HIV Infection of the Nervous System

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HIV Infection of theNervous System

• Neuropsychological Factors

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How Does HIV Affect the Nervous System?

• HIV easily crosses the blood-brain barrier

Dave R, Pomerantz RJ. (2005). HIV
neuropathogenesis persistent infection,
persistent questions. Science Medicine.
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How Does HIV Affect the Nervous System?

• HIV indirectly destroys cells in the nervous
  system

Kaul, Garden Lipton (2001). Pathways to
neuronal injury and apoptosis in HIV-associated
dementia. Nature 410, 988-994.
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Classification of HIV Nervous System Disease

• Primary (caused by HIV alone)
• HIV Dementia
• Secondary (opportunistic infections associated
  with immunodeficiency)
• Fungal, Parasitic, Viral, TB, Bacterial, Cancer
• Tertiary (treatment complications)
• Immune Reconstitution Inflammatory Syndrome (IRIS)

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How Does HIV Affect the Nervous System?

• General immunosuppression can lead to
• Opportunistic Infections
• Fungal (Cryptococcal Meningitis)
• Parasitic (Toxoplasmosis)
• Viral (Progressive Multifocal Leukoencephalopathy)
  
• HIV-Related Tumors

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How Does HIV Affect the Nervous System?

• Primary HIV Disease can lead to
• AIDS Dementia Complex (brain)
• Vacuolar Myelopathy (spinal cord)
• Peripheral Neuropathy (nerve)
• Meningitis (acute and chronic)

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How Does HIV Affect the Nervous System?

• 10-15 of AIDS patients present with neurologic
  symptoms only (5 with dementia).
• 35-50 of AIDS patients have neurologic symptoms
  during life1 (35 develop minor cognitive/motor
  disorder 15-20 progress to dementia2)
• 75-90 have neuropathologic abnormalities at
  death3
• 1) Brouwman et al, Neurology. 1998 501814-20.
  
• 2) McArthur J Neuroimmunol 2004 157 3-10
• 3) Vago et al., AIDS. 2002161925-8.

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Progression of HIV Infection of the Nervous System
HIV neg
HIV positive, but otherwise asymptomatic
Constitutional Symptoms Severe
Immunosuppression, but no OIs
AIDS
Acute
Chronic Meningitis
Schematic diagram of HIV-related diseases that
affect central nervous system (solid border) and
peripheral nervous system (dotted border).
Adapted from Johnson et al., 1988.
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Progression of HIV Infection of the Nervous System
HIV neg
HIV positive, but otherwise asymptomatic
Constitutional Symptoms Severe
Immunosuppression, but no OIs
AIDS
Acute
Chronic Meningitis
HIV-Associated Neurocognitive Disorders
Schematic diagram of HIV-related diseases that
affect central nervous system (solid border) and
peripheral nervous system (dotted border).
Adapted from Johnson et al., 1988.
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HIV-associated Neurocognitive Disorders
(HAND)(HIV-1-Associated Dementia)
(HIV-associated Cognitive/Motor
Complex)(HIV-associated Mild Neurocognitive
Disorder)(Asymptomatic Neurocognitive
Impairment)(HIV-Associated Mild Cognitive/Motor
Disorder)(HIV-Related Encephalopathy)(AIDS
Dementia Complex)

• Patients with the AIDS dementia complex present
  with a variable, yet characteristic,
  constellation of abnormalities in cognitive,
  motor, and behavioral function. Perhaps the
  salient aspects of the disorder are the slowing
  and loss of precision in both mentation and motor
  control . These patients often lose interest in
  their work as well as in their social and
  recreational activities. (Price et al., 1988)

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Diagnostic Criteria for HIV-1 Dementia(American
Academy of Neurology, 1991)(NINDS/NIMH Working
Group, 2007)

• Severe acquired abnormality in at least two
  ability domains
• Attention, Speed of processing, Abstraction,
  Learning skills
• Marked interference with day-to-day functioning

