Transcript Modified HIV Dementia Scale

Cognitive Disorders in HIV
Marshall Forstein, MD
Associate Professor of Psychiatry
Harvard Medical School
Chair, Steering Committee on HIV Psychiatry
American Psychiatric Association
Disclosures
• Nothing to disclose
Overview
• What do we mean by cognitive disorders?
• What are the underlying causes for changes
in mental functioning?
• What should clinicians be looking for?
• How is HIV-related cognitive impairment
assessed and treated?
HIV Impacts Brain and Mind
• Primary effects of HIV
• Consequences of immunological
compromise
• Metabolic/endocrine dysfunction
• Iatrogenic effects of treatment
• Impact of disease on psychological state
• Acute/chronic psychiatric disorders
CNS Dysfunction Due to Treatment
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Antiretrovirals
Antimicrobials
Chemotherapies
Herbal medicines
Substances of abuse
Psychoactive
medications
HIV Cognitive Impairment
The CNS May Be an Independent
Sanctuary Site for HIV
Replication, Particularly in the
Symptomatic Stages of HIV
Illness
The Brain
Compartments
CSF
Brain
CSF
Blood Brain Barrier
Organ
Tissues
Blood
Course of HIV Infection
1,400
Acute “Spike” in VL: CNS Seeded Early in Infection

OD4 Count
1,200
1,000
800
600
400
200
0
CD4 < 500:
Constitution
al
Symptoms
Develop

Virologic
Setpoint:
Carries
Prognostic
Significance

<---- Months------><----------Years--------------------------->

Time Since Infection
Primary HIV
Infection
OI = opportunistic infection; VL = viral load
CD4
VL (x1000)
CD4 < 200: AIDS
Diagnosis, Development
of OI’s Including CNS
Disorders

