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Canine Necrotizing Encephalitis Associated with Anti-glomerular Basement Membrane Glomerulonephritis
ARTICLE IN PRESS J. Comp. Path. 2007,Vol. 136, 279^282
www.elsevier.com/locate/jcpa
SHORT PAPER
Canine Necrotizing Encephalitis Associated with Anti-glomerular Basement Membrane Glomerulonephritis L. Aresu, A. D’Angelo, R. Zanatta, F. Valenza and M. T. Capucchio Dipartimento di Patologia Animale, FacoltaØ di MedicinaVeterinaria,Via L. daVinci 44-10095 Grugliasco,Torino, Italy
Summary A 2-year-old male West Highland white terrier with a 4-month history of seizures was referred for investigation. Depressed mentation, proprioceptive de¢cit and decreased menace response were noted at neurological examination. Post-mortem examination of the brain revealed multifocal lesions located principally in the left side of the diencephalon and mesencephalon. The lesions consisted of non-suppurative in£ammation and large areas of cavitation. The clinical evaluation and histopathological ¢ndings were consistent with a diagnosis of necrotizing meningoencephalitis (NME). Immuno£uorescence performed on frozen sections of kidney revealed strong smooth linear labelling of the glomerular basement membrane with anti-IgG serum as well as weaker linear labelling with anti-IgM serum. This histomorphological pattern was consistent with anti-glomerular basement membrane glomerulonephritis. The association of this type of glomerulonephritis with a necrotizing encephalitis would support the hypothesis of an immune-mediated aetiology for NME. r 2007 Elsevier Ltd. All rights reserved. Keywords: autoimmunity; dog; encephalitis; glomerulonephritis; kidney; necrotizing meningoencephalitis
Canine necrotizing meningoencephalitis (NME) is a rarely observed in£ammatory disease of undetermined aetiology. It has been described predominantly in small breeds, and in particular in pugs, Pekingese, Maltese terriers and Yorkshire terriers (Cordy and Holliday, 1989; Tipold et al., 1993; Stalis et al., 1995; Summers et al.,1995; Uchida et al.,1999; Cantile et al., 2001; Suzuki et al., 2003). The most common clinical features are seizures and abnormal behaviour such as depression, ataxia, and circling. Pathologically, NME is characterized by in£ammatory lesions consisting of lymphocytic, plasmacytic and histiocytic perivascular in¢ltrates and large areas of necrosis. Uchida et al. (1999) reported autoantibodies (IgG) against canine brain tissue cells, suggesting an autoimmune origin. A 2-year-old male West Highland white terrier was referred to the Teaching Hospital of the Faculty of Veterinary Medicine of Turin with a 4-month history Correspondence to: L. Aresu (e-mail: [email protected]). 0021-9975/$ - see front matter
doi:10.1016/j.jcpa.2007.02.008
of progressive generalized tonic/clonic seizures, associated with salivation, urination and defaecation. Complete blood count and biochemical analysis, performed by the referring veterinarian, were normal. Oral administration of phenobarbital (2.5 mg/kg BID) failed to control the seizures. Physical examination was normal. Neurological examination showed depressed mentation and pacing. Hind limb proprioception and visual placing were decreased on the right side. Spinal re£exes were within normal limits. Evaluation of the cranial nerves revealed the absence of the menace response on the right side. Both direct and consensual pupillary light re£exes were normal. Electrophoretic pro¢ling of serum proteins (Kit Hydragel Proteinurie 5; Sebia Laboratories, Issy-les-Moulineaux, France), serum biochemical analysis (including bile acids and ammonia) and urinalysis were performed. All results were within normal limits except for a mild proteinuria (5 mg/dl), demonstrated by the Pyrogallol Red method (Sentinel Laboratories, Milan, Italy), with a very low r 2007 Elsevier Ltd. All rights reserved.
