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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

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
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
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



Depression testosterone
Depression & Testosterone

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

    • Fatigue

    • Decreased libido

    • Decreased appetite

    • Decreased mood


Screening tests
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


Cns hiv s most important sanctuary site

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

HIV Neuropathogenesis

Early and continuous seeding

Importance of Blood Brain Barrier


Had a diagnosis of exclusion
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
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
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
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
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
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
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
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
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 use np function n 130 avg age 41 42 nw 82 aids

HAART

N 69

CD 4 254

UVL 42%

NPI 22%

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


Correlation of plasma vl to csf vl

P regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severe CSF

< 200 >200

No No

No Yes*

No Yes

No Yes*

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
Favorable CNS Characteristics regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severeof ARVs

  • % protein binding ( = better)

  • lipid solubility ( = better)

  • molecular weight ( = better)

  • inhibitory concentration ( = better)


Medical rx of had

Medical Rx of HAD regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severe

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
Factors Influencing Efficacy of ARV Rx: regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severe

  • Stage of HIV disease

  • Degree of CNS replication/resistance

  • Integrity of BBB

  • Specific treatment strategy/ARV choice


Some neuroprotective disappointments
Some Neuroprotective regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severeDisappointments

Nimodipene  interaction with CAH

Peptide T block gp-120

*Memantine NMDA antagonist/showing efficacy for ADV

*Deprenyl Anti-oxidant/anti-poptotic

Lexipafant PAF antagonist

*some benefits


Case History - “JC” regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severe

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

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

HPI Two 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.

PMH HIV infected x 10 years; current CD4 count = 70.

No OI’s. No previous psych hx.


Case History - “JC” (cont.) regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severe

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.) regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severe

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 regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severe

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
Psychotropic Medication Use regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severe

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 regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severe

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 regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severe

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) regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severe(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 Benzodiazepines Anti-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
Methadone regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severe

  • 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
Other Pharm Issues regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severe

  • 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
ARV Classes regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severe


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