AFIP Wednesday Slide Conference - No. 11
November 25, 1998

Conference Moderator: Dr. F. Yvonne Schulman
Diplomate, ACVP
Department of Veterinary Pathology
Armed Forces Institute of Pathology
Washington, DC 20306-6000

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Case I - 6122-98 (AFIP 2636443)
Signalment: Tissue from an eight-year-old, neutered, male Italian greyhound.
History: The dog had an acute onset of mild to moderate ataxia involving all four limbs. Continued decline in the face of corticosteroid and lamustine therapy resulted in euthanasia about 10 weeks later.
Gross Pathology: An increased amount of fleshy tan tissue was evident on the dorsal aspect of the medulla oblongata, extending down along the external dorsal surface of the cervical spinal cord. Sections through this area into the adjacent brain revealed extension of this tissue into the parenchyma grossly, blurring architectural landmarks. Less obvious, ill-defined discoloration was evident in other regions of the brain. The ventricular system was severely dilated.

Laboratory Results: Spinal fluid analysis identified a protein content of 70 mg/dl and a total nucleated cell count of 45/ml. The cells were predominantly mononuclear; some appeared atypical. MRI revealed marked and irregular contrast enhancement in the brain stem, cerebellum and medial to each lateral ventricle.
Contributor's Diagnosis and Comments: Round cell sarcoma, possibly rhabdoid tumor.
Although the submitted specimens contain a single grossly visible lesion, there were additional areas of neuropil involvement that were generally peripheral in location involving the brain from the meningeal space inwards. Because extra-neural tissues were not submitted, the extent of somatic involvement, such as might occur in some round cells tumors, could not be defined. This patient is relatively old compared to patients with rhabdoid tumors described in the literature. Although the histological appearance and multifocal localization are suggestive of rhabdoid tumor, myeloproliferative disease, lymphosarcoma, histiocytosis, and plasma cell tumor should be considered as differentials.
Plasmacytoma has been recently reported in a single adult dog with a similar pattern of lesions. A case of myelocytic leukemia had more extensive peripheral nervous system involvement and an abnormal peripheral blood smear. There was no indication of abnormal hemogram in this patient, but some possibility of neoplastic cells was evident in the cerebrospinal fluid (the slide is no longer available for examination). Individual cell morphology is more varied and atypical than that usually associated with nervous system lymphoma or microglioma. Immunohistochemical staining and electron microscopic examination might help in better establishing the diagnosis.
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Case 11-1. Spinal cord. A densely cellular neoplasm effaces normal neuropil.
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Case 11-1. Spinal cord. Neoplastic cells have pleomorphic nuclei, anisocytosis, and mitotic figures.
AFIP Diagnosis: Brain stem: Malignant pleomorphic round cell tumor, favor T-cell lymphoma, Italian greyhound, canine.
Conference Note: A poorly differentiated neoplasm effaces portions of the brain stem and infiltrates the meninges and subpial parenchyma. The neoplasm is composed of highly pleomorphic round cells. Neoplastic cells multifocally occur within Virchow-Robins space in less affected areas of the brainstem, and there are perivascular inflammatory infiltrates both within the tumor and less affected areas of neuropil. Neoplastic cells are characterized by variably-distinct cell borders with abundant, eosinophilic cytoplasm which is occasionally vacuolated or contains phagocytized cells or debris. There is marked variation in nuclear size and shape.
The differential diagnosis compiled by conference participants for this poorly differentiated neoplasm was somewhat similar to that mentioned by the contributor and included histiocytic sarcoma, malignant lymphoma, meningeal sarcomatosis, undifferentiated astrocytoma, rhabdoid tumor, meningioma, and melanoma. In the absence of immunohistochemical studies, conference participants generally favored the diagnosis of a poorly differentiated round cell neoplasm of histiocytic or lymphoid origin.
A few attendees considered a rhabdoid tumor, but most did not identify microscopic features described for this neoplasm. Rhabdoid tumors are typically composed of a monomorphic population of deceptively bland polygonal cells which contain globoid, eosinophilic cytoplasmic inclusions and eccentric, round to oval to reniform nuclei. Rhabdoid tumors in humans typically occur in young children or juvenile individuals and are highly aggressive. The single case report of rhabdoid tumor in a dog was also in a young animal (18 months old). While an atypical variant of human rhabdoid tumor has been described in children, cells of these neoplasms maintain some degree of "rhabdoid" morphology.
