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Neuropsychological aspects of HIV infection V. Egan
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Regional Infectious Diseases Unit, City Hospital , Edinburgh, UK Published online: 25 Sep 2007.
To cite this article: V. Egan (1992) Neuropsychological aspects of HIV infection, AIDS Care: Psychological and Socio-medical Aspects of AIDS/HIV, 4:1, 3-10, DOI: 10.1080/09540129208251615 To link to this article: http://dx.doi.org/10.1080/09540129208251615
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AIDS CARE, VOL. 4, NO. 1, 1992
EDITORIAL REVIEW
Neuropsychological aspects of HIV infection V. EGAN Downloaded by [The University of Manchester Library] at 10:14 10 October 2014
Regional Infectious Diseases Unit, City Hospital, Edinburgh,
UK
Abstract There is considerable consensus regarding the entity, aetiology, and assessment of HIV-1-caused cognitive impairment. Early fears that this would be very common, and early in onset, have not been realized. Research and clinical criteria should reflect current statistical standards. The large cohorts, broad test battm’es and repeated testing of population samples provide a special opportunity to resolve perennial questions regarding the relationship between mood, health, and cognitive functions. It appears that A Z T prevents mild cognitive impairment associated with HIV-1, though there is no strong evidence that it treatsfrank HIV-1 dementia complex. The management of patients with dementia requires proper consideration, as even if the incidence of HIV-1 dementia complex is only 5-lo%, this is still a substantial number of patients for population centres with large numbers of people with HIV and AIDS. The distressing nature of this condition, combined with the specialized management required for HIV itself; make it advisable that more nurses with psychiatric training are employed in wards or units specializing in HIV. Introduction
The human immunodeficiency virus (HIV) enters the brain early in infection via the macrophages and lymphocytes of an individual’s immune system (Resnick et al., 1988). The primary and secondary effects of HIV’s assault on the brain can produce a range of cognitive deficits, which can be quantified by formal neuropsychological testing. This enables the precise and potentially serial measurement of specific mental processes, and their possible deterioration or recovery. The current editorial provides an overview of neuropsychological factors affecting patients with HIV or AIDS, and where possible directs readers to more detailed references (e.g. Egan & Goodwin, 1992). Definition and classification
The early term ‘AIDS dementia complex’ (ADC) was used to describe the cognitive and behavioural deterioration seen in some patients with AIDS (Navia et al., 1986; Tross et al., 1988). As it was discovered that patients with apparent ADC did not necessarily have AIDS, and that the term ‘dementia’ was too severe a description of the memory impairment and cognitive/motor slowing generally seen, the World Health Organization proposed the more
Address for correspondence: Dr Vincent Egan, Regional Infectious Diseases Unit, City Hospital, Greenbank Drive, Edinburgh EHlO 5SB, UK.
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V.EGAN
accurate term ‘HIV-1 associated cognitive/motor complex’ (HACC) (WHO, 1990). Revised formal criteria for defining neurological manifestations of HIV- 1 infection have recently been produced (Report of a Working Group of the American Academy of Neurology AIDS Task Force, 1991) and readers should use this reference for more detailed diagnostic criteria. The paper divides HACC into severe and mild forms, the severe forms being HIV-1associated dementia complex (HDC), which subsumes the previous interchangeable terms ‘subacute encephalitis’, ‘HIV encephalitis’ and ADC, and HIV- 1 associated myelopathy (HAM). HIV-1 associated minor cognitive/motor disorder (HMCD) is a mild expression of HACC, and replaces the previous overlapping terms ‘HIV- 1-associated neurocognitive disorder’ and ‘HIV- 1-associated neurobehavioural abnormalities’. HAM is a specific neurophysiological condition, and has an established protocol for diagnosis by neurologists; neuropsychological procedures are required as part of the diagnostic process for HDC and HMCD. Differentiation of HMCD and HDC is primarily based on the degree of impairment of daily living; social or occupational functioning must be conspicuously affected for a diagnosis of HDC, whereas patients with HMCD would be expected to function relatively normally, except for more demanding day-to-day activities. Evaluating this deterioration involves a consideration of their illness and social context, and their premorbid personality and ability. Neuropsychological assessment should be used to back up the reports of decline in attention or concentration, abstraction or reasoning, speed of information processing, visuospatial skills, memory/learning, and speech/language described by the patient, their informant or clinical impression. This should be conducted when the patient does not have any clouding of consciousness. Decline in emotional control, motivation, or changes in social behaviour should be noted. Evidence of other aetiologies should be sought from the patient’s social, medical and psychiatric histories, and the patient should have appropriate laboratory and radiological investigations. If another possible etiology is identified, this should not be the cause of the cognitive-motor and behavioural signs seen in the patient.
