Methodologic issues in neuropsychological research with HIV-spectrum disease

Arcliver of Clinical Neumprychology. Vol. 8, pp. 17-33.1993 printed in the. USA. All rights rcscwed.

@X87-6177193 SS.00 + .OO National Academy of Nwcpsycholcgy

Methodologic Issues in Neuropsychological

Research With HIV-

Spectrum Disease Wilfred G. Van Gorp Department of Veteran’s Affairs Medical Center West Los Angeles, and UCLA School of Medicine

David G. lamb University of Kentucky

Frederick A. Schmitt University of Kentucky School of Medicine, Sanders-Brown Center on Aging, and Department of Veteran’s Affairs Medical Center Lexington, Lexington, Kentucky

Conflicting data have emerged from the initial studies of the neuropsychological sequelae of human immunodejiciency virus (HN) infection. This paper reviews key methodologic issues that must be addressed when embarking upon new research on the neuropsychology of HN spectrum disease. Finally, suggestions are given for methodologic pitfalls to be avoided when conducting or interpreting research in this domain.

A number of studies have now reported on the nature and pattern of neuropsychological dysfunction that appears to be related to human immunodeficiency virus (HIV) infection (e.g., Goethe et al., 1989; Grant et al., 1987; McArthur et al., 1989; Miller et al., 1990; Saykin et al., 1988; Schmitt et al., 1988; Selnes et al., 1990; Stern et al., 1991; Tross et al., 1988; Van Gorp, Miller, Correspondence should be addressed to Wilfred G. van Gorp, PhD, VA Medical Center West Los Angeles, Neuropsychology Laboratory (Bill), 11301 Wilshire Boulevard, Los Angeles, CA 90073. 17

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W! G. Van Gorp et al.

Satz, & Visscher, 1989; Wilkie, Eisdorfer, Morgan, Loewenstein, & Szapocznik, 1990). These studies have attempted to provide data on the incidence, prevalence, and pattern of cognitive and motor deficits associated with different stages of HIV infection. In one of the initial studies on this illness, Grant and colleagues (1987) reported neuropsychological abnormalities in 44% of a small sample of asymptomatic seropositive (ASP) subjects and in the majority of symptomatic patients studied. Subsequent to this report, several studies confirmed an increasing number of neuropsychological abnormalities in symptomatic patients (Miller et al., 1990; Van Gorp et al., 1989), while conflicting findings have emerged in the studies on asymptomatic seropositive individuals (Goethe et al., 1989; Miller et al., 1990; Selnes et al., 1990; Wilkie et al., 1990). The Miller et al. and Selnes et al. studies were based upon a large cohort of over 1,000 seropositive and seronegative gay men participating in the Multicenter AIDS Cohort Study (MACS). Miller, Satz, and Visscher (1991) also administered a novel computerized reaction time task requiring simple and complex reaction time, divided attention, and recognition memory to the Los Angeles cohort in the MACS study, and did not find any differences in performance between ASP and normal control subjects on these more experimental measures. However, Wilkie and colleagues (1990) did find significant differences on reaction time in their group of asymptomatic seropositives relative to controls’ performance. As can be seen in the examples above, these initial studies have often reported conflicting results and many appear to have suffered from a number of methodologic pitfalls. Although this prevents definitive conclusions about the timing of the effects of HIV on the central nervous system (CNS) at the present time (despite autopsy findings of CNS pathology; e.g., DeGirolami, Smith, Henin, & Hauw, 1990; Petito, Cho, Lemann, Navia, & Price, 1986), public and military policy was significantly influenced by these initial reports of neuropsychological dysfunction (cf. Harter, 1989). Because this research has the potential to impact on public policy for affected individuals, attention to potential methodologic pitfalls is crucial. Problems with methodology may result in erroneous conclusions about the neuropsychological sequelae of HIV infection and may therefore create unwarranted public concern and premature policy decisions. This paper is intended to highlight some of the central methodologic issues that investigators frequently confront in research on the neuropsychological sequelae of HIV infection in adults, and to offer some guidelines for addressing these difficulties. This issue has been addressed to some extent in previous publications on clinical methodology in neuropsychological research (Parsons & Prigatano, 1978), and by Kaemingk and Kaszniak’s (1989) review of the early reports of neuropsychological findings for HIV infection. While Kaemingk and Kaszniak provided a thorough review of the relevant literature at that time, many important studies have appeared in this area since their

