February 2017



Signalment JPC #2292125: 5 1/2-year-old Simmental cow


HISTORY:  The first signs of a neurological disorder were observed about one month before euthanasia, including anxiety, falling over, and difficulty rising from a recumbent position.  Clinical examination revealed tremor of the head, tooth grinding, hyperesthesia to sound and touch, and hypermetric movements of the forelimbs.



Brainstem:  Within the solitary tract nucleus, and to a lesser extent the dorsal vagal motor nucleus, there are few scattered neurons in which the perikaryon is expanded with one or more clear, round, distinct vacuoles up to 50 um in diameter.  Multifocally, adjacent to the solitary tract nucleus, there is mild spongiosis characterized by clear spaces up to 60 um in diameter within the neuropil.  Multifocally astrocytes are increased in number and size with enlarged, pale nuclei containing peripheralized chromatin (astrocytosis) and there is gliosis in the surrounding neuropil.


MORPHOLOGIC DIAGNOSIS:  Brain stem, solitary tract nucleus:  Neuronal degeneration and vacuolation, multifocal, mild, with spongiosis and gliosis, Simmental, bovine.


ETIOLOGIC DIAGNOSIS: Bovine prion spongiform encephalopathy


CAUSE:  Bovine prion


CONDITION:  Bovine spongiform encephalopathy (BSE)


SYNONYMS:  Mad cow disease



·       BSE is a fatal, neurodegenerative disease that affects the central nervous system (CNS) of adult cattle, usually 3 to 5 years of age

·       First reported in the UK in the 1980s

·       The origin of the first outbreak is unknown; however, the recycling of ruminant tissues into ruminant feed amplified the BSE prions to cause an epidemic

·       Caused by a resistant prion protein, PrPres ("res" for resistant)

·       No nucleic acids; the only known infectious agent to replicate without nucleic acids

·       Extremely resistant to heat and sterilization; can be inactivated by incineration at 1,832 degrees F, extended autoclave runs at high temperatures (4.5 hours at 273.2 degrees F), or protein denaturants such as guanidine salts

·       Zoonotic; associated with variant Creutzfeldt-Jakob disease (vCJD) in humans; BSE is the only TSE transmissible to humans

·       There are at least 3 strains of BSE in cattle:  Classical BSE strain, atypical L-type strain, and atypical H-type strain; L and H denotes characteristic light and heavy molecular prion banding patterns seen using Western blot

·       L-type BSE is characterized by the presence of PrPsc – positive amyloid plaques in the brain = Bovine amyloidotic spongiform encephalopathy (BASE)

·       Both BSE cases in US native-born cattle were atypical H-type strain; atypical L-type strain has not been detected in US cattle



·       Not well understood

·       PrPres is a modified, protease-resistant form of a normal tissue protein, PrPc, which accumulates in neuronsand whose exact function remains unclear

·       PrPc is encoded by the gene PRNP; this gene is highly conserved in animals and humans

·       Transmissible spongiform encephalopathies (TSEs) are unique since they can be transmitted by inoculation of infectious tissue into susceptible species or genetically by spontaneous mutation of the prion protein gene in a parent

·       Inherited prion protein diseases of humans are associated with coding mutations of the PRNP gene

·       In humans, TSEs can be either heritable, such as CJD, or acquired, as in vCJD

·       For most transmissible spongiform encephalopathies (TSEs), PrPc ("c" for cellular), normally accumulates in particularly high concentrations within lymphoreticular and nervous tissues

·       In cattle with BSE, over 95% of PrPres is in the nervous system with minimal accumulation in lymphoreticular tissues

·       PrPres is thought to arise from posttranslational processing of PrPc that results in a conformational change

·       Sporadic and genetically determined TSEs have not been detected in cattle

·       There is no evidence of horizontal transmission in cattle

·       Vertical transmission is documented in sheep; this is highly significant because the ewe could give birth to and infect several lambs before showing clinical signs

·       Propagation - during development of a transmissible prion disease, an exogenous infectious prion isoform converts a native prion protein into a replicate of the infectious prion isoform; this newly formed isoform can then convert other native prion proteins in a kind of chain reaction; thus, the infectious prion isoform replicates and propagates the infection

·       Ingestion of PrPres > replication the Peyer’s patches of the ileum > ascending spread to CNS via autonomic tracts that innervate the gastrointestinal tract > PrPres contacts PrPc > folds into isoform of beta-pleated sheet > propagation of misfolded proteins with accumulation in neurons > clinical signs

·       Clinical signs are apparent when infection of target nuclei in the CNS causes progressive neuronal dysfunction

·       Neuroinflammation elicited by PrPres deposits in the CNS has been shown to involve cellular and oxidative stress responses in BSE and murine models of TSE; PrPres elicits significant astroglial and microglial reactions; there is altered expression of metallothionein and heat shock protein 25 (HSP25); in contrast, there is no change in expression of membrane-associated water channel aquaporin 1 when PrPres accumulates in the brain; however, deregulation of water homeostasis by some other mechanism may be a component of changes observed in TSEs

·       BSE agent has been identified within the brain, spinal cord, retina, lymphoid tissue, bone marrow, trigeminal and dorsal root ganglia, and olfactory bulbs in various spp.

