SEMINARS IN NEUROLOGY-VOLUME
10,NO. 3 SEPTEMBER 1990
The Neuropsychiatry of Human Immunodeficiency Virus Igor Grant, M.D., F.R.C.P.(C)
NEUROGENIC PHENOMENA Neurogenic sequelae are those that can be attributed to direct central nervous system (CNS) disturbance produced by HIV-I, other infections, neoplasia, or vascular diseases consequent on progressive immunodeficiency, or adverse effects of treatment. Some of the principal causes are summarized in 'Table 1. 'l'he earliest reports of neurogenic consequences appear to be have been those of Horowitz et aP and Britton et al."The former investigators observed a neurologic disorder that included mental status disturbance in seven of nine patients with cytomegalovirus (CMV) retinopathy. T h e latter de-
Table 1. Neurobehavioral Disorders Associated with HIV-I Infection I. Neurogenic A. Primary neurogenic disorder 1. Mild cognitive disorder due to HIV-I 2. Dementia due to HIV-I (AIDS dementia complex) B. Secondary neurogenic disorders Other hfections a. Viruses-cytomegalovirus (CMV), herpes viruses, papovavirus b. Protozoa-Toxoplasma gondii c. Fungi-Cryptococcus neoformans d. Bacteria-Mycobacteria, including M. tuberculosis, M. avium Neoplasia a. Primary Lymphoma Kaposi's sarcoma b. Metastatic tumors Cerebrovascular disease-strokes, vasculitis Delirium or mild cognitive impairment from systemic disease Hypoxemia Metabolic derangement Iatrogenic illness a. Antiretroviral agents Mania, "Rebound" encephalitis from zidovudine b. Other treatments, such as drugs with psychopharmacologic side effects II. Psychogenic A. Adjustment disorders, including "worried well" syndrome B. New onsets of major psychiatric disorders 1. Anxiety disorders 2. Mood disorders C. Reactivation or continuation of preexisting disorders 1. Anxiety disorders 2. Mood disorders 3. Schizophrenia 4. Substance abuse
Department o f Psychiatry, University of' California at San Diego, and Psychiatry Service, San Diego Veterans Administration Medical Center, San Diego, Califbrnia Reprint requcsts: Dr. Grant, Dept. o f Psychiatry ( M - 0 0 3 ) , University of' California at San Diego, La Jolla, C A 92093 Copyright 1990 by T h i e n l e Medical Publishers, Inc., 381 Park Avenue South, New Y o r k , NY 10016. All rights reserved.
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Commencing in the early 1980s, infection with type I human immunodeficiency virus (HIV-I), the causal agent of acquired immune deficiency syndrome (AIDS), has brought to the fore a new and growing source of neuropsychiatric morbidity, affecting especially young and middle-aged adults. Elsewhere, we have discussed the evolution of such neuropsychiatric phenomena in relation to the natural history of HIV disease' and have suggested that the terms "neurogenic" and "psychogenic" may offer a convenient shorthand to refer to the two basic etiologies of such phenomena.' In this article I shall summarize some of the concepts we articulated earlier, while providing an update based on new research that has emerged in the interim.
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scribed psychosis and dementia in three of' four im- illustrating some of these HIV-associated brain munosuppressed patients with neurologic disease. changes. T h e pathogenesis of HIV-related brain disBoth groups suggested that CMV might be one of ease is poorly understood. For example, even durthe causal agents of the encephalopathic process. T h e first systematic autopsy-based study of ing the medically asymptomatic phase of HIV inCNS complications was reported by Snider et fection (that is, long before a person develops aL5 In 18 of 50 brains of patients dying from symptoms of ARC or AIDS), as many as 50% AIDS, these investigators found neuropathologic of such infected individuals undergoing lumbar evidence of what they termed "subacute encepha- puncture yield evidence of HIV presence in the celitis." Many of these patients had cognitive impair- rebrospinal fluid (CSF).1"'5 Furthermore, other ment, mood disturbances, and problems in activi- indicators of CSF and brain envelope infection ties of daily living prior to death. Furthermore, tend to get more pronounced as the disease there was evidence of brain atrophy on computed progre~ses.l"~'For example, CSF protein, antiHIV-specific IgG (indicating intrablood-brain bartonlographic (CT) scanning. The first comprehensive description of the en- rier synthesis of antibody), pleocytosis, and oligocephalopathic process associated with AIDS came clonal bands all increase as a function of length of from the Memorial Sloan-Kettering group headed infection.'" Despite this evidence of ubiquitous penetraby Richard Price. These investigators coined the termed "AIDS dementia complex" (ADC) to de- tion of HIV into the CSF, there is, at present, poor scribe the neurologic, cognitive, and behavioral clinicopathologic correlation. For example, an ascomplications of late-stage AIDS.6 Although this sociation between recovery of HIV from the CSF term has been heuristically useful, it is limited by and neuropsychologic (NP) abnormality has not the fact that some people with HIV infection, par- been e~tabIished.'~.'"urthermore, magnetic resoticularly those with AIDS and AIDS-related com- nance imaging (MRI) changes show statistical asplex (AKC), can have subtle neurocognitive distur- sociation to NP deficits in some studies'Qut not bances short of the usual meaning of the term others.In An additional problem is that neurons "dementia." For this reason, we have suggested themselves are not commonly infected by HIV; that the term "neurobehavioral disorder associated rather, the HIV in infected brains tends to be localized in mononuclear cells, glia, and endothelial with HIV" might be more appropriate.' cells."' While the CD4 receptor appears critical to entry of HIV into monocytes and lymphocytes, the same has not been established for cells from neural lines. Indeed, some data indicate that the ROLE OF HIV IN CD4 receptor is not involved in entry of HIV into NEUROBEHAVIORAL DISORDER neural and muscle cells; this observation raises the Until the mid-1980s, it was commonly as- possibility that other receptor sites may be imporsumed that the organic mental disorder associated tant.'' Thus, the mechanism of brain damage by with AIDS resulted from opportunistic infections and other influences consequent on progres- HIV remains obscure. Since, at present at least, it sive immunodeficiency. In particular, CMV was does not appear that entry of virus into neurons is principally responsible, it has been suggested that strongly implicated." With the discovery of HIV-I, it became clear neurons may suffer through sort of "bystander" efthat this retrovirus itself was capable of invading fect. For example, it may be that infected macrothe CNS.7.8 Virions, thought to be HIV-I, have phages within the brain secrete products that are been visualized on electronmicroscopic study of toxic to the neurons; alternatively, viral constituthe brain, and HIV products have been recovered ents such as gp120, which binds to CD4 receptor sites, might also have homology with neurotrophic through in situ hybridization studies.' There appears to be a predictable neuro- peptides, such as vasoactive intestinal peptide. pathologic picture associated with HIV infection of Conceivably, constituents such as gp120 may octhe brain. Among the commonest findings, whose cupy sites critical to the trophic function of such specificity is still unknown, is "myelin pallor," seen peptides. Another possibility is that HIV, in comparticularly in the centrum semiovale. Addition- mon with certain other viruses, may cause disturally, the brains of persons dying with an AIDS- bance in tryptophan metabolism, leading to proassociated dementing disorder typically show duction of toxic metabolites such as quinolinic acid. microglial nodules, necrotic foci, foci of demyeli- Some reports suggest that concentration of' CSF nation, and collections of multinucleated giant quinolinic acid is related to degree of neurocogni268 cells.q- '* Figures 1A and 1B are photomicrographs tive impairment in HIV-infected person^.^"
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SEMINARS I N NEUROLOGY
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NEUKOPSYCHIATRY O F H I V INFECTION-GRANT
Figure 1. A: Hematoxylin and eosin-stained, paraffin embedded section of AlDS brain tissue. A large microglial nodule is present in the center of the section (surrounded by three arrows). Numerous elongated microglial nuclei are present both within the nodule and in the surrounding tissue (arrowheads). Original magnification x 600. B: HIV p24 immunoperoxidase-stained, paraffin embedded section of AlDS brain tissue. Several large multinucleated giant cells (surrounded by arrows) contain black, amorphous immunoprecipitate of density similar to that of the oval nuclei. Numerous mononuclear macrophages (arrowheads) are distributed throughout the tissue. Original magnification x 300. (Photomicrographs courtesy of Clayton A. Wiley, M.D., Ph.D., Dept. of Pathology, University of California, San Diego.)
