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The International HIV Dementia Scale: a new rapid screening test for HIV dementia

Sacktor, Ned Ca; Wong, Matthewb; Nakasujja, Noelinec; Skolasky, Richard La; Selnes, Ola Aa; Musisi, Segganec; Robertson, Kevind; McArthur, Justin Ca; Ronald, Allane; Katabira, Ellyc

doi: 10.1097/01.aids.0000180790.77379.3a
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Objective: HIV dementia is an important neurological complication of advanced HIV infection. The use of a cross-cultural screening test to detect HIV dementia within the international community is critical for diagnosing this condition. The objective of this study was to evaluate the sensitivity and specificity of a new screening test for HIV dementia, the International HIV Dementia Scale (IHDS) in cohorts from the US and Uganda.

Design: Two cross-sectional cohort studies designed to evaluate for the presence of HIV dementia.

Methods: Sixty-six HIV-positive individuals in the US and 81 HIV-positive individuals in Uganda received the IHDS and full standardized neurological and neuropsychological assessments. The sensitivity and specificity of varying cut-off scores of the IHDS were evaluated in the two cohorts.

Results: In the US cohort, the mean IHDS score for HIV-positive individuals without dementia and with dementia were 10.6 and 9.3 respectively (P < 0.001). Using the cut-off of ≤ 10, the sensitivity and specificity for HIV dementia with the IHDS were 80% and 57% respectively in the US cohort, and 80% and 55% respectively in the Uganda cohort.

Conclusions: The IHDS may be a useful screening test to identify individuals at risk for HIV dementia in both the industrialized world and the developing world. Full neuropsychological testing should then be performed to confirm a diagnosis of HIV dementia.

From the aDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

bDepartment of Medicine, University of Calgary, Calgary, Alberta, Canada

cDepartment of Medicine, Makerere University, Kampala, Uganda

dDepartment of Neurology, University of North Carolina, Chapel Hill, North Carolina, USA

eDepartment of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

Received 10 April, 2005

Revised 7 June, 2005

Accepted 27 June, 2005

Correspondence to N. Sacktor, Johns Hopkins Bayview Medical Center, Department of Neurology, B Building, Room 122, 4940 Eastern Avenue, Baltimore, MD 21224, USA. Tel: +1 410 550 0978; fax: +1 410 550 0539; e-mail: sacktor@jhmi.edu

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Introduction

The HIV/AIDS epidemic is a major global public health crisis with an estimated 40 million adults and children living with HIV infection [1]. The vast majority of HIV cases globally, an estimated 26.6 million people, are in Sub-Saharan Africa [1]. The frequency of neurological complications such as HIV-1-associated dementia complex (HIV dementia), a dementia affecting cognitive and motor abilities, is largely unknown in resource-limited countries, although preliminary surveys in Uganda suggest a relatively high frequency of cognitive dysfunction [2].

In the US, HIV dementia is characterized by cognitive, behavioral, and motor dysfunction and occurs in 10–15% of HIV-seropositive (HIV+) individuals with advanced infection [3]. If a similar proportion were to be seen on a global scale, then HIV dementia would be the most common cause of dementia worldwide in patients under the age of 40 years. The diagnosis of HIV dementia is dependent upon a clinical history and neurological examination consistent with criteria developed by the American Academy of Neurology (AAN) [4]. Neuropsychological testing is a critical component of the diagnosis, but it is time consuming, language and education dependent, and often not available in developing countries.

Screening tests are essential for directing limited resources for the diagnosis of dementia to those most at risk for the development of this complication. Brief instruments have been developed to screen for specific dementia syndromes, for example the Mini Mental State Exam (MMSE) [5,6]. However, the MMSE was designed to screen for cortical dementia such as Alzheimer's disease, and it is therefore less sensitive for detecting subcortical dementia such as HIV dementia [7]. The HIV Dementia Scale (HDS) was designed as a brief but sensitive screening instrument to identify HIV+ patients at risk for dementia [8]. The HDS includes subtests that evaluate motor speed (timed written alphabet), memory (recall of four words at 5 min), constructional praxis (cube copy time), and executive functions (antisaccadic errors subtest). The HDS has been validated as a sensitive and well-tolerated screening instrument for dementia in patients with HIV disease [9] and in patients with subcortical vascular ischemic disease [10]. The antisaccadic error subtest, however, has proven difficult for non-neurologists to administer [11]. The HDS also includes subtests (alphabet writing and cube-copying tests) which may be difficult for individuals with a non-Western educational background. Thus, the objective of this study was to evaluate a new practical cross-cultural screening instrument, the International HIV Dementia Scale (IHDS). The IHDS eliminates the antisaccades subtest and replaces the timed written alphabet and cube copy time subtests with tests of motor speed and psychomotor speed which can easily be performed across different cultures. The IHDS was initially evaluated in a US clinic, and then was applied in an Infectious Disease clinic in Kampala, Uganda. Results from both studies are described below.

