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Rev. Med. 1990. 41: 159-68
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CENTRAL NERVOUS SYSTEM
Annu. Rev. Med. 1990.41:159-168. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 01/29/15. For personal use only.
EFFECTS OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 11 T. Peter Bridge, M.D., and Loring J. Ingraham, Ph.D.
Division of Intramural Research and Laboratory of Psychology and Psychopathology, National Institute of Mental Health, Bethesda, Maryland 20892 KEY
WORDS:
AIDS, HIV-I, dementia, neuropsychiatry, neuropsychology.
ABSTRACT Following its early entry into the central nervous system (eNS), HIV-l alters cerebral cell architecture and may subsequently affect higher cog nitive functions, leading eventually in some patients to HIV-1 encepha lopathy. The eNS may also be the target of opportunistic infections and malignancy secondary to HIV-I immunosuppression. Studies at the cellular, anatomical, and behavioral levels present evidence for significant involvement of the eNS in HIV-l disease, while initial reports of treatment strategies hold promise for providing some amelioration in affected indi viduals. INTRODUCTION
Altered central nervous system (eNS) structure and function accompany human immunodeficiency virus type 1 (HIV-l ) infection. From early case reports (1, 2) to recent reviews (3-7), the description of neuropsychiatric
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changes that occur over the course of HIV-I disease is convincing evidence of the potentially profound effects of HIV-1 infection on the human CNS. Disordered mood states were initially attributed to the affected indi viduals' perceptions of being fatally ill, while observed cognitive and psy chomotor abnormalities were considered sequelae of CNS opportunistic infection and neoplasms. Demonstration that HIV -1 enters the brain (8), even before the appearance of any of the classical symptoms of the illness (9), suggests that observed CNS functional impairments may be the result of direct infection of the brain by HIV-1. Following a brief epidemiological overview, recent studies that address the role of HIV-l in the eNS from a cellular, anatomical, or behavioral perspective are reviewed below. Some brief considerations of the clinical management of HIV-I-related CNS pathology follow, as do comments on some as yet unresolved questions of HIV-I-CNS interactions. EPIDEMIOLOGY AND INCIDENCE
The Centers for Disease Control estimate 1.0 to 1 .5 million individuals are infected with HIV-l in the United States ( 1 0, 11), and the yearly number of new cases of AIDS is projected to increase from 39,000 in 1 988 to 80,000 in 1992, with 365,000 individuals diagnosed as having AIDS by the end of 1992 (1 2). That the majority of these individuals will experience CNS involvement starkly presents the magnitude of the effect of HIV-1 disease on the human eNS. Navia, Price, and their colleagues defined a pattern of impairment they labeled the AIDS dementia complex (ADC) (13, 1 4) in a sample of patients referred to a neurologic clinic. They noted that neurologic changes were the first sign of HIV-I infection in one third of their sample of 70 patients, while one half of the sample went on to develop severe generalized neuropsychiatric impairment within two months of the first cognitive symptom of ADC. Selection for referral for neurologic evaluation in the Navia and Price sample may have overestimated the prevalence of neurological dysfunction associated with HIV-1 infection in all HIV-I patients, but subsequent work (4, 1 5- 1 8) demonstrated convincingly that cognitive changes are present in a substantial portion of individuals with AIDS and may be the sole presenting feature of HIV-l infection ( 1 9-21 ). The Centers for Disease Control 1 987 amendment of the case definition of AIDS to include those individuals presenting solely with HIV sero positivity and dementia ( 22) formally recognizes CNS dysfunction as one of the defining manifestations of HIV-l disease. Ten percent of HIV-l infected individuals may have HIV-1 encephalopathy as the first presenting
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sign of AIDS, while many more infected individuals go on to develop HIV I encephalopathy or neuropsychiatric abnormalities after the onset of AIDS.
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ETIOLOGY
Multiple mechanisms are possible for CNS changes associated with HIV I infection. There may be direct infection and associated cell death, toxicity from by-products of HIV-I-infected cells in the CNS, cell death or toxicity due to sequelae of opportunistic infections of the CNS, and impaired CNS function due to reduced functional capacity of other essential organ systems. CNS Infection by HIV-J
HIV-I has been isolated from the cerebrospinal fluid of seropositive but otherwise asymptomatic individuals (23), which indicates that the virus
may enter the CNS early in the course of infection. Evidence of early intrathecal immune response viral isolation (24-26) confirms the existence of HIV-I within the blood-brain barrier during the initial stages of HIV disease. Pert and her colleagues (27, 28) have mapped the location of gp-120, the entry protein for HIV-I (29) in brain, confirming the ability of HIV-I to bind within the CNS. Opportunistic Infections and Malignancy
While this review focuses on the direct effects of HIV-I on the human brain, there are many other sources of HIV- I-related CNS pathology. A number of the opportunistic infections seen in AIDS may substantially affect CNS function. Cytomegalovirus (30, 31) and toxoplasmosis (32) have been implicated, as well as more unusual cerebral infections (33, 34). Malignancies are another potential source of CNS dysfunction in HIV I infection. Cerebral lymphomas (35) as well as less common malignancies (36, 37) have been identified as CNS concomitants of HIV-I infections. Interested readers are referred to recent reviews focusing on the incidence and treatment of HIV-I-related malignancy (38, 39). PATHOLOGY Cytopathology
It is likely that HIV-I enters the CNS through a vector of infected mono cyte/macrophage cells (40). Within the CNS, hematopoietically derived glial cells and giant multinucleated cells have been found to contain HIV1 viral material, while such material is rarely, if ever, found within neuronal
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cells (19, 41). Dysfunction of neuronal cells in the absence of direct infec tion is most likely the result of a neurotoxic effect associated with HIV-I infection, e.g. the direct cytopathic effect of gp-120 on murine hippocampal cell culture (42).
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Neuroanatomy
The brains of HIV-I-infected individuals exhibit substantial neuro pathology (14, 43). A recent unselected series found abnormalities in the majority of brains on postmortem examination, with evidence of neo plasms, opportunistic infections, vascular lesions, nodular encephalitis, and HIV encephalitis (44). Magnetic resonance imaging (MRI), which is useful in diagnosing space occupying lesions in HIV-l disease (45) has also shown white matter hyperlucencies in TI/T2-weighted images of the brains of some HIV-l patients. While such hyperlucencies are not as yet diagnostically specific to HIV-I-related neuropsychiatric impairment, future use of low magnetic field MRI may prove more sensitive to HIV-I-related changes (46). In general, reports of other neurodiagnostic imaging techniques have shown general decrements rather than changes specific to HIV-l (47, 48).
