AFIP SYSTEMIC PATHOLOGY

 JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

March 2017

N-T01

 

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: Locoism

 

CONDITION SYNONYM: Pea struck (Australia)

 

GENERAL DISCUSSION:

·       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

 

PATHOGENESIS:

·       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

 

ULTRASTRUCTURAL FINDINGS:

·       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

 

DIFFERENTIAL DIAGNOSIS:

·       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

 

COMPARATIVE PATHOLOGY:

·       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

·       Cattle

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

 

References:

1.      Anjos BL, et al. Poisoning by the swainsonine-containing plant Sida carpinifolia in captive sambar deer (Cervus unicolor). J Zoo Wild Med. 2016;47(3):862-867.

2.      Armien AG, Tokarnia P, Peixoto PV, Frese K. Spontaneous and experimental glycoprotein storage disease of goats induced by Ipomoea carnea subsp fistulosa (Convolvulaceae). Vet Pathol. 2007;44(2):170-184.

3.      Cantile C, Youssef S. Nervous system.  In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:292.

4.      Constable PD, Hinchcliff KW, Done SH, Gruenberg W. Veterinary Medicine: A Textbook of the Diseases of Cattle, Horses, Sheep, Pigs, and Goats. 11th ed. St. Louis, MO: Elsevier; 2017:1195-1197.

5.      Furlan FH, Lucioli J, Veronezi AL, et al. Spontaneous lysosomal storage disease caused by Sida carpinifolia (Malvaceae) poisoning in cattle. Vet Pathol. 2009;46(2):343-347.

6.      Haschek WM, Rousseaux CG, Wallig MA. Fundamentals of Toxocologic Pathology. 2nd ed. London, UK: Academic Press;2010:395.

7.      Loretti AP, Colodel EM, Gimeno EJ, Driemeier D. Lysosomal storage disease in Sida carpinifolia toxicosis: An induced mannosidosis in horses. Equine Vet J. 2003;35(5):434-438.

8.      Miller AD, Zachary JF. Nervous system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:855-856.

9.      Panter KE, Gardner DR, Lee ST, et al. Important poisonous plants of the United States. In: Gupta RC ed. Veterinary Toxicology Basic and Clinical Principles. 1st ed. New York, NY: Academic Press; 2007:826-831.

 


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