HIV Neuropsychiatric Issues Warren Y.K. Ng, M.D. NYPH/ Harlem Hospital HIV Mental Health Training...

HIV Neuropsychiatric IssuesHIV Neuropsychiatric Issues

Warren Y.K. Ng, M.D.Warren Y.K. Ng, M.D.

NYPH/ Harlem HospitalNYPH/ Harlem Hospital

HIV Mental Health Training ProjectHIV Mental Health Training Project

Columbia UniversityColumbia University

2828thth Year of AIDS Year of AIDS

World AIDS Day World AIDS Day Dec 1, 2009Dec 1, 2009

Twenty-Five year trends in HIV Twenty-Five year trends in HIV and AIDS cases 1984-2007and AIDS cases 1984-2007

Good News and Bad News

Steven Deeks MD IAS-USA May 2009

Poor life expectancy 10-30 years less “Patients receiving long

term antiretroviral therapy are at increased risk of age associated non-AIDS related morbidity/mortality…”

Higher rates of non-AIDS dx Cardiovascular disease Cancers Osteopenia LV Dysfunction Liver Failure Kidney Failure Cognitive Decline

Accelerated aging/chronic inflammation

New York Magazine 11-9-09The New HIV Scare

Article: Another Kind of AIDS Crisis

“Brain impairments are the unexpected new minefield among HIV positive people who have been on protease inhibitors. According to research presented this summer … in Capetown, 52 % of all Americans infected with HIV (mean age 43) suffer from some type of cognitive impairment- mostly mild or moderate dementias, … impeding one’s ability to function on a day-to-day basis.”

Another Kind of AIDS Crisis CHARTER (CNS HIV antiretroviral therapy

effects research) Igor Grant UCSD Started in 2002 $38 million in NIH grants Follows 1500 patients living with HIV Scott Letendre UCSD viral replication in CNS

Manhattan HIV Brain Bank 250 volunteers Persistent inflammation, little viral replication High rates of psychiatric/substance abuse disorders

Overview of Psychiatric issues Psychiatric disorders are common with Individual

living with HIV/AIDS (Bing 2001, Mellins 2002, McKinnon 2008)

50% Mood and Anxiety disorder 25% current Substance abuse or dependence 26% Personality Disorder

Psychiatric dx are linked to slower rates of virologic suppression and treatment (Pence et al 2007)

Treatment of Psychiatric disorders is associated Slower disease progression and mortality (Belanoff 2005)

Improved treatment adherence (Wyatt 2004)

Decrease in HIV transmission risk behavior (Sikkema 2008, Wyatt 2004)

Improved quality of life (Sikkema 2005)

Assessing Neuropsychiatric issuesAssessing Neuropsychiatric issues

Look for underlying biological cause

1. Medications: HIV, psychiatric, other

2. Substances: Alcohol, drugs, herbal, other

3. Non-HIV medical problems4. HIV-related illnesses:

• CNS lesions, infections• Non-CNS medical problems

Psychiatric Syndromes

HIV-neuropsychiatric manifestations: • MCMD• HAD

and/or

Initial Approach to ManagementInitial Approach to Management

Exclude other treatable causesExclude other treatable causes

▪ ▪ MRI to exclude OIs; Labs: thyroid, B12, hematology/chemistry; MRI to exclude OIs; Labs: thyroid, B12, hematology/chemistry; CSF for OI or VL CSF for OI or VL

▪ ▪ Rule out substance abuse issues- crystal meth, ETOHRule out substance abuse issues- crystal meth, ETOH

Self-reports of cognitive problems and bedside cognitive Self-reports of cognitive problems and bedside cognitive status tests may be insensitive, particularly to subtler forms status tests may be insensitive, particularly to subtler forms of impairmentof impairment

Neuropsychological screenersNeuropsychological screeners

Family and collateral historyFamily and collateral history

HIV-Neuropsychiatric HIV-Neuropsychiatric Manifestations Manifestations

HIV Associated Neurocognitive HIV Associated Neurocognitive Disorders (HAND)Disorders (HAND)

Asymptomatic neurocognitive Asymptomatic neurocognitive impairment (ANI)impairment (ANI)

Minor Cognitive Motor Disorder/ Mild Minor Cognitive Motor Disorder/ Mild Neurocognitive DisorderNeurocognitive Disorder

HIV Associated Dementia/ Moderate HIV Associated Dementia/ Moderate Neurocognitive DisorderNeurocognitive Disorder

