Evaluation of brief screening tools for neurocognitive impairment in HIV/AIDS: a systematic review of the literature
Zipursky, Amy R.a,b; Gogolishvili, Davida; Rueda, Sergioa,b; Brunetta, Jasonc; Carvalhal, Adrianab,d; McCombe, Jennifer A.e; Gill, M. Johne; Rachlis, Anitab,f; Rosenes, Rona; Arbess, Gordonb,d; Marcotte, Thomasg; Rourke, Sean B.a,b,d
aOntario HIV Treatment Network
bUniversity of Toronto
cMaple Leaf Clinic, Toronto, Ontario
dSt. Michael's Hospital, Toronto, Ontario
eSouthern Alberta HIV Clinic and University of Alberta, Edmonton, Alberta
fSunnybrook Hospital, Toronto, Ontario, Canada
gUniversity of California, San Diego, La Jolla, California, USA.
Correspondence to Dr Sean B. Rourke, Centre for Research on Inner City Health, Li Ka Shing Knowledge Institute of St. Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada. Tel: +1 416 864 6060 ext 6482; fax: +1 416 864 5135; e-mail: Sean.email@example.com
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website ( http://www.AIDSonline.com).
Received April 05, 2013
Revision received May 29, 2013
Accepted May 29, 2013
To systematically review literature on brief screening tools used to detect and differentiate between normal cognition and neurocognitive impairment and HIV-associated neurocognitive disorders (HANDs) in adult populations of persons with HIV.
A formal systematic review.
We searched six electronic databases in 2011 and contacted experts to identify relevant studies published through May 2012. We selected empirical studies that focused on evaluating brief screening tools (<20 min) for neurocognitive impairment in persons with HIV. Two reviewers independently reviewed retrieved literature for potential relevance and methodological quality. Meta-analyses were completed on screening tools that had sufficient data.
Fifty-one studies met inclusion criteria; we focused on 31 studies that compared brief screening tools with reference tests. Within these 31 studies, 39 tools were evaluated and 67% used a comprehensive neuropsychological battery as a reference. The majority of these studies evaluated HIV-associated dementia (HAD). Meta-analyses demonstrated that the HIV Dementia Scale (HDS) has poor pooled sensitivity (0.48) and the International HIV Dementia Scale (IHDS) has moderate pooled sensitivity (0.62) in detecting a range of cognitive impairment. Five newer screening tools had relatively good sensitivities (>0.70); however, none of the tools differentiated HAND conditions well enough to suggest broader use. There were significant methodological shortcomings noted in most studies.
HDS and IHDS perform well to screen for HAD but poorly for milder HAND conditions. Further investigation, with improved methodology, is required to understand the utility of newer screening tools for HAND; further tools may need to be developed for milder HAND conditions.
Since the introduction of combination antiretroviral therapy (cART), the incidence of severe forms of HIV-associated neurocognitive impairment has declined significantly, whereas the prevalence of the milder forms has increased [1,2]. The nomenclature originally developed by the American Academy of Neurology Task Force on AIDS in 1991 was recently updated in 2007 in response to the change in presentation and research available on the natural history of HIV-associated neurocognitive complications . There are now three different HIV-associated neurocognitive disorder (HAND) conditions. In order of increasing severity and related impact on everyday functioning, these are first, asymptomatic neurocognitive disorder (ANI) with a prevalence of 30–35% and characterized by at least mild neurocognitive impairment in two domains (at least 1.0 SD below the mean for age-education-appropriate norms) but with no evidence of difficulty with day-to-day functioning; second, mild neurocognitive disorder (MND) with a prevalence of 20–25% and characterized by at least mild neurocognitive impairment in two domains (at least 1.0 SD below the mean for age–education appropriate norms) and with mild interference with day-to-day functioning; and third, HIV-associated dementia (HAD) with a prevalence of 2–3% with generally moderate to severe impairments in neurocognitive functioning in multiple domains (2 SD or greater than demographically corrected means) and marked difficulties with everyday functioning . Overall, the prevalence of HAND based on the new criteria is approximately 50–60% [1,4].
