Neuropsychiatric aspects of hiv
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Neuropsychiatric Aspects of HIV. University of Hawaii James Dilley, MD and Emily Leavitt, LCSW. Prevalence of MH Disorders among People with HIV/AIDS n = 1489. Vitiello et al. AJPsych 2003, 160:547-54 from “HIV Cost and Services Utilization Study—1996”. Depression in HIV.

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Neuropsychiatric Aspects of HIV

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Neuropsychiatric Aspects of HIV

University of Hawaii

James Dilley, MD and Emily Leavitt, LCSW


Prevalence of MH Disorders among People with HIV/AIDSn = 1489

Vitiello et al. AJPsych 2003, 160:547-54

from “HIV Cost and Services Utilization Study—1996”


Depression in HIV

  • Most common dx in outpt settings

  • Concern re: diagnosis in medically ill

  • Emphasize cognitive/affective vs. neurovegatative signs/sxs

  • Assoc with CD4, soc support and  phys limitations and HIV sx

  • Excellent pharmacologic response

  • Give benefit of the doubt


Pharmacotherapy of Depression in HIV


Depression & Testosterone

  • 50% of men with Sx HIV/AIDS have deficiency and sx of hypogonadism:

    • Fatigue

    • Decreased libido

    • Decreased appetite

    • Decreased mood


Screening Tests

  • Total Serum Testosterone: <300-400ng/dl

  • Serum Free testosterone: <5-7 pcg/ml

  • Tx: depot IM injections q ii wks (100-200mg IM; max 400 mg/wk)

  • Patch (5-10mg; 1-2 times daily)

  • Gel (25-100 mg to skin daily)

  • Can see mood improvement


HIV produces at diff rates in CNS vs. plsma

Diff phen/genotypes: esp later in disease

All ARV’s not = in treating CNS cx

May result in peripheral success (pVL) but central failure

CNS: HIV’s Most Important Sanctuary Site


HIV Neuropathogenesis

Early and continuous seeding

Importance of Blood Brain Barrier


HAD: A Diagnosisof Exclusion

  • HIV antibody positive

  • No other treatable disorder known to be associated with mental status changes (e.g., no other CNS OI’s, trauma, metabolic disorders, etc.


Diagnosis Requires (continued):

  • “Clinical findings of disabling cognitive and /or motor dysfunction interfering with occupation or activities of daily living”

  • Neuropsychological testing often needed, especially in early cases--

  • (1 SD below age/education adjusted norms on 2/8 tests) AND

  • Either impairment in lower ext or fine motor skills or selfreported depression interfering with function


Pseudo-Dementia

  • Depression in “dementia’s clothing”

  • Index of suspicion high if:

    • unremitting and detailed c/o memory pblms

    • “I don’t know” responses to cog questions: communicates distress/emphasizes disability

    • Behavior often incongruent w/level of complaint

    • In early stages of HIV disease

    • Frequently has past hx of psychiatric pblms


Cognitive Functions

A. Memory

Short-term vs. delayed

B. Concentration, Calculation and

Constructional Ability

C. Personality Change: alteration or accentuation of pre-morbid traits

D. Language

E. Judgement

“Reasonable plans”


Early Manifestations of HAD

  • Cognitive

    Memory Loss(names, historical details, etc.)

    Impaired Concentration(difficulty reading, loses track of conversation)

    Mental slowing(“not as quick,” less verbal)

    Confusion(time, especially)


Early Manifestations of HAD (continued)

  • Behavioral

    Apathy, withdrawal, “depression”

    Agitation, hallucination

  • Motor

    Unsteady gait

    Bilateral leg weakness

    Tremor

    Loss of fine motor coordination


Late Manifestations

  • Cognitive

    global dementia in all spheres

    confusion and distractability

    slow verbal responsiveness

  • Behavioral

    vacant stare

    disinhibition and restlessness

    organic psychosis


Late Manifestations (cont.)

  • Motor

    general slowing

    truncal ataxia

    weakness: legs > arms

    pyramidal tract signs: spasticity, hyperreflexia


Effect of HAART

  • Significant changes in the epidemiology of CNS disorders since HAART

  • In Sx illness

    • Studies are more consistent with subcortical dementia

  • In asx illness, NP findings are inconsistent

    • > Length of battery>NP deficits

    • Significance clinically is unclear


Pathological Findings in CNS of AIDS Patients at Autopsy N = 1597

1984-1987

(No therapy)

1988-1994

(monotherapy)

1995-1996

(dual comb. therapy)

1997-2000

(triple comb. therapy)

Vago L., et al. AIDS 2002, 16:1925-28


Risk Factors for Cognitive Impairment in HIVCase Control: 90 HIV- ; 88 ASX; 94 SXCI = Scores of 2SD below the means of the control on 2 or more standard neuropsychological tests


HAART

N69

CD 4254

UVL42%

NPI22%

Non-HAART

61

342

20% p<0.01

54% p<0.0001

HAART Use & NP FunctionN = 130; Avg Age = 41; 42% NW; 82% AIDS

Ferrando et al., AIDS, 1998, 12F 65-70

NOTE: IMP =  25D in the impaired direction of age-matched

population-based norms

HAART=  NRTI + Ritanavir, Indinavir or Nelfinavir


Median HIV RNA levels for brain (for all available brain regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severe

