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CASE I – P98-6925/3 (AFIP 2739547)
Signalment: 11-week-old, male rottweiler, canine
History: This puppy had a 3-week history of blindness, incoordination, aggressive behavior, and hip problems. The pup was submitted for postmortem examination after humane euthanasia.
Gross Pathology: The puppy was in good body condition, with no muscle atrophy or skeletal malformations. There was a persistent hyaloid artery and lenticonus in the right eye, and lenticonus in the left eye. No gross abnormalities were found within the central nervous system, or with hepatic circulation.
Laboratory Results: Histopathological lesions were confined to the central nervous system. In the pons, brainstem, and cerebellar nuclei, single to multiple empty, intracytoplasmic, 2-10 um diameter, neuronal vacuoles were present, with distention of the perikaryon. There was slight neuropil spongiosis, few necrotic neurons, and incidental chromatolysis (not present in all slides). Wallerian degeneration was not found. There was bilateral cataractous change, in addition to the lesions seen grossly.
Contributor’s Diagnosis and Comment: Cerebellum: Neuronal vacuolar degeneration, mild to moderate, with few necrotic neurons and incidental chromatolysis.
Etiology: Unknown; probably a genetic disorder.
Neuronal vacuolation has recently been described as a separate entity in at least eight young rottweiler pups. Clinically, it is characterised by progressive neurologic signs starting at about seven weeks, with paresis and ataxia most severe in the pelvic limbs. Additionally, ataxia of the head, decreased proprioception, exaggeration of spinal reflexes, inspiratory laryngeal stridor, and inappropriate aggressive behavior towards littermates may be seen. Histologically, the lesion is characterized by neuronal vacuolation in the cerebellum, brainstem, and spinal cord, with associated spinocerebellar Wallerian-type degeneration and spongiform change. Some dogs also had microvacuolation of Purkinje cells. Within the peripheral nervous system, similar vacuolation occurred sporadically. Ultrastructural studies could not determine the subcellular organelle involved, or the evolution of the vacuolar change. Immunoblotting and immunohistochemistry for scrapie PrP-res were negative. The etiology is yet unknown, but the familial pattern might suggest a genetic background.
The clinical differential diagnosis includes: 1. Familial lower motor neuron disease, characterized by chromatolysis and swelling of the perikarya of large motor neurons in the spinal cord ventral gray matter; vacuolation is not observed. 2. Neuroaxonal dystrophy, characterized by progressive sensory ataxia in adult dogs, with axonal spheroids lacking vacuolation. 3. Leukoencephalomyelopathy, a syndrome in adult animals, with symmetrical demyelination of the brainstem, cerebellar and spinal cord white matter. Scrapie-like spongiform encephalopathy is unknown in dogs.
AFIP Diagnosis: Cerebellum, nucleus of spinal tract of trigeminal nerve, vestibular nucleus, and Purkinje cells: Neuronal vacuolation and degeneration, multifocal, moderate, rottweiler, canine.
Conference Comment: An important point stressed by the moderator is that firm understanding of neuroanatomy is equally important as signalment and clinical signs in localization of a neurologic lesion and in interpretation of neuropathological changes. The limited information provided to conference participants consisting of “tissue from a dog” is insufficient to thoroughly evaluate neurohistologic specimens. In this case, the persistence of an external germinal layer in the cerebellar molecular layer suggests that the tissue section is from a young animal.
The clinicopathologic presentation often assists in determination of neurologic lesion location. The reported observation of incoordination indicates a neural lesion of either the spinal cord or caudal brainstem. Blindness may result from a lesion anywhere along the optic tract. Aggression is suggestive of a lesion in the prosencephalon. The spectrum of clinical signs in this dog implies a diffuse lesion within the central nervous system, possibly due to a degenerative, inflammatory, or malformative process.
Tissue quality is also very important for sound histologic evaluation and interpretation in neuropathology. In this case, autolytic changes resulted in artificial vacuolation surrounding Purkinje cells and other neurons, making histologic evaluation of this vacuolating disease more difficult. The differential diagnosis might also include a metabolic storage disease; however, with storage diseases the intracytoplasmic neuronal vacuoles usually are not as discrete.