ARTICLE IN PRESS 280
L. Aresu et al.
urine speci¢c gravity (1.005) (refractometric method). Qualitative evaluation of proteinuria by the sodium dodecyl sulphate agar gel electrophoresis (SDS-AGE) method revealed the presence of albumin, suggesting a lesion selectively targeting the glomerulus. Due to the progressive worsening of clinical signs, the dog was humanely destroyed (Propofol and Tanax; Intervet, Milan, Italy). Atlanto-occipital cerebrospinal £uid (CSF) was collected just before euthanasia. CSF analysis values were normal (protein, 26 mg/dl; white blood cells, 2/ml, mononuclears). Macroscopically, moderate dilatation of the lateral ventricles and a small pale brown area in the left side of the thalamus were observed. No gross lesions were found in the kidneys or other organs. Tissue samples from all the systemic organs were ¢xed in 10% neutral bu¡ered formalin and embedded in para⁄n wax. Brain sections (4 mm) were processed by routine methods for histological examination and stained with hematoxylin and eosin (HE) and Luxol fast blue. Sections of kidneys (4 mm) were stained by periodic acid-Schi¡ (PAS), acid^fuchsin orange G (AFOG) and phosphotungstic acid haematoxylin (PTAH) methods. Frozen sections of renal tissue were examined by a £uorescence method with the following £uorescence isothiocyanate (FISH)-conjugated antibodies: dog IgG (H+L), dog IgA, dog IgM and dog complement component 3 (C3) (Bethyl Laboratories, Montgomery, USA). Immunohistochemistry for canine distemper virus (CDV) was performed on selected sections of brain, with a monoclonal antibody (D110) speci¢c for the nucleoprotein of the virus (Bollo et al.,1986). Histological examination showed moderate and disseminated perivascular cu¡s of lymphocytes, plasma cells and macrophages especially within the thalamus, basal nucleus area and cerebral white matter. Oedema was observed near the in£ammatory lesions, associated with gliosis, and myelin vacuolation was occasionally noted (Fig. 1). The major lesion consisted of large cavitations within the thalamus and mesencephalon on the left side of the brain (Fig. 2). The malacic areas a¡ected the corpus genicolatus medialis, the crus cerebri, the tractus opticus and the white matter surrounding the thalamic dorsal nuclei. Haemorrhages, swollen axons, reactive astrocytes and activated microglia were present in these areas. A large in£ammatory lesion was observed within the left side of the thalamus near the ventro-caudal nucleus. Also seen in this area were severe perivascular in¢ltrates, extensive haemorrhages, macrophages containing haemosiderin, proliferation and congestion of capillaries with hypertrophy of the vascular endothelium and intense peripheral oedema. The leptomeninges and the neurons within the cortical grey matter were una¡ected. The cerebellum and lower brainstem showed only a small number of multifocal
Fig. 1. Thalamus; mononuclear perivascular cu¡s surrounded by glial reaction, haemorrhages, oedema and sparse degenerated axons. HE. 100.
Fig. 2. Thalamus; voluminous malacic area a¡ecting the white matter adjacent to the thalamic dorsal nuclei. HE. 50.
perivascular mononuclear in¢ltrates. CDV immunolabelling was negative. These histological and immunohistochemical ¢ndings suggested necrotizing meningoencephalitis. The kidneys exhibited strong and smooth linear immuno£uorescent labelling with anti-IgG serum along all glomerular basement membranes (GBMs) (Fig. 3), and weaker linear labelling with anti-IgM serum. Renal histology showed di¡use damage in the cortical area. Enlargement of Bowman’s space was observed in the glomeruli. PAS staining showed a focal increase in mesangial matrix, with evidence of compression of capillary tufts. In some glomeruli, epithelial crescent formations were observed (Fig. 4). AFOG staining revealed normal capillary walls in glomerular remnants. A di¡use in¢ltration of mononuclear cells, predominantly lymphocytes and plasma cells, was
ARTICLE IN PRESS 281
Canine Necrotizing Encephalitis
Fig. 3. Kidney; linear labelling with anti-IgG serum along capillary walls. Immuno£uorescence. 400.
are still unknown, and although several authors have suggested a viral aetiology no evidence of viral particles has been obtained. Uchida et al. (1999) reported an autoantibody against astrocytes in the CSF and serum of some pug dogs with NME, and suggested an autoimmune pathological basis to NME, as in many other neurological disorders. Natural anti-GBM glomerulonephritis is rare in domestic animals (Trautwein and Trautwein-Hewicker, 2000). Little is known about the mechanism of induction of anti-GBM antibodies. Environmental agents, infectious organisms and endogenous stimuli may be associated with anti-GBM disease in man (Kluth and Rees,1999). Anti-GBM glomerulonephritis has been induced experimentally in dogs (Trautwein and Trautwein-Hewicker, 2000), but its aetiology has not been completely de¢ned (Bruijn et al., 1989; Sugimoto et al., 1996). Explanation of the pathogenesis has focused on production of antibodies that react with the antigens on the glomerular basement membrane (Ang et al., 1998). Linear deposition of IgG, as demonstrated by immuno£uorescence, is a signi¢cant diagnostic ¢nding. The demonstration of this type of glomerulonephritis in NME may be an important step in con¢rming that an autoimmune mechanism is responsible for NME. Many viral infections not only directly induce in£ammatory lesions but also result in subsequent autoimmune responses in multiple organs (Ang et al.,1998). The identi¢cation of IgG and IgM in linear deposition along the basement membrane suggests that an autoimmune mechanism plays a role in the glomerulonephritis, supporting the hypothesis of Uchida et al. (1999) regarding the autoimmune pathogenesis of NME.
