Progressive Multifocal Leukoencephalopathy (PML)

Content of This Page

 1- Introduction

2- Causes

3- Symptoms

4- Investigations & Lab Results

5- Complications

6- Treatment

Introduction

Progressive Multifocal Leukoencephalopathy (PML) is a rare, often fatal, demyelinating disease of the central nervous system caused by reactivation of the John Cunningham (JC) virus. It primarily affects immunocompromised individuals, such as those with HIV/AIDS, organ transplant recipients, or patients on immunosuppressive therapies. PML leads to widespread destruction of the white matter in the brain, resulting in progressive neurological deficits. Symptoms depend on the areas affected and can include weakness, visual disturbances, cognitive decline, and speech difficulties. There is no specific antiviral treatment, and management focuses on restoring immune function to control the infection.

 
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Causes

  • Reactivation of JC virus (John Cunningham virus):

    • A common, usually harmless polyomavirus that remains latent in most people.

  • Immunosuppression or Immunodeficiency:

    • HIV/AIDS (most common cause historically)

    • Immunosuppressive therapies (e.g., natalizumab, rituximab, fingolimod) used in multiple sclerosis, lymphoma, or autoimmune diseases

    • Organ transplantation with immunosuppressants

    • Hematologic malignancies

    • Other causes of weakened immune systems

  • Underlying diseases causing immune dysfunction:

    • Chronic lymphocytic leukemia (CLL)

    • Sarcoidosis or other systemic disorders

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Symptoms

-Neurological Symptoms (depending on the brain areas affected) :

  • Progressive weakness or hemiparesis (one-sided weakness)

  • Visual disturbances (hemianopia, cortical blindness)

  • Cognitive impairment (memory loss, confusion)

  • Speech difficulties (aphasia or dysarthria)

  • Ataxia (loss of coordination and balance)

  • Sensory deficits (numbness or tingling)

  • Personality or behavioral changes

-Clinical Course

  • Symptoms typically progress over weeks to months.

  • No fever or systemic signs of infection usually present.

Investigations & Lab Results

1. Neuroimaging

  • MRI of the brain (gold standard):

    • Multiple, asymmetric, non-enhancing white matter lesions

    • Lesions are hyperintense on T2-weighted and FLAIR images

    • No mass effect or edema usually

    • Lesions commonly affect parietal and occipital lobes but can be widespread

2. Cerebrospinal Fluid (CSF) Analysis

  • Usually normal or mildly elevated protein and lymphocytes

  • JC virus DNA PCR in CSF:

    • Highly specific and sensitive for PML diagnosis

    • Positive result confirms infection

3. Blood Tests

  • Evaluate immune status:

    • HIV test if not already known

    • CD4 count (in HIV-positive patients)

    • Other immunosuppressive workup as indicated

4. Brain Biopsy

  • Reserved for unclear cases

  • Shows demyelination, enlarged oligodendrocyte nuclei with viral inclusions, and bizarre astrocytes

Complications

  • Severe neurological disability:
    Progressive white matter damage leads to paralysis, cognitive decline, speech difficulties, and loss of coordination.

  • Persistent neurological deficits:
    Even with treatment, many patients have lasting impairments.

  • Progression to coma:
    As disease advances, brain function can deteriorate severely.

  • Death:
    PML has a high mortality rate, especially if underlying immune dysfunction is not reversed.

  • Immune Reconstitution Inflammatory Syndrome (IRIS):
    In some cases, rapid immune recovery (e.g., after starting HIV therapy) causes an exaggerated inflammatory response that can worsen symptoms temporarily.

Treatment

1. Restore Immune Function (Mainstay of Treatment)

  • In HIV/AIDS patients:

    • Start or optimize antiretroviral therapy (ART) to improve immune status and increase CD4 count.

  • In patients on immunosuppressive drugs:

    • Reduce or discontinue immunosuppressive medications if possible (e.g., stop natalizumab in MS patients).

2. Supportive Care

  • Manage neurological symptoms (e.g., physical therapy for weakness, speech therapy).

  • Prevent complications like infections or deep vein thrombosis.

3. Experimental and Adjunct Therapies

  • No FDA-approved antiviral specifically for JC virus.

  • Some trials have explored agents like mirtazapine or cidofovir, but evidence is limited.

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