Contributor: Utrecht University, Faculty of Veterinary Medicine, Department of Veterinary Pathology, Yalelaan 1, PO Box 80158, 3508 TD The Netherlands
References: 1. Kortz GD, Meier WA, Higgins RJ, French RA, McKiernan BC, Fatzer R, Zachary JF: Neuronal vacuolation and spinocerebellar degeneration in young rottweiler dogs. Vet Pathol 34:296-302, 1997
2. Pumarola M, Fondevila D, Borras D, Majo N, Ferrer I: Neuronal vacuolation in young rottweiler dogs. Acta Neuropathol 97:192-195, 1999
3. van den Ingh TSGAM, Mandigers PJJ, van Nes JJ: A neuronal vacuolar disorder in young rottweiler dogs. Vet Rec 142:245-247, 1998
CASE II – 41147 (AFIP 2741454)
Signalment: Six-year-old, female Mexican red brocket deer (Mazama americana temama)
History: One month prior to death, this animal presented with an upper airway obstruction caused by plant material, and ataxia. Respiratory signs resolved after the plant material was removed. Despite treatment, the deer never fully recovered. The deer also had severe, chronic, mandibular osteomyelitis. Because of the poor prognosis, the animal was euthanized.
Gross Pathology: Gross lesions were limited to chronic mandibular osteomyelitis, with tooth loss.
Laboratory Results: None provided.
Contributor’s Diagnosis and Comment: Brain: Encephalopathy, with Rosenthal fiber formation.
Within the brain there were large numbers of globular to elongate, brightly eosinophilic bodies. This material is most consistent with Rosenthal fibers, as described in humans. The fibers were periodic acid-Schiff negative, and only the margins stained with glial fibrillary acidic protein immunostaining. In this case, the fibers were most numerous in the cerebellum and periventricular regions, and were absent from the cerebral cortex. In humans, Rosenthal fiber formation occurs in Alexander’s disease, and is also found adjacent to areas of brain injury (e.g., astrocytomas, glial scars). In dogs and humans, it has been demonstrated that the fibers contain alphaB-crystallin. Distribution of the fibers in this case differs from that seen with Alexander’s disease in man, where Rosenthal fibers are generally most numerous in the cerebrum.
Cases of Alexander’s disease have been described in dogs and sheep. In dogs and humans, there may be a hereditary basis for this disease, but in sheep the disease appears to be sporadic. We have not seen Rosenthal fiber formation in other Mexican red brocket deer in our collection.
AFIP Diagnosis: Cerebellum: Encephalopathy, with numerous Rosenthal fibers, and multifocal, moderate demyelination, Mexican red brocket deer (Mazama americana temama), cervid.
Conference Comment: When found in association with encephalopathy, Rosenthal fibers tend to accumulate beneath the pia mater, around blood vessels, and ependyma in both gray and white matter. The fibers are located within the cytoplasm of reactive astrocytes, and are thought to represent a chronic metabolic stress response to unknown deleterious stimuli. They are composed of alphaB-crystallin and a closely related heat shock protein. By immunohistochemistry, the cytoplasm immediately surrounding the fibers is positive for glial acidic fibrillary protein. Ultrastructurally, the inclusions consist of granular osmiophilic deposits within the perikarya and cell processes of astrocytes. In man, the deposits can be recognized with computerized tomography as increased contrast enhancement in areas of the brain most affected when examined histopathologically. The role that these fibers play in diseases such as Alexander’s disease is unknown.
Contributor: Zoological Society of San Diego, Department of Pathology, PO Box 120551, San Diego, CA 92112-0551
References: 1. Davis RL, Robertson DM: Neurons and astrocytes. In: Textbook of Neuropathology, 3rd ed., pp. 85-88, 467-469. Williams & Wilkins, Baltimore, MD, 1997
2. Fankhauser R, Fatzer R, Bestetti G, Deruaz JP, Perentes E: Encephalopathy with Rosenthal fibre formation in a sheep. Acta Neuropathol 50:57-60, 1980
3. Sorjonen DC, Cox NR, Kwapien RP: Myeloencephalopathy with eosinophilic refractile bodies (Rosenthal fibers) in a Scottish terrier. J Am Vet Med Assoc 190(8):1004-1006, 1987
4. Weissenböck H, Obermaier G, Dahme E: Alexander’s disease in a Bernese mountain dog. Acta Neuropathol 91:200-204, 1996
CASE III – E99-506 (AFIP 2738757)
Signalment: 8-year-old, castrated, male mixed breed dog
History: This dog had a long history of Lyme disease, and was treated with doxycycline in May of 1999 after an episode of lameness and collapse. In June and July, the dog was described as “not normal,” with vague clinical signs. No diagnosis was made. In September, the owner noticed temporal muscle atrophy over the right eye. Neurologic examination revealed bilateral dysfunction of the seventh cranial nerves, and right sided dysfunction of the fifth (motor) and eighth cranial nerves. The cerebrospinal fluid was normal. Magnetic resonance imaging of the brain was inconclusive. The dog was placed on clindamycin, trimethoprim sulfa, and prednisolone. The neurologic deficits persisted and no specific diagnosis was made. The dog’s condition continued to deteriorate until the owner requested euthanasia at the end of November, 1999.
Gross Pathology: There were no gross lesions evident in the brain.
Laboratory Results: None provided.