Acknowledgments We thank Professor Gianna Mazzucco, Department of Medical Sciences and Human Oncology, University of Torino, Italy for her assistance in the preparation of this case report, and DrJames Baily, Division of Pathological Sciences, Institute of Comparative Medicine, Faculty of Veterinary Medicine, Glasgow, for help with English. Fig. 4. Kidney; a glomerulus with cellular crescent formation associated with capillary compression. PAS. 400.
References
observed in the interstitium. Proteinaceous casts were observed in some tubular lumina. The histopat hological and immuno£uorescent ¢ndings in the kidney of this dog were similar to those described in antiGBM glomerulonephritis in human patients (Ang et al., 1998; Kluth and Rees,1999). This paper represents the ¢rst report of NME in the West Highland white terrier breed.The causes of NME
Ang, C., Savige, J., Dawborn, J., Miach, P., Heale, W., Clarke, B. and Sinclair, R. S. (1998). Anti-glomerular basement membrane (GBM)-antibody-mediated disease with normal renal function. Nephrology DialysisTransplant, 13, 935^939. Bollo, E., Zurbriggen, A., Vandevelde, M. and Fankhauser, R. (1986). Canine distemper virus clearance in chronic in£ammatory demyelinization. Acta Neuropathologica, 72, 69^73.
ARTICLE IN PRESS 282
L. Aresu et al.
Bruijn, J. A., Hoedemaeker, P. J. and Fleuren, G. J. (1989). Pathogenesis of anti-basement membrane glomerulopathy and immune-complex glomerulonephritis: dichotomy dissolved. Laboratory Investigation, 61, 480^488. Cantile, C., Chianini, F., Arispici, M. and Fatzer, R. (2001). Necrotizing meningoencephalitis associated with cortical hippocampal hamartia in a Pekinese dog.Veterinary Pathology, 38,119^122. Cordy, D. R. and Holliday,T. A. (1989). A necrotizing meningoencephalitis of Pug dogs. Veterinary Pathology, 26, 191^194. Kluth, D. C. and Rees, A. J. (1999). Anti-glomerular basement membrane disease. Journal of the American Society of Nephrology, 10, 2446^2453. Stalis, I. H., Chadwick, B., Dayrell-Hart, B., Summers, B. A. and Van-Winkle, T. J. (1995). Necrotizing meningoencephalitis of Maltese dogs. Veterinary Pathology, 32, 230^235. Sugimoto, J.,Wasaki, M., Inoue,Y., Shirota, K. and Nomura, Y. (1996). Alterations in glomerular anionic sites in the autologous phase of canine anti-glomerular basement membrane nephritis.Toxicologic Pathology, 24, 627^635. Summers, B.A., Cummings, J.F. and De Lahunta, A. (1995). In£ammatory diseases of the central nervous system. In:
Veterinary Neuropathology, Mosby-Year Book, St Louis, MO, pp. 95^188. Suzuki, M., Uchida, K., Morozumi, M., Hasegawa, T., Yanai, T., Nakayama, H. and Tateyama, S. (2003). A comparative pathological study on canine necrotizing meningoencephalitis and granulomatous meningoencephalomyelitis. Journal of Veterinary Medical Science, 65,1233^1239. Tipold, A., Fatzer, R., Jaggy, A., Zurbriggen, A. and Vandevelde, M. (1993). Necrotizing encephalitis inYorkshire terriers. Journal of Small Animal Practice, 34, 623^628. Trautwein, G. andTrautwein-Hewicker, M. (2000). Immunopathological mechanisms of glomerulonephritis in domestic animals. European Journal of Veterinary Pathology, 6, 83^94. Uchida, K., Hasegawa,T., Ikeda, M.,Yamaguchi, R. andTateyama, S. (1999). Detection of an autoantibody from Pug Dogs with necrotizing encephalitis (Pug Dog encephalitis).Veterinary Pathology, 36, 301^307.
