious onset, subacute progression over weeks.
Diagnosis
- Initial Test: Brain MRI with contrast
- High-yield findings: Non-enhancing, asymmetric, multiple, confluent white matter lesions (demyelination) in subcortical parieto-occipital regions. c
- No mass effect and no surrounding edema (distinguishes from lesions with mass effect).
- Confirmatory / Gold Standard: CSF PCR for JC virus DNA
- High sensitivity and specificity; avoids invasive brain biopsy.
- Biopsy: Brain biopsy (reserved for cases with negative CSF PCR but high clinical suspicion).
- Histology: Oligodendrocytes with viral intranuclear inclusions, bizarre enlarged astrocytes, demyelination.
- Key Labs: CSF routine (cell count/protein) usually normal or mild protein elevation.
Contrast Enhancement
- Pathophysiology of Contrast Enhancement
- Intact BBB: Contrast agent (Gadolinium) stays within blood vessels → No enhancement.
- Disrupted BBB: Inflammation/neovascularization increases capillary permeability → Contrast leaks into brain parenchyma → Enhancement.
- Why PML is Non-Enhancing
- Pure demyelinating disease caused by JC virus lytic infection of oligodendrocytes (not endothelial cells).
- Lack of CD4+ T-cells prevents a robust cellular immune response
- Without an active cell-mediated inflammatory cascade, vascular endothelium remains intact
Differential Diagnostics
- Cerebral Toxoplasmosis:
- Differs by ring-enhancing lesions on MRI with surrounding edema/mass effect (basal ganglia), CD4 < 100/mm³, (+) Toxoplasma IgG.
- Primary CNS Lymphoma:
- Differs by solitary (or few), periventricular, ring/homogeneous enhancing lesion with mass effect, CD4 < 50/mm³, (+) CSF EBV PCR.
- HIV Encephalopathy (AIDS Dementia Complex):
- Differs by symmetric diffuse cerebral atrophy, ventricular enlargement, subcortical dementia, lack of focal focal non-enhancing white matter lesions on MRI.
- CMV Encephalitis:
- Differs by periventricular enhancement, ventriculitis, CD4 < 50/mm³, CMV DNA in CSF.
- Multiple Sclerosis (MS):
- Differs by acute enhancement of active lesions, periventricular “Dawson fingers”, (+) CSF oligoclonal bands, relapsing-remitting pattern in immunocompetent pts.
Management
- First-line (HIV pts): Immediate initiation/optimization of cART (HAART) to restore CD4 count and immune function.
- Drug-induced PML:
- Immediately discontinue offending agent (e.g., Natalizumab).
- Consider Plasma exchange (PLEX) to rapidly clear drug from circulation.
- Antiviral therapy: No effective specific antiviral agent available for JC virus.
Complications
- Immune Reconstitution Inflammatory Syndrome (IRIS):
- Rapid clinical/radiological worsening after cART initiation due to brisk immune response to JC virus.
- MRI shows new lesion enhancement and mass effect.
- Management: High-dose Corticosteroids.
- Severe, irreversible neuro deficits (e.g., permanent paralysis, blindness).
- High mortality rate within months if underlying immunosuppression is uncorrected.