Immunohistochemically, neoplastic cells in the tumor of this Italian greyhound are negative for glial fibrillary acidic protein, lysozyme, pan-cytokeratin, synaptophysin, CD45RA and CD79a. Tumor cells stained positively for CD3 and CD30; scattered cells were positive for vimentin. The diagnosis of malignant pleomorphic round cell tumor, favor T-cell lymphoma, is based on histomorphology, immunohistochemical results, and consultation with the Departments of Hematopathology and Neuropathology.
This canine neoplasm shares several histologic and immunohistochemical similarities described for a variant of human lymphoid malignancy known as anaplastic large cell lymphoma (ALCL). A relatively rare malignant neoplasm of Null T-cell types, the tumor is histologically characterized by large blastic round cells which may grow in a cohesive pattern and contain pleomorphic, sometimes horsehoe-shaped or multiple nuclei with prominent nucleoli. Tumor cells are usually strongly positive for CD30, and this finding coupled with the presence of large, anaplastic lymphoid cells make this tumor a distinct clinicopathologic entity among human lymphomas. There may be a variable admixture of granulocytes and macrophages within the tumor, and a lymphohistiocytic variant also occurs. Many cases of ALCL were previously diagnosed as malignant histiocytic tumors, regressing atypical histiocytosis, metastatic melanoma, sarcoma, or carcinoma.

Contributor: Veterinary Medical Diagnostic Laboratory, University of Missouri, P.O. Box 6023, Columbia, MO 65205.
1. Steele KE, Schulman FY, Mena H, Strimple EO: Rhabdoid tumor in the brain of a dog. Vet Pathol 34:359-363, 1997.
2. Sheppard BJ, Chrisman CL, Newell SM, Raskin RE, Homer BL: Primary encephalitic plasma cell tumor in a dog. Vet Pathol 34:621-627, 1997.
3. Christopher MM, Metz AL, Klausner J, Polzin D, Hayden DW: Acute myelomonocytic leukemia with neurologic manifestation in the dog. Vet Pathol 23:140-147, 1986.
4. Benko l: A case of reticulum cell sarcoma in the brain of a dog. Vet Rec:100-101, 26 Jul 1969.
5. Rubenstein LJ: Tumors of the Lymphoreticular System. In: Tumors of the Central Nervous System, pp. 215-234, Armed Forces Institute of Pathology, Washington DC, 1972.
6. Burger PC, et al.: Atypical teratoid/rhabdoid tumor of the central nervous system: A highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma. Amer J Surg Pathol 22:1083-1092, 1998.
7. Harris NL, et al.: A revised European-American classification of lymphoid neoplasms: A proposal from the international lymphoma study group. Blood 84(5):1361-1392, 1994.
Case II - 97P12580 (AFIP 2643798)
Signalment: Two-week-old, Salers crossbred, male, bovine (Bos taurus).
History: The calf was unable to stand from the time of birth. Physical examination revealed a slightly domed skull, bobbing and weaving of the head when not being rested on the floor or against the body, ventral rotation of the eyes, oscillating nystagmus, and the maxilla was shorter than the mandible.
Gross Pathology: The thyroid gland was enlarged (1.5X) and greenish-brown with several black foci about 0.5 cm in diameter. The kidneys were enlarged (1.5X) and greenish-tan. The brain had a green tint with reduced prominence of white matter, and mild hydrocephalus.
Laboratory Results: The hemogram was unremarkable.
Contributor's Diagnosis and Comments:
Neuronal cell bodies and neurites throughout the brain were swollen, pale and foamy or vacuolated. The neuronal changes were more prominent in the thalamus and cerebrum than in the caudal brain stem. Fine neuropil vacuolation was especially common in the cerebral gray matter near the gray-white interface and in the cerebellar Purkinje cell layer. Swollen, pale, foamy or vacuolated cells also were found in ganglia of all organs, pars nervosa of the pituitary, lymph nodes, thymic cortex, thyroid follicular lining cells, adrenal glands, bile ducts and Kupffer cells, and renal tubular cells.
