Approach to HIV Approach to HIV Associated Associated Neurocognitive Neurocognitive disorders (HAND)disorders (HAND)

Dinesh Singh Dinesh Singh MB ChB (Natal), M Med (Psych) MB ChB (Natal), M Med (Psych)

(Natal) ,(Natal) ,

F CPsych (SA), MS (epi) (Columbia, USA), PhD (candidate UKZN)F CPsych (SA), MS (epi) (Columbia, USA), PhD (candidate UKZN)

2 October 20092 October 2009

ICC, DurbanICC, Durban

OverviewOverview NeurobiologyNeurobiology

Classification of HANDsClassification of HANDs

Epidemiological evidence to use HAARTEpidemiological evidence to use HAART Screening toolsScreening tools

Brief neuropsychiatric batteriesBrief neuropsychiatric batteries

Treatment of HANDsTreatment of HANDs

Primary CNS Infection by Primary CNS Infection by HIVHIV Asymptomatic neurocognitive Asymptomatic neurocognitive

impairmentimpairment Minor neurocognitive disorderMinor neurocognitive disorder HIV-associated dementiaHIV-associated dementia DeliriumDelirium Aseptic meningitisAseptic meningitis Vacuolar myelopathyVacuolar myelopathy Psychotic and mood disorders due to a Psychotic and mood disorders due to a

general medical conditiongeneral medical condition

Secondary CNS Diagnoses Secondary CNS Diagnoses Due to Systemic Due to Systemic ImmunosuppressionImmunosuppression

Non-viral opportunistic infectionsNon-viral opportunistic infections Viral opportunistic infectionsViral opportunistic infections NeoplasmsNeoplasms Cerebrovascular disordersCerebrovascular disorders

B. Peripheral nervous system B. Peripheral nervous system disordersdisorders

HIV HIV neuropathogenesisneuropathogenesis HIV does not infect neurones and HIV does not infect neurones and

oligodenrocytes but the monocytes, oligodenrocytes but the monocytes, microglia, astrocytes and endothelial microglia, astrocytes and endothelial cells. cells.

Once in the CNS the virus persist and Once in the CNS the virus persist and evolves into different strains independent evolves into different strains independent of the systemic reservoir. of the systemic reservoir.

HIV is not evenly distributed in the CNS. HIV is not evenly distributed in the CNS. It has a predilection for the basal ganglia.It has a predilection for the basal ganglia.

CSF HIV RNA levels do not correlate with CSF HIV RNA levels do not correlate with the peripheral circulation, especially in the peripheral circulation, especially in the advanced stages.the advanced stages.

NIMH Panel Diagnostic Classification of HANDNIMH Panel Diagnostic Classification of HAND

Acquired impairment in cognitive functioning, involving ≥ 2 ability domains, documented by performance of ≥ 1 standard deviation below the mean for age/ education-appropriate norms on standardized neuropsychological tests, including

Verbal/ language Attention/ working memory Abstraction/ executive Memory (learning, recall) Speed of information processing Sensory perceptual, motor skills

Impairment does not interfere with everyday functioning Impairment does not meet criteria for delirium or dementia

ANI

No evidence of another preexisting cause for the ANI

Acquired impairment in cognitive functioning, as defined for ANI above At least mild interference in daily functioning, including ≥ 1 of the following

Self-reported reduced mental acuity, inefficiency in work, homemaking or social functioning

Observation by knowledgeable others of at least mild decline in mental acuity, resulting in inefficiency at work, homemaking or social functioning

Impairment does not meet criteria for delirium or dementia

MND

No evidence of another preexisting cause for the MND

Marked acquired impairment in cognitive functioning, involving ≥ 2 ability domains (typically, multiple domains), especially in learning new information, slowed information processing, and defective attention/ concentration Impairment must be ascertained by neuropsychological testing with ≥ 2 domains 2 standard deviations or greater than demographically corrected means

Marked interference with day-to-day functioning (work, home life, social activities)

Does not meet criteria for delirium (eg. Clouding of consciousness not a prominent feature) or If delirium is present, criteria for dementia need to have been met on a previous examination when delirium was not present.

HIV-1 associated dementia

No evidence of another, preexisting cause for the dementia (eg. Other CNS infection, CNS neoplasm, cerebrovascular disease, preexisting neurological disease, or severe substance abuse)

Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007;69:1789-99.