To date no HIV-I-specific gross anatomic localization within the CNS has been identified; infected monocyte/macrophage cells may be disseminated throughout the CNS. Behavioral Pathology HIV-I ENCEPHALOPATHY AIDS dementia complex (4, 13, 14) defines a syndrome characterized by HIV-l infection, progressive cognitive loss, and the frequent presence of motor symptoms. Onset is usually insidious, with subjective initial complaints of forgetfulness, poor concentration, and mental slowing. Neuropsychological invcstigation of impairment associated with HIV I infection (15-18, 49) reveals a range of consequences of HIV-I infection, including deficits of memory, attention, and concept formation. The natu ral history of ADC is under active investigation, with current debate focused on how early, how severely, and how frequently HIV-I-related cognitive and behavioral changes occur (50-53a). Currently, predictive relationships between early immunological changes and the onset of HIV1 encephalopathy have not been demonstrated. PSYCHIATRIC CONCOMITANTS Psychiatric morbidity is also a concomitant of HIV-I infection of the CNS. While an episode of major depression following diagnosis of a fatal illness such as AIDS is not unexpected, there may be additional evidence for HIV-I-related psychiatric morbidity in
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case reports of hypomania (54) and psychosis (55, 56). Some observed psychiatric morbidity may also be a side effect of the potent medication used in the treatment of HIV-I disease (57). Regardless of the cause, the high morbidity for psychiatric disorders among individuals with AIDS (58) warrants careful evaluation throughout the course of illness. In addition to the sensitive monitoring and treat ment of individual patients' psychiatric symptomatology recommended above, a variety of approaches to the assessment of behavioral mani festations of HIV-I infection of the eNS are possible. In the later stages of infection and when gross pathology is evident, the traditional mental status examination may adequately characterize the extent of dysfunction and document the need for neurological consultation and referral. Early in the course of HIV-l infection, patients' complaints may be primarily subjective and confounded by affective reactions to recently
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ASSESSMENT TECHNIQUES
discovered seropositivity and the presence of initial symptoms of immune
dysfunction. At this time, neuropsychological evaluation can assess the level of intact function and serve to reassure patients of existing strengths, while identifying areas of potential weakness. Repeated assessments can help in monitoring the course of illness and the reaction to therapeutic regImens. While a wide range of neuropsychological instruments is available, the choice of assessment tools for a particular individual is best made by the neuropsychologist after a preliminary evaluation of the patient. For research purposes, and to provide cross-site comparison, the consistcnt use of basic core instruments is valuable. Suggested instruments include the Vocabulary, Block Design, and Digit Span subtests of the Wechsler Adult Intelligence Scale-Revised (59); immediate and 30-minute delayed recall of the Logical Memory and Visual Reproduction subtests of the Wechsler Memory Scale-Revised (60); the Trail Making Test (61); and the Finger Tapping test (62).
APPROACHES TO MANAGEMENT
Treating the eNS effects of HIV-1 is part of the overall management of HIV-I disease. A primary effort must be directed against HIV-I itself, while treatment of opportunistic infections and neoplasms with impact on the eNS follows. In addition, careful monitoring of the potential effect of therapeutic agents on the eNS must be maintained; psychotherapeutic interventions and specific psychopharmacologic agents may be useful for some individuals.
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Antiretrovirals
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Reports in adults (63, 64) and children (65) suggest that treatment with the antiretroviraI3'-azido-3'-deoxythymidine (azidothymidine, AZT) may reverse some of the decrements on neuropsychological testing seen in HIV-l disease. These encouraging findings must be viewed with caution, however, because there have also been case reports of hypomanic response to this agent (66). Psychotropic Medication
HIV-l-infeeted individuals may exhibit increased sensitivity, including extrapyramidal toxicities, to conventional psychotropic agents (67, 68). When psychotropic medication is indicated, a reduced-dosage regimen similar to that in use in geriatric neuropsychopharmacology is recom mended. Initial reports indicate that psychostimulants may be helpful in some patients to improve the cognitive and affective deficits associated with ADC (69). In addition, as the CNS effects of HIV-l are more frequently recognized by clinicians alerted to their presence, more extended guidelines for management are being developed (57, 70-72). Novel Peptidic Agents
Psychoneuroimmunologic research has revealed shared peptidergic trans mitter/receptor mechanisms between the nervous and immune systems (73). Such shared mechanisms suggest that pharmacological manipulation of one system will also affect the reciprocal system. Novel treatment approaches are now being studied for their potential to modify the course of HIV-1 infection and its effects on the CNS (68, 74). CONCLUSIONS AND CONTROVERSIES
Both the structure and the function of the CNS may be altered by a variety of mechanisms following HIV-l infection, and the initial study of these processes has led to the development of promising neuropsychophar macological treatments. Clinicians' increasing awareness of the possible CNS effects of HIV-1 can contribute to earlier identification and effective treatment; concurrent clinical and laboratory investigation will also broaden our understanding and open new approaches for treatment. Two promising goals for continuing investigation are to confirm the mechanism (or mechanisms) of CNS cytotoxicity following HIV-l entry into the CNS and to map the distribution of such cytotoxicity. While the existence of CNS dysfunction secondary to HIV-1 infection
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in some individuals is not contested, debate continues over the incidence, onset, and course of such changes. Longitudinal studies will soon begin to present a picture of the natural history of HIV-I encephalopathy, and more importantly, report the most successful approaches to treatment of the many eNS sequelae of HIV-I infection.
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Literature Cited AIDS and human immunodeficiency virus infection in the United States: 1988 update. Morbid. Mortal. Wkly. Rep. 38(Suppl. S-4): 1-38 12. Centers for Disease Control. 1989. Mor bid. Mortal. Wkly. Rep. 38(Suppl. S-4):
1. Horowitz, S. L., Benson, D. F., Gottlieb, M. S., Davos, I., Bentson, J. R. 1982. Neurological complications of Gay Related Immunodeficiency Disorder. Ann. Neurol. 12: 80 2. Snider, W. D., Simpson, D. M., Nielson, S., Gold, J. W. M., Metroka, C. E., et al. 1983. Neurological complications of acquired immune deficiency syndrome: Analysis of 50 patients. Ann. Neurol. 14:
13. Navia, B. A., Jordan, B. D., Price, R. W. 1986. The AIDS Dementia Complex: I. Clinical features. Ann. Neurol. 19: 517-
3. Levy, R. M., Bredesen, D. E. 1988. Central nervous system dysfunction in acquired immunodeficiency syndrome. J. Acquired Immune Defic. Syndrome I: 41-64 4. Price, R. W., Brew, 8., Sidtis, J., Rosen blum, M., Scheck, A., ct al. 1988. The brain in AIDS: central nervous system HIV- l infection and AIDS Dementia Complex. Science 239: 586--92 5. Kennedy, P. G. 1988. Neurological com plications of human immunodeficiency virus infection. Postgrad. Med. J. 64: 180--87 6. Budka, H. 1989. Human immuno deficiency virus (HIV}-induced disease of the central nervous system: patho logy and implications for pathogenesis. Acta Neuropathol. 77: 225-36 7. Dalakas, M., Wichman, A., Sever, J. 1989. AIDS and the nervous system. J: Am. Med. Assoc. 261: 2396--99 8. Shaw, G. M., Harper, M. E., Hand, B. H., et al. 1985. HTLV-III infection in the brains of children and adults with AIDS encephalopathy. Science 227: 177-81 9. Marshall, D. W., Brey, R. L., Cahill, W. T., Houk, R. W., Zajac, R. A., et al. 1988. Spectrum of cerebrospinal fluid findings in various stages of human immunodeficiency virus infection. Arch. Neurol. 45 : 954--58 10. Centers for Disease Control. 1987. Human immunodeficiency virus infec tion in the United States: a review of current knowledge. Morbid. Mortal. Wkly. Rep. 36(Suppl. S-6): 1-48 11. Centers for Disease Control. 1989.