Prevalence of HIV Associated Prevalence of HIV Associated Neurocognitive Disorders - HANDNeurocognitive Disorders - HAND

NP Normal

“Sub-clinical” NP Test

Impairment 30-50%

MCMD20%

HAD2-4%

Functional Impairment

NP – Neuro-Psychological

Minor Cognitive Motor Minor Cognitive Motor Disorder – MCMD/Mild Disorder – MCMD/Mild Neurocognitive DisorderNeurocognitive Disorder

HIV Associated Dementia HIV Associated Dementia – – HAD/Moderate-Severe ND)HAD/Moderate-Severe ND)

≠

Neuroimaging studiesNeuroimaging studies

Pre ARV- Pre ARV- subcortical & subcortical & Periventricular Periventricular White Matter White Matter ChangesChanges

Post ARV-Post ARV-mixed cortical mixed cortical and subcortical and subcortical featuresfeatures

HIV and the CNSHIV and the CNS

HIV enters the central nervous system (CNS) soon HIV enters the central nervous system (CNS) soon after initial infection and is responsible for a range after initial infection and is responsible for a range of neuropsychiatric complications of neuropsychiatric complications

Although HIV is neuroinvasive, it does not directly Although HIV is neuroinvasive, it does not directly infect neurons infect neurons

The major brain reservoirs for HIV infection and The major brain reservoirs for HIV infection and replication are microglia and macrophages. replication are microglia and macrophages. Astrocytes can be infected but are not a site of Astrocytes can be infected but are not a site of active HIV replication active HIV replication

HIV-associated neurological complications are HIV-associated neurological complications are indirect effects of viral neurotoxins (viral proteins indirect effects of viral neurotoxins (viral proteins gp120 and tat) and neurotoxinsgp120 and tat) and neurotoxins

Nomenclature of HIV-1 CNS Nomenclature of HIV-1 CNS Disorders 1Disorders 1

Mild ManifestationsMild Manifestations• HIV-Associated HIV-Associated

Mild Mild Cognitive/Motor Cognitive/Motor Disorder (MCMD)Disorder (MCMD)

• Mild Mild Neurocognitive Neurocognitive Disorder (MND)Disorder (MND)

Diagnostic CriteriaDiagnostic Criteria1 At least 2 symptoms: At least 2 symptoms:

impaired attention, impaired attention, concentration, memory, concentration, memory, mental and psychomotor mental and psychomotor slowing, impaired slowing, impaired coordination, personality coordination, personality change.change.

2 >1 month>1 month

Minor Cognitive-Motor Disorder/ Minor Cognitive-Motor Disorder/ Mild Neurocognitive Disorder (MND)Mild Neurocognitive Disorder (MND)

Clinical FeaturesClinical Features

• Mild impairment in Mild impairment in

functioningfunctioning• Impaired attention or Impaired attention or

concentrationconcentration• Memory/concentration Memory/concentration

problemsproblems• Low energy/slowed Low energy/slowed

movementsmovements• Impaired coordinationImpaired coordination• Personality change, Personality change,

irritability or emotional irritability or emotional labilitylability

Patient Complaints/SymptomsPatient Complaints/Symptoms• Patients may not recognize the Patients may not recognize the

problem since their is mild problem since their is mild functional impairmentfunctional impairment

• Has difficulty with complex Has difficulty with complex tasks tasks

• Mild memory problemsMild memory problems• Distractibility/confusion Distractibility/confusion • Needs to make lists Needs to make lists • Adherence problems Adherence problems • May make excuses for May make excuses for

forgettingforgetting

Minor Cognitive-Motor DisorderMinor Cognitive-Motor Disorder / / Mild Neurocognitive Disorder (MND)Mild Neurocognitive Disorder (MND)

OverviewOverview

Prevalence pre ARV Prevalence pre ARV • 20-30% for asymptomatic clients20-30% for asymptomatic clients• 60%-90% for late stage clients60%-90% for late stage clients

Prevalence post ARVPrevalence post ARV• 5%, 15% & 25% in asymptomatic, early or late 5%, 15% & 25% in asymptomatic, early or late

stagestage

Possible Risk FactorsPossible Risk Factors• Age, late stage disease, viral loadAge, late stage disease, viral load

Minor Motor-Cognitive Disorder /Minor Motor-Cognitive Disorder / Mild Neurocognitive Disorder (MND) Mild Neurocognitive Disorder (MND)

Often does not present for any treatment and not recognized nor diagnosed

Differential Diagnosis: Diagnosis of ExclusionDifferential Diagnosis: Diagnosis of Exclusion