The incidence and mechanisms of HACC The homosexual cohorts seen during the multi-centre AIDS cohort studies (MACS) provide evidence, at least for individuals from higher educational and socio-economic groups, that the serious neurocognitive complications associated with HIV infection are late in onset, and are rather less common than once feared (Grant et al., 1987; Miller et al., 1990; Selnes et al., 1990). Similar studies are now in progress for drug users, and suggest similar results (Goodwin et al., 1992). It should be emphasized that HACC presents in a similar fashion whether one considers populations of homosexual men, drug users or the mentally handicapped (McArthur et al., 1989; Maxwell et al., 1991; Brown, 1991). The variation in incidence of ADC has been due to the source of the survey, the patients’ stage of infection, and the criteria used to infer cognitive impairment. The most comprehensive study of ADC incidence assessed all 38666 cases of AIDS reported to the CDC from 1st September 1987 to 31st December, 1988. ADC was defined as disabling cognitive/motor dysfunction, in the absence of any condition other than HIV to account for this finding. Of the adults, 6.5% had ADC, with just 3% having it as the exclusive early manifestations of AIDS; it was slightly more common (around 10%) in children and elderly patients with AIDS (Janssen et al., 1989). This did not estimate subclinical impairment of the kind described by HMCD, which may be rather more common. Brain imaging of patients with HDC using computerized tomography and magnetic resonance has demonstrated widened cortical sulci and dilated central ventricles. These
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NEUROPSYCHOLOGICAL ASPECTS OF HIV INFECTION
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patients also show patchy or diffusely increased signals on MRI, in keeping with increased water content in the hemispheric white matter, basal ganglia and thalamus (Price & Brew, 1988). There is some evidence of neuronal loss in the frontal cortex (Everall et al., 1991). Two major pathologies are believed to underlie HACC, gliosis and pallor of the subcortical nuclei, typically seen in individuals with mild HMCD; and a viral-induced cell fusion leading to multinucleated cell encephalitis with focal white matter rarefaction, seen in patients with HDC. These events are thought to be caused by the loss of immune system control over HIV replication. One particularly fruitful avenue of enquiry considers immunopathology; as immune control declines, as seen, for example, among AIDS patients, cytokines (mediators of cellular immunity such as neopterin and quinolinic acid) appear to be either poorly broken-down or found in excessive quantities, poisoning neural tissue (Melmed ez al., 1989; Brew et al., 1990; Heyes et al., 1991).
Neuropsychological test batteries and the interpretation of results There is now general agreement regarding the choice in measures appropriate for a relatively brief test battery sensitive to deficits seen in HDC and HMCD. Ideally, testing should involve; estimates of premorbid IQ (using the NART in either the British or North American form (Nelson & Willison, 1991; Blair & Spreen, 1989) or, less efficiently, the WAIS-R Vocabulary subtest (Wechsler, 1981); memory (Wechsler Logical Memory subtest, the Auditory-Verbal-Learning Test (Wechsler, 1987; Rey, 1964; Peaker & Stewart, 1989)); mood (the Beck Depression Inventory, the Hospital Anxiety and Depression scale (Beck et al., 1961; Zigmond & Snaith, 1983)); motor functioning (Finger Tapping or Grooved Pegboard (Reitan, 1979; Matthews & Kldve, 1964)) and performance measures of frontal lobe function, mental flexibility and information-processing speed (WAIS-R Block Design, Trail-Making parts A and B, and the WAIS-R Digit Symbol subtest (Reitan & Wolfson, 1985; Wechsler, 1981)). All these tests are quite commonly used, and all appear appropriate, reliable and sensitive measures of the processes they measure. Psychophysiological measures of information-processing speed such as reaction times and auditory event-related potentials are sensitive to panencephalopathy and are thus of considerable clinical value in the diagnosis of HACC syndromes-particularly as they are free of the evaluation anxieties that cognitive testing can generate (Perdices & Cooper, 1989a; Goodwin et al., 1990. Unfortunately, the technology these measures require makes their application likely to remain specific to specialized research centres. The interpretation of neuropsychological test values depends crucially upon the sample being discussed. Clinical populations, whether they be homosexual, drug-using, haemophiliac, or from ethnic minorities, all differ from one another regarding ‘normal’ values (Nakajima & Rubin, 1991). By way of example and utility, Table 1 presents summary statistics and percentile values for HIV positive drug users on standard neuropsychological measures. These values can be used heuristically when evaluating the degree of cognitive impairment in methadone-maintained, white HIV-positive drug users. This table demonstrates that a considerable degree of functional abnormality can be apparent in a sample without any corresponding difficulty in activities of daily living; the 5th and 95th percentiles provide conservative cutting points for inferring impairment in an already abnormal population.