Brain/ Mind function
• Cognition
• Psychomotor
• Behavior
Cognitive Dysfunction in HIV/AIDS
• HIV impact on brain function
– Direct or indirect
• Hepatitis C virus (HCV) in CNS
– Evidence of cognitive dysfunction
independent of liver function tests
(LFTs)
• Substances of abuse
– Alcohol abuse
– Methamphetamine X, K, G, etc.
HIV and Methamphetamine
• The combined effects are consistent with an additive
model, suggesting additional neuronal injury and glial
activation due to the comorbid conditions1
• Addictive drug increases HIV replication and mutation2
• The combination increases subcortical brain cell injury
and death3
• Barrier to HIV medication adherence4
1Chang
L (2005), Am J Psychiatry 162(2):361-369; 2Ahmad K (2002), Lancet Infec Dis 2(8):456;
3Langford D et al. (2003), J of Acq Immune Def Synd 34(5):467-474; 4Reback CJ et al. (2003),
AIDS Care 15(6):775-785
Domains of Cognition
• Attention
• Orientation
• Memory
– New memory
– Recall
– Long term
• Verbal fluency- language/ communication
• Executive function- organization, decision
making, judgment
• Spatial orientation
– Construction
• Thinking / reasoning
Cognitive Domains
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mental flexibility
concentration
speed of mental processing
memory
Visuo-spatial
constructional abilities
fine motor functions
Classification System
Asymptomatic Neurocognitive
Impairment
Mild Neurocognitive
Impairment
HIV-Associated
Dementia
1 SD
2 Domains
1 SD
2 Domains
2 SD
2 Domains
No Functional
Impairment
Mild Functional
Impairment
Moderate to Severe Functional
Impairment
NIMH, NINDS Panel, June 2005
Cells of the CNS
• Microglia: brain macrophages
– Parenchymal: long-lived, fixed-cells of CNS
– Perivascular: slow turnover with
blood monocytes
• Macroglial cells
– Astrocytes: maintain optimal micro environment for
neurons, maintain integrity of BBB
– Oligodendrocytes: surround neuronal axons
with myelin sheath; electrical insulator for
proper conduction
• Neurons: functional unit
HIV-1 neuroinvasion
Risk Factors for HIV
Neurocognitive Impairment
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Serocoversion illness
Early cognitive impairment, MCMD
Anemia
Vitamin deficiencies (B6, B12)
Low CD4
High CSF viral burden
More physical limitations
Depression
MRI in HIV Dementia
MRI findings in a patient with HIV-associated dementia (right) in comparison to normal (left) at
approximately The same level. T2-weighted images show diffuse, symmetrical,confluent
hyperintensities throughout the hemispheric white matter with prominent atrophy (widened sulcal
markings). There is no enhancement with gadolinium contrast (not shown) and there is no mass effect.
This appearance is typical in HIV associated dementia but is neither sensitive (i.e., some HIV associated
dementia patients may not show this finding) nor pathognomonic (i.e., other disease processes may yield a
very similar MRI picture).
HIV and the CNS
Relationship between concentration of HIV-1 RNA in CSF
and cognitive impairment : unclear association
Ellis RJ, Moore DJ, Childers ME, Letendre S, McCutchan JA, Wolfson T, et al. Progression to neuropsychological
Impairment in human immunodeficiency virus infection predicted by elevated cerebrospinal fluid levels of human
Immunodeficiency virus RNA. Arch Neurol 2002; 59:923–928
McArthur JC, McClernon DR, Cronin MF, Nance-Sproson TE, Saah AJ, St Clair M, Lanier ER. Relationship between
Human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain. Ann Neurol 1997;
42:689–698.
Ellis RJ, Hsia K, Spector SA, Nelson JA, Heaton RK, Wallace MR, et al. Cerebrospinal fluid human immunodeficiency
virus type1 RNA levels are elevated in neurocognitively impaired individuals with acquired immunodeficiency syndrome.
Ann Neurol 1997; 42:679–688.
Conrad AJ, Schmid P, Syndulko K, Singer EJ, Nagra RM, Russell JJ, Tourtellotte WW. Quantifying HIV-1 RNA using
the polymerase chain reaction on cerebrospinal fluid and serum of seropositive individuals with and without neurologic
abnormalities. J Aquir Immune Defic Syndr Hum Retrovirol 1995; 10:425–435.
HIV and the CNS
• AIDS patients with severe cognitive
impairment found to have higher CSF VL
than those cognitively intact or at only
minor neurological signs
• HIV positive patients without AIDS: no
association reported between CSF VL and
cognitive impairment
Important Questions
• What is the relationship between plasma
HIV RNA and CSF HIV RNA?
• How does antiretroviral medication affect
the long term outcome of central nervous
system dysfunction due to HIV?
• Does penetration of anti-retroviralsinto the
CSF correlate with improvement of
cognitive function?
Potential problems with HAART
and cognitive function
• Neurologically active antiretrovirals may:
– Not penetrate equally all brain tissue
– May include mitochondrial toxicity
– May not sustain improvements over the long
term
• Other mechanisms for CNS impairment
may be unaffected by HAART
– Inflammatory response
– Cytokine cascade
Impact of HAART on NP fx
• HAART does not lead to uniform neurocognitive
function
– Psychomotor slowing improves with HAART
• (at least initially)
– Verbal memory and executive function may not
improve with HAART
• Despite lack of change in overall prevalence of
NP impairment there are quantitative and
qualitative changes in the patterns of cognitive
impairment in post HAART
Prevalence and Pattern of Neuropsych
Impairment in HIV/AIDS: pre and post HAART
• Study: neuropsych deficits
– Patients with overt Dementia excluded
– -2 SD in 2 neuropsychological measures
– Pre-HAART = 41.1% Post HAART = 38.8%
• No significant reduction in patients with undetectable plasma
VL
• Pattern of impairment different pre/post HAART
– Improvement in attention, verbal fluency, visuoconstruction
deficits
– Deterioration in learning efficiency and complex attention
– Meaning?: deficits do not reflect “burnt out” damage
but the presence of an active intra-cerebral process
