Definitional Criteria Working Group 1: Toward an Updated ... · PDF fileToward an Updated Nosology for HIV-associated Neurocognitive Disorders ... Toward an updated nosology for HIV-associated

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

2

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


3

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


4

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.


5

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


6

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.


7

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.



8

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.



9

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


10

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


Sensitivity: Number of cases with HIVE who have NP impairment


Specificity: Number of cases deemed NP Normal who do not have HIVE



11

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


12

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


13

What is the course of neurocognitive impairment over time?

*************Some data from HNRC, the Hawaii Aging with HIV Cohort, and NEAD


14

Stability of NP Impairment

Longitudinal data from HNRC

534 HIV+141 HIV-

at least 3 visits

(total number of visits = 3722)


15

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


16

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


17

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


18

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


19

Importance of demographic adjustments in interpreting neurocognitive results

Data from New York and San Diego


20

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


21

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


22

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


23

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


24

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.


25

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.


26

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.


27

Additional slides


28

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.


29

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

--


30

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--

--


31

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


32

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+


33

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+


34

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


35

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

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