JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

March 2023

N-T02

 

Slide A: Signalment (JPC #2137343): 5-year-old cat

 

HISTORY: None

 

HISTOPATHOLOGIC DESCRIPTION: Medulla oblongata and cerebellum: Within the vestibular nuclei and minimally extending into the adjacent white matter are bilaterally symmetrical, 2mm diameter, foci of increased pallor (rarefaction) and neuropil vacuolation (spongiosis) with neuropil loss and replacement by hemorrhage, fibrin, edema, and cellular debris (liquefactive necrosis), as well as increased glial cells (gliosis) including reactive astrocytes and gemistocytes. Affected foci are centered on dilated small caliber blood vessels that are lined by hypertrophied, reactive endothelium with large, vesiculate nuclei and occasionally are lined by fragmented endothelium and surrounded by abundant hyaline material (fibrinoid and necrotizing vasculitis). Neurons in affected foci are shrunken and hypereosinophilic with pyknotic nuclei (necrotic) or have dispersion of Nissl substance and a peripheralized nucleus (chromatolysis). There are occasional round, swollen, hypereosinophilic axons within dilated myelin sheaths (spheroids). Neuronal cell bodies within adjacent, less affected nuclei are pale and swollen (degeneration).  

 

MORPHOLOGIC DIAGNOSIS: Medulla oblongata, vestibular nuclei: Polioencephalomalacia, bilaterally symmetric, marked, with fibrinoid and necrotizing vasculitis, hemorrhage, neuronal necrosis, degeneration, and chromatolysis, and gliosis, breed unspecified, feline.

 

Slide B: Signalment (JPC #1199288): Holstein calf

 

HISTORY: This calf was prostrate with a temperature of 102.2F when first examined.  It had been ill for 10 days with CNS signs and transient diarrhea. After an additional week, it was euthanatized. Six other calves out of 17 were found dead.  

 

HISTOPATHOLOGIC DESCRIPTION: Cerebrum: There is diffuse moderate to marked rarefaction of the middle to deep cortical gray matter in a laminar pattern as well as moderate vacuolation (spongiosis) of the cortical gray matter and superficial white matter. The rarefied laminar cortical area is characterized by neuronal necrosis and loss of the neuropil with replacement by abundant edema, gliosis, moderate numbers of gitter cells, and fewer gemistocytic astrocytes (liquefactive necrosis). There are few swollen, hypereosinophilic axons (spheroids). Vessels within affected areas are often lined by hypertrophied endothelial cells and cuffed by lymphocytes, plasma cells, and macrophages that occasionally extend into the surrounding neuroparenchyma. The meninges are expanded by clear space (edema) and infiltrated by the previously described inflammatory cells.  

 

MORPHOLOGIC DIAGNOSIS: Cerebrum, cortex: Polioencephalomalacia, laminar, diffuse, moderate to marked, with neuronal necrosis, spongiosis, and mild lymphoplasmacytic and histiocytic meningoencephalitis, Holstein, bovine.

 

CAUSE: Thiamine (Vitamin B₁) deficiency

 

ETIOLOGIC DIAGNOSIS: Nutritional polioencephalomalacia

 

CONDITION: Polioencephalomalacia

 

SYNONYMS: Chastek paralysis (carnivores)

 

GENERAL DISCUSSION: 

• Progressive encephalopathy associated with thiamine deficiency in carnivores (fox, cat, mink) and a less well-established association with thiamine deficiency in young ruminants
• Thiamine is a dietary requirement of carnivores; deficiency may be caused by:

• Decreased thiamine intake
• Consumption of fish containing thiaminase
• Excessive heating of foods
• Preservation of meat with sulfur dioxide
• Upper gastrointestinal disease causing decreased absorption of thiamine

• Thiamine is produced in ruminants by microbial synthesis; deficiency may be seen in the very young prior to establishing a functional ruminal flora or in adults caused by:

• Grain overload and overgrowth of thiaminase-producing bacteria
• Ingestion of thiaminase-containing plants (bracken fern, horsetails)
• Ingestion of sulfur and sulfur compounds 
• Associated with cobalt deficiency, molasses, and high urea diets

• Liver and muscle are primary sites of thiamine storage
• Highest incidence in sheep weaning to 18mos of age, less severe in pastured animals.
• Merino sheep more resistant than other breeds

 

PATHOGENESIS:

• Phosphorylated thiamine is the coenzyme cocarboxylase, which is involved in oxidative decarboxylation reactions throughout the body
• Cocarboxylase is a cofactor for: Transketolase, alpha-ketoglutarate dehydrogenase, pyruvate dehydrogenase, and branched-chain alpha-keto acid dehydrogenase
• Transketolase is utilized in the hexose monophosphate shunt, is active in the white matter, and is important in the metabolism of oligodendrocytes
• The exact pathogenesis is unknown; however, the following factors are believed to play a role:

• Free-radical injury to the blood-brain barrier > vacuolation of neuropil
• Degenerative changes in glia > rupture > increased extracellular space > vascular dilation
• Decreased transketolase activity > decreased glucose utilization > metabolic burst > production of lactic acid > focal lesions
• Activity of ATP-dependent sodium and water transport mechanisms in neurons is reduced leading to intraneuronal swelling, elevated intracranial pressure, and necrosis of neurons

• Ruminants: Increased sulfur intake > sulfate reduced to sulfite > sulfite cleaves thiamine into pyrimidine and thiazole
• Neurons in mid to deep lamina of parietooccipital lobes are preferentially affected

 

TYPICAL CLINICAL FINDINGS:

