Major or Mild Neurocognitive Disorder Due to HIV

Clinical Features

HIV-Associated Neurocognitive Disorders (HAND)

HAND is characterized by a triad of cognitive, behavioral, and motor dysfunction.

-Cognitive Slowing

-Impairment of Memory and Attention

-Disturbances in processing speed and fine motor functions

-Behavioral Manifestations

(ie. irritability)

• Incidence has decreased in HAART/cART era
• Prevalence of less severe forms are on a rise

-1/3 to over 1/2 have at least mild neurocognitive disturbance (NCD)

-Estimated 25% will have signs and symptoms that meet criteria for mild NCD

-Fewer than 5% will meet criteria for major NCD

• 3 conditions (Frascati criteria Antinori et al)

-ANI: Asymptomatic Neurocognitive Impairment

-MND: Mild Neurocognitive Disorder

-HAD: HIV Associated Dementia

Persistence of HAND Explanations

Clinical Features in Children

Clinical Features in Adults

HAD

ANI

MND

• Most severe condition
• Prevalence is 2% to 8% in HAART treated individuals
• Criteria:

-Impairment of cognitive functioning, involving at least 2 ability domains (typically multiple), performance is at least 2 SD below mean on neurological tests and for age-education-appropriate norms

-Produces cognitive impairment interference w/everyday functioning[inefficiency in work, homemaking, social functioning and reduced mental acuity (self-reported and observation)]

-Does not meet requirement for another medical condition

-No evidence of another pre-existing cause for the ANI

• Mildest from of HAND
• Occurs in approximately 30% of individuals
• Criteria:

-Impairment of cognitive functioning, involving at least 2 ability domains, performance is at least 1 SD below mean on neurological tests and for age-education-appropriate norms

-Cognitive impairment doesn’t interfere w/everyday functioning

-Does not meet requirement for another medical condition

-No evidence of another pre-existing cause for the ANI

-Survival before HAART was 6 to 24 months

-Prevalence before HAART was 30%

-McArthur et al. 2010 labels features of severe CNS involvement include:

• microcephaly
• spastic paraparesis
• delayed or regressing developing milestones

• More severe form than ANI
• 20-30% of HIV+ Adults
• Criteria:

-Impairment of cognitive functioning, involving at least 2 ability domains, performance is at least 1 SD below mean on neurological tests and for age-education-appropriate norms

-At least mild cognitive impairment interference w/everyday functioning

[inefficiency in work, homemaking, social functioning and reduced mental acuity (self-reported and observation)]

-Does not meet requirement for another medical condition

-No evidence of another pre-existing cause for the ANI

-Most have static form of neurocognitive impairment

-Clinical features include:

• short term memory loss
• mental slowing
• reading and comprehension difficulties
• apathy
• Stumbling and tripping
• Impairment of fine manual dexterity
• rapid eye movement
• hyper-reflexia

• Incidence has decreased with the introduction of HAART/cART, yet prevalence has increased.
• Possible Explanations:

-“Legacy” effect

-An immune restoration disorder

-Inadequate medical and psychiatric confounds

-Inadequate CNS levels of HAART

-Accelerated brain ageing

-CNS toxicity of HAART

-Depletion of neural stem cells

HIV & The Central Nervous System (CNS)

Neuropsychological Testing

• Virus enters the CNS during earliest stages of infection
• After infection, macophages carry HIV to brain via “Trojan horse” mechanism.
• As it progresses, the virus can use receptors (ie.CXCR4) to evolve into lymphoid tissues.
• Leads to opportunistic infections affecting CNS
• Powerful cause of AIDS

-Halstead-Reitan Neuropsychological Test Battery (HRB)

-Digit Vigilance Time

-WAIS-III Symbol Search

-WAIS-III Digit Symbol

-Store Memory Test

-Figure Memory Test

-Wisconsin Card Sorting Test

-Controlled Oral Association

-Category Fluency

-WAIS-Digit Span

-WAIS-III Letter-Number Sequencing

-PASAT

-Grooved Pegboard Test

References

Other Assessments

• Clinical & Biopsychosocial History

• Examination

• Lab Tests

• Neuroimagining

• Global Deficit Score (GDS) proposed by Heaton et al.

