Prion Spongiform Encephalopathy (Scrapie)



February 2017



Signalment Slide A (JPC 1945671): A 4-year-old Suffolk ewe


HISTORY: This ewe presented with loss of wool around the tailhead, hyperesthesia, mild hypermetria and some difficulty in prehension and swallowing. The ewe was euthanized.


HISTOPATHOLOGIC DESCRIPTION: Brainstem, medulla: Diffusely within the gray matter, there is vacuolization of neuronal perikarya and neuritic processes with variably sized, intracytoplasmic clear vacuoles up to 30 um diameter. The associated neuropil often contains variably sized clear spaces up to 25 um in diameter (spongiform change). Other neurons are shrunken, hypereosinophilic, angular with pyknosis (necrosis). Multifocally, there are degenerate neurons with rounded perikarya and peripheralized Nissl substance and eccentrically placed nuclei (central chromatolysis). There are increased numbers of astrocytes which are frequently reactive (astrocytosis) as well as increased microglial cells (gliosis), which occasionally align along the perikaryon of neurons (satellitosis).


MORPHOLOGIC DIAGNOSIS: Brainstem, gray matter: Neuronal vacuolization, degeneration, and necrosis, diffuse, moderate, with spongiform change, and astrocytosis, Suffolk, ovine.


ETIOLOGIC DIAGNOSIS: Prion spongiform encephalopathy


CONDITION: Scrapie (Ovine spongiform encephalopathy)


Signalment Slide B (JPC 1232805): Tissue from a mink.

HISTORY: This mink was inoculated intracerebrally with an infectious agent. Seven months later, the animal began to display nervous signs, went progressively “downhill” and was euthanized.


HISTOPATHOLOGIC DESCRIPTION: Cerebrum and midbrain at the level of the hippocampus: Diffusely, there is bilaterally symmetric, severe vacuolization of the gray matter neuropil, with variably sized, round, discrete clear spaces up to 25 um in diameter (spongiform change). Multifocally, there is expansion of neuronal perikarya and neuritic processes by variably sized, discrete, intracytoplasmic, clear vacuoles. There is multifocal neuronal necrosis and astrocytosis as previously described.


MORPHOLOGIC DIAGNOSIS: Cerebrum and brainstem, gray matter: Spongiform change, diffuse, moderate, with neuronal vacuolization, degeneration, and necrosis, and astrocytosis, breed not specified, mink.


ETIOLOGIC DIAGNOSIS: Prion spongiform encephalopathy


CONDITION: Transmissible mink encephalopathy (TME)



       Scrapie: Natural disease of sheep (and rarely goats); prototype prion-induced transmissible spongiform encephalopathy (TSE)

       TME: Affects ranch mink in North America and northern Europe; contamination of feed by the scrapie agent suggested as source of infection

       Other TSEs: Bovine spongiform encephalopathy (BSE), chronic wasting disease (CWD) of cervids, feline spongiform encephalopathy (FSE), and several human spongiform encephalopathies

       Prion diseases are characterized by chronic progressive fatal neurologic manifestations, with both sensory and motor deficits and spongiform encephalopathy, and result from accumulation of an abnormal isoform PrPsc of the host prion protein PrPc

       Transmissible prion diseases result from infection with an external PrPsc and accumulation of host-produced PrPsc

       Prions are resistant physical and chemical agents



       TSEs in general:

o   Most widely-accepted is the “protein-only hypothesis”:

1.    PrPsc is the etiologic agent of TSEs

2.    Transformation from alpha-helical PrPc to beta-pleated PrPsc requires either a genetic predisposition or protein cofactors (“protein X”)

3.    PrPsc triggers additional production of PrPsc by PRNP (self-replication); PrPsc acts as a template and catalyst for the abnormal folding and polymerization of PrPc in target cells such as neurons