Statistical criteria and research considerations Interpreting the results from large test batteries requires caution, in just the same way that
6 V.EGAN Table 1. Summay statistics for HIVpositive drug users Percentile
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Cognitive test NART-estimated WAIS-R FSIQ WAIS-R Arithmetic WAIS-R Digit Span WAIS-R Block Design WAIS-R Digit Symbol Trail-making test part A (sec) Trail-making test part B (sec) Logical memory-immediate recall Logical memory-delayed recall AVLT trial 1 AVLT trial 2 AVLT trial 3 AVLT trial 4 AVLT trial 5 AVLT 1 trials 1 to 5 AVLT interrupt trial AVLT trial 6 AVLT delayed recall AVLT recognition memory to list A AVLT recognition memory to list B Benton visual retention test-C Benton visual retention test-E HAD depression scale HAD anxiety scale Beck depression inventory Tapping task-dominant hand Tapping task-non-dominant hand 2-Choice reaction time (median msec) Movement time (median msec) Decision time (median msec) Word fluency: animals B
S
J
n
Mean
SD
5
95
197 196 195 194 194 196
93.9 7.8 8.3 7.4 6.3 42.5 119.2 12.5 10.4 5.3 7.8 9.3 10.2 10.8 43.4 4.7 8.8 8.4 12.9 4.3 5.8 6.7 7.7 10.6 19.8 61.4 57.5 944.3 276.5 661.9 19.2 12.0 13.4 7.7
11.4 2.4 2.1 2.3 2.1 19.5 86.4 3.9 3.9 1.4 2.2 2.5 2.3 2.3 9.1 1.7 2.9 3.0 2.1 2.8 1.8 3.2 4.1 4.5 10.1 11.2 9.5 236.9 121.4 171.6 8.1 4.5 6.1 6.2
76 5 6 5 3 21 48 6 5 3 4 5 6 7 28 2 3 3 9 0 3 2 1 3 5 45 38 670 130 459 9 5 5 3
113 12 12 12 10 80 279 19 18 8 12 14 14 14 59 8 13 13 15 9 9 12 14 18 37 77 70 1387 550 987 29 20 22 14
195 187
128 191 191 97 146
119
Mean and SD values provide norms for HIV positive drug users; 5th and 95th percentile values provide cutting points for interpreting the observed performance of the subject.
one should be careful of making multiple statistical comparisons between groups; if an unduly liberal attitude is taken to data, results which are a product of chance variation, rather than some genuine process, will be produced. In the clinical case, taking a criterion of a change on 2 independent tests (ie. in two separate cognitive domains) of 2 standard deviations is unlikely to occur by chance unless one is using more than 15 assessment measures (Ingraham & Bridge, 1990). Statistical analysis of test batteries should either specify comparisons in advance, make corrections to significant values in accordance with the number of comparisons being made, or use conservative post-hoc tests. Confidence intervals, effect-sizes and the power of results or null findings should be reported where appropriate (Howell, 1987). One needs to remember that effective neuropsychological measures are predicated on an understanding of cognitive processes and, ultimately, good science. Thus, though neuro-
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psychological studies of HIV-infected patients have obvious clinical value, psychologists should also consider the processes underlying their observations. Many of the cognitive tests administered to HIV-positive patients will correlate significantly with one another; this colinearity provides an opportunity to model the processes underlying changes in neuropsychological function. For large cohorts tested on standard test batteries, one could start by using a data reduction technique such as factor analysis and then use the factor scores as the basis of further analysis-provided that the factors themselves are replicable or easily interpretable. The advent of the large cohort studies such as MACS, and intercorrelated test batteries being given repeatedly, mean that structural modelling using LISREL (Joreskog & Sorbom, 1985) is likely to provide useful results regarding the causal paths between changes on psychological or psychophysiological measures at different time and disease points. All too often mood or psychological reactions to HIV seropositivity are said to affect HIV-illness progression, falling CD4 count, or neuropsychological performance; it is about time this perennial post hoccery was empirically resolved. A lesson regarding the overenthusiastic expansion of mood to account for changes in immune function was recently provided by Stein et al. (1991). This study comprised a survey of 22 peer-reviewed and published studies looking at the relation between depressive disorders and the immune system; it concluded that the results are inconsistent, inconclusive, have poor design and little conceptual clarity. The concept of ‘pseudodementia’ (Caine, 1986), generally considered to be specific to patients with endogenous chronic depression, has been expanded to accommodate the poor cognitive performance sometimes seen in patients with HIV and AIDS with concurrent dysthymic or (understandably) reactive mood states (Rubinow et al., 1988). A meta-analysis of the effects of depressive mood states on cognitive performance is also clearly due. Treatment and management