In the early years of the HIV epidemic, 20–30% of patients presented with severe cognitive impairment that was later classified as HIV-1-associated dementia complex . The HIV Dementia Scale (HDS) was developed to screen for HAD  and later the International HDS (IHDS)  was developed for use in global settings. These instruments have had varying degrees of success in screening of those with the milder forms of HAND (i.e. ANI and MND). The clinical significance of identifying the milder forms of HAND is important, as they can have a significant impact on the lives of people living with HIV. They have been shown to interfere with medication adherence [8,9], workplace performance , driving  and ability to carry out tasks independently [12,13]. The consequences of these effects have been seen in decreased health-related quality of life  and increased mortality rates [2,15] in people with HAND.
To better assist in prevention, treatment and management of HAND, it is important that screening tools be developed and evaluated. Before widespread use for clinical treatment decision-making, these tools need to be shown to have adequate sensitivity and specificity with HAND; they need to be brief enough to be used in the clinic or health centre, and able to be administered by a trained individual with minimal equipment.
To determine which screening tools for HAND meet these criteria, we have undertaken the first systematic review of the literature with respect to the screening tools for HAND. Our objective is to systematically review the literature on brief screening tools that can detect neurocognitive impairment and are able to differentiate among the various forms of HAND in the adolescent and adult population of persons living with HIV and AIDS.
Materials and methods
We conducted literature searches in MEDLINE, EMBASE, PsycINFO, LILACS and CINAHL in May 2011 for published, full-length research articles. An experienced librarian in systematic review methods assisted us in developing a search strategy (included in Appendix A, http://links.lww.com/QAD/A370). We did not apply date or language restrictions in the search strategy because we did not want to limit the investigation to tools administered only in English. We also contacted key experts in the field for recommendations and received articles for potential inclusion until the start of May 2012.
Only studies reporting on participants who were adolescent or adult age were included (generally age >16 years). To be included in the review, individual studies needed to include participants who were HIV-positive and with some form of documented HIV-associated neurocognitive impairment, or be characterized/diagnosed with having any HAND [i.e. ANI, MND, minor cognitive motor disorder (MCMD), or HAD] [3,5]. The studies evaluated neurocognitive impairment in different ways, and this is a limitation of the current state of the literature.
We considered studies that focused on screening for ‘neurocognitive’ or ‘neuropsychological’ impairments or HAND [3,5]. The ways in which studies addressed screening tools included evaluating the utility of a specific screening tool, comparing different screening tools and validating screening tools. The focus of the review was then restricted to include only those articles that evaluated the utility of screening tool(s) against a separate reference or criterion. We defined screening tools to include pen and paper tests, algorithms and computerized tests and excluded biological tests (i.e. studies looking at biomarkers). In addition, we focused on ‘brief’ screening tools, and we defined this as those that took approximately 20 min or less to perform. This was done because the focus was screening tests that might be potentially useful in a clinic or healthcare setting to detect HAND.
All studies needed to report findings from empirical research. We included primary studies and considered both cross-sectional and longitudinal investigations. We excluded primary studies that used qualitative methods or case study methods. We also considered systematic review articles.
Search and data extraction
Two reviewers independently assessed the titles and abstracts of the citations from the search according to the selection criteria. For the citations that met the criteria, data from full texts were extracted by one reviewer and checked independently for accuracy by a second reviewer. We contacted study authors to obtain any information that was missing. Any disagreements between reviewers on data extracted were resolved by consensus or by a third reviewer.
Two reviewers independently appraised the quality of the selected articles from the search using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool . This 14-item tool was specifically designed to assess the quality of primary studies addressing diagnostic accuracy. Disagreements between the reviewers on the different QUADAS items were resolved by consensus.
