291
Psychiatry Research, 42:291-294
Elsevier
Letter Borna Disease Virus: Possible Causal Agent in Psychiatric and Neurological Disorders in Two Families To the Editors:
Borna Disease (BD) is a well-known encephalomyelitis in horses and sheep in Central Europe (Zwick et al., 1926). The strongly neurotropic Borna Disease Virus (BDV) is not yet clearly characterized. It seems to combine properties of conventional and unconventional viruses and typically leads to persistent infection (Narayan et al., 1983; Duchala et al., 1989). After spontaneous and experimental intranasal infection of rats, the virus spreads intra-axonally from the olfactory epithelia to the brain (Carbone et al., 1987; Morales et al., 1988). The experimental BD of animals clearly demonstrates a great variability in symptomatology and course of illness that is dependent upon the host species and the virus variant (Sprankel et al., 1978; Narayan et al., 1983). Both neurological symptoms and behavioral abnormalities have been observed. A possible role of BDV in the etiology of human mental disorders such as affective psychosis or schizophrenia has been suggested, but it has remained unclear (Crow, 1984; Amsterdam et al., 1985; Rott et al., 198.5; Bechter and Herzog, 1990). Despite the fact that higher prevalence rates of BDV serum antibodies in psychiatric than in surgical patients have been found, the distribution of psychiatric diagnoses between BDV-seropositive and BDV-seronegative psychiatric patients was
very similar (Bechter and Herzog, 1990). An etiologic role of BDV for one specific psychiatric disorder is therefore unlikely, but a contributing or initiating role of BDV to different psychiatric syndromes is possible. The virus-specificity of the human antibodies was substantiated by the recent finding that they recognize a BDV-specific 24 kd antigen encoded by a cDNA, which hybridized specific transcripts from BDV-infected rats and MDCK cells (Vande Woude et al., 1990). Therefore, interesting clinical cases may prove useful. Here we report on two family cases with antibodies in the serum against BDV: If BDV played a pathogenic role in mental disorders, we hypothesized that BDV serum antibodies and psychiatric or neurological disorders would occur in family members. The onset of these disorders should also coincide in time. We reviewed the charts of 200 BDV-seropositive psychiatric patients in an attempt to find the coincident onset of mental and neurological disorders in a time span of 1 year in each family. Four families who met these criteria were identified in this way; we were able to study two of the families. In both families we found not only in our primary patient but also in a second family member psychiatric or neurological illness as well as BDV serum antibodies.
0 165-l 78 l/92/ $05.00 @ I992 Elsevier Scientific Publishers Ireland Ltd
292 Family H. In a 26-year-old man DBV serum antibodies (1:20) had been found on his seventh treatment as an inpatient. He had not been tested earlier. He was suffering from a chronic schizophrenic disorder, disorganized type (295.14, DSM-III-R) that began in 1979. It was noted in the patient’s records that some months before subacute onset of his disease, his mother had encephalitis. With his mother’s consent, we reviewed her neurological records and tested her for BDV serum antibodies. Her serum showed BDV serum antibodies with a titer of 1:40. In the chart from her inpatient treatment in 1979, a severe encephalitis was described with disorientation, aphasia, reflex disturbances, slight right hemiparesis, and typical organic brain syndrome without meningism. The encephalitis with high cell numbers (130/ mm3) was interpreted as viral encephalitis. Many standard etiologic agents had been tested in serum and cerebrospinal fluid (CSF) with negative results. She never recovered completely from this disease. She continued to suffer from chronic headache and subsequently developed an organic personality syndrome with a tendency toward depressive reactions (310.10, DSM-III-R), which we found in our current examination. About 5 years and 2 years before 1979, she also suffered from periods of severe headache, hemihypesthesia, and discrete left facial paresis. In 1982, she suffered a slight relapse, with aphasia and paresthesias. An examination of the patient’s CSF failed to disclose abnormalities. Elevations of antinuclear antibodies and gamma globulins were found in the patient’s serum. Magnetic resonance imaging (MRI) of the mother now revealed severe leukodystrophy-like white matter lesions that were compatible with a postencephalitic state. An MRI examination of the son was normal. CSF samples from both subjects were not obtained in the current investigation. Family H. reported that they kept three sheep over several years in the time period before and during the onset of the neuropsychiatric disorders. Family S. Our primary patient was a 34year-old woman with schizophrenic disorder, paranoid type (295.34, DSM-III-R), who had had a subacute onset of the disorder 7 years ago. After several relapses, she current-