14. Navia, B. A., Cho, E., Petito, C. K., Price, R. W. 1986. The AIDS Dementia Complex: II. Neuropathology. Ann. Neurol. 19: 525-35 15. Joffe, R. T., Rubinow, D. R., Squillace, 8. S., Lane, C. H., Duncan, C. c., et al. 1986. The neuropsychiatric aspects of acquired immune deficiency syndrome (AIDS). Psychopharmacol. Bull. 22: 684--88 16. Ayers, M. R., Abrams, D. I., Newell, T. G., Friedrich, F. 1987. Performance of individuals with AIDS on the Luria Nebraska neuropsychological battery. Int. J. Clin. Neuropsychol. 9: 101-5 17. Price, R. W., Sidtis, J., Rosenblum, M. 1988. The AIDS dementia complex: some current questions. Ann. Neurol. 23: S27-S23 (Supp!.) 18. World Health Organization. 1988. Report of the Consultation Oil the Neu ropsychiatric Aspects of HIV Infec tion, Geneva, 14-17 March 1988. Geneva: WHO 19. Navia, B. A., Price, R. W. 1987. The Acquired Immunodeficiency Syndrome Dementia Complex as the presenting or sole manifestation of human immuno deficiency virus infection. Arch. Neural. 44: 65--66 20. Beckett, A., Summergrad, P., Man schreck, T., Vitagliano, H., Henderson, M., et a!. 1987. Symptomatic HIV infec tion of the CNS in a patient without clinical evidence of immune deficiency. Am. J. Psychiatry 144: 1342--44 21. Riccio, M., Thompson, C. 1987. AIDS and dementia. Br. J. Hasp. Med. 38: 11
403-18
5
24
Annu. Rev. Med. 1990.41:159-168. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 01/29/15. For personal use only.
1 66
BRIDGE & INGRAHAM
22. Centers for Disease Control. 1987. Revision of the CDC surveillance case definition for acquired immunodefi ciency syndrome. Morbid. Morral. Wkly. Rep. 36: IS-14S 23. Ho, D. D., Rota, T. R., Schooley, R. T., Kaplan, J. C., Allan, J. D., et al. 1985. Isolation of HTLV-III from cerebro spinal fluid and neural tissue of patients with neurologic syndromes related to the acquired immunodeficiency syn dromc. N. Engl. J. Med. 313: 149397 24. Goudsmit, 1., Epstein, L. G., Paul, D. A., van der Helm, H. J., Dawson, G. J., et al. 1987. Intra-blood-brain barrier
synthesis of human immunodeficiency virus antigen and antibody in humans and chimpanzees. Proc. Nat!. Acad. Sci.
USA 84: 3876-80 25. Elovaara, I., Seppala, I., Poutiainen, E., Suni, J., Valle , S. L. 1988. Intrathecal humoral immunologic response in neu rologically symptomatic and asympto matic patients with human immuno deficiency virus infection. Neurology 38: 1451-56 26. Chiodi, F., Sonnerborg, A., Albert, 1.,
Gaines, H., Norkrans, G., et al. 1988. Human immunodeficiency virus infec tion of the brain. I. Virus isolation and
27.
28.
29.
30.
dctcction of HIV specific antibodies in the cerebrospinal fluid of patients with varying clinical conditions. J. Neurol. Sci. 85: 245-57 Pert, C. B., Hill, J. M., Ruff, M. R., Berman, R. M., Robey, W. G., et al. 1986. Octapeptides deduced from the neuropeptide receptor-like pattern of antigen T4 in brain potentially inhibit human immunodeficiency virus receptor binding and T-cell infectivity. Proc. NaIl. Acad. Sci. USA 83: 9254-58 Pert, C B., Ruff, M. R. , Ruscetti , F., Farrar, W. L., Hill, 1. 1988. HIV re ceptor in brain and deduced peptides that block infectivity. In Psychological, Neuropsychiatric and Substance Abuse Aspects of Aids, ed. T. P. Bridge, A. F. Mirsky, F. K. Goodwin, pp. 73-84. New York: Raven Dalgliesh, A. G., Beverly, P. C. L., Clapham, P. R., Crawford, D. H., Greaves, M. F., et al. 19R4. The CD4 (T4) antigen is an essential component of the receptor for the AIDS virus. Nature 763-67 Mahieux, F., Gray, F., Fenelon, G., Gherardi, R., Adams, D., et al. 1989. Acute myeloradiculitis due to cyto megalovirus as thc initial manifestation of AIDS. J. Neurol. Neurosurg. Psy chiatry 52: 270-74
31. Vinters, H. V., Kwok, M. K., Ho, H. W., Anders, K. H., Tomiyasu, D., et al. 1989. Cytomegalovirus in the nervous system of patients with the acquired immune deficiency syndrome. Brain 112(part I): 245-68 32. Israelski, D. M., Remington, J. S. 1988.
Toxoplasmic encephalitis in patients
33.
34.
35.
36.
with AIDS. Infect. Dis. Clin. North Am. 2:429-45 Gilden, D. H., Murray, R. S., Wellish, M., Kleinschmidt-DeMasters, B. K., Vafai, A. 1988. Chronic progressive varicella-zoster virus encephalitis in an AIDS patient. Neurology 38: 1150-53 Jarvi k, 1. G., H esselink, 1. R., Wiley, C, Mercer, S., Robbins, B., et al. 1988. Coccidioidomycotic brain abscess in an HIV-infected man. West. J. Med. 149: 83-86 Anders, K. H., Latta, H., Chang, B. S., Tomiyasu, D., Quddusi, A. S., et al. 1989. Lymphomatoid granulomatosis and malignant lymphoma of the central nervous system in the acquired immu nodeficiency syndrome. Hum. Pathol. 20: 326-34 Tirelli, D., Vaccher, E., Zagonel, V., Rezza, G., Palmieri, G., et al. 1988.