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review. For example, there is now a basic consensus that cognitive deficits, when present, are more common in the symptomatic stages of infection (Janssen et al., 1989). In addition, methodologic concerns specific to neuropsychological research on HIV have not received careful attention as seen in other publications with small numbers of subjects and other methodologic concerns. Certainly the recommendations offered by Parsons and Prigatano (1978) for neuropsychological research are applicable to efforts to study cognitive functions in HIV infected persons. Unfortunately, not only the early papers, but many of the more recent studies of the neuropsychology of HIV infection demonstrate continued limitations in methodology. It would therefore seem that a more indepth presentation of this topic is needed.

SUBJECT

SELECTION

AND SAMPLE

SIZE

Because the number and type of observations made in this area of research have historically been limited, increased attention to issues of sample size and statistical power are warranted. The need for preliminary data to encourage and guide initial efforts in this emerging research area has prompted publication of studies with relatively small sample sizes. This of course may be defended on the grounds that pilot data are needed to generate hypotheses and discussion in the scientific arena. However, these studies should make clear that the data are preliminary and that public policy generated from such data alone would be premature and ill-advised. What constitutes an adequate sample size will clearly depend on the nature of the question being asked, the number of dependent variables examined, effect size, etc. These issues are well delineated by Cohen (1987) in his discussion of power analysis, providing a guideline for investigators in determining sufficient sample size. The exploratory nature of initial efforts to study possible HIV-related neuropsychological dysfunction requires adequate assessment of all relevant cognitive domains, since only some of these may be differentially affected. Careful assessment of attention, language, memory, visuospatial abilities, psychomotor speed, executive functions, affect, and personality is necessary. However, the large number of statistical analyses that comes from an expanded battery raises the likelihood of committing a Type I error - concluding that there are differences between groups when none may actually exist. Hence, the use of statistical corrections for multiple comparisons (e.g., Bonferroni correction) is important. At the same time, a more stringent alpha criterion may then increase the probability of a Type II error - not finding a difference when in fact one exists. For instance, if a researcher reports the results of a sample size given 12 neuropsychological measures used as dependent variables (Bonfetroni correction = .05/12 = .004), a stringent alpha criterion is required to diminish the likelihood of a Type I error, and consequently, a much stronger effect would be required to pass this more stringent requirement. Researchers must weigh the

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chances and risks of committing these errors when choosing the number and type of dependent measures to be used. One potential solution in preliminary reports with relatively small sample sizes (if multivariate approaches, which, though preferable, are not used) is to report both the actual p values obtained in univariate analyses and the probability values following Bonferroni correction. Then the reader may use a more strict alpha cutoff (decreasing the probability of a Type I error while increasing the possibility of a Type II error), or accept a more liberal alpha, knowing that the chances of committing a Type I error are increased. The statistical issues regarding sample size and analyses employed become even more critical as investigators attempt to control for potential “nuisance variables” which could involve many risk factors for impaired neuropsychological dysfunction (e.g., history of learning disability, alcohol and drug abuse, premorbid neurological history) that would further confound interpretation. For example, Wilkins et al. (1990) provide an empirical example of the effect that these confounds have on neuropsychological performance in HIV. In their study, 40 volunteers (28 ASP and 12 AIDS-related complex [ARC]) were screened for preexisting neurological disease or prior psychiatric hospitalization, history of educational or developmental difficulties, and history of significant substance abuse. Subjects were then classified as having insignificant/no confounds, moderate confounds, or severe confounds, and then evaluated with an extensive neuropsychologic test battery. The relationship between the level of confounds and degree of test impairment was subsequently found to be significant, such that, not surprisingly, impairment tended to be greater in subjects with more confounding factors. Finally, as is made clear in the Centers for Disease Control (CDC) definition of HIV encephalopathy (CDC, 1987), certain secondary conditions affecting the CNS will affect test performance (e.g., toxoplasmosis, lymphoma, stroke), and therefore, subjects known to manifest these conditions must be excluded if the researcher wishes to study the specific effects of HIV alone. Additionally, some conditions (e.g., pneumocystis carinii pneumonia [PCP]) may produce primary effects on the brain, only secondary to HIV infection, with the primary dysfunction resulting from other conditions (e.g., hypoxia secondary to oxygen deprivation during a PCP condition or radiation treatments for Kaposi’s sarcoma). Thus, individuals known to suffer from secondary medical conditions that have been determined to produce neuropsychological effects of their own in those patients must be excluded in the study of HIV encephalopathy, unless the focus of the research is on these secondary effects.