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NATURAL HISTORY OF NEUROBEHAVIORAL DISORDER The evolution of neurobehavioral changes remains imperfectly understood. Neurocognitive disturbances have been reported in 29 to 87% of patients with frank AIDS, and 40 to 50% of patients with ARC.2,"4,2"m ong patients with AIDS, approximately one third of those living long enough will develop actual clinical signs of dementia.24,'"It is estimated that an additional third will have deficits on NP testing, indicating CNS disturbance insufficiently severe to make the diagnosis of dementia.24T h e incidence of dementia in patients with AIDS who were neurologically asymptomatic at the time of diagnosis has been estimated at 14% ann~ally.~~ When and how often the earliest signs of CNS involvement can be detected remains a matter of hot debate. Early on, our group suggested that HIV-infected persons who are either medically asymptomatic, or whose symptoms are mild enough not to qualify them for the diagnoses of ARC or AIDS, nevertheless can sometimes manifest subtle NP deficits.'VOther early reports reached the conclusion that HIV seropositive asymptomatic individuals were not at increased risk for NP di~turbance.~" A review of over 20 neurobehavioral studies that had been either presented or published by early 1990 revealed that roughly half suggested some increased risk for neurobehavioral disorder in the seropositive asymptomatic phase, while the remaining half found no differences between asymptomatic seropositives and appropriately matched seronegative controls.' Despite this, opinion among marly workers in the field appears to have swung to the notion that the seropositive asymptomatic individual is at no (or extremely minimal) increased risk for neurobehavioral disturbance. This view has been supported largely by three influential investigations. T h e first, emerging from the Multicenter AIDS Cohort Study (MACS) conducted in the United States concluded, on the basis of brief NP assessment of 727 HIV seropositive asymptomatic men and 769 homosexual controls, that the rates of NP disturbance were equal in the two groups (5.5% versus 3.9%)." Additional studies with the Baltimore sample of the MACS cohort noted no MKI differences between asymptomatic seropositives and seronegatives.18 A second study, emerging from the United States Air Force, reached the same conclusion." A study from the Centers for Disease Control (CDC) and San Francisco cohorts, which involves 100 seropositives and 157 sero270 negatives, also failed to detect NP differences be-
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SEPTEMBER 1990
tween the two groups, although the rate of NP impairment in patients with ARC was 31 to 4476, depending on extent of NP testing p e r f ~ r m e d . ~ ~ Although the results of these three large studies, and several other smaller ones,l provide reassurance that gross NP impairment is unlikely to be seen in a cohort free from other medical symptoms of HIV infection, it is probably premature to dismiss the possibility that subtle evidence of CNS involvement can be present prior to a person's reaching ARC or AIDS. Studies from a number of investigative groups continue to suggest that there may be NP,32-97e l e c t r o p h y ~ i o l o g i c and , ~ ~ ~brain~ imaging difference^""^' between some groups of asymptomatic seropositives and appropriately matched controls. Furthermore, the early presence of CSF abnormalities, including ability to culture HIV in about 50% of asymptomatic seropositives, plus the apparently progressive nature of CSF changes, strongly suggests early presence of HIV in the CNS. It is possible, of course, that HIV is "neurotropic," (has a predilection to enter the CNS) but not "neuropathic," (does not cause pathologic changes) until immunodeficiency becomes profound. Another line of evidence that suggests we should be cautious in our conclusions comes from early longitudinal data. Whereas a 2-year followu p of the MACS sample has not demonstrated any changes on the five NP tests employed,4-'data from our group indicate that about a quarter of seropositive men who do not qualify for the diagnosis of AIDS or ARC are rated as neuropsychologically more impaired after a 1-year follow-up. T h e rate of NP worsening in patients with AIDS and ARC appears to be closer to 40% after I year.44 In sum, at the present state of our knowledge, it is recommended that clinicians and investigators keep an open mind regarding the incidence and prevalence of CNS involvement in the earlier phases of HIV-I infection. While it is clear that most seropositive individuals who have not progressed to ARC and AIDS are free of' szgnzficant cognitive loss, this does not preclude the possibility that subtle changes, either static o r slowly progressive, may be confirmed using more sophisticated diagnostic techniques.
CLINICAL FEATURES OF HIV NEUROBEHAVIORAL DISORDER Early subjective complaints that might suggest CNS involvement include forgetfulness, inattention, and subjective sense of slowness and inefficiency. Sometimes these complaints are accompanied by a sense of fatigue and excess sleepiness.
