Full text of DOI:10.1017/S0317167100001372

ORIGINALARTICLE
Neurocognitive Symptoms and
Impairment in an HIV Community Clinic
D.H. Kim, D.L. Jewison, G.R. Milner, S.B. Rourke, M.J. Gill, C. Power
ABSTRACT: Background: Neurocognitive impairment is a frequent complication of HIV infection
and heralds a poor survival prognosis. With the availability of highly active antiretroviral therapy
(HAART), survival times for HIV-infected patients have markedly increased although the effects of
HAART on the prevalence of neurocognitive impairment remain uncertain. Objective: To determine the
relationship between self-reported neurocognitive symptoms and neuropsychological (NP) performance
together with the impact of HAART among HIV-infected patients. Methods: A cross-sectional study was
performed in which patients without previously documented neurocognitive impairment attending an
HIV community clinic were questioned about neurocognitive symptoms and a NP test battery was
administered. Results: Of the eighty-three patients examined, neurocognitive symptoms were reported
by 34% of patients and were associated with a shorter duration of HAART and higher viral loads.
Patients reporting neurocognitive symptoms were also more likely to exhibit impaired NP performance
(p<0.005) with NP impairment being detected in 46% of all patients examined (12% with HIV-
associated dementia). Neuropsychological impairment was directly correlated with age (p<0.001),
plasma viral load (p<0.005) and inversely correlated with the number of prescribed antiretroviral drugs
(p<0.01). Conclusions: These results suggest that neurocognitive symptoms are predictive of impaired
NP performance and that NP impairment remains a frequent finding among older patients with higher
viral loads. An increased number of antiretroviral drugs may be neuroprotective.
RÉSUMÉ: Symptômes neurocognitifs et invalidité chez les patients d’une clinique communautaire anti-VIH.
Introduction: Le déficit neurocognitif est une complication fréquente de l’infection par le VIH et comporte un
mauvais pronostic quant à la survie. Avec l’arrivée de la thérapie antirétrovirale hautement efficace (HAART), la
survie des patients infectés par le VIH a augmenté de façon appréciable, bien que l’influence de HAART sur la
prévalence du déficit neurocognitif demeure inconnue. Objectif: Déterminer la relation entre les symptômes
neurocognitifs rapportés par les patients et la performance neuropsychologique (NP) ainsi que l’impact de HAART
chez les patients infectés par le VIH. Méthodes: Dans cette étude transversale, on a questionné des patients d’une
clinique communautaire anti-VIH sans déficit neurocognitif documenté sur leurs symptômes neurocognitifs et on
leur a administré une batterie de tests NP. Résultats: Parmi les quatre-vingt-trois patients examinés, des symptômes
neurocognitifs ont été rapportés par 34% et ils étaient associés à une administration plus brève de HAART et à une
charge viral plus élevée. Les patients qui rapportaient des symptômes neurocognitifs étaient également plus
susceptibles d’avoir une performance NPaltérée (p < 0.005); une altération NPa été détectée chez 46% de tous les
patients examinés (démence associée au VIH chez 12%). Le déficit NPétait directement corrélé à l’âge (p < 0.001),
la charge virale plasmatique (p < 0.005) et inversement corrélé au nombre de médicaments antirétroviraux prescrits
(p < 0.01). Conclusions: Ces résultats suggèrent que les symptômes neurocognitifs sont indicateurs d’une
performance NP altérée et que l’altération NP demeure une constatation fréquente chez les patients plus âgés qui
ont une charge virale plus élevée. Un nombre croissant de médicaments antirétroviraux puissent être
neuroprotecteurs.
Can. J. Neurol. Sci. 2001; 28: 228-231
Human immunodeficiency virus-type 1 (HIV-1) infection
causes a spectrum of neurocognitive syndromes ranging from
minor cognitive impairment, detectable on neuropsychological
(NP) testing, to frank dementia.1 Most reports assessing NP
performance in HIV-infected patients have been conducted as
multicentre studies and are usually composed of self-selected
From the Departments of Clinical Neurosciences (DHK,CP), Microbiology and
Infectious Diseases (MJG, CP), University of Calgary, Calgary AB; Southern Alberta
Clinic (DLJ, GRM. MJG, CP), Calgary AB; Department of Psychiatry (SBR),
University of Toronto, Toronto ON, Canada.