DEMOGRAPHICS As with any research in the social or biological sciences, demographic variables play an important role in comparisons across groups. Researchers in

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neuropsychology must be particularly careful to make certain that differences between groups are not the result of differences in premorbid education, age, cultural background, or premorbid intellectual abilities (Parsons & Prigatano, 1978). For instance, in one study (Saykin et al., 1988), the control group obtained a significantly higher verbal IQ score than the clinical group, making it difficult to interpret neuropsychological test differences, particularly on verbally oriented tests (such as the Boston Naming Test). This issue is further illustrated in the report by Miller et al. (1990) from the MACS sample who reported slight, although statistically significant, group differences on age and education. When multivariate analysis of covariance (MANCOVA, using age and education as covariates) for the neuropsychological measures was employed, the statistically significant differences on the neuropsychological measures in the asymptomatic group evident on the multivariate analysis of variance (MANOVA) were no longer present. Since intelligence is so strongly correlated with most neuropsychological measures, it is important that the groups to be compared are equivalent in estimated level of premorbid intellectual capacity. However, estimating premorbid abilities is often times difficult. For example, if one uses a performance measure which is also thought to estimate premorbid intelligence (such as Vocabulary from the WAIS-R), one cannot be certain whether obtained differences between the groups are a result of acquired or native differences. For instance, Van Gorp et al. (1989) found their seronegative group to have higher WAIS-R Vocabulary scores relative to the two clinical groups, despite these having no significant differences in years of education. Should we have covaried for the Vocabulary score, and risked covarying out a true effect (i.e., that this measure itself was affected by HIV), or if not, risk having obtained differences on measures possibly as an artifact of premorbid intellectual differences? We chose to address this dilemma by reporting both sets of analyses (ANOVA and ANCOVA). It might also be stressed that covariance methods are not, themselves, wholly adequate in attempting to “correct for” preexisting differences between groups (Adams, Brown, & Grant, 1985). All would agree that the optimal solution is to have groups adequately matched on all relevant variables initially. Several methods exist for determining comparability of groups on premorbid intellectual abilities. One may use an empirically derived estimate of premorbid IQ derived from large population data and multiple regression analyses utilizing demographic variables (e.g., Barona, Reynolds, & Chastain, 1984). However, there are limitations with this approach, and Barona et al. themselves note that their formula is less reliable for samples in the lower and upper ends of the IQ spectrum (i.e., Full Scale IQs c 85 or > 120). In a neuropsychologically impaired population or in a highly educated sample (as appears in many HIV studies with gay or bisexual men, such as in the MACS), the obtained IQ scores may fall in the lower or upper ends of the IQ range, making

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the use of demographically based IQ estimations questionable. An alternative approach is to use a performance based measure, such as the National Adult Reading Test (NARF Nelson, 1982), which has now been adapted for a North American sample (Blair & Spreen, 1989). Recent research suggests that the optimal approach might be to combine both performance based (e.g., the NART) and demographic variables to arrive at a final estimation of level of premorbid intellectual ability (Willshire, Kinsella, & Prior, 1991).