The empowering of HIV-positive patients as active ‘participants’, rather than passive ‘subjects’ of research, has shifted the ethics of controlled trials regarding the efficacy (or otherwise) of antiviral treatments to treat HACC. An early study of the neurotoxicity of zidovudine (AZT) predated open drug trials, and involved a double-blind, placebocontrolled trial of oral AZT, in which patients with advanced ARC or AIDS were tested over 16 weeks to assess changes in neuropsychological function following drug treatment. Patients on AZT, in particular AIDS patients, had improved mental function compared to those on placebo (Schmitt et al., 1988). Though these results implied that HIV-related cognitive abnormalities may be partially treated by AZT, the sample did not include any patients with frank dementia. Other studies have claimed that the incidence of severe ADC has significantly reduced following the introduction of AZT, (Portegies et al., 1989; Chiesi et al., 1991). One hopes that a more prosaic reason-practice or familiarity with the tests, shown to account for improved neuropsychological performance in both people being treated with AZT, and matched HIV-negative controls-does not account for this effect (Perdices & Cooper, 1989b). The patient with HDC has brain damage that combines subcortical and frontal features; they are thus slow, inattentive, forgetful, and somewhat disinhibited. This severely limits the ability of the patient to function independently, whether they be in their own home, or in the relative autonomy of an AIDS hospice, and makes in-patient management intensive. In one study, some 63% of patients with moderate to severe HIV-1 related cognitive impairment had residential problems secondary to their impairment. These problems were primarily associated with home safety, wandering, confusion and memory problems (Boccellari et al.,
8 V.EGAN 1991). There are no guidelines regarding management of patients with HDC, though principles used to help psychogeriatric patients, such as structured environments, reality orientation, and personalized nursing may reduce the confusion of the patient. Though looking after an individual with HDC demands time and patience, it is likely to be of relatively short duration as these patients tend to pass rapidly from the unequivocal cognitive impairment described by Price stages 2 and 3, to the terminal stage 4 (Price & Brew, 1988). This stage is characterized by severe physical incapacity, incontinence, and eventually coma. When a patient is so ill, neurocognitive considerations become irrelevant to management, as death is imminent.
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Conclusions This article has intentionally omitted several issues, namely the neuropsychological consequences of HIV-infection in children, and the application of testing routines to Third World settings. Paediatric neuroAIDS is becoming a speciality in its own right, and interested readers should examine the relevant literature (e.g. Brouwers et al., 1991). The general principles of adult neuropsychology are applicable to any setting, provided that the tests and techniques are translated sensibly, are culturally appropriate, and have norms for the local population (Lezak, 1983). AIDS presents a daunting challenge in the Third World; and problems such as poverty, poor medical infrastructure, lack of anti-viral treatments, and the debilitating effects of 'Slim' disease make death probable before the individual becomes sufficiently immunocompromised to develop neuropsychological difficulties. Whether the incidence of neuropsychological impairment following HIV-infection of the brain will increase or reduce in the next decade is unclear; on the one hand, people live with AIDS for longer than ever, and the management of secondary infections is constantly improving; will the brain become the focus of HIV? On the other hand, AZT may be reducing the incidence of HMCD, and antiviral drugs that cross the blood-brain barrier, administered while the HIV-positive person is still asymptomatic, may prevent cognitive problems developing in the first place. Whatever emerges as the truth of the matter, it is likely that formal neuropsychological assessments will continue to provide an economical, sensitive way of describing and quantifying specific mental processes, and will contribute to a proper understanding of the effect of HIV on the brain.