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Diagnostic Criteria for Mild Neurocognitive
Disorder (NINDS/NIMH Working Group, 2007)

• Mild to moderate acquired abnormality in at least
  two ability domains
• Attention, Speed of processing, Abstraction,
  Learning skills
• Mild interference in daily functioning

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Diagnostic Criteria for Asymptomatic
Neurocognitive Impairment (NINDS/NIMH Working
Group, 2007)

• Mild to moderate acquired abnormality in at least
  two ability domains
• Attention, Speed of processing, Abstraction,
  Learning skills
• No interference in daily functioning

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General Algorithm for HNRC / Neurology HAND
Classifications
Classify ADLs
Asymp. or Minor Neurocog.
Unknown
Normal
Mild to Major Deficit
Mild
Normal to Mild
Major
Minor Neurocog or Dementia
Unknown
Major Deficit
Classification also requires that other
potential diagnoses be ruled out.
Woods, SP, et. al. Interrater reliability of
clinical ratings and neurocognitive diagnoses in
HIV. Journal of Clinical and Experimental
Neuropsychology, 2004,26, p 759-778. Antinori A,
et al. Neurology 2007 691789-1799
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Incidence and Prevalence of HIV Dementia in the
MACS (Prior to HAART)

• After a diagnosis of AIDS, new cases of dementia
  occurred at a rate of 7 per year
• 15-40 of individuals developed dementia prior to
  death
• Median survival after dementia was 6 months

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Incidence and Prevalence of HIV Dementia in the
MACS (Since HAART)

• Incidence of all types of primary HIV
  neuropsychiatric disease have decreased
  dramatically.
• Incidence of dementia has been halved.
• Survival time since diagnosis of dementia has
  increased dramatically.

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Changes in Incidence of Cryptococcal Meningitis
Incidence rates are number per 1000 person-years.
(Sacktor et al., 2001)
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Changes in Incidence of HIV Dementia
Incidence rates are number per 1000 person-years.
(Sacktor et al., 2001)
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HIV Dementia in the Era of HAART

• Although incidence of HIV-dementia has decreased,
  it continues to be a problem for many
  individuals.
• After over 25 years of research, the specific
  triggers for HIV dementia remain unknown.
• Improved survival means that more individuals
  with dementia must learn to cope with the
  disabling effects of impaired cognition.

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HIV Dementia in the Era of HAART

• Effective treatments for HIV dementia are not yet
  available.
• Individuals who are treated with HAART shortly
  after the first symptoms of dementia appear may
  show dramatic improvement.
• Individuals who have shown symptoms of dementia
  for a while do not seem responsive to treatment.

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• HIV indirectly destroys cells in the nervous
  system

Kaul, Garden Lipton (2001). Pathways to
neuronal injury and apoptosis in HIV-associated
dementia. Nature 410, 988-994.
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Assessment of HIV Dementia

• HIV dementia is generally considered a
  subcortical dementia.

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Assessment of HIV Dementia

• HIV dementia is generally considered a
  subcortical dementia.
• HIV dementia symptoms are more associated with
  motor slowing and loss of executive control than
  with language and memory disturbance.

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Assessment of HIV Dementia

• HIV dementia is generally considered a
  subcortical dementia.
• HIV dementia symptoms are more associated with
  motor slowing and loss of executive control than
  with language and memory disturbance.
• Later stage illness affects both cortical and
  subcortical regions and may affect memory.

