PATHOGENS

• HIV is found in brain in macrophages, microglia, and multinucleated giant cells, especially of the deep white matter, basal ganglia, and brain stem.
• HAND is due to the direct effect of HIV with injury located primarily in the subcortical white matter.

CLINICAL

• HAND identifies a spectrum of neurocognitive impairment:
  • Asymptomatic neurocognitive impairment (ANI)
  • Mild neurocognitive disorder (MND)
  • HIV-associated dementia (HAD)
• Developed in 2007, HAND criteria (also called the Frascati criteria) were developed for use in research and included ANI, which identified cognitive disorder by low performance on cognitive tests without evidence of functional limitation.[1]
  
  • In current era, HAND presents as mixed pattern of both cortical and subcortical features with deficits in executive function and working memory.[8]
  • In pre-ART era, HAND was characterized by psychomotor slowing, motor dysfunction/gait disturbances, and memory impairment.[6]
  • Risk factors for HAND include Hx of severe immunosuppression (nadir CD4 < 200), so earlier treatment to prevent severe immunosuppression may decrease risk.
• HIV-associated dementia (HAD)
  • Early Sx: apathy, impaired memory, difficulty with reading and calculation, decreased libido, depressive symptoms, waning interest in work and 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.
  • Severe HAD may be accompanied by HIV-related myelopathy or neuropathy.
  • 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.
  • Severity rated from 0 to 4: 0-normal, 0.5-subclinical, 1-mild, 2-moderate, 3-severe, 4-end stage.
  • When untreated with ART, mean survival was ~6 months.

DIAGNOSIS

• 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 once HAND is suspected includes brain MRI, neuropsychological testing, serologic testing as needed to rule out vitamin deficiency and syphilis because the diagnosis is one of exclusion.
• 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%.

TREATMENT

FOLLOW UP

Basis for recommendation

1. Nightingale S, Dreyer AJ, Saylor D, et al. Moving on From HAND: Why We Need New Criteria for Cognitive Impairment in Persons Living With Human Immunodeficiency Virus and a Proposed Way Forward. Clin Infect Dis. 2021;73(6):1113-1118.  [PMID:33904889]

   Comment: Authors propose new framework to define cognitive impairment by eliminating asymptomatic neurocognitive impairment, basing diagnosis on clinical history rather than cognitive tests, and recognizing comorbid factors. HIV brain pathology and comorbidities are considered separate overlapping entities.
   

2. Sacktor NC, Wong M, Nakasujja N, et al. The International HIV Dementia Scale: a new rapid screening test for HIV dementia. AIDS. 2005;19(13):1367-74.  [PMID:16103767]

   Comment: Widely used quick clinical screen for HAD, applicable to international settings.
   

References

3. Masters MC, Perez J, Wu K, et al. Baseline Neurocognitive Impairment (NCI) Is Associated With Incident Frailty but Baseline Frailty Does Not Predict Incident NCI in Older Persons With Human Immunodeficiency Virus (HIV). Clin Infect Dis. 2021;73(4):680-688.  [PMID:34398957]

   Comment: ACTG A5322, also known as HAILO - HIV Infection, Aging, and Immune Function Long-term Observational Study, followed 929 individuals (178 women) with median age of 51yrs, 16% with neurocognitive impairment, and 6% frail at baseline for 3 years. Authors conclude that cognitive frailty may better capture vulnerability to poor health than frailty alone.
   Rating: Important
   

4. Molinaro M, Sacktor N, Nakigozi G, et al. Utility of the International HIV Dementia Scale for HIV-Associated Neurocognitive Disorder. J Acquir Immune Defic Syndr. 2020;83(3):278-283.  [PMID:32032278]

   Comment: Rakai Community Cohort Study conducted longitudinal assessments (2013-2015) to determine diagnostic utility of International HIV Dementia Scale (IHDS). In 399 ART-naive and in 312 ART-experienced individuals, IHDS demonstrated higher sensitivity for detecting more severe HAND. Authors find utility as screening test given adequate sensitivity, but note that lower specificity may limit widespread use due to high rate of false positives.
   Rating: Important
   

5. De Francesco D, Underwood J, Bagkeris E, et al. Depression, lifestyle factors and cognitive function in people living with HIV and comparable HIV-negative controls. HIV Med. 2019;20(4):274-285.  [PMID:30734983]

   Comment: Cross-sectional study of 637 people living with HIV and 50 year or older, 340 PLWH and younger than 50 years, and 276 matched HIV-unifected participants in the Pharmacokinetic and Clinical Observations in People over Fifty (POPPY) found that cognitive impairment was associated with HIV infection, depressive symptoms, and recreational drug use.
   

6. Sacktor N. Changing clinical phenotypes of HIV-associated neurocognitive disorders. J Neurovirol. 2018;24(2):141-145.  [PMID:28752495]

   Comment: Author recognizes milder clinical phenotype of HAND attributable to modern ART. However, as people living with HIV age, cerebrovascular disease risk factors including hypertension, diabetes, and hypercholesterolemia are important modifiable risk factors.
   Rating: Important
   

7. Clifford DB, Ances BM. HIV-associated neurocognitive disorder. Lancet Infect Dis. 2013;13(11):976-86.  [PMID:24156898]

   Comment: Excellent review of HAND.
   

8. McArthur JC, Steiner J, Sacktor N, et al. Human immunodeficiency virus-associated neurocognitive disorders: Mind the gap. Ann Neurol. 2010;67(6):699-714.  [PMID:20517932]

   Comment: Comprehensive review of HAND includes discussion of pathobiology and pathophysiology and recognizes "therapeutic gap" whereby ART-induced systemic suppression of HIV replication incompletely reverses neurocognitive dysfunction.
   

9. Heaton RK, Clifford DB, Franklin DR, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology. 2010;75(23):2087-96.  [PMID:21135382]

   Comment: Though HAD is rare, milder forms of HAND are common even among those on ART.
   

10. Cysique LA, Vaida F, Letendre S, et al. Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy. Neurology. 2009;73(5):342-8.  [PMID:19474412]

    Comment: Neuropsychological improvement peaked 24-36 wks after starting ART; CNS penetration index associated with improvement.
    

11. McArthur JC, McClernon DR, Cronin MF, et al. Relationship between human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain. Ann Neurol. 1997;42(5):689-98.  [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.