McClernon D.R, et al. Neurology 2001, 57:1396-1401


P  CSF

< 200>200

No No

NoYes*

NoYes

NoYes*

No No

CSF  NP Status

< 200>200

Yes No

Yes No

Yes No

Yes No

Yes No

Correlation of Plasma VL to CSF VL

Brew (Aus)

Ellis (US)

MacArthur (US)

Dore (US)

DiStephano (Italy)

___________________________

* Correlation exists in ASX state


Favorable CNS Characteristics of ARVs

  • % protein binding ( = better)

  • lipid solubility ( = better)

  • molecular weight ( = better)

  • inhibitory concentration ( = better)


Medical Rx of HAD

1. Aggressive ARV: neuroprotective

2. Use combinations of 3, 4 or more

Should include:

• AZT, D4T, 3TC, Abac-NRTI

• Nevirapine, Efavirenz-NNRTI

• Indinavir - PI

(best BBB penetrance)


Factors Influencing Efficacy of ARV Rx:

  • Stage of HIV disease

  • Degree of CNS replication/resistance

  • Integrity of BBB

  • Specific treatment strategy/ARV choice


Some NeuroprotectiveDisappointments

Nimodipene interaction with CAH

Peptide Tblock gp-120

*MemantineNMDA antagonist/showing efficacy for ADV

*DeprenylAnti-oxidant/anti-poptotic

LexipafantPAF antagonist

*some benefits


Case History - “JC”

ID: 42 y/o GWM architect admitted for agitation,

irritability, decreased sleep, and grandiose delusions. Brought in by lover of 7 yrs.

HPITwo mos intermittent confusion/ hypomania (rapid speech, disorganized thinking over last 3 days; focus on spiritual issues. Felt friends were trying to harm him, stated he had been cured of AIDS; claimed he was a millionaire.

PMHHIV infected x 10 years; current CD4 count = 70.

No OI’s. No previous psych hx.


Case History - “JC” (cont.)

MS: Alert, mildly agitated, unable to sit still.

Speech: mildly pressured, loud, but interruptable.

Thought process: overly inclusive, loose assns.

Content: grandiose, “richest family in California,”

had “cured himself of AIDS.” Some paranoia.

Cognitive: 0 x 2.

Memory: Imm = 4/4; 2/4 @ 5 mins. 3/4 with prompts.

Attention: Serial 7’s = mult. Errors;

WORLD backwards, “d-l-o-w.”

Abstraction: Some concreteness.

Construction: OK

Insight: none

Judgement: impaired


Case History - “JC” (cont.)

Diff Dx:

Axis 1: Delirium due to HIV disease (293.0).

Dementia due to HIV disease (294.1)

R/O BAD

R/O Toxic Psychosis

Axis II: Deferred

Axis III: AIDS


Hospital Course

LAB:

MRI: Extensive cortical atrophy.

LP: unremarkable

Rx: Trilafon 2mg p.o. BID and 4 mg @ HS

Valproic acid 250mg p.o. BID and 500 mg @ HS

Ativan 0.5 mg p.o. BID and prn agitation


Psychotropic Medication Use

NOTE: Use among Af-Am was significantly lower than White or Hispanic.

Vitiello et al. AJPsych 2003, 160:547-54

from “HIV Cost and Services Utilization Study—1996”


Psychopharmacology in HIV Disease

Consider geriatric dosing - “start low and

go slow”

Look for low-anticholinergic meds

ConsiderPay special attention to Ritonavir (NORVIR - strong CYP3A4 inhibitor)

Overall, anti-HIV meds are not problematic


Pharmacotherapy of Anxiety Disorders

1. “Reactive” Anxiety -Lorazepam 0.5 mg B/TID

Max: 4 mg q 4 hrs

2. Panic Disorders with or without Agoraphobia

Paroxetine (Paxil) 10-40 mg/D

Lorazepam for breakthrough

3. GAD - Paroxetine;Buspirone (Buspar) 5-10 mg BID - 20 mg TID

Note: Buspirone is the “does not” drug: cause tolerance, physical dependence or a withdrawal syndrome, have abuse potential (hypnotic, muscle relaxant activity), work right away


Ritonavir (Norvir)(Potent inhibitor of CP450, esp. 2D6 and 3A4)

1. AdjustAnti-depressants SSRI’s - initially  by 1/2 TCA’s - initially  by 1/2 to 1/3

Nefazodone and St. John’s Wort

2. Avoid BenzodiazepinesAnti-psychotics

Clonazepam (Klonopin)Clozapine

Alprazolam (Xanax)Pimozide

Diazepam (Valium)

Flurazepam (Dalmane)

Triazolam (Halcion)

Zolpidem (Ambien)

2. Allow

Temazepam (Restoril)

Oxazepam (Serax)

Lorazepam (Ativan)

Bupropion (Wellbutrin)


Methadone

  • Ritonavir and Nevirapine (and likely Efavirenz) has been shown to lead to significant withdrawal symptoms in stable methadone users

  • Should follow serum meth levels before & after initiation; may need to increase by 25-30%


Other Pharm Issues

  • Sildenafil levels may be significantly raised by Ritonavir, Saquinavir and Indinavir--potentially serious CV effects (DNE 25mg)

  • Fatal case reports have been filed suggesting Ritonavir in combination with methamphetamine and Ecstasy (MDMA) was the cause of death

  • St. John’s Wort: may decrease PI’s


ARV Classes


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