Definitional Criteria Working Group 1: Toward an Updated Nosology for HIV-associated Neurocognitive Disorders
Prepared by Igor Grant for Working Group 1 consisting of:
Desiree Byrd, Mariana Cherner, David Clifford, Igor Grant, Jeymohan Joseph, Justin McArthur,
Michael Nunn, Victor Valcour, Valerie Wojna
Frascati, June 13, 2005
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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AAN 1991 Criteria: Probable HAD
1. a. Acquired abnormality in at least two cognitive (not motor) abilitiesb. Cognitive dysfunction causing impairment in work or ADLs
2. At least one of:a. Motor abnormalityb. Behavioral abnormality (motivation, emotional control, social behavior)
3. Sufficient consciousness to assess cognitive abilities 4. Absence of other etiology
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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AAN 1991 Criteria: Probable HAD Subtypes
HAD-both:• Criteria 1 & 2 met, with both motor and
behavioral Sx
HAD-motor:• Criterion 1 met & Criterion 2 met with
only motor Sx
HAD-behavioral:• Criterion 1 met & Criterion 2 met with
only behavioral Sx
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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AAN 1991 Criteria: Probable MCMD
Must have EACH of the following:1. Cognitive/motor/behavioral abnormalities.
a. Hx of at least 2 of: impaired attention/concentration; mental slowing; impaired memory; slowed movements; incoordination; personality change/irritability/lability.
b. Acquired cognitive/motor abnormality verified by clinical exam or NP testing (# abnormal areas not specified).
2. Abnormalities from #1 cause mild impairment in work or activities of daily living.
3. Does not meet criteria for HAD or HIV-associated myelopathy.
4. No evidence of other etiology.
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Some issues that emerged regarding the AAN 1991 criteria
• Degree of NP impairment is underspecified in AAN HAD and MCMD criteria
• Number of areas showing objectively documented decline underspecified in AAN MCMD criteria
• Ability to classify HAD with "mild" ADL decline has some overlap with MCMD diagnosis
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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HNRC Criteria for HIV neurocognitive complications: Asymptomatic
Neuropsychological Impairment (ANI)
1. Performance at least 1 standard deviation below demographically corrected norms in at least 2 different cognitive areas*
2. Impairment has been present at least one month.
3. The impairment cannot be explained by comorbid conditions (e.g., substance abuse, medications, developmental disorder)†
4. The impairment does not occur solely as part of a delirium (e.g., due to CNS toxoplasmosis, lymphoma, CMV)
*At least 5 of the following 8 ability areas must be assessed: attention/information processing; language; abstraction/executive; complex perceptual motor; learning; recall/forgetting; motor skills; sensory
From: Grant, I. (2002). The neurocognitive complications of HIV infection. In Encyclopedia of the Human Brain (V.S. Ramachandran, Ed.) San Diego, Academic Press, 2, 475-489.
†If the individual with suspected ANI also satisfies criteria for a major depressive episode or substance dependence, the diagnosis of ANI should be deferred to a subsequent examination conducted at a time when the major depression has remitted or at least 1 month has elapsed following termination of dependent-substance use.
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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HNRC Criteria for HIV neurocognitive complications: HIV-1 Associated Mild
Neurocognitive Disorder (MND)
1. Acquired mild-moderate impairment in cognitive function documented by performance at least 1.0 standard deviation below demographically corrected norms in at least 2 different cognitive areas
2. Cognitive impairment produces at least mild interference in daily functioning (report of reduced mental acuity, inefficiency at work, home, social activities)
3. Cognitive impairment has been present at least one month.4. Cognitive impairment does not meet criteria for delirium or dementia.5. There is no evidence of another preexisting cause for the MND†.†If the individual with suspected MND also satisfies criteria for a major depressive episode or substance dependence, the
diagnosis of MND should be deferred to a subsequent examination conducted at a time when the major depression has remitted or at least 1 month has elapsed following termination of dependent-substance use.