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Thompson Neuroimaging Laboratory, UCLA (2005)
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Assessment of HIV Dementia

• Behavioral Observations

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Assessment of HIV Dementia

• Behavioral Observations
• Acquired abnormality

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Assessment of HIV Dementia

• Behavioral Observations
• Acquired abnormality
• Change in normal Activities of Daily Living

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Assessment of HIV Dementia

• Behavioral Observations
• Acquired abnormality
• Change in normal Activities of Daily Living
• Change in mood or normal social relationships

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Assessment of HIV Dementia

• Behavioral Observations
• Acquired abnormality
• Change in normal Activities of Daily Living
• Change in mood or normal social relationships
• Rule out other medical conditions

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HIV-Associated Neuro-cognitive Disorder
Other medical conditions

• HIV-Associated Neurocognitive Disorders may share
  symptoms with
• Mood disorders
• Drug and alcohol abuse
• Mania and psychosis
• Other infections and neurologic problems
• Oversedation with medications commonly given for
  sleep, mood problems and other disorders

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Assessment of HIV Dementia

• Behavioral Observations
• Acquired abnormality
• Change in normal Activities of Daily Living
• Change in mood or normal social relationships
• Rule out other medical conditions
• Neuropsychological (Cognitive) Tests

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Neuropsychological Tests

• Functional Domains
• Attention and Concentration
• Gross and Fine Motor Skills
• Verbal and Nonverbal Memory
• Language Skills
• Visuoperceptual Skills
• Executive Skills/Higher Order Reasoning

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Neuropsychological Tests

• Functional Domains Impaired in HIV
• Attention and Concentration
• Gross and Fine Motor Skills
• Verbal and Nonverbal Memory
• Language Skills
• Visuoperceptual Skills
• Executive Skills/Higher Order Reasoning

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Neuropsychological Tests

• Mini-mental status exam lacks sensitivity (no
  measures of psychomotor change)
• Standard psychological measures (personality,
  aptitude, achievement) are helpful, but lack
  specificity

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Core Cognitive Impairments

• Cognitive and motor slowing
• Reaction time tests
• Motor measures
• Poor divided attention / executive skills
• Trail Making test
• Symbol Digit substitution
• Memory (usual in later stages)

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Specialized Mental Status Testing
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Grooved Pegboard
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Neuropsychological Assessment of HIV Dementia

• Neuropsychological tests are used to
• Identify specific patterns of cognitive
  impairment that are associated with HIV dementia.
• Potentially identify different subtypes of HIV
  dementia.
• Track the progression of cognitive changes
  typically seen in HIV dementia.

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Models of HIV-Associated Dementia

• Progressive cognitive decline starting at time of
  initial infection
• Latency period followed by decline
• Multiple latent or dormant periods and declines

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Changes in Performance on Trails BBefore and
After HIV-1 Seroconversion
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Changes in Performance on Trails BBefore and
After Diagnosis of AIDS
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Stage of HIV Disease and Neuropsychological Test
Performance

• Decline on neuropsychological testing is closely
  linked to general systemic illness.
• In general, observable cognitive changes are not
  seen during early, medically asymptomatic, stages
  of HIV disease.
• Data from HIV-positive subjects with known dates
  of seroconversion suggest that there is no
  relationship between duration of HIV
  seropositivity and neuropsychological decline.

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What is Going on Cognitively During Earlier
Stages of HIV Disease?

• Many patients report changes in cognitive skills
  even during the asymptomatic phase.

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What is Going on Cognitively During Earlier
Stages of HIV Disease?

• Many patients report changes in cognitive skills
  even during the asymptomatic phase.
• There is a significant correlation between
  cognitive complaints and self-reported symptoms
  of depression.

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What is Going on Cognitively During Earlier
Stages of HIV Disease?

• Many patients report changes in cognitive skills
  even during the asymptomatic phase.
• There is a significant correlation between
  cognitive complaints and self-reported symptoms
  of depression.
• Very sensitive cognitive psychology measures
  sometimes show subtle changes during otherwise
  asymptomatic HIV disease (Asymptomatic
  Neurocognitive Impairment).

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What is Going on Cognitively During Earlier
Stages of HIV Disease?