• Blindness (cortical) and dullness, head pressing, anorexia
• More severe cases with abrupt onset of muscle tremors, intermittent opisthotonos, if they survive, become partially decorticate, blind and stupid
• Ataxia progressing to recumbency with opisthotonus, teeth grinding, nystagmus, and extensor rigidity
• Ventroflexion of neck in carnivores
• Thiamine deficiency is always attended by elevation of blood pyruvate
• Increased neutrophilia due to cerebrocortical necrosis

 

TYPICAL GROSS FINDINGS:

• Carnivores: lesions pass through the sequence of vacuolation > vascular dilation > hemorrhage > necrosis

• Lesions are in areas of vulnerability, primarily periventricular grey matter and occasionally the middle laminae of the occipital and temporal cortex; more specifically, the inferior colliculi and the medial, red, and lateral geniculate nuclei are affected  
• Petecchial hemorrhages, bilaterally symmetrical in brain stem nuclei, most often the caudal colliculi and other paraventricular nuclei; often grossly visible in colliculi and vestibular nuclei
• May see myocardial degeneration and necrosis that is more prominent in the right versus the left ventricle

• Ruminants: Swollen cerebrum; flattened gyri; narrow sulci; prominent cerebral cortical necrosis with unaffected cerebellar cortex; cerebral cortical atrophy; rare tentorial herniation and coning of the cerebellum in severe cases
• Yellow/brown discoloration of cerebrocortical gray matter; affected areas autofluoresce under ultraviolet light; due to the presence of lipid metabolites in macrophages or high molecular weight collagen-like material
• Hydrocephalus ex vacuo occurs in long term cases
• In advanced cases with prolonged survival, areas of marked atrophy of cerebral gyri with attenuated or absent gray matter zone

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Carnivores: Caudal colliculi most consistently affected

• Initial change is vacuolation in nuclei of special susceptibility (lateral geniculate bodies, caudal colliculi, red nuclei)
• Vacuolation of neuropil (status spongiosis), vascular dilation, endothelial hypertrophy, edema, and hemorrhage (often terminal event)
• Gliosis and neuronal necrosis
• Recovered animals develop intense astrogliosis (astroglial scar) in affected areas

• Ruminants: Marked laminar cerebral cortical necrosis

• Degeneration and necrosis of neurons of the middle to deep cortical laminae
• Laminar pattern of cerebral cortical edema and necrosis; astrocyte swelling
• Infiltration by moderate numbers of macrophages in necrotic areas

 

ADDITIONAL DIAGNOSTIC TESTS:  

• Response to injectable thiamine  
• Rumenal gas elevation for sulfur
• Elevated blood pyruvate; decreased erythrocytic transketolase activity 

 

DIFFERENTIAL DIAGNOSIS:

• Microscopic differentials for laminar necrosis in ruminants:

• Lead poisoning (N-T05): basophilic stippling of RBCs, intranuclear inclusions in renal tubular epithelia, hepatocytes and osteoclasts
• Salt toxicity: circumstantial in ruminants but well established in pigs
• Hypoxia 
• Sulfur toxicity: high sulfur intake

 

COMPARATIVE PATHOLOGY:

• Polioencephalomalacia also reported in penguins, camelids, and pronghorn; presumptively reported in 2 cats due to starvation (Anholt Vet Pathol 2016)
• Horse: 
  • Ingestion of bracken fern and horsetail (Equisetum arvense) (thiaminase containing plants)
  • Other encephalomalacias in equine include:  
    • Leukoencephalomalacia (N-T10, moldy corn disease): Fumonisin B1 from Fusarium verticillioides (formerly F. moniliforme) and F. proliferatum results in necrosis of white matter of the cerebral hemispheres 
    • Nigropallidal encephalomalacia (N-T11): Yellow star thistle ingestion causes malacia of pallidus and substantia nigra 
• Swine: Salt toxicity or water deprivation (N-T08): Laminar necrosis with infiltrate of eosinophils
• Human: Wernicke’s encephalopathy, due to thiamine deficiency results in symmetric paraventricular malacia of the gray matter 
• Sled dogs encephalopathy: thalamic necrosis 
• Small breed dogs (pug, Yorkies, maltese, shihtzu, Chihuahua): Necrotizing meningoencephalitis or granulomatous meningoencephalitis (N-M26); unilateral
• Cats: Leukoencephalomyelopathy by feeding a gamma-irradiated dry diet with elevated peroxide and reduced vitamin A concentrations
• Aquatic animals: Higher susceptibility due to fish-based diet that may contain thiaminase (especially smelt)
• Ataxia with white matter degeneration is reported in lions, cheetahs, cats, English Foxhounds, Landrace-cross pigs, rats, and nonhuman primates where deficiencies in vitamins A, B12 (cobalamin), B3 (nicotinamide), B6 (pyridoxine), and B1 (thiamine) have been implicated

 

References:

1. Anholt H, Himsworth C, Britton A. Polioencephalomalacia and heart failure secondary to presumptive thiamine deficiency, hepatic lipidosis, and starvation in 2 abandoned Siamese cats. Vet Pathol. 2016 Jul;53(4):840-3.
2. Cantile C, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier Ltd; 2016:309-314. 
3. Levine GJ, Cook JR. Cerebrospinal Fluid and Central Nervous System Cytology. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2020:219. 
4. Miller AD, Zachary JF. Nervous system. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:937, 971-973.
5. Summers BA, Cummings JF, de Lahunta A. Veterinary Neuropathology. St. Louis, MO: Mosby-Year Book Inc.; 1995:277-2801.
6. Terio KA, McAloose D, St. Leger J. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Academic Press; 2018: 119, 187, 655.

 

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