*At least 5 of the following 8 ability areas must be assessed: attention/information processing; language; abstraction/executive; complex perceptual motor; learning; recall/forgetting; motor skills; sensory
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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HNRC Criteria for HIV neurocognitive complications: HIV-1 Associated Dementia (HAD)
1. Acquired moderate-severe impairment in cognitive function documented by performance below 2 standard deviations below demographically corrected norms in at least 2 different cognitive areas*
2. Cognitive impairment produces marked interference in daily functioning (work, home, social activities)
3. Cognitive impairment has been present at least one month.
4. Cognitive impairment does not meet criteria for delirium or dementia.
5. There is no evidence of another preexisting cause†.
†If the individual with suspected MND also satisfies criteria for a major depressive episode or substance dependence, the diagnosis of MND should be deferred to a subsequent examination conducted at a time when the major depression has remitted or at least 1 month has elapsed following termination of dependent-substance use.
*At least 5 of the following 8 ability areas must be assessed: attention/information processing; language; abstraction/executive; complex perceptual motor; learning; recall/forgetting; motor skills; sensory
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Predictive validity of AAN and HNRC criteria with autopsy confirmation of HIV encephalitis based on cases (n=39) in Cherner et al Neurology 2002
AAN91 HNRC HIVE #Cases
HAD HAD HIVE+ 4
HAD MND HIVE+ 9
HAD NPI HIVE+ 1
MCMD normal HIVE+ 1
MCMD normal HIVE- 2
normal MND HIVE+ 2
normal NPI HIVE+ 2
normal NPI HIVE- 1
normal normal HIVE+ 8
normal normal HIVE- 9
Diagnostic agreement = 21/39 = 54%
Agreement on normal/abnormal dx = 31/39=79%
AAN dx corresponds to HIVE
HNRC dx corresponds to HIVE
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Diagnostic Accuracy of AAN and HNRC Nomeclatures vis-à-vis post mortem HIVE
Positive Predictive Power: Number of cases with NP impairment who have HIVE
Using AAN criteria: 15/17 = 88%Using HNRC criteria: 18/19 = 95%
Misses: Number of cases deemed NP Normal who have HIVE
Using AAN criteria: 12/22 = 54%Using HNRC criteria: 9/20 = 45%
Sensitivity: Number of cases with HIVE who have NP impairment
Using AAN criteria: 15/27 = 56%Using HNRC criteria: 18/27 = 67%
Specificity: Number of cases deemed NP Normal who do not have HIVE
Using AAN criteria: 10/12 = 83%Using HNRC criteria: 11/12 = 92%
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Three scenarios of diagnostic disagreement
1) Normal by AAN criteria and impaired by HNRC criteria3 cases: Have mild cognitive impairment but no ADL decline
1 case: Has mild cognitive impairment and mild ADL decline but no self-reported complaints/ Hx of cognitive, motor, or behavioral decline
2) MCMD by AAN criteria and normal by HNRC criteria3 cases: Have normal cognitive functioning but motor or behavioral changes, along with mild ADL decline
3) HAD by AAN criteria and MND by HNRC criteria6 cases: Have mild cognitive impairment
4 cases: Have mild to moderate cognitive impairment
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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17.4%
42%
29%
11.6%
46.4%
33.3%
20.3%
53.6%
18.8%
23.2%
31.1%
20.3%
18.8%
23.2%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
MSK HDS AAN M-AANScales for HIV Dementia
<82 & 3HADmild CIMC/MDasymptomaticequivocalnormal
Source: Valerie Wojna
Diagnosis of HIV neurocognitive disorders among women in Puerto Rico based on
several available scales
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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What is the course of neurocognitive impairment over time?
