JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

January 2023

N-M17

 

Signalment (JPC # 2415344): An 11-week-old female smooth coated collie

 

HISTORY: This dog presented with a three-week history of unusual behavior and circling. Prior to euthanasia, she displayed excessive salivation, head pressing, and opisthotonos. This puppy was approximately one-half the size of her three littermates. 

 

HISTOPATHOLOGIC DESCRIPTION: Brainstem: Affecting approximately 80% of the section are bilaterally symmetric, focally extensive areas of spongiform change throughout the white matter and at the junction with the grey matter, characterized by variably sized (up to 30µm in diameter) and occasionally coalescing (up to 85 µm in diameter) round to oval, clear vacuoles within the neuroparenchyma. There are increased numbers of astrocytes with enlarged nuclei and an increased amount of cytoplasm (astrogliosis). Within the affected areas there are moderate numbers of single and occasionally paired Alzheimer type II astrocytes characterized by visible cytoplasm and swollen, vesiculate nuclei with marginated chromatin. Occasionally, neurons are swollen and pale with an eccentric nucleus, prominent nucleolus, and dispersal of Nissl substance (central chromatolysis).

 

Liver: Diffusely, there is a loss of portal vein profiles within portal triads. There is mild lobular hypoplasia characterized by portal triads in close approximation to one another, and mild hepatocellular atrophy characterized by shrunken, small hepatocytes. Within portal triads there is mild bile duct and moderate arteriolar hyperplasia and ectatic lymphatic vessels (edema). Randomly, within hepatic sinusoids and portal areas there are small aggregates of extramedullary hematopoiesis.

 

MORPHOLOGIC DIAGNOSIS: Brainstem: Spongiform change, multifocal, bilaterally symmetrical, moderate, with astrogliosis and Alzheimer type II astrocytosis, smooth coated collie, canine.

 

Liver, portal areas: Portal venous hypoplasia, diffuse, marked, with arteriolar and biliary hyperplasia and mild lobular hypoplasia.

 

ETIOLOGIC DIAGNOSIS: Hepatic encephalopathy 

 

CAUSE: Congenital portosystemic shunt

 

GENERAL DISCUSSION:  

• Hepatic encephalopathy (HE) is a form of autointoxication where accumulation of primarily ammonia and other metabolites causes nervous dysfunction 
  1. To a lesser extent, renal failure can cause renal encephalopathy
• Associated with acute and chronic liver failure, as well as hepatic atrophy due to congenital or acquired portosystemic shunts in dogs and cats (D-M13) and to hepatic failure in horses and ruminants
  1. Secondary to hepatic insufficiency, in which the liver is unable to carry out its normal detoxifying role
  2. Congenital portosystemic shunts are more common in purebreds (miniature schnauzers, Irish wolfhound, Old English sheepdog, and Cairn terrier); intrahepatic shunts occur most often in large breed dogs; extrahepatic shunts occur most often in cats and small breed dogs; mixed breed cats more commonly affected than purebred

 

PATHOGENESIS:  

• Ammonia is normally detoxified in the liver by conversion to urea by the ornithine citrulline arginine urea cycle à urinary excretion
• Ammonia crosses the blood-brain barrier where it has several neurotoxic effects:
  1. Altered transit of amino acids, water, and electrolytes across neuronal cell membranes
  2. Inhibition of excitatory and inhibitory postsynaptic potentials
  3. Increased permeability of the blood-brain barrier à vasogenic edema
  4. Altered osmoregulation within the CNS
• Astrocytes play a key role in regulating fluid and electrolyte balance within the CNS
  1. Detoxify ammonia in the brain using glutamine synthetase à Converts ammonia into glutamine
     • High glutamine concentrations lead to astrocyte dysfunction and swelling
     • Glutamate leads to upregulation of N-methyl-D-aspartate (NMDA) receptors à neuronal damage
       • Eventually there is reduction in NMDA receptors and glutamate signaling à neuroinhibition
• Pathogenesis varies
  1. Acute hepatic failure: Cerebral edema may be the leading cause of death
     • Swollen astrocytes release vasogenic factors (e.g., nitric oxide) à intracerebral hyperemia à edema
  2. Chronic hepatic failure: Ammonia and neuroinflammation contribute synergistically to hepatic encephalopathy
     • Alterations in the blood-brain barrier à increased CNS uptake of neurotoxins (short-chain fatty acids, mercaptans, false (pseudo-) neurotransmitters (tyramine, octopamine, and β-phenylethanolamine), ammonia, and γ-aminobutyric acid (GABA)) à neuronal dysfunction and neuroinhibition
• Causes 
  1. Small animals
     • Congenital or acquired portosystemic shunts à amines absorbed from the intestine but not cleared by the liver à hyperammonemia
     • Acquired hepatic disease (e.g., dissecting hepatic fibrosis, chronic-active hepatitis, etc.) à reduced functional detoxifying capacity of the liver à hyperammonemia
     • Congenital deficiency of urea cycle enzymes (e.g., arginosuccinate synthetase)
  2. Ruminants:
     • Subacute or chronic phyto- or mycotoxic liver injury
     • In sheep, copper toxicosis may lead to massive myelin vacuolation

 

TYPICAL CLINICAL SIGNS:

• Clinical signs range from dullness to complete and unawareness and compulsive aimless movement, to mania and generalized convulsions; other signs can vary with species:
  1. Sheep: Dullness and central blindness +/- compulsive chewing movements and tremors
  2. Cattle: Similar to sheep with mania and aggression
  3. Horses: Similar to sheep with frenzy
  4. Dogs and cats: inappetence and vomiting; ptyalism common in cats 
• Hepatic disease signs: Polydipsia/polyuria, vomiting, diarrhea, weight loss, anorexia, +/- ascites; stunted growth with congenital portosystemic shunts
• In animals with acute hepatic disease, HE is a serious sign, usually indicating imminent death