4.    PrPsc itself can be infectious; there is an incomplete species barrier to transmission of TSE agents between species; some TSEs are attributed to ingestion of feedstuffs contaminated with TSE agents of other species

o   Less accepted theories are that prion diseases are immune-mediated and could result from ingestion of feed contaminated with certain bacteria (eg Acinetobacter spp.) which show molecular mimicry to CNS tissue

o   Proposed mechanisms of nerve cell degeneration:

o   Mechanical destruction of nerve cell membranes from excessive accumulation

o   Lysosomal accumulation of PrPsc may trigger apoptosis by release of cathepsin D

o   PrPsc may be a direct neurotoxin


o   Infection probably around the time of birth probably via ingestion

o   Goats sharing pasture with affected sheep maybe infected; not reported in other species sharing pasture with infected sheep

o   Proliferates in lymphoid tissues and lower intestine > long incubation period (up to 2 years) > retrograde axonal transport via splanchnic nerves to thoracic spinal cord to brain > gradual accumulation of PrPsc in neurons (medulla oblongata and diencephalon) > neurodegeneration and loss (likely via astrocyte and microglial activation and apoptosis) > neurologic signs up to several years after PrPsc reaches CNS

o   The agent may proliferate in the lymphoid tissues up to 2 years before it reaches the CNS; a further 2 years may lapse before clinical signs appear

o   In the CNS, PrPsc first accumulates in astroglial cells, which may be the primary site of replication in the brain

o   Genetic variation in the PrP gene affects susceptibility to disease:

§  Most susceptible = Homozygous VRQ/VRQ

§  Most resistant = ARR

o   Scrapie incubation period gene, sip, controls the incubation period in sheep

o   Recently two distinct strains of scrapie have been isolated in the US: No. 13-7 and x124

       TME: Not determined but contamination of feed by scrapie agent is suggested



       Pruritus, causing sheep to rub and excoriate fleece, is thought to be due to cutaneous paresthesia

       Alert but excitable, trembles, progression to ataxia, head tremors, emaciation, seizures, paralysis, and death from 10 days to several months after clinical manifestation



       No gross CNS lesions

       Self-trauma secondary to pruritus; emaciation



       TSEs in general:

o   Distribution, nature, and severity of CNS lesions depend on agent strain and host genotype; medulla oblongata (particularly at obex) is most consistently affected

o   Hallmarks of TSEs are neuronal vacuolation, spongiform change, and astrocytic hypertrophy and hyperplasia; PrPsc accumulation precedes these findings

§  Neuronal vacuolation: Single, multiple, or chains of vacuoles in soma, perikaryon, or neurites +/- spongiform change; neuronophagia is absent

§  Spongiform change: Diffuse or clustered to confluent small round vacuoles in the cerebral gray matter neuropil +/- extension into neurites; extracellular space is normal

§  Astrocytosis: Usually involves gray matter affected by spongiform change

o   Cerebrovascular amyloid plaques, thought to contain prion protein, are rare in most animal TSEs but common in human variant Creutzfeldt-Jakob disease (vCJD)

o   No inflammatory reaction

       Scrapie: Most characteristic finding is large intraneuronal vacuoles in medullary reticular, medial vestibular, lateral cuneate, and papilliform nuclei (may be present throughout brainstem and spinal cord); vacuoles generally appear empty and displace organelles

o   +/- shrunken, degenerate neurons in mesencephalic, medullary, and deep cerebellar nuclei and intermediolateral nucleus of spinal cord

o   +/- neuronal loss in late stages

o   +/- fibrillary astrogliosis in mesencephalon and molecular layer of cerebellum

o   Spongiform vacuolation of neuropil is rarely found in scrapie; generally seen with long incubation periods

o   Lesions are bilaterally symmetrical and cortex is rarely involved

       TME: In contrast to scrapie, neuronal vacuolation is sparse and generally confined to the brainstem; spongiform degeneration and astrocytosis predominate and are most prominent in the neocortex and amygdala, corpus striatum, caudodorsal thalamus, and medial geniculate bodies



       Scrapie-associated fibrils consist of two (sometimes four) twisted filaments, each 4-6 nm in diameter (resemble amyloid fibrils)