Contributor’s Diagnosis and Comment: Gliomatosis cerebri.
The sample is a cross section of the caudal brainstem at the level of the facial nerve nucleus, with a portion of adjacent cerebellum. There is bilateral, diffuse, but focally concentrated, hypercellularity that is most prominent in the facial motor, vestibular, and deep cerebellar nuclei and adjacent white matter. This appearance is due to an excessive number of nuclei, with inapparent cytoplasm, and with general histologic characteristics suggestive of reactive microglial cells. They tend to be small and dark staining, and irregularly round to ovoid to elongate. Plumper, ovoid nuclei range to dimensions of approximately 10 x 20 um. Some nuclei have assumed tadpole, pear-shaped or dumbbell shapes. Other nuclei are elongate and slender, up to 40 or 50 um in length, often with slightly curved profiles, and are sometimes twisted. The dense chromatin is finely stippled to granular.
Similar proliferative changes were extensive throughout the brainstem and cerebrum in this case, principally in the white matter. Areas most affected were the corpus callosum, a number of corona radiata, lateral thalamus, medial geniculate nuclei, and motor nuclei of the trigeminal nerve. In some affected nuclei, neuronal cell bodies had intracytoplasmic vacuoles, and some cell loss may have occurred.
Immunohistochemical staining revealed proliferating cells to be negative for glial fibrillary acidic protein, briskly positive for vimentin, and patchily positive for the macrophage marker CD18.
In the submitted section, the widespread proliferative process is accompanied by axonal and myelin degeneration around the median raphe in the reticular formation, and by a few spheroidal axonal swellings in deep cerebellar white matter. Scattered, very small nuclei (0.5 to 1.0 um) or nuclear fragments, and localized spongy change may represent postmortem autolysis.
In humans, gliomatosis cerebri is the term used to describe a widely disseminated proliferative disease of neuroglial cells which is conventionally regarded as neoplastic, but in which there is no formation of solid masses. Instead, there is insidious, diffuse, infiltrative growth that may extensively involve both the brain and spinal cord. Perivascular accumulation of these neuroglial cells is often a feature. The phenotype of the proliferating cells can be clearly oligodendroglial or fusiform, the latter encompassing microglia or pilocytic astrocytes. Cell markers are required for definitive classification. In the submitted case, the immunohistochemical profile pointed towards a microglial rather than astrocytic lineage, but was not definitive.
Accounts of gliomatosis cerebri, or related disorders, are sparse in the veterinary literature, and few studies have been made. Some 30 years ago, canine “microgliomatosis” was documented by Fankhauser, et al. within the group of the “reticuloses,” but as a localized, rather than generalized, infiltrative neoplastic disease. Subsequently, Vandevelde, et al. described seven cases of gliomatosis in an immunohistochemical study of canine neuroectodermal tumors.
Both microgliomatosis and gliomatosis cerebri are broadly discussed in “Veterinary Neuropathology,” the text by Summers, de Lahunta and Cummings. The submitted case features diffuse proliferation, and does not have prominent perivascular accumulations, but does exhibit some subpial infiltration in the cerebellar molecular layer. Thus, it shares features of both gliomatosis cerebri and microgliomatosis.
AFIP Diagnosis: Cerebellum and brainstem: Gliomatosis cerebri, mixed breed dog, canine.
Conference Comment: Microglia are a constituent part of the phagocytic and immunocompetent system of the central nervous system, and are believed to originate from bone marrow derived macrophages. It is unclear whether microgliomatosis represents a true microglial neoplasm or some kind of primitive neuroectodermal tumor. Neoplastic cells in gliomatosis cerebri show variation in immunohistochemical staining with astrocytic markers and the neoplasm is considered to possibly have some overlap with microgliomatosis.
Grossly, gliomatosis cerebri blends with the surrounding neuropil and may be detected only by recognition of a subtle enlargement of the infiltrated structures. It is considered a rare neoplasm predominantly of brachycephalic breeds.
A few sections displayed focal, neutrophilic infiltrates within the choroid plexus. The significance of this inflammation is uncertain.
