What are the potential causes of demyelinating brain lesions in patients with Human Immunodeficiency Virus (HIV)?

Demyelinating Brain Lesions in HIV: Causes

Demyelinating brain lesions in HIV patients are most commonly caused by Progressive Multifocal Leukoencephalopathy (PML), followed by HIV-associated brain injury (HABI), immune reconstitution inflammatory syndrome (IRIS), and less commonly CD8+ T-cell encephalitis. 1, 2

Primary Causes to Consider

Progressive Multifocal Leukoencephalopathy (PML)

• PML is the most frequent opportunistic infection causing demyelination in HIV patients, caused by JC virus reactivation in the setting of severe immunosuppression 2
• Presents with characteristic white matter lesions without mass effect or enhancement on MRI, though IRIS-associated PML may show contrast enhancement 3, 2
• Diagnosis requires molecular detection of JC virus DNA in CSF combined with compatible imaging findings 2
• Critical management point: Never interrupt antiretroviral therapy in patients with PML, as continued viral suppression is essential for immune recovery 1

HIV-Associated Brain Injury (HABI)

HABI encompasses direct HIV-mediated brain damage and should be differentiated into two categories 4:

Legacy HABI

• Represents irreversible CNS damage sustained during periods of untreated HIV infection, particularly with advanced immunosuppression 4
• Manifests as inactive, permanent brain injury that occurred before ART initiation 4
• Not amenable to treatment but may lower cognitive reserve 4

Active HABI

• CSF HIV RNA escape is a key cause, indicating compartmentalized HIV replication in the CNS due to inadequate ART penetration, resistance, or poor adherence 4
• Can present with rapidly progressive neurological disease and diffuse white matter signal abnormality on MRI 4
• When progressive CNS damage occurs despite plasma viral suppression, CSF HIV RNA testing is mandatory 4
• Treatment requires ART optimization directed at CSF resistance profiles 4

Immune Reconstitution Inflammatory Syndrome (IRIS)

• Occurs within weeks to months after ART initiation in severely immunosuppressed patients 4, 3
• Pathologically characterized by severe CD8+ T-cell infiltration with perivascular and intraparenchymal inflammation causing demyelination 3
• Imaging shows contrast enhancement of lesions, distinguishing it from non-inflammatory PML 3
• Fatal cases demonstrate dysregulated CD8+/CD4+ T-cell balance with fulminant inflammation, while reversible cases show more balanced immune responses with macrophage activation 3
• Responsive to corticosteroids in severe cases with brain edema 4

CD8+ T-Cell Encephalitis

• A severe inflammatory disorder with T-cell infiltration causing brain swelling and raised intracranial pressure that can be fatal 4
• Typically occurs in patients already on ART 4
• Associated with CSF HIV RNA escape and overlaps with IRIS 4
• Responsive to corticosteroid therapy 4

Severe HIV-Associated Leukoencephalopathy

• Emerging entity in patients failing HAART with poorly controlled HIV replication 5
• Characterized by intense perivascular infiltration by HIV-infected monocytes/macrophages, widespread myelin loss, and axonal injury 5
• Brain tissue demonstrates high HIV RNA levels 5
• May represent immune restoration-mediated injury paradoxically worsening with ART 5

Diagnostic Approach

When evaluating demyelinating lesions in HIV patients, the critical distinguishing features are:

• Immune status: CD4 count and HIV viral load (plasma and CSF) 2, 5
• ART status: Treatment-naïve, on ART with viral suppression, or failing therapy 4, 5
• Timing: Recent ART initiation suggests IRIS 4, 3
• MRI characteristics: Non-enhancing lesions suggest PML or direct HIV effect; enhancing lesions suggest IRIS or CD8 encephalitis 3, 2
• CSF analysis: JC virus PCR for PML, HIV RNA for CSF escape, and cell counts/cytology 4, 2

Critical Pitfalls to Avoid

• Do not assume all demyelination in HIV is PML—multiple etiologies can coexist 4
• Do not stop ART when PML is diagnosed; this worsens outcomes 1
• Do not miss CSF HIV RNA escape in patients with progressive disease despite plasma suppression 4
• Recognize that IRIS can be fatal if not treated with immunomodulation when severe 3
• Consider that demyelination may worsen paradoxically after starting ART due to immune reconstitution 3, 5