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Case 11-2. Cerebrum. Diffusely, neurons are expanded by clear cytoplasmic vacuoles. There are also moderately increased numbers of astrocytes, with clear cytoplasm.
The owner had used pasture breeding on the herd of 70 cows. A Salers bull had been in use for three years and a Braunvieh for two years. Some heifers were kept as herd replacements. Last year, there was one affected calf, but it was not presented for necropsy. This year, there were five affected calves, and two were presented for necropsy. Blood samples from this affected calf, its dam and both bulls were submitted to the Michigan State University Molecular Pathology Laboratory for DNA analysis. The beta mannosidosis mutation is a single base pair change. The calf, dam and Salers bull were positive for the mutant DNA.
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Case 11-2. Lymph Node. Foamy histiocytic cells efface and replace normal nodal architecture.
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Case 11-2. Lymph node. Foamy macrophages replace lymphoid cells. Rare neutrophils and eosinophils are also present.
AFIP Diagnosis: Lymph node: Histiocytosis, diffuse, moderate, with intrahistiocytic vacuoles, Salers crossbred calf, bovine.
Conference Note: Beta-mannosidosis in Salers cattle is a rapidly fatal, inherited autosomal recessive lysosomal storage disease which results in the accumulation of oligosaccharides and subsequent cytoplasmic vacuolation in neurons, tubular epithelial cells, thyroid follicular cells, and macrophages of nervous, renal, thyroid, and lymphoid tissues. Deficiency of b-mannosidase results in accumulation of disaccharide and trisaccharide with a terminal mannose b-linked to N-acetyl-glucosamine. The disease has also been reported in humans and in Anglo-Nubian goats.
Clinical signs in affected Salers calves include weakness, fine head tremor which becomes exacerbated by movement, occasional opisthotonus, and ventromedial rotation of the eyes and/or intermittent ocular oscillations while in lateral recumbency. Gross pathological findings often include dome-shaped calvarium, brachygnathism, atrophy of the brain with hydrocephalus, and enlargement of the kidneys, liver, lymph nodes, and thyroid gland. The most significant microscopic finding is marked cytoplasmic vacuolation of multiple cell types, with nervous, renal, thyroid, and lymphoid tissues being the most severely affected.
Beta-mannosidosis causes acute, severe demyelination in the brain of affected calves, and this is important in distinguishing this disease from other bovine storage diseases. Inherited a-mannosidosis, a more economically important storage disease of Angus, Murray Grey and Galloway cattle, causes a mild demyelinating lesion which tends to occur later in the course of the disease. Acquired a-mannosidosis of herbivores may also occur secondary to ingestion of toxic plants from the genera Swainsona, Oxytropis, and Astragalus. Bovine GM1 gangliosidosis of Friesian cattle causes gliosis and demyelination in the terminal stages of disease. Type II glycogenosis in Brahman cattle does not cause significant demyelinating lesions in the white matter of the brain.
While signalment, history, clinical signs, gross and histologic findings are useful indicators in suspect cases of b-mannosidase deficiency, definitive diagnosis of the disease relies on genetic analysis and/or measurement of plasma b-mannosidase activity of affected calves and genitors. Conference participants noted that hyperlipidemia may cause accumulation of high numbers of vacuolated macrophages in various tissues, and was considered in the differential diagnosis for the microscopic findings in this lymph node.
Contributor: Department of Veterinary Pathology, Iowa State University, Christiansen Drive, Ames, IA 50011.
1. Bryan L, Schmutz S, Hodges SD, Snyder FF: Bovine b-mannosidosis: Pathologic and genetic findings in Salers calves. Vet Pathol 30:130-139, 1993.
2. O'Toole D, Welch V, Redland K, Williams ES: Ubiquitinated inclusions in brains from Salers calves with b-mannosidosis. Vet Pathol 30:381-385, 1993.
3. Cavanagh KT, Jones MZ, Abbitt B, Skinner R: Bovine plasma b-mannosidase activity and its potential use for b-mannosidosis carrier detection. J Vet Diagn Invest 4:434-440, 1992.
4. Jolly RD, Walkley SU: Lysosomal storage diseases of animals: An essay in comparative pathology. Vet Pathol 34:527-548, 1997.