*************Some data from HNRC, the Hawaii Aging with HIV Cohort, and NEAD
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Stability of NP Impairment
Longitudinal data from HNRC
534 HIV+141 HIV-
at least 3 visits
(total number of visits = 3722)
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Proportion NP Impaired at baselineby HIV Status (HIV+ = 541; HIV- = 141)
14
27
44
52
0
10
20
30
40
50
60
% Im
paire
d at
bas
elin
e
HIV- CDC A CDC B CDC C
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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NP Course for HIV neurocognitive states N=534
47
11
18
4
19
0
10
20
30
40
50
60
All HIV+
%
stably normal n=249stably impaired n=60stably improved n=95stably declined n=24fluctuated n=102
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Hawaii data: Diagnostic Transitions from Baseline to Year 1
Hawaii Aging with HIV Cohort
• Nearly 1/3 (53/159) of participants who have at least some NP impairment do not meet MCMD or HAD criteria
• Approximately 45% of these “NP abnormal” participants progress at one year
60.98%
21.95%
17.07%
17.65%
38.24%
41.18%
2.94%
10.71%
17.86%
53.57%
17.86%
3.57%
28.57%
67.86%
0%
100%
Normal(N=37)
NP Abnormal(N=53)
MC/MD(N=39)
HAD(N=30)
Baseline Diagnosis
Normal NP Abnormal MC/MD HAD
Year 1 Diagnosis as a % of Baseline
Diagnosis
Source: Victor Valcour
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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NEAD Data: Frequency of transitions among neurological states in NEAD cohort (subjects with at least 1 transition): 55% showed ≥ 1 transition
Transition pattern Frequency %
Normal MCMD 49 23
Normal HIV-D 10 4.6
MCMD Normal 45 21
MCMD HIV-D 39 18
HIV-D Normal 26 12
HIV-D MCMD 48 22Source: Justin McArthur
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Importance of demographic adjustments in interpreting neurocognitive results
Data from New York and San Diego
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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New York data: Diagnoses based on AAN vs. Clinical Ratings: Ethnic Disparities
0102030405060708090
100
% F
requ
ency
Normal HIV Impaired Normal HIV Impaired
AAN CR
** p<0.01
**
**
**
Ethnic MinoritiesEthnic Minorities(n=216)
CaucasiansCaucasians(n=69)
**
Age = 44.2 (7.6)Education = 12.2 (2.9)Median CD4 = 191.4
Source: Desireé Byrd
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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33
1915
71
4438
0
10
20
30
40
50
60
70
80
% Im
paire
d
Normal Controls HIV+
African American(Heaton et al 1991norms)
African American(AANP 1994 norms)
White (Heaton et al1991 norms)
(n=114)(n=21) (n=401)(n=89)
Results of Using Different Normative Data Sets to Identify NP Impairment in African American Subjects
-14%
-27%
New Heaton et al 2004 norms are appropriate for use with African Americans
Source: Bob Heaton
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Proportion of healthy (HIV-) Spanish-speaking subjects classified as impaired using the
HRB 2004 norms vs new Spanish language norms
31
15
0
10
20
30
40
% Im
paire
d
Figure Learning Test
English NormsSpanish Norms
n=363
Source: Cherner et a,, INS, Feb. 2005
Expected base rate
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Misclassification most salient at lower levels of education/literacy (Figure Learning Test)
Expected base rate
0%
20%
40%
60%
80%
100%
% Im
paire
d
0 1-5 6-10 11-13 14+Education
English norms Spanish Norms
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Review of Findings
1. Current AAN criteria have good sensitivity and specificity for predicting future HIVE diagnosis, but positive predictive power can be enhanced by considering asymptomatic neurocognitive impairment.
2. Approximately 20% of cases with documented neurocognitive impairment do not have sufficient everyday functioning change to meet current AAN criteria.
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Review of Findings3. A substantial proportion of cases with HIV have bi-
directional changes in presence or level neurocognitive impairment, and a revised nosology needs to recognize this.
4. Presence and degree of neurocognitive impairment should constitute the fundamental criterion for establishing diagnosis. Other criteria, e.g., motor disorders, emotional or personality changes, should be considered ancillary or corroborative, or criteria for defining disorder subtypes.
5. Determination of neurocognitive impairment should be based on appropriately normed tests and consider additional possible confounds.
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Recommendation
Working Group 1 recommends revision of diagnostic criteria for HIV-associated neurocognitive disorders taking into account the observations above. Revised criteria should be field tested and refined accordingly before final recommendations are made.