There were 2030 citations in the database searches and 334 of these were duplicates between databases. The review of titles and abstracts resulted in the identification of 316 articles for full assessment, with 1380 articles being excluded because they did not meet our inclusion criteria. We completed a full appraisal of 304 articles (we were unable to locate 12 full articles despite contacting the authors), and at this stage found that 253 of the 304 did not meet inclusion criteria resulting in 51 studies for inclusion. Articles that did not meet inclusion criteria were for the following reasons: six did not focus on people living with HIV; 185 did not evaluate screening tools; 28 did not include screening tools that are brief; eight did not report on empirical studies; and 26 articles did not include participants with HAND or impairment. [See Fig. 1 for Search strategy].
Of the 51 studies that met criteria [6,7,17–65], we identified two main categories into which these studies could be divided: first, studies that evaluated screening tools by comparing them with a reference standard or criterion (n = 31 of 51 or 61% of studies evaluated) [6,7,17–44,64], and second, studies that evaluated screening tools by other methods (n = 20 of 51 or 39% of studies) [45–63,65]. For the purposes of the current article, we decided to focus our systematic review analyses on the first category of studies (n = 31), [see Table 1 for Characteristics of studies on brief screening tools for HIV-associated neurocognitive disorders] as this is the most accepted method of evaluating a diagnostic tool (Results from the second category of studies can be found in Appendix B).
Study characteristics (N = 31 studies)
Thirty-one studies are the focus of this subsequent analysis. Thirty of the 31 used a cross-sectional design [6,7,17–36,38–44,64] and one used a longitudinal design . Eighteen of these studies (60% of all studies examined) were conducted in the USA [6,7,17–19,22,23,26,27,31,33–38,42,44]; three in Australia [20,21,32]; three in South Africa [24,28,41]; one each in the UK ; Germany ; Belgium and the Netherlands ; Switzerland ; Uganda ; Kenya ; India ; and one at sites across the world . The participants in all of the studies combined totalled a sample of 5837 participants, and the individual study samples ranged from 20  to 1549  participants. Twenty-five studies used convenience sampling [6,7,17–19,22,24,25,27–33,35–41,43,44,64], and two used random sampling [20,34].
Neurocognitive screening tool evaluations
Types of screening tools evaluated
Within these 31 studies, 39 screening tool evaluations were conducted with 21 unique screening tools. Eleven studies evaluated the HDS (35%) [6,18,19,24,31,34,38,40,42–44]; four the IHDS (13%) [7,28,41,64]; three the CogState Computerized Battery (10%) [20,32,35]; three the Mini-Mental State Examination (MMSE) (10%) [6,31,64]; and other tools were evaluated in the remaining 16 studies [6,17,19,21–23,25–27,29,30,33,36,37,39,64]. Twenty-one (68%) [6,7,17–23,26,27,30,32,33,35–39,41,42] studies reported evaluating screening tools in English and eight (26% of studies overall) [7,24,28–30,41,43,44] in another language.
Presence and severity of neurocognitive impairment assessed
Of the 31 studies, 11 (35%) focused on detecting HAD [6,7,18,22,28,30,31,34,40,44,64], four also screened for MND [28,30,40,64] or MCMD [18,22,34,44], and five screened for ANI [28,30,34,40,64]. Seventeen studies (55%) focused on detecting neurocognitive impairments and/or deficits [17,18,20–23,25–27,29,33,35,36,38,41,42,66]. Eight studies (26%) [6,7,18,19,22,31,34,44] used 1991 criteria  and five studies (16%) [21,28,30,40,64] used the revised 2007 criteria  for diagnosing HAND. It is important to note that many of the studies were published prior to the establishment of the 2007 HAND criteria.
Assessment of functional status
Functional status was measured objectively in nine studies (29%) [20–22,30,34,38,39,44,64] (29%) and subjectively in seven studies (23%) [23,26,28,29,37,40,42]. It is worth noting that functional status was assessed differently across studies, and only three of the studies that objectively assessed functional status [20,29,63] used the recent 2007 Frascati criteria to classify participants.