Acknowledgement Financial support for this article was provided by MRC Special Grant 69006357.
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Neuropsychological aspects of HIV infection V. Egan
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Regional Infectious Diseases Unit, City Hospital , Edinburgh, UK Published online: 25 Sep 2007.
To cite this article: V. Egan (1992) Neuropsychological aspects of HIV infection, AIDS Care: Psychological and Socio-medical Aspects of AIDS/HIV, 4:1, 3-10, DOI: 10.1080/09540129208251615 To link to this article: http://dx.doi.org/10.1080/09540129208251615
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AIDS CARE, VOL. 4, NO. 1, 1992
EDITORIAL REVIEW
Neuropsychological aspects of HIV infection V. EGAN Downloaded by [The University of Manchester Library] at 10:14 10 October 2014
Regional Infectious Diseases Unit, City Hospital, Edinburgh,
UK
Abstract There is considerable consensus regarding the entity, aetiology, and assessment of HIV-1-caused cognitive impairment. Early fears that this would be very common, and early in onset, have not been realized. Research and clinical criteria should reflect current statistical standards. The large cohorts, broad test battm’es and repeated testing of population samples provide a special opportunity to resolve perennial questions regarding the relationship between mood, health, and cognitive functions. It appears that A Z T prevents mild cognitive impairment associated with HIV-1, though there is no strong evidence that it treatsfrank HIV-1 dementia complex. The management of patients with dementia requires proper consideration, as even if the incidence of HIV-1 dementia complex is only 5-lo%, this is still a substantial number of patients for population centres with large numbers of people with HIV and AIDS. The distressing nature of this condition, combined with the specialized management required for HIV itself; make it advisable that more nurses with psychiatric training are employed in wards or units specializing in HIV. Introduction
The human immunodeficiency virus (HIV) enters the brain early in infection via the macrophages and lymphocytes of an individual’s immune system (Resnick et al., 1988). The primary and secondary effects of HIV’s assault on the brain can produce a range of cognitive deficits, which can be quantified by formal neuropsychological testing. This enables the precise and potentially serial measurement of specific mental processes, and their possible deterioration or recovery. The current editorial provides an overview of neuropsychological factors affecting patients with HIV or AIDS, and where possible directs readers to more detailed references (e.g. Egan & Goodwin, 1992). Definition and classification
The early term ‘AIDS dementia complex’ (ADC) was used to describe the cognitive and behavioural deterioration seen in some patients with AIDS (Navia et al., 1986; Tross et al., 1988). As it was discovered that patients with apparent ADC did not necessarily have AIDS, and that the term ‘dementia’ was too severe a description of the memory impairment and cognitive/motor slowing generally seen, the World Health Organization proposed the more
Address for correspondence: Dr Vincent Egan, Regional Infectious Diseases Unit, City Hospital, Greenbank Drive, Edinburgh EHlO 5SB, UK.
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accurate term ‘HIV-1 associated cognitive/motor complex’ (HACC) (WHO, 1990). Revised formal criteria for defining neurological manifestations of HIV- 1 infection have recently been produced (Report of a Working Group of the American Academy of Neurology AIDS Task Force, 1991) and readers should use this reference for more detailed diagnostic criteria. The paper divides HACC into severe and mild forms, the severe forms being HIV-1associated dementia complex (HDC), which subsumes the previous interchangeable terms ‘subacute encephalitis’, ‘HIV encephalitis’ and ADC, and HIV- 1 associated myelopathy (HAM). HIV-1 associated minor cognitive/motor disorder (HMCD) is a mild expression of HACC, and replaces the previous overlapping terms ‘HIV- 1-associated neurocognitive disorder’ and ‘HIV- 1-associated neurobehavioural abnormalities’. HAM is a specific neurophysiological condition, and has an established protocol for diagnosis by neurologists; neuropsychological procedures are required as part of the diagnostic process for HDC and HMCD. Differentiation of HMCD and HDC is primarily based on the degree of impairment of daily living; social or occupational functioning must be conspicuously affected for a diagnosis of HDC, whereas patients with HMCD would be expected to function relatively normally, except for more demanding day-to-day activities. Evaluating this deterioration involves a consideration of their illness and social context, and their premorbid personality and ability. Neuropsychological assessment should be used to back up the reports of decline in attention or concentration, abstraction or reasoning, speed of information processing, visuospatial skills, memory/learning, and speech/language described by the patient, their informant or clinical impression. This should be conducted when the patient does not have any clouding of consciousness. Decline in emotional control, motivation, or changes in social behaviour should be noted. Evidence of other aetiologies should be sought from the patient’s social, medical and psychiatric histories, and the patient should have appropriate laboratory and radiological investigations. If another possible etiology is identified, this should not be the cause of the cognitive-motor and behavioural signs seen in the patient.
