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Borna disease virus and psychiatric disorders
Schizophrenia Research 57 (2002) 303 – 305 www.elsevier.com/locate/schres
Letter to the Editors
Borna disease virus and psychiatric disorders Borna disease virus (BDV) is an infectious agent which can persistently infect the central nervous system of a broad spectrum of animal species. Horses and sheep are natural hosts, but BDV can be transmitted to other animal species. It is a neurotropic, enveloped, negative-strand RNA virus. It is the prototype genus of a new family, Bornaviridae, within the order of the Mononegavirals. In animals, BDV infection spreads intra-axonally and exhibits a preferential tropism for the limbic system, including the hippocampus. The symptomatology in animals ranges from subclinical infection to meningoencephalitis and to rare cases of encephalitis. Several seroepidemiologic data suggest that BDV might be present in humans, possibly associated with neuropsychiatric disorders. Furthermore, viral antigen was detected in human autopsy brain tissue by immunohistochemical staining. BDV antibodies, antigen or BDV RNA were also found significantly more frequently in blood of patients with schizophrenia, depression, and unspecific psychiatric disorders than in controls (Rott et al., 1985; Waltrip et al., 1995, 1997; Chen et al., 1999). However, some studies did not find any relationship between BDV detection and psychiatric disorders (Bode et al., 1992; Kubo et al., 1997; Fukuda et al., 2001). In this context, this study researched the relationship between depression, schizophrenia and BDV by detection of BDV antibodies in sera. Eighty-seven patients (inpatients and outpatients) were investigated in the psychiatry department of the university hospital center in Caen (Centre Esquirol, France). Inpatients were investigated just before discharge. Sixty-three were subjects with schizophrenia and 24 had unipolar depression (DSM IV criteria). Fifty-four patients were categorized in the deficit (N = 8) and nondeficit (N = 46)
subtypes with the Schedule of the Deficit Syndrome (SDS) (Kirkpatrick et al., 1989). Written informed consent was obtained from all patients after complete description of the study. Two hundred and ninety healthy subjects were included in this study. They were blood donors (N = 200) or workers in the hospital departments other than in psychiatry (N = 90). Antibodies to BDV were detected in human sera by an indirect immunofluorescence assay (IFA) as previously described by Rott et al. (1985). Slides of persistently infected MDCK-cells and FITC-conjugated goat antiserum to human IgG were used in the test. In human sera containing BDV antibodies, virus-infected MDCK-cells showed typical granular, focal fluorescence in the nucleus. BDV antibodies containing serum did not react with uninfected cells and were retested on a new batch of MDCK-cells to be confirmed. The immunofluorescence test was carried out in blind of the psychiatric diagnosis to avoid any subjectivity in the interpretation of results. For this purpose, clinical and serum data were always collected independently. Out of the 87 psychiatric patients, 11 (12.6%) were seropositive. Eight (12.7%) subjects with schizophrenia and three (12.5%) depressed patients were seropositive. No deficit patient was seropositive and seven (15.2%) non deficit patients were seropositive. Forty-five (15.5%) healthy subjects also presented a BDV seropositivity, without significant difference between blood donors and hospital workers. Our study has the advantage of focusing on subjects originating from the same region in France (Normandy). This is the first human study of the sort realized in France. Images obtained of the BDV are characteristic and specific in IFA. Moreover, each seropositive serology was controlled on uninfected cells so as to make sure of the specificity of the result. For all that, this study did not find any relation
0920-9964/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 9 2 0 - 9 9 6 4 ( 0 1 ) 0 0 3 1 7 - 6
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Letter to the Editors
between depression or schizophrenia and BDV serology by IFA. Furthermore, no relation was observed between the deficit syndrome and BDV seropositivity. Our study is limited by the small size of the sample (especially for the depressive patient group). However, Bode et al. (1988, 1992) and Kubo et al. (1997) have described no correlation by IFA on larger populations of patients with affective disorders. Similarly, some studies (Waltrip et al., 1995; Kubo et al., 1997) have not shown a more frequent seropositivity by IFA among subjects with schizophrenia. On the other hand, some studies have shown (by IFA) a more frequent seropositivity among the patients who suffer either from various psychiatric pathologies (Rott et al., 1985) or affective disorders and/or schizophrenia (Igata-Yi et al., 1996; Yamaguchi et al., 1999). Furthermore, no deficit subjects with schizophrenia was seropositive in our study. This is opposite to the results of Waltrip et al. (1997) showing an association between deficit syndrome and BDV seropositivity by the method of the Western Blot (WB). This discrepancy could be due to the different methods used, WB in Waltrip’s study and IFA in ours. According to Waltrip et al. (1995), the discrimination between patients and healthy subjects is best shown by analysis by WB than by the IFA. As no relationship between BDV and deficit syndrome was found in our study, further investigations are needed with larger samples and using the WB method. In conclusion, our study does not confirm the existence of an association between BDV and psychiatric disorders especially schizophrenia or depression. This study does however have the advantage of certifying the presence of BDV in human being in a region in France (Normandy) which is a rural region well-known for horse rearing.