ly needed another inpatient stay. She was tested for the first time for BDV serum antibodies and showed positive results (1:360). During the year in which her illness began, the patient’s mother developed major depression with melancholia (296.35, DSMIII-R). Serum from the mother was also tested and showed BDV serum antibodies (1:40). The mother’s illness has a more chronic course. From age 18 the mother had been working at a shepherd’s farm in an endemic BD region for 3 years. Since about that time, she suffered from chronic relapsing headache. In the year of onset of the two disorders, the primary patient’s brother (the mother’s son) also developed a schizophrenic disorder, paranoid type (295.32, DSM-IIIR). He showed no BDV serum antibodies. (It has been reported in acute BD in horses that serum antibody titers may be extremely low [Lange et al., 19871. A failure to detect BDV serum antibodies is therefore possible.) The mother described a possibly interesting pattern of symptomatology at the beginning of her disorder: severe pain of a drawing character in the whole body. (In BDVinfected rats a hyperpathia can be observed in the acute phase of the disease; S. Herzog, personal communication.) At the onset of their illnesses, the afflicted members of both Family H. and Family S. shared a common household. However, the healthy fathers in both households were BDV-seronegative. Two additional families have been investigated. In these families, the onsets of the disorders were not coincident in time. Only the primary patients from these families showed BDV serum antibodies, which were not found in any of the other psychiatrically ill family members. Conclusion The findings in Family H. and Family S. could suggest a possible coinfection of family members by BDV and a possible pathogenic role of BDV for the subjects’ neurologic and psychiatric disorders. This speculation is compatible with the complex~pathogenesis of the variable symptomatology in BD in animals, which is mainly influenced by the route of infection, age, and immune status of the host and also by genetic factors of the
293
host. Experimental infection of blackhooded rats with BDV showed that genetic factors not only control whether persisting BDV infections occur, with or without inflammatory lesions, but also whether inflammatory lesions lead to clinical symptomatology (Herzog et al., 1991). The factors responsible for occurrence of clinical symptomatology are unknown but may suggest different underlying neurotransmitter disturbances. Long viral latencies and relapses after years or months have been described in natural BD (Schmidt, I9 12; Gorttler and Vohringer, 1954) and in experimental BDV infection in the rat. These relapses show the typical symptoms of the disease and an increased virus replication in the brain (S. Herzog, personal communication). A parallel to that pattern may also occur in human patients. Our observations could suggest a common infection by BDV as a means of horizontal transmission of BDV in humans. However, the following methodological weaknesses of our case study should be considered: the charts of the patients were examined retrospectively, so the data must be considered incomplete; the onset of psychiatric disorders, especially schizophrenia, may be slowly progressive and therefore hard to define (we used the reported age of onset of severe symptomatology and subsequent hospital treatment). But our observation should encourage further research in BDV, which earlier was thought to be nonpathogenic for humans. A most recent investigation suggests that BDV serum antibodies occur in a remarkable number of newly admitted psychiatric (n = 2377) and neurologic (n = 1791) patients. In a subgroup of psychiatric patients with functional psychoses and personality disorders, such as neurologic patients with unclear syndromes (including acute lymphocytic meningoencephalitis, possibly BDV-related), these findings may have etiologic relevance (Bechter et al., in press). The possible significance of BDV for certain human psychiatric and neurologic disorders is supported by recent results obtained by inoculation of CSF into rabbits and cell cultures, which suggested the presence of BDV or a related agent in CSF of three of our BDV-seropositive patients (Rott et al., 1991).
References Amsterdam, J.D.; Winokur, A.; Dyson, W.; Herzog, S.; Gonzales, F.; Rott, R.; and Koprowski, H. Borna Disease Virus: A possible etiologic factor in human affective disorders? Archives of General Psychiatr_v. 42:1093-1096,
1985.