The incidence and mechanisms of HACC The homosexual cohorts seen during the multi-centre AIDS cohort studies (MACS) provide evidence, at least for individuals from higher educational and socio-economic groups, that the serious neurocognitive complications associated with HIV infection are late in onset, and are rather less common than once feared (Grant et al., 1987; Miller et al., 1990; Selnes et al., 1990). Similar studies are now in progress for drug users, and suggest similar results (Goodwin et al., 1992). It should be emphasized that HACC presents in a similar fashion whether one considers populations of homosexual men, drug users or the mentally handicapped (McArthur et al., 1989; Maxwell et al., 1991; Brown, 1991). The variation in incidence of ADC has been due to the source of the survey, the patients’ stage of infection, and the criteria used to infer cognitive impairment. The most comprehensive study of ADC incidence assessed all 38666 cases of AIDS reported to the CDC from 1st September 1987 to 31st December, 1988. ADC was defined as disabling cognitive/motor dysfunction, in the absence of any condition other than HIV to account for this finding. Of the adults, 6.5% had ADC, with just 3% having it as the exclusive early manifestations of AIDS; it was slightly more common (around 10%) in children and elderly patients with AIDS (Janssen et al., 1989). This did not estimate subclinical impairment of the kind described by HMCD, which may be rather more common. Brain imaging of patients with HDC using computerized tomography and magnetic resonance has demonstrated widened cortical sulci and dilated central ventricles. These
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patients also show patchy or diffusely increased signals on MRI, in keeping with increased water content in the hemispheric white matter, basal ganglia and thalamus (Price & Brew, 1988). There is some evidence of neuronal loss in the frontal cortex (Everall et al., 1991). Two major pathologies are believed to underlie HACC, gliosis and pallor of the subcortical nuclei, typically seen in individuals with mild HMCD; and a viral-induced cell fusion leading to multinucleated cell encephalitis with focal white matter rarefaction, seen in patients with HDC. These events are thought to be caused by the loss of immune system control over HIV replication. One particularly fruitful avenue of enquiry considers immunopathology; as immune control declines, as seen, for example, among AIDS patients, cytokines (mediators of cellular immunity such as neopterin and quinolinic acid) appear to be either poorly broken-down or found in excessive quantities, poisoning neural tissue (Melmed ez al., 1989; Brew et al., 1990; Heyes et al., 1991).
Neuropsychological test batteries and the interpretation of results There is now general agreement regarding the choice in measures appropriate for a relatively brief test battery sensitive to deficits seen in HDC and HMCD. Ideally, testing should involve; estimates of premorbid IQ (using the NART in either the British or North American form (Nelson & Willison, 1991; Blair & Spreen, 1989) or, less efficiently, the WAIS-R Vocabulary subtest (Wechsler, 1981); memory (Wechsler Logical Memory subtest, the Auditory-Verbal-Learning Test (Wechsler, 1987; Rey, 1964; Peaker & Stewart, 1989)); mood (the Beck Depression Inventory, the Hospital Anxiety and Depression scale (Beck et al., 1961; Zigmond & Snaith, 1983)); motor functioning (Finger Tapping or Grooved Pegboard (Reitan, 1979; Matthews & Kldve, 1964)) and performance measures of frontal lobe function, mental flexibility and information-processing speed (WAIS-R Block Design, Trail-Making parts A and B, and the WAIS-R Digit Symbol subtest (Reitan & Wolfson, 1985; Wechsler, 1981)). All these tests are quite commonly used, and all appear appropriate, reliable and sensitive measures of the processes they measure. Psychophysiological measures of information-processing speed such as reaction times and auditory event-related potentials are sensitive to panencephalopathy and are thus of considerable clinical value in the diagnosis of HACC syndromes-particularly as they are free of the evaluation anxieties that cognitive testing can generate (Perdices & Cooper, 1989a; Goodwin et al., 1990. Unfortunately, the technology these measures require makes their application likely to remain specific to specialized research centres. The interpretation of neuropsychological test values depends crucially upon the sample being discussed. Clinical populations, whether they be homosexual, drug-using, haemophiliac, or from ethnic minorities, all differ from one another regarding ‘normal’ values (Nakajima & Rubin, 1991). By way of example and utility, Table 1 presents summary statistics and percentile values for HIV positive drug users on standard neuropsychological measures. These values can be used heuristically when evaluating the degree of cognitive impairment in methadone-maintained, white HIV-positive drug users. This table demonstrates that a considerable degree of functional abnormality can be apparent in a sample without any corresponding difficulty in activities of daily living; the 5th and 95th percentiles provide conservative cutting points for inferring impairment in an already abnormal population.
