Signalment:  

Bavarian Warmblood, 11 yrs, female, equineTwo week history of fever, depression, gait abnormalities and anorexia. The animal was euthanized after unsuccessful symptomatic treatment.

Gross Description:  

At macroscopic inspection, the brain appeared normal.

Histopathologic Description:

Slices of the brain reveal moderate, multifocal, perivascular and parenchyma infiltrating mononuclear immune cells (Fig. 2-1) affecting slightly more gray than white matter with a severe generalized astrogliosis and microglia activation throughout the whole brain. Lesions are most severe in the lateroventral parts of the cerebral cortex, mesencephalon and hippocampal gyrus. Inflammation cells are also infiltrating plexus epithelia and leptomeninges. Moderate neuronal and axonal degeneration (spheroids) can be found and some neurons undergo neuronophagia(Fig. 2-2). No neuronal intranuclear acidophilic inclusion bodies, Cowdry type B, (Joest Degen bodies) are detectable in these slices.

Morphologic Diagnosis:  

Polioencephalitis, meningitis, plexitis, nonpurulent, multifocal, subacute, moderate

Lab Results:  

Brain was positive for Borna disease virus (BDV) antigen by immunohistochemistry and negative for Rabies virus antigen by immunoflourescence test.

Condition:  

Borna disease

Contributor Comment:  

Borna disease occurs naturally in horses, sheep (1), rarely in cats (2, 3), and other warm-blooded animals.(1,4) Borna disease virus has been classified as the prototype of a new virus family, Bornaviridae (mononegavirales) (1, 5), though the disease has been recognized in Central Europe for more than 250 years and apparently in Asia.(6,8) Because experimental infection of rodents, sheep and horses is achievable by intranasal application of virus, some researches already assume that the natural infection with BDV might occur by the olfactory nerve (1, 8, 9) and several studies indicate wild rodents being a common virus reservoir.(1,10)

The highly neurotropic but noncytolytic virus (9), similar to rabies virus, is transported by retrograde axonal transport from the periphery to the CNS. After infection, BDV causes a persistent infection of the central nervous system and induces an immune-mediated encephalomyelitis. The infiltrating immune cells have been characterized as CD4- positive T-cells, CD8-positive T-cells, macrophages and B cells.(11) The virus can then also spread centrifugally via the peripheral nervous system, resulting in infection of nonneural tissue.(9) A proposed mechanism for the behavioral changes involves protein interference with neurotransmitter function of infected neurons, especially those located in the limbic lobe.(12)

The first evidence that some human psychiatric patients might be infected with BDV, or a BDV-related virus, came from serological studies using immunofluorescence assays.(13) However, several key experiments could not be reproduced by independent laboratories and started a still ongoing, highly controversial, worldwide debate about whether BDV infects humans and causes psychiatric problems.(1,14,15) In this case, the detection of viral antigen in fresh brain tissue by immunohistochemistry, the clinical manifestations and the characteristic histopathological changes within the brain all contribute to the diagnosis of Borna disease.

JPC Diagnosis:  

Brain, thalamus: Meningoencephalitis, lymphocytic, multifocal, moderate

Conference Comment:  

Borna disease virus (BDV) is a single-stranded RNA virus and is the sole member of the family Bornaviridae in the order Mononegavirales.(4) It is named after the village Borna in Germany where the first major outbreak of this disease was recognized in the late 1800s.(15) BDV has a very wide host range, but sheep and horses are the most susceptible species to disease. Borna disease is most prevalent in Europe, but positive titers have been found in the United States.(10) Recently, Borna disease virus has been suggested as a potential cause of proventricular dilatation disease in birds. Research is currently ongoing to prove this link. 

