Progressive Multifocal Leukoencephalopathy (PML)
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Progressive Multifocal Leukoencephalopathy (PML) is a severe, often fatal, demyelinating disease of the central nervous system. It is caused by the reactivation of the JC Virus (John Cunningham Virus) in immunocompromised individuals. Historically associated with AIDS, it is now a critical concern in Multiple Sclerosis patients treated with Natalizumab (Tysabri).
Clinical Scenario: The Clumsy Hand
A 40-year-old man with Multiple Sclerosis (on Natalizumab for 3 years) presents with a 'useless' left hand and dragging of the left leg. He is also forgetting words. An MRI shows a new non-enhancing white matter lesion.
Key Teaching Points
- **Diagnosis**: **PML** (until proven otherwise).
- **Risk Stratification**: He is JCV Antibody positive + Long duration of treatment (>2 years).
- **Differentiation**: Unlike an MS relapse, PML lesions do not enhance (usually) and cause subacute severe decline rather than acute attack.
- **Action**: Stop Natalizumab immediately + Plasma Exchange.
Image Integration Plan
| Image Type | Source | Status |
|---|---|---|
| Management Algorithm | AI-generated | PENDING |
| MRI (T2 Hyperintensity) | Web Source | PENDING |
| MRI (U-fibre involvement) | Web Source | PENDING |
| Histology (Oligodendrocyte) | Web Source | PENDING |
[!NOTE] Image Generation Status: Diagrams illustrating the lytic infection of oligodendrocytes are queued.
MRI Findings: The "Barn Door" Sign
- Location: Parieto-occipital white matter.
- Appearance: Asymmetric, Multifocal, Confluent.
- U-Fibres: Involvement of the subcortical U-fibres gives a sharp, scalloped border at the grey-white junction (MS plaques often spare these).
- Enhancement: Typically Non-enhancing (unless IRIS occurs).
- Prevalence: Rare in general population.
- Risk Groups:
- HIV/AIDS: 1-5% of untreated patients.
- Natalizumab: Risk is ~1 in 1000 (higher if JCV+ and long treatment).
- Haematological: Lymphoma / Leukaemia.
- JC Virus: A Polyomavirus. Latent in kidneys/bone marrow of 50-80% of healthy adults.
- Reactivation: Immunosuppression allows the virus to replicate and cross the Blood-Brain Barrier.
- Lytic Infection: The virus primarily infects Oligodendrocytes (the myelin-producing cells).
- Demyelination: Lysis of oligodendrocytes leads to expanding areas of demyelination. Astrocytes become enlarged and bizarre ("bizarre astrocytes").
Image: JC Virus Lifecycle
Image: Histology - Viral Inclusions
Subacute progression (weeks to months).
- Visual Fields: Homonymous Hemianopia.
- Cognition: MMSE/MOCA decline.
- Motor: Pyramidal signs.
- MRI Brain: Essential.
- T2/FLAIR: High signal.
- T1: Low signal ("T1 holes").
- DWI: Restricted diffusion at the leading edge (active infection).
Image: MRI Brain Findings
- CSF Analysis:
- JC Virus PCR: High specificity (92-99%). Sensitivity can be lower in early disease (ultra-sensitive PCR < 50 copies/ml may be needed).
- Routine microscopy: Normal protein, normal glucose, no cells (acellular).
- HIV Test: Mandatory.
- Brain Biopsy: Only if PCR negative but clinical suspicion remains high.
Image: IRIS Mechanism
A. HIV-Associated PML
- Start HAART immediately.
- Restoring CD4 count allows the body to fight the virus.
- Survival: 50% in the HAART era.
B. Drug-Associated PML (e.g. Natalizumab)
- Stop the Drug.
- Plasma Exchange (PLEX): To rapidly remove the monoclonal antibody from circulation.
- Monitoring: Daily MRI/Clinical checks for IRIS.
C. Immune Reconstitution Inflammatory Syndrome (IRIS)
- The Paradox: As the immune system wakes up (CD4 rises), it violently attacks the widespread virus in the brain.
- Signs: Worsening neurological deficit + MRI shows Contrast Enhancement and Oedema (Mass effect).
- Treatment: Corticosteroids (Dexamethasone).
- Balance: Dampen the inflammation (to stop herniation) BUT do not suppress the immune system so much that the virus starts growing again.
- Protocol: High dose steroid taper.
D. Experimental Therapies (Rescue)
- Pembrolizumab (PD-1 Inhibitor):
- Theory: "Unmasks" the virus to the immune system (checkpoint inhibition).
- Evidence: Case series success. Used in refractory cases.
- Interleukin-7: To boost T-cell counts.
- Severe Disability: Survivors often have permanent deficits.
- Seizures.
- Death.
- HIV: 50% one-year survival.
- Natalizumab: 80% survival (if caught early and PLEX started).
- Haematological Malignancy: Very poor prognosis (<10%).
- BHIVA Guidelines: Management of Opportunistic Infection in HIV.
- AAN Guidelines: PML in Multiple Sclerosis.
What is PML? It is a rare brain infection caused by a common virus called the JC Virus. Most of us carry this virus harmlessly in our kidneys. However, if your immune system is severely weakened (by HIV or strong drugs), the virus can wake up, travel to the brain, and attack the insulation around the nerves.
What are the symptoms? It comes on over weeks. It can cause clumsiness, weakness on one side, blindness in half of your vision, or confusion. It looks a bit like a stroke, but it gets worse gradually instead of happening suddenly.
Can it be cured? We don't have a drug that kills the virus directly. The only cure is to fix your immune system so it can kill the virus. In HIV, we start strong HIV drugs. In MS, we stop the MS medication and wash it out of your blood. Sometimes, as the immune system wakes up, it gets over-excited and causes swelling in the brain (IRIS), which we have to treat with steroids.
- Berger JR, et al. PML in patients with HIV infection. J Neurovirol. 2003.
- Clifford DB, et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis. N Engl J Med. 2010.
- Cortese I, et al. Progressive Multifocal Leukoencephalopathy: Pathogenesis and Treatment. Ann Neurol. 2021.