Received, May 25th, 2006 Accepted, February 12th, 2007
www.elsevier.com/locate/jcpa
SHORT PAPER
Canine Necrotizing Encephalitis Associated with Anti-glomerular Basement Membrane Glomerulonephritis L. Aresu, A. D’Angelo, R. Zanatta, F. Valenza and M. T. Capucchio Dipartimento di Patologia Animale, FacoltaØ di MedicinaVeterinaria,Via L. daVinci 44-10095 Grugliasco,Torino, Italy
Summary A 2-year-old male West Highland white terrier with a 4-month history of seizures was referred for investigation. Depressed mentation, proprioceptive de¢cit and decreased menace response were noted at neurological examination. Post-mortem examination of the brain revealed multifocal lesions located principally in the left side of the diencephalon and mesencephalon. The lesions consisted of non-suppurative in£ammation and large areas of cavitation. The clinical evaluation and histopathological ¢ndings were consistent with a diagnosis of necrotizing meningoencephalitis (NME). Immuno£uorescence performed on frozen sections of kidney revealed strong smooth linear labelling of the glomerular basement membrane with anti-IgG serum as well as weaker linear labelling with anti-IgM serum. This histomorphological pattern was consistent with anti-glomerular basement membrane glomerulonephritis. The association of this type of glomerulonephritis with a necrotizing encephalitis would support the hypothesis of an immune-mediated aetiology for NME. r 2007 Elsevier Ltd. All rights reserved. Keywords: autoimmunity; dog; encephalitis; glomerulonephritis; kidney; necrotizing meningoencephalitis
Canine necrotizing meningoencephalitis (NME) is a rarely observed in£ammatory disease of undetermined aetiology. It has been described predominantly in small breeds, and in particular in pugs, Pekingese, Maltese terriers and Yorkshire terriers (Cordy and Holliday, 1989; Tipold et al., 1993; Stalis et al., 1995; Summers et al.,1995; Uchida et al.,1999; Cantile et al., 2001; Suzuki et al., 2003). The most common clinical features are seizures and abnormal behaviour such as depression, ataxia, and circling. Pathologically, NME is characterized by in£ammatory lesions consisting of lymphocytic, plasmacytic and histiocytic perivascular in¢ltrates and large areas of necrosis. Uchida et al. (1999) reported autoantibodies (IgG) against canine brain tissue cells, suggesting an autoimmune origin. A 2-year-old male West Highland white terrier was referred to the Teaching Hospital of the Faculty of Veterinary Medicine of Turin with a 4-month history Correspondence to: L. Aresu (e-mail: [email protected]). 0021-9975/$ - see front matter
doi:10.1016/j.jcpa.2007.02.008
of progressive generalized tonic/clonic seizures, associated with salivation, urination and defaecation. Complete blood count and biochemical analysis, performed by the referring veterinarian, were normal. Oral administration of phenobarbital (2.5 mg/kg BID) failed to control the seizures. Physical examination was normal. Neurological examination showed depressed mentation and pacing. Hind limb proprioception and visual placing were decreased on the right side. Spinal re£exes were within normal limits. Evaluation of the cranial nerves revealed the absence of the menace response on the right side. Both direct and consensual pupillary light re£exes were normal. Electrophoretic pro¢ling of serum proteins (Kit Hydragel Proteinurie 5; Sebia Laboratories, Issy-les-Moulineaux, France), serum biochemical analysis (including bile acids and ammonia) and urinalysis were performed. All results were within normal limits except for a mild proteinuria (5 mg/dl), demonstrated by the Pyrogallol Red method (Sentinel Laboratories, Milan, Italy), with a very low r 2007 Elsevier Ltd. All rights reserved.
