How do Progressive Multifocal Leukoencephalopathy (PML) and Multiple Sclerosis (MS) differ on a brain Magnetic Resonance Imaging (MRI)?

MRI Differentiation Between PML and Multiple Sclerosis

PML lesions are typically large (>3 cm), subcortical, involve U-fibers and cortical gray matter with ill-defined borders, while MS lesions are smaller, focal, periventricular with sharp borders and characteristic "Dawson's fingers" appearance. 1

Lesion Location and Distribution

PML:

• Subcortical location rather than periventricular 1
• Affects U-fibers and extends into the gyrus 1
• Cortical gray matter involvement in 50% of cases 1
• Posterior fossa is a less frequent site 1
• Spinal cord presentation is rare 1

MS:

• Focal, generally periventricular in location 1
• Lesions occur particularly in corpus callosum and spinal cord 1
• Periventricular lesions perpendicular to corpus callosum ("Dawson's fingers") 1
• Juxtacortical lesions involving U-fibers are common 1

Lesion Size and Morphology

PML:

• Generally large lesions >3 cm in unifocal, multifocal, or widespread distribution 1, 2
• Irregular shape with ill-defined borders toward white matter 1
• Sharp border toward cortical gray matter 1
• Diffuse appearance 1

MS:

• Smaller focal lesions 1
• Sharp edges; mostly round or flame-shaped (especially periventricular lesions) 1
• Well-defined borders 1

Lesion Evolution and Progression

PML:

• Lesion volume increases continuously and sometimes rapidly to contiguous (multifocal) and non-contiguous regions (widespread) 1
• Confined to white matter tracts, sparing the cortex 1
• Progressive expansion over weeks 1

MS:

• Initially focal, lesions enlarge within days or weeks and later decrease in size within months 1
• May become confluent with other lesions 1

Signal Characteristics

PML on T2/FLAIR:

• Diffuse hyperintensity with irregular signal intensity within lesions 1
• Can have punctate microcystic appearance 1
• Small punctate T2 lesions may be seen in proximity to the main lesion 1, 3
• FLAIR is the preferred sequence for PML diagnosis due to subcortical location 1, 2, 4

MS on T2/FLAIR:

• Homogeneous hyperintensity 1
• Sharply delineated 1

PML on T1:

• Slightly hypointense at onset 1
• Signal intensity decreases over time in affected area 1
• No reversion to isointense signal intensity 1

MS on T1:

• Acute lesions: hypointense (due to edema) or isointense 1
• Increasing signal intensity over time in 80%; decreasing signal intensity (axonal loss) in about 20% 1

Contrast Enhancement Patterns

PML:

• Less than half of cases show enhancement at presentation 1
• Often patchy or punctate appearance when present 1
• Punctate or miliary enhancement pattern 1
• Rim enhancement at leading edge can be seen in larger lesions 1
• Contrast enhancement is variable and not diagnostic of PML 1

MS:

• Acute lesions show homogeneous nodular or ring enhancement with sharp edges 1
• Open-ring or closed-ring enhancement patterns 1
• Enhancement resolves over 1-2 months 1
• Chronic lesions show no enhancement 1

Mass Effect and Atrophy

PML:

• No mass effect even in large lesions, except when inflammatory response is present 1
• No focal atrophy initially, but can be seen in late stages of progression 1

MS:

• Large acute lesions may have mass effect 1
• Focal atrophy possible due to focal white matter degeneration, but no progression 1

Diffusion-Weighted Imaging (DWI)

PML:

• Acute PML lesions are hyperintense but not specific for PML 1
• Helpful to detect new PML lesions within confluent areas of chronic white matter disease 1, 2
• ADC maps not helpful 1

MS:

• Acute lesions hyperintense 1
• Chronic lesions isointense 1
• Conforms to shape of lesions on FLAIR and T2W 1

Key Discriminating Features for Asymptomatic Detection

Strongly predictive of PML:

• Punctate T2 lesions 3
• Cortical gray matter involvement 3
• Ill-defined and mixed lesion borders toward both gray and white matter 3
• Lesion size >3 cm 3

Strongly predictive of MS:

• Focal lesion appearance 3
• Periventricular localization 3

Critical Clinical Pitfalls

• FLAIR is more sensitive than T2-weighted MRI for detecting PML-associated lesions 1, 2, 4
• None of the MRI features are pathognomonic of MS or PML in isolation 1
• PML can be present on MRI before clinical symptoms develop 5, 6
• In natalizumab-treated patients, any new lesions beyond 18 months of therapy should be treated with suspicion for PML 1, 4
• A multivariable prediction model using punctate T2 lesions, cortical gray matter involvement, focal lesion appearance, and periventricular localization achieves 100% sensitivity and 80.6% specificity for distinguishing PML from MS 3