RISK GROUPS Homosexual males and intravenous (IV) drug abusers constitute the groups currently at highest risk for HIV infection. However, combining a group of homosexual males with no history of substance abuse (or only recreational drug use) with a group of long-term IV drug abusers will introduce an inherent confound because chronic, heavy use of psychoactive substances may well produce effects on the central nervous system that result in neuropsychological impairment. Studies that do not exclude IV drug abusers in neuropsychological research on HIV spectrum disease or include a seronegative drug abuse group must address this potential confound (Wilkins et al., 1990). This may be accomplished by studying them as a separate group and comparing them to a group of HIV-seronegative IV drug abusers (matched for type and extent of substance abuse) or comparing them to non-IV drug abusing subjects matched for HIV exposure and degree of symptomatology and/or level of immunosuppression. Specific study inclusion/exclusion variables must also be spelled out carefully and thoroughly. For instance, how were subjects screened for alcohol/ drug abuse or prior neurological disease/trauma (including migraine, learning disability, or even minor head injury)? Ingraham, Bridge, Janssen, Stover, and Mirsky (1990) also list visual defects, concurrent medications, malnutrition (often associated with chronic substance abuse), and proficiency with the English language as added variables which should be accounted for when studying persons with HIV infection. Failure to assess and screen for these variables may produce artifactual differences between groups on neuropsychological measures, given the differences in base rates for neurological and/or psychiatric risk factors for neuropsychological impairment.

MEDICAL

STATUS

Extent and type of medical illness is also import~t to note as a potential confounding variable. It is known that systemic illness can affect general level of cognitive arousal and vigilance. In the more medically ill, a general dampening effect can be apparent on neuropsychological tests. Thus, comparing acutely medically ill AIDS inpatients (e.g., with active systemic oppor-

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tunistic infections) with a healthy seronegative control group will likely produce statistically different performance levels across a variety of cognitive measures simply as a result of nonspecific illness factors unrelated to HIV infection of the CNS. Likewise, comparing acutely ill inpatients with more stable and less symptomatic outpatients (who are suffering from the same underlying illness) may produce artifactual differences. Comparison of groups in which one consists of acutely ill patients must attempt to either match for level of acute medical distress, or compare one group suspected of having cognitive dysfunction with another group of medically ill patients to account for the potential confound of acute systemic illness. For instance, a group of subjects who are symptomatic with influenza might demonstrate decreased performance on measures of reaction time or vigilance because of the acute effects of systemic illness that are independent of the direct effects of the condition on the CNS. If symptomatic HIV-infected patients are to be studied, an additional control group might be selected to address the issue of systemic illness on neuropsychological performance. Therefore, a control group experiencing chronic illness (known not to affect the CNS) should be considered for comparison with an HIV-infected group. Of course, attempts to find an “ideal” control group (i.e., with chronic, systemic, but nonneurotropic illnesses; with the same type of psychosocial overlay; and with similar demographics to persons with terminal aspects of HIV conditions) is a difficult, if not impossible, task. But in the end, ignoring the need for a control group which accounts for many of these confounding variables will produce results that are less than fully interpretable.

AFFECTIVE/MOOD

VARIABLES

It is well known that major (primary or secondary) psychiatric conditions, such as thought disorder, psychosis, and clinical depression, can have signiticant effects on cognitive test performance, especially in older adults who are experiencing significant levels of clinical depression (cf. Grant & Adams, 1986). It is also widely known that persons with AIDS and ARC are prone to a variety of secondary psychiatric conditions, including severe depression and psychosis (Maj, 1990a,b). Research with this population must attempt to assess and deal with those with secondary psychiatric conditions that could seriously impinge upon performance. While most of these patients will have some dysphoria and/or anxiety, those meeting criteria for a major affective disorder or organic affective syndrome might be studied as a separate group. To date, however, no clear association between cognitive performance and affective state have been reported in young individuals (e.g., Kovner et al., 1989). although a small degree of variance in neuropsychological performance was accounted for by affective measures in the treatment study by Schmitt et al. (1988).

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Care must also be taken to avoid the use of measures of affect that contain many items relating to (and hence, seriously elevated by) physical disease or complaints. For example, while the Beck Depression Inventory (Beck, Ward, Mendelson, Mock, & Erbaugh, 1961) and Minnesota Multiphasic Personality Inventory (Hathaway & McKinley, 1943) Scale 2 have a subset of items reflecting preoccupation with illness, items on other depression scales (e.g., the Self-Rating Depression Scale by Zung, 1965) appear to be somewhat biased towards somatic symptoms. Thus, a symptomatic group may obtain significantly elevated scores on measures of affect compared to a non-ill control group simply as an artifact of increasing physical somatic compl~nts in the clinical group. For instance, the UCLA neuropsychology group has (E.N. Miller, personal communication, 1989) performed a factor analysis of the Center of Epidemiologic Studies-Depression (CES-D) measure, and found one factor to relate to items reflecting disease and preoccupation with health. Because of the many medical problems found in the elderly, scales have been devised to assess depression independent of health status (Yeasavage et al., 1983) for this population. Perhaps similar studies of the relationship between somatic complaints and depression should also be made in populations with HIV infection (e.g., Chuang, Devins, Hunsley, & Gill, 1989). Anxiety is also (as mentioned below) an important variable to quantify, as it may be a significant covariate for neuropsychological performance.

