JPC SYSTEMIC PATHOLOGY
Signalment (JPC #2077161): Two‑year‑old horse
HISTORY: This horse exhibited aggressive behavior, then refused to eat or drink and died.
HISTOPATHOLOGIC DESCRIPTION: Cerebrum and brainstem: Diffusely within the gray matter, neurons are moderately to markedly swollen with foamy to microvacuolated cytoplasm, which occasionally displaces the nucleus. Glial cells and macrophages are similarly affected. There is a mild increase in glial cells within the neuropil (gliosis). Multifocally, surrounding vessels and within the meninges, there are low to moderate numbers of macrophages and few lymphocytes.
Kidney: Multifocally, tubular epithelial cells are degenerate and expanded by foamy to microvacuolated cytoplasm. Multifocally adjacent tubular epithelial cells often contain a large vesiculate nucleus that occasionally is stacked up with brightly eosinophilic cytoplasm (regeneration).
MORPHOLOGIC DIAGNOSIS: 1. Cerebrum and brainstem: Neuronal and glial swelling and microvacuolation, diffuse, moderate, with multifocal, mild lymphohistiocytic leptomeningitis, breed unspecified, equine.
2. Kidney, proximal tubules: Epithelial degeneration and vacuolar change, diffuse, moderate, with tubular regeneration.
CAUSE: Swainsonine toxicity
ETIOLOGIC DIAGNOSIS: Renal and cerebral swainsonine intoxication
CONDITION SYNONYM: Pea struck (Australia)
· Swainsonine (indolizidine alkaloid) is found in plants of the genera Oxytropis, Astragalus (North America), Swainsona (Australia), Ipomoea carnea (Mozambique), Sida carpinifolia and Turbinia (Brazil)
· Toxic principle is swainsonine, but is identified as locoine or swainsonine N-oxide in some texts (same toxin)
· Recent discoveries have pinpointed the fungal endophyte Undifilum oxytropis as the ultimate source of swainsonine
· Swainsonine causes an induced alpha-mannosidosis which is biochemically distinct from genetic alpha-mannosidosis (deficiency of lysosomal a-mannosidase only); toxin also inhibits Golgi mannosidase II, an enzyme involved in post-translational trimming of the protein
· Requires ingestion of toxic plants for several weeks (14-60 days)
· Swainsonine is rapidly absorbed > high serum concentration > inhibits two enzymes, lysosomal α-mannosidase and Golgi mannosidase II (Golgi body), that aid in metabolism of saccharides > lysosomal accumulation of mannose > neuronal swelling and vacuolization
· Golgi mannosidase II is not inhibited in the inherited mannosidosis disorder
· Swainsonine is also passed through the milk to suckling animals
· Mannosidases are found in all mammalian cells, however, neurons, epithelial cells in organ systems (e.g. liver), and macrophages of the spleen and lymph nodes are commonly affected
TYPICAL CLINICAL FINDINGS:
· Loss of condition, failure to grow (swainsonine affects production of growth hormone and thyroxine; decreased nutrient absorption in affected intestine), ataxia, visual/proprioceptive deficits, behavioral abnormalities (especially when stressed)
· Young animals – since maturing neurons are more vulnerable to toxic effects, may see more severe signs and more likely to be irreversible compared to adults
· Short-term exposure - animals usually recover after removal from source
· Long-term exposure or more severely affected animals - residual neurologic damage
· Abortion and terata (malformed fetus) are well recognized as is suppressive effects on fertility
TYPICAL GROSS FINDINGS:
· No specific gross lesions; emaciation, stomach ulcers, thyroid hypertrophy, and pale liver and kidneys may be seen
TYPICAL LIGHT MICROSCOPIC FINDINGS:
· Vacuolation of neurons in CNS and/or PNS (including Auerbach’s and Meissner plexuses) and parenchymal cells (e.g. kidney tubular epithelial cells; interstitial cells and pericytes of the myocardium (in rats); exocrine pancreas; thyroid follicular epithelium; cerebellar Purkinje cells; Kupffer cells; macrophages in spleen and lymph nodes; urinary bladder transitional cell epithelium)
· Material in vacuoles identified as mannose-rich oligosaccharide
· Axonal spheroids persist in large numbers often in cerebellar roof nuclei and caudal brainstem
· Later stages – neuronal necrosis, axonal degeneration
· Diffuse perivascular edema in CNS
· Meganeurites (irregular fusiform enlargements) in proximal axon segment with aberrant synapses
· Cytoplasmic vacuoles, most prominent in purkinje cells; vacuoles are electron lucent; may contain amorphous electron-dense material and occasional membranous fragments of fibrillar material
ADDITIONAL DIAGNOSTIC TESTS:
· Diagnosis confirmed by characteristic histopathologic lesions
· Blood (short half-life) and tissue levels of swainsonine
· High urine content of mannose-containing oligosaccharides
· Microscopically indistinguishable from hereditary a‑mannosidosis
· Other lysosomal storage diseases
· Castanospermum australe (Morton Bay chestnut tree) - similar to swainsonine (inhibitory effects on glucosidases)
· Gomen disease - cerebellar degenerative disease in horses from New Caledonia; marked absence of Purkinje cells; moderate to severe accumulation of lipoprotein pigmentation in neurons of brain and cord
· Conium spp. piperidine alkaloids
· Lupinus spp. quinolizidine alkaloids
· Nicotiana spp. alkaloids
· Affects all grazing animals; cattle, sheep, horses, goats - most commonly affected
· Ipomoea calobra also contains calystegine B2 (nortropane alkaloid) induces phenotypic expression of alpha-galactosidosis and beta-glucosidosis in cattle and sheep
· Ipomoea verbascoidea in Brazil contains swainsonine and calystegines and causes alpha-mannosidosis in goats
· Sida carpinifolia causes this in captive sambar deer
o Abortion, infertility, hydrops allantois, subcutaneous edema in fetus, fetal deformities, fetal resorption
o Placenta - most susceptible during the first 90 days of gestation, but can be affected at any time
o "High mountain disease" (congestive right heart failure) - cytoplasmic vacuolation in lungs – may add to effects of high-altitude hypoxia on pulmonary vasculature, causing pulmonary hypertension and eventual right heart failure
· Sheep – abortion; birth of weak lambs that die within a few days; congenital anomalies include mandibular aplasia, joint contracture (arthrogryposis), or joint laxity
· Rams - testicular atrophy; decreased spermatogenesis; vacuolated cells in seminiferous tubules, epididymis, vas deferens; similar changes in bulls can be anticipated
· Can be experimentally induced in monogastric and laboratory animals
· Hereditary alpha‑mannosidosis - Angus, Murray Grey and Galloway cattle breeds and Persian cats
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