JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

March 2023

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 minimal increase in glial cells within the neuroparenchyma (gliosis). Multifocally, there are low to moderate numbers of macrophages and few lymphocytes and plasma cells that expand the Virchow Robin space and the leptomeninges.  

 

Kidney: Multifocally, tubular epithelial cells are either swollen with accumulations of foamy to microvacuolated intracytoplasmic material (degenerate) or have brightly eosinophilic cytoplasm and a large, vesiculate nucleus and occasionally stack up to several cell layers thick (regeneration).

 

MORPHOLOGIC DIAGNOSIS:  

1. Cerebrum and brainstem: Neuronal and glial swelling and cytoplasmic microvacuolation, diffuse, moderate, with multifocal, mild lymphohistiocytic leptomeningitis, breed unspecified, equine.

2. Kidney, proximal tubules: Epithelial degeneration and cytoplasmic vacuolar change, diffuse, moderate, with tubular regeneration.

 

CAUSE: Swainsonine toxicity

 

CONDITION: Locoism (North America); pea struck (Australia)

 

GENERAL DISCUSSION: 

• Plant-based toxicity found in grazing animals, most commonly cattle, sheep, horses, goats; results in neurological disease but also causes poor condition, reproductive failure or birth defects
• Swainsonine (an indolizidine alkaloid) is found in plants of the genera Oxytropis, Astragalus (locoism, North America), Swainsona spp. (poison pea, pea struck, Australia), Sida carpinifolia (broomweed, Brazil), Turbinia cordata (Brazil) and Ipomea spp. 
• Toxic principle is swainsonine (referred to as locoine or swainsonine N-oxide in some texts); a prototypic toxicant-induced neural storage disease that causes an induced alpha-mannosidosis
  1. Lesions are microscopically and ultrastructurally identical to, but biochemically distinct from, genetic alpha-mannosidosis (N-M14), which is a deficiency of lysosomal a-mannosidase only, while swainsonine also inhibits Golgi mannosidase II, an enzyme involved in post-translational trimming of the protein 

 

PATHOGENESIS:

• Swainsonine is rapidly GI absorbed à High serum concentration à Inhibits two enzymes, lysosomal α-mannosidase and Golgi mannosidase II that aid in metabolism of saccharides à Lysosomal accumulation of mannose à Neuronal swelling and vacuolization
  1. Mannosidase enzymes are found within the Golgi, lysozmes, and cytoplasm of all mammalian cells; neurons, epithelial cells in organ systems (e.g. liver), and macrophages of the spleen and lymph nodes are commonly affected
  2. Golgi mannosidase II is not inhibited in inherited α-mannosidosis 
  3. Secondary neuronal changes, including meganeurite and aberrant synapse formation in higher neurons may have a role in pathogenesis
• Requires ingestion of toxic plants for several weeks (14-60 days) 
• Signs may persist after cessation of exposure: Within 2 weeks of last exposure, much of the storage disease resolves, but axonal spheroids may persist in large numbers in the cerebellar roof nuclei and caudal brainstem
  1. May be permanent in growing animals
• The fungal endophyte Undifilum oxytropis (previously referred to as Embellisia), which grows on the plant, appears to be the source of swainsonine 
• The toxic principle responsible for skeletal birth defects is unknown, but likely separate from that which causes neurological defects

 

TYPICAL CLINICAL FINDINGS:

• Poor condition, depression, head pressing, incoordination, stumbling, circling, recumbency, and paddling
• Blindness (unknown the toxin results in central or retinal blindness)
• Reproductive: Abortion and terata (malformed fetus); decreased fertility

 

 

TYPICAL GROSS FINDINGS:

• No specific gross lesions in acquired swainsonine-induced storage diseases
• Reduced size of testes
• Fetal abnormalities: Brachygnathia, angular limb deformities including contracture or overextension of joints, limb rotations, as well as osteoporosis and bone fragility

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Vacuolation (foamy/finely vacuolated cytoplasm) of cell body that may peripheralize the nucleus due to intralysosomal accumulation of mannose-rich oligosaccharides (does not stain as lipid)
  1. Affects multiple cells, including neurons in CNS and/or PNS (including Auerbach’s and Meissner plexuses) and parenchymal cells (e.g., renal tubular epithelial cells; interstitial cells and pericytes of the myocardium (in rats); exocrine pancreas; thyroid follicular epithelium; parathyroid, adrenal, cerebellar Purkinje cells; Kupffer cells; macrophages in spleen and lymph nodes; urinary bladder transitional cell epithelium)
• Additional CNS lesions:
  1. Diffuse perivascular edema
  2. Spheroids persist in large numbers often in cerebellar roof nuclei and caudal brainstem
  3. Later stages – neuronal necrosis with mineralization, axonal degeneration 
  4. Meganeurites (irregular fusiform enlargements) in proximal axon segment with aberrant synapses
  5. Astrocytes are hydropic or swollen (depends on degree to which α-mannosidase is expressed in individual cell populations)
  6. Microgliosis and neuronophagia are present, but inconspicuous
• Eye: Diffuse photoreceptor atrophy and patchy hyperplasia of retinal pigment epithelium in addition to swelling and vacuolation of retinal neurons as well as axon degeneration
• Reproductive: Similar lesions may be present in aborted or weak neonates; testicular degeneration and atrophy