KNOWLEDGE

OF SEROSTATUS AND SYM~OM

STATE

Most commonly, confirmed HIV-seronegative subjects are used as controls. It may be that a control subject’s awareness of his or her serostatus is an important variable, because a recent assurance of noninfection may result in less clinical depression or anxiety, which could result in differences on cognitive tasks relative to an infected sample with higher levels of anxiety or depression. Studies should indicate, if possible, how long after being informed of their serostatus subjects were tested, and an assessment of current depression and anxiety state should be made at the time of ne~opsychologic~ testing, so that it can be determined whether obtained differences are merely the result of an acute anxiety reaction to knowledge of symptom or serostatus. An excellent example of the association between mood and cognitive performance in HIV infection can be found in Schmitt et al. (1989). In this study, patients with symptomatic HIV infection showed decreases in levels of global distress, depression, and anxiety from screening to baseline mood assessments. Such findings are potentially due to the subjects’ knowledge that they had been accepted into a treatment protocol. These mood changes were paralleled by improvements in performance on neuropsychological tests before patients began treatment.

Neuropsychological Research with HIV-Spectrum Disease

MEANS

2.5

OF DETERMINING NEUROPSYCHOLOGICAL IMPAIRMENT

Investigators have defined neuropsychological impairment related to HIV infection in various ways, and some use the term “impairment” synonymously with “dementia.” Others use “impairment” as an indication of mental status or neuropsychological abnormalities short of meeting formal criteria for dementia. Idiosyncratic definitions of impairment or dementia (based on deviations of varying degrees from normative values, use of different normative groups for comparison, or individual investigator judgments in the determination of clinical abnormalities) contribute to the difficulties inherent in determining the prevalence of HIV-related neuropsychological deficits. Most studies have made statistical comparisons of the neuropsychological performance across subjects in the spectrum of HIV infection (e.g., seronegative, asymptomatic seropositive, ARC, AIDS) using the neuropsychological measures as continuous variables. Others have compared the frequency of individual “neuropsychological outliers” in a larger group of infected patients based on clinical or statistical classification (e.g., Grant et al., 1987; Miller et al., 1990; Schmitt et al., 1988). For instance, Tross et al. (1988) defined impairment as neuropsychological scores falling “below one standard deviation” from the normative comparison values. Grant et al. (1987) rated each subject’s performance as “definitely impaired” if performance on one or more tests fell at least two standard deviations below normal and “probably impaired” if at least two test scores fell one standard deviation below normal. Saykin et al. (1988) rated each subject’s overall performance as “impaired” or “nonimpaired” based on blind but subjective clinical judgment. Miller et al. (1990) defined impairment as any subject scoring two or more standard deviations below the mean for seronegative controls on two or more neuropsychological measures. Of course, attempts to determine what test performance constitutes “impairment” is a crucial issue in the assessment of HIV-related dementia or encephalopathy. Cross-sectional studies may statistically define abnormal performance in one group relative to performance in one or more comparison groups. In contrast, longitudinal studies may define impairment or even dementia in terms of within-subject change in neuropsychological functioning over time. For example, one may decide impairment has occurred when there is a decline of some previously determined test score (in comparison to a prior chosen published normative data) on two or more tests over at least a 6-month interval where no artifactual factors are readily identified. Such an approach must take into account the overall number of variables present and the number of subjects who improve or remain stable in performance, longitudinally, using the same operational criteria. Further, issues of sensitivity as well as specificity of the measurement instrument should be addressed. It may be that the test instruments used in the most recent studies of asymptomatic seropositives were not sufficiently sensitive to

