Skip to content

Progressive Multifocal Leukoencephalopathy (PML)

Summary

fleuron

  • PML is a rare, often fatal demyelinating disease of the central nervous system caused by reactivation of the JC virus in immunocompromised individuals
  • Characterised by multifocal areas of demyelination in the white matter
  • Imaging typically shows asymmetric, multifocal white matter lesions without mass effect or enhancement

Pathophysiology

  • Caused by reactivation of latent JC virus in immunocompromised hosts
  • Virus infects oligodendrocytes, leading to demyelination
  • Predominantly affects subcortical white matter, with occasional involvement of grey-white matter junction
  • Lesions typically progress and coalesce over time

Demographics

  • Rare disease, with an incidence of 0.2 cases per 100,000 person-years
  • Most commonly affects:
    • HIV/AIDS patients (80% of cases)
    • Patients with hematological malignancies
    • Organ transplant recipients
    • Patients on immunosuppressive therapies (e.g., natalizumab for multiple sclerosis)

Diagnosis

  • Clinical presentation:
    • Cognitive decline
    • Motor deficits
    • Visual disturbances
    • Seizures
  • Cerebrospinal fluid analysis:
    • JC virus PCR (sensitivity 72-92%, specificity 92-100%)
  • Brain biopsy (gold standard, but rarely performed)
  • Neuroimaging plays a crucial role in diagnosis and follow-up

Imaging

  • MRI is the modality of choice
  • Typical findings:
    • Asymmetric, multifocal white matter lesions
    • Subcortical and periventricular predilection
    • Hypointense on T1-weighted images
    • Hyperintense on T2-weighted and FLAIR sequences
    • No mass effect or surrounding oedema
    • Minimal or no enhancement (10-15% may show faint peripheral enhancement)
  • Advanced techniques:
    • Diffusion-weighted imaging: restricted diffusion in acute lesions
    • MR spectroscopy: decreased NAA, increased choline and lipid peaks
    • Perfusion imaging: typically shows hypoperfusion in affected areas

panels-1

  • A 70-year-old patient, who was undergoing chemotherapy for thyroid cancer, presented with a change in personality and right sided weakness.
  • MRI showed multifocal subcortical T2-weighted hyperintensity with a rim of diffusion restriction and no enahncement.

panels-1

  • 75-year-old patient on immunosuppression for rhematoid arthritis presented with subacute cerebellar ataxia.
  • MRI showed a T2 and diffusion-weighted hyperintensity in the cerebellar white matter without enhancement.
  • JC virus was positive and the lesions regressed after cessation of immunosuppressants.

panels-1

  • 60-year-old patient on long term immunosuppression for rheumatoid arthritis presented following a seizure.
  • MRI showed left frontal white matter hyperintensity extending into the juxtacortical white matter with no mass effect or diffusion restriction.

panels-1 panels-2

  • 70-year-old patient undergoing treatment for lymphoma. Presented with seizures, confusion, and aphasia.
  • MRI showed peripheral FLAIR-hyperintense and T1-hypointense lesions extending up to the cortex with no mass effect or enhancement.
  • After one month and treatment with pembrolizumab, the lesions had enlarged with a more obvious leading edge of diffusion weighted hyperintensity. There was no contrast enhancement to suggest PML-IRIS.

panels-1 panels-2

  • A 40-year-old patient who had recently underwent CAR-T treatment for lymphoma presented after a 2 week history of headache and photophobia.
  • MRI showed a large confluent subcortical region of T2-hyperintensity with a subtle rim of relative diffusion restriction and enhancement.
  • Biopsy confirmed PML.
  • On follow-up imaging 2 years later, following successful remission of lymphoma, the region matured into a region of gliosis.

Treatment

  • No specific antiviral therapy available
  • Management focuses on immune reconstitution:
    • HIV patients: optimisation of antiretroviral therapy
    • Withdrawal or reduction of immunosuppressive medications when possible
  • Supportive care and management of complications
  • Experimental therapies:
    • Cidofovir (limited evidence of efficacy)
    • Mefloquine (clinical trials ongoing)
    • Immune checkpoint inhibitors (case reports of success in some patients)

Differential diagnosis

Differential Diagnosis Distinguishing Feature
Multiple Sclerosis Ovoid periventricular and calloso-septal interface lesions (Dawson fingers); well-defined borders; subcortical U-fibres spared
Acute Disseminated Encephalomyelitis Bilateral asymmetric lesions involving both grey and white matter; lesions typically enhance; basal ganglia involvement common
Primary CNS Lymphoma Tends to enhance with contrast; often periventricular
HIV Encephalopathy More diffuse white matter involvement; typically spares U-fibres
Cerebral Toxoplasmosis Ring-enhancing lesions; often affects basal ganglia
Stroke Follows arterial vascular territory; DWI restriction in acute phase with ADC corresponding signal; no subcortical U-fibre predilection
Posterior Reversible Encephalopathy Syndrome Posterior cortical and subcortical vasogenic oedema; ADC map elevated (not restricted); involves grey and white matter
Glioblastoma Usually single, large enhancing mass; significant mass effect
Metastatic Brain Tumours Multiple lesions at grey-white matter junction; ring or nodular enhancement; surrounding vasogenic oedema
Cryptococcosis Predilection for basal ganglia; meningeal involvement common