Malignant tumors other than lymphoma
and Kaposi's sarcoma in association with HIV infection. Cancer Detect. Prevo 12: 267-72 37. Gasnault, 1., Roux, F. X., Vedrenne, C. 1988. Cerebral astroc ytoma in associ ation with HIV infection. J. Neurol. Neurosurg. Psychiatry 51: 422-24 38. Volberding, P. 1988. Treatment of malignant disease in AIDS patients. AIDS 2(Suppl. 1): S169-75 39. Munro, A. J., Stewart, J. S. W. 1989. AIDS: incidence and management of malignant disease. Radio/her. Oncol. 14:
121-31
40. Gartner, S., Markovits, P., Markovitz, D. M., Kaplan, M. H., Gallo, R. C., et al. 1986. The role of mononuclear phagocytes in HTL V -III/LAV infection. Science 233: 215--1 9 S., Gendelman, H. E., 41. Koenig, Orenstein, J. M., Dal Canto, M. C., Pezeshkpour, G. H., et al. 1986. Detec tion of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233:108993 42. Brenneman, D., Westerbrook, G., Fitz gerald, S., Ennist, D. L., Elkins, K. L., et al. 1988. Neuronal killing by the envel ope protein of HIV and its prevention by vasoactive intestinal peptide. Nature 335:639-42 43. McAllister, R. H., Harrison, M. 1. G.,
CNS EFFECTS OF HIV-l
Johnson, M. J. 1988. HIV and the ner vous system. Br. J. Hosp. Med. 40: 2126 Lantos, P. L., McLaughlin, J. E., Scholtz, C. L., Berry, C. L., Tighe, J. R. 1989. Neuropathology of the brain in HIV infection. Lancet I: 309-11 Post, M. J. D., Sheldon, J. J., Hensley, G. T.,Soila,K., Tobias,J. A.,et aI. 1986. Central nervous system disease in AIDS: Prospective correlation using CT, MRI, and pathologic studies. Radiology 158: 141-48 Sonnerborg, A. 8., Ehrnst, A. c., Berg dahl, S. K. M., Soila, K., Tobias, J. A., et at. 1988. HIV isolation from cer ebrospinal fluid in relation to immu nological deficiency and neurological symptoms. AIDS 2: 89-93 Yarchoan, R., Brouwers, P., Spitzer, A. R., Grafman, J., Safai, B., et at. 1987. Response of HIV associated neuro logical disease to 3'-azido-3'-deoxy
53a. Ingraham, L. J., Bridge, T. P., Janssen, R., Stover, E., Mirsky, A. F. 1990. Neu ropsychological effects of early HIV- I infection: assessment and methodology. J. Neuropsychiatry Clin. Neurosci. In press 54. Schmidt, U., Miller, D. 1988. Two cases of hypomania in AIDS. Br. J. Psychia try 152:839-42 55. Thomas, C. S. 1987. HlV and schizo phrenia. Lancet 2: 101 56. Olie, J. P., Lesur, A., Denis, H. P., Caroli, F., Loo,H. 1987. Manifestations psychiatriques et infection par Ie HIV. L'encephale 13: 31-33 57. Taylor, K., Lavallee, D. 1989. Neuro psychiatric management of AIDS. AIDS Patient Care 3(3): 8-12 58. Atkinson, J. H., Grant, I., Kennedy, C. J., Richman, D. D., Spector, S. A., et at. 1988. Prevalence of psychiatric disorders among men infected with the human immunodeficiency virus. Arch. Gen. Psy
48. Schaerf, F., Pearlson, G., McArthur, J., LaFrance, N., Polk, B. F. 1988. Single photon emission computed tomography changes in HIV-J infection. Abstr. 7015 presented at IV Int. Conf. on AIDS, Stockholm 49. Tross, S., Price, R. W., Navia, B., Thaler, H. T., Gold, J., et at. 1988. Neu ropsychological characterization of the AIDS dementia complex: a preliminary report. AIDS 2: 81-88 50. Grant, I., Atkinson, J. H., Hesselink, J. R., Kennedy, C. J., Richman, D. D., et at. 1987. Evidence for early central nervous system involvement in Acquired Immunodeficiency Syndrome (AIDS) and other Human Immunodeficiency Virus (HIV) infections: studies with neUl:opsychologic testing and magnetic resonance imaging. Ann. Intern. Med. 107: 828-36 51. Grant, I., Heaton, R. K. 1990. Human Immunodeficiency Virus-I and the brain. J. Consult. Clin. Psychol. In press 52. Seines, O. A., McArthur, J. c., Munoz, A., Cohn, S., Gordon, B., et al. 1988. Longitudinal neuropsychological evalu ation of healthy HIV-I infected men: The Multicenter AIDS Cohort Study (MACS). Abstr. 8561 presented at IV Int. Conf. on AIDS, Stockholm 53. Seines, O. A., Miller, E. N., Becker, J. T., Cohen, B. A., McArthur, J. c., et at. 1988. Normal neuropsychological per formance in healthy HIV-J infected homosexual men: The Multicenter AIDS Cohort Study (MACS). Abstr. 8562 pre sented at IV Int. Conf. on AIDS, Stock holm
59. Wechsler, D. 1981. Wechsler Adult Intel ligence Scale-Revised. New York: Psy chological Corp. 60. Wechsler, D. 1987. Wechsler Memory Scale-Revised. New York: Psychologi cal Corp. 61. Lezak, M. D. 1983. Neuropsychological Assessment. New York: Oxford 62. Halstead, W. C. 1947. Brain and Intel ligence. Univ. Chicago Press 63. Yarchoan, R., Brouwers, P., Spitzer, A. R., Grafman, J., et at. 1987. Re sponse of Human-Immunodeficiency Virus-associated neurological disease to 3'-azido-3'-deoxythymidine. Lancet I : 132-35 64. Schmitt, F. A., Bigley, J. A., McKinnis, R., Logue, P. E., Evans, R. W., et al. 1988. Neuropsychological outcome of Zidovudine (AZT) treatment of patients with AIDS and AIDS-Related Complex. N. Engl. J. Med. 319: 1573-78 65. Moss, H., Brouwers, P., Wolters, P., Eddy, J., Maha, M., et at. 1988. Revers ible neuropsychological deficits: the effect of AZT therapy in a pediatric AIDS population. Abstr. 7252 presented at IV Int. Conf. on AIDS, Stockholm 66. Maxwell, S., Scheftner, W. A., Kess ler, H. A., Busch, K. 1988. Manic syn drome associated with zidovudine treat ment. J. Am. Med. Assoc. 259: 34047 67. Bridge, T. P. 1988. HIV-I: Neuro psychological manifestations and their treatment. Psychopharmacul. Bull. 24: 320-24 68. Bridge, T. P., Ingraham, L. J., Goodwin, F. K. 1989. Neuropsychiatry of AIDS:
44.
45.
46.
Annu. Rev. Med. 1990.41:159-168. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 01/29/15. For personal use only.
167
47.
thYITlidine. Lancet 1: 132-35
chiatry 45: 859--64
168
BRIDGE
& INGRAHAM
Clinical presentation and treatment research. In Neuropsychopharmacology: Proc. 16th ClNP Congr., 1988, ed. W. E. Bunney, H. Hippius, G. Laakmann, M. Schmauss. Berlin: Springer-Verlag. In press 69. Fernandez, F., Adams, F., Levy, J. K Holmes, V. F., Neidhart, M., et a!. 1988. Cognitive impairment due to AIDS related complex response to psycho stimulants. Psychosomatics 29: 38-46 70. Ostrow, D., Grant, I., Atkinson, H. 1988. Assessment and management of the AIDS patient with neuropsychiatric disturbances. J. Clin. Psychiatry 49 (May): 14-21 (Supp!.) 71. Woo. S. K. C. 1989. The psychiatric and
Annu. Rev. Med. 1990.41:159-168. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 01/29/15. For personal use only.
.•
neuropsychiatric aspects of HIV disease.
J. Palliative Care 4: 50-53
72. Aronow, H. A., Brew, B. J., Price, R. W. 1988. The management of the neuro logical complications of HIV infection and AIDS. AIDS 2(Suppl. I): S15159 73. Pert, C. M., Ruff, M. A., Weber, R., Herkenham, M. 1985. Neuropeptides and their receptors: a psychosomatic network. J. Immunol. 135: 820s-26s 74. Smith, D. H., Byrn, R. A., Marsters, S. A., Gregory, T., Groopman, J., et a!. 1987. Blocking of HIV- I infectivity by a soluble, secreted form of the CD4 antigen. Science 238: 1704-7
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CENTRAL NERVOUS SYSTEM
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EFFECTS OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 11 T. Peter Bridge, M.D., and Loring J. Ingraham, Ph.D.