Contributor: Cornell University, College of Veterinary Medicine, Department of Biomedical Sciences, Ithaca NY 14853
References: 1. Balko MG, Blisard KS, Samaha FJ: Oligodendroglial gliomatosis cerebri. Hum Pathol 23(6):706-707, 1992
2. Cervos-Navarro J, Artigas J, Aruffo C, Iglesias J: The fine structure of gliomatosis cerebri. Virchows Arch A 411:93-98, 1987
3. Koestner A, Bilzer T, Fatzer R, Schulman FY, Summers BA, Van Winkle TJ: Histological Classification of Tumors of the Nervous System of Domestic Animals, 2nd series, vol. V, pp. 21, 32. Armed Forces Institute of Pathology, Washington, DC, 1999
4. Ng HK: Diffuse gliomatosis of the central nervous system with histologic features of microgliomatosis. Clin Neuropathol 7(5):266-270, 1988
5. Summers B, Cummings JF, de Lahunta A: Tumors of the central nervous system. In: Veterinary Neuropathology, p. 380. Mosby, St. Louis, MO, 1995
6. Vandevelde M, Fankhauser R, Luginbühl H: Immunocytochemical studies in canine neuroectodermal brain tumors. Acta Neuropathol 66:111-116,1985
CASE IV – 00-3151 (AFIP 2736965)
Signalment: 3-year-old, spayed, female beagle dog (Canis familiaris)
History: This dog had progressive ataxia since the age of 6-12 months. Proprioceptive deficits that affected all limbs were present for several months. According to the owner, the dog seemed mentally dull since birth.
Gross Pathology: The cerebellum appeared smaller than normal, and was almost entirely covered by the hemispheres.
Laboratory Results: None provided.
Contributor’s Diagnosis and Comment: Cerebellum: Cerebellar cortical abiotrophy.
According to de Lahunta, the cerebellum is one of the most common sites of abiotrophy in domestic animals. The clinical hallmark of this condition is progressive cerebellar deficits in the postnatal period. This condition has been reported in three beagle dogs of the same litter, with early onset of symptoms (3 weeks-of-age). A case of late onset cerebellar degeneration has been observed in a 6-year-old schnauzer-beagle cross dog. The present case is similar to the cerebellar cortical abiotrophy in Gordon setter dogs seen at 6-24 months-of-age.
AFIP Diagnosis: Cerebellum: Purkinje cell degeneration and loss, diffuse, moderate, with secondary granular cell loss and molecular layer atrophy (cortical abiotrophy), beagle dog (Canis familiaris), canine.
Conference Comment: A progressive degeneration and loss of Purkinje cells, with a decrease in overall cerebellar mass, is the hallmark of cerebellar cortical abiotrophy. The degeneration is the consequence of an intrinsic metabolic disorder, rather than an acquired insult from an infectious agent or toxicant. Most neuronal abiotrophies target the Purkinje cells. Because of the nutritive synaptic relationship of Purkinje cells with neurons in the granular cell layer, loss of Purkinje cells often results in a reduction of granule cell neurons. Severely affected areas may show atrophy of the molecular layer as well. A secondary gliosis surrounding astrocytes in the cerebellar roof nuclei may also be present.
Normally, the cerebellum is 10-12% of the entire brain weight. Reduction in cerebellar mass to 5-6% of brain weight is indicative of cortical abiotrophy. Wallerian degeneration may result in thinning of dorsal white matter folia, often with preservation of ventral folia thickness. Combined with the reduction in cerebellar weight, this thinning may allow a gross diagnosis of abiotrophy.
In utero viral infections (parvoviruses, bovine viral diarrhea, classical swine fever) and toxicants may cause cerebellar hypoplasia by producing degeneration and necrosis of germinal cells, which histologically results in disorganization of Purkinje cells and disruption of normal architecture. Clinically, cerebellar ataxia is present at birth, but is not progressive and may even improve slightly as the animal learns to compensate. Conversely, abiotrophy affects the cerebellum after it has developed fully. Animals are usually normal at birth, followed by progressively worsening deficits in the postnatal period. The cerebellar cortical abiotrophy of Gordon setter dogs is unusual in that the onset of clinical signs ranges from 6 months up to 2 years-of-age.
Contributor: University of Montreal, Faculty of Veterinary Medicine, Department of Pathology and Microbiology, CP 5000, Saint-Hyacinthe, Quebec, Canada J2S 7C6
References: 1. Chrisman CL, Spencer CP, Crane SW, Mayhew IG, Averill DR, Buergelt CD: Late-onset cerebellar degeneration in a dog. J Am Vet Med Assoc 182(7):717-720, 1983
2. de Lahunta A: Abiotrophy in domestic animals: a review. Can J Vet Res 54:65-76, 1990.
3. de Lahunta A, Fenner WR, Indrieri RJ, Mellick PW, Gardner S, Bell JS: Hereditary cerebellar cortical abiotrophy in the Gordon setter. J Am Vet Med Assoc 177(6):538-541, 1980
4. Summers BA, Lummings JF, de Lahunta A: Degenerative diseases of the central nervous system. In: Veterinary Neuropathology, pp. 300-307. Mosby, St. Louis, MO, 1995
5. Yasuba M, Okimoto K, Iida M, Itakura C: Cerebellar cortical
degeneration in beagle dogs. Vet Pathol 25:315-317, 1988
*Sponsored by the American Veterinary Medical Association, the American College of Veterinary Pathologists and the C. L. Davis Foundation.
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