- HIV is found in brain in macrophages, microglia, and multinucleated giant cells.
- Neurons injured indirectly when infected cells release noxious substances.
- HAD is subacute decline in cognitive function due to HIV.
- Also known as HIV encephalopathy or AIDS-dementia complex.
- Milder cognitive impairment is called HIV-associated cognitive/motor complex. The term HIV-associated neurocognitive dysfunction (HAND) is now frequently used and refers to neurocognitive dysfunction of any degree of severity, since severe forms (HAD) are now relatively rare and mild forms much more frequent.
- Dementia is AIDS-defining illness in 3%.
- Prevalence 2% for HAD, 12% for mild neurocognitive disorder, and 33% for asymptomatic neurocognitive impairment.
- Risk factors for HAND include Hx of more severe immunosuppression (nadir CD4 < 200), so earlier treatment to prevent severe immunosuppression may decrease risk.
- Early Sx: apathy, impaired memory, difficulty with reading and calculation, decreased libido, depressive symptoms, waning interest in work & hobbies causing social withdrawal, occasionally mania or psychosis.
- Later Sx: psychomotor slowing, poor memory, slowed movement. At end-stage patients can be mute, bedbound, and incontinent.
- Considered a "subcortical dementia" due to absence of signs like aphasia and apraxia seen in "cortical dementias" like Alzheimer disease.
- Motor symptoms like gait dysfunction, poor balance, and tremor may be present.
- Often accompanied by HIV-related myelopathy or neuropathy.
- Severity rated from 0 to 4: 0-normal, 0.5-subclinical, 1-mild, 2-moderate, 3-severe, 4-end stage.
- When untreated, mean survival ~6 months.
- DDx includes PML, CNS toxoplasmosis, primary CNS lymphoma, CMV encephalitis, neurosyphilis, vitamin B12 or thiamine deficiency, delirium, depression, medication/drug effect, or other causes of dementia.
- Differs from delirium in that there is no alteration of consciousness or attention.
- Exam may show frontal release signs, hyperreflexia, and increased tone.
- Consider OI if focal signs or fever present.
- Workup includes brain MRI, neuropsychological testing, serologic testing as needed to rule out vitamin deficiency, syphilis.
- MRI usually shows atrophy and ill-defined white matter hyperintensities on T2-weighted scans.
- CSF analysis not essential, but may be needed to rule out OI.
- CSF findings nonspecific: may be acellular or show a lymphocytic pleocytosis; protein elevated in 65%.
- ART is mainstay of treatment.
- Drugs with greater CNS penetration, including AZT, d4T, 3TC, ABC, NVP, IDV, and LPV/r, are more effective at decreasing CSF viral load, but evidence is mixed regarding whether this results in greater clinical benefit.
- IRIS can occasionally be seen following initiation of ART-usually due to PML.
- No other adjunctive treatments have proven benefit.
- Treatment of co-morbid depression, mania, or psychosis may be necessary.
- HAD patients are sensitive to psychoactive medications.
Selected Drug Comments
ART is only effective treatment for HAD. Use CNS-penetrating agents if possible without sacrificing virologic suppression.
- Monitor response to ART.
- If neurologic deterioration, perform brain MRI to rule out IRIS or OI.
- Neuropsychological testing can be repeated to evaluate longitudinal change.
- McArthur JC et al: Relationship between human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain. Ann Neurol 42:689, 1997 [PMID:9392567]
Comment: Association between plasma HIV RNA and CSF levels of HIV and beta-2-microglobulin suggests that both viral load and CNS immune activation are important determinants of neurological disease.
- Kandanearatchi A et al: Suppression of human immunodeficiency virus replication in human brain tissue by nucleoside reverse transcriptase inhibitors. J Neurovirol 10:136, 2004 [PMID:15204933]
Comment: Authors observed statistically significant reduction in rate of viral replication for d4T added 24 hrs prior to infection.
- Cysique LA et al: Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy. Neurology 73:342, 2009 [PMID:19474412]
Comment: Neuropsychological improvement peaked 24-36 wks after starting ART; CNS penetration index associated with improvement.
- Letendre S et al: Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol 65:65, 2008 [PMID:18195140]
Comment: Drugs with higher CNS penetration associated with lower CSF viral loads.
- Garvey L et al: Antiretroviral therapy CNS penetration and HIV-1-associated CNS disease. Neurology 76:693, 2011 [PMID:21339496]
Comment: A non-significant association was seen between lower ART CNS penetration effectiveness score and CNS OIs. Lower CNS penetration effectiveness score was associated with higher mortality, though it is unclear whether or not this is a causative association.
- Heaton RK et al: HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 75:2087, 2010 [PMID:21135382]
Comment: Though HAD is rare, milder forms of HAND are common even among those on ART.
- Shiramizu B et al: HIV DNA and dementia in treatment-naïve HIV-1-infected individuals in Bangkok, Thailand. Int J Med Sci 4:13, 2007 [PMID:17211496]
Comment: High HIV-1 DNA levels in PBMCs correlate with HAD in pts on ART.
- Nath A, Geiger J: Neurobiological aspects of human immunodeficiency virus infection: neurotoxic mechanisms. Prog Neurobiol 54:19, 1998 [PMID:9460791]
Comment: Review provides in-depth analysis of pathophysiological mechanisms by which these viral and cellular products affected by HIV virotoxins cause neural dysfunction.
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