Division of Intramural Research and Laboratory of Psychology and Psychopathology, National Institute of Mental Health, Bethesda, Maryland 20892 KEY
WORDS:
AIDS, HIV-I, dementia, neuropsychiatry, neuropsychology.
ABSTRACT Following its early entry into the central nervous system (eNS), HIV-l alters cerebral cell architecture and may subsequently affect higher cog nitive functions, leading eventually in some patients to HIV-1 encepha lopathy. The eNS may also be the target of opportunistic infections and malignancy secondary to HIV-I immunosuppression. Studies at the cellular, anatomical, and behavioral levels present evidence for significant involvement of the eNS in HIV-l disease, while initial reports of treatment strategies hold promise for providing some amelioration in affected indi viduals. INTRODUCTION
Altered central nervous system (eNS) structure and function accompany human immunodeficiency virus type 1 (HIV-l ) infection. From early case reports (1, 2) to recent reviews (3-7), the description of neuropsychiatric
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changes that occur over the course of HIV-I disease is convincing evidence of the potentially profound effects of HIV-1 infection on the human CNS. Disordered mood states were initially attributed to the affected indi viduals' perceptions of being fatally ill, while observed cognitive and psy chomotor abnormalities were considered sequelae of CNS opportunistic infection and neoplasms. Demonstration that HIV -1 enters the brain (8), even before the appearance of any of the classical symptoms of the illness (9), suggests that observed CNS functional impairments may be the result of direct infection of the brain by HIV-1. Following a brief epidemiological overview, recent studies that address the role of HIV-l in the eNS from a cellular, anatomical, or behavioral perspective are reviewed below. Some brief considerations of the clinical management of HIV-I-related CNS pathology follow, as do comments on some as yet unresolved questions of HIV-I-CNS interactions. EPIDEMIOLOGY AND INCIDENCE
The Centers for Disease Control estimate 1.0 to 1 .5 million individuals are infected with HIV-l in the United States ( 1 0, 11), and the yearly number of new cases of AIDS is projected to increase from 39,000 in 1 988 to 80,000 in 1992, with 365,000 individuals diagnosed as having AIDS by the end of 1992 (1 2). That the majority of these individuals will experience CNS involvement starkly presents the magnitude of the effect of HIV-1 disease on the human eNS. Navia, Price, and their colleagues defined a pattern of impairment they labeled the AIDS dementia complex (ADC) (13, 1 4) in a sample of patients referred to a neurologic clinic. They noted that neurologic changes were the first sign of HIV-I infection in one third of their sample of 70 patients, while one half of the sample went on to develop severe generalized neuropsychiatric impairment within two months of the first cognitive symptom of ADC. Selection for referral for neurologic evaluation in the Navia and Price sample may have overestimated the prevalence of neurological dysfunction associated with HIV-1 infection in all HIV-I patients, but subsequent work (4, 1 5- 1 8) demonstrated convincingly that cognitive changes are present in a substantial portion of individuals with AIDS and may be the sole presenting feature of HIV-l infection ( 1 9-21 ). The Centers for Disease Control 1 987 amendment of the case definition of AIDS to include those individuals presenting solely with HIV sero positivity and dementia ( 22) formally recognizes CNS dysfunction as one of the defining manifestations of HIV-l disease. Ten percent of HIV-l infected individuals may have HIV-1 encephalopathy as the first presenting
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sign of AIDS, while many more infected individuals go on to develop HIV I encephalopathy or neuropsychiatric abnormalities after the onset of AIDS.
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ETIOLOGY
Multiple mechanisms are possible for CNS changes associated with HIV I infection. There may be direct infection and associated cell death, toxicity from by-products of HIV-I-infected cells in the CNS, cell death or toxicity due to sequelae of opportunistic infections of the CNS, and impaired CNS function due to reduced functional capacity of other essential organ systems. CNS Infection by HIV-J
HIV-I has been isolated from the cerebrospinal fluid of seropositive but otherwise asymptomatic individuals (23), which indicates that the virus
may enter the CNS early in the course of infection. Evidence of early intrathecal immune response viral isolation (24-26) confirms the existence of HIV-I within the blood-brain barrier during the initial stages of HIV disease. Pert and her colleagues (27, 28) have mapped the location of gp-120, the entry protein for HIV-I (29) in brain, confirming the ability of HIV-I to bind within the CNS. Opportunistic Infections and Malignancy
While this review focuses on the direct effects of HIV-I on the human brain, there are many other sources of HIV- I-related CNS pathology. A number of the opportunistic infections seen in AIDS may substantially affect CNS function. Cytomegalovirus (30, 31) and toxoplasmosis (32) have been implicated, as well as more unusual cerebral infections (33, 34). Malignancies are another potential source of CNS dysfunction in HIV I infection. Cerebral lymphomas (35) as well as less common malignancies (36, 37) have been identified as CNS concomitants of HIV-I infections. Interested readers are referred to recent reviews focusing on the incidence and treatment of HIV-I-related malignancy (38, 39). PATHOLOGY Cytopathology
It is likely that HIV-I enters the CNS through a vector of infected mono cyte/macrophage cells (40). Within the CNS, hematopoietically derived glial cells and giant multinucleated cells have been found to contain HIV1 viral material, while such material is rarely, if ever, found within neuronal
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cells (19, 41). Dysfunction of neuronal cells in the absence of direct infec tion is most likely the result of a neurotoxic effect associated with HIV-I infection, e.g. the direct cytopathic effect of gp-120 on murine hippocampal cell culture (42).
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Neuroanatomy
The brains of HIV-I-infected individuals exhibit substantial neuro pathology (14, 43). A recent unselected series found abnormalities in the majority of brains on postmortem examination, with evidence of neo plasms, opportunistic infections, vascular lesions, nodular encephalitis, and HIV encephalitis (44). Magnetic resonance imaging (MRI), which is useful in diagnosing space occupying lesions in HIV-l disease (45) has also shown white matter hyperlucencies in TI/T2-weighted images of the brains of some HIV-l patients. While such hyperlucencies are not as yet diagnostically specific to HIV-I-related neuropsychiatric impairment, future use of low magnetic field MRI may prove more sensitive to HIV-I-related changes (46). In general, reports of other neurodiagnostic imaging techniques have shown general decrements rather than changes specific to HIV-l (47, 48).