-Assigning scores for performance ranging from 0-5

-Emphasizes the impairment on a particular test

Ances, B. & Clifford, D. HIV-Associated Neurocognitive Disorders and the Impact of Combination Antiretroviral Therapies. Current Neurology and Neuroscience Reports. 2008; 8:455-561

Ellis, R., Langford, D., & Masliah, E. HIV and Anitretroviral Therapy in the Brain: Neuronal Injury and Repair. Nature Reviews Neuroscience. 2007; 8:33-44

McArthur, J., Steiner, J., Sacktor, N., & Nath, A. Human Immunodeficiency Virus-Associated Neurocognitive Disorders Mind the Gap. ANNALS of Neurology. 2010; 67:6:699-714

Grant, I. Neurocognitive Disturbances in HIV. International Review of Psychiatry. 2008; 20:1:33-47

Heaton, R., Clifford, D., Franklin, D., Woods, S., Ake, C., Vaida, F., Ellis, R., Letendre, S., Marcotte, T., Atkinson, J., Rivera-Mindt, M., Vigil, O., Taylor, M., Collier, A., Marra, C., Gelman, B., McArthur, J., Morgello, S., Simpson, D., McCutchan, J., Abramson, I., Gamst, A., Fennema-Notestine, C., Jernigan, T., Wong, J., Grant, I. HIV –Associated Neurocognitive Disorders Persist in the Era of Potent Antiretroviral Therapy CHARTER Study. Neurology. 2010; 75:2087-2096

Mothobi, N. & Brew, B. Neurocognitive Dysfunction in the Highly Active Antiretroviral Therapy Era. Curr Opin Infect Disease. 2012; 25:1:4-9

Heaton, R., Franklin, D., Ellis, R., McCutchan, J., Letendre, S., LeBlanc, S., Corkran, S., Duarte, N., Clifford, D., Woods, S., Collier, A., Marra, C., Morgello, S., Rivera-Mindt, M., Taylor, M., Marcotte, T., Atkinson, J., Wolfson, T., Gelman, B., McArthur, J., Simpson, D., Abramson, I., Gamst, A., Fennema-Notestine, C., Jernigan, T., Wong, J., Grant, I. HIV-Associated Neurocognitive Disorders Before and During the Era of Combination Antiretroviral Therapy: Differences in Rates, Nature, and Predictors. Journal of Neurovirology. 2011; 17:3-16

McArthur, J. & Brew, B. HIV-Associated Neurocognitive Disorders: Is there a Hidden Epidemic? AIDS. 2010; 24:1367-1370

Tozzi, V., Balestra, P., Bellagamba, R., Corpolongo, A., Salvatori, M., Comandini, U., Vlassi, C., Giulianelli, M., Galgani, S., Antinori, A., & Narciso, P. Persistence of Neuropsychologic Deficits Despite Long-Term Highly Active Antiretroviral Therapy in Patients With HIV-Related Neurocognitive Impairment Prevalence and Risk Factors. Journal of Acquired Immune Deficiency Syndrome. 2007; 45:2:174-182

Simioni, S., Cavassini, M., Annoni, J., Abraham, A., Bourquin, I., Schiffer, V., Clamy, A., Chave, J., Giacobini, E., Hirschel, B., & Pasquier, D. Cognitive Dysfunction in HIV patients despite long-standing Suppression of Viremia. AIDS. 2010; 24:1243-1250

Cysique, L., Vaida, F., Letendre, S., Gibson, S., Cherner, M., Woods, S., McCutchan, J., Heaton, R., Ellis, R. Dynamics of Cognitive Change in Impaired HIV-Positive Patients Initiating Antiretroviral Therapy. Neurology. 2009; 73:342-348

Anthony, I. & Bell, J. The Neuropathology of HIV/AIDS. International Review of Psychiatry. 2008; 20:1:15-24

Price, R. & Spudich, S. Antiretroviral Therapy and Central Nervous System HIV Type 1 Infection. The Journal of Infectious Disease. 2008; 197:S294-306

Tozzi, V., Balestra, P., Galgani, S., Narciso, P. , Ferri, F., Sebastiani, G., D’Amato, C., Affricano, C., Pigorini, F., Pau, F., Felici, A. & Benedetto, A. Positive and Sustained Effects og Highly Active Antiretroviral Therapy on HIV-1-Assocaited Neurocognitive Impairment. AIDS. 1999; 13:1889-1897