Statistical criteria and research considerations Interpreting the results from large test batteries requires caution, in just the same way that
6 V.EGAN Table 1. Summay statistics for HIVpositive drug users Percentile
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Cognitive test NART-estimated WAIS-R FSIQ WAIS-R Arithmetic WAIS-R Digit Span WAIS-R Block Design WAIS-R Digit Symbol Trail-making test part A (sec) Trail-making test part B (sec) Logical memory-immediate recall Logical memory-delayed recall AVLT trial 1 AVLT trial 2 AVLT trial 3 AVLT trial 4 AVLT trial 5 AVLT 1 trials 1 to 5 AVLT interrupt trial AVLT trial 6 AVLT delayed recall AVLT recognition memory to list A AVLT recognition memory to list B Benton visual retention test-C Benton visual retention test-E HAD depression scale HAD anxiety scale Beck depression inventory Tapping task-dominant hand Tapping task-non-dominant hand 2-Choice reaction time (median msec) Movement time (median msec) Decision time (median msec) Word fluency: animals B
S
J
n
Mean
SD
5
95
197 196 195 194 194 196
93.9 7.8 8.3 7.4 6.3 42.5 119.2 12.5 10.4 5.3 7.8 9.3 10.2 10.8 43.4 4.7 8.8 8.4 12.9 4.3 5.8 6.7 7.7 10.6 19.8 61.4 57.5 944.3 276.5 661.9 19.2 12.0 13.4 7.7
11.4 2.4 2.1 2.3 2.1 19.5 86.4 3.9 3.9 1.4 2.2 2.5 2.3 2.3 9.1 1.7 2.9 3.0 2.1 2.8 1.8 3.2 4.1 4.5 10.1 11.2 9.5 236.9 121.4 171.6 8.1 4.5 6.1 6.2
76 5 6 5 3 21 48 6 5 3 4 5 6 7 28 2 3 3 9 0 3 2 1 3 5 45 38 670 130 459 9 5 5 3
113 12 12 12 10 80 279 19 18 8 12 14 14 14 59 8 13 13 15 9 9 12 14 18 37 77 70 1387 550 987 29 20 22 14
195 187
128 191 191 97 146
119
Mean and SD values provide norms for HIV positive drug users; 5th and 95th percentile values provide cutting points for interpreting the observed performance of the subject.
one should be careful of making multiple statistical comparisons between groups; if an unduly liberal attitude is taken to data, results which are a product of chance variation, rather than some genuine process, will be produced. In the clinical case, taking a criterion of a change on 2 independent tests (ie. in two separate cognitive domains) of 2 standard deviations is unlikely to occur by chance unless one is using more than 15 assessment measures (Ingraham & Bridge, 1990). Statistical analysis of test batteries should either specify comparisons in advance, make corrections to significant values in accordance with the number of comparisons being made, or use conservative post-hoc tests. Confidence intervals, effect-sizes and the power of results or null findings should be reported where appropriate (Howell, 1987). One needs to remember that effective neuropsychological measures are predicated on an understanding of cognitive processes and, ultimately, good science. Thus, though neuro-
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psychological studies of HIV-infected patients have obvious clinical value, psychologists should also consider the processes underlying their observations. Many of the cognitive tests administered to HIV-positive patients will correlate significantly with one another; this colinearity provides an opportunity to model the processes underlying changes in neuropsychological function. For large cohorts tested on standard test batteries, one could start by using a data reduction technique such as factor analysis and then use the factor scores as the basis of further analysis-provided that the factors themselves are replicable or easily interpretable. The advent of the large cohort studies such as MACS, and intercorrelated test batteries being given repeatedly, mean that structural modelling using LISREL (Joreskog & Sorbom, 1985) is likely to provide useful results regarding the causal paths between changes on psychological or psychophysiological measures at different time and disease points. All too often mood or psychological reactions to HIV seropositivity are said to affect HIV-illness progression, falling CD4 count, or neuropsychological performance; it is about time this perennial post hoccery was empirically resolved. A lesson regarding the overenthusiastic expansion of mood to account for changes in immune function was recently provided by Stein et al. (1991). This study comprised a survey of 22 peer-reviewed and published studies looking at the relation between depressive disorders and the immune system; it concluded that the results are inconsistent, inconclusive, have poor design and little conceptual clarity. The concept of ‘pseudodementia’ (Caine, 1986), generally considered to be specific to patients with endogenous chronic depression, has been expanded to accommodate the poor cognitive performance sometimes seen in patients with HIV and AIDS with concurrent dysthymic or (understandably) reactive mood states (Rubinow et al., 1988). A meta-analysis of the effects of depressive mood states on cognitive performance is also clearly due. Treatment and management
