JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

March 2023

N-T07 (NP)

 

SIGNALMENT (JPC #1340595): Pig

 

HISTORY: This was one of a group of pigs that developed a severe CNS disturbance after having been fed colored seed grain.

 

HISTOPATHOLOGIC DESCRIPTION: Cerebrum, level of the hippocampus, and thalamus: Multifocally, primarily within the thalamus, the tunicae media of arterioles are expanded by brightly eosinophilic, homogenous to beaded material admixed with scattered cellular and karyorrhectic debris (fibrinoid necrosis). Affected vessels have hypertrophied endothelial and smooth muscle cells and are surrounded by few perivascular macrophages, neutrophils, and lymphocytes admixed with scant hemorrhage, fibrin, and edema. Multifocally, throughout both gray and white matter, there are increased numbers of astrocytes and microglia (astrocytosis and microgliosis).  Most prominently within the hippocampus, few neurons are shrunken and hypereosinophilic with pyknotic nuclei (necrosis). Increased numbers of astrocytes and other glial cells surround neurons (satellitosis). Within the white matter, there are dilated, often empty myelin sheaths that occasionally contain gitter cells or swollen hypereosinophilic axons.

 

MORPHOLOGIC DIAGNOSIS: Cerebrum, level of the hippocampus, and thalamus:  Vascular fibrinoid necrosis, multifocal, moderate, with multifocal neuronal necrosis, astrocytosis, and microgliosis, breed not specified, porcine.

 

ETIOLOGIC DIAGNOSIS: Cerebral organomercurial neurotoxicity

 

CAUSE: Organic mercury (Hg) toxicity

 

GENERAL DISCUSSION:  

• Organic Hg: Most common type of Hg poisoning
  • Occurs via ingestion or percutaneous
  • Mostly a chronic condition in swine, occasionally cattle
  • Organomercurial compounds are cumulative poisons that form salts with acids (chlorides and acetates) and react with cell ligands
  • Problems in veterinary medicine primarily involve feeding seed grain treated with organic mercury fungicides containing mercurial salts 
    • Treated seed must be 10% or more of ration and fed for long periods for clinical signs to appear
    • Compounds include ethyl mercury phosphate and mercury p-toluene sulfonanilide
  • Manifestations are usually neurologic (neuronal degeneration & necrosis)
• Inorganic Hg (e.g., HgCl₂): Toxicosis is rare in animals
  • Highly soluble and toxic to cells of the gastrointestinal tract and kidney if ingested
  • Acute toxicity following ingestion - severe abdominal pain, vomiting, and diarrhea; mercury chloride has a coagulative effect on the gut lining
  • After initial episode, death can occur several days later, a result of nephrosis with uremia
• Elemental Hg
  • Exposure occurs under laboratory or industrial settings

 

PATHOGENESIS:

• Mechanisms: 
  • Inhibition of protein synthesis
  • Disruption of microtubules
  • Disturbance of neurotransmitter function
  • Oxidative stress
  • Triggering of excitotoxicity mechanisms (e.g. glutaminergic excitotoxicity)

 

TYPICAL CLINICAL FINDINGS:

• Acute (inorganic Hg) – severe abdominal pain, vomiting, and diarrhea; death in as little as a few hours
• Chronic (organic Hg) – signs may not occur for several weeks after the first exposure and are similar in swine and cattle
  • Loss of appetite
  • Wasting 
  • Dullness
  • Blindness
  • Severe weakness and incoordination
  • Coma

 

TYPICAL GROSS FINDINGS:  

• Generally minimal
• Cattle – moderately swollen kidneys, mild to moderate cerebral swelling, loss of color distinction between white and gray matter due to pallor of the cortex
• Swine – moderately swollen kidneys, hydropericardium, unusual whiteness of cerebral cortex

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• CNS lesions:
  • Acute neuronal degeneration
    • Due to ischemia
    • Most profound in the middle laminae of the cerebral cortex
    • Moderate gliosis – both microgliosis and astrocytic
  • Fibrinoid necrosis of the media of the leptomeningeal arteries – more prominent in swine than in cattle
  • Necrosis of granule cells in the cerebellum
• Lesions in other organs:
  • Kidney: Acute renal tubular injury
  • Heart: Degeneration of cardiac Purkinje cells

 

ULTRASTRUCTURAL FINDINGS:  

• Astrocyte foot processes abutting capillaries may be swollen
• Disorganization of the linear cisternal arrays of rough endoplasmic reticulum that normally form the Nissl granules of spinal ganglia

 

ADDITIONAL DIAGNOSTIC TESTS:  

• Lesions are usually secondary to vascular/ischemic changes and thus are fairly non‑specific and may be mimicked by other disease processes causing vascular, ischemic, or hypoxic changes
• Hg level detection in hair, or plasma and erythrocytes antemortem
• Hg detection in liver, kidney, muscle, and brain at necropsy

 

DIFFERENTIAL DIAGNOSIS:

For microscopic findings:

• Heavy metal toxicity:
  • Lead (N-T05) – similar clinical signs, gross lesions in CNS and GI; vascular endothelial hypertrophy and hyperplasia with hemorrhage; spongiosis of cortical neuropil, bilateral symmetrical demyelination and axonal degeneration; hyaline change in vessel walls with intranuclear lead inclusions in renal tubular epithelial cells, anemia, erythrocytic basophilic stippling
  • Arsenilic acid – Wallerian degeneration of optic nerves, optic tracts and peripheral nerves
• Thiamine deficiency (N-T02) – polioencephalomalacia, similar to lead toxicity
• Salt toxicity (N-T08)– in pigs, eosinophil infiltration with cerebral edema, laminar cortical necrosis, and prominent cerebral blood vessels with hypertrophied endothelium

 

COMPARATIVE PATHOLOGY:  

• Horses – total body alopecia, experimental chronic intoxication induces exudative dermatitis 
• “Minamata disease” – chronic mercurialism of cats, birds, and humans in the Minamata Bay area of Japan; associated with fish/shellfish containing organomercurials (methylmercury) from industrial waste effluent
• Mercury levels can affect DNA methylation status and is implicated in the pathogenesis of schistosomus reflexus syndrome in Olive Ridley sea turtles (Martin-Del-Campo, Vet Pathol. 2019)
• Free-ranging Florida panthers and museum specimens
• Egyptian and Javan mongooses

 

References:

1. 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; 2016:320-321.
2. Martin-Del-Campo R, et al. Mercury concentration, DNA methylation, and mitochondrial DNA damage in Olive Ridley sea turtle embryos with schistosomus reflexus syndrome. Vet Path. 2019;56(6):940-949.
3. Miller AD and Zachary JF: Nervous system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Mosby, Inc.; 2022:734.
4. Terio, K. A., McAloose, D., & St Leger, J. (2018). Pathology of Wildlife and Zoo Animals. Academic Press.

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