Bechter, K.; and Herzog, S. LJber Beziehungen der Borna’schen Krankheit zu endogenen Psychosen. In: Kaschka, W.P., and Aschauer, H.N., eds. Psychoimmunologie. Stuttgart: Thieme Verlag, 1990. pp. 133-141. Bechter, K.; Herzog, S.; and Schiittler, R. Possible significance of Borna Disease for humans. Neurology, Psychiatry and Brain Research, in press. Carbone, K.M.; Duchala, C.S.; Griffin, J.W.; Kincaid, A.L.; and Narayan, 0. Pathogenesis of Borna Disease in rats: Evidence that intra-axonal spread is the major route for virus dissemination and the determinant for disease incubation. Journal of Virology, ll:3431-3440, 1987. Crow, T.J. A re-evaluation of the viral hypothesis: Is psychosis the result of retroviral integration at a site close to the cerebral dominance gene? British Journal of Psychiatry,
145:243-253,
1984.
Duchala, C.S.; Carbone, K.M.; and Narayan, 0. Preliminary studies on the biology of Borna Disease Virus. Journal of General Virology, 70:3507-35 I 1, 1989. Gorttler, V., and Vohringer, K. Die Behandlung der Borna’schen Krankheit mit Sulfonamiden. Monatshefte fir Veteriniirmedizin (Leipzig), 9:245-252, 1954. Herzog, S.; Frese, K.; and Rott, R. Studies on the genetic control of resistance of blackhooded rats to Borna Disease. Journal of General Virology, 721535-540, 1991. Lange, H.; Herzog, S.; Herbst, W.; and Schliesser, T. Seroepidemiologische Untersuchungen zur Borna-schen Krankheit (Ansteckende Gehirn- und Rtickenmarksentziindung) der Pferde. Tiertirztliche Umschau.
42:938-946,
1987.
Morales, J.A.; Herzog, S.; Kompter, C.; Frese, K.; and Rott, R. Axonal transport of Borna Disease Virus along olfactory pathways in spontaneously and experimentally infected rats. Medical Microbiology and Immunology. 177151-68, 1988.
294 Narayan, 0.; Herzog, S.; Frese, K.; Scheefers, H.; and Rott, R. Pathogenesis of Borna Disease in rats: Immune-mediated viral opthalmoencephalopathy causing blindness and behavioral abnormalities. Journal of Infectious Diseases, 148:305-3 15, 1983. Rott, R.; Herzog, S.; Bechter, K.; and Frese, K. Borna Disease, a possible hazard for man? Archives of Virology, 118:143-149, 1991. Rott, R.; Herzog, S.; Fleischer, B.; Winokur, A.; Amsterdam, J.; Dyson, W.; and Koprowski, H. Detection of serum antibodies to Borna Disease Virus in patients with psychiatric disorders. Science, 228755-756, 1985. Schmidt, J. Untersuchungen iiber das klinische Verhalten der seuchenhaften Gehirnund Riickenmarksentziindung (Borna’schen Krankheit) des Pferdes nebst Angaben iiber diesbeztigliche therapeutische Versuche. Berliner tieriirztliche Wochenschrift, 28:58 I586, 597-603, 1912. Sprankel, H.; Richarz, K.; Ludwig, H.; and Rott, R. Behavior alterations in tree shrews (Tupaia glis; Diard, 1820) induced by Borna Disease Virus. Medical Microbiology and Immunology, 165:1-18, 1978. Vande Woude, S.; Richt,J.A.; Zink, M.C.; Rott, R.; Narayan, 0.; and Clements, J.E. A Borna Virus cDNA encoding a protein recognized by antibodies in humans with behavioral diseases. Science, 250: 1278-1281, 1990.
Zwick, W.; Seifried, 0.; and Witte, J. Experimentelle Untersuchungen iiber die seuchenhafte Gehirn- und Riickenmarksentziindung der Pferde (Borna’sche Krankheit). Infektionskrankheiten der Haustiere, 30:42136, 1926. Karl Bechter, M.D.’ Reinhold Schiittler, M.D. Department of Psychiatry 11 University of Ulm and Department of Psychiatry Bezirkskrankenhaus Giinzburg, Germany
of the
Sibylle Herzog, Ph.D. Institute of Virology Justus-Leibig-University Gieben, Germany November 20, 1991
1. Reprint requests to Dr. K. Bechter, Department of Psychiatry II, University of Ulm, LudwigHeilmeyer-Str. 2. D-8870 Giinrburg, Germany.