Length of time of reference test/criterion
We were interested in determining whether the quality and rigour of the criterion or reference test used was related to the outcome of the screening tests. We examined and coded the length and comprehensiveness of the neuropsychological test battery into ‘short’, ‘medium’ and ‘long and comprehensive’ battery (See Table 2 for ‘short’, ‘medium’ and ‘long’ battery criteria). Nine studies (29%) used a ‘short’ [6,23–25,27,33,37,41,43], 11 (35%) used a ‘medium’ [7,22,28–30,32,35,38,40,42,44] and seven (23%) used a ‘long’ [17–21,26,36] battery. For the HDS and IHDS, there were sufficient data to evaluate the associations between sensitivity and specificity and battery size. There was a significant association for the HDS between sensitivity and size of battery (P < 0.05), with sensitivity decreasing with increasing battery size. There was a trend for increasing specificity with increasing battery size, but this association was not significant.
Type of reference test / criterion and sensitivity performance
Twenty-six of the 39 tool evaluations (67%) used a detailed neuropsychological battery as the reference standard [18–22,26,28–30,32,35,36,38,40–44,64]. Fifteen tool evaluations (38%) reported adequate sensitivities (≥0.75). Adequate sensitivities (≥0.75) were reported for the HDS [6,24,31,40,44], IHDS [7,41], CogState , Grooved Pegboard , Hopkins Verbal Learning Test-Revised/Grooved Pegboard Test Non-Dominant Hand , Hopkins Verbal Learning Test/WAIS-III Digit Symbol , Mental Alternation Test , Motor Battery , the Screening Algorithm  and the Timed Gait Test .
The HDS and IHDS have been sufficiently studied to perform a meta-analysis for each tool. For inclusion in the meta-analysis, the articles we reviewed were required to use a neuropsychological battery as the reference test; use the neuropsychological battery to classify the participants as ‘impaired’; and report the incidence of impairment, sensitivity and specificity of the tools. Seven studies on the HDS [6,19,34,38,40,42,44] and three studies on the IHDS met these criteria [7,28,41]. One study on the IHDS looked at this tool in two different participant pools , and as such, the results from each of the participant pools were included in the meta-analysis.
Meta-analysis and qualitative results with the HIV Dementia Scale
The Forest Plot of the meta-analysis of the HDS (Fig. 2a) shows a large range in the sensitivities for the HDS across studies; four studies [19,34,38,42] reported poor sensitivity (i.e. ≤0.55) and three studies [6,40,44] reported good sensitivity (i.e. >0.80). Overall, the pooled sensitivity of these studies (i.e. 0.48) would suggest that the HDS (without any corrections for demographics) is not useful for detecting a range of HAND conditions.
The studies that report adequate sensitivities for the HDS fall into three main groups. The first group, the study by Power et al. (sensitivity 0.81), utilized the HDS to detect frank dementia. The second group, studies by Simioni et al. and Wojna et al. (sensitivity 0.82 and 0.87), used a high cut-off score (13 or 14). We meta-analysed these two studies together (Fig. 2b) and determined that the pooled sensitivity increased greatly when only evaluations with higher cut-offs were used (0.84). Finally, Morgan et al. used demographic corrections for age and education (T-scores) and increased the sensitivity from 0.17 with a cut-off of 10 or less to 0.71. These results suggest that the utility of the HDS can be improved by increasing the cut-off score, or by using demographically adjusted T-scores, but only for the detection of dementia.
The two studies with the lowest and comparable sensitivities [i.e. 0.09 and 0.17; Preliminary results from our CIHR Screening study (n = 20) also produced similar results with a sensitivity of 0.12 using a ‘long and comprehensive’ battery (personal communication, S.B.R., 13 March 2013)] both used a ‘long and comprehensive’ reference battery [19,34], whereas those that used a ‘medium’ reference battery [38,40,42,44] had not only higher sensitivities but also a larger range of sensitivities (0.39–0.87). These discrepancies in results using ‘medium’ versus ‘long’ reference batteries suggest that the rigour and comprehensiveness of the battery may be important determinants to consider when evaluting the overall test performance of screening tests for HAND.