 

TYPICAL GROSS FINDINGS:  

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• Characteristic lesions of spongiform change (status spongiosus) and Alzheimer type II astrocytes
  1. Spongiform change: Bilaterally symmetrical typically at areas of intermingling of gray and white matter (most intense at the junction of the cerebral cortex and adjacent white matter, and often around the deep cerebellar nuclei); caused by intramyelinic edema, causing splitting and vacuolation of myelin sheaths
     • Spongy changes also found in deep cerebrocortical gray-white matter interface where the peripheral fibers that radiate from the corona radiata are found, basal nuclei and adjacent internal capsule, reticular areas throughout the brainstem, and deep cerebellar nuclei
     • Horses do not have significant spongiform change
  2. Alzheimer type II astrocytes: Swollen, visible cytoplasm and an enlarged open-faced, vesiculate nucleus with a prominent nucleolus; often occur in diads, triplets, or clusters of even high numbers
     • Although the cytoplasm is increased to be visible by light microscopy, glial fibrillary acid protein (GFAP) intermediate filaments are not increased during this process, possibly indicating a toxic effect on astrocytes
     • Common in horses (the only CNS change observed in horses with hepatic failure) and humans; less common in other species; rare in dogs
• Acute liver failure produces minimal brain lesions 
• Liver (portosystemic shunt, D-M13):
  1. Hepatocyte atrophy, small hepatic acini, decreased numbers of portal venous branches, and a proliferation (reduplication) of hepatic arterial branches in the portal triad
  2. Thick-walled arteries and distended portal vein branches
  3. Sinusoidal congestion, periportal vacuolization, biliary hyperplasia, lipogranulomas, increased periportal connective tissue

 

ADDITIONAL DIAGNOSTIC TESTS:  

• Clinical pathology: Evidence of hepatic insufficiency/decreased functional hepatic mass: 
  1. CBC: Erythrocyte abnormalities (acanthocytosis, codocytosis, microcytosis), anemia
  2. Chemistry: Decreased urea nitrogen, hyperammonemia, hyperbilirubinemia, hypercholesterolemia, hypoalbuminemia, hypoglycemia, hyporproteinemia, lipemia (grossly).
  3. Urinalysis: Ammonium (bi)urate crystalluria, hyposthenuria or isosthenuria, urate crystalluria, 
• IHC: Alzheimer type II astrocytes exhibit weak or negative GFAP immunoreactivity but retain S-100 immunoreactivity 

 

DIFFERENTIAL DIAGNOSIS:  

• Microscopic:  
  1. Dogs and cats
     • Hepatic microvascular dysplasia, ductal plate malformation of boxer dogs
     • Congenital urea enzyme deficiency
     • Severe renal disease may cause similar brain lesions to include Alzheimer type II cells (renal encephalopathy) but this condition is rare in animals
     • Infectious diseases: Canine distemper (N-V11, may see viral intranuclear and intracytoplasmic inclusions and nonsuppurative inflammation in Virchow-Robin space), FIP (N-V17, pyogranulomatous periventriculitis, perivasculitis), FIV (nonsuppurative encephalomyelitis), FeLV, toxoplasmosis (N-P02)
     • Hydrocephalus
     • Idiopathic epilepsy
     • Metabolic disorders: Hypoglycemia, thiamine deficiency (N-T02), citrullinemia
  2. Ruminants, horses
     • Branched-chain a-ketoacid decarboxylase deficiency (N-M05, maple syrup urine disease): White matter; cattle (increased amino acids in plasma and CSF)   
     • Hexachlorophene toxicosis: Diffuse spongiform change in white matter (doesn’t center at the gray matter/white matter junction)
     • Bovine citrullinemia: Autosomal recessive disease in Holstein-Friesian due to deficiency of arginosuccinate synthetase 
     • Scrapie and related encephalopathies (N-M08, N-M09)
     • Chronic copper poisoning in sheep: Look for intravascular hemolysis and hemoglobinuric nephrosis (U-T10)
     • Intestinal disease in horses can produce hyperammonemia with clinical signs of colic and encephalopathy, possibly due to bacterial overgrowth

 

COMPARATIVE PATHOLOGY

• HE reported in a wide variety of species, including non-human primates
• Cheetahs and snow leopards: HE rarely been caused by veno-occlusive disease, a disease characterized by progressive accumulation of collagen in perisinusoidal spaces (space of Disse) and subintimal spaces of central and sublobular veins.

 

References:  

1. Brady AG, Carville AAL. Digestive System Diseases of Nonhuman Primates. In: Abee, C., Mansfield, K., Tardif, S. et al. Nonhuman Primates in Biomedical Research Volume 2: Diseases. 2nd ed. Waltham: Elsevier, 2012:610.
2. 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: 262, 344.
3. Cullen JM, Stalker MJ. Liver and biliary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer's Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016:291-2.
4. Miller AD, Porter BF. Nervous System. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier Mosby; 2022: 899, 935.
5. Stalker MJ, Hayes MA. Liver and biliary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer's Pathology of Domestic Animals. Vol 2. 5th ed. Philadelphia, PA: Elsevier Ltd; 2007:292-4.
6. Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Pathology. 2nd ed. Hoboken, NJ: Wiley; 2013: 677-681, 699-700.
7. Terio KA, McAloose D, Mitchell (née Lane) E. Felidae. In: Terio KA, McAloose D, St. Leger J eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018: 267. 

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