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Additional slides
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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AAN 1991 Criteria: Probable HAD Resulting Diagnoses - ADL decline
Severity of ADL decline• Mild: Conspicuous decline in work performance, daily
living activities, social activities, and complicated tasks, but not completely dependent. Can perform self-care.
• Moderate: Can’t work; needs assistance with daily living activities, self care, and walking. Can communicate basic needs.
• Severe: Unable to perform any activities of daily living or self-care without assistance; requires continual supervision; nearly or completely mute.
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Baseline background characteristics by HIV status
Mean (sd) or % HIV+n=534
HIV-n=141
p
Age 37.1 (8.7) 35.6 (9.0) ns
Education 13.5 (2.4) 14.2 (2.6) .001
% women 15 26 .003
% white 68 68 ns
CD4 count 390.1 (261.0) 895.4 (303.4) .0001
Nadir CD4 255.9 (233.7) -
Log Plasma RNA 4.0 (1.2) -
% HAART% other ARV
3229
--
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Baseline background characteristics by HIV status and baseline NP impairment
HIV+ p HIV- p
Mean (sd) or % Impaired(n=199)
Normal(n=331)
Impaired(n=20)
Normal(n=121)
Age 38.3 (9.0) 36.3 (8.3) .008 33.8 (9.33 35.9 (8.9) ns
Educ 13.5 (2.4) 13.5 (2.4) ns 14.1 (2.2) 14.3 (2.7) ns
% women 16 14 ns 25 26 ns
% white 62 72 .04 70 69 ns
CD4 count 373.7 (265.9) 400.0 (257.9) ns 837.9 (243.4) 905.4 (312.6) ns
Nadir CD4 224.5 (203.8) 276.2 (249.6) .05 - -
Log Plasma RNA 4.0 (1.3) 4.02 (1.1) ns - -
% HAART% other ARV
3930
2729
.002--
--
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Baseline background characteristics of HIV+ Ss by NP course over all available visits (minimum 3)
HIV+ p
Mean (sd) or % Stably Normal(n=249)
Stably Impaired(n=60 )
Improved(n=95)
Wobbler(n=102)
Declined(n=24)
Age 36.3 (8.5) 41.5 (8.7) 37.6 (8.6) 35.8 (8.3) 36.2 (7.8) .0004
Education 13.6 (2.2) 13.9 (2.9) 13.6 (2.2) 12.9 (2.3) 13.0 (3.7) .08
% women 15 15 17 16 8 ns
% white 75 67 61 61 67 .06
CD4 count 422.1 (272.1) 391.6 (264.8) 363.1 (255.7) 341.8 (236.2) 373.4 (232.6) .08
Nadir CD4 287.8 (263.1) 196.0 (201.7) 235.8 (203.9) 243.6 (199.4) 240.9 (227.051) ns
Log Plasma RNA 3.9 (1.2) 3.7 (1.3) 4.2 (1.2) 4.2 (1.2) 4.4 (1.03) ns
% HAART% other ARV
2628
4326
3635
3131
4225
.06
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Stability of NP status over time in 534 HIV+ and 141 HIV- Ss (minimum 3 visits)
75
25
58
42
0
10
20
30
40
50
60
70
80
NP Stable NP Change
% HIV-HIV+
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Proportion NP Impaired Over Time by HIV Status
3
72
11
47
0
10
20
30
40
50
60
70
80
Stably Impaired Stably normal
% HIV-HIV+
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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NP Course by Baseline NP Status, HIV+ only
30
48
22
75
7
18
0102030405060708090
100
stablynormal
stablyimpaired
stablyimproved
stablydeclined
wobbled
course
%
HIV+Impaired
HIV+ WNL
Definitional Criteria Work Group 1: Toward an updated nosology for HIV-associated neurocognitive disorders
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Transitions in neurocognitive category between first and last visit in HIV+ HNRC participants (minimum 3 visits)
90
68
45
13
6
19
16
12
312
35
25
1 0 4
50
0%
20%
40%
60%
80%
100%
normal n=332 NPI=114 MND=80 HAD=8
Baseline
HADMNDNPINormal