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SEMINARS I N NEUROLOGY
Polysomnographic studies of HIV-infected patients have indicated disturbance in sleep architecture and excess stage IV sleep late in the sleep cycle of some HIV-infected person^.^' Comprehensive NP testing may reveal difficulties with learning of new material (both verbal and nonverbal), impaired abstracting ability, and, in particular, reduction in speed of information processing and psychomotor ~ p e e d . ' ~ , ' "At , ~ ~this stage, the subjective complaints may be difficult to differentiate from those attributable to depression and anxiety, both of which also occur more frequently in seropositive individuals (see later). NP testing, properly performed and interpreted, should, however, resolve the issue, since there is little evidence that mild or moderate mood disorder has significant impact on such test^.'^,^^.^" If the disorder progresses to a clinically symptomatic phase, which is seen primarily in patients with frank AIDS, then the more typical features of ADC, as described by Navia et al,%ay be observed. These include substantial cognitive and psychomotor slowing, defects in attending, and disturbance in memory. There can be accompanying changes in mood, which will range from depression to apathy. Occasionally, in later stages of ADC, there may be labile affect, irritability, and violent outbursts. As the dementia evolves, a person may become frankly disoriented, develop language disturbances (such as naming difficulties), and perceptual motor disturbances, in addition to worsening amnesia, inattention, and disturbance of abstracting ability. Neurophysical signs may include some weakness and incoordination, beginning in the lower limbs and later evident in the upper limbs. Peripheral neuropathy, and other neurologic signs (for example, autonomic neuropathy, ophthalmo1,ogic disease) can also complicate the later stages of AIDS but are apparently not regularly associated with severity of dementia. In the latest stages of dementia, a person may progress to being bed bound, disoriented, stuporous, and incontinent. Generally speaking, the onset of clear clinical signs of dementia is a poor prognostic indicator. Many patients die within 6 months of onset of dementia.27 Ancillary examination of persons with clinical dementia can reveal slowing of electroencephalographic background rhythm," disturbed smooth pursuit eye rno~ement,~%nd several abnormalities on brain imaging. More specifically, AIDS dementia is accompanied by evidence of sulcal and ventricular dilation on C T ~canning,~',''" as well as similar indicators of "brain shrinkage" on MKI."' MRI appears to be more sensitive to earlier signs of CNS involvement, revealing areas of hyperintensity (especially on T, weighted images) in the white
matter, as well as in subcortical gray. Such hyperintensities, which may represent areas of demyelination or necrotic foci, are poorly visualized on CT, although larger areas may be seen as areas of relative radiolucency without mass effect." In more advanced cases, confluent areas of high signal suggestive of an encephalitis can be seen on MKI (Fig. 2). Whether focal hyperintense areas gradually progress to the "encephalitic" picture is not presently known. In terms of differential diagnosis, although it is difficult to be certain, while the patient is living, whether dementia can be attributed solely to HIVI infection, the presenting symptoms can often give good clues as to presence of some of the more common secondary infections. For example, cerebral toxoplasmosis usually presents with rapidly declining mental status and clouding of consciousness. Headache and lateralizing neurologic signs are common. C T scan is often helpful, revealing multiple ring-enhancing lesions. MRI almost always demonstrates multiple masses of high signal intensity on the 'I-, weighted image. Cryptococcal meningitis is usually heralded by headache, stiff neck, fever, photophobia, clouding of consciousness, and other signs of meningitis. Confirmation is by visualizing Cryptococcus neoformans on India ink staining of CSF, as well as obtaining positive culture and antigen from the CSF. Brain imaging tends to be nonspecific, with some cases of atrophy and rare focal lesions. Generally speaking, large focal abnormalities on C T or MRI suggest toxoplasmosis, lymphoma, or progressive multifocal leukoencephalopathy (PML-papovavirus infection). Atrophy or diffuse areas of high signal on MRI may be due to CMV as well as to HIV-I.51 T h e response of' HIV-associated CNS complications to antiretroviral treatment also remains a matter of controversy. Several reports indicate that children infused with zidovudine (AZT) respond favorably, both in terms of improved developmental milestones, NP performance, and some reversal in brain-imaged abnormalities." Also, data from adults undergoing the AZ'I' licensing trial suggest some NP improvement in those receiving active treatment."" limited series from our group indicated little difference in the incidence of dementia in previously nondemented AIDS and ARC patients receiving AZ'I' or a placebo-the 2year cumulative incidence was 2896, with essentially all persons being crossed over to AZT after the first 6 month^.'^ Thus, at present, it seems prudent to maintain an attitude of cautious optimism that AZ1' does retard the progression of neurogenic complications; at the same time, it does not appear to confer longlasting or universal protection.
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NEUKOPSYCHIATKY OF HIV INFEC'I'ION-GRANT
27 1
B Figure 2. Two magnetic resonance brain scans of a 40year-old man with HIV-associated neuropsychologic deficit. (At time of scanning, this patient was diagnosed as having AIDS and had difficulties with speeded information processing, abstracting ability, complex perceptual-motor tasks, and learning of verbal material.) A: This relatively TI weighted axial section shows dilation of lateral ventricles, sulcal enlargement, and a periventricular area of high signal. B: This axial view shows bilateral areas of high signal in the centrum semiovale.
NEUROBEHAVIORAL DISORDERS OF PSYCHOGENIC ORIGIN A fundamental premise of modern neuropsychiatry is that moods and behaviors have biologic underpinnings. Hence, the present use of the term "psychogenic" should not be construed as harkening back to Cartesian or psychoanalytical mindbody dualism. Rather, the term is meant as a shorthand to describe disturbances in mood and behavior that cannot be attributed to brain disease caused by HIV or other neuropathologic processes attendant on progressive immunodeficiency or its treatment.
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One concern expressed commonly in the early days of'the AIDS epidemic was that there would be marked increase in psychologic disturbance related to the issue of serotesting, knowledge of serostatus, or realization that one has AIDS. Interestingly, such predictions have not been borne out. Kecent studies of persons given the news that they were seropositive have confirmed that the period immediately surrounding serotesting is accompanied by an increased prevalence of anxiety, depression, and sometimes a sense of alienat i ~ n . ~ " -Such " ~ reactions appear to be self-limited in most instances, however. Preliminary data from follow-up of those informed of their serostatus indicate that such psychologic distress tends to abate by 6 months. j4." Furthermore, it is now clear that mood and other kinds of behavioral disturbances in seropositive individuals need to be understood in the context of an individual's own lifetime history of psychiatric disorder. As an example, studies involving structured diagnostic psychiatric interviews indicate that current prevalence (defined as either l-month or 6month prevalence) of anxiety and depressive disorders among seropositive individuals who do not have AKC or AIDS runs in the order of 10 to 20%.',"7It is important to note, however, that the rate among seronegative persons "at risk" to become infected (in this case, seronegative homosexual men) was comparable to the seropositives, and substantially higher than that for those "not at risk" (that is, sociodemographically matched heterosexual men)."," The implication is that "at risk" persons have higher background rates of mood disturbance; therefore, finding an increase in mood disturbance in seropositives need not necessarily mean that H I V status is solely responsible. This interpretation is given further credence by the observation that syndromic depression and anxiety are only modestly elevated in persons with AKC and AIllS compared with the incidence of those mood disturbances among asymptomatic seropositive~.Another way of looking at this is that people, in general, are remarkably resilient in the face of knowledge of seropositivity and realization of the possibility of a fatal illness. To the extent that they experience increases in psychopathology in relationship to these events, at least some of this increase can be seen as reflecting recrudescence of longer standing propensities to disturbance in mood and behavior. While prevalence of mood and behavioral disturbances does not appear to be as much increased as might have been expected given the seriousness of HIV infection, there is a small subgroup of individuals, known as the "worried well,"" who report anxiety, depression, obsessional rumina-
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SEMINARS I N NEUKOLOGY
N E U K O P S Y C H I A T K Y OF H I V INFECTION-GRANT
SUMMARY With the advent of HIV infection, a new causal group of rieurobehavioral disorders has emerged. 'l'hese are the neurogenic and psychogenic neurobehavioral disturbances associated with HIV. Neurogenic disorders are those caused by the direct effects of HIV on the CNS, or by other infectious agents, neoplasms, vascular events, or side effects of biologic treatments in HIV-infected persons. Psychogenic disorders include anxiety, depression, adjustment reactions, and other behavioral disturbances related to knowledge of HIV seropositivity and recognition of being afflicted with a serious illness. In many instances, the psycho-
genic disorders appear to represent recrudescences of preexisting psychopathology. l'he comprehensive management of the patient with HIV infection requires early recognition and proper treatment of such complications.