·       TSEs can be spread by blood transfusions in sheep and humans

·       Experimentally, transmissible mink encephalopathy has been shown to cause both functional and morphologic alterations in the retinas of TSE-infected cattle



·       Long incubation period, usually 2 to 8 years

·       Long clinical course, usually 2 weeks to 6 months

·       Apprehension, nervousness, truncal ataxia, aggression, hypermetria, progressive weakness, emaciation, and ultimately death



·       None



·       Triad of lesions of the transmissible spongiform encephalopathies:

·       Spongiform change in the gray matter neuropil, primarily swollen dendrites

·       Vacuolation of the neuronal cell bodiesand processes primarily in the dorsal vagal, medullary reticular, vestibular, solitary, spinal, trigeminal, and red nuclei

·       Astrocyte hyperplasia and hypertrophy

·       Neuronal degeneration and necrosis

·       Little to no inflammatory response; no change in cerebrospinal fluid



·       Scrapie-associated fibrils:  2 to 4 twisted filaments that are 4 to 6 nm in diameter

·       Neurons are enlarged, usually with a single, membrane-bound cytoplasmic vacuole that may contain granular material



·       Currently, there is no test for BSE in living animals

·       Rapid screening testing of fresh CNS tissue

·       ELISA

·       Lateral flow immunoassay (dipstick)

·       If positive using a rapid assay, then BSE is confirmed with additional tests:

·       IHC

·       Western blot

·       Histopathological examination of medulla oblongata at the level of the obex; spongiform change typically occurs in the nucleus of the solitary tract and the spinal tract nucleus of the trigeminal nerve

·       Relatively few atypical BSE prions are found in the obex; more commonly found in the thalamus and olfactory bulb

·       BSE can be differentiated from scrapie based on decreased immunohistochemical staining of PrP with the 84-102 amino acid sequences within the phagocytic cells of the brain and lymphoreticular tissue

·       Analysis of banding patterns of proteinase K-digested pathologic prion proteins also can differentiate between BSE and scrapie



Microscopic lesions

·       Bovine citrullinemia

·       Autosomal recessive defect in Holstein-Friesian calves

·       Deficiency of arginosuccinate synthetase interferes with urea cycle metabolism leading to hyperammonemia and citrullinemia

·       Astrocyte swelling leads to spongy vacuolation of the deep laminae of the cerebral cortex

·       Congenital brain edema

·       Hereford calves in New Zealand

·       Vacuolation of the myelin and gray matter, and hydropic degeneration of astrocytes

·       Hereditary neuraxial edema

·       Polled Hereford calves in Great Britain

·       Myelin vacuolation without hypomyelinogenesis

·       Maple syrup urine disease

·       Autosomal recessive - Holstein calves

·       Deficiency of branched-chain alpha-ketoacid decarboxylase

·       Metabolic defect leads to accumulation of leucine, isoleucine, and valine, and their ionized acidic forms

·       Spongiform change is primarily in large myelinated tracts of cerebral hemispheres and cerebellum, and those near the brain stem nuclei and spinal gray matter

·       Vacuolation within the white matter, primarily in the substantia nigra, and the red and vestibular nuclei in cattle may be an incidental finding



·       Sheep and goats - Scrapie

·       Felids (domestic and exotic) - Feline spongiform encephalopathy

·       Mink - Transmissible mink encephalopathy

·       Deer and elk - Chronic wasting disease

·       Exotic ruminants (Greater kudu, Arabian oryx, nyala, gemsbok, eland) - BSE/Exotic ungulate spongiform encephalopathy

·       Non-human primates – lemurs and one rhesus macaque in France

·       Humans – Kuru (cannibalism); Creutzfeldt-Jakob disease (inherited; aka "sporadic CJD"); Gerstmann-Straussler-Scheinker syndrome; variant Creutzfeldt-Jakob disease (from eating contaminated beef); fatal familial insomnia

·       Pigs and dogs are not susceptible to BSE via oral ingestion



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