References Bode, L., Riegel, S., Ludwig, H., et al., 1988. Borna disease virusspecific antibodies in patients with HIV infection and with mental disorders. Lancet 2 (8612), 689. Bode, L., Riegel, S., Lange, W., et al., 1992. Human infections with Borna disease virus: seroprevalence in patients with chronic diseases and healthy individuals. J. Med. Virol. 36, 309 – 315. Chen, C.-H., Chiu, Y.-L., Wei, F.-C., et al., 1999. High seroprevalence of Borna virus infection in schizophrenic patients, family members and mental health workers in Taiwan. Mol. Psychiatry 4, 33 – 38. Fukuda, K., Takahashi, K., Iwata, Y., et al., 2001. Immunological and PCR analyses for Borna disease virus in psychiatric patients and blood donors in Japan. J. Clin. Microbiol. 39 (2), 419 – 429. Igata-Yi, R., Yamaguchi, K., Yoshiki, K., et al., 1996. Borna disease virus and the consumption of raw horse meat. Nat. Med. 2 (9), 948 – 949. Kirkpatrick, B., Buchanan, R.W., Mc Kennedy, P.D., et al., 1989. The schedule for the deficit syndrome: an instrument for research in schizophrenia. Psychiatry Res. 30 (2), 119 – 123. Kubo, K., Fujiyoshi, T., Yokoyama, M.M., et al., 1997. Lack of association of Borna disease virus and human T-Cell leukemia virus Type 1 infections with psychiatric disorders among Japanese patients. Clin. Diagn. Lab. Immunol. 4 (2), 189 – 194. Rott, R., Herzo, S., Fleischer, B., et al., 1985. Detection of serum antibodies to Borna disease virus in patients with psychiatric disorders. Science 228 (4700), 755 – 756. Waltrip II, R.W., Buchanan, R.W., Summerfelt, A., et al., 1995. Borna disease virus and schizophrenia. Psychiatry Res. 56 (1), 33 – 44. Waltrip II, R.W., Buchanan, R.W., Carpenter, W.T., et al., 1997. Borna disease virus antibodies and the deficit syndrome of schizophrenia. Schizophr. Res. 23, 157 – 253. Yamaguchi, K., Sawada, T., Naraki, T., et al., 1999. Detection of Borna disease virus-reactive antibodies from patients with psychiatric disorders and from horses by electrochemiluminescence immunoassay. Clin. Diagn. Lab. Immunol. 6 (5), 696 – 700.
Pierrick Lebain Centre Esquirol, Centre Hospitalier Universitaire, Avenue Coˆte de Nacre, 14033 Caen Cedex, France
Acknowledgements We are grateful to Sibylle M. Herzog for kindly providing us with BDV-infected MDCK cells and the French health Ministry which sponsored this study in a Programme Hospitalier de Recherche Clinique.
Astrid Vabret Francßois Freymuth Laboratoire de Virologie Humaine et Mole´culaire, Centre Hospitalier Universitaire, Avenue G. Cle´menceau, 14033 Caen Cedex, France
Letter to the Editors
Perrine Brazo Benoıˆt Chabot Sonia Dollfus * Centre Esquirol, Centre Hospitalier Universitaire, Avenue Coˆte de Nacre, 14033 Caen Cedex, France Groupe d’Imagerie Neurofonctionnelle (GIN), UMR 6095 CNRS/CEA/Universite´ de Caen/ Universite´ de Paris V, Centre Cyce´ron, Bd Henri Becquerel. 14000 Caen, France E-mail address: [email protected] 20 June 2001 * Corresponding author. GIN and Centre Esquirol, Centre Hospitalier et Universitaire, CHU de Caen, Avenue Cote de Nacre, 14033 Caen, France. Tel.: +33-231065018; fax: +33-231064987.
