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Psychosis Induced by Decreased CD4+ T Cell and High Viral Load in Human Immunodeficiency Virus Infection: A Case Report
CORRESPONDENCE Psychosis Induced by Decreased CD4ⴙ T Cell and High Viral Load in Human Immunodeficiency Virus Infection: A Case Report To the Editor: nfection by the human immunodeficiency virus (HIV) causes direct and indirect damage to the central nervous system (CNS) (1). This may result in different psychiatric syndromes associated with the onset and progression of the infection. Human immunodeficiency virus-related psychiatric conditions are very diverse and include cognitive impairment (acquired immune deficiency syndrome [AIDS] dementia complex), depression, mania, obsessive-compulsive disorder, and psychosis (2,3). Manifestations of HIV-related psychosis include persecutory, grandiose, and somatic delusions; auditory and visual hallucinations; and affective disturbances, anxiety, and agitation (4). Although these psychiatric symptoms are not directly related to the stage of the disease or its course and they may overlap with other psychiatric syndromes such as drug-related intoxication or withdrawal symptoms, psychosis appears mainly in the later stages of HIV infection, with a prevalence of .2% to 15% (5). Unlike the psychiatric symptoms caused by cell loss after neuronal infection in viral encephalitis, the pathophysiology of HIV-related psychosis depends on the action of viral toxins (6). People with HIV/AIDS have neurological problems that overlap with diseases associated with abnormal dopaminergic synaptic transmission. The most recent studies have found that individuals with HIV encephalitis experience synaptic changes resembling the shifts that occur when dopaminergic tone is increased experimentally. Increased dopaminergic tone leads to heightened predisposition for drugs of abuse, increases behavior that leads to risk of HIV transmission, and could decrease adherence to antiretroviral medication regimens (7). In the context of HIV infection, the presence of psychotic symptoms may also be a direct and reversible side effect of highly active antiretroviral therapy (HAART) (8 –11). Nevertheless, in some cases, HAART has reversed psychosis that was presumably induced by HIV (12). We present a case of HIVinduced psychosis that remitted after HAART.
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Case Report. The patient was a 57-year-old male referred to our inpatient psychiatric ward with a second psychotic episode. The first psychotic episode had occurred 3 years previously, with new-onset symptoms of paranoia and grandiosity. He had a 6-year history of HIV infection (heterosexual transmission). There was no other medical or psychiatric history of interest (including alcohol or illegal substance abuse or dependence). The patient had a successful professional life (estate agent) for many years and was happy both socially and at home. The current admission to the inpatient psychiatric ward was due to paranoid and grandiose delusions and auditory hallucinations. After 1 week of oral antipsychotic and antiretroviral treatment (the patient had discontinued his antiretroviral treatment about 8 months before this second admission), his mental state improved markedly. The patient was discharged after 18 days and remained on antipsychotic and antiretroviral medication. One month after discharge, his psychotic symptoms had remitted. 0006-3223/08/$34.00
A review of the patient’s records revealed that the two psychotic episodes (the only two he had ever experienced) had occurred after discontinuation of antiretroviral treatment, with no data suggestive of psychosis before discontinuation. In addition, psychiatric manifestations occurred when viral load was highest and the CD4/CD8 ratio lowest and remitted with a normalization of these values (undetectable viral load and CD4/CD8 ratio greater than 1). In the first episode, viral load was 222,871 copies/mL and the CD4/CD8 ratio was .17. In the second episode, viral load was 146,679 copies/mL and the CD4/CD8 ratio was .1. The results of other clinical examinations and laboratory tests (complete blood count, vitamin B12, thyroid-stimulating hormone, hepatitis C virus [HCV] serology, syphilis screening, and neurological workup) were completely normal. Magnetic resonance imaging revealed atrophy that was probably secondary to HIV encephalopathy. With regard to the neuropsychological functioning, this patient showed the following scores on the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) (13): full IQ ⫽ 96; verbal IQ ⫽ 104; performance IQ ⫽ 86, with an impairment index ⫽ 17%. The low scores in performance IQ justify this impairment apparently degenerative. The more affected WAIS-III subtests were those related to attention (Digit Forward and Backward) and processing speed (Digit Symbol), both of them related to subcortical impairment. In the Bender Visual Motor Gestalt Test (14), the patient showed a light tremor and difficulties with visuomotor discrimination and the visuospatial construction.