To date no HIV-I-specific gross anatomic localization within the CNS has been identified; infected monocyte/macrophage cells may be disseminated throughout the CNS. Behavioral Pathology HIV-I ENCEPHALOPATHY AIDS dementia complex (4, 13, 14) defines a syndrome characterized by HIV-l infection, progressive cognitive loss, and the frequent presence of motor symptoms. Onset is usually insidious, with subjective initial complaints of forgetfulness, poor concentration, and mental slowing. Neuropsychological invcstigation of impairment associated with HIV I infection (15-18, 49) reveals a range of consequences of HIV-I infection, including deficits of memory, attention, and concept formation. The natu ral history of ADC is under active investigation, with current debate focused on how early, how severely, and how frequently HIV-I-related cognitive and behavioral changes occur (50-53a). Currently, predictive relationships between early immunological changes and the onset of HIV1 encephalopathy have not been demonstrated. PSYCHIATRIC CONCOMITANTS Psychiatric morbidity is also a concomitant of HIV-I infection of the CNS. While an episode of major depression following diagnosis of a fatal illness such as AIDS is not unexpected, there may be additional evidence for HIV-I-related psychiatric morbidity in
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case reports of hypomania (54) and psychosis (55, 56). Some observed psychiatric morbidity may also be a side effect of the potent medication used in the treatment of HIV-I disease (57). Regardless of the cause, the high morbidity for psychiatric disorders among individuals with AIDS (58) warrants careful evaluation throughout the course of illness. In addition to the sensitive monitoring and treat ment of individual patients' psychiatric symptomatology recommended above, a variety of approaches to the assessment of behavioral mani festations of HIV-I infection of the eNS are possible. In the later stages of infection and when gross pathology is evident, the traditional mental status examination may adequately characterize the extent of dysfunction and document the need for neurological consultation and referral. Early in the course of HIV-l infection, patients' complaints may be primarily subjective and confounded by affective reactions to recently
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ASSESSMENT TECHNIQUES
discovered seropositivity and the presence of initial symptoms of immune
dysfunction. At this time, neuropsychological evaluation can assess the level of intact function and serve to reassure patients of existing strengths, while identifying areas of potential weakness. Repeated assessments can help in monitoring the course of illness and the reaction to therapeutic regImens. While a wide range of neuropsychological instruments is available, the choice of assessment tools for a particular individual is best made by the neuropsychologist after a preliminary evaluation of the patient. For research purposes, and to provide cross-site comparison, the consistcnt use of basic core instruments is valuable. Suggested instruments include the Vocabulary, Block Design, and Digit Span subtests of the Wechsler Adult Intelligence Scale-Revised (59); immediate and 30-minute delayed recall of the Logical Memory and Visual Reproduction subtests of the Wechsler Memory Scale-Revised (60); the Trail Making Test (61); and the Finger Tapping test (62).
APPROACHES TO MANAGEMENT
Treating the eNS effects of HIV-1 is part of the overall management of HIV-I disease. A primary effort must be directed against HIV-I itself, while treatment of opportunistic infections and neoplasms with impact on the eNS follows. In addition, careful monitoring of the potential effect of therapeutic agents on the eNS must be maintained; psychotherapeutic interventions and specific psychopharmacologic agents may be useful for some individuals.
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Antiretrovirals
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Reports in adults (63, 64) and children (65) suggest that treatment with the antiretroviraI3'-azido-3'-deoxythymidine (azidothymidine, AZT) may reverse some of the decrements on neuropsychological testing seen in HIV-l disease. These encouraging findings must be viewed with caution, however, because there have also been case reports of hypomanic response to this agent (66). Psychotropic Medication
HIV-l-infeeted individuals may exhibit increased sensitivity, including extrapyramidal toxicities, to conventional psychotropic agents (67, 68). When psychotropic medication is indicated, a reduced-dosage regimen similar to that in use in geriatric neuropsychopharmacology is recom mended. Initial reports indicate that psychostimulants may be helpful in some patients to improve the cognitive and affective deficits associated with ADC (69). In addition, as the CNS effects of HIV-l are more frequently recognized by clinicians alerted to their presence, more extended guidelines for management are being developed (57, 70-72). Novel Peptidic Agents
Psychoneuroimmunologic research has revealed shared peptidergic trans mitter/receptor mechanisms between the nervous and immune systems (73). Such shared mechanisms suggest that pharmacological manipulation of one system will also affect the reciprocal system. Novel treatment approaches are now being studied for their potential to modify the course of HIV-1 infection and its effects on the CNS (68, 74). CONCLUSIONS AND CONTROVERSIES
Both the structure and the function of the CNS may be altered by a variety of mechanisms following HIV-l infection, and the initial study of these processes has led to the development of promising neuropsychophar macological treatments. Clinicians' increasing awareness of the possible CNS effects of HIV-1 can contribute to earlier identification and effective treatment; concurrent clinical and laboratory investigation will also broaden our understanding and open new approaches for treatment. Two promising goals for continuing investigation are to confirm the mechanism (or mechanisms) of CNS cytotoxicity following HIV-l entry into the CNS and to map the distribution of such cytotoxicity. While the existence of CNS dysfunction secondary to HIV-1 infection
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in some individuals is not contested, debate continues over the incidence, onset, and course of such changes. Longitudinal studies will soon begin to present a picture of the natural history of HIV-I encephalopathy, and more importantly, report the most successful approaches to treatment of the many eNS sequelae of HIV-I infection.
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Literature Cited AIDS and human immunodeficiency virus infection in the United States: 1988 update. Morbid. Mortal. Wkly. Rep. 38(Suppl. S-4): 1-38 12. Centers for Disease Control. 1989. Mor bid. Mortal. Wkly. Rep. 38(Suppl. S-4):
1. Horowitz, S. L., Benson, D. F., Gottlieb, M. S., Davos, I., Bentson, J. R. 1982. Neurological complications of Gay Related Immunodeficiency Disorder. Ann. Neurol. 12: 80 2. Snider, W. D., Simpson, D. M., Nielson, S., Gold, J. W. M., Metroka, C. E., et al. 1983. Neurological complications of acquired immune deficiency syndrome: Analysis of 50 patients. Ann. Neurol. 14:
13. Navia, B. A., Jordan, B. D., Price, R. W. 1986. The AIDS Dementia Complex: I. Clinical features. Ann. Neurol. 19: 517-
3. Levy, R. M., Bredesen, D. E. 1988. Central nervous system dysfunction in acquired immunodeficiency syndrome. J. Acquired Immune Defic. Syndrome I: 41-64 4. Price, R. W., Brew, 8., Sidtis, J., Rosen blum, M., Scheck, A., ct al. 1988. The brain in AIDS: central nervous system HIV- l infection and AIDS Dementia Complex. Science 239: 586--92 5. Kennedy, P. G. 1988. Neurological com plications of human immunodeficiency virus infection. Postgrad. Med. J. 64: 180--87 6. Budka, H. 1989. Human immuno deficiency virus (HIV}-induced disease of the central nervous system: patho logy and implications for pathogenesis. Acta Neuropathol. 77: 225-36 7. Dalakas, M., Wichman, A., Sever, J. 1989. AIDS and the nervous system. J: Am. Med. Assoc. 261: 2396--99 8. Shaw, G. M., Harper, M. E., Hand, B. H., et al. 1985. HTLV-III infection in the brains of children and adults with AIDS encephalopathy. Science 227: 177-81 9. Marshall, D. W., Brey, R. L., Cahill, W. T., Houk, R. W., Zajac, R. A., et al. 1988. Spectrum of cerebrospinal fluid findings in various stages of human immunodeficiency virus infection. Arch. Neurol. 45 : 954--58 10. Centers for Disease Control. 1987. Human immunodeficiency virus infec tion in the United States: a review of current knowledge. Morbid. Mortal. Wkly. Rep. 36(Suppl. S-6): 1-48 11. Centers for Disease Control. 1989.