Psychiatry Research, 42:291-294
Elsevier
Letter Borna Disease Virus: Possible Causal Agent in Psychiatric and Neurological Disorders in Two Families To the Editors:
Borna Disease (BD) is a well-known encephalomyelitis in horses and sheep in Central Europe (Zwick et al., 1926). The strongly neurotropic Borna Disease Virus (BDV) is not yet clearly characterized. It seems to combine properties of conventional and unconventional viruses and typically leads to persistent infection (Narayan et al., 1983; Duchala et al., 1989). After spontaneous and experimental intranasal infection of rats, the virus spreads intra-axonally from the olfactory epithelia to the brain (Carbone et al., 1987; Morales et al., 1988). The experimental BD of animals clearly demonstrates a great variability in symptomatology and course of illness that is dependent upon the host species and the virus variant (Sprankel et al., 1978; Narayan et al., 1983). Both neurological symptoms and behavioral abnormalities have been observed. A possible role of BDV in the etiology of human mental disorders such as affective psychosis or schizophrenia has been suggested, but it has remained unclear (Crow, 1984; Amsterdam et al., 1985; Rott et al., 198.5; Bechter and Herzog, 1990). Despite the fact that higher prevalence rates of BDV serum antibodies in psychiatric than in surgical patients have been found, the distribution of psychiatric diagnoses between BDV-seropositive and BDV-seronegative psychiatric patients was
very similar (Bechter and Herzog, 1990). An etiologic role of BDV for one specific psychiatric disorder is therefore unlikely, but a contributing or initiating role of BDV to different psychiatric syndromes is possible. The virus-specificity of the human antibodies was substantiated by the recent finding that they recognize a BDV-specific 24 kd antigen encoded by a cDNA, which hybridized specific transcripts from BDV-infected rats and MDCK cells (Vande Woude et al., 1990). Therefore, interesting clinical cases may prove useful. Here we report on two family cases with antibodies in the serum against BDV: If BDV played a pathogenic role in mental disorders, we hypothesized that BDV serum antibodies and psychiatric or neurological disorders would occur in family members. The onset of these disorders should also coincide in time. We reviewed the charts of 200 BDV-seropositive psychiatric patients in an attempt to find the coincident onset of mental and neurological disorders in a time span of 1 year in each family. Four families who met these criteria were identified in this way; we were able to study two of the families. In both families we found not only in our primary patient but also in a second family member psychiatric or neurological illness as well as BDV serum antibodies.
0 165-l 78 l/92/ $05.00 @ I992 Elsevier Scientific Publishers Ireland Ltd
292 Family H. In a 26-year-old man DBV serum antibodies (1:20) had been found on his seventh treatment as an inpatient. He had not been tested earlier. He was suffering from a chronic schizophrenic disorder, disorganized type (295.14, DSM-III-R) that began in 1979. It was noted in the patient’s records that some months before subacute onset of his disease, his mother had encephalitis. With his mother’s consent, we reviewed her neurological records and tested her for BDV serum antibodies. Her serum showed BDV serum antibodies with a titer of 1:40. In the chart from her inpatient treatment in 1979, a severe encephalitis was described with disorientation, aphasia, reflex disturbances, slight right hemiparesis, and typical organic brain syndrome without meningism. The encephalitis with high cell numbers (130/ mm3) was interpreted as viral encephalitis. Many standard etiologic agents had been tested in serum and cerebrospinal fluid (CSF) with negative results. She never recovered completely from this disease. She continued to suffer from chronic headache and subsequently developed an organic personality syndrome with a tendency toward depressive reactions (310.10, DSM-III-R), which we found in our current examination. About 5 years and 2 years before 1979, she also suffered from periods of severe headache, hemihypesthesia, and discrete left facial paresis. In 1982, she suffered a slight relapse, with aphasia and paresthesias. An examination of the patient’s CSF failed to disclose abnormalities. Elevations of antinuclear antibodies and gamma globulins were found in the patient’s serum. Magnetic resonance imaging (MRI) of the mother now revealed severe leukodystrophy-like white matter lesions that were compatible with a postencephalitic state. An MRI examination of the son was normal. CSF samples from both subjects were not obtained in the current investigation. Family H. reported that they kept three sheep over several years in the time period before and during the onset of the neuropsychiatric disorders. Family S. Our primary patient was a 34year-old woman with schizophrenic disorder, paranoid type (295.34, DSM-III-R), who had had a subacute onset of the disorder 7 years ago. After several relapses, she current-