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NIMH Panel Diagnostic Classification of HANDNIMH Panel Diagnostic Classification of HAND

Acquired impairment in cognitive functioning, involving ≥ 2 ability domains, documented by performance of ≥ 1 standard deviation below the mean for age/ education-appropriate norms on standardized neuropsychological tests, including

Verbal/ language Attention/ working memory Abstraction/ executive Memory (learning, recall) Speed of information processing Sensory perceptual, motor skills

Impairment does not interfere with everyday functioning Impairment does not meet criteria for delirium or dementia

ANI

No evidence of another preexisting cause for the ANI

Acquired impairment in cognitive functioning, as defined for ANI above At least mild interference in daily functioning, including ≥ 1 of the following

Self-reported reduced mental acuity, inefficiency in work, homemaking or social functioning

Observation by knowledgeable others of at least mild decline in mental acuity, resulting in inefficiency at work, homemaking or social functioning

Impairment does not meet criteria for delirium or dementia

MND

No evidence of another preexisting cause for the MND

Marked acquired impairment in cognitive functioning, involving ≥ 2 ability domains (typically, multiple domains), especially in learning new information, slowed information processing, and defective attention/ concentration Impairment must be ascertained by neuropsychological testing with ≥ 2 domains 2 standard deviations or greater than demographically corrected means

Marked interference with day-to-day functioning (work, home life, social activities)

Does not meet criteria for delirium (eg. Clouding of consciousness not a prominent feature) or If delirium is present, criteria for dementia need to have been met on a previous examination when delirium was not present.

HIV-1 associated dementia

No evidence of another, preexisting cause for the dementia (eg. Other CNS infection, CNS neoplasm, cerebrovascular disease, preexisting neurological disease, or severe substance abuse)

Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007;69:1789-99.

6 domains to be 6 domains to be assessedassessed Attention-information Attention-information

processing;processing; Language; Language; Abstraction- executive; Abstraction- executive; Complex perceptual motor; Complex perceptual motor; Memory Memory Sensory perceptual/motor skills Sensory perceptual/motor skills

Asymptomatic Asymptomatic neurocognitive neurocognitive impairment (ANI) impairment (ANI) 1 SD1 SD Two domainsTwo domains No impairmentNo impairment

Minor neurocognitive Minor neurocognitive DisorderDisorder Old defintion:Two or more of the Old defintion:Two or more of the

following for following for >> 1 month: 1 month:– Impaired attention or concentrationImpaired attention or concentration– Mental slowingMental slowing– Impaired memoryImpaired memory– Slowed movementsSlowed movements– IncoordinationIncoordination– Personality change, irritability or Personality change, irritability or

emotional emotional labilitylability

New definition: 2 domains, 1 SD, mild New definition: 2 domains, 1 SD, mild impairmentimpairment

HIV Associated DementiaHIV Associated Dementia

Old definition: Old definition: Acquired abnormality in at least two Acquired abnormality in at least two of the following cognitive abilities for at least one month:of the following cognitive abilities for at least one month:– Attention/concentrationAttention/concentration– Speed of information processingSpeed of information processing– Abstraction/reasoningAbstraction/reasoning– Visuospatial skillVisuospatial skill– Memory/learningMemory/learning– Speech/languageSpeech/language

New definition: 2 domains, 2 SD, marked New definition: 2 domains, 2 SD, marked impairmentimpairment

Table 1. Criteria for HIV ASSOCIATED NEUROCOGNITVE IMPAIRMENT ( summarized from Antori et al (3))

AsymptomaticNeuro cognitiveimpairment(ANI)

Minor neurocognitive disorder(MND)

HIV- dementia(HAD)

Level of impairment

none Mild everyday activities: reduced mental acuity, inefficiency in work, homemaking or social activities

Marked impairment in day-to-day activities at work, home or social functioning

Number SD below population norm on neuropsychological test

1 2

Number of domains impaired

2(Attention/working memory; verbal/language; Abstraction/executive; Complex perceptual motor; Memory (learning and recall); speed of information processing; Sensory perceptual/motor skills)

Exclusion criteria

Absence of criteria for delirium or other causes for dementia.The condition cannot be explained by another comorbid condition e.g. substance abuse, infections, pre-existing neurological condition.