Discussion. We present a case of psychosis induced by decreased CD4⫹ T-cell count and high viral load secondary to discontinuation of antiretroviral medication in a patient diagnosed with HIV infection. Several attempts have been made to define and elucidate the relationship between HIV infection and psychosis, although there is no epidemiological evidence to date that allows us to establish direct causality (4). A number of hypotheses have been proposed in an attempt to explain the pathogenesis of new-onset psychosis in HIV infection: brain damage from some other opportunistic infection, an inferior immune response in the CNS (15), subcortical neurodegeneration caused by HIV itself or in the presence of other viral infections (16), psychosis secondary to HIV encephalopathy (15,17), underlying dementia (18), and high levels of intracellular free calcium (19). It is unlikely that any one of these hypotheses fully explains the pathogenesis of new-onset psychosis in HIV disease. Future research on this topic has to consider the possible coincidental association of HIV infection and psychiatric illness as a possible cause of new-onset psychosis in HIV-infected patients (17). Treatment of HIV-related psychiatric symptoms has not yet been well defined. In some case reports, antipsychotic agents did not improve HIV-related psychotic symptoms, while in others they did (4). In the case we present, the psychiatric manifestations were probably the result of a high viral load and a low CD4/CD8 ratio. Although neuropsychological data could point to subcortical neurodegeneration, the fact that symptoms improved with the antiretroviral treatment would suggest that the psychosis may be related to neurotropic activity of the HIV infection and could be a direct result of brain infection (12). BIOL PSYCHIATRY 2008;64:e3– e4 © 2008 Society of Biological Psychiatry
e4 BIOL PSYCHIATRY 2008;64:e3– e4 Mar Álvarez-Segura, M.D. Department of Psychiatry Hospital General Universitario Gregorio Marañón Madrid Spain Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM E-mail: [email protected] Sonia Villero Enrique Portugal Department of Psychiatry Hospital General Universitario Gregorio Marañón Madrid Spain Maria Mayoral Department of Psychiatry Hospital General Universitario Gregorio Marañón Madrid Spain Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM Pedro Montilla Department of Infections Diseases Hospital General Universitario Gregorio Marañón Madrid Spain David Fraguas Department of Psychiatry Hospital Infanta Sofía San Sebastián de los Reyes Madrid Spain This study was not supported by any grant. This study was supported by CIBER07/09, CIBER de Salud Mental (CIBERSAM), Spanish Ministry of Health, Instituto de Salud Carlos III. The authors appreciate the support of the staff of the Psychiatric Service.
www.sobp.org/journal
Correspondence All authors reported no biomedical financial interest or potential conflicts of interest. 1. Perry S, Jacobsen P (1986): Neuropsychiatric manifestations of AIDSspectrum disorders. Hosp Community Psychiatry 37:135–142. 2. Schmidt U, Miller D (1988): Two cases of hypomania in AIDS. Br J Psychiatry 152:839 – 842. 3. Rundell JR, Wise MG, Ursano RJ (1986): Three cases of AIDS-related psychiatric disorders. Am J Psychiatry 143:777–778. 4. Chen EY, Harrison G, Standen PJ (1991): Management of first episode psychotic illness in Afro-Caribbean patients. Br J Psychiatry 158:517–522. 5. Sewell DD (1996): Schizophrenia and HIV. Schizophr Bull 22:465– 473. 6. Chacko ST, Sudarsanam TD, Thomas K (2004): A young man with organic psychosis. J Postgrad Med 50:70 –72. 7. Siegelman SS, Gold JA, Simon M, Soifer I (1969): Ulceration of intramural gastric neoplasms. Am J Dig Dis 14:127–134. 8. Maxwell S, Scheftner WA, Kessler HA, Busch K (1988): Manic syndrome associated with zidovudine treatment. JAMA 259:3406 –3407. 9. O’Dowd MA (1988): Manic syndrome associated with zidovudine. JAMA 260:3587–3588. 10. de la Garza CL, Paoletti-Duarte S, Garcia-Martin C, Gutierrez-Casares JR (2001): Efavirenz-induced psychosis. AIDS 15:1911–1912. 11. Wise ME, Mistry K, Reid S (2002): Drug points: Neuropsychiatric complications of nevirapine treatment. BMJ 324:879. 12. Hashimoto T, Nishio M, Sakai T, Fujimoto K, Sato N, Endo T, Koike T (2006): Acute schizophrenic symptoms as the initial manifestation of HIV infection that respond to highly active antiretroviral therapy. Clin Infect Dis 42:1653–1655. 13. Wechsler D (1997): Wechsler Adult Intelligence Scale-Third Edition. San Antonio, TX: The Psychological Corporation. 14. Bender L (1938): A visual motor Gestalt test and its clinical use. AmeryOrthopsychiatric Assoc Res Monograph N 3. 15. Sewell DD, Jeste DV, Atkinson JH, Heaton RK, Hesselink JR, Wiley C, et al. (1994): HIV-associated psychosis: A study of 20 cases. San Diego HIV Neurobehavioral Research Center Group. Am J Psychiatry 151:237–242. 16. Hinkin CH, Castellon SA, Atkinson JH, Goodkin K (2001): Neuropsychiatric aspects of HIV infection among older adults. J Clin Epidemiol 54:S44 – S52. 17. Barnes TR, Crighton P, Nelson HE, Halstead S (1995): Primitive (developmental) reflexes, tardive dyskinesia and intellectual impairment in schizophrenia. Schizophr Res 16:47–52. 18. el-Mallakh RS (1992): HIV-related psychosis. J Clin Psychiatry 53:293–294. 19. el-Mallakh RS (1991): Mania in AIDS: Clinical significance and theoretical considerations. Int J Psychiatry Med 21:383–391.