REFERENCES 1. Grant I, Atkinson J H . Neurogenic arltl psychogenic hehavioral correlates of' HIV irtf'ection. In: Waksman BH, ed. Imnlunologic mechanisms in neurologic and psychiatric disease. New York: Raven Press, 199O:29 1-304 2. Grant I, Atkinson .JH. T h e evolution of. neurobehavioural complications of HIV inlectiort. Psychol Metl 1 WO;2O:Itt press 3. Horowitz SL, Benson DF, Gottleib MS, et al. Neurological complications of gay-related imrrlurlodeficiency disortier (Abstr.) Ann Neut-01 1982; 12:XO 4. Britton CB, Marquardt MU, Koppel B, et al. Ncurological cornplications of the gay immunosuppressed syndrome: clinical and pathological features. (Abstt-.)Artn Neurol 1982; l2:8O 5. Snider WD, Simpso11 D M , Nielsen S, ct al. Neurological complication of acquired itnrnune deficiency syrtdrome: arlalysis of' 50 patients. Ann Neurol 1983; 14:403-18 6. Navia BA, .Jordan BD, Price KW. 'l'he AIIjS dementia complex: I. clinical features. Ann Neurol 1!)86;19: 5 17-24 7. Levy JA, Shimat)ukuro,J,flollantler H , et al. Isolation of AIDS associated retroviruses ft-otn cerel,rospinal fluid and brain of patienrs with neurological symptortts. Lancet 1985;2:586-8 8. H o DD, Rota .1'R, Schoolcy KT, et al. Isolation ot H.I'LV111 lrom cerebrospinal fluid and neural tissues of patients with neurologic syndromes related t o the acquired immunotlcficiet~cysyndrome. N Engl ,I Med 198533 13: 1495-7 9. Price KW, Brew B, Sidtis J , et al. 'l'he brain in AIDS: central nervous system IIIV-I infection a n d AI1)S tletnentia complex. Science 1988;239:586-92 10. Vintet-s HV, Kwok hlK, H o HW, et al. Cytomegalovirus in the nervous system of' patients with the acquired immune deficiency syndrotr~e.Hrain 1989; 112:245-68 I I. Lantos I'L, McLaughlin J E , Scholtz CL, ct al. Neuropathology of the brain in HIV infection. 1.ancet 1989; 1 :3N-11 12. Gray F, Fenelon (;, Gherarcli K, er al. Neuropathologic study of 15 cases of' multinucleated giant cell encephalitis in acquired imn~urtodeficiet~cy syndrome (AIDS). Ann Pathol 1988;8:281-9 13. McArthur JC, Cohen BA, Farzedegan H , et al. Ccrebrospinal fluitl abnormalities in homosexual men with and without neuropsychiatric findiugs. Ann Ncurol 1988; 23(Suppl):S34-7 14. Grant I, Hesselittk .J,Jernigan I', et al. Ncuropsychology and magnetic resonance imaging in HIV infection. Presented at Fourth Internatiorral (:onference o n A1 DS, Stockholm, Sweden, I988 15. Sonncrborg A B , Ehrnst A(:, Bergdahl SKM, et al. HIV isolation from cerebrospinal fluitl in relation to irnn~unologicaldeficiency and neurological symptoms. AIDS 1988;2:8Y-93 16. Marshall DU', Brey KL, Butzin (;A, et al. Logitudinal (;SF cell counts and protein levels in 258 HIV infected US Ail- Force Personnel. Fifth International Conference o n AIDS, Montreal, Canada, J u n e 1989 17. MacArthur J C , Cohcn HA, Selnes Oil, ct al. Low prevalence of' neurological and neuropsychological abnormalities in otherwise healthy HlV-I-infected intlividu-
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tion, and phobic symptoms even though they are healthy physically. Indeed, some of the "worried well" are actually seronegative, but continue to believe that they may be infected, and therefore interpret minor symptoms as indicating serious disease. Some such individuals undergo repeated serologic testing and, despite this, cannot convince themselves that they are in good health. The treatment of "psychogenic" disorders associated with HIV follows much the same principles as the treatment of psychopathology generally. For milder symptoms of anxiety and depression, supportive counseling, cognitive therapy, and expressive psychotherapy can be beneficial. More serious forms of depression may require antidepressant treatment. For those patients with more advanced HIV infection, or when neurogenic complications coexist, care should be taken to prescribe lower doses than usual, at least to begin with. Susceptibility to central anticholinergic syndrome may be increased in such persons. Individuals requiring anxiolytics should also be treated with lower doses of such agents if they are medically ill or show signs of CNS disturbance. Once again, excess sensitivity to the sedativehypnotic effects of these drugs has been reported. Psychotic symptoms are an uncommon complication, usually signifying evolving dementia. Symptoms can include suspiciousness, hallucinations, and severe agitation. Occasionally, the first presentation of AIDS can be as a schizophrenia-like syndrome."" T h e syndrome can be managed with neuroleptic drugs. Low doses of neuroleptics should be used to begin with because of tendency toward excessive sedation and experience of extrapyramidal symptoms. Another late complication is severe apathy and withdrawal, often combined with cognitive impairment. Methylphenidate has been reported to be beneficial in preliminary reports."',""
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with a matched HIV negative population. Fifth International Conferencc o n AIDS, Montreal, Canada, J u n e 1989 Claypoole KH.J, Townes R, White D, et al. Neuropsychological aspects of early HIV infection. J Clin Exp Neuropsychol 1990; 12:72 Martin A, Salazar AM, Kampen D, et al. Patterns of neuropsychological dysfunction in a select g r o u p of H I V + individuals in cornparison to psychiatric controls. Fifth International Conferencc on AIDS, Montreal, Canada, J u n e 1989 Koralnik 1, Heaurnanoir A, Hausler R, et al. Abnormalities of EEG and otoneurologic tests in asymptomatic H I V infected homosexuals: a prospective controlled study. Fifth International Conference on AIDS, Montreal, Canada, J u n e 1989 McAllister RH, Harrison MJG, Griffin GA, et al. Prospective neurological and neuropsychological assessment in a cohort of hornosexual men. Fifth International Conference o n AIDS, Montreal, Canada, J u n e 1989 Ollo C, J o h n s o n R J r , Grafman J , et al. Event-related potential measures of dementia in H I V disease. Fifth International Conference on AIDS, Montreal, Canada, J u n e 1989 Norman SE, Kesnick I., Cohn MA, et al. Sleep disturbances in HIV-seropositive patients. J A M A 1988;260: 922 Coats M, Salazar AM, Martin A, ct al. Neurological findings in carly HIV infection. Fifth International Conference on AIDS, Montreal, Canada, J u n e 1989 Selnes OA, Miller E, McArthur ,J, Gordon B, Munor A, Sheridan K, Fox K, Saah AJ, a n d the Multicenter AIDS Cohort Study. HIV-1 infection: n o evidence of cognitive decline during the asymptomatic stages. Neurology (Cleve) l990;40:204-8 Heaton R, Atkir~sonH , Grant I, et al. Relating depression to neuropsychological impairment. Fifth International Conference on AIDS, Montreal, Canada, J u n e 1989 Holland JC, Tross S. T h e psychological and neuropsychiatric sequelae of the acquired immunodeficiency syndrome and related disorders. Ann Intcrn Med 1985; 1033760-4 Becker JT, Zegar S, Dew MA, ct al. A longitudinal analysis of perception of physical health a n d symptoms o f depression in gayibisexual men: the multicenter AIDS cohort study (MACS). Fifth International Conference or1 AIDS, Montreal, Canada, J u n e 1989 Parisi A, Di Perri G, Strosselli M, et al. Usefulness of computerized electroencephalography in diagnosing, staging and monitoring AIDS-dementia complex. AIDS 1989;3:209-13 Currie J , Ramsden BM, Lynch JM, et al. Antisaccadic eye movement abnormalities in asymptomatic HIV seropositive individuals. Fifth International Conference o n AIDS, Montreal, Canada, J u n e 1989 Post MJD, Sheldon J J , Hensley (;T, et al. Central nervous systcm disease in acquired imrnunodel'iciency syndrome: prospective correlation using CT, MR imaging, and pathologic studies. Radiology 1986; 158: 14 1-8 Post MJ, 'late I.G, Quencer KM, et al. C'I', MR, a n d pathology in HIV encephalitis a n d meningitis. Am J Ro 1988;151:373-80 Levy RM, Bredesen DE. Central nervous system dysfunction in acquired immunodeficiency syndrome. J Acquired Irr~rnuneDefic Syndromes 1988; 1:41-64 Pizzo PA, Eddy ,J, Falloon J , et al. Effect of continuous intravenous infusion of zidovudine (AZ'I') in children with asymptomatic H I V infection. N Engl J Med l988;3 19:889-96 Schmitt FA, Biglcy J W , McKinnis R, et al. Neuropsychological outcome of zidovudine (AZT) treatment of patients with AIDS and AIDS-related complcx. N Engl J Med l988;319: 1573-8
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59. 60. 61. 62.