• Many patients report changes in cognitive skills
  even during the asymptomatic phase.
• There is a significant correlation between
  cognitive complaints and self-reported symptoms
  of depression.
• Very sensitive cognitive psychology measures
  sometimes show subtle changes during otherwise
  asymptomatic HIV disease (Asymptomatic
  Neurocognitive Impairment).
• Functional neuroimaging suggests that some
  changes in brain metabolism may occur at
  relatively early stages of HIV disease.

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HAND Classification Using NP and IADLs MACS
(2010)
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Clinical Diagnoses of Dementia and corresponding
Neurology 2007 HAND Criteria in the MACS (2010)
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What are the Practical Implications of These
Research Findings?

• Changes in brain metabolism may be present even
  during early stages of HIV infection.
• When viral load is adequately controlled, these
  changes in brain metabolism do not affect
  day-to-day functioning, motor skills, or higher
  order reasoning even though very subtle changes
  may appear on cognitive testing.

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What are the Practical Implications of These
Research Findings?

• With heightened viral load and immunosuppression,
  HIV may cause a potentially reversible
  inflammation of brain tissue.
• With sustained viral replication, HIV may cause
  permanent cell death.
• Even with uncontrolled viral load and
  immunosuppression, many people do not develop HIV
  dementia.

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Critical Issues to be Addressed

• Potential Triggers/Risk Factors The specific
  triggers that lead some individuals to develop
  dementia while others remain cognitively healthy
  need to be identified.
• Medical Treatments Treatments still need to be
  developed to reverse or delay the progression of
  dementia.

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Potential Triggers/Risk Factors

• Potential explanatory factors
• Brain reserve capacity?
• Genetic susceptibility?
• Greater CNS responsiveness to certain
  medications?
• Demographic factors (age, education, etc.)

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Potential Triggers/Risk Factors

• Individuals with less education are at greater
  risk
• Older individuals may be at greater risk

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HIV and Aging

• Study of 653 men age 40 (Becker, 2009 Sacktor,
  2009)
• Best predictors of poorer cognitive functioning
  were markers of early cerebrovascular disease
  (carotid intima-media thickness and glomerular
  filtration rate).
• HIV serostatus was not an important predictor of
  cognitive impairment.
• Presence of detectable plasma HIV RNA was
  associated with poorer memory performance.

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HIV and Aging

• HIV infection may not be the most important
  predictor of cognitive functions among
  gay/bisexual men in the post-HAART era, at least
  among individuals with access to medical care and
  to appropriate medications.
• Medical factors associated with normal aging are
  significantly associated with performance on
  neuropsychological tests and should be a primary
  focus of case management.

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Medical Treatments for HIV Dementia

• High dose zidovudine (AZT) (ACTG 005)
• Nimodipine (ACTG 162 Calcium channel
  antagonist)
• Memantine (ACTG 301 NMDA antagonist)
• Selegiline (ACTG A5090
  antioxidant/cell repair)
• Highly Active Antiretroviral Therapies (HAART)

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Medical Treatments for HIV Dementia

• Method of action of HAART is not understood
• Reduced systemic viral load?
• Reduced brain viral load?
• Disruption of release of neurotoxins?

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Medical Treatments for HIV Dementia

• Does HAART penetrate the blood-brain-barrier?
• Many types of HAART do not easily cross into the
  brain in laboratory studies
• However, HIV-infected individuals may show
  increased permeability of the blood-brain-barrier

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Medical Treatments for HIV Dementia

• HAART usually reduces viral load both in the
  periphery and in the CNS.
• Reduction of viral load in the CNS is associated
  with reduced cognitive symptoms. (Ellis et al.,
  2003)
• Individuals with stable viral load do not show
  increased risk for cognitive decline, even after
  5 years of monitoring. (Cole et al., 2007)

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Goals of Current Research

• Identify risk factors for developing dementia
• Identify biological mechanisms that lead to cell
  death and dementia
• Establish effective screening tools to identify
  early stage dementia
• Develop medical interventions that will reverse
  the symptoms of dementia before permanent damage
  occurs

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