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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
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