Meta-analysis with the International HIV Dementia Scale
The meta-analysis of the IHDS (Fig. 2c) demonstrated more consistency than the HDS, although these studies employed only ‘small’ and ‘medium’ length reference batteries. One  study reported a poor sensitivity for the IHDS (0.45) and the other three [7,41] studies reported good sensitivities (≥0.80). Overall, the pooled sensitivity of these studies (0.62) demonstrates that the IHDS may be moderately useful in detecting HAND.
The quality assessment demonstrated that there are specific areas in which the studies tend to have methodological shortcomings (Fig. 3). Very few studies fulfilled criteria 10 and 11: 10, ‘Were the index test results interpreted without knowledge of the results of the reference standard?’ (6/31, 19%) [19,22,30,31,41,44] and 11, ‘Were the reference standard results interpreted without knowledge of the results of the index test?’ (7/31, 23%) [19,22,30,31,39,41,44]. This low level suggests that there may be some introduction of bias in the data interpretation, which may result in an overestimation of sensitivity.
Only about half the studies fulfilled criterion 1, ‘Was the spectrum of patients representative of the patients who will receive the test in practice?’ (17/31, 54%) [6,7,17,19,21,22,24,25,27,28,31,32,34,36,37,39,41]. This suggests that there are a good number of studies that may have limited applicability to real-life clinical settings.
The quality assessment did highlight some successful methodologies that should be continued in further evaluations. First, the majority of studies administered the same reference test and screening test to all study participants [criterion 5, ‘Did the whole sample or a random selection of the sample receive verification using a reference standard of diagnosis?’ (30/31, 97%) [6,7,17–28,30–44,64] and criterion 6, ‘Did patients receive the same reference standard regardless of the index test result?’ (30/31, 97%) [6,7,17–33,35–44,64]]. This allowed for proper and comprehensive calculation of sensitivity and specificity. Second, the majority of studies described their procedures with sufficient detail for replication of criterion 8 - ‘Was the executive of the index test described in sufficient detail to permit replication of the test?’ (30/31, 97%) [6,7,17–22,24–44,64], enabling future comparison of newer screening tools to already evaluated tools.
With the prevalence of milder forms of HAND increasing, and limited resources available for formal neuropsychological examinations, there is a critical need to be able to screen and identity people with HAND. Our current systematic review identified 51 peer-reviewed articles that focused on screening for neurocognitive impairments associated with HIV/AIDS. Of these, about two-thirds (31/51) used a criterion or reference to characterize the performance of 21 unique screening instruments. About half of the 31 studies examined the performance of the HDS or the IHDS as screening tests. Fifty-five percent of studies focused on detecting neurocognitive impairments, 35% on HAD and 15% in identifying MND or ANI. Only 16% of studies employed the latest 2007 HAND criteria .
The results of this systematic review suggest that the HDS and IHDS are not ideal tools for identifying a range of neurocognitive impairment. From the meta-analysis on the HDS and IHDS, we were able to determine that these tools have generally poor (0.48) and moderate (0.62) pooled sensitivities, respectively, in identifying a range of neurocognitive impairment. We also identified a potential relationship between the reference test and criterion with the range of sensitivities on the HDS and the IHDS, that is those studies using the most comprehensive neuropsychological test battery as the ‘gold standard’ criterion had the lowest (and similar) sensitivity values, whereas those that were considered ‘short’ or ‘medium’ in time (and comprehensiveness) resulted in much larger ranges of sensitivities. The association between lower sensitivity (ability to identify true positives) and large reference battery was significant for the HDS (P < 0.05). These findings suggest that a longer, more comprehensive neuropsychological battery may be a more stringent and appropriate reference test. Future studies evaluating sensitivity may want to consider using a large neuropsychological battery as a reference test to classify participants in a more discerning way. Studies using the HDS to identify a range of neurocognitive impairment reported higher sensitivities when higher cut-offs were used [40,44] or demographically adjusted T-scores were used .