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detect subtle cognitive impairment. For instance, Grant et al. (1987) found the Halstead Category Test to be differentially sensitive to early compromise in this group, and neither Selnes et al. (1990) nor Goethe et al. (1989) included this measure in their battery. Additionally, the “normal control” group in the Goethe et al. (1989) study may have been inappropriate: it was small (N = 18) and consisted of Air Force personnel who had sustained minor head injury with loss of consciousness not exceeding 24 hr, Use of such a comparison group may have prevented the detection of subtle cognitive deficits in an HIV-infected asymptomatic group. Other reports have focused primarily on infected patients without reference to a matched control sample. Grant et al. (1987) and Saykin et al. (1988) used blind clinical ratings as one means of determining the percent of subjects exhibiting abnormal performance. Tross et al. (1988) studied the percent of HIV-infected individuals falling beyond a priori “cutoff scores” within various diagnostic groupings, while Schmitt et al. (1988) used test-based cutoff scores such that patients had to meet impairment criteria on two repeated evaluations separated by approximately 1 week. Regardless of the exact criteria used by investigators to define impairment, comparisons between studies would be assisted by researchers listing the instruments used and reporting the number of subjects who demonstrated deficits of one and two standard deviations on each test, as suggested by Ingraham et al. (1990).

DIAGNOSTIC

NOMENCLATURE

Until 1987, there was no consensual operational definition of HIV encephalopathy. This changed with the inclusion of HIV encephalopathy into the CDC diagnostic schema for HIV-related diseases. The CDC (1987) defined RIV encephalopathy as: Clinical findings of disabling cognitive and/or motor dysfunction interfering with occupation or activities of daily living, or loss of behavioral developmental milestones affecting a child, progressing over weeks to months, in the absence of a concurrent illness or other condition other than HIV infection that could exphtin the findings. Methods to rule out such concurrent illness and conditions must include cerebrospinal fluid examination and either brain imaging (computer tomography or magnet resonance) or autopsy.

By offering this definition, the CDC introduced an essential ftrst step in the research on the concept of the AIDS dementia complex (ADC) by providing at least an initial consensual definition of HIV encephalopathy. This definition, which required that symptoms of impairment be persistent and progressive while interfering with activities of daily living (ADL), presumably

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27

excluded an acute and likely reversible confusional state (delirium) which is common in patients with HIV infection. However, a closer inspection suggests some limitations in this definition. First, subtle cognitive dysfunction (often reliably documented only by neuropsychological procedures) in certain individuals may not necessarily lead to impairment in ADL, especially if the individuals are high functioning, premorbidly. Such subtle impairment may not be overtly apparent in such persons until the degree of cognitive dysfunction is great enough to preclude the maintenance of daily activities. Once again, the question of how and to what extent individuals compensate for early cognitive dysfunction and gradual decline has not yet been studied (Ingraham et al., 1990). Second, this definition appears to preclude the possibility of coexisting problems. For example, a person with cognitive impairment may also be suffering from a concurrent depression as a result of changes to the CNS, or in reaction to perceived cognitive loss. Finally, the definition may classify individuals as impaired as a result of the repeated impact of opportunistic infection (01) on patient functioning even though an 01 is not present when the classification is made. An additional problem with the CDC definition is that it lacks specificity in an operational definition of dysfunction in order to diagnose encephalopathy. Clearly, linking HIV encephalopathy symptoms to structured mental status examinations, neurological evaluations, and neuropsychological tests results would help to strengthen this definition. Such an application might combine neuropsychological test findings and neurological examination, while linking these data to the staging of the HIV encephalopathy as suggested by Sidtis and Price (1990). For example, a patient who is HIV seropositive and shows test findings that are below predicted premorbid estimates of functioning, yet still within normal limits for test scores and daily activities, might be classified as Stage 0.5 (equivocal/subclinical). Another individual with either below average test scores or documented decline on test scores accompanied by minimal day-to-day impairment could be classified as “mild” encephalopathy. Both classifications would occur in the absence of other coexisting physical conditions (that might be reversible) but could allow for affective dysfunction to coexist with CNS impairment. Finally, the American Academy of Neurology (AAN) recently published proposed nomenclature and case definitions for HIV-associated neurological conditions (AAN AIDS Task Force, 1991). Diagnosis of HIV-l-associated cognitive/motor complex requires confirmed laboratory evidence of infection and is broken down into severe (HIV-I -associated dementia complex) and mild (HIV-l-associated minor cognitive/motor disorder) manifestations. While the CDC definition of HIV encephalopathy includes both cognitive and motoric dysfunction, the AAN criteria split the severe manifestation category into a primarily cognitive HIV-I-associated dementia complex (encompassing the earlier concepts of subacute encephalitis, HIV encephalopathy, and AIDS-