ARTICLE IN PRESS 280
L. Aresu et al.
urine speci¢c gravity (1.005) (refractometric method). Qualitative evaluation of proteinuria by the sodium dodecyl sulphate agar gel electrophoresis (SDS-AGE) method revealed the presence of albumin, suggesting a lesion selectively targeting the glomerulus. Due to the progressive worsening of clinical signs, the dog was humanely destroyed (Propofol and Tanax; Intervet, Milan, Italy). Atlanto-occipital cerebrospinal £uid (CSF) was collected just before euthanasia. CSF analysis values were normal (protein, 26 mg/dl; white blood cells, 2/ml, mononuclears). Macroscopically, moderate dilatation of the lateral ventricles and a small pale brown area in the left side of the thalamus were observed. No gross lesions were found in the kidneys or other organs. Tissue samples from all the systemic organs were ¢xed in 10% neutral bu¡ered formalin and embedded in para⁄n wax. Brain sections (4 mm) were processed by routine methods for histological examination and stained with hematoxylin and eosin (HE) and Luxol fast blue. Sections of kidneys (4 mm) were stained by periodic acid-Schi¡ (PAS), acid^fuchsin orange G (AFOG) and phosphotungstic acid haematoxylin (PTAH) methods. Frozen sections of renal tissue were examined by a £uorescence method with the following £uorescence isothiocyanate (FISH)-conjugated antibodies: dog IgG (H+L), dog IgA, dog IgM and dog complement component 3 (C3) (Bethyl Laboratories, Montgomery, USA). Immunohistochemistry for canine distemper virus (CDV) was performed on selected sections of brain, with a monoclonal antibody (D110) speci¢c for the nucleoprotein of the virus (Bollo et al.,1986). Histological examination showed moderate and disseminated perivascular cu¡s of lymphocytes, plasma cells and macrophages especially within the thalamus, basal nucleus area and cerebral white matter. Oedema was observed near the in£ammatory lesions, associated with gliosis, and myelin vacuolation was occasionally noted (Fig. 1). The major lesion consisted of large cavitations within the thalamus and mesencephalon on the left side of the brain (Fig. 2). The malacic areas a¡ected the corpus genicolatus medialis, the crus cerebri, the tractus opticus and the white matter surrounding the thalamic dorsal nuclei. Haemorrhages, swollen axons, reactive astrocytes and activated microglia were present in these areas. A large in£ammatory lesion was observed within the left side of the thalamus near the ventro-caudal nucleus. Also seen in this area were severe perivascular in¢ltrates, extensive haemorrhages, macrophages containing haemosiderin, proliferation and congestion of capillaries with hypertrophy of the vascular endothelium and intense peripheral oedema. The leptomeninges and the neurons within the cortical grey matter were una¡ected. The cerebellum and lower brainstem showed only a small number of multifocal
Fig. 1. Thalamus; mononuclear perivascular cu¡s surrounded by glial reaction, haemorrhages, oedema and sparse degenerated axons. HE. 100.
Fig. 2. Thalamus; voluminous malacic area a¡ecting the white matter adjacent to the thalamic dorsal nuclei. HE. 50.
perivascular mononuclear in¢ltrates. CDV immunolabelling was negative. These histological and immunohistochemical ¢ndings suggested necrotizing meningoencephalitis. The kidneys exhibited strong and smooth linear immuno£uorescent labelling with anti-IgG serum along all glomerular basement membranes (GBMs) (Fig. 3), and weaker linear labelling with anti-IgM serum. Renal histology showed di¡use damage in the cortical area. Enlargement of Bowman’s space was observed in the glomeruli. PAS staining showed a focal increase in mesangial matrix, with evidence of compression of capillary tufts. In some glomeruli, epithelial crescent formations were observed (Fig. 4). AFOG staining revealed normal capillary walls in glomerular remnants. A di¡use in¢ltration of mononuclear cells, predominantly lymphocytes and plasma cells, was
ARTICLE IN PRESS 281
Canine Necrotizing Encephalitis
Fig. 3. Kidney; linear labelling with anti-IgG serum along capillary walls. Immuno£uorescence. 400.
are still unknown, and although several authors have suggested a viral aetiology no evidence of viral particles has been obtained. Uchida et al. (1999) reported an autoantibody against astrocytes in the CSF and serum of some pug dogs with NME, and suggested an autoimmune pathological basis to NME, as in many other neurological disorders. Natural anti-GBM glomerulonephritis is rare in domestic animals (Trautwein and Trautwein-Hewicker, 2000). Little is known about the mechanism of induction of anti-GBM antibodies. Environmental agents, infectious organisms and endogenous stimuli may be associated with anti-GBM disease in man (Kluth and Rees,1999). Anti-GBM glomerulonephritis has been induced experimentally in dogs (Trautwein and Trautwein-Hewicker, 2000), but its aetiology has not been completely de¢ned (Bruijn et al., 1989; Sugimoto et al., 1996). Explanation of the pathogenesis has focused on production of antibodies that react with the antigens on the glomerular basement membrane (Ang et al., 1998). Linear deposition of IgG, as demonstrated by immuno£uorescence, is a signi¢cant diagnostic ¢nding. The demonstration of this type of glomerulonephritis in NME may be an important step in con¢rming that an autoimmune mechanism is responsible for NME. Many viral infections not only directly induce in£ammatory lesions but also result in subsequent autoimmune responses in multiple organs (Ang et al.,1998). The identi¢cation of IgG and IgM in linear deposition along the basement membrane suggests that an autoimmune mechanism plays a role in the glomerulonephritis, supporting the hypothesis of Uchida et al. (1999) regarding the autoimmune pathogenesis of NME.