       Vacuoles bounded by single or double membranes within neuronal perikarya, dendrites, and axons



       Immunohistochemical staining of suspect brain and lymphoid tissue (medial retropharyngeal lymph node, tonsil, nictitating membrane)

       Detection of glycoprotein component of SAF in lymphoid tissue allows a preclinical diagnosis of scrapie

       Western blot assays of solubilized brain extracts and cerebrospinal fluid detects prion protein



       Atypical scrapie (Nor98):

o   First identified in Norway and described in 2003

o   Cause is a newly identified TSE agent with a western blot signature distinct from the classical scrapie TSE agent

o   Affects older animals (5 to >10 years) than classical scrapie (3-5 years)

o   Affects sheep genetically resistant to classical scrapie

o   Salient clinical sign is ataxia; pruritus and wool-loss absent

o   Neuroanatomical distribution of PrPsc differs from classical scrapie; neuronal vacuolation and spongiform change are largely absent

o   PrPsc has not been detected in lymphoid tissues of sheep with atypical scrapie in contrast to classical scrapie

       BSE - experimentally transmitted in sheep

       Neuronal vacuolar degeneration of Angora goats - scrapie-like neuronopathy in young (3 months-of-age) Angora goats in Australia; vacuolation in brainstem nuclei and spinal motor neurons

       Lysosomal or other storage diseases - vacuolization of neurons

       Rabies - occasionally spongiform change



       TME in ferrets: Albino ferrets are documented to have recovered from experimental TME

       BSE: Mainly in 3- to 6-year-old cattle; SAF demonstrated from BSE brain, most frequently in basal nuclei and brainstem; an atypical form has recently been described as for scrapie

o   Differential diagnosis: Bovine citrullinemia - Newborn Holstein-Friesian calves - autosomal recessive defect; deficiency of arginosuccinate synthetase resulting from a blockade of the urea cycle leading to hyperammonemia and citrullinemia; spongy vacuolation of deep lamina of the cerebral cortex due to astrocytic swelling

       CWD: Mule deer, white-tailed and black-tailed deer, and Rocky Mountain elk; usually 3- to 5-year-old; spongiform change, neuronal vacuolation, gliosis, and amyloid deposition prominent in olfactory tubercle, cortex hypothalamus, and vagal nuclei

       FSE: Domestic cats and captive felids; likely transmitted by ingestion of BSE-contaminated food; primarily spongiform change in deep cerebral laminae, corpus striatum, thalamus, medial geniculate body, and cerebellar cortex; neuronal vacuolation in medulla is less prominent

       Exotic ungulate encephalopathy (EUE): Captive nyala, greater kudu, oryx; associated with ingestion of BSE-contaminated feed

       Spongiform encephalopathy in nonhuman primates: Associated with ingestion of primate food containing BSE-contaminated beef

       Dogs: Focal spongiform encephalopathies (not TSEs):

o   Bull mastiffs, salukis: Familial cerebellar ataxia, hydrocephalus, spongiform change in gray matter (deep cerebellar nuclei, posterior colliculi, lateral ventricular nuclei) with axonal spheroids; nerve cell bodies appear normal

o   Rottweilers: Unknown etiology; progressive laryngeal paralysis, tetraparesis, cerebellar ataxia beginning at 8 weeks of age; neuronal vacuolation in cerebellar roof nuclei, extrapyramidal nuclei, dorsal nerve root ganglia, myenteric plexus, other ganglia of autonomic nervous system

o   Australian cattle dog: Autosomal recessive defect in astrocytic mitochondria; neuronal, neuropilar, and astrocytic vacuolation especially in ventral horn of spinal cord, cerebellar and brainstem nuclei

o   Alaskan husky: Hereditary familial encephalopathy; clinical signs begin before 1 year of age; bilateral symmetrical malacia, spongiosis, gemistocytic astrocytosis, marked intracytoplasmic vacuolation, gliosis, vascular hyperplasia; relative neuronal sparing




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