What is the difference between HIV (Human Immunodeficiency Virus) encephalopathy and PML (Progressive Multifocal Leukoencephalopathy) in terms of diagnosis and treatment?

Differences Between HIV Encephalopathy and Progressive Multifocal Leukoencephalopathy (PML)

HIV encephalopathy and PML are distinct neurological conditions with different etiologies, clinical presentations, diagnostic features, and management approaches, with PML carrying a significantly higher mortality rate compared to HIV encephalopathy.

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
• 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
• JCV is present in approximately 60% of the European population but remains dormant until immunosuppression allows for viral mutation into a neurotropic strain 1

Clinical Presentation

• HIV Encephalopathy:

  • Typically presents with gradual cognitive decline, behavioral changes, and motor dysfunction
  • Often accompanied by other HIV-related symptoms

• PML:

  • Subacute onset with progressive symptoms over weeks 1
  • Characteristic presentations include aphasia, behavioral and neuropsychological alterations, retrochiasmal visual deficits, hemiparesis, and seizures 1
  • Unlike HIV encephalopathy, PML rarely presents with diplopia, paresthesia, paraparesis, optic neuritis, or myelopathy 1

MRI Features

• HIV Encephalopathy:

  • Often shows diffuse atrophy and white matter changes
  • Lesions are typically periventricular with sharp edges
  • Homogeneous hyperintensity on T2-weighted images 1

• PML:

  • Diffuse, large (>3 cm) lesions in unifocal, multifocal, or widespread distribution 1
  • Subcortical location rather than periventricular, affecting U fibers and extending into the gyrus 1
  • Irregular shape with ill-defined borders toward white matter but sharp borders toward cortical gray matter 1
  • Lesions continuously increase in volume, sometimes rapidly, confined to white matter tracts 1
  • No mass effect even in large lesions (unless inflammatory response is present) 1
  • FLAIR is the preferred sequence for PML diagnosis due to the subcortical location 1
  • Less than half of cases show enhancement at presentation, often with patchy or punctate appearance 1

Diagnostic Approach

• HIV Encephalopathy:

  • Diagnosis primarily based on clinical features and exclusion of other causes
  • MRI findings supportive but not specific

• PML:

  • Definitive diagnosis requires: clinical presentation + JCV DNA in CSF + MRI findings suggestive of PML 1
  • Alternatively, detection of PML on histopathology of biopsy material with presence of JCV by electron microscopy or immunohistochemistry 1
  • Important: A negative CSF JCV result does not rule out PML, especially in early stages when viral loads may be below detection threshold 1
  • In one study of 28 patients with natalizumab-associated PML, 16 initially had undetectable JCV DNA 1

Treatment

• HIV Encephalopathy:

  • Primarily managed with effective antiretroviral therapy (ART)

• PML:

  • No specific effective therapy has been proven in clinical trials 2
  • Early detection followed by rapid cessation of immunosuppressive therapy (if applicable) and immune reconstitution is the main approach 1
  • In HIV patients, initiation or optimization of antiretroviral therapy is the cornerstone of management 2, 3
  • Paradoxically, immune reconstitution may lead to PML-IRIS (immune reconstitution inflammatory syndrome), which can worsen symptoms 4, 5
  • Some evidence suggests steroids may be beneficial in PML-IRIS, particularly when started early and used for longer durations 4

Prognosis

• HIV Encephalopathy:

  • Often stabilizes or improves with effective ART

• PML:

  • Generally poor prognosis, especially if diagnosed late 6, 3
  • Mortality remains high despite treatment interventions 6
  • Early detection and immune reconstitution appear to be associated with better outcomes 1
  • PML with delayed IRIS (worsening of preexisting PML after ART initiation) has shorter survival duration and higher mortality compared to simultaneous PML-IRIS 4

Key Diagnostic Pitfalls

• PML can be misdiagnosed as HIV encephalopathy or other neurological conditions due to overlapping features 1
• JCV may not be detectable in CSF in early PML, leading to false-negative results 1
• MRI should be performed as soon as possible in all immunocompromised patients with suspected encephalitis 1
• Any new lesions beyond 18 months of natalizumab therapy should be treated with suspicion for PML 1
• Fluid-attenuated inversion recovery (FLAIR) has been shown to be more sensitive than T2-weighted MRI for detection of PML-associated lesions 1