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Methods

Study population

US study

Sixty-six HIV+ participants over a period of 5 months from July 2002 to November 2002 underwent the IHDS and standardized neurological, neuropsychological, and functional assessments as part of a longitudinal cohort at Johns Hopkins Hospital [12] (the NorthEastern AIDS Dementia–NEAD–cohort). The NEAD cohort includes HIV+ individuals at high risk for HIV dementia with either a CD4 cell count < 200 × 106 cells/l or a CD4 cell count < 300 × 106 cells/l and demonstrating cognitive impairment defined as performance on neuropsychological testing that was 2 SD below the appropriate mean on one test or 1 SD below the mean on two tests [12]. Exclusion criteria for the US study were current or past opportunistic central nervous system (CNS) infection at study entry, or history of severe medical, psychiatric, or neurologic disorder believed to interfere with the ability to perform the study evaluations.

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Uganda study

Eighty-one HIV+ individuals also received standardized neurological, neuropsychological, and functional assessments at an Infectious Disease Clinic in Kampala, Uganda over a period of 8 months from August 2003 to March 2004. This clinic is part of the Academic Alliance for AIDS Care and Prevention in Africa, a collaboration between HIV-AIDS care experts from North America and Makerere University Medical School in Uganda [13]. Exclusion criteria for the Uganda study included HIV+ individuals less than 18 years of age, HIV+ individuals with an active or known past CNS opportunistic infection, fever > 37.5°C, a history of a chronic neurological disorder, active psychiatric disorder, alcoholism, physical deficit (e.g., amputation), severe functional impairment (Karnofsky < 50), or severe medical illness that would interfere with the ability to perform the study evaluations. Fluency in English was not a requirement for the study. All evaluations were translated into the local language, Luganda.

Normative data were also collected on 100 HIV-seronegative (HIV−) individuals recruited at an AIDS Information Center (AIC) in Kampala, Uganda. The AIC is a voluntary counseling and testing center. Inclusion and exclusion criteria were identical to the Uganda HIV+ cohort except that the HIV− individuals had documentation of a negative HIV test within 1 year preceding the evaluation.

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International HIV Dementia Scale

The IHDS consists of three subtests: timed fingertapping, timed alternating hand sequence test, and recall of four items at 2 min (Fig. 1), and is administered as follows. The timed fingertapping test from the Unified Parkinson's Disease Rating Scale (UPDRS) was used [14]. The number of fingertaps of the first two fingers of the non-dominant hand was measured by instructing the participant to open and close the fingers as widely and as quickly as possible over a 5-s period. The scale from the UPDRS was used with 4 points assigned for normal performance (i.e.≥ 15 taps/5 s). The alternating hand sequence test was adapted from the Luria Motor test [15]. Individuals were asked to perform the following movement with the non-dominant hand as quickly as possible over a 10s period: (i) clench the hand in a fist on a flat surface; (ii) put the hand flat on the surface with the palm down; and (iii) put the hand perpendicular to the flat surface on the side of the fifth digit. The three hand positions were demonstrated to the participant by the examiner, and the participant would then perform the sequence correctly twice for practice before the 10-s subtest was performed. The number of sequences correctly performed within 10s up to a maximum number of 4 was scored. A participant unable to perform the alternating hand sequence was assigned a score of 0. The verbal recall subset of the IHDS was similar to the verbal recall subtest of the HDS. Registration (new learning) was measured by reciting four words to the subject and then asking him/her to repeat them immediately. The words were repeated by the examiner until the subject could repeat all four words correctly. The subject was then asked to recall the four words after the timed fingertapping and alternating hand sequence tests were performed. The number of items recalled was scored out of 4. For words not recalled, the subject was prompted with a ‘semantic’ clue as follows: animal (dog), piece of clothing (hat), vegetable (bean), and color (red). A half-point was assigned for each correct word recalled after prompting. A total score out of 12 was calculated for each participant, with each of the three subtests contributing 4 points to the total score.