agnosis before serological testing for the human immunodeficiency virus. Am J Psychiatry 1990;147:8993 Miller D, Acton TMG, Hedge B. T h e worried well: their identification and management. J R Coll Physicians Lond l988;22: 158-65 Cummings MA, Cummings KL, Rapaport MH, et al. Acquired immunodeficiency syndrome presenting as schizophrenia. West J Med 1987; l46:6 15-618 Holmes VF, Fernandez F, Levy JK. Psychostimulant response in AIDS-related complex patients. J Clin Psychiatry 1989;50:5-8 Fernandez F, Adams F, Levy J K , et al. Cognitive impairment d u e to AIDS-related complex and its response to psychostimulants. Psychosomatics 1988;29:38-46
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54. Fishman B, Perry S, Jacobsberg L, Frances A. Psychological factors predicting distress after HIV testing. Fifth International Conference o n AIDS, Montreal, Canada, J u n e 1989 55. Jadresik D, Riccio M, Hawkins D, et al. Impact of HIV diagnosis on mood-St. Stephen's cohort study. Fifth International Conference o n AIDS, Montreal, Canada, J u n e 1989 35. Korniewicz D. Psychosocial adaptation among HIV positive patients. Fifth International Conference o n AIDS, Montreal, Canada, J u n e 1989 57. Atkinson J H , Grant I , Kennedy CJ, et al. Prevalence of psychiatric disorders among men infected with human immunodeficiency virus: a controlled study. Arch Gen Psychiatry 1988;45:859-64 58. Perry S, Jacobsberg LB, Fishman B, et al. Psychiatric di-
10,NO. 3 SEPTEMBER 1990
The Neuropsychiatry of Human Immunodeficiency Virus Igor Grant, M.D., F.R.C.P.(C)
NEUROGENIC PHENOMENA Neurogenic sequelae are those that can be attributed to direct central nervous system (CNS) disturbance produced by HIV-I, other infections, neoplasia, or vascular diseases consequent on progressive immunodeficiency, or adverse effects of treatment. Some of the principal causes are summarized in 'Table 1. 'l'he earliest reports of neurogenic consequences appear to be have been those of Horowitz et aP and Britton et al."The former investigators observed a neurologic disorder that included mental status disturbance in seven of nine patients with cytomegalovirus (CMV) retinopathy. T h e latter de-
Table 1. Neurobehavioral Disorders Associated with HIV-I Infection I. Neurogenic A. Primary neurogenic disorder 1. Mild cognitive disorder due to HIV-I 2. Dementia due to HIV-I (AIDS dementia complex) B. Secondary neurogenic disorders Other hfections a. Viruses-cytomegalovirus (CMV), herpes viruses, papovavirus b. Protozoa-Toxoplasma gondii c. Fungi-Cryptococcus neoformans d. Bacteria-Mycobacteria, including M. tuberculosis, M. avium Neoplasia a. Primary Lymphoma Kaposi's sarcoma b. Metastatic tumors Cerebrovascular disease-strokes, vasculitis Delirium or mild cognitive impairment from systemic disease Hypoxemia Metabolic derangement Iatrogenic illness a. Antiretroviral agents Mania, "Rebound" encephalitis from zidovudine b. Other treatments, such as drugs with psychopharmacologic side effects II. Psychogenic A. Adjustment disorders, including "worried well" syndrome B. New onsets of major psychiatric disorders 1. Anxiety disorders 2. Mood disorders C. Reactivation or continuation of preexisting disorders 1. Anxiety disorders 2. Mood disorders 3. Schizophrenia 4. Substance abuse
Department o f Psychiatry, University of' California at San Diego, and Psychiatry Service, San Diego Veterans Administration Medical Center, San Diego, Califbrnia Reprint requcsts: Dr. Grant, Dept. o f Psychiatry ( M - 0 0 3 ) , University of' California at San Diego, La Jolla, C A 92093 Copyright 1990 by T h i e n l e Medical Publishers, Inc., 381 Park Avenue South, New Y o r k , NY 10016. All rights reserved.
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Commencing in the early 1980s, infection with type I human immunodeficiency virus (HIV-I), the causal agent of acquired immune deficiency syndrome (AIDS), has brought to the fore a new and growing source of neuropsychiatric morbidity, affecting especially young and middle-aged adults. Elsewhere, we have discussed the evolution of such neuropsychiatric phenomena in relation to the natural history of HIV disease' and have suggested that the terms "neurogenic" and "psychogenic" may offer a convenient shorthand to refer to the two basic etiologies of such phenomena.' In this article I shall summarize some of the concepts we articulated earlier, while providing an update based on new research that has emerged in the interim.