 

ULTRASTRUCTURAL FINDINGS:

 

ADDITIONAL DIAGNOSTIC TESTS:

• Lectin histochemical examination of maternal and fetal samples to identify specific complex carbohydrate structures in glycoproteins and glycopeptides (Reis, J Vet Diag Invest 2019)
• Leaf and stem analysis (high-performance liquid chromatography) to identify swainsonine (Marin, J Vet Diag Invest 2020)

 

DIFFERENTIAL DIAGNOSIS:

• Microscopically indistinguishable from hereditary a‑mannosidosis (N-M14)
• Other lysosomal storage diseases
• Castanospermum australe (Moreton Bay chestnut tree in Australia): Similar to swainsonine (inhibitory effects on glucosidases)
• Gomen disease (N-M12B): 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:

• Swainsonine toxicity affects all grazing animals and is commonly seen as lysosomal storage disease and occasional reproductive problems in cattle, goats, equids, sheep, and deer; also affects hindgut-fermenting rodents
• Cattle: 
  1. Abdominal distension and mild ataxia due to hydroallantois with placental edema and adventitial placentation; cytoplasmic granular vacuolation of neurons in the cerebellum and obex of the fetus (Reis, J Vet Diag Invest 2020)
• Llamas
  1. Intoxication by Astragalus garbancillo var. garbancilloin in Argentina presented with staggering, ataxia, hypermetria, and progressive weight loss; histological lesions included Purkinje cell degeneration, necrosis, and loss, associated with intracytoplasmic vacuolation, meganeurite formation, and Wallerian degeneration; plant analysis confirmed the presence of swainsonine (Marin, J Vet Diag Invest 2020)
  2. Intoxication by Astragalus punae in Argentina presented with moderate ataxia, incoordination of hindlimbs, and progressive loss of body condition; histological lesions included fine cytoplasmic microvacuolation in the renal proximal convoluted tubule; ultrastructural changes consisted of severely dilated lysosomes; plant analysis confirmed the presence of swainsonine (Marin, J Vet Diag Invest 2022)
• Rodents: Swainsonine toxicity may manifest as nephrotoxicosis and acquired alpha-mannosidosis; nephrotoxicosis manifests as diffuse, severe vacuolation of tubular epithelial cells
• Hereditary alpha‑mannosidosis (N-M14): Angus, Murray Grey and Galloway cattle breeds and Persian cats

 

References:

1. Craig LE, Dittmer KE, Thompson KG. Bones and Joints. In: Maxie MG, ed. Jubb, Kennedy & Palmer's Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:92. 
2. Cantile C, Youssef S. Nervous System. In: Maxie MG, ed. Jubb, Kennedy & Palmer's Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:292. 
3. Delaney MA, Treuting PM, Rothenburger JL. Rodentia. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:499-516. 
4. Durham AC, Boes KM. Bone Marrow, Blood Cells, and the Lymphoid/Lymphatic System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:874.
5. Foster RA. Male Genital System. In: Maxie MG, ed. Jubb, Kennedy & Palmer's Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016:482. 
6. Foster RA, Premanandan C. Male Reproductive System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1321.
7. Labelle P. The Eye. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1423.

1. Marin RE, Micheloud JF, et al. Intoxication by Astragalus garbancillo var. garbancillo in llamas. J Vet Diagn Invest. 2020 May;32(3):467-470. 
2. Marin RE, Gardner DR, et al. Intoxication of llamas by Astragalus punae in Argentina. J Vet Diagn Invest. 2022 Jul;34(4):674-678.
3. Meador VP and Cheville NF. Neurotoxins and Neurodegeneration. In: Ultrastructural Pathology: The Comparative Cellular Basis of Disease. 2nd ed. John Wiley & Sons, 2009:672.

1. Miller AD, Porter, BF. Nervous System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:940.

1. Reis MO, Cruz RAS, et al. Hydrallantois in cows naturally poisoned by Sida carpinifolia in Brazil. J Vet Diagn Invest. 2019 Jul;31(4):581-584. 

1. Van Wettere AJ, Brown DL. Hepatobiliary System and Exocrine. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:544. 
2. Wilcock BP, Njaa BL. Special Senses. In: Maxie MG, ed. Jubb, Kennedy & Palmer's Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:471-772. 

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