Case III - 98-3956 (AFIP 2642345)
Signalment: The patient was a nine-month-old, female, Himalayan cat.
History: The cat had a swollen lip one week prior to presentation at an emergency clinic. This was treated with a 20mg injection of Depo-Medrolä. The owners felt since that point the cat slowed down and was sleeping a lot. The cat was presented to the emergency clinic prostrate and gasping, with cyanotic mucous membranes and clear fluid exuding from the nose. The cat had a grade III holosystolic murmur, was hypotensive, and died within 10 minutes of arrival.
Gross Pathology: The cat was an intact, female, blue point Himalayan weighing 3.1 kilograms. The mucous membranes were pale and cyanotic, and blood-tinged fluid was present around the nares and in the pharynx. The lungs were heavy, wet, and exuded fluid on cut surface. The heart was small, pale, and weighed 18 grams. The endocardial surface was tan/white, and there were hemorrhages on the epicardial surface and around the coronary veins. A few, patchy hemorrhages were also present on the endocardial surface. The stomach contained cat food, the intestine had a small amount of fluid contents, and the colon had formed stool.
Laboratory Results: Routine cultures of lung were negative for microorganisms.
Contributor's Diagnosis and Comments: Endomyocardial fibrosis with hemorrhage (restrictive cardiomyopathy).

This appeared to be an unusual form of cardiomyopathy, and the only references were linked to hypereosinophilic syndromes. However, this cat did not have evidence of eosinophilic infiltrates in any organ. This may reflect the prior injection of corticosteroids. The cat was a "show cat" and appeared relatively normal until the week before its death. Yet, the myocardial lesions were extensive and severe, with involvement of papillary muscles as well as both ventricles. The lesions were more extensive in the left ventricle, but were present throughout the heart. Some sections contain papillary muscle, while other sections extend into dilated atria.
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Case 11-3. Heart. Papillary muscle is partly replaced by adipose (fat) cells, a mixture of inflammatory cells, and wispy fibrillar basophilic material.
AFIP Diagnosis: Heart: Endomyocarditis, neutrophilic and lymphoplasmacytic, subacute, diffuse, mild to moderate, Himalayan cat, feline.
Conference Note: While conference participants carefully considered the contributor's diagnosis of restrictive cardiomyopathy, most preferred the one indicated above. Microscopically, the endocardium and subendocardium of the left ventricle are moderately expanded by an amphophilic, acellular, fibrillar material (edema) with low to moderate numbers of neutrophils, lymphocytes, macrophages, plasma cells, and fewer reactive fibroblasts and hemorrhage. Multifocally within in the epicardium there is mild hemorrhage. Some of the submitted slides contain sections of right ventricle, with minimal microscopic change. A Masson's trichrome stain demonstrated minimal amounts of endocardial collagen.
Conference participants agreed that the clinical history and microscopic lesions in the heart of this cat are most consistent with the recently described syndrome of feline endomyocarditis (EMC)5. Histologic lesions in cats with EMC include varying degrees of endocardial inflammation characterized by infiltrates of neutrophils and macrophages, and occasionally lymphocytes and plasma cells with varying amounts of hemorrhage. Lesions primarily involve the left heart and are most severe in the dorsal septal wall, though minimal to mild myodegeneration with small numbers of inflammatory cells may be present in the right ventricle. Interstitial pneumonia occurs frequently in cats diagnosed with EMC. Left ventricular endocardial fibrosis (LVEF) is thought to be a chronic sequela of EMC based upon the predilection of the left ventricular outflow tract in both diseases and the gradation of microscopic lesions with respect to the type of inflammation and amount of fibrosis.
Affected cats with EMC are most often young (less than 4 years), frequently present to the attending veterinarian with signs of respiratory distress and rarely hindlimb paresis, and often have a history of some stressful event within the preceding three months. Examples of such stressful events include neutering, declawing, or vaccination, cystitis, boarding and/or grooming, movement to a new house, and loss or acquisition of another cat in the household. There is no apparent breed predilection.
