Diagnostic and Therapeutic Considerations for HIV Encephalopathy and Progressive Multifocal Leukoencephalopathy (PML)

Etiology and Pathophysiology

HIV encephalopathy is directly caused by HIV infection of the brain, leading to neuronal damage and inflammation, while PML is caused by JC virus (JCV) reactivation in immunocompromised patients, resulting in lytic infection of oligodendrocytes and astrocytes 1, 2
PML occurs almost exclusively in immunosuppressed patients, most commonly in HIV-infected individuals, but also in those with malignancies, organ transplants, rheumatic diseases, or those on immunomodulatory therapies like natalizumab 1, 2
JCV is present in approximately 60% of the European population but remains dormant until immunosuppression allows for viral mutation into a neurotropic strain 2

PML has a subacute onset with progressive symptoms over weeks, characteristic presentations include aphasia, behavioral and neuropsychological alterations, retrochiasmal visual deficits, hemiparesis, and seizures 3, 4
Unlike HIV encephalopathy, PML rarely presents with diplopia, paresthesia, paraparesis, optic neuritis, or myelopathy 4

PML is characterized by diffuse, large (>3 cm) lesions in unifocal, multifocal, or widespread distribution, subcortical location rather than periventricular, affecting U fibers and extending into the gyrus 3, 4
Lesions have an irregular shape with ill-defined borders toward white matter but sharp borders toward cortical gray matter, and continuously increase in volume, sometimes rapidly, confined to white matter tracts 3, 4
FLAIR is the preferred sequence for PML diagnosis due to the subcortical location 6

Definitive diagnosis of PML requires clinical presentation + JCV DNA in CSF + MRI findings suggestive of PML 7, 3
A negative CSF JCV result does not rule out PML, especially in early stages when viral loads may be below detection threshold 6, 5

Early detection followed by rapid cessation of immunosuppressive therapy (if applicable) and immune reconstitution is the main approach for PML management 6, 5
Early detection and immune reconstitution appear to be associated with better outcomes in PML 6, 5

PML can be misdiagnosed as HIV encephalopathy or other neurological conditions due to overlapping features 4
JCV may not be detectable in CSF in early PML, leading to false-negative results 6, 5
Any new lesions beyond 18 months of natalizumab therapy should be treated with suspicion for PML 7
Fluid-attenuated inversion recovery (FLAIR) has been shown to be more sensitive than T2-weighted MRI for detection of PML-associated lesions 7