14. Navia, B. A., Cho, E., Petito, C. K., Price, R. W. 1986. The AIDS Dementia Complex: II. Neuropathology. Ann. Neurol. 19: 525-35 15. Joffe, R. T., Rubinow, D. R., Squillace, 8. S., Lane, C. H., Duncan, C. c., et al. 1986. The neuropsychiatric aspects of acquired immune deficiency syndrome (AIDS). Psychopharmacol. Bull. 22: 684--88 16. Ayers, M. R., Abrams, D. I., Newell, T. G., Friedrich, F. 1987. Performance of individuals with AIDS on the Luria Nebraska neuropsychological battery. Int. J. Clin. Neuropsychol. 9: 101-5 17. Price, R. W., Sidtis, J., Rosenblum, M. 1988. The AIDS dementia complex: some current questions. Ann. Neurol. 23: S27-S23 (Supp!.) 18. World Health Organization. 1988. Report of the Consultation Oil the Neu ropsychiatric Aspects of HIV Infec tion, Geneva, 14-17 March 1988. Geneva: WHO 19. Navia, B. A., Price, R. W. 1987. The Acquired Immunodeficiency Syndrome Dementia Complex as the presenting or sole manifestation of human immuno deficiency virus infection. Arch. Neural. 44: 65--66 20. Beckett, A., Summergrad, P., Man schreck, T., Vitagliano, H., Henderson, M., et a!. 1987. Symptomatic HIV infec tion of the CNS in a patient without clinical evidence of immune deficiency. Am. J. Psychiatry 144: 1342--44 21. Riccio, M., Thompson, C. 1987. AIDS and dementia. Br. J. Hasp. Med. 38: 11
403-18
5
24
Annu. Rev. Med. 1990.41:159-168. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 01/29/15. For personal use only.
1 66
BRIDGE & INGRAHAM
22. Centers for Disease Control. 1987. Revision of the CDC surveillance case definition for acquired immunodefi ciency syndrome. Morbid. Morral. Wkly. Rep. 36: IS-14S 23. Ho, D. D., Rota, T. R., Schooley, R. T., Kaplan, J. C., Allan, J. D., et al. 1985. Isolation of HTLV-III from cerebro spinal fluid and neural tissue of patients with neurologic syndromes related to the acquired immunodeficiency syn dromc. N. Engl. J. Med. 313: 149397 24. Goudsmit, 1., Epstein, L. G., Paul, D. A., van der Helm, H. J., Dawson, G. J., et al. 1987. Intra-blood-brain barrier
synthesis of human immunodeficiency virus antigen and antibody in humans and chimpanzees. Proc. Nat!. Acad. Sci.
USA 84: 3876-80 25. Elovaara, I., Seppala, I., Poutiainen, E., Suni, J., Valle , S. L. 1988. Intrathecal humoral immunologic response in neu rologically symptomatic and asympto matic patients with human immuno deficiency virus infection. Neurology 38: 1451-56 26. Chiodi, F., Sonnerborg, A., Albert, 1.,
Gaines, H., Norkrans, G., et al. 1988. Human immunodeficiency virus infec tion of the brain. I. Virus isolation and
27.
28.
29.
30.
dctcction of HIV specific antibodies in the cerebrospinal fluid of patients with varying clinical conditions. J. Neurol. Sci. 85: 245-57 Pert, C. B., Hill, J. M., Ruff, M. R., Berman, R. M., Robey, W. G., et al. 1986. Octapeptides deduced from the neuropeptide receptor-like pattern of antigen T4 in brain potentially inhibit human immunodeficiency virus receptor binding and T-cell infectivity. Proc. NaIl. Acad. Sci. USA 83: 9254-58 Pert, C B., Ruff, M. R. , Ruscetti , F., Farrar, W. L., Hill, 1. 1988. HIV re ceptor in brain and deduced peptides that block infectivity. In Psychological, Neuropsychiatric and Substance Abuse Aspects of Aids, ed. T. P. Bridge, A. F. Mirsky, F. K. Goodwin, pp. 73-84. New York: Raven Dalgliesh, A. G., Beverly, P. C. L., Clapham, P. R., Crawford, D. H., Greaves, M. F., et al. 19R4. The CD4 (T4) antigen is an essential component of the receptor for the AIDS virus. Nature 763-67 Mahieux, F., Gray, F., Fenelon, G., Gherardi, R., Adams, D., et al. 1989. Acute myeloradiculitis due to cyto megalovirus as thc initial manifestation of AIDS. J. Neurol. Neurosurg. Psy chiatry 52: 270-74
31. Vinters, H. V., Kwok, M. K., Ho, H. W., Anders, K. H., Tomiyasu, D., et al. 1989. Cytomegalovirus in the nervous system of patients with the acquired immune deficiency syndrome. Brain 112(part I): 245-68 32. Israelski, D. M., Remington, J. S. 1988.
Toxoplasmic encephalitis in patients
33.
34.
35.
36.
with AIDS. Infect. Dis. Clin. North Am. 2:429-45 Gilden, D. H., Murray, R. S., Wellish, M., Kleinschmidt-DeMasters, B. K., Vafai, A. 1988. Chronic progressive varicella-zoster virus encephalitis in an AIDS patient. Neurology 38: 1150-53 Jarvi k, 1. G., H esselink, 1. R., Wiley, C, Mercer, S., Robbins, B., et al. 1988. Coccidioidomycotic brain abscess in an HIV-infected man. West. J. Med. 149: 83-86 Anders, K. H., Latta, H., Chang, B. S., Tomiyasu, D., Quddusi, A. S., et al. 1989. Lymphomatoid granulomatosis and malignant lymphoma of the central nervous system in the acquired immu nodeficiency syndrome. Hum. Pathol. 20: 326-34 Tirelli, D., Vaccher, E., Zagonel, V., Rezza, G., Palmieri, G., et al. 1988.