RECEIVED FEBRUARY 2, 2001. ACCEPTED INFINALFORM MAY 29, 2001.
Reprint requests to: Christopher Power, Department of Clinical Neurosciences, 3330
Hospital Drive NW, Calgary, Alberta, Canada, T2N 4N1
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volunteers who are motivated to remain in a longitudinal study.2,3
These circumstances may not reflect the circumstances for many
HIV community clinics and neurology referrals from such
clinics. To date, there has been limited evaluation of NP
impairment following use of highly active antiretroviral therapy
(HAART) with variable results.4-7 Furthermore, few studies have
addressed the relationship between neurocognitive symptoms
and impairment in the setting of an HIV community clinic
among patients receiving HAART. The purpose of this cross-
sectional study was to examine the relationship between
neurocognitive symptoms and NP impairment among patients
receiving HAART in a community clinic.
Table: Demographic and clinical features of patients who were
neurocognitively asymptomatic and symptomatic
Characteristic
Asymptomatic Symptomatic p Value
(N=55)
(N=28)
Demographic
Median Age (yr)(Range)
Gender, No. (%) Male
No. (%) Homo/Bisexual
No. (%) IVDrug Users
42 (27-66)
51 (92.7)
38 (69.1)
4 (7.3)
45.5 (24-55)
26 (92.8)
17 (60.7)
5 (17.9)
NS
NS
NS
NS
NS
Median (Range) Education (yr) 16 (8-21)
13 (10-21)
Clinical
Median (Range) Time of
METHODS
HIVseropositivity (mo)
Median (Range) Log10 Viral
Load (copies/ml)
Median (Range) Nadir CD4
(Count/ml)
89 (15-168) 71.5 (6-189)
NS
The Southern Alberta Clinic (SAC) is a community HIV
clinic that serves all HIV seropositive patients (n=780) in
southern Alberta. All patients attending SAC receive free
antiretrovirals and are followed regularly with viral loads and
CD4 counts. During routine visits to SAC, patients and/or
primary care givers were randomly selected and subsequently
questioned, by a registered nurse or a social worker, about
symptomatology indicative of (1) memory and concentration
dysfunction, (2) difficulty with gait and coordination, (3) change
in behavior or social interactions and (4) related difficulties with
activities of daily living including self-care (cooking, dressing,
management of financial issues) or employment. Patients were
designated as symptomatic or asymptomatic depending on the
self-reported presence or absence, respectively, of at least two of
the above neurological symptomatologies. Patients were
excluded from the analysis if they exhibited CNS opportunistic
infections, depression confirmed by the clinic psychiatrists
(DSM-IVR definitions), debilitating neuropathy, or had a
previous diagnosis of cognitive impairment, including
previously diagnosed HIV-associated dementia (HAD). After
questioning about neurocognitive symptoms, patients underwent
routine NP testing including Grooved Pegboard (dominant and
non-dominant hands), Trail Making Test: Parts A and B, and
Symbol Digit Modalities Test, administered in a standardized
manner. These tests were selected because of their proven utility
in previous studies of HIV-related NP performance.8,9 Results of
these NP tests were assessed in relation to previously reported
normative data according to age and education.8 The mean
deficit score (MDS) was calculated, as previously reported,9
using the Symbol-Digit Modalities, Trail Making: Part B and
Grooved Pegboard (non-dominant hand) Tests. To ensure
reliability of the categorization of NP impairment, two
definitions were used including (1) a MDS value of greater than
0.50 or (2) a single test score two standard deviations or any two
scores one standard deviation below the demographically
corrected normative mean for those tests. Relevant demographic
and clinical data from the medical records were recorded. The
diagnosis of HAD was predicated on testing with the HIV
Dementia Scale10 and established criteria,11 following
administration of the NP test battery. Univariate comparisons
were made using the Fisher exact test for categorical variables,
the Mann-Whitney or Welch-corrected unpaired t tests for
continuous variables, and derivation of correlation co-efficients
by multiple and single regression analyses (Instat2, Graphpad,
1.59 (1.59-6.86) 3.24 (1.59-6.28)0.0346*
76 (1-582)
81 (2-537)
NS
NS
NS
Median (Range) Present CD4 285 (1-1332) 244.5 (4-924)
(Count/ml)
No. (%) on HAARTa
Median (Range) Time on
HAART (mo)
49 (89)
20 (71)
20 (0-69)
3.5 (0-118) 0.0073*
No. (%) HIV Dementia
1 (1.8)
9 (32.1) 0.0002*
a highly active antiretroviral treatment (minimum of three antiretrovirals)
* statistically significant difference, NS-nonsignificant
San Diego CA). P values less than 0.05 were considered
statistically significant.