ly needed another inpatient stay. She was tested for the first time for BDV serum antibodies and showed positive results (1:360). During the year in which her illness began, the patient’s mother developed major depression with melancholia (296.35, DSMIII-R). Serum from the mother was also tested and showed BDV serum antibodies (1:40). The mother’s illness has a more chronic course. From age 18 the mother had been working at a shepherd’s farm in an endemic BD region for 3 years. Since about that time, she suffered from chronic relapsing headache. In the year of onset of the two disorders, the primary patient’s brother (the mother’s son) also developed a schizophrenic disorder, paranoid type (295.32, DSM-IIIR). He showed no BDV serum antibodies. (It has been reported in acute BD in horses that serum antibody titers may be extremely low [Lange et al., 19871. A failure to detect BDV serum antibodies is therefore possible.) The mother described a possibly interesting pattern of symptomatology at the beginning of her disorder: severe pain of a drawing character in the whole body. (In BDVinfected rats a hyperpathia can be observed in the acute phase of the disease; S. Herzog, personal communication.) At the onset of their illnesses, the afflicted members of both Family H. and Family S. shared a common household. However, the healthy fathers in both households were BDV-seronegative. Two additional families have been investigated. In these families, the onsets of the disorders were not coincident in time. Only the primary patients from these families showed BDV serum antibodies, which were not found in any of the other psychiatrically ill family members. Conclusion The findings in Family H. and Family S. could suggest a possible coinfection of family members by BDV and a possible pathogenic role of BDV for the subjects’ neurologic and psychiatric disorders. This speculation is compatible with the complex~pathogenesis of the variable symptomatology in BD in animals, which is mainly influenced by the route of infection, age, and immune status of the host and also by genetic factors of the
293
host. Experimental infection of blackhooded rats with BDV showed that genetic factors not only control whether persisting BDV infections occur, with or without inflammatory lesions, but also whether inflammatory lesions lead to clinical symptomatology (Herzog et al., 1991). The factors responsible for occurrence of clinical symptomatology are unknown but may suggest different underlying neurotransmitter disturbances. Long viral latencies and relapses after years or months have been described in natural BD (Schmidt, I9 12; Gorttler and Vohringer, 1954) and in experimental BDV infection in the rat. These relapses show the typical symptoms of the disease and an increased virus replication in the brain (S. Herzog, personal communication). A parallel to that pattern may also occur in human patients. Our observations could suggest a common infection by BDV as a means of horizontal transmission of BDV in humans. However, the following methodological weaknesses of our case study should be considered: the charts of the patients were examined retrospectively, so the data must be considered incomplete; the onset of psychiatric disorders, especially schizophrenia, may be slowly progressive and therefore hard to define (we used the reported age of onset of severe symptomatology and subsequent hospital treatment). But our observation should encourage further research in BDV, which earlier was thought to be nonpathogenic for humans. A most recent investigation suggests that BDV serum antibodies occur in a remarkable number of newly admitted psychiatric (n = 2377) and neurologic (n = 1791) patients. In a subgroup of psychiatric patients with functional psychoses and personality disorders, such as neurologic patients with unclear syndromes (including acute lymphocytic meningoencephalitis, possibly BDV-related), these findings may have etiologic relevance (Bechter et al., in press). The possible significance of BDV for certain human psychiatric and neurologic disorders is supported by recent results obtained by inoculation of CSF into rabbits and cell cultures, which suggested the presence of BDV or a related agent in CSF of three of our BDV-seropositive patients (Rott et al., 1991).
References Amsterdam, J.D.; Winokur, A.; Dyson, W.; Herzog, S.; Gonzales, F.; Rott, R.; and Koprowski, H. Borna Disease Virus: A possible etiologic factor in human affective disorders? Archives of General Psychiatr_v. 42:1093-1096,
1985.