Significance of NCISignificance of NCI

ARVS decrease incidenceARVS decrease incidence Better QoLBetter QoL Improved AdherenceImproved Adherence Poor prognostic signPoor prognostic sign HIV-D- WHO stage 4 disease- HIV-D- WHO stage 4 disease-

Qualify for ARVsQualify for ARVs

HIV-D PRE-HAARTHIV-D PRE-HAART

MOST STUDIES PRIOR TO HAART MOST STUDIES PRIOR TO HAART SHOWED SOME CORRELATION SHOWED SOME CORRELATION BETWEEN DEMENTIA AND-BETWEEN DEMENTIA AND-– CD4 LEVELCD4 LEVEL– PLASMA VIRAL LOADPLASMA VIRAL LOAD– CSF VIRAL LOADCSF VIRAL LOAD

VIRAL LOAD MAY ALSO HAVE PREDICTIVE VIRAL LOAD MAY ALSO HAVE PREDICTIVE VALUEVALUE

0

10

20

30

40

50

60

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Combined Probable Possible

1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001

Declining incidence of HIV dementia in the Multicenter AIDS Cohort Study: This reflects the increasing use of HAART (large arrow) in this population of homosexual men and probably represents a best-case scenario in that other population groups, particularly, injection drug users, may be unable to achieve such good virological control, and may therefore continue to be at risk for HIV-D.

HAART TREATMENTHAART TREATMENT

GENERALLY RAPID REDUCTION IN GENERALLY RAPID REDUCTION IN CSF HIV RNACSF HIV RNA– Particularly in naïveParticularly in naïve

BUT CSF VIROLOGICAL FAILURES BUT CSF VIROLOGICAL FAILURES FAIRLY COMMONFAIRLY COMMON

HAART TREATMENTHAART TREATMENT

HOWEVERHOWEVER– STILL SIGNIFICANT DEFICITS IN STILL SIGNIFICANT DEFICITS IN

TREATED POPULATIONSTREATED POPULATIONS– PROGRESSIVE DEFICITS REPORTED PROGRESSIVE DEFICITS REPORTED

IN SOME TREATED SUBJECTSIN SOME TREATED SUBJECTS

PROGRESSIONPROGRESSION

MOVEMENT IN BOTH DIRECTIONSMOVEMENT IN BOTH DIRECTIONS

NEAD COHORT AT JHUNEAD COHORT AT JHU– 44% OF DEMENTED HAD PROGRESSED 44% OF DEMENTED HAD PROGRESSED

FROM NON-DEMENTED TO DEMENTED IN FROM NON-DEMENTED TO DEMENTED IN 6MTH6MTH

– 37.5 OF DEMENTED IMPROVED TO NON-37.5 OF DEMENTED IMPROVED TO NON-DEMENTED IN 6 MTHDEMENTED IN 6 MTH

Effect of HAART on Effect of HAART on cognition in Africacognition in Africa Sacktor et al (2009)- ‘Benefits Sacktor et al (2009)- ‘Benefits

and risks of stavudine therapy for and risks of stavudine therapy for HIV-associated neurologic HIV-associated neurologic complications in Uganda’complications in Uganda’

Summary Summary

New classification incorporates New classification incorporates milder asymptomatic phasemilder asymptomatic phase

Emphasis on neuropsych testing!!Emphasis on neuropsych testing!! Functional assessment Functional assessment

Problem with Problem with diagnosis of NCIdiagnosis of NCI Research criteria availableResearch criteria available HIV screens unreliable, unprovenHIV screens unreliable, unproven Screening tools need neuro-battery, Screening tools need neuro-battery,

insensitive to milder formsinsensitive to milder forms Neuro-psych batteries: resources, specialists, Neuro-psych batteries: resources, specialists,

time consumingtime consuming Norms derived from well educated CaucasiansNorms derived from well educated Caucasians SKILLS, EQUIPMENTSKILLS, EQUIPMENT Even with skills: no local norms, African Even with skills: no local norms, African

population, tests are biased to Western population, tests are biased to Western constructsconstructs

Clinical Work-up for Clinical Work-up for CNS Disorders in HIV CNS Disorders in HIV InfectionInfection

General medical work-upGeneral medical work-up Psychiatric work-up and Psychiatric work-up and

differential diagnosisdifferential diagnosis Cognitive screening/neuropsych Cognitive screening/neuropsych

work-upwork-up Functional status assessmentFunctional status assessment

Cognitive Screening Cognitive Screening Work-upWork-up

Mini-Mental Status Exam Mini-Mental Status Exam – InsensitiveInsensitive– Higher cut offs may be useful (Higher cut offs may be useful (<<26/30 should be 26/30 should be

suspect)suspect) HIV Dementia Scale HIV Dementia Scale

– Concerns regarding reliability and validityConcerns regarding reliability and validity– Not proven useful for MCMDNot proven useful for MCMD– Cut off <10 of total 16 points- Cut off <10 of total 16 points- – Gansen et al – tested in SAGansen et al – tested in SA