Gross lesions are not seen in infections with BDV. Histologic lesions are generally present in the grey matter of the olfactory bulbs, hippocampus, limbic system, basal ganglia, and brain stem. The cerebellum and dorsal aspect of the cerebrum are usually unaffected.(10) Common histologic lesions are a nonsuppurative encephalitis with perivascular cuffing composed of mononuclear cells, gliosis, and neuronophagia. Perivascular cuffing is often pronounced with cells layering upon one another up to seven cells deep.(10) Inclusion bodies (Joest-Degen bodies) are nearly pathognomonic for BDV infection, and, if present, are normally in nuclei and rarely in the cytoplasm. The hippocampus is reported as the best area to find inclusions.(10) This virus is also unique because it replicates in the nucleolus of the host cell.(10)

Dr. Van Winkle discussed the importance of narrowing this particular case down to a list of differentials, and then using the tools available at your particular institution to make a diagnosis. In horses, differentials for this lesion include: West Nile virus, Japanese encephalitis virus, Murray Valley encephalitis, St. Louis encephalitis, Western equine encephalitis, Eastern equine encephalitis, and Venezuelan equine encephalitis.(1) Other potential differentials discussed during the conference included equine protozoal myelitis and equine herpesvirus type 1. Dr. Van Winkle commented that geographic location in many cases of equine encephalitis is a good indicator of what differential should be at the top of the list. 

References:

1. Bode L, Ludwig H: Borna disease virus infection, a human mental-health risk. Clin Microbiol Rev 16:534-545, 2003
2. Carbone KM: Borna disease virus and human disease. Clin Microbiol Rev 14:513-527, 2001
3. Carbone KM, Duchala CS, Griffin JW, Kincaid AL, Narayan O: Pathogenesis of Borna disease in rats: evidence that intra-axonal spread is the major route for virus dissemination and the determinant for disease incubation. J Virol 61:3431-3440, 1987
4. Carbone KM, Rubin SA, Nishino Y, Pletnikov MV: Borna disease: virus-induced neurobehavioral disease pathogenesis. Curr Opin Microbiol 4:467-475, 2001
5. de la Torre JC, Carbone KM, Lipkin WI: Molecular characterization of the Borna disease agent. Virology 179:853-856, 1990
6. Hagiwara K, Okamoto M, Kamitani W, Takamura S, Taniyama H, Tsunoda N, Tanaka H, Iwai H, Ikuta K: Nosological study of Borna disease virus infection in race horses. Vet Microbiol 84:367-374, 2002
7. Honkavuori KS, Shivaprasad HL, Williams BL, Quan PL, Hornig M, Street C, Palacios G, Hutchison SK, Franca M, Egholm M, Briese T, Lipkin WI: Novel borna virus in psittacine birds with proventricular dilatation disease. Emerg Inf Dis Vol 14, Num 12, Dec 2008
8. Inoue Y, Yamaguchi K, Sawada T, Rivero JC, Horii Y: Demonstration of continuously seropositive population against Borna disease virus in Misaki feral horses, a Japanese strain: a four-year follow-up study from 1998 to 2001. J Vet Med Sci 64:445-448, 2002
9. Kamhieh S, Flower RL: Borna disease virus (BDV) infection in cats. A concise review based on current knowledge. Vet Q 28:66-73, 2006
10. Maxie MG, Youssef S: Nervous system. In: Jubb, Kennedy and Palmers Pathology of Domestic Animals, ed. Maxie MG, 5th ed., vol 1, pp.421-426. Elsevier Limited, Philadelphia, PA, 2007
11. Morales JA, Herzog S, Kompter C, Frese K, Rott R: Axonal transport of Borna disease virus along olfactory pathways in spontaneously and experimentally infected rats. Med Microbiol Immunol 177:51-68, 1988
12. Planz O, Bilzer T, Stitz L: Immunopathogenic role of T-cell subsets in Borna disease virus-induced progressive encephalitis. J Virol 69:896-903, 1995
13. Reeves NA, Helps CR, Gunn-Moore DA, Blundell C, Finnemore PL, Pearson GR, Harbour DA: Natural Borna disease virus infection in cats in the United Kingdom. Vet Rec 143:523-526, 1998
14. Rott R, Herzog S, Fleischer B, Winokur A, Amsterdam J, Dyson W, Koprowski H: Detection of serum antibodies to Borna disease virus in patients with psychiatric disorders. Science 228:755-756, 1985
15. Staeheli P, Sauder C, Hausmann J, Ehrensperger F, Schwemmle M: Epidemiology of Borna disease virus. J Gen Virol 81:2123-2135, 2000
16. Weissenbock H, Nowotny N, Caplazi P, Kolodziejek J, Ehrensperger F: Borna disease in a dog with lethal meningoencephalitis. J Clin Microbiol 36:2127-2130,1998

Click the slide to view.

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2-1. Cerebrum, horse.

2-2. Cerebrum, horse.

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