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:
Hatalski et al's article is comprehensive and substantial, and appears to be
an excellent contribution toward increasing awareness of this important
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
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
As disease progresses, centrifugal spread occurs to ganglia of peripheral
nerves. Recently, BDV has been isolated from peripheral blood mononuclear
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.
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