Mental Alternation test Mental Alternation test Executive interview Executive interview IHDSIHDS

Cognitive-Motor Cognitive-Motor Screening Work-upScreening Work-up Neurological examinationNeurological examination

– Timed GaitTimed Gait Neuropsychological screening testsNeuropsychological screening tests

– Trails Making Test A & BTrails Making Test A & B– Figural Visual Scanning TaskFigural Visual Scanning Task– California Verbal Learning TestCalifornia Verbal Learning Test– Digit-Symbol Task (WAIS-R)Digit-Symbol Task (WAIS-R)

Trail making test ATrail making test A

17 2115

16 20 19

13

7

18

1

5

4

22

2

3

108

11

6

Trail making test BTrail making test B

E 10

139

4

D

13 7

5

1

B

I

3

A

5

28

C

Age 30-50Age 30-50

Educ <10yrsEduc <10yrs1 SD1 SD 2 SD2 SD

memorymemory 33 33

DSFDSF 55 33

DSBDSB 33 22

TMT ATMT A 6464 8080

TMT BTMT B 124124 155155

Normative scores for a brief neuropsychiatric Normative scores for a brief neuropsychiatric battery for the detection of HIV-associated battery for the detection of HIV-associated neurocognitive deficits (HANDS) among South neurocognitive deficits (HANDS) among South AfricansAfricans( BMC research notes)( BMC research notes)

Developed at McCordDeveloped at McCord 4 neuropsych tests: DSB, DSF, TMT A, TMT B4 neuropsych tests: DSB, DSF, TMT A, TMT B No special equipment, 12-15 minsNo special equipment, 12-15 mins Lay counsellors with training tested patients.Lay counsellors with training tested patients.

Reference tables: age and sex.Reference tables: age and sex.

Implemented battery in clinic- starting ARVs Implemented battery in clinic- starting ARVs irrespective of CD4. irrespective of CD4.

NeuropsychologicalTest

Description Domains assessed

Rey Auditory Verbal Learning Test

Recall as many words from a list of 15 words memory

Grooved peg-board

motor

Digit span forward

Patient is given an increasing number of random digits. They must repeat digits in the same order

Attention and concentration

Digit span backward

Patient is given an increasing number of random digits. They must repeat the digits in reverse order

Attention, concentration and working memory

Trail making Test A

Join 25 circles with numbers in the correct sequence as quickly as possible. The numbers are distributed across the page and are not in order

Motor and speed of information processing

Trail making Test B

Join 25 circles with numbers and letters in alternating sequence. i.e. Join 1, A, 2, B, 3, C as quickly as possible

Motor and speed of information processing and executive function

Singh D.;HIV neurocognitive impairmentHIV Journal; September 2009

Functional Status Functional Status Assessment Assessment (continued)(continued)

Assessment instrumentsAssessment instruments– Karnofsky Performance ScaleKarnofsky Performance Scale– The Global Assessment of FunctionThe Global Assessment of Function– The Social and Occupational The Social and Occupational

Functioning Assessment ScaleFunctioning Assessment Scale– The Sickness Impact ProfileThe Sickness Impact Profile– The Direct Assessment of Functional The Direct Assessment of Functional

StatusStatus

Pharmacotherapy of Pharmacotherapy of HIV Associated HIV Associated Cognitive-Motor DisordersCognitive-Motor Disorders

Antiretroviral medicationsAntiretroviral medications Immunostimulants and Immunostimulants and

inflammatory mediatorsinflammatory mediators Neurotransmitter manipulationNeurotransmitter manipulation Nutritional interventionsNutritional interventions

WHY HAART MAY NOT WHY HAART MAY NOT STOP CNS STOP CNS PROGRESSIONPROGRESSION ARVs HAVE POOR PENETRANCE ARVs HAVE POOR PENETRANCE