305
Letter to the Editors
Borna disease virus and psychiatric disorders Borna disease virus (BDV) is an infectious agent which can persistently infect the central nervous system of a broad spectrum of animal species. Horses and sheep are natural hosts, but BDV can be transmitted to other animal species. It is a neurotropic, enveloped, negative-strand RNA virus. It is the prototype genus of a new family, Bornaviridae, within the order of the Mononegavirals. In animals, BDV infection spreads intra-axonally and exhibits a preferential tropism for the limbic system, including the hippocampus. The symptomatology in animals ranges from subclinical infection to meningoencephalitis and to rare cases of encephalitis. Several seroepidemiologic data suggest that BDV might be present in humans, possibly associated with neuropsychiatric disorders. Furthermore, viral antigen was detected in human autopsy brain tissue by immunohistochemical staining. BDV antibodies, antigen or BDV RNA were also found significantly more frequently in blood of patients with schizophrenia, depression, and unspecific psychiatric disorders than in controls (Rott et al., 1985; Waltrip et al., 1995, 1997; Chen et al., 1999). However, some studies did not find any relationship between BDV detection and psychiatric disorders (Bode et al., 1992; Kubo et al., 1997; Fukuda et al., 2001). In this context, this study researched the relationship between depression, schizophrenia and BDV by detection of BDV antibodies in sera. Eighty-seven patients (inpatients and outpatients) were investigated in the psychiatry department of the university hospital center in Caen (Centre Esquirol, France). Inpatients were investigated just before discharge. Sixty-three were subjects with schizophrenia and 24 had unipolar depression (DSM IV criteria). Fifty-four patients were categorized in the deficit (N = 8) and nondeficit (N = 46)
subtypes with the Schedule of the Deficit Syndrome (SDS) (Kirkpatrick et al., 1989). Written informed consent was obtained from all patients after complete description of the study. Two hundred and ninety healthy subjects were included in this study. They were blood donors (N = 200) or workers in the hospital departments other than in psychiatry (N = 90). Antibodies to BDV were detected in human sera by an indirect immunofluorescence assay (IFA) as previously described by Rott et al. (1985). Slides of persistently infected MDCK-cells and FITC-conjugated goat antiserum to human IgG were used in the test. In human sera containing BDV antibodies, virus-infected MDCK-cells showed typical granular, focal fluorescence in the nucleus. BDV antibodies containing serum did not react with uninfected cells and were retested on a new batch of MDCK-cells to be confirmed. The immunofluorescence test was carried out in blind of the psychiatric diagnosis to avoid any subjectivity in the interpretation of results. For this purpose, clinical and serum data were always collected independently. Out of the 87 psychiatric patients, 11 (12.6%) were seropositive. Eight (12.7%) subjects with schizophrenia and three (12.5%) depressed patients were seropositive. No deficit patient was seropositive and seven (15.2%) non deficit patients were seropositive. Forty-five (15.5%) healthy subjects also presented a BDV seropositivity, without significant difference between blood donors and hospital workers. Our study has the advantage of focusing on subjects originating from the same region in France (Normandy). This is the first human study of the sort realized in France. Images obtained of the BDV are characteristic and specific in IFA. Moreover, each seropositive serology was controlled on uninfected cells so as to make sure of the specificity of the result. For all that, this study did not find any relation
0920-9964/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 9 2 0 - 9 9 6 4 ( 0 1 ) 0 0 3 1 7 - 6
304
Letter to the Editors
between depression or schizophrenia and BDV serology by IFA. Furthermore, no relation was observed between the deficit syndrome and BDV seropositivity. Our study is limited by the small size of the sample (especially for the depressive patient group). However, Bode et al. (1988, 1992) and Kubo et al. (1997) have described no correlation by IFA on larger populations of patients with affective disorders. Similarly, some studies (Waltrip et al., 1995; Kubo et al., 1997) have not shown a more frequent seropositivity by IFA among subjects with schizophrenia. On the other hand, some studies have shown (by IFA) a more frequent seropositivity among the patients who suffer either from various psychiatric pathologies (Rott et al., 1985) or affective disorders and/or schizophrenia (Igata-Yi et al., 1996; Yamaguchi et al., 1999). Furthermore, no deficit subjects with schizophrenia was seropositive in our study. This is opposite to the results of Waltrip et al. (1997) showing an association between deficit syndrome and BDV seropositivity by the method of the Western Blot (WB). This discrepancy could be due to the different methods used, WB in Waltrip’s study and IFA in ours. According to Waltrip et al. (1995), the discrimination between patients and healthy subjects is best shown by analysis by WB than by the IFA. As no relationship between BDV and deficit syndrome was found in our study, further investigations are needed with larger samples and using the WB method. In conclusion, our study does not confirm the existence of an association between BDV and psychiatric disorders especially schizophrenia or depression. This study does however have the advantage of certifying the presence of BDV in human being in a region in France (Normandy) which is a rural region well-known for horse rearing.