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scribed psychosis and dementia in three of' four im- illustrating some of these HIV-associated brain munosuppressed patients with neurologic disease. changes. T h e pathogenesis of HIV-related brain disBoth groups suggested that CMV might be one of ease is poorly understood. For example, even durthe causal agents of the encephalopathic process. T h e first systematic autopsy-based study of ing the medically asymptomatic phase of HIV inCNS complications was reported by Snider et fection (that is, long before a person develops aL5 In 18 of 50 brains of patients dying from symptoms of ARC or AIDS), as many as 50% AIDS, these investigators found neuropathologic of such infected individuals undergoing lumbar evidence of what they termed "subacute encepha- puncture yield evidence of HIV presence in the celitis." Many of these patients had cognitive impair- rebrospinal fluid (CSF).1"'5 Furthermore, other ment, mood disturbances, and problems in activi- indicators of CSF and brain envelope infection ties of daily living prior to death. Furthermore, tend to get more pronounced as the disease there was evidence of brain atrophy on computed progre~ses.l"~'For example, CSF protein, antiHIV-specific IgG (indicating intrablood-brain bartonlographic (CT) scanning. The first comprehensive description of the en- rier synthesis of antibody), pleocytosis, and oligocephalopathic process associated with AIDS came clonal bands all increase as a function of length of from the Memorial Sloan-Kettering group headed infection.'" Despite this evidence of ubiquitous penetraby Richard Price. These investigators coined the termed "AIDS dementia complex" (ADC) to de- tion of HIV into the CSF, there is, at present, poor scribe the neurologic, cognitive, and behavioral clinicopathologic correlation. For example, an ascomplications of late-stage AIDS.6 Although this sociation between recovery of HIV from the CSF term has been heuristically useful, it is limited by and neuropsychologic (NP) abnormality has not the fact that some people with HIV infection, par- been e~tabIished.'~.'"urthermore, magnetic resoticularly those with AIDS and AIDS-related com- nance imaging (MRI) changes show statistical asplex (AKC), can have subtle neurocognitive distur- sociation to NP deficits in some studies'Qut not bances short of the usual meaning of the term others.In An additional problem is that neurons "dementia." For this reason, we have suggested themselves are not commonly infected by HIV; that the term "neurobehavioral disorder associated rather, the HIV in infected brains tends to be localized in mononuclear cells, glia, and endothelial with HIV" might be more appropriate.' cells."' While the CD4 receptor appears critical to entry of HIV into monocytes and lymphocytes, the same has not been established for cells from neural lines. Indeed, some data indicate that the ROLE OF HIV IN CD4 receptor is not involved in entry of HIV into NEUROBEHAVIORAL DISORDER neural and muscle cells; this observation raises the Until the mid-1980s, it was commonly as- possibility that other receptor sites may be imporsumed that the organic mental disorder associated tant.'' Thus, the mechanism of brain damage by with AIDS resulted from opportunistic infections and other influences consequent on progres- HIV remains obscure. Since, at present at least, it sive immunodeficiency. In particular, CMV was does not appear that entry of virus into neurons is principally responsible, it has been suggested that strongly implicated." With the discovery of HIV-I, it became clear neurons may suffer through sort of "bystander" efthat this retrovirus itself was capable of invading fect. For example, it may be that infected macrothe CNS.7.8 Virions, thought to be HIV-I, have phages within the brain secrete products that are been visualized on electronmicroscopic study of toxic to the neurons; alternatively, viral constituthe brain, and HIV products have been recovered ents such as gp120, which binds to CD4 receptor sites, might also have homology with neurotrophic through in situ hybridization studies.' There appears to be a predictable neuro- peptides, such as vasoactive intestinal peptide. pathologic picture associated with HIV infection of Conceivably, constituents such as gp120 may octhe brain. Among the commonest findings, whose cupy sites critical to the trophic function of such specificity is still unknown, is "myelin pallor," seen peptides. Another possibility is that HIV, in comparticularly in the centrum semiovale. Addition- mon with certain other viruses, may cause disturally, the brains of persons dying with an AIDS- bance in tryptophan metabolism, leading to proassociated dementing disorder typically show duction of toxic metabolites such as quinolinic acid. microglial nodules, necrotic foci, foci of demyeli- Some reports suggest that concentration of' CSF nation, and collections of multinucleated giant quinolinic acid is related to degree of neurocogni268 cells.q- '* Figures 1A and 1B are photomicrographs tive impairment in HIV-infected person^.^"
+
.'"
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Figure 1. A: Hematoxylin and eosin-stained, paraffin embedded section of AlDS brain tissue. A large microglial nodule is present in the center of the section (surrounded by three arrows). Numerous elongated microglial nuclei are present both within the nodule and in the surrounding tissue (arrowheads). Original magnification x 600. B: HIV p24 immunoperoxidase-stained, paraffin embedded section of AlDS brain tissue. Several large multinucleated giant cells (surrounded by arrows) contain black, amorphous immunoprecipitate of density similar to that of the oval nuclei. Numerous mononuclear macrophages (arrowheads) are distributed throughout the tissue. Original magnification x 300. (Photomicrographs courtesy of Clayton A. Wiley, M.D., Ph.D., Dept. of Pathology, University of California, San Diego.)
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NATURAL HISTORY OF NEUROBEHAVIORAL DISORDER The evolution of neurobehavioral changes remains imperfectly understood. Neurocognitive disturbances have been reported in 29 to 87% of patients with frank AIDS, and 40 to 50% of patients with ARC.2,"4,2"m ong patients with AIDS, approximately one third of those living long enough will develop actual clinical signs of dementia.24,'"It is estimated that an additional third will have deficits on NP testing, indicating CNS disturbance insufficiently severe to make the diagnosis of dementia.24T h e incidence of dementia in patients with AIDS who were neurologically asymptomatic at the time of diagnosis has been estimated at 14% ann~ally.~~ When and how often the earliest signs of CNS involvement can be detected remains a matter of hot debate. Early on, our group suggested that HIV-infected persons who are either medically asymptomatic, or whose symptoms are mild enough not to qualify them for the diagnoses of ARC or AIDS, nevertheless can sometimes manifest subtle NP deficits.'VOther early reports reached the conclusion that HIV seropositive asymptomatic individuals were not at increased risk for NP di~turbance.~" A review of over 20 neurobehavioral studies that had been either presented or published by early 1990 revealed that roughly half suggested some increased risk for neurobehavioral disorder in the seropositive asymptomatic phase, while the remaining half found no differences between asymptomatic seropositives and appropriately matched seronegative controls.' Despite this, opinion among marly workers in the field appears to have swung to the notion that the seropositive asymptomatic individual is at no (or extremely minimal) increased risk for neurobehavioral disturbance. This view has been supported largely by three influential investigations. T h e first, emerging from the Multicenter AIDS Cohort Study (MACS) conducted in the United States concluded, on the basis of brief NP assessment of 727 HIV seropositive asymptomatic men and 769 homosexual controls, that the rates of NP disturbance were equal in the two groups (5.5% versus 3.9%)." Additional studies with the Baltimore sample of the MACS cohort noted no MKI differences between asymptomatic seropositives and seronegatives.18 A second study, emerging from the United States Air Force, reached the same conclusion." A study from the Centers for Disease Control (CDC) and San Francisco cohorts, which involves 100 seropositives and 157 sero270 negatives, also failed to detect NP differences be-
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tween the two groups, although the rate of NP impairment in patients with ARC was 31 to 4476, depending on extent of NP testing p e r f ~ r m e d . ~ ~ Although the results of these three large studies, and several other smaller ones,l provide reassurance that gross NP impairment is unlikely to be seen in a cohort free from other medical symptoms of HIV infection, it is probably premature to dismiss the possibility that subtle evidence of CNS involvement can be present prior to a person's reaching ARC or AIDS. Studies from a number of investigative groups continue to suggest that there may be NP,32-97e l e c t r o p h y ~ i o l o g i c and , ~ ~ ~brain~ imaging difference^""^' between some groups of asymptomatic seropositives and appropriately matched controls. Furthermore, the early presence of CSF abnormalities, including ability to culture HIV in about 50% of asymptomatic seropositives, plus the apparently progressive nature of CSF changes, strongly suggests early presence of HIV in the CNS. It is possible, of course, that HIV is "neurotropic," (has a predilection to enter the CNS) but not "neuropathic," (does not cause pathologic changes) until immunodeficiency becomes profound. Another line of evidence that suggests we should be cautious in our conclusions comes from early longitudinal data. Whereas a 2-year followu p of the MACS sample has not demonstrated any changes on the five NP tests employed,4-'data from our group indicate that about a quarter of seropositive men who do not qualify for the diagnosis of AIDS or ARC are rated as neuropsychologically more impaired after a 1-year follow-up. T h e rate of NP worsening in patients with AIDS and ARC appears to be closer to 40% after I year.44 In sum, at the present state of our knowledge, it is recommended that clinicians and investigators keep an open mind regarding the incidence and prevalence of CNS involvement in the earlier phases of HIV-I infection. While it is clear that most seropositive individuals who have not progressed to ARC and AIDS are free of' szgnzficant cognitive loss, this does not preclude the possibility that subtle changes, either static o r slowly progressive, may be confirmed using more sophisticated diagnostic techniques.