Acknowledgments We thank Professor Gianna Mazzucco, Department of Medical Sciences and Human Oncology, University of Torino, Italy for her assistance in the preparation of this case report, and DrJames Baily, Division of Pathological Sciences, Institute of Comparative Medicine, Faculty of Veterinary Medicine, Glasgow, for help with English. Fig. 4. Kidney; a glomerulus with cellular crescent formation associated with capillary compression. PAS. 400.
References
observed in the interstitium. Proteinaceous casts were observed in some tubular lumina. The histopat hological and immuno£uorescent ¢ndings in the kidney of this dog were similar to those described in antiGBM glomerulonephritis in human patients (Ang et al., 1998; Kluth and Rees,1999). This paper represents the ¢rst report of NME in the West Highland white terrier breed.The causes of NME
Ang, C., Savige, J., Dawborn, J., Miach, P., Heale, W., Clarke, B. and Sinclair, R. S. (1998). Anti-glomerular basement membrane (GBM)-antibody-mediated disease with normal renal function. Nephrology DialysisTransplant, 13, 935^939. Bollo, E., Zurbriggen, A., Vandevelde, M. and Fankhauser, R. (1986). Canine distemper virus clearance in chronic in£ammatory demyelinization. Acta Neuropathologica, 72, 69^73.
ARTICLE IN PRESS 282
L. Aresu et al.
Bruijn, J. A., Hoedemaeker, P. J. and Fleuren, G. J. (1989). Pathogenesis of anti-basement membrane glomerulopathy and immune-complex glomerulonephritis: dichotomy dissolved. Laboratory Investigation, 61, 480^488. Cantile, C., Chianini, F., Arispici, M. and Fatzer, R. (2001). Necrotizing meningoencephalitis associated with cortical hippocampal hamartia in a Pekinese dog.Veterinary Pathology, 38,119^122. Cordy, D. R. and Holliday,T. A. (1989). A necrotizing meningoencephalitis of Pug dogs. Veterinary Pathology, 26, 191^194. Kluth, D. C. and Rees, A. J. (1999). Anti-glomerular basement membrane disease. Journal of the American Society of Nephrology, 10, 2446^2453. Stalis, I. H., Chadwick, B., Dayrell-Hart, B., Summers, B. A. and Van-Winkle, T. J. (1995). Necrotizing meningoencephalitis of Maltese dogs. Veterinary Pathology, 32, 230^235. Sugimoto, J.,Wasaki, M., Inoue,Y., Shirota, K. and Nomura, Y. (1996). Alterations in glomerular anionic sites in the autologous phase of canine anti-glomerular basement membrane nephritis.Toxicologic Pathology, 24, 627^635. Summers, B.A., Cummings, J.F. and De Lahunta, A. (1995). In£ammatory diseases of the central nervous system. In:
Veterinary Neuropathology, Mosby-Year Book, St Louis, MO, pp. 95^188. Suzuki, M., Uchida, K., Morozumi, M., Hasegawa, T., Yanai, T., Nakayama, H. and Tateyama, S. (2003). A comparative pathological study on canine necrotizing meningoencephalitis and granulomatous meningoencephalomyelitis. Journal of Veterinary Medical Science, 65,1233^1239. Tipold, A., Fatzer, R., Jaggy, A., Zurbriggen, A. and Vandevelde, M. (1993). Necrotizing encephalitis inYorkshire terriers. Journal of Small Animal Practice, 34, 623^628. Trautwein, G. andTrautwein-Hewicker, M. (2000). Immunopathological mechanisms of glomerulonephritis in domestic animals. European Journal of Veterinary Pathology, 6, 83^94. Uchida, K., Hasegawa,T., Ikeda, M.,Yamaguchi, R. andTateyama, S. (1999). Detection of an autoantibody from Pug Dogs with necrotizing encephalitis (Pug Dog encephalitis).Veterinary Pathology, 36, 301^307.
Received, May 25th, 2006 Accepted, February 12th, 2007