The empowering of HIV-positive patients as active ‘participants’, rather than passive ‘subjects’ of research, has shifted the ethics of controlled trials regarding the efficacy (or otherwise) of antiviral treatments to treat HACC. An early study of the neurotoxicity of zidovudine (AZT) predated open drug trials, and involved a double-blind, placebocontrolled trial of oral AZT, in which patients with advanced ARC or AIDS were tested over 16 weeks to assess changes in neuropsychological function following drug treatment. Patients on AZT, in particular AIDS patients, had improved mental function compared to those on placebo (Schmitt et al., 1988). Though these results implied that HIV-related cognitive abnormalities may be partially treated by AZT, the sample did not include any patients with frank dementia. Other studies have claimed that the incidence of severe ADC has significantly reduced following the introduction of AZT, (Portegies et al., 1989; Chiesi et al., 1991). One hopes that a more prosaic reason-practice or familiarity with the tests, shown to account for improved neuropsychological performance in both people being treated with AZT, and matched HIV-negative controls-does not account for this effect (Perdices & Cooper, 1989b). The patient with HDC has brain damage that combines subcortical and frontal features; they are thus slow, inattentive, forgetful, and somewhat disinhibited. This severely limits the ability of the patient to function independently, whether they be in their own home, or in the relative autonomy of an AIDS hospice, and makes in-patient management intensive. In one study, some 63% of patients with moderate to severe HIV-1 related cognitive impairment had residential problems secondary to their impairment. These problems were primarily associated with home safety, wandering, confusion and memory problems (Boccellari et al.,
8 V.EGAN 1991). There are no guidelines regarding management of patients with HDC, though principles used to help psychogeriatric patients, such as structured environments, reality orientation, and personalized nursing may reduce the confusion of the patient. Though looking after an individual with HDC demands time and patience, it is likely to be of relatively short duration as these patients tend to pass rapidly from the unequivocal cognitive impairment described by Price stages 2 and 3, to the terminal stage 4 (Price & Brew, 1988). This stage is characterized by severe physical incapacity, incontinence, and eventually coma. When a patient is so ill, neurocognitive considerations become irrelevant to management, as death is imminent.
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Conclusions This article has intentionally omitted several issues, namely the neuropsychological consequences of HIV-infection in children, and the application of testing routines to Third World settings. Paediatric neuroAIDS is becoming a speciality in its own right, and interested readers should examine the relevant literature (e.g. Brouwers et al., 1991). The general principles of adult neuropsychology are applicable to any setting, provided that the tests and techniques are translated sensibly, are culturally appropriate, and have norms for the local population (Lezak, 1983). AIDS presents a daunting challenge in the Third World; and problems such as poverty, poor medical infrastructure, lack of anti-viral treatments, and the debilitating effects of 'Slim' disease make death probable before the individual becomes sufficiently immunocompromised to develop neuropsychological difficulties. Whether the incidence of neuropsychological impairment following HIV-infection of the brain will increase or reduce in the next decade is unclear; on the one hand, people live with AIDS for longer than ever, and the management of secondary infections is constantly improving; will the brain become the focus of HIV? On the other hand, AZT may be reducing the incidence of HMCD, and antiviral drugs that cross the blood-brain barrier, administered while the HIV-positive person is still asymptomatic, may prevent cognitive problems developing in the first place. Whatever emerges as the truth of the matter, it is likely that formal neuropsychological assessments will continue to provide an economical, sensitive way of describing and quantifying specific mental processes, and will contribute to a proper understanding of the effect of HIV on the brain.
Acknowledgement Financial support for this article was provided by MRC Special Grant 69006357.
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