TreatmentTreatment• Antiretroviral medications Antiretroviral medications • Neurotransmitter manipulationNeurotransmitter manipulation• Non-pharmacological treatments and Non-pharmacological treatments and

issues issues

Nomenclature of HIV-1 CNS Nomenclature of HIV-1 CNS Disorders 2Disorders 2

Severe ManifestationsSevere Manifestations• HIV-Associated HIV-Associated

Dementia (HAD)Dementia (HAD)• Moderate to severe Moderate to severe

neurocognitive disorderneurocognitive disorder

Diagnostic CriteriaDiagnostic Criteria1 Acquired cognitive abnormality Acquired cognitive abnormality

in 2 or more domains, causing in 2 or more domains, causing functional impairmentfunctional impairment

2 Acquired abnormality in motor Acquired abnormality in motor performance or behaviorperformance or behavior

3 No clouding of consciousness No clouding of consciousness or other confounding etiology or other confounding etiology (e.g. other CNS OIs, (e.g. other CNS OIs, psychopathology, drug abuse)psychopathology, drug abuse)

HIV-Associated Dementia (HAD)/HIV-Associated Dementia (HAD)/Moderate to Severe Neurocognitive DisorderModerate to Severe Neurocognitive Disorder

Clinical Features• Cognitive, motor, and

behavioral problems• Attention/

concentration problems

• Slowed decision-making

• Abstraction/reasoning problems

• Visuospatial skill problems

• Memory/learning impairment

• Speech/language problems

Patient Complaints, SymptomsPatient Complaints, Symptoms

• Memory problems/“I’m very Memory problems/“I’m very forgetful”forgetful”

• Distractibility/“I lose track of Distractibility/“I lose track of conversations”conversations”

• ““I can’t keep up with work”I can’t keep up with work”• Anger/irritabilityAnger/irritability• Fatigued/slowFatigued/slow• ““I am depressed”/sadnessI am depressed”/sadness• Complains of poor balance, Complains of poor balance,

clumsinessclumsiness


OverviewOverview

Prevalence pre ARVPrevalence pre ARV• Early studies estimated 15-20%Early studies estimated 15-20%• Current studies estimate 5-10%Current studies estimate 5-10% Prevalence post ARV Prevalence post ARV • 50% reduction; not as prominent as other CNS OIs50% reduction; not as prominent as other CNS OIs

Possible Risk FactorsPossible Risk Factors• Older age, low CD4 count, high viral load, drug Older age, low CD4 count, high viral load, drug

interactions, co-infections, gender, previous interactions, co-infections, gender, previous deliriumdelirium


Differential Diagnosis: Diagnosis by ExclusionDifferential Diagnosis: Diagnosis by ExclusionTreatmentTreatment

• Antiretroviral medications Antiretroviral medications • Neurotransmitter manipulationNeurotransmitter manipulation• Non-pharmacological treatmentsNon-pharmacological treatments

• Environmental engineeringEnvironmental engineering• EducationEducation• Supportive TherapySupportive Therapy


ARV and HAD: Improvement in Cognitive StatusARV and HAD: Improvement in Cognitive Status Improvement in immune status? Improvement in immune status?

Increased CD4 cell count and decrease in Increased CD4 cell count and decrease in plasma viral load and cerebral spinal fluid plasma viral load and cerebral spinal fluid (CSF) viral load (CSF) viral load

Some studies, CSF HIV viral load correlates with Some studies, CSF HIV viral load correlates with severity of cognitive dysfunction, particularly if severity of cognitive dysfunction, particularly if CD4 <200CD4 <200 Measurement of viral load in CSF is a research Measurement of viral load in CSF is a research

tool, rather than routine standard of caretool, rather than routine standard of care

HIV Dementia Scale Screening TestHIV Dementia Scale Screening Test

ScoreScore Memory-Registration Memory-Registration Give four words to recall (dog, hat, green, peach) - 1 second to 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.) say each. Then ask the patient all 4 after you have said them.)