ACROSS THE BLOOD BRAIN BARRIERACROSS THE BLOOD BRAIN BARRIER POTENTIAL FOR VIRAL POTENTIAL FOR VIRAL

SEQUESTRATION IN THE BRAINSEQUESTRATION IN THE BRAIN MAY CAUSE CONTINUING MAY CAUSE CONTINUING

NEUROLOGICAL DECLINENEUROLOGICAL DECLINE MAY INCREASE POTENTIAL FOR MAY INCREASE POTENTIAL FOR

RESISTANCE WITH RESEEDING OF RESISTANCE WITH RESEEDING OF SYSTEMIC COMPARTMENTSYSTEMIC COMPARTMENT

CNS PENETRANCE OF CNS PENETRANCE OF ARVsARVs

GENERALLY POORGENERALLY POOR

NRTI PENETRANCE MEDIATED BY NRTI PENETRANCE MEDIATED BY ORGANIC ACID TRANSPORT SYSTEMSORGANIC ACID TRANSPORT SYSTEMS

PROTEASE INHIBITORS ELIMINATED PROTEASE INHIBITORS ELIMINATED VIA P-GLYCOPROTEINS, WHICH ARE VIA P-GLYCOPROTEINS, WHICH ARE LOCATED AT THE BBBLOCATED AT THE BBB

CSF PENETRANT ARVsCSF PENETRANT ARVs

SOME STUDIES SUGGESTED SOME STUDIES SUGGESTED IMPROVEMENT IN SOME FEATURE OF IMPROVEMENT IN SOME FEATURE OF NEUROPSYCHOLOGICAL TESTINGNEUROPSYCHOLOGICAL TESTING

OTHERS SHOWED NONE OTHERS SHOWED NONE

THEREFORE-THEREFORE-MIXED RESULTS BUT INCREASING MIXED RESULTS BUT INCREASING

EVIDENCE PENETRANCE HAS A EVIDENCE PENETRANCE HAS A SIGNIFICANT EFFECT ON SIGNIFICANT EFFECT ON NEUROLOGICAL FUNCTIONINGNEUROLOGICAL FUNCTIONING

WOULD EARLY TX WOULD EARLY TX PROTECT THE CNSPROTECT THE CNS PRE- HAART INCIDENCE OF PRE- HAART INCIDENCE OF

DEMENTIADEMENTIA– 0.4% IN ASYMPTOMATIC STAGES0.4% IN ASYMPTOMATIC STAGES– 16% WITH SYMPTOMATIC DISEASE16% WITH SYMPTOMATIC DISEASE

MORE DEMENTIA WITH ADVANCING MORE DEMENTIA WITH ADVANCING AGEAGE– POSSIBLY DUE TO AGE-INDUCED LOSS POSSIBLY DUE TO AGE-INDUCED LOSS

OF NEURONAL RESERVEOF NEURONAL RESERVE MCMD IS PREDICTIVE OF DEMENTIAMCMD IS PREDICTIVE OF DEMENTIA

WOULD EARLY TX WOULD EARLY TX PROTECT THE CNSPROTECT THE CNS HIGH BASELINE PLASMA VIRAL HIGH BASELINE PLASMA VIRAL

LOAD PREDICTS DEMENTIALOAD PREDICTS DEMENTIA– CSF NOT ADEQUATELY STUDIEDCSF NOT ADEQUATELY STUDIED

STRUCTURED TREATMENT STRUCTURED TREATMENT INTERRUPTION LEADS TO INTERRUPTION LEADS TO ELEVATED CSF LYMPHOCYTE ELEVATED CSF LYMPHOCYTE COUNT AND VIRAL LOADCOUNT AND VIRAL LOAD

Classify as normal, ANI, MND or HAD

Assess all newly diagnosed HIV positive patients with Neuropsychological subtests (TMT-A, TMT-B, DSF, DSB)

ANI and MNDHAD

Start ARVs,Monitor and reinforce adherence

MonitorRepeat in six months If progress to HAD start ARV

Treat depression and other medical conditions

CD4 <200

CD4 >200

CD4 >200

Baseline investigation e.ge.g. FBC, U& E, LFT – CT and LP (if indicated)

Singh D.;HIV neurocognitive impairment

HIV Journal; September 2009

Clinical challenges in Clinical challenges in busy ARV clinicbusy ARV clinic We are systematically screening We are systematically screening

people and starting HAART people and starting HAART

BUTBUT No guidance on regimesNo guidance on regimes What happens to people with What happens to people with

persistent or progressive HADpersistent or progressive HAD

Help and contact infoHelp and contact info

Up coming article in HIV JournalUp coming article in HIV Journal

Reference tables: BMC research notes Reference tables: BMC research notes Easier toolsEasier tools ?? Accepted into ARV rollout?? Accepted into ARV rollout

dsingh@mrc.ac.zadsingh@mrc.ac.za 08365841570836584157 Durdoc hospital Durdoc hospital