What is the appearance of Progressive Multifocal Leukoencephalopathy (PML) on an MRI (Magnetic Resonance Imaging) brain scan?

MRI Appearance of Progressive Multifocal Leukoencephalopathy (PML)

FLAIR is the preferred MRI sequence for diagnosing PML due to its subcortical location, showing large (>3 cm) diffuse lesions with irregular borders that affect U-fibers and extend into the gyrus. 1

Key Imaging Characteristics by MRI Sequence

Location and Distribution

• Subcortical rather than periventricular location is the hallmark feature distinguishing PML from other white matter diseases 1
• Lesions are typically large (>3 cm) in unifocal, multifocal, or widespread distribution 1, 2
• U-fibers are characteristically involved, extending into the gyrus with cortical gray matter involvement in 50% of cases 1
• Frontal and parietal lobes are most commonly affected (77.8% and 22.2% respectively in natalizumab-associated PML) 1
• Posterior fossa and spinal cord involvement are rare 1

Lesion Borders and Shape

• Irregular shape with ill-defined borders toward white matter but sharp borders toward cortical gray matter 1
• This creates a characteristic sharp demarcation at the gray-white junction 1, 3

T2-Weighted Sequences

• Diffuse hyperintensity with irregular signal intensity within lesions 1
• May demonstrate a punctate microcystic appearance 1
• Small punctate T2 lesions may be visible in proximity to the main lesion 1

T1-Weighted Sequences

• Slightly hypointense at onset, with signal intensity progressively decreasing over time 1
• No reversion to isointense signal occurs, unlike MS lesions 1

FLAIR Sequences

• FLAIR is the preferred sequence for PML diagnosis because it best demonstrates the subcortical location 1, 2
• More sensitive than T2-weighted imaging for detecting PML-associated lesions 1

Contrast Enhancement

• Less than half of cases show enhancement at presentation 1
• When present, enhancement appears as patchy or punctate rather than homogeneous 1
• Rim enhancement at the leading edge can occur in larger lesions 1
• Some cases show transient punctuate gadolinium-enhancing lesions in frontal, parietal, and thalamic regions that may precede T2 hyperintensity by approximately 2 months 1

Diffusion-Weighted Imaging (DWI)

• Acute PML lesions are hyperintense on DWI but this finding is not specific for PML 1
• DWI is particularly helpful for detecting new PML lesions within confluent areas of chronic white matter disease 1
• ADC maps are not helpful for diagnosis 1

Lesion Evolution and Mass Effect

Progression Pattern

• Lesion volume increases continuously and sometimes rapidly to contiguous (multifocal) and non-contiguous regions (widespread) 1
• Lesions are confined to white matter tracts, sparing the cortex 1

Mass Effect

• No mass effect even in large lesions is characteristic, except when inflammatory response (IRIS) is present 1

Atrophy

• No focal atrophy initially, but can develop in late stages of PML progression 1
• Long-term survivors show leukomalacia with ventricular enlargement and focal subcortical atrophy with preservation of the cortical ribbon 4

Critical Diagnostic Pitfalls

None of the MRI features are pathognomonic of PML, requiring correlation with clinical presentation and CSF JCV DNA testing 1. The differential diagnosis includes:

• Small-vessel disease: Multiple subcortical and deep white matter lesions, but these are typically smaller and more symmetric 1
• HIV leukoencephalitis: Diffuse lesions that are less intense on T2, not visible on T1, and do not involve arcuate fibers 3
• Anti-MOG syndrome: Prominent involvement of cerebellar peduncles with fluffy, cloud-like lesions 1
• Neuromyelitis optica spectrum disorders: Periaqueductal and area postrema lesions 1

A negative CSF JCV result does not exclude PML, especially in early stages when viral loads may be below detection threshold 1, 2. If clinical suspicion remains high based on MRI findings, CSF testing should be repeated over several months or brain biopsy performed 1.