Cognitive Disorders in HIV Marshall Forstein, MD Associate Professor of Psychiatry Harvard Medical...
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Cognitive Disorders in HIV Marshall Forstein, MD Associate Professor of Psychiatry Harvard Medical School Chair, Steering Committee on HIV Psychiatry American
Cognitive Disorders in HIV Marshall Forstein, MD Associate
Professor of Psychiatry Harvard Medical School Chair, Steering
Committee on HIV Psychiatry American Psychiatric Association
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Disclosures Nothing to disclose
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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?
Slide 4
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
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CNS Dysfunction Due to Treatment Antiretrovirals Antimicrobials
Chemotherapies Herbal medicines Substances of abuse Psychoactive
medications
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HIV Cognitive Impairment
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The CNS May Be an Independent Sanctuary Site for HIV
Replication, Particularly in the Symptomatic Stages of HIV
Illness
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The Brain
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Compartments Organ Tissues Brain CSF Blood CSF Blood Brain
Barrier
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Course of HIV Infection Virologic Setpoint: Carries Prognostic
Significance Primary HIV Infection CD4 < 200: AIDS Diagnosis,
Development of OIs Including CNS Disorders Acute Spike in VL: CNS
Seeded Early in Infection CD4 < 500: Constitution al Symptoms
Develop Time Since Infection OI = opportunistic infection; VL =
viral load OD4 Count 0 200 400 600 800 1,000 1,200 1,400 CD4 VL
(x1000)
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Brain/ Mind function Cognition Psychomotor Behavior
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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.
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HIV and Methamphetamine The combined effects are consistent
with an additive model, suggesting additional neuronal injury and
glial activation due to the comorbid conditions 1 Addictive drug
increases HIV replication and mutation 2 The combination increases
subcortical brain cell injury and death 3 Barrier to HIV medication
adherence 4 1 Chang L (2005), Am J Psychiatry 162(2):361-369; 2
Ahmad K (2002), Lancet Infec Dis 2(8):456; 3 Langford D et al.
(2003), J of Acq Immune Def Synd 34(5):467-474; 4 Reback CJ et al.
(2003), AIDS Care 15(6):775-785
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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
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Cognitive Domains mental flexibility concentration speed of
mental processing memory Visuo-spatial constructional abilities
fine motor functions
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Classification System Asymptomatic Neurocognitive Impairment
Mild Neurocognitive Impairment HIV-Associated Dementia No
Functional Impairment Mild Functional Impairment Moderate to Severe
Functional Impairment 1 SD 2 Domains 2 SD 2 Domains NIMH, NINDS
Panel, June 2005 1 SD 2 Domains
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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
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HIV-1 neuroinvasion
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Risk Factors for HIV Neurocognitive Impairment Serocoversion
illness Early cognitive impairment, MCMD Anemia Vitamin
deficiencies (B 6, B 12 ) Low CD 4 High CSF viral burden More
physical limitations Depression
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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).
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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; 59:923928 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; 42:689698.
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; 42:679688.
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; 10:425435.
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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
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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?
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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
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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
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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
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HIV, Age, and Cognitive Impairment RISK FACTORS: Older age
Depression Substance use Detectable VL in Cerebrospinal Fluid
References: 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 S18, 2004. Cherner M
et al. Effects of HIV-1 infection and aging on neurobehavioral
functioning: preliminary findings AIDS 18 (suppl. 1): S27 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.
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Treatment of HIV Cognitive Impairment
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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)
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Modafinil ( Provigil) 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]
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Psychostimulants 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 Infrequently seen Beware in
patients with history of seizures May exacerbate any disposition to
seizures/movement disorders Watch for appetite suppression
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Assessment of HIV Cognitive impairment
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Modified HIV Dementia Scale Max Score Pt. ScoreTask
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.) 6 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) 4 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 2
Construction Copy the cube below; record time: ____ seconds. ( 35
sec = 0) Total Score Max= 12/12 < 7.5 may indicate dementia and
should be evaluated by full battery if possible
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Modified HIV Dementia Scale Write Alphabet: Modified from the
Johns Hopkins University Department of Neurology HIV Dementia
Scale- Powers, et al.
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International HIV Dementia Scale (IHDS)
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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.
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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
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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
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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. _____
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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
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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.
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Protecting the Brain Reducing cardiovascular risk Preventing
hypertension Mental and physical Exercise Diet Attitude
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Living with Cognitive Impairment Will to live Spiritual issues
Sexuality issues Use of complimentary/alternative Rxs
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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