Fig. 1

Fig. 1

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Neurological, neuropsychological, and functional assessments

The neurological, neuropsychological, and functional assessments in the US study have been described in detail previously [12]. In brief, all HIV+ individuals received a structured demographic assessment, medical history, and neurological examination. The neuropsychological testing battery covered six domains including verbal memory (Rey Auditory Verbal Learning test), constructional praxis (Rey Complex Figure Copy test), psychomotor performance (Digit Symbol test, Trail Making test), motor speed (Grooved Pegboard test), frontal systems (Verbal Fluency, Odd Man Out tests), and reaction time [California Computerized Assessment Package (CALCAP)] [16–22]. An age and education adjusted z score was used to quantify performance for each of the neuropsychological tests [12,23,24]. Functional performance and depression symptomatology also were assessed [20,25–27]. These assessments were used to assign a Memorial Sloan Kettering (MSK) dementia stage [28], by a consensus conference including a neurologist (N.S.) and neuropsychologist (O.S.).

For the Uganda study, HIV+ and HIV− individuals received clinical assessments using standardized questionnaires assessing demographic information including primary language used and reading abilities, medical history, psychiatric history, neurological symptoms assessments, and a neurological examination. The neuropsychological testing battery included the World Health Organization (WHO) University of California Los Angeles (UCLA) Verbal Learning test for verbal memory [29]. This test is similar to the Rey Auditory Verbal Learning test (RAVLT) in that it uses a list-learning task. However, all of its items have been carefully selected (from categories such as parts of the body, tools, household objects, and common transportation vehicles) to be familiar in a variety of cultures. The Timed Gait and Grooved Pegboard tests were used to assess motor performance. The Digit Symbol test [17] and the Color Trails test [29] were used to assess psychomotor speed performance. The Color Trails 1 and 2 are similar to the Trail Making test except that to minimize cultural bias, no letters or written instructions are used. Both Color Trails 1 and 2 consist of several numbered circles colored in pink or yellow; in Color Trails 1, each number is represented by only one color, whereas in Color Trails 2, each number is printed twice, once in pink and once in yellow. In Color Trails 1, the participant is instructed to draw a line between the numbered circles one after the other, following the number sequence. In Color Trails 2, the participant must maintain the sequence of numbers and alternate between pink and yellow. Digit span forward and backward was used to assess attention. The functional assessment included the Karnofsky Performance Scale [25]. These assessments were used to assign a MSK dementia stage of 0, 0.5, or ≥ 1 by a consensus conference including the primary examiners (M.W. and N.N.), a neurologist (N.S.), a neuropsychologist (K.R.), and a psychiatrist (N.N.).

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Data analysis

US study

HIV+ individuals were classified by MSK stage, and mean values for demographic and laboratory variables were compared using t tests. Chi-square tests were used to compare proportions among the groups. IHDS results and performance on the Grooved Pegboard test with the non-dominant hand, a test frequently used to screen for HIV dementia, were each evaluated as a screening instrument in HIV+ individuals stratified by MSK dementia stage using a t test. The IHDS and Grooved Pegboard results also were correlated with a correlation coefficient. A receiver–operator characteristic (ROC) curve was performed to determine the cut-off which maximizes sensitivity and specificity for the diagnosis of HIV dementia in the US study [30]. This same cut-off was then evaluated in the Uganda study.

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Uganda study

HIV+ and HIV− individuals were compared with respect to demographic, neuropsychological test, functional, and IHDS performance. Using the entire battery of assessments to assign the MSK dementia stage, the IHDS score was then compared to the MSK dementia stage to define the sensitivity and specificity of the IHDS in the Uganda study using the cut-off determined by the US study.