RESULTS
Ninety-five patients were screened regarding the presence of
neurocognitive signs and symptoms, of which 83 were included
in the present analysis, while the remaining met the predefined
exclusion criteria. Fifty-five patients (66%) were classified as
asymptomatic and 28 (34%) as symptomatic, based on the
presence of at least two or more self-reported symptoms.
Comparison of demographic and clinical characteristics (Table)
revealed that the symptomatic group had a shorter median
duration of antiretroviral drug treatment (p<0.005) with higher
viral loads (p<0.05) and a greater number of individuals
diagnosed with HAD (p<0.0001). The prevalence of HAD was
12% (10/83) with a median HIV Dementia Scale score of 8
(range: 4-12) based on the criteria outlined in the Methods
section. The asymptomatic and neurocognitively symptomatic
groups did not differ significantly in the frequencies of head
injury, presence of cytomegalovirus, hepatitis C or B viral
infections, antidepressant use, median time since AIDS
diagnosis, median nadir CD4 counts and the median number of
antiretroviral drugs taken at the time of testing.
Analysis of NP findings revealed that symptomatic patients
performed significantly worse on all tests although these
differences were least apparent for the Grooved Pegboard tests
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A
B
Figure 1: Neuropsychlogical test findings among asymptomatic (n=55), symptomatic (n=28), unimpaired (n=47) and impaired (n=36) HIV-infected
patients. (A) Grooved Pegboard and Trail Making Tests (Welch corrected unpaired t test ) and (B) Mean Deficit Score (MDS) (Mann Whitney U test,
p<0.005) showed significant differences between asymptomatic and symptomatic (A, B) or impaired and unimpaired patients (B). Mean Symbol-Digit
Modalities Test scores also differed between symptomatic and asymptomatic patients (p<0.001). Horizontal line indicates median MDS value for each
group (*p<0.05, **p<0.01, ***p<0.001 )
(Figure 1A). Similar prevalences of impairment among all
patients were found using either definition of neurocognitive
impairment: 46% (38/83) with the mean deficit score (MDS)
criteria and 43% (36/83) using the standard deviations definition.
Using the MDS criterion for NPimpairment, a greater number of
symptomatic patients were found to be NP impaired: 67%
(19/28) versus 35% (19/55) in the asymptomatic group
(p<0.005). All test scores with the exception of the dominant
hand Grooved Pegboard (p<0.05) (Figure 1A) were markedly
different between the impaired and unimpaired groups
(p<0.0001). The mean MDS (±SEM) for the HAD patients was
2.19 (±0.35). To compare the severity of neurocognitive
impairment among asymptomatic versus symptomatic or NP
impaired versus NP unimpaired, the MDS for each patient was
calculated for both classifications (Figure 1B), revealing similar
differences for each classification (p<0.0001). Since MDS
provided a continuous variable for each patient with which other
variables could be compared, MDS was used in the subsequent
analyses.