CLINICAL FEATURES OF HIV NEUROBEHAVIORAL DISORDER Early subjective complaints that might suggest CNS involvement include forgetfulness, inattention, and subjective sense of slowness and inefficiency. Sometimes these complaints are accompanied by a sense of fatigue and excess sleepiness.
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Polysomnographic studies of HIV-infected patients have indicated disturbance in sleep architecture and excess stage IV sleep late in the sleep cycle of some HIV-infected person^.^' Comprehensive NP testing may reveal difficulties with learning of new material (both verbal and nonverbal), impaired abstracting ability, and, in particular, reduction in speed of information processing and psychomotor ~ p e e d . ' ~ , ' "At , ~ ~this stage, the subjective complaints may be difficult to differentiate from those attributable to depression and anxiety, both of which also occur more frequently in seropositive individuals (see later). NP testing, properly performed and interpreted, should, however, resolve the issue, since there is little evidence that mild or moderate mood disorder has significant impact on such test^.'^,^^.^" If the disorder progresses to a clinically symptomatic phase, which is seen primarily in patients with frank AIDS, then the more typical features of ADC, as described by Navia et al,%ay be observed. These include substantial cognitive and psychomotor slowing, defects in attending, and disturbance in memory. There can be accompanying changes in mood, which will range from depression to apathy. Occasionally, in later stages of ADC, there may be labile affect, irritability, and violent outbursts. As the dementia evolves, a person may become frankly disoriented, develop language disturbances (such as naming difficulties), and perceptual motor disturbances, in addition to worsening amnesia, inattention, and disturbance of abstracting ability. Neurophysical signs may include some weakness and incoordination, beginning in the lower limbs and later evident in the upper limbs. Peripheral neuropathy, and other neurologic signs (for example, autonomic neuropathy, ophthalmo1,ogic disease) can also complicate the later stages of AIDS but are apparently not regularly associated with severity of dementia. In the latest stages of dementia, a person may progress to being bed bound, disoriented, stuporous, and incontinent. Generally speaking, the onset of clear clinical signs of dementia is a poor prognostic indicator. Many patients die within 6 months of onset of dementia.27 Ancillary examination of persons with clinical dementia can reveal slowing of electroencephalographic background rhythm," disturbed smooth pursuit eye rno~ement,~%nd several abnormalities on brain imaging. More specifically, AIDS dementia is accompanied by evidence of sulcal and ventricular dilation on C T ~canning,~',''" as well as similar indicators of "brain shrinkage" on MKI."' MRI appears to be more sensitive to earlier signs of CNS involvement, revealing areas of hyperintensity (especially on T, weighted images) in the white
matter, as well as in subcortical gray. Such hyperintensities, which may represent areas of demyelination or necrotic foci, are poorly visualized on CT, although larger areas may be seen as areas of relative radiolucency without mass effect." In more advanced cases, confluent areas of high signal suggestive of an encephalitis can be seen on MKI (Fig. 2). Whether focal hyperintense areas gradually progress to the "encephalitic" picture is not presently known. In terms of differential diagnosis, although it is difficult to be certain, while the patient is living, whether dementia can be attributed solely to HIVI infection, the presenting symptoms can often give good clues as to presence of some of the more common secondary infections. For example, cerebral toxoplasmosis usually presents with rapidly declining mental status and clouding of consciousness. Headache and lateralizing neurologic signs are common. C T scan is often helpful, revealing multiple ring-enhancing lesions. MRI almost always demonstrates multiple masses of high signal intensity on the 'I-, weighted image. Cryptococcal meningitis is usually heralded by headache, stiff neck, fever, photophobia, clouding of consciousness, and other signs of meningitis. Confirmation is by visualizing Cryptococcus neoformans on India ink staining of CSF, as well as obtaining positive culture and antigen from the CSF. Brain imaging tends to be nonspecific, with some cases of atrophy and rare focal lesions. Generally speaking, large focal abnormalities on C T or MRI suggest toxoplasmosis, lymphoma, or progressive multifocal leukoencephalopathy (PML-papovavirus infection). Atrophy or diffuse areas of high signal on MRI may be due to CMV as well as to HIV-I.51 T h e response of' HIV-associated CNS complications to antiretroviral treatment also remains a matter of controversy. Several reports indicate that children infused with zidovudine (AZT) respond favorably, both in terms of improved developmental milestones, NP performance, and some reversal in brain-imaged abnormalities." Also, data from adults undergoing the AZ'I' licensing trial suggest some NP improvement in those receiving active treatment."" limited series from our group indicated little difference in the incidence of dementia in previously nondemented AIDS and ARC patients receiving AZ'I' or a placebo-the 2year cumulative incidence was 2896, with essentially all persons being crossed over to AZT after the first 6 month^.'^ Thus, at present, it seems prudent to maintain an attitude of cautious optimism that AZ1' does retard the progression of neurogenic complications; at the same time, it does not appear to confer longlasting or universal protection.
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27 1
B Figure 2. Two magnetic resonance brain scans of a 40year-old man with HIV-associated neuropsychologic deficit. (At time of scanning, this patient was diagnosed as having AIDS and had difficulties with speeded information processing, abstracting ability, complex perceptual-motor tasks, and learning of verbal material.) A: This relatively TI weighted axial section shows dilation of lateral ventricles, sulcal enlargement, and a periventricular area of high signal. B: This axial view shows bilateral areas of high signal in the centrum semiovale.
NEUROBEHAVIORAL DISORDERS OF PSYCHOGENIC ORIGIN A fundamental premise of modern neuropsychiatry is that moods and behaviors have biologic underpinnings. Hence, the present use of the term "psychogenic" should not be construed as harkening back to Cartesian or psychoanalytical mindbody dualism. Rather, the term is meant as a shorthand to describe disturbances in mood and behavior that cannot be attributed to brain disease caused by HIV or other neuropathologic processes attendant on progressive immunodeficiency or its treatment.