Conference participants did not identify microscopic features of feline restrictive cardiomyopathy (RCM). Histologic lesions of RCM include endomyocardial fibrosis, myocardial interstitial fibrosis, myocyte hypertrophy, and myocardial necrosis. Severe endomyocardial fibrosis of the interventricular septum, left ventricular free wall, and atria occurs in advanced cases of RCM. The clinical, historical, and histopathological findings in this Himalayan cat are more consistent with EMC. If the cat had survived, this lesion may have progressed to LEVF, one of several idiopathic feline cardiovascular diseases grouped together clinically as RCM.
Contributor: Central Veterinary Laboratory for Veterinarians, 5645 199th Street, Langley, British Columbia V3A 1H9.
1. Saxon B, Hendrick M, Waddle JR: Restrictive cardiomyopathy in a cat with hypereosinophilic syndrome. Can Vet J 32:367, 1991.
2. McEwen SA, Valli VEO, Hulland TJ: Hypereosinophilic syndrome in cats: A report of three cases. Can J Com Med 49:248-253, 1985.
3. Sisson DD, Thomas WP: Myocardial diseases. In: Textbook of Veterinary Internal Medicine, Ettinger SJ, Feldman EC, eds., 4th ed., vol. 1, pp. 1020-1022, WB Saunders, Philadelphia, PA, 1995.
4. Bonagura JD, Fox PR: Restrictive cardiomyopathy. In: Veterinary Current Therapy XII, Bonagura JD, Kirk RW, eds., pp. 863-867, WB Saunders, Philadelphia, PA, 1995.
5. Stalis IH, Bossbaly MJ, Van Winkle TJ: Feline endomyocarditis and left ventricular endocardial fibrosis. Vet Pathol 32:122-126, 1995.
Case IV - 98C 1819 (AFIP 2642054)
Signalment: Four-month-old, Alaskan Husky, male, canine.
History: The owner of a kennel of Alaskan Huskies used for competitive long-distance sled-dog racing noticed that a four-month-old, male, 14 kg pup had a high-stepping gait and difficulty locating his bowl. The dog's condition worsened over the next 30 days. On presentation, the dog was ambulatory, bright, alert and responsive. The principal clinical signs were moderate ataxia and proprioceptive deficits. Laboratory work-up revealed no significant changes, other than hemorrhage into the cerebrospinal fluid. The dog's condition deteriorated, and a seizure occurred. The dog was euthanized. His unfixed head with attached C1 spinal cord was submitted on ice packs for examination.
Gross Pathology: Bilaterally symmetrical, 5 x 3 mm areas of malacia were present in the thalamus (see photograph). Multifocal areas in ventral portions of the cerebellum had thin folia.
Case 11-4. Cerebrum. (see description above)
Laboratory Results: None.
Contributor's Diagnoses and Comments:
1. Encephalomalacia, severe, bilaterally symmetrical, subacute, diencephalon.
2. Atrophy, moderate, multifocal, Purkinje and granular cell layers, with hypertrophy of Bergmann glia, cerebellum.
3. Atrophy, moderate, multifocal, subacute, laminar, cerebrocortical sulci, with neuronal necrosis and gliosis.

Etiology: Familial Alaskan Husky Encephalopathy ("sled dog encephalopathy").

Note: Since several blocks were cut for this case, there is variability in the severity of lesions, particularly in the presence of cerebellar changes and the degree of malacia in thalamus.
Bilaterally symmetrical gray matter encephalopathies of dogs were reviewed recently. It is likely that some of these conditions are inherited. They resemble subacute necrotizing encephalopathy in children (Leigh's disease), a primary mitochondrionopathy due to abnormal thiamine metabolism. The condition in children is inherited as an autosomal dominant trait. Similar encephalopathies occur in kindreds of Australian cattle dogs, Malinois-crosses, salukis, bull mastiffs and Alaskan sled dogs.

The principal lesion in this brain is subacute bilaterally symmetrical malacia in the diencephalon. I have no objective criteria for establishing whether the cerebellar lesion was abiotrophic or hypoplastic, but its multifocal distribution and the presence of gliosis suggest the former. The cerebrocortical lesions may have been caused (or exacerbated) by hypoxia during convulsions. These lesions in sulci appear to have occurred at different times, since some are more acute than others.