44 AttentionAttention Anti-saccadic eye movements Anti-saccadic eye movements11: 20 (twenty) commands. ____ errors of 20 : 20 (twenty) commands. ____ errors of 20 trials. (less than or equal to 3 errors = 4; 4 errors = 3; 5 errors = 2; 6 errors = 1; > 6 trials. (less than or equal to 3 errors = 4; 4 errors = 3; 5 errors = 2; 6 errors = 1; > 6 errors = 0) errors = 0)

66

Psychomotor SpeedPsychomotor Speed Ask patient to write the alphabet in upper case letters Ask patient to write the alphabet in upper case letters horizontally across the page (use back of this form) and record time: ___seconds. horizontally across the page (use back of this form) 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 = (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) 3; 30.1 - 33 sec = 2; 33.1 - 36 sec = 1; > 36 sec = 0)

44

Memory - RecallMemory - Recall Ask for 4 words from Registration above. Give 1 point for each 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 correct. For words not recalled, prompt with a "semantic" clue, as follows: animal (dog); piece of clothing (hat), color (green), fruit (peach). (dog); piece of clothing (hat), color (green), fruit (peach). Give 1/2 point for each Give 1/2 point for each correct after prompting.correct after prompting.

22ConstructionConstruction

Copy the cube; record time: __ seconds. (Copy the cube; record time: __ seconds. (< 25 sec = 2; 25 - 35 sec = 1; > 35 sec = 0)< 25 sec = 2; 25 - 35 sec = 1; > 35 sec = 0)

1616 (10 or less ~ HIV dementia)(10 or less ~ HIV dementia)

1 Hold both hands up at patient's shoulder width and eye height, and ask patient to look at your nose. Move the index finger of one hand, and instruct patient to look at the finger that moves, then look back to your nose. Practice until patient is familiar with task. Then, instruct patient to look at the finger which is NOT moving. Practice until patient understands task. Perform 20 trials. An error is recorded when the patient looks towards the finger that is moving.

HIV Dementia Scale Screening Test HIV Dementia Scale Screening Test (modified)(modified)

ScoreScore Memory-Registration Memory-Registration Give four words to recall (dog, hat, green, peach) - 1 second to 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.) say each. Then ask the patient all 4 after you have said them.)

66

Psychomotor SpeedPsychomotor Speed Ask patient to write the alphabet in upper case letters Ask patient to write the alphabet in upper case letters horizontally across the page (use back of this form) and record time: ___seconds. horizontally across the page (use back of this form) 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 = (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) 3; 30.1 - 33 sec = 2; 33.1 - 36 sec = 1; > 36 sec = 0)

44

Memory - RecallMemory - Recall Ask for 4 words from Registration above. Give 1 point for each 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 correct. For words not recalled, prompt with a "semantic" clue, as follows: animal (dog); piece of clothing (hat), color (green), fruit (peach). (dog); piece of clothing (hat), color (green), fruit (peach). Give 1/2 point for each Give 1/2 point for each correct after prompting.correct after prompting.

22ConstructionConstruction

Copy the cube; record time: __ seconds. (Copy the cube; record time: __ seconds. (< 25 sec = 2; 25 - 35 sec = 1; > 35 sec = 0)< 25 sec = 2; 25 - 35 sec = 1; > 35 sec = 0)

1212 (7.5 or less ~ HIV dementia)(7.5 or less ~ HIV dementia)

Screening for HIV Associated Screening for HIV Associated Neurocognitive Disorders – HAND: Neurocognitive Disorders – HAND:

MOS HIV Cognitive Functional MOS HIV Cognitive Functional Status ScaleStatus Scale

1.1. Difficulty reasoning and solving problems?Difficulty reasoning and solving problems?

2.2. Forget things that happened recently?Forget things that happened recently?

3.3. Trouble keeping your attention on any Trouble keeping your attention on any activity?activity?

4.4. Difficulty doing activities involving Difficulty doing activities involving concentration and thinking?concentration and thinking?

Validated against NP overall performanceKnippels et al., AIDS 2002

Mainstay of Treatment Mainstay of Treatment

for Neurocognitive Disorders for Neurocognitive Disorders

Is ARVIs ARV

NP Improvement with ARVNP Improvement with ARV

Greater numbers of CSF-penetrating drugs Greater numbers of CSF-penetrating drugs showed greater reduction in CSF viral load. showed greater reduction in CSF viral load.

CSF virological suppression demonstrated greater CSF virological suppression demonstrated greater global deficit score (GDS) improvement global deficit score (GDS) improvement

NP improvement was greater in ART-naive versus NP improvement was greater in ART-naive versus treatment-experienced subjects. treatment-experienced subjects.

