A synopsis of this potentially important emerging disease has been published in the journal Emerging Infectious Diseases. The article (by Hatalski, Lewis and Lipkin) can be located at:

http://www.cdc.gov/ncidod/EID/vol3no2/hatalski.htm

Hatalski et al's article is comprehensive and substantial, and appears to be an excellent contribution toward increasing awareness of this important pathogen.

We have been interested in this virus for some time because of its possible connection with schizophrenia, and present our own review below.

Borna Disease Virus -- Malloy CD and Marr JS

Introduction. Borna Disease Virus (BDV) is a unique agent associated with neurologic disease in a broad array of animals, and has recently been implicated as a possible cause of human affective disorders. Named after a town in Saxony, Germany where the disease was first described in 1766 in horses, (1) BDV has continued to cause epizootics among horses in that country, as well as other animal species worldwide.

Agent. BDV is a non-classified, enveloped, nonsegmented, negative-strand RNA virus (2) which replicates in cell nuclei. Although the virus has never been visualized, it has been successfully grown in vitro in embryonic brain cells (astrocytes and oligodendrocytes) in a variety of animal species.

Host range. In equids, BD has been referred to as "Sad Horse" Disease. Symptomatic infection manifests itself with agitated and aggressive changes, often progressing to inanition and death in several weeks. (3) In horses, other natural hosts and experimental animal models, BDV infection can develop neurologic, cognitive and behavioral changes including hyperactivity, somnolence, apathy, anorexia and depression. As a natural infection, BDV was initially identified in horses and later sheep; it was then observed infecting donkeys, mules, llamas, alpacas,cattle, rabbits, and ostriches. (4) Experimentally, BDV has been transmitted to "an extraordinary wide range of host species, including chickens, shrews, rats, mice and Rhesus monkeys." (5)

Recent attention has been placed on feline Borna disease virus, isolated from the CSF of cats suffering from a spontaneous non-suppurative encephalomyelitis, also referred to as "staggering disease." (6) (7) In some animals, behavioral changes include both aggressive and passive stages. (8) Such biphasic manifestations, present in a broad array of species, led to initial hypotheses that BDV could be related to affective disorders among humans.

Incubation period, mode of transmission. An incubation period of four weeks has been estimated for horses and sheep. (4) In animals, the mode of spread appears to be by direct contact and exposure to the virus via saliva and nasal secretions. (4)

Animal pathophysiology. Although almost every cell line can be experimentally infected, (9) BDV is primarily a neurotropic virus. The agent enters axons of peripheral nerves, spreading centripetally toward the central nervous system through peripheral nerves or the olfactory bulb. (10) Experimentally, BDV has been induced by intracerebral injection and nasal inoculation. (4) In animal models, BDV has been identified as targeting the limbic/hypothalamic region, (8) causing changes in the dopamine neurotransmission. (11)

As disease progresses, centrifugal spread occurs to ganglia of peripheral nerves. Recently, BDV has been isolated from peripheral blood mononuclear cells. (12)

Morbidity and mortality rates. Although some species of infected animals are asymptomatic, some studies have shown mortality rates in horses as high as 80-100%; in sheep, mortality rates are >50%. (4)

Seroepizoological studies. Subclinical BDV infections have been shown to predominate in horses, with the only symptoms being attacks of colic. (4) Longitudinal monitoring of asymptomatic seropositive horses resulted in the observation of several cases; however, the majority of these horses did not manifest clinical symptoms over the following five years. (4) Seroprevalence studies have demonstrated a 13% seropositivity in cats in Germany suffering neurological disorders. (7)

Hypotheses for an exogenous cause for schizophrenia. A number of researchers have posited an infectious etiology for human affective disorders. Descriptive epidemiologic studies have shown that schizophrenia is unequally distributed in time and place. (13) A majority of sporadic cases of schizophrenia as well as monozygotic twin studies (14) do not demonstrate a clear genetic etiology. These sporadic cases were more likely to be born in winter (15); other studies link schizophrenia to prenatal environmental factors such as malnutrition, (16, 17) and other gestational factors. (18, 19) Numerous viruses have also been implicated as a cause of schizophrenia, (20) including influenza (13) and tick born viral agents. (21) More recently, a case control study supported the association of cat ownership with schizophrenia. (22)

Studies linking BDV to human affective disorders. In the United States, seropositivity to BDV of 4.5% was found in 265 patients with diagnoses of primary depressive disorders. (8) Bode summarizes these results, as well as other studies in various psychiatric/neurologic disorders, (10) with seroprevalence findings ranging from a low of 0% in chronic fatigue syndrome to a high of 23.3% in acute psychiatric patients in follow-up testing. These findings have demonstrated a wide geographic distribution of BDV, with studies conducted in Central Europe, North America, East Africa and Japan. (10)

Discussion and conlusion. Viral diseases demonstrate a range of host specificity -- extending from those viruses that exclusively infect humans (i.e., smallpox), to those that are zoonotic in nature (i.e., the influenza group). Other viruses have been shown to have recently "jumped" species (canine parvovirus 2). (23) Most viruses demonstrate organ specificity, including nervous tissue.

Human neurotropic viral illnesses range from a benign, acute illness (mumps), to acute progressive disease (subacute sclerosing panencephalitis), to an acute progressive, uniformly fatal illness (rabies). Other neurotrophic viral illnesses are subacute (cytomegalovirus disease), or persistent and remittent (herpes) which may be activated by unknown mechanisms. The rabies virus is an example of a zoonotic neurotropic viral agent, transmitted by saliva and spread intra-axonally to the central nervous system causing a fatal encephalitis. The rabies reservoir includes a wide variety of mammals which, upon occasion, include humans.