doi:10.1016/j.biopsych.2008.07.016
I
Case Report. The patient was a 57-year-old male referred to our inpatient psychiatric ward with a second psychotic episode. The first psychotic episode had occurred 3 years previously, with new-onset symptoms of paranoia and grandiosity. He had a 6-year history of HIV infection (heterosexual transmission). There was no other medical or psychiatric history of interest (including alcohol or illegal substance abuse or dependence). The patient had a successful professional life (estate agent) for many years and was happy both socially and at home. The current admission to the inpatient psychiatric ward was due to paranoid and grandiose delusions and auditory hallucinations. After 1 week of oral antipsychotic and antiretroviral treatment (the patient had discontinued his antiretroviral treatment about 8 months before this second admission), his mental state improved markedly. The patient was discharged after 18 days and remained on antipsychotic and antiretroviral medication. One month after discharge, his psychotic symptoms had remitted. 0006-3223/08/$34.00
A review of the patient’s records revealed that the two psychotic episodes (the only two he had ever experienced) had occurred after discontinuation of antiretroviral treatment, with no data suggestive of psychosis before discontinuation. In addition, psychiatric manifestations occurred when viral load was highest and the CD4/CD8 ratio lowest and remitted with a normalization of these values (undetectable viral load and CD4/CD8 ratio greater than 1). In the first episode, viral load was 222,871 copies/mL and the CD4/CD8 ratio was .17. In the second episode, viral load was 146,679 copies/mL and the CD4/CD8 ratio was .1. The results of other clinical examinations and laboratory tests (complete blood count, vitamin B12, thyroid-stimulating hormone, hepatitis C virus [HCV] serology, syphilis screening, and neurological workup) were completely normal. Magnetic resonance imaging revealed atrophy that was probably secondary to HIV encephalopathy. With regard to the neuropsychological functioning, this patient showed the following scores on the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) (13): full IQ ⫽ 96; verbal IQ ⫽ 104; performance IQ ⫽ 86, with an impairment index ⫽ 17%. The low scores in performance IQ justify this impairment apparently degenerative. The more affected WAIS-III subtests were those related to attention (Digit Forward and Backward) and processing speed (Digit Symbol), both of them related to subcortical impairment. In the Bender Visual Motor Gestalt Test (14), the patient showed a light tremor and difficulties with visuomotor discrimination and the visuospatial construction.