Median age was the only variable found to differ between the
NP impaired, 46 years (range: 34-66) and the unimpaired
patients, 38 years (range: 24-58) (p<0.0005). While the median
number of patients on HAART did not differ between the NP
impaired and unimpaired groups (p>0.05), age (p<0.001) and
viral load (p<0.005) in plasma were found to be correlated
positively with MDS. In addition, the number of antiretroviral
drugs patients were taking was inversely correlated with MDS
(Spearman r=-0.2725; p<0.01). The remaining continuous
variables (education, duration of HAART, and nadir CD4 levels)
were not significantly correlated with the MDS.
tology were cognitively impaired, compared to asymptomatic
patients. Despite the exclusion of patients with CNS
opportunistic infections, debilitating neuropathy, a previous
history of cognitive impairment together with the universal
availability of HAART within this clinic, NP impairment was
detected in 46% of tested patients and was correlated with viral
load and age. Finally, the number of antiretrovirals taken by
patients was inversely related to the severity of NP impairment
with a predominant effect on improved psychomotor efficiency,
which is in agreement with earlier studies.6,12
Although median plasma viral loads did not differ
significantly between the NP impaired and unimpaired groups,
there was a trend towards an increased viral load among the NP
impaired group. Moreover, the present findings indicate that
viral load was correlated with MDS among all eighty-three
patients. This latter observation is at odds with earlier studies,
performed prior to the availability of HAART in which plasma
viral load was not correlated with neurocognitive
impairment.13,14 More recent studies suggest that plasma viral
loads may be higher in patients with NPimpairment who receive
HAART.5,7 Since the number of antiretrovirals taken was also
correlated with NP performance, the implication of these
findings is that HAART-associated reductions in viral load might
have a beneficial effect on NP performance. Indeed, this may
reflect combined therapeutic effects on viral replication in the
brain and plasma and perhaps, neurocognitive symptoms and
impairment may be useful surrogate indicators of rising viral
load and/or drug resistance. Within the Southern Alberta Clinic,
there is preference towards using CNS penetrating drugs
including stavudine, zidovudine, abacavir and lamivudine to
minimize lipodystrophy occurrence. The effects of the
predominant use of these drugs on CNS function remains
uncertain.
DISCUSSION
Neurocognitive symptoms are often difficult to interpret
clinically in the face of significant systemic disease that occurs
in illnesses such as HIV/AIDS. However, the present study
illustrates several relevant points that address this issue among
patients who were followed routinely in an HIV community
clinic. Patients who report neurocognitive symptomatology
performed significantly worse on NP testing and furthermore, a
greater percentage of patients with neurocognitive symptoma-
Group ages differed between the NPimpaired and unimpaired
groups with the impaired patients tending to be older and
similarly, MDS was also significantly correlated with age.
Earlier studies show conflicting results on the effect of age on
HIV-related NP impairment1,15,16 with one study showing no
effect and the other showing a positive correlation. However,
several concerns in the current study should be considered. The
cross-sectional design and relatively small sample size may
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5. Ferrando S, van Gorp W, McElhiney M, et al. Highly active
antiretroviral treatment in HIV infection: benefits for
neuropsychological function. AIDS 1998; 12: F65-70.
6. Tozzi V, Balestra P, Galgani S, et al. Positive and sustained effects
of highly active antiretroviral therapy on HIV-1-associated
neurocognitive impairment [In Process Citation]. AIDS 1999; 13:
1889-1897.
7. Price RW,Yiannoutos T, Clifford DB, et al. Neurological outcomes
in late HIVinfection: adverse impact of neurological survival and
protection effect of antiretroviral therapy. AIDS 1999; 13: 1677-
1685.
8. Selnes OA, Jacobson L, Machado AM, et al. Normative data for a
brief neuropsychological screening battery. Multicenter AIDS
Cohort Study. Percept Mot Skills 1991; 73: 539-550.
9. Heseltine PN, Goodkin K, Atkinson JH, et al. Randomized double-
blind placebo-controlled trial of peptide T for HIV- associated
cognitive impairment. Arch Neurol 1998; 55: 41-51.