References Bode, L., Riegel, S., Ludwig, H., et al., 1988. Borna disease virusspecific antibodies in patients with HIV infection and with mental disorders. Lancet 2 (8612), 689. Bode, L., Riegel, S., Lange, W., et al., 1992. Human infections with Borna disease virus: seroprevalence in patients with chronic diseases and healthy individuals. J. Med. Virol. 36, 309 – 315. Chen, C.-H., Chiu, Y.-L., Wei, F.-C., et al., 1999. High seroprevalence of Borna virus infection in schizophrenic patients, family members and mental health workers in Taiwan. Mol. Psychiatry 4, 33 – 38. Fukuda, K., Takahashi, K., Iwata, Y., et al., 2001. Immunological and PCR analyses for Borna disease virus in psychiatric patients and blood donors in Japan. J. Clin. Microbiol. 39 (2), 419 – 429. Igata-Yi, R., Yamaguchi, K., Yoshiki, K., et al., 1996. Borna disease virus and the consumption of raw horse meat. Nat. Med. 2 (9), 948 – 949. Kirkpatrick, B., Buchanan, R.W., Mc Kennedy, P.D., et al., 1989. The schedule for the deficit syndrome: an instrument for research in schizophrenia. Psychiatry Res. 30 (2), 119 – 123. Kubo, K., Fujiyoshi, T., Yokoyama, M.M., et al., 1997. Lack of association of Borna disease virus and human T-Cell leukemia virus Type 1 infections with psychiatric disorders among Japanese patients. Clin. Diagn. Lab. Immunol. 4 (2), 189 – 194. Rott, R., Herzo, S., Fleischer, B., et al., 1985. Detection of serum antibodies to Borna disease virus in patients with psychiatric disorders. Science 228 (4700), 755 – 756. Waltrip II, R.W., Buchanan, R.W., Summerfelt, A., et al., 1995. Borna disease virus and schizophrenia. Psychiatry Res. 56 (1), 33 – 44. Waltrip II, R.W., Buchanan, R.W., Carpenter, W.T., et al., 1997. Borna disease virus antibodies and the deficit syndrome of schizophrenia. Schizophr. Res. 23, 157 – 253. Yamaguchi, K., Sawada, T., Naraki, T., et al., 1999. Detection of Borna disease virus-reactive antibodies from patients with psychiatric disorders and from horses by electrochemiluminescence immunoassay. Clin. Diagn. Lab. Immunol. 6 (5), 696 – 700.
Pierrick Lebain Centre Esquirol, Centre Hospitalier Universitaire, Avenue Coˆte de Nacre, 14033 Caen Cedex, France
Acknowledgements We are grateful to Sibylle M. Herzog for kindly providing us with BDV-infected MDCK cells and the French health Ministry which sponsored this study in a Programme Hospitalier de Recherche Clinique.
Astrid Vabret Francßois Freymuth Laboratoire de Virologie Humaine et Mole´culaire, Centre Hospitalier Universitaire, Avenue G. Cle´menceau, 14033 Caen Cedex, France
Letter to the Editors
Perrine Brazo Benoıˆt Chabot Sonia Dollfus * Centre Esquirol, Centre Hospitalier Universitaire, Avenue Coˆte de Nacre, 14033 Caen Cedex, France Groupe d’Imagerie Neurofonctionnelle (GIN), UMR 6095 CNRS/CEA/Universite´ de Caen/ Universite´ de Paris V, Centre Cyce´ron, Bd Henri Becquerel. 14000 Caen, France E-mail address: [email protected] 20 June 2001 * Corresponding author. GIN and Centre Esquirol, Centre Hospitalier et Universitaire, CHU de Caen, Avenue Cote de Nacre, 14033 Caen, France. Tel.: +33-231065018; fax: +33-231064987.
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