Malignant tumors other than lymphoma
and Kaposi's sarcoma in association with HIV infection. Cancer Detect. Prevo 12: 267-72 37. Gasnault, 1., Roux, F. X., Vedrenne, C. 1988. Cerebral astroc ytoma in associ ation with HIV infection. J. Neurol. Neurosurg. Psychiatry 51: 422-24 38. Volberding, P. 1988. Treatment of malignant disease in AIDS patients. AIDS 2(Suppl. 1): S169-75 39. Munro, A. J., Stewart, J. S. W. 1989. AIDS: incidence and management of malignant disease. Radio/her. Oncol. 14:
121-31
40. Gartner, S., Markovits, P., Markovitz, D. M., Kaplan, M. H., Gallo, R. C., et al. 1986. The role of mononuclear phagocytes in HTL V -III/LAV infection. Science 233: 215--1 9 S., Gendelman, H. E., 41. Koenig, Orenstein, J. M., Dal Canto, M. C., Pezeshkpour, G. H., et al. 1986. Detec tion of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233:108993 42. Brenneman, D., Westerbrook, G., Fitz gerald, S., Ennist, D. L., Elkins, K. L., et al. 1988. Neuronal killing by the envel ope protein of HIV and its prevention by vasoactive intestinal peptide. Nature 335:639-42 43. McAllister, R. H., Harrison, M. 1. G.,
CNS EFFECTS OF HIV-l
Johnson, M. J. 1988. HIV and the ner vous system. Br. J. Hosp. Med. 40: 2126 Lantos, P. L., McLaughlin, J. E., Scholtz, C. L., Berry, C. L., Tighe, J. R. 1989. Neuropathology of the brain in HIV infection. Lancet I: 309-11 Post, M. J. D., Sheldon, J. J., Hensley, G. T.,Soila,K., Tobias,J. A.,et aI. 1986. Central nervous system disease in AIDS: Prospective correlation using CT, MRI, and pathologic studies. Radiology 158: 141-48 Sonnerborg, A. 8., Ehrnst, A. c., Berg dahl, S. K. M., Soila, K., Tobias, J. A., et at. 1988. HIV isolation from cer ebrospinal fluid in relation to immu nological deficiency and neurological symptoms. AIDS 2: 89-93 Yarchoan, R., Brouwers, P., Spitzer, A. R., Grafman, J., Safai, B., et at. 1987. Response of HIV associated neuro logical disease to 3'-azido-3'-deoxy
53a. Ingraham, L. J., Bridge, T. P., Janssen, R., Stover, E., Mirsky, A. F. 1990. Neu ropsychological effects of early HIV- I infection: assessment and methodology. J. Neuropsychiatry Clin. Neurosci. In press 54. Schmidt, U., Miller, D. 1988. Two cases of hypomania in AIDS. Br. J. Psychia try 152:839-42 55. Thomas, C. S. 1987. HlV and schizo phrenia. Lancet 2: 101 56. Olie, J. P., Lesur, A., Denis, H. P., Caroli, F., Loo,H. 1987. Manifestations psychiatriques et infection par Ie HIV. L'encephale 13: 31-33 57. Taylor, K., Lavallee, D. 1989. Neuro psychiatric management of AIDS. AIDS Patient Care 3(3): 8-12 58. Atkinson, J. H., Grant, I., Kennedy, C. J., Richman, D. D., Spector, S. A., et at. 1988. Prevalence of psychiatric disorders among men infected with the human immunodeficiency virus. Arch. Gen. Psy
48. Schaerf, F., Pearlson, G., McArthur, J., LaFrance, N., Polk, B. F. 1988. Single photon emission computed tomography changes in HIV-J infection. Abstr. 7015 presented at IV Int. Conf. on AIDS, Stockholm 49. Tross, S., Price, R. W., Navia, B., Thaler, H. T., Gold, J., et at. 1988. Neu ropsychological characterization of the AIDS dementia complex: a preliminary report. AIDS 2: 81-88 50. Grant, I., Atkinson, J. H., Hesselink, J. R., Kennedy, C. J., Richman, D. D., et at. 1987. Evidence for early central nervous system involvement in Acquired Immunodeficiency Syndrome (AIDS) and other Human Immunodeficiency Virus (HIV) infections: studies with neUl:opsychologic testing and magnetic resonance imaging. Ann. Intern. Med. 107: 828-36 51. Grant, I., Heaton, R. K. 1990. Human Immunodeficiency Virus-I and the brain. J. Consult. Clin. Psychol. In press 52. Seines, O. A., McArthur, J. c., Munoz, A., Cohn, S., Gordon, B., et al. 1988. Longitudinal neuropsychological evalu ation of healthy HIV-I infected men: The Multicenter AIDS Cohort Study (MACS). Abstr. 8561 presented at IV Int. Conf. on AIDS, Stockholm 53. Seines, O. A., Miller, E. N., Becker, J. T., Cohen, B. A., McArthur, J. c., et at. 1988. Normal neuropsychological per formance in healthy HIV-J infected homosexual men: The Multicenter AIDS Cohort Study (MACS). Abstr. 8562 pre sented at IV Int. Conf. on AIDS, Stock holm
59. Wechsler, D. 1981. Wechsler Adult Intel ligence Scale-Revised. New York: Psy chological Corp. 60. Wechsler, D. 1987. Wechsler Memory Scale-Revised. New York: Psychologi cal Corp. 61. Lezak, M. D. 1983. Neuropsychological Assessment. New York: Oxford 62. Halstead, W. C. 1947. Brain and Intel ligence. Univ. Chicago Press 63. Yarchoan, R., Brouwers, P., Spitzer, A. R., Grafman, J., et at. 1987. Re sponse of Human-Immunodeficiency Virus-associated neurological disease to 3'-azido-3'-deoxythymidine. Lancet I : 132-35 64. Schmitt, F. A., Bigley, J. A., McKinnis, R., Logue, P. E., Evans, R. W., et al. 1988. Neuropsychological outcome of Zidovudine (AZT) treatment of patients with AIDS and AIDS-Related Complex. N. Engl. J. Med. 319: 1573-78 65. Moss, H., Brouwers, P., Wolters, P., Eddy, J., Maha, M., et at. 1988. Revers ible neuropsychological deficits: the effect of AZT therapy in a pediatric AIDS population. Abstr. 7252 presented at IV Int. Conf. on AIDS, Stockholm 66. Maxwell, S., Scheftner, W. A., Kess ler, H. A., Busch, K. 1988. Manic syn drome associated with zidovudine treat ment. J. Am. Med. Assoc. 259: 34047 67. Bridge, T. P. 1988. HIV-I: Neuro psychological manifestations and their treatment. Psychopharmacul. Bull. 24: 320-24 68. Bridge, T. P., Ingraham, L. J., Goodwin, F. K. 1989. Neuropsychiatry of AIDS:
44.
45.
46.
Annu. Rev. Med. 1990.41:159-168. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 01/29/15. For personal use only.
167
47.
thYITlidine. Lancet 1: 132-35
chiatry 45: 859--64
168
BRIDGE
& INGRAHAM
Clinical presentation and treatment research. In Neuropsychopharmacology: Proc. 16th ClNP Congr., 1988, ed. W. E. Bunney, H. Hippius, G. Laakmann, M. Schmauss. Berlin: Springer-Verlag. In press 69. Fernandez, F., Adams, F., Levy, J. K Holmes, V. F., Neidhart, M., et a!. 1988. Cognitive impairment due to AIDS related complex response to psycho stimulants. Psychosomatics 29: 38-46 70. Ostrow, D., Grant, I., Atkinson, H. 1988. Assessment and management of the AIDS patient with neuropsychiatric disturbances. J. Clin. Psychiatry 49 (May): 14-21 (Supp!.) 71. Woo. S. K. C. 1989. The psychiatric and
Annu. Rev. Med. 1990.41:159-168. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 01/29/15. For personal use only.
.•
neuropsychiatric aspects of HIV disease.
J. Palliative Care 4: 50-53
72. Aronow, H. A., Brew, B. J., Price, R. W. 1988. The management of the neuro logical complications of HIV infection and AIDS. AIDS 2(Suppl. I): S15159 73. Pert, C. M., Ruff, M. A., Weber, R., Herkenham, M. 1985. Neuropeptides and their receptors: a psychosomatic network. J. Immunol. 135: 820s-26s 74. Smith, D. H., Byrn, R. A., Marsters, S. A., Gregory, T., Groopman, J., et a!. 1987. Blocking of HIV- I infectivity by a soluble, secreted form of the CD4 antigen. Science 238: 1704-7