related dementia) and a predominantly motor HIV-1 -associated myelopathy, both of which may be diagnosed as probable or possible. Although most of the drawbacks mentioned for the CDC definition remain valid for these diagnoses, the AAN effort has produced greater specificity in describing clinical measures and procedures for deriving a diagnosis. They provide specific behavioral criteria for determining levels of cognitive and motor impairment, as well as recommending neuropsychologic~ tests for each of the seven cognitive domains to be assessed.

MEASUREMENT VARIABLES Finally, there is the question of exactly which tests should be used to study the cognitive deficits associated with HIV infected patients. Butters et al. (1990), from an NIMH Working Group on neuropsychology and HIV, have recommended the use of a battery to detect early cognitive changes in a seropositive, asymptomatic population. Both extended (7-9 h) and brief (l-2 h) versions were outlined. This NIMH workshop approach provides a comprehensive battery of instruments with demons~ated sensitivity in detecting deftciencies in 10 cognitive domains. The choice of areas covered by the battery highlights the different functions which should be addressed by researchers in this arena. However, as implied above, the extended battery might not be practical for more symptomatic patients. Certainly 7-9 h of testing may not be feasible with such symptomatic persons, and many asymptomatic subjects might not be willing to volunteer for such rigorous examinations if they were part of a longitudinal study that required multiple follow-up visits. Perhaps the extended battery could be used as a baseline assessment, with the recornmended brief battery providing folow-up data. While the NIMH Workgroup’s goal of providing a common database is admirable, it may be premature. Choice of tests and assessment instruments should be driven by experimental design and the specific questions being asked within the context of a particular study. Less rigorous examinations of the domains laid out by Butters et al. (1990) may not be ideal, but will still provide valuable data to the field. This is not to suggest their batteries should not be used if they are appropriate for a specific study. Other batteries which may prove useful are the Short Form Impairment Index (Horton, Anilane, Slone, & Shapiro, 1986), the brief 45-min battery proposed by Ingraham et al. (1990) and the core battery ~o~ended for use in studying multiple sclerosis (MS) by Peyser, Rao, LaRocca, and Kaplan (1990). This latter battery is a feasible alternative to the NIMH suggestion given the presumed subcortical nature of both diseases and the similar practical problems faced by HIV and MS investigators in developing adequate clinical and treatment research programs. For natural history and treatment studies, the awareness of practice effects in longitudinal research is important. These research efforts may be

Neuropsychological Research with HIV-Spectrum Disease

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accomplished by testing subjects with a core battery at yearly or biannual periods. If more frequent assessments are utilized, an abbreviated battery consisting of alternate forms of these tests or a different group of measures might be used in between the annual tests. Unfortunately, many tests do not have validated alternate forms and so could not be included in such batteries. The use of research designs which allow for the examination of interactions between testing and experimental manipulations are another option. For example, the Solomon Four Group Design would provide both a built-in replication of any treatment manipulations and an assessment of the effects of pretesting subjects (e.g., Beck, Andrasik, & Arena, 1984). The major drawback to this approach is the considerable number of subjects required, which, as already mentioned, is particularly problematic in this area of research. A more workable solution may be to control for the practice effects within individual subjects. This could be accomplished by using a multiple baseline approach, thus providing another measure of HIV-related encephalopathy by allowing practice effects to occur at the beginning of the study and then assessing for change against the subject’s optimal performance (e.g., Schmitt et al., 1988). Such an examination is important because practice effects may be an indicator of impairment in and of themselves (i.e., a subject may be experiencing increased deficits if they do not improve their scores via practice effects).