Cysique, Maruff, Brew 2004 Journal of NeuroVirology 10:350-357, 2004
HIV, Age, and Cognitive Impairment
• RISK FACTORS:
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Older age
Depression
Substance use
Detectable VL in Cerebrospinal Fluid
– References:
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Alcour VG at al. Cognitive impairment in older HIV-1-seropositive individuals: prevalence and
potential mechanisms. AIDS 18 (suppl. 1): S79 - 86, 2004.
Becker JT et al. Prevalence of cognitive disorders differs as a function of age in HIV virus
infection. AIDS 18 (suppl. 1): S11 ﾐ S18, 2004.
Cherner M et al. Effects of HIV-1 infection and aging on neurobehavioral functioning: preliminary
findings AIDS 18 (suppl. 1): S27 ﾐ S34, 2004.
Justice AC et al. Psychaitric and neurocognitive disorders among HIV-positive and negative
veterans in care: Veterans Aging Cohort Five-Site Study. AIDS 18 (suppl. 1): 49 -59, 2004.
Treatment of HIV Cognitive
Impairment
Pharmacotherapy of HIV Associated
Cognitive-Motor Disorders
• Primary Treatments
–Antiretroviral medications
• Secondary Treatments
–Immunostimulants and inflammatory
mediators
• Palliative Treatments
–Neurotransmitter manipulation
• Stimulants (methylphenidate/Ritalin)
• Neuroprotective agents (selegiline/L-Depryl)
Modafinil ( Provigil)
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Rabkin JG, et al : pilot study
Open label, 4 weeks
30 pts all completed 4 weeks of treatment
24/30 (80%) rated as responders:
– Improvement on measures of fatigue, depressive
sxs and executive fx
– Side effects: headache, irritability, “hyper”
– Caution re: cognitive effects vs. affective/energy
– [J of Clin Psyciatry, 2004, Dec, Vol 65(12) pges 1688-95]
Psychostimulants
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Methylphenidate
– Dopamine agonist
• 5-10 mg daily
• Move to tid dosing (7 am, 10 am, and 1 pm)
• Usual dose range 30-60 mg/daily
• Beware of potential for abuse
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Infrequently seen
• Beware in patients with history of seizures
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May exacerbate any disposition to
seizures/movement disorders
• Watch for appetite suppression
Assessment of HIV Cognitive
impairment
Modified HIV Dementia Scale
Max Score Pt. Score
Task
Memory-Registration Give four words to recall (dog, hat, green,
peach) - 1 second to say each. Then ask the patient all 4 after you
have said them.)
Psychomotor Speed Ask patient to write the alphabet in upper
case letters horizontally across the page below and record time:
____ seconds.
less than or equal to 21 sec = 6; 21.1 - 24 sec = 5; 24.1 - 27 sec = 4;
27.1 - 30 sec = 3; 30.1 - 33 sec = 2; 33.1 - 36 sec = 1; > 36 sec = 0)
6
Memory - Recall Ask for 4 words from Registration above. Give 1
point for each correct. For words not recalled, prompt with a
"semantic" clue, as follows: animal (dog); piece of clothing (hat),
color (green), fruit (peach). Give 1/2 point for each correct after
prompting
4
Construction Copy the cube below; record time: ____ seconds.
(< 25 sec = 2; 25 - 35 sec = 1; > 35 sec = 0)
2
Total Score
Max= 12
/12
< 7.5 may indicate dementia and should be evaluated by full
battery if possible
Modified HIV Dementia Scale
Write Alphabet:
Modified from the Johns Hopkins University Department of Neurology HIV Dementia Scale- Powers, et al.
International HIV Dementia
Scale (IHDS)
1. Memory-Registration
• Give four words to recall
– (dog, hat, bean, red) – 1 second to say each.
• Then ask the patient all four words after you
have said them. Repeat words if the patient
does not recall them all immediately. Tell the
patient you will ask for recall of the words again
a bit later.
2. Motor Speed
Have the patient tap the first two fingers of the
non-dominant hand as widely and as quickly as
possible.
4 = 15 in 5 seconds
3 = 11-14 in 5 seconds
2 = 7-10 in 5 seconds
1 = 3-6 in 5 seconds
0 = 0-2 in 5 seconds
_____
3. Psychomotor Speed
Have the patient perform the following movements with the
non-dominant hand as quickly as possible:
– 1) Clench hand in fist on flat surface.
– 2) Put hand flat on surface with palm down.
– 3) Put hand perpendicular to flat surface on the side of the 5th
digit.
– Demonstrate and have patient perform twice for practice.
4 = 4 sequences in 10 seconds
3 = 3 sequences in 10 seconds
2 = 2 sequences in 10 seconds
1 = 1 sequence in 10 seconds
0 = unable to perform
_____
4. Memory-Recall
• Ask the patient to recall the four words. For words
not recalled, prompt with a semantic clue as
follows:
– animal (dog); piece of clothing (hat); vegetable (bean);
color (red).
• Give 1 point for each word spontaneously
recalled.
• Give 0.5 points for each correct answer after
prompting
• Maximum – 4 points.
_____
Total International HIV
Dementia Scale Score
This is the sum of the scores on items 2-4. ____
The maximum possible score is 12 points.
A patient with a score of
 10
should be evaluated further for possible dementia.
N. Sacktor, et.al. Department of Neurology Johns Hopkins University Baltimore, Maryland
Living with Cognitive
Impairment
• Adapting to the diagnosis
• Accurate assessment of specific deficits
– Self report is not accurate
• Depression most commonly confused with
cognitive slowing
• Adherence to medications, appts.
Protecting the Brain
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Reducing cardiovascular risk
Preventing hypertension
Mental and physical Exercise
Diet
Attitude
Living with Cognitive
Impairment
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Will to live
Spiritual issues
Sexuality issues
Use of complimentary/alternative Rx’s
Living with Cognitive
Impairment
• Diet
• Exercise increases BDNF
– Brain Derived Neurotropic Factor
• Shown to increase neuron growth and increase
synaptic transmission
• Protein encoded by BNDF gene on Chromosome 11
• Meditation, relaxation training
• Psychotherapy
– Individual, group, self help, volunteerism