JPC SYSTEMIC PATHOLOGY
Signalment (JPC #2038191): Age and breed unspecified horse
HISTORY: This horse had hypertonia of the lips, tongue, and facial muscles causing the animal to have a fixed or wooden expression. The horse died after an acute inability to eat or drink.
HISTOPATHOLOGIC DESCRIPTION: Midbrain: Within the substantia nigra there is a focal, well demarcated, up to 5 mm diameter area of cavitation and loss with complete loss of neuropil and replacement by numerous gitter cells and abundant clear space (necrosis). The area of cavitation contains few scattered thin strands of eosinophilic fibrillar material as well as pre-existing vessels lined by reactive endothelium. Multifocally, within the surrounding neuropil and white matter, there are moderately increased numbers of glial cells (gliosis), moderate numbers of dilated myelin sheaths containing brightly eosinophilic 15-20 um diameter swollen axons (spheroids), and few scattered degenerate and necrotic neurons. Blood vessels within the meninges and neuropil are mildly congested.
MORPHOLOGIC DIAGNOSIS: Midbrain, substantia nigra: Necrosis, focally extensive, with cavitation, gliosis, and spheroids, breed unspecified, equine.
CAUSE: Yellow star thistle (Centaurea solstitialis), Russian knapweed (Centaurea repens), or purple star thistle (Centaurea calcitropa)
CONDITION: Nigropallidal encephalomalacia (NPE); Toxic Equine Parkinsonism
CONDITION SYNONYMS: "Chewing disease"
· NPE is a sporadic condition in horses associated with chronic ingestion of Centaurea spp. plants leading to nigropallidal encephalomalacia
· Yellow star thistle (Centaurea solsitialis)grows in dry weedy pastures in California and other western states; Russian knapweed (Centaurea repens) occurs in the intermountain region of the western USA and the Great Plains
· The condition has also been reported in Australia and Argentina
· The entire plant, green or dried, is toxic
· Poisonings can occur at any time of the year, but are more common on dry late summer or early fall pastures when other forage is dry and unpalatable
· Signs appear suddenly when a toxic threshold is reached after the animal has been eating the plant for one to three months and has consumed several hundred pounds of it
· The exact toxic agent and mechanism has not been proven
· Many sesquiterpene lactones isolated from Centaurea spp. are toxic in vitro; the rank order of toxicity (from most to least toxic) is repin > subluteolide > janerin > cynaropicrin > acroptilin > solstitialin
· The putative neurotoxin is repincauses glutathione depletion > increase in reactive oxygen species > oxidative damage > mitochondrial dysfunction > neuronal cell death
o High concentrations of monoamine oxidase in the striatonigral tract, involved in dopamine metabolism, may render these areas more susceptible to oxidative injury
o Repin also inhibits dopamine release, contributing to neurological signs similar to Parkinson’s disease in humans
· Local vasospasm theory:
o Local vasospasms have been postulated to be responsible for the abrupt appearance of necrotic foci
o Vasospasms may be induced by local action of vascular smooth muscle, or through vasomotor nerve fibers
o This mechanism would require either high local susceptibility of nigropallidal vessels for development of vasospasms, or selective passage and accumulation of the spasmogenic agent into this location
· Aspartate and glutamate are present in these plants; these non-essential amino acids are neuroexcitatory and may play a role in the pathogenesis of the disease
· Encephalomalacia of nigropallidal area > increased muscle tone and loss of coordination of muscles of prehension > starvation and dehydration > death
TYPICAL CLINICAL FINDINGS:
· Clinical signs appear acutely after the animal has been grazing on the plants for one to three months
· Severe depression, persistent chewing movements and difficulty in prehension, salivation, tongue flicking, dysphagia, intestinal bloat, paralysis, recumbency, and death
· Yawning and somnolence are evident but the horse is easily aroused
· A fixed facial expression is common, the mouth being held half-open or the lips drawn into a straight line; wrinkling of the skin and muzzle and protrusion of the tongue are present in many cases; lips fasciculate while the horse is trying to eat
· Sensation and reflexes are normal; no flaccid paralysis
· Death is due to starvation and dehydration or intercurrent disease
TYPICAL GROSS FINDINGS:
· Encephalomalacia of one or both of the globus pallidus and the substantia nigra
· Lesions are sharply demarcated, bilateral and symmetrical; unilateral lesions can occur
· Malacic areas may appear discolored yellow, gelatinous or cavitated
· Less frequently, lesions may be unilateral
· Russian knapweed has been reported to be more toxic and may show gross lesions at the inferior colliculus, mesencephalic nucleus of the trigeminal nerve, and the dentate nucleus
TYPICAL LIGHT MICROSCOPIC FINDINGS:
· Sharply demarcated areas of necrosis and cavitation with virtually no transitional zone
· Neuronal degeneration and necrosis, minimal to moderate gliosis, and necrosis of blood vessels
· Swollen axons in areas adjacent to liquefactive lesions
· Areas of liquefactive necrosis in the substantia nigra and globus pallidus may contain a delicate meshwork of connective tissue, vascular strands, and gitter cells
· Rabies virus induces perivascular cuffing and gliosis with eosinophilic cytoplasmic inclusion bodies (Negri bodies)
· Leukoencephalomalacia due to fumonisin B1 intoxicationFusarium verticillioides and F. proliferatum (formerly grouped together as Fusarium moniliforme contaminated corn) produces bilateral but unequal encephalomalacia of the white matter tracts of the cerebrum
· Hepatoencephalopathy due to hepatotoxic plants (Crotalaria, Senecio)
· Other causes of necrosis (not typically bilaterally symmetrical or confined to the globus pallidus and substantia nigra): Equine protozoal myelitis, EHV-1, etc.
· The plants do not appear to be toxic to ruminants, rodents, other small laboratory animals, monkeys, or dogs; sheep do well on sole diets of these plants
· Other plants with sesquiterpene lactones include Chrysanthemum spp. (contact dermatitis) and Geigeria, Helenium and Hymenoxys spp. that produce regurgitation, salivation, dysphagia, and coughing in cattle
· Humans: various forms of neurodegenerative parkinsonism (eg, supranuclear palsy, multiple-system atrophy, parkinsonism with dementia, corticobasal degeneration) and parkinsonism due to exposure to dopamine blocking drugs are not associated with pallidal or nigral necrosis
· Bilateral pallidal necrosis in humans is a well-known consequence of severe hypoxia or toxic injury due to carbon monoxide, manganese, methanol, or cyanide
· Rodents and Pigs: similar nigral necrosis, often accompanied by pallidal necrosis, has been described with experimental seizures in rodents and toxin ingestion in pigs
o Theories have favored severe mitochondrial dysfunction in globus pallidal neurons; the importance of mitochondrial function in GP neurons is further demonstrated by recent studies of the PKAN, a group of human autosomal recessive neurodegenerative diseases that preferentially affect bilateral GP
o The defective pantothenate kinase in PKAN results in deficiency of coenzyme A, which is critical for normal fatty acid metabolism in mitochondria
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