Bechter, K.; and Herzog, S. LJber Beziehungen der Borna’schen Krankheit zu endogenen Psychosen. In: Kaschka, W.P., and Aschauer, H.N., eds. Psychoimmunologie. Stuttgart: Thieme Verlag, 1990. pp. 133-141. Bechter, K.; Herzog, S.; and Schiittler, R. Possible significance of Borna Disease for humans. Neurology, Psychiatry and Brain Research, in press. Carbone, K.M.; Duchala, C.S.; Griffin, J.W.; Kincaid, A.L.; and Narayan, 0. Pathogenesis of Borna Disease in rats: Evidence that intra-axonal spread is the major route for virus dissemination and the determinant for disease incubation. Journal of Virology, ll:3431-3440, 1987. Crow, T.J. A re-evaluation of the viral hypothesis: Is psychosis the result of retroviral integration at a site close to the cerebral dominance gene? British Journal of Psychiatry,
145:243-253,
1984.
Duchala, C.S.; Carbone, K.M.; and Narayan, 0. Preliminary studies on the biology of Borna Disease Virus. Journal of General Virology, 70:3507-35 I 1, 1989. Gorttler, V., and Vohringer, K. Die Behandlung der Borna’schen Krankheit mit Sulfonamiden. Monatshefte fir Veteriniirmedizin (Leipzig), 9:245-252, 1954. Herzog, S.; Frese, K.; and Rott, R. Studies on the genetic control of resistance of blackhooded rats to Borna Disease. Journal of General Virology, 721535-540, 1991. Lange, H.; Herzog, S.; Herbst, W.; and Schliesser, T. Seroepidemiologische Untersuchungen zur Borna-schen Krankheit (Ansteckende Gehirn- und Rtickenmarksentziindung) der Pferde. Tiertirztliche Umschau.
42:938-946,
1987.
Morales, J.A.; Herzog, S.; Kompter, C.; Frese, K.; and Rott, R. Axonal transport of Borna Disease Virus along olfactory pathways in spontaneously and experimentally infected rats. Medical Microbiology and Immunology. 177151-68, 1988.
294 Narayan, 0.; Herzog, S.; Frese, K.; Scheefers, H.; and Rott, R. Pathogenesis of Borna Disease in rats: Immune-mediated viral opthalmoencephalopathy causing blindness and behavioral abnormalities. Journal of Infectious Diseases, 148:305-3 15, 1983. Rott, R.; Herzog, S.; Bechter, K.; and Frese, K. Borna Disease, a possible hazard for man? Archives of Virology, 118:143-149, 1991. Rott, R.; Herzog, S.; Fleischer, B.; Winokur, A.; Amsterdam, J.; Dyson, W.; and Koprowski, H. Detection of serum antibodies to Borna Disease Virus in patients with psychiatric disorders. Science, 228755-756, 1985. Schmidt, J. Untersuchungen iiber das klinische Verhalten der seuchenhaften Gehirnund Riickenmarksentziindung (Borna’schen Krankheit) des Pferdes nebst Angaben iiber diesbeztigliche therapeutische Versuche. Berliner tieriirztliche Wochenschrift, 28:58 I586, 597-603, 1912. Sprankel, H.; Richarz, K.; Ludwig, H.; and Rott, R. Behavior alterations in tree shrews (Tupaia glis; Diard, 1820) induced by Borna Disease Virus. Medical Microbiology and Immunology, 165:1-18, 1978. Vande Woude, S.; Richt,J.A.; Zink, M.C.; Rott, R.; Narayan, 0.; and Clements, J.E. A Borna Virus cDNA encoding a protein recognized by antibodies in humans with behavioral diseases. Science, 250: 1278-1281, 1990.
Zwick, W.; Seifried, 0.; and Witte, J. Experimentelle Untersuchungen iiber die seuchenhafte Gehirn- und Riickenmarksentziindung der Pferde (Borna’sche Krankheit). Infektionskrankheiten der Haustiere, 30:42136, 1926. Karl Bechter, M.D.’ Reinhold Schiittler, M.D. Department of Psychiatry 11 University of Ulm and Department of Psychiatry Bezirkskrankenhaus Giinzburg, Germany
of the
Sibylle Herzog, Ph.D. Institute of Virology Justus-Leibig-University Gieben, Germany November 20, 1991
1. Reprint requests to Dr. K. Bechter, Department of Psychiatry II, University of Ulm, LudwigHeilmeyer-Str. 2. D-8870 Giinrburg, Germany.