10. Power C, Selnes OA, Grim JA, et al. HIV Dementia Scale: a rapid
screening test. J Acquir Immune Defic Syndr Hum Retrovirol
1995; 8: 273-278.
11. Janssen R. Nomenclature and research case definitions for
neurologic manifestations of human immunodeficiency virus-
type 1 (HIV-1) infection. Report of a Working Group of the
American Academy of Neurology AIDS Task Force [see
comments]. Neurology 1991; 41: 778-785.
predispose to biased results. Although a limited, highly-selected
NP battery is practical on day-to-day basis as shown in the
present study, a small NP test battery (less than nine tests) has
been shown to miss subtle deficits.17 Nonetheless, the present
study battery was sufficient to identify patients that had
previously unrecognized HAD. Finally, since this study was
performed in a Canadian HIV community clinic, the impact of
universal health care may result in findings that differ from those
in the United States where optimized HAART regimens may not
be as available to all patients.
We conclude that in the setting of an HIV community clinic,
it is useful to assess HIV/AIDS patients who report
neurocognitive symptoms because these symptoms are
frequently associated with impaired NPperformance, which may
respond to an increased number of antiretroviral drugs. Future
prospective studies examining the relationship between HAART
use and the development of neurocognitive symptoms and NP
impairment may identify optimal HAART regimens that are
neuroprotective and elucidate some of the neuropathogenic
mechanisms underlying HIV-induced NP impairment.
12. Sacktor NC, Skolasky RL, Lyles RH, et al. Highly active
antiretroviral therapy (HAART) improves cognitive impairment
in HIV+ homesexual men. Neuroscience of HIV infection. J
Neurovirol 1998; 4 (suppl): 365.
13. McArthur JC, McClernon DR, Cronin MF, et al. Relationship
between human immunodeficiency virus-associated dementia
and viral load in cerebrospinal fluid and brain [see comments].
Ann Neurol 1997; 42: 689-698.
14. Ellis RJ, Deutsch R, Heaton RK, et al. Neurocognitive impairment
is an independent risk factor for death in HIV infection. San
Diego HIV Neurobehavioral Research Center Group. Arch
Neurol 1997; 54: 416-424.
ACKNOWLEDGEMENTS
The authors thank Bill Richardson and Brenda Beckthold for
assistance with data analysis and Belinda Ibrahim for manuscript
preparation.
REFERENCES
1. Janssen RS, Nwanyanwu OC, Selik RM, et al. Epidemiology of
human immunodeficiency virus encephalopathy in the United
States. Neurology 1992; 42: 1472-1476.
15. McArthur JC, Hoover DR, Bacellar H, et al. Dementia in AIDS
patients: incidence and risk factors. Multicenter AIDS Cohort
Study. Neurology 1993; 43: 2245-2252.
16. van Gorp WG, Miller EN, Marcotte TD, et al. The relationship
between age and cognitive impairment in HIV-1 infection:
findings from the Multicenter AIDS Cohort Study and a clinical
cohort. Neurology 1994; 44: 929-935.
17. White DA, Heaton RK and Monsch AU. Neuropsychological
studies of asymptomatic human immunodeficiency virus- type-1
infected individuals. The HNRC Group. HIV Neurobehavioral
Research Center. J Int Neuropsychol Soc 1995; 1: 304-315.
2. Heaton RK, Grant I, Butters N, et al. The HNRC 500 –
neuropsychology of HIV infection at different disease stages.
HIV Neurobehavioral Research Center. J Int Neuropsychol Soc
1995; 1: 231-251.
3. Miller EN, Selnes OA, McArthur JC, et al. Neuropsychological
performance in HIV-1-infected homosexual men: the Multicenter
AIDS Cohort Study (MACS) [see comments]. Neurology 1990;
40: 197-203.
4. Dore GJ, Correll PK, Li Y, et al. Changes to AIDS dementia
complex in the era of highly active antiretroviral therapy. AIDS
1999; 13: 1249-1253.
Volume 28, No. 3 – August 2001
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