Little information has been published to date on the disease in Alaskan sled dogs, apart from a description in a veterinary neuropathology text. The disease has been identified in Minnesota, Alaska and Wyoming. Diagnosis can be made clinically on the basis of brain scans. The distribution of the malacic "butterfly" lesions is characteristic. The biochemical basis for the disease in these dogs is unknown. The owners were not aware of other cases in their kennel or pedigree. The sire, dam, and a sibling of the affected dog were healthy at the time of diagnosis.
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Case 11-4. Cerebrum. There is a poorly defined zone of cellular loss and vacuolation representing laminar cortical necrosis.
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Case 11-4. Thalamus. At this magnification, cellular loss is much more noticable. Note the central Gitter cell, vacuolar degeneration, karyorrhectic debris, and scattered microglia (gliosis).
AFIP Diagnoses:
1. Thalamus: Cavitation and necrosis, focally extensive, with gitter cells and mild gliosis, Alaskan Husky, canine.
2. Cerebral cortex: Necrosis, laminar, focally extensive, with mild to moderate gliosis.
3. Cerebellum: Purkinje and granular cell loss, multifocal, segmental, with moderate gliosis.
Conference Note: Histologically, the gray matter of the thalamus contains a focally extensive, necrotic, cavitary lesion, with loss of neuropil, replacement by numerous lipid-laden macrophages, mild gliosis, and mild vascular proliferation. Within the cerebral cortex there is a focally extensive, laminar area of necrosis, with vacuolation of the neuropil, and gliosis; endothelial hypertrophy and hyperplasia are not evident in this area. The cerebellum exhibits segmental loss of both internal granular cell layer neurons and Purkinje cells, with associated Bergmann's gliosis.
The comparison of "Alaskan Husky" or "sled dog" encephalopathy to the human entity of Leigh's disease has been based primarily on the distribution of the neurodegenerative lesions within the brain and is described as extensive, bilaterally symmetrical cavitation within the diencephalon extending into the tegmentum of the mesencephalon and hindbrain. The confluence of the gross cavitary lesions into a butterfly shape (oblique "V" shape) seems to be a classical feature of Leigh's disease in humans and is a consistent finding in affected dogs (BA Summers, personal communication).
An apparently consistent microscopic finding in human brains with Leigh's disease is prominent vascular endothelial proliferation with sparing of the neuronal perikarya in the thalamus, and mild degenerative changes in the neuronal processes and myelin sheaths. Several sections of brain from affected dogs may need to be examined microscopically to identify the vascular changes associated with the canine disease. While capillary endothelial proliferation can be seen in early stages of the canine disease, this microscopic feature may become inapparent in lesions in later stages of the disease. The progression of the disease over a period of one month to the point of clinical seizures suggests this dog was euthanized during endstage disease.
The cerebellar changes, characterized by Purkinje cell loss, gliosis, and granular cell loss can be part of "sled dog encephalopathy" (BA Summers, personal communication). As mentioned by the contributor, the cerebrocortical lesions are likely due to ischemia or hypoxia, and probably resulted from seizures.
Contributor: Wyoming State Veterinary Laboratory, 1174 Snowy Range Road, Laramie, WY 82070.
1. Summers BA, Cummings JF, de Lahunta A: Degenerative diseases. In: Veterinary Neuropathology, pp. 212-213, Mosby Yearbook, St. Louis, MO, 1995.
2. Brenner O, de Lahunta A, Summers BA, Cummings JF, Cooper BJ, Valentine BA, Bell JS: Hereditary polioencephalomyelopathy of the Australian cattle dog. Acta Neuropathol 94:54-66, 1997.
3. Duchen LW, Jacobs JM: Nutritional deficiencies and metabolic disorders. In: Greenfield's Neuropathology, Adams JH, Duchen LW eds., 5th ed., pp. 847-850, Oxford University Press, New York, 1992.
4. Montgomery DL, Storts RW: Hereditary and striatonigral and cerebello-olivary degeneration of the Kerry blue terrier. Vet Pathol 20:143-159, 1983.
Ed Stevens, DVM
Captain, United States Army
Registry of Veterinary Pathology*
Department of Veterinary Pathology
Armed Forces Institute of Pathology
(202)782-2615; DSN: 662-2615
* The American Veterinary Medical Association and the American College of Veterinary Pathologists are co-sponsors of the Registry of Veterinary Pathology. The C.L. Davis Foundation also provides substantial support for the Registry.
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