Woods, S., Rippeth, J., Frol, A., Levy, J., Ryan, E., Soukup, V., Hinkin, C., Lazzaretto, D., Cherner, M., Marcotte, T., Gelman, B., Morgello, S., Singer, E., Grant, I., and Heaton, R. Interrater Reliability of Clinical Ratings and Neurocognitive Diagnosis in HIV. Journal of Clinical and Experimental Neuropsychology. 2004; 26:6:759-778

Human Immunodeficiency Virus

Treatments

What Does HIV do?

Biological, Cognitive, & Social Etiologies

-An infectious RNA form that must be transformed into proviral DNA that must be incorporated into a host cell genome.

-Transmission by exposure to the following:

1.Injection drug use

2.Unprotected sexual contact

3.Vertical Exposure

4.Accidental exposure

Recommended drug initiation when CD4 count is <350/mm or plasma RNA is >100,000 copies/mL

• Highly potent cART (Cysique et al. 2009)

-Reduction of NP impairment in 75% of new cases

-Typically 3 or more antiretrovirals are standard

-Reduces replication in brain and blood

-Strongest results (80% supression) at 24 and 48 wk

• Neuro-HAART

-Penetrates CNS w/Protein Inhibitors

-Only has been studied in one longitudinal study

• HIV typically reaches the brain soon after inital infection.
• Causes of Neurocognitive disorders can be explained through biological, cognitive, and social factors.

-Targets and Attacks immune cells"T-Helper" (CD4)lymphocytes

-Binds to surface of T cell

-Releases enzyme into cell and fuzes own RNA with the T cells DNA

-The compromised cell starts to replicate

-Virus slips out the infected cell and begins to attack other T cells

-Leads to opportunistic infections & neoplasms

-Pathogenic effects both in the immune system and nervous system

Tx Continued

(Ellis et al., 2007)

Cognitive

• Gene therapy

-Provides trophic or protective factors

-Reverses exisiting injury or stop further damage

-Seen in Alzheimer disease

• Pharmacological agents

-Facilitate endogenous repair of trophic mechanisms

-Seen in the treatment of bipolar disorder

• In vitro

-Lithium prevents the induction of dendritic spine loss and simplification by HIV-1 gp120

-Improved neurocognitive performance in a single arm 12 week study

-Reduced severity of encephalitis

-Awaiting phase III clinical trial licensing

Biological

Synaptodendritic Injury (Ellis et al. 2007)

• Synaptodendritic changes in HIV correlate closely to the presence and severity of impairment

• Comprises various structural and chemical changes that affect the “business ends” of neurons

• Dendritic bending and aberant sprouting

• Results in disruption or loss of normal synaptodendritic communication and axoplasmic flow.

• Individual can have abnormal output, measured as deficiencies in cognitive skills and behavior.

Social

• “Trojan Horse” Theory (Mothobi & Brew,2012)

-Viral entrance through infected monocytes trafficking across the blood brain barrier (BBB) settling as macrophages. Virus spread by cell to cell contact w/microglia cells.

• Cerebrospinal Fluid (CSF) Theory (McArthur et al., 2010)

-Cell free virus directly crossing the BBB or entering through CSF.

• Simian Immunodeficiency Virus (SIV)/SIV Macaque Model

-HIV enters CNS blood, with the ingress of activated and infected monocytes through the BBB via diapedesis

• Pathological changes are typically mild, with abnormalities occurring in central white matter, frontal cortices, basal ganglia, thalamus, and brain stem.

• Developing Countries

• Socioeconomic Status

• Access to Care

• Educational Status

• Injection Drug Use/Sexual Behaviors
• 26% IDU

Conclusions

• Neuropsychological evaluation remains an essential part of assessments, therefore more research needs to be done to update current assessment techniques for the new cART era

• Best cognitive outcomes may be associated with successful viral response to cART and absence of historical severe immunosuppression

• Viral suppression alone is not sufficient

• Increasing prevalence of HAND is still unknown

Major or Mild Neurocognitive Disorder Due to HIV

Jasmin Prudon