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Results

IHDS Performance in the US

The mean demographic and clinical characteristics of the HIV+ individuals stratified by MSK stage in the US study are shown in Table 1. There were no differences between the MSK stages for age, education, or CD4 cell count. The IHDS scores and the Grooved Pegboard non-dominant hand test score are also shown in Table 1. Individuals with HIV dementia (MSK stage 1–3) performed worse on both the IHDS (t, 5.1; P < 0.001) and the Grooved Pegboard non-dominant hand test (t, 3.6, P < 0.001), compared to those HIV+ individuals without dementia (MSK stage 0–0.5). With advancing MSK dementia stage severity, both the IHDS score and the Grooved Pegboard non-dominant hand test score became progressively more impaired. The mean IHDS score for both the MSK 0 (no impairment) and MSK 0.5 (equivocal/subclinical dementia) groups was 10.6 whereas the mean IHDS score for the MSK 1 (mild dementia) group was 9.3, suggesting that 10.0 may be a useful cutoff to distinguish HIV+ individuals with and without dementia. The correlation of the IHDS score and the Grooved Pegboard non-dominant hand test score is shown in Fig. 2. Performance on the IHDS correlated well with performance on the Grooved Pegboard non-dominant hand test (r, 0.42; P < 0.001).

Table 1

Table 1

Fig. 2

Fig. 2

To determine the optimal cut-off value for the IHDS to maximize sensitivity and specificity, a receiver–operator characteristic (ROC) curve analysis was performed. Cut-off values in 0.5 increments from 8.0 to 12.0 are shown in Table 2 with the corresponding sensitivities and specificities for HIV dementia. The cut-off value of 9.5 for the IHDS maximized the sensitivity (71%) and specificity (79%) for HIV dementia. However, the cut-off value of 10.0 for the IHDS improved the sensitivity (80%) with fewer false negative results. Because a screening test should have a high sensitivity of at least 80% to minimize false negative results, the cut-off of ≤ 10 for HIV dementia was used in the Uganda study.

Table 2

Table 2

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IHDS Performance in Uganda

The clinical characteristics of the HIV+ individuals and HIV− individuals in Uganda are described in Table 3. HIV+ individuals were older (mean age ± SD, 37.0 ± 9.4 years) compared to HIV− individuals (31.4 ± 7.3 years) (P < 0.001).

Table 3

Table 3

The IHDS total score and each of its three subscores, as well as each neuropsychological test and the Karnofsky functional performance scores are summarized in Table 3 for both HIV+ individuals and HIV− individuals. HIV+ individuals performed worse on the IHDS total score and each of the three IHDS subscores (the fingertapping, alternating hand position, and verbal recall subtests) compared to HIV− individuals. In the full neuropsychological test battery, HIV+ individuals performed worse on the AVLT Total score test, AVLT Delayed Recall score, the Color Trails 1 and 2 tests, and the Symbol Digit Modalities test. In the functional (Karnofsky) assessment, HIV+ individuals self-reported more functional impairment.

Using normative data from HIV− individuals in Uganda, 31% of the HIV+ individuals in this study were diagnosed with dementia. The mean IHDS total score among HIV+ individuals with an MSK score of 0 was 10.8, whereas the mean IHDS total score among HIV+ individuals with an MSK score of 0.5 was 10.1. The mean IHDS total score among HIV+ individuals with an MSK score of 1 was 8.9, which was decreased compared to the other two MSK stages, P < 0.05. The sensitivity of the IHDS for HIV dementia in this cohort was 80%, and the specificity for HIV dementia was 55% using a cut-off of ≤ 10 for abnormal performance (see Table 2). If the cut-off of ≤ 10.5 for abnormal performance is used, the sensitivity of the IHDS for HIV dementia in the Uganda cohort is increased to 88% with a mild decrease in the specificity to 48%.

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Discussion

A sensitive and rapid screening test for HIV dementia is essential for future international studies in developing countries. The IHDS does not require knowledge of the English language, can be performed briefly in 2–3 min by non-neurologists in an outpatient setting, and requires no special instrumentation other than a watch with a second hand. Thus, it is ideally suited for an international setting where resources may be limited.

Our results suggest that the IHDS is a useful screening test for HIV dementia in both the industrialized world and the developing world. The sensitivity and specificity of the IHDS are comparable to the sensitivity (71%) and specificity (46%) of the Grooved Pegboard non-dominant hand test, an established test for HIV dementia (using a cut-off of 1.5 SD below the age- and education-adjusted mean) [11,31,32]. The IHDS has a major advantage in that the IHDS requires no special instrumentation. The IHDS is useful for HIV+ individuals with and without a complete high school education (US cohort mean education, 13 years; Uganda cohort mean education, 9 years).