Independent of present day serosurveys and limited intervention studies, to hypothesize that a virion such as BDV causes lingering, subacute central nervous dysfunction, is not implausible or irresponsible. The work of Bode (10, 22-26) and others suggest that further epidemiologic and epizoologic studies are needed to clarify the relationship between BDV, human host companions, modes of transmission, and human disease.

References

1. Gellert M, " 'In the beginning the horse is sad,': A historical abstract of Borna Disease," Tierarztl Prax, 23(3):207-16, 1995.

2. Schneeman A, Schneider PA, Lamb RA and Lipkin WI, "The remarkable coding strategy of Borna disease virus: A new member of the nonsegmented negative strand RNA viruses," Virology, 210(1):1-8, 1995.

3. Lipkin WI, Schneeman A and Solbrig MV, "Borna disease virus: Implications for human neuropsychiatric illness," Trends in Microbiology, 3(2):64-9, 1995.

4. Rott R and Becht H, "Natural and experimental Borna disease in Animals,"Current Topics in Microbiology and Immunology, 190:17-30, 1995.

5. Briese T, Lipkin WI and de la Torre JC, "Molecular biology of Borna disease virus," Current Topics in Microbiology and Immunology, 190:1-16, 1995.

6. Bignall J, "Staggering cats at Queens'," Lancet, 349, (9057), 1997.

7. Lundgren AL, Zimmerman W, Bode L, Czech G, Gosztonyi G, Lindberg R and Ludwig H, "Staggering disease in cats: Isolation and characterization of the feline Borna disease virus," Journal of General Virology, 76(Pt 9):2215-22, 1995.

8. Amsterdam JD, Winokur A, Dyson W, et al, "Borna disease virus: A possible etiologic factor in human affective disorders?," Archives of General Psychiatry, 42(11):1093-6, 1985.

9. Ludwig H, Bode L and Gosztonyi G, "Borna disease: A persistent virus infection of the central nervous system," Progress in Medical Virology, 35:107-51, 1988.

10. Bode L, "Human infections with Borna disease virus and potential pathogenic implications,"Current Topics in Microbiology and Immunology, 190:103-30, 1995.

11. Solbrig MV, Fallon JH and Lipkin WI, "Behavioral disturbances and pharmacology of Borna disease," Current Topics in Microbiology and Immunology, 190:93-101, 1995.

12. Nakaya T, Takahashi H, Nakamura Y, Asahi S, Tobiume M, Kuratsune H, Kitani T, Yamanishi K and Ikuta K, "Demonstration of Borna disease virus RNA in peripheral blood mononuclear cells derived from Japanese patients with chronic fatigue syndrome," FEBS Letters, 378(2):145-9, 1996.

13. Wright P and Murray RM, "Schizophrenia: Prenatal influenza and autoimmunity," Annals of Medicine, 25(5):497-502, 1993.

14. Torrey EF, Taylor EH, Bracha HS, et al, "Prenatal origin of schizophrenia in a subgroup of discordant monozygotic twins," Schizophrenia Bulletin, 20(3):423-32, 1994.

15. Roy MA, Flaum MA, Gupta S, et al, "Epidemiological and clinical correlates of familial and sporadic schizophrenia," Acta Psychiatrica Scandinavica, 89(5):324-8, 1994.

16. Susser ES and Lin SP, "Schizophrenia after prenatal exposure to the Dutch Hunger Winter of 1944-1945," Archives of General Psychiatry, 49(12):983-8, 1992.

17. Susser E, Neugebauer R, Hoek HW, et al, "Schizophrenia after prenatal famine. Further evidence," Archives of General Psychiatry, 53(1):25-31, 1996.

18. Huttunen MO, Machon RA and Mednick SA, "Prenatal factors in the pathogenesis of schizophrenia," British Journal of Psychiatry - Supplement, 164(23):15-19, 1994.

19. Rifkin L, Lewis S, Jones P, et al, "Low birth weight and schizophrenia," British Journal of Psychiatry, 165(3):357-62, 1994.

20. Yolken RH and Torrey EF, "Viruses, schizophrenia, and bipolar disorder," Clinical Microbiology Reviews, 8(1):131-45, 1995.

21. Brown JS, "Geographic correlation of schizophrenia to ticks and tick-borne encephalitis," Schizophrenia Bulletin, 20(4):755-75, 1994.

22. Torrey EF and Yolken RH, "Could schizophrenia be a viral zoonosis transmitted from house cats?," Schizophrenia Bulletin, 21(2):167-71, 1995.

23. Morse SS, Emerging Viruses, Oxford University Press, New York, 1993.

24. Bode L, Dietrich DE, Stoyloff R, Emrich HM and Ludwig H, "Amantadine and human Borna disease virus in vitro and in vivo in an infected patient with bipolar depression," Lancet, 349:178, 1997.

25. Bode L, Komaroff and Ludwig H, "No serologic evidence of Borna disease virus in patients with chronic fatigue syndrome," Clinical Infectious Diseases, 15(6):1049, 1992.

26. Bode L, Rigel S, Ludwig H, Amsterdam JD, Lange W and Koprowski H, "Borna disease virus-specific antibodies in patients with HIV infection and with mental disorders," Lancet, 2(8612):689, 1988.