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One concern expressed commonly in the early days of'the AIDS epidemic was that there would be marked increase in psychologic disturbance related to the issue of serotesting, knowledge of serostatus, or realization that one has AIDS. Interestingly, such predictions have not been borne out. Kecent studies of persons given the news that they were seropositive have confirmed that the period immediately surrounding serotesting is accompanied by an increased prevalence of anxiety, depression, and sometimes a sense of alienat i ~ n . ~ " -Such " ~ reactions appear to be self-limited in most instances, however. Preliminary data from follow-up of those informed of their serostatus indicate that such psychologic distress tends to abate by 6 months. j4." Furthermore, it is now clear that mood and other kinds of behavioral disturbances in seropositive individuals need to be understood in the context of an individual's own lifetime history of psychiatric disorder. As an example, studies involving structured diagnostic psychiatric interviews indicate that current prevalence (defined as either l-month or 6month prevalence) of anxiety and depressive disorders among seropositive individuals who do not have AKC or AIDS runs in the order of 10 to 20%.',"7It is important to note, however, that the rate among seronegative persons "at risk" to become infected (in this case, seronegative homosexual men) was comparable to the seropositives, and substantially higher than that for those "not at risk" (that is, sociodemographically matched heterosexual men)."," The implication is that "at risk" persons have higher background rates of mood disturbance; therefore, finding an increase in mood disturbance in seropositives need not necessarily mean that H I V status is solely responsible. This interpretation is given further credence by the observation that syndromic depression and anxiety are only modestly elevated in persons with AKC and AIllS compared with the incidence of those mood disturbances among asymptomatic seropositive~.Another way of looking at this is that people, in general, are remarkably resilient in the face of knowledge of seropositivity and realization of the possibility of a fatal illness. To the extent that they experience increases in psychopathology in relationship to these events, at least some of this increase can be seen as reflecting recrudescence of longer standing propensities to disturbance in mood and behavior. While prevalence of mood and behavioral disturbances does not appear to be as much increased as might have been expected given the seriousness of HIV infection, there is a small subgroup of individuals, known as the "worried well,"" who report anxiety, depression, obsessional rumina-
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N E U K O P S Y C H I A T K Y OF H I V INFECTION-GRANT
SUMMARY With the advent of HIV infection, a new causal group of rieurobehavioral disorders has emerged. 'l'hese are the neurogenic and psychogenic neurobehavioral disturbances associated with HIV. Neurogenic disorders are those caused by the direct effects of HIV on the CNS, or by other infectious agents, neoplasms, vascular events, or side effects of biologic treatments in HIV-infected persons. Psychogenic disorders include anxiety, depression, adjustment reactions, and other behavioral disturbances related to knowledge of HIV seropositivity and recognition of being afflicted with a serious illness. In many instances, the psycho-
genic disorders appear to represent recrudescences of preexisting psychopathology. l'he comprehensive management of the patient with HIV infection requires early recognition and proper treatment of such complications.
REFERENCES 1. Grant I, Atkinson J H . Neurogenic arltl psychogenic hehavioral correlates of' HIV irtf'ection. In: Waksman BH, ed. Imnlunologic mechanisms in neurologic and psychiatric disease. New York: Raven Press, 199O:29 1-304 2. Grant I, Atkinson .JH. T h e evolution of. neurobehavioural complications of HIV inlectiort. Psychol Metl 1 WO;2O:Itt press 3. Horowitz SL, Benson DF, Gottleib MS, et al. Neurological complications of gay-related imrrlurlodeficiency disortier (Abstr.) Ann Neut-01 1982; 12:XO 4. Britton CB, Marquardt MU, Koppel B, et al. Ncurological cornplications of the gay immunosuppressed syndrome: clinical and pathological features. (Abstt-.)Artn Neurol 1982; l2:8O 5. Snider WD, Simpso11 D M , Nielsen S, ct al. Neurological complication of acquired itnrnune deficiency syrtdrome: arlalysis of' 50 patients. Ann Neurol 1983; 14:403-18 6. Navia BA, .Jordan BD, Price KW. 'l'he AIIjS dementia complex: I. clinical features. Ann Neurol 1!)86;19: 5 17-24 7. Levy JA, Shimat)ukuro,J,flollantler H , et al. Isolation of AIDS associated retroviruses ft-otn cerel,rospinal fluid and brain of patienrs with neurological symptortts. Lancet 1985;2:586-8 8. H o DD, Rota .1'R, Schoolcy KT, et al. Isolation ot H.I'LV111 lrom cerebrospinal fluid and neural tissues of patients with neurologic syndromes related t o the acquired immunotlcficiet~cysyndrome. N Engl ,I Med 198533 13: 1495-7 9. Price KW, Brew B, Sidtis J , et al. 'l'he brain in AIDS: central nervous system IIIV-I infection a n d AI1)S tletnentia complex. Science 1988;239:586-92 10. Vintet-s HV, Kwok hlK, H o HW, et al. Cytomegalovirus in the nervous system of' patients with the acquired immune deficiency syndrotr~e.Hrain 1989; 112:245-68 I I. Lantos I'L, McLaughlin J E , Scholtz CL, ct al. Neuropathology of the brain in HIV infection. 1.ancet 1989; 1 :3N-11 12. Gray F, Fenelon (;, Gherarcli K, er al. Neuropathologic study of 15 cases of' multinucleated giant cell encephalitis in acquired imn~urtodeficiet~cy syndrome (AIDS). Ann Pathol 1988;8:281-9 13. McArthur JC, Cohen BA, Farzedegan H , et al. Ccrebrospinal fluitl abnormalities in homosexual men with and without neuropsychiatric findiugs. Ann Ncurol 1988; 23(Suppl):S34-7 14. Grant I, Hesselittk .J,Jernigan I', et al. Ncuropsychology and magnetic resonance imaging in HIV infection. Presented at Fourth Internatiorral (:onference o n A1 DS, Stockholm, Sweden, I988 15. Sonncrborg A B , Ehrnst A(:, Bergdahl SKM, et al. HIV isolation from cerebrospinal fluitl in relation to irnn~unologicaldeficiency and neurological symptoms. AIDS 1988;2:8Y-93 16. Marshall DU', Brey KL, Butzin (;A, et al. Logitudinal (;SF cell counts and protein levels in 258 HIV infected US Ail- Force Personnel. Fifth International Conference o n AIDS, Montreal, Canada, J u n e 1989 17. MacArthur J C , Cohcn HA, Selnes Oil, ct al. Low prevalence of' neurological and neuropsychological abnormalities in otherwise healthy HlV-I-infected intlividu-
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tion, and phobic symptoms even though they are healthy physically. Indeed, some of the "worried well" are actually seronegative, but continue to believe that they may be infected, and therefore interpret minor symptoms as indicating serious disease. Some such individuals undergo repeated serologic testing and, despite this, cannot convince themselves that they are in good health. The treatment of "psychogenic" disorders associated with HIV follows much the same principles as the treatment of psychopathology generally. For milder symptoms of anxiety and depression, supportive counseling, cognitive therapy, and expressive psychotherapy can be beneficial. More serious forms of depression may require antidepressant treatment. For those patients with more advanced HIV infection, or when neurogenic complications coexist, care should be taken to prescribe lower doses than usual, at least to begin with. Susceptibility to central anticholinergic syndrome may be increased in such persons. Individuals requiring anxiolytics should also be treated with lower doses of such agents if they are medically ill or show signs of CNS disturbance. Once again, excess sensitivity to the sedativehypnotic effects of these drugs has been reported. Psychotic symptoms are an uncommon complication, usually signifying evolving dementia. Symptoms can include suspiciousness, hallucinations, and severe agitation. Occasionally, the first presentation of AIDS can be as a schizophrenia-like syndrome."" T h e syndrome can be managed with neuroleptic drugs. Low doses of neuroleptics should be used to begin with because of tendency toward excessive sedation and experience of extrapyramidal symptoms. Another late complication is severe apathy and withdrawal, often combined with cognitive impairment. Methylphenidate has been reported to be beneficial in preliminary reports."',""
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