The IHDS though does have several limitations. It is not useful for detecting mild cognitive impairment associated with HIV infection, as there was no difference between HIV+ individuals with normal neuropsychological testing (MSK stage 0) and HIV+ individuals with mild impairment on neuropsychological testing but not severe enough to meet criteria for dementia (MSK stage 0.5). The IHDS cannot be used to distinguish between different stages of HIV dementia, although progressively lower mean IHDS scores did correspond to greater dementia severity in the US study. The role that depression may have on IHDS performance also requires further evaluation. The practice effects of the IHDS have not been determined.

The IHDS should not be used as a replacement for a full neuropsychological test battery in the clinical diagnosis of HIV dementia. Using a cut-off of ≤ 10, the false negative rate of the IHDS for the diagnosis of HIV dementia is relatively low. A cut-off of ≤ 10.5 provides even greater sensitivity with a minimal loss of specificity. Thus, most HIV+ individuals with HIV dementia will be identified and can be referred for subsequent full neuropsychological testing. However, using the cut-off of ≤ 10, the false positive rate is notable, and HIV+ individuals with an abnormal IHDS score may upon further testing have normal neurocognitive functioning. Thus, a full neuropsychological test battery is essential before a diagnosis of dementia is made. The IHDS is useful to screen for HIV dementia in a resource-limited environment, but it should not be used in place of a full neuropsychological test battery. In settings where full neuropsychological testing cannot be performed, the IHDS would be useful to identify those individuals at high risk for dementia.

The area under the curve analysis suggests a cut-off of ≤ 9.5 maximizes the sensitivity and specificity of the IHDS. However, the sensitivity of the IHDS would only be 71% with a cut-off of ≤ 9.5, and there would be a significant false negative rate. For clinical purposes, a screening test should have a low false negative rate, and the sensitivity of the test should be at least 80%. Thus, despite the overall lower combined sensitivity and specificity of the ≤ 10 cut-off, this value was chosen for use on a practical basis, because it achieves a sensitivity of 80%, and thus is within acceptable limits as a screening tool.

The study in Uganda has separate limitations. The HIV+ cohort is older than the HIV− cohort. Because many of the differences between the HIV+ cohort and HIV− cohort were in motor performance tests, and age is associated with motor performance decline, one cannot rule out the possibility that the differences between the two groups are due to age and not HIV infection. However, age-associated motor slowing is more prominent in the fifth and sixth decades of life rather than the third and fourth decades of life. Individuals in the HIV− cohort may have had undetected etiologies of potential cognitive impairment such as tuberculosis, malaria, syphilis, alcohol use, or depression. The diagnosis of dementia in the HIV+ cohort is limited by the lack of neuroimaging to rule out a CNS opportunistic infection, malignancy, or cerebrovascular disease and the lack of a cerebrospinal fluid examination to rule out a CNS opportunistic meningoencephalitis. Given the frequency of cryptococcal or tuberculous meningitis in this population, this is a significant concern. However, none of the HIV+ subjects in this study had either a fever or a focal neurological examination to suggest a focal CNS lesion or meningoencephalitis.

HIV dementia is an important complication to diagnose in patients with AIDS for several reasons: (i) it is associated with an increased risk of mortality [31,33]; (ii) the presence of dementia can affect antiretroviral medication adherence which is essential for suppression of virological replication [34]; and (iii) HIV dementia is a potentially treatable condition with highly active antiretroviral therapy [35,36]. The IHDS may have great value as a screening test for HIV dementia in the industrialized world and the developing world. The diagnosis of HIV dementia may then be an indication for initiation of antiretroviral therapy which could have enormous benefit for the individuals themselves, their families, and their communities.

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Acknowledgements

Amanda Barnes, Jason Creighton, Alice Namudde and Fred Sebuma assisted in the evaluations of subjects. The studies of HIV+ subjects were conducted in the Infectious Disease Institute of Makerere University.

Sponsorship: Supported by NS044807, NS049465, NS036519, MH71150, RR00052, the Bill and Melinda Gates Foundation, and the Academic Alliance Foundation (which has received support from Pfizer Pharmaceuticals).

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Keywords:

HIV; dementia; screening test; Uganda; international; scale

© 2005 Lippincott Williams & Wilkins, Inc.