RECOMMENDATIONS In addition to pitfalls common to any area of clinical study, research in the neuropsychology of HIV-related CNS compromise is complicated by many factors such as confounds of systemic illness, unique demographic group membership, and vague diagnostic criteria for outcome measures. However, careful attention to these variables is particularly important in light of public policy decisions and implications that may be considered or instituted based upon research findings in this area. First, we recommend that research in this area incorporate an operational definition of HIV-related neuropsychological deficits, such as the American Academy of Neurology diagnostic criteria for HIV-Associated Cognitive/Motor Complex. Elements of DSM-III-R or a variant of the NINCDS/ ADRDA criteria (McKhann et al., 1984) might be included as well. This would require that patients who are considered to be clinically demented show significant neuropsychological impairment in more than one realm of cognitive functioning. Patients might be classified as “possibly impaired” when they show performance decrements in one cognitive area such as memory or motor ability. “Probable impairment” would involve impairment in memory or motor skills plus one other area of functioning while “probable impairment” would be reflected in dysfunction in at least three areas of cognitive and motor

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functioning or stable or progressive dysfunction after other cofactors have been ruled out. Second, researchers presenting data on the neuropsychological effects of HIV infection should include not only the overall statistical differences in impairment between groups on various measures, but also other criteria of imp~ment, such as the number of individual “outliers” as recommended by the NIMH Working Group described above. For example, if one wishes to assess the prevalence of subtle cognitive changes in a high functioning group, choice of a one standard deviation below the mean cutoff might provide a better estimate than several tests at two standard deviations below the mean. A similar approach in a longitudin~ study would use a change score equivalent to a decline of one standard deviation on a test score to indicate imp~ment. It would also be intriguing to include a summary score similar to the Halstead Reitan Impairment Index by collapsing over the abnormal tests (cf., Grant & Adams, 1986; Pocock, Geller, & Tsiatis, 1987). Also included should be some estimate of the number of tests that were abnormal for each patient as well as critical medical variables (cf., Goethe et al., 1989), such as measures of HIV titers from serum or CSF, level of CD4 counts, imaging measures, and ADL measures whenever possible. Finally, standardized test scores might be used to generate categorizations of possible and probable HIV encephalopathy, paralleling the work seen in Alzheimer’s disease (McCann et al., 1984). Use of clinical rating scales such as the Clinical Dementia Rating (CDR) (Hughes, Berg, Danziger, Cohen, & Martin, 1982) and standard neuropsychological tests and mental status exams could assist in documenting possible versus probable ADC (see also Sidtis & Price, 1990). This method of classification will become critical in studies of possible ~eatment of HIV infection. In certain clinical trials where neurological symptoms are targeted for treatment, the development of ADC could be used as an endpoint for a trial assessing for treatment effects in early disease stages (e.g., Price & Sidtis, 1990). This task would be difficult, however, if such a definition of ADC is not agreed upon. Clearly, more objective criteria are needed in this area in order to specify patient groups and determine the incidence and prevalence of HIV related CNS effects. Based on the studies reviewed in this paper and the current state of knowledge of the neuropsychological sequelae of HIV infection of the CNS, we offer several proposals for future research in this area. First, studies and publications seeking to document the effects of HIV on the CNS should provide as much information as possible on the immunologic (e.g., CD4, P24), neurological (e.g. magnetic resonance imaging), and psychiatric (e.g., mood) status of patients being studied with neuropsychological methods. Markers of level of immunocompetence should be presented (eg. absolute CD4 and CDS and percent (33%) in order to make the data more inte~re~ble in light of data that have already been published. CDC and Walter Reed staging information might

Neuropsychological

Research

with HN-Spectrum

Disease

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be included to operationally define severity/quantity of symptoms and immunocompetence. Further, inclusion of this information will facilitate comparisons across studies in the future. Researchers should also include clinical and test-norm based cut points for determination of cognitive impairment. This is important in determining the degree of impairment that may be present in premorbidly high and low functioning individuals. Consideration of the subcortical nature of the disease (similar to MS) would suggest that depression and neuropsychological impairment could coexist (cf. Cummings & Benson, 1983). and that seropositive patients’ neuropsychological impairment should not be discounted if there are coexisting psychiatric conditions. More data will be required to determine which measures are sensitive to change at different disease stages, ADL correlates, and what biological thresholds are important for the appearance of neuropsychological impairment.

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