Discussion. We present a case of psychosis induced by decreased CD4⫹ T-cell count and high viral load secondary to discontinuation of antiretroviral medication in a patient diagnosed with HIV infection. Several attempts have been made to define and elucidate the relationship between HIV infection and psychosis, although there is no epidemiological evidence to date that allows us to establish direct causality (4). A number of hypotheses have been proposed in an attempt to explain the pathogenesis of new-onset psychosis in HIV infection: brain damage from some other opportunistic infection, an inferior immune response in the CNS (15), subcortical neurodegeneration caused by HIV itself or in the presence of other viral infections (16), psychosis secondary to HIV encephalopathy (15,17), underlying dementia (18), and high levels of intracellular free calcium (19). It is unlikely that any one of these hypotheses fully explains the pathogenesis of new-onset psychosis in HIV disease. Future research on this topic has to consider the possible coincidental association of HIV infection and psychiatric illness as a possible cause of new-onset psychosis in HIV-infected patients (17). Treatment of HIV-related psychiatric symptoms has not yet been well defined. In some case reports, antipsychotic agents did not improve HIV-related psychotic symptoms, while in others they did (4). In the case we present, the psychiatric manifestations were probably the result of a high viral load and a low CD4/CD8 ratio. Although neuropsychological data could point to subcortical neurodegeneration, the fact that symptoms improved with the antiretroviral treatment would suggest that the psychosis may be related to neurotropic activity of the HIV infection and could be a direct result of brain infection (12). BIOL PSYCHIATRY 2008;64:e3– e4 © 2008 Society of Biological Psychiatry
e4 BIOL PSYCHIATRY 2008;64:e3– e4 Mar Álvarez-Segura, M.D. Department of Psychiatry Hospital General Universitario Gregorio Marañón Madrid Spain Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM E-mail: [email protected] Sonia Villero Enrique Portugal Department of Psychiatry Hospital General Universitario Gregorio Marañón Madrid Spain Maria Mayoral Department of Psychiatry Hospital General Universitario Gregorio Marañón Madrid Spain Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM Pedro Montilla Department of Infections Diseases Hospital General Universitario Gregorio Marañón Madrid Spain David Fraguas Department of Psychiatry Hospital Infanta Sofía San Sebastián de los Reyes Madrid Spain This study was not supported by any grant. This study was supported by CIBER07/09, CIBER de Salud Mental (CIBERSAM), Spanish Ministry of Health, Instituto de Salud Carlos III. The authors appreciate the support of the staff of the Psychiatric Service.
www.sobp.org/journal
Correspondence All authors reported no biomedical financial interest or potential conflicts of interest. 1. Perry S, Jacobsen P (1986): Neuropsychiatric manifestations of AIDSspectrum disorders. Hosp Community Psychiatry 37:135–142. 2. Schmidt U, Miller D (1988): Two cases of hypomania in AIDS. Br J Psychiatry 152:839 – 842. 3. Rundell JR, Wise MG, Ursano RJ (1986): Three cases of AIDS-related psychiatric disorders. Am J Psychiatry 143:777–778. 4. Chen EY, Harrison G, Standen PJ (1991): Management of first episode psychotic illness in Afro-Caribbean patients. Br J Psychiatry 158:517–522. 5. Sewell DD (1996): Schizophrenia and HIV. Schizophr Bull 22:465– 473. 6. Chacko ST, Sudarsanam TD, Thomas K (2004): A young man with organic psychosis. J Postgrad Med 50:70 –72. 7. Siegelman SS, Gold JA, Simon M, Soifer I (1969): Ulceration of intramural gastric neoplasms. Am J Dig Dis 14:127–134. 8. Maxwell S, Scheftner WA, Kessler HA, Busch K (1988): Manic syndrome associated with zidovudine treatment. JAMA 259:3406 –3407. 9. O’Dowd MA (1988): Manic syndrome associated with zidovudine. JAMA 260:3587–3588. 10. de la Garza CL, Paoletti-Duarte S, Garcia-Martin C, Gutierrez-Casares JR (2001): Efavirenz-induced psychosis. AIDS 15:1911–1912. 11. Wise ME, Mistry K, Reid S (2002): Drug points: Neuropsychiatric complications of nevirapine treatment. BMJ 324:879. 12. Hashimoto T, Nishio M, Sakai T, Fujimoto K, Sato N, Endo T, Koike T (2006): Acute schizophrenic symptoms as the initial manifestation of HIV infection that respond to highly active antiretroviral therapy. Clin Infect Dis 42:1653–1655. 13. Wechsler D (1997): Wechsler Adult Intelligence Scale-Third Edition. San Antonio, TX: The Psychological Corporation. 14. Bender L (1938): A visual motor Gestalt test and its clinical use. AmeryOrthopsychiatric Assoc Res Monograph N 3. 15. Sewell DD, Jeste DV, Atkinson JH, Heaton RK, Hesselink JR, Wiley C, et al. (1994): HIV-associated psychosis: A study of 20 cases. San Diego HIV Neurobehavioral Research Center Group. Am J Psychiatry 151:237–242. 16. Hinkin CH, Castellon SA, Atkinson JH, Goodkin K (2001): Neuropsychiatric aspects of HIV infection among older adults. J Clin Epidemiol 54:S44 – S52. 17. Barnes TR, Crighton P, Nelson HE, Halstead S (1995): Primitive (developmental) reflexes, tardive dyskinesia and intellectual impairment in schizophrenia. Schizophr Res 16:47–52. 18. el-Mallakh RS (1992): HIV-related psychosis. J Clin Psychiatry 53:293–294. 19. el-Mallakh RS (1991): Mania in AIDS: Clinical significance and theoretical considerations. Int J Psychiatry Med 21:383–391.
doi:10.1016/j.biopsych.2008.07.016