What are the signs of Progressive Multifocal Leukoencephalopathy (PML)?

Signs of Progressive Multifocal Leukoencephalopathy (PML)

PML presents with subacute, progressive neurological symptoms developing over weeks, most characteristically including aphasia, behavioral and neuropsychological alterations, retrochiasmal visual deficits, hemiparesis, and seizures. 1, 2

Clinical Presentation

Core Neurological Features

• Cognitive and behavioral changes: Confusion, altered behavior, and neuropsychological dysfunction are hallmark features 1, 2
• Motor deficits: Progressive hemiparesis or weakness, typically asymmetric 1, 3
• Speech disturbances: Aphasia and dysarthria are common presenting symptoms 1, 4
• Visual impairment: Retrochiasmal visual deficits (cortical blindness, hemianopsia) rather than optic neuritis 1, 4
• Seizures: Can occur, though less typical, and may indicate more aggressive disease course 1, 3
• Limb incoordination: Ataxia and coordination difficulties 4

Temporal Pattern

• Subacute onset progressing over weeks, not hours to days 1, 2
• Relentlessly progressive course without spontaneous stabilization or improvement 1
• Symptoms continuously worsen even without treatment 1

Features That Argue AGAINST PML

PML rarely presents with diplopia, paresthesia, paraparesis, optic neuritis, or myelopathy—these symptoms suggest alternative diagnoses like multiple sclerosis 1, 2

MRI Characteristics

Lesion Appearance

• Large lesions: Generally >3 cm in unifocal, multifocal, or widespread distribution 1, 2
• Subcortical location: Affecting U-fibers and extending into the gyrus, rather than periventricular 1, 2
• Cortical gray matter involvement in 50% of cases 1
• Irregular shape with ill-defined borders toward white matter but sharp borders toward cortical gray matter 1

Imaging Sequences

• FLAIR is the preferred sequence for PML diagnosis due to subcortical location 1, 2
• T2-weighted: Diffuse hyperintensity with punctate microcystic appearance 1
• T1-weighted: Slightly hypointense at onset with decreasing signal intensity over time 1
• Contrast enhancement: Less than half show enhancement, typically patchy or punctate when present 1
• No mass effect even in large lesions (unless inflammatory response present) 1
• DWI: Acute PML lesions are hyperintense, helpful for detecting new lesions within confluent chronic white matter disease 1

Lesion Evolution

Lesion volume increases continuously and sometimes rapidly to contiguous and non-contiguous regions, confined to white matter tracts while sparing cortex 1

Diagnostic Confirmation

Definitive Diagnosis Requires

• Clinical presentation consistent with PML 1, 2
• JCV DNA detected in CSF by PCR 1, 2
• MRI findings suggestive of PML 1, 2

Critical Diagnostic Pitfall

A negative CSF JCV PCR 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 and symptoms, CSF testing should be repeated over several months or brain biopsy performed 1

Risk Factors and Context

High-Risk Populations

• HIV/AIDS patients (85% of cases historically) 4
• Natalizumab-treated patients with multiple sclerosis 1, 5
• Immunosuppressive therapy recipients (rituximab, transplant medications) 1, 6
• Lymphoproliferative disorders and malignancies 1, 6

Asymptomatic Detection

Routine surveillance MRI can detect PML in presymptomatic phases, particularly in high-risk patients on natalizumab therapy 1. Early detection with rapid cessation of immunosuppressive therapy and immune reconstitution is associated with improved outcomes—mean EDSS scores of 4.1 (fully independently ambulant) in asymptomatic patients versus 5.4 in symptomatic patients 1, 2

Key Clinical Pearls

• PML is usually fatal without intervention, caused by JC virus reactivation 1
• Progressive course over weeks distinguishes PML from acute demyelinating conditions 1
• Behavioral changes, aphasia, and hemiparesis form the classic triad 1, 2
• Subcortical U-fiber involvement on FLAIR is the most characteristic imaging finding 1, 2
• Repeat CSF testing is warranted when suspicion remains high despite initial negative results 1, 2