Including CSF-penetrating drugs in the ART Including CSF-penetrating drugs in the ART regimen and monitoring CSF viral loadregimen and monitoring CSF viral load

Letendre et al., Ann Neurol 2004

Conceptualization of CNS Conceptualization of CNS Treatment StrategiesTreatment Strategies

Antiretroviral medications with higher CPEAntiretroviral medications with higher CPE• stavudine stavudine (D4T)(D4T)• zidovudine zidovudine (ZDV) (ZDV) • abacavir abacavir (ABV) (ABV) • efavirenz efavirenz (EFV)(EFV)• nevirapine nevirapine (NVP) (NVP) • indinavir indinavir (IDV)(IDV) • lamivudine (3TC)lamivudine (3TC)

CNS penetration-effectiveness CNS penetration-effectiveness (CPE) Rank (CPE) Rank

CHARTER Study (CNS HIV Antiretroviral Therapy Effects

Research)

00 LowLow 0.5 Intermediate0.5 Intermediate 1 1 HighHigh

Based on chemical properties (large molecular Based on chemical properties (large molecular weight) weight)

concentrations in CSF (measurable concentrations in CSF (measurable animal/human)animal/human)

effectiveness in CNS in clinical studieseffectiveness in CNS in clinical studies

Letendre et al., 2008

CNS penetration–effectiveness (CPE) score to CNS penetration–effectiveness (CPE) score to estimating HAART ability to improve cognitionestimating HAART ability to improve cognition

n = 92 at risk for, and n = 93 with HIV-associated neurocognitive n = 92 at risk for, and n = 93 with HIV-associated neurocognitive disorders disorders underwent neuropsychological (NP) testing before HAART initiation underwent neuropsychological (NP) testing before HAART initiation and at follow-upand at follow-up

Higher CPE scores Higher CPE scores correlatedcorrelated with greater improvements in NP with greater improvements in NP testing testing

The correlation was stronger among NP-impaired patients.The correlation was stronger among NP-impaired patients. No association was seen between CD4 and plasma viral load No association was seen between CD4 and plasma viral load

changes with both scores.changes with both scores.

CPE scores

1 high

zidovudine, abacavir, delavirdine,nevirapine, amprenavir-ritonavir, fosamprenavir-ritonavir, atazanavir-ritonavir, indinavir-ritonavir, lopinavir-ritonavir

0.5 intermediate

stavudine, lamivudine, emtricitabine, efavirenz, amprenavir, fosamprenavir atazanavir, indinavir

0 low remaining antiretrovirals

Tozzi et al, J Acquir Immune Defic Syndr 2009;52:56–63

Copyright restrictions may apply.

Letendre et al., Arch Neurol 2008

Subjects who had lower CNS Penetration-Effectiveness (CPE) ranks were more likely to have detectable cerebrospinal fluid (CSF) viral load when CPE rank was analyzed

as a continuous variable (A) or as a categorical variable (B)

How important is CPE?

In theory, this is an important issue since the use of “neuroactive” HAART regimens appears promising

However, standardized CPE ratings and specific clinical guidelines for antiretroviral medications

At this time, the selection of antiretroviral regimens must be based on sensitivity/resistance patterns Adherence issues quality of life considerations

Conceptualization of CNS Treatment Conceptualization of CNS Treatment StrategiesStrategies

• Adjuvant agents (SSRIs, SNRIs, Stimulants, Adjuvant agents (SSRIs, SNRIs, Stimulants, Modafinil, others) Modafinil, others)

• RehabilitativeRehabilitative• Supportive therapy and cognitive skills trainingSupportive therapy and cognitive skills training• Anti-inflammatory agents: Vitamin E, SeleniumAnti-inflammatory agents: Vitamin E, Selenium• If deficient:If deficient:• Hormone (replace/supplement): Testosterone, Hormone (replace/supplement): Testosterone,

DHEADHEA• Nutritional interventions: Vitamin E, B6, B12, Nutritional interventions: Vitamin E, B6, B12,

Zinc, Selenium, SAM, Folate, Omega-3 fatty Zinc, Selenium, SAM, Folate, Omega-3 fatty acidsacids

Conclusion

HIV Neuropsychiatric Manifestations Disease of the immune system and CNS

HIV Assoc Neurocognitive Disorders (HAND) and new terms ANI, Mild-severe ND

Increasingly prevalent with advancing age CHARTER recommendations regarding HAND Primary focus of treatment is ARVs

Neuroactive HAART regimens ARV Adherence is critical Symptomatic improvement is secondary

HIV Neuropsychiatric Issues Warren Y.K. Ng, M.D. NYPH/ Harlem Hospital HIV Mental Health Training...

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Transcript of HIV Neuropsychiatric Issues Warren Y.K. Ng, M.D. NYPH/ Harlem Hospital HIV Mental Health Training...