The review identified 10 other screening tools with adequate sensitivities (≥0.75). Of these, four tools or combinations of tests were used to detect HAND conditions and overall neurocognitive impairment (as opposed to impairment in specific domains) and they used a ‘gold-standard’ neuropsychological battery as the reference test or criterion. These four tools include the CogState , the Screening Algorithm , the paired Hopkins Verbal Learning Test and WAIS-III Digit Symbol combination and the paired Hopkins Verbal Learning Test and Grooved Pegboard Non-Dominant Hand combination . It is important to note that the other studies defined neurocognitive impairment in different ways and evaluated these conditions using different criteria; thus, the comparison of efficacy across all studies needs to be carried out with caution given these limitations. In addition to these four tests, Becker et al.  reported a slightly lower sensitivity (0.72) for the Computer Assessment of Mild Cognitive Impairment (CAMCI) against a comprehensive neuropsychological battery. These are the five tools identified by our review that show some promise to be used to identify HAND in a clinical setting, although they warrant further study and validation.
In the 20 studies that met review criteria and are reported in Appendix B, http://links.lww.com/QAD/A370, one other potentially useful tool, The Montreal Cognitive Assessment (MoCA) , was highlighted. This tool is worth note because of its rising popularity in clinical settings, although the reliability and validity to detect HAND remains to be determined.
The review also highlighted key methodological issues in this body of literature. First, in order to properly determine whether a screening tool can detect the target condition, it is imperative that the reference test properly classifies the condition . Only 19 studies of the 31 (61%) [18–22,26,28–30,32,35,36,38,40–44,64] used the ‘gold-standard’ neuropsychological battery as the reference test. Furthermore, only seven (23%) studies [17–21,26,36] used more comprehensive reference tests (>90 min) and functional status was measured objectively in only nine studies [20–22,30,34,38,39,44,64] (29%). In addition, only five studies [21,28,30,40,64] used the most recent 2007 criteria to classify HAND . The QUADAS assessment reported that only 17 of the 31 (54%) [6,7,17,21,22,24,25,27,28,31,32,34,36,37,39,41] were using representative samples, noting a severe limitation in the applicability of the studies. For cognitive screening tools to be properly evaluated, and for these evaluations to inform clinical practice, more stringent methodological procedures are needed.
The results of this systematic review provide insights into the performance of the current screening instruments available for HAND and identify key methodological issues that need to be addressed in future studies. In this current context of mild cognitive impairment associated with HIV, it is clear that improved screening tools could go a long way in improving the care, quality of life and study of treatment interventions for individuals living with HIV and AIDS.
A.R.Z. contributed to development of systematic review project; reviewed articles for inclusion; extracted data; appraised quality of articles; created figures/tables; analysed data; and wrote the manuscript.
D.G. reviewed articles for inclusion; extracted data; appraised quality of articles; and edited the manuscript.
S.R. contributed to development of systematic review project; edited manuscript; and reviewed articles that were in Spanish.
J.B. contributed to development of systematic review project; and edited the manuscript. A.C. edited the manuscript. J.A.M. contributed to development of systematic review project; and edited the manuscript. M.J.G. contributed to development of systematic review project; and edited the manuscript. A.R. edited the manuscript. R.R. edited the manuscript. G.A. edited the manuscript. T.M. contributed to development of systematic review project; and edited the manuscript. S.B.R. developed systematic review project; organized systematic review team; lead systematic review project; and edited the manuscript.
Funding for this study was provided by the Canadian Institutes of Health Research (CIHR) and the Ontario Ministry of Health and Long-Term Care (MOHLTC) AIDS Bureau. The findings, opinions and conclusions are those of the authors and no endorsement of these by CIHR or MOHLTC is intended or should be inferred.
Conflicts of interest
There are no conflicts of interest.
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Journal of Neuroimmune PharmacologyIdentifying Risk Factors for HIV-Associated Neurocognitive Disorders Using the International HIV Dementia ScaleJournal of Neuroimmune Pharmacology
diagnosis; HIV/AIDS; HIV-associated neurocognitive disorder; neurocognitive impairment; screening tool
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