JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

January 2023

N-M05 

 

Signalment (JPC #2077169): Young polled Hereford calf

 

HISTORY: Calf was found alive but was unable to rise and exhibited extensor spasms.

 

HISTOPATHOLOGIC DESCRIPTION: Brain, cerebellum: Diffusely, there is marked white matter vacuolation (status spongiosis) characterized by dilated myelin sheaths up to 30-100 µm in diameter that typically either contain normal axons or lack axons. Vacuolation rarely extends into the deep granular layer of the cerebellar cortex. There is diffuse mild gliosis in the white matter predominantly composed of astrocytosis.  

 

MORPHOLOGIC DIAGNOSIS: Cerebellum, white matter, myelin: Spongiform change, diffuse, severe, polled Hereford, bovine.

 

CONDITION: Hereditary neuraxial edema

 

SYNONYM: Maple syrup urine disease (MSUD)

 

GENERAL DISCUSSION:  

• Hereditary neuraxial edema includes two discrete neurologic syndromes:
  • Branched-chain α-ketoacid decarboxylase deficiency (BCKD): Affects 2-4 day old Hereford, polled Hereford and polled shorthorn calves
    • Autosomal recessive
  • Inherited congenital myoclonus: Affects polled Hereford calves at birth

 

PATHOGENESIS:  

• BCKD: Genetic mutation à deficiency of mitochondrial branched-chain α-ketoacid decarboxylase à deficiency of the mitochondrial branched-chain α-ketoacid dehydrogenase (BCKD) complex à accumulation of branched-chain amino acids valine, isoleucine, and leucine and their respective ketoacids (ketoisovaleric, keto-b-methylvaleric, ketoisocaproic, respectively) à molecular mechanism of intoxication is not well defined but likely involves toxic metabolites and ketoacids 
• Disease may be expressed in utero; calves are dull and recumbent by 2-4 days of age à opisthotonos and death
• Inherited congenital myoclonus: Lack of glycinergic receptors on spinal inhibitory neurons (analogous to strychnine poisoning)

 

TYPICAL CLINICAL FINDINGS:  

• BCKD: 
  • Calves may be normal at birth, but this is a rapidly fatal neonatal neurologic disease with rapid progression from walking and suckling to dullness, recumbency, opisthotonos, and death
  • Urine odor resembles that of maple syrup due to an isoleucine derivative 
• Inherited congenital myoclonus: Severe myoclonic muscle spasms, unable to stand (+/- coxofemoral fractures); absence of significant CNS signs 

 

TYPICAL GROSS FINDINGS:  

• BCKD: Lesions range from none to swollen brain with flat cerebral gyri
• Congenital myoclonus: Coxofemoral joint trauma, cartilage erosion

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• BCKD: Status spongiosus – severe spongy vacuolation of myelin sheaths in the CNS; most pronounced in large, myelinated tracts; spongiosis affects both gray and white matter (spinal white matter is usually less affected) and is most noticeable in areas where there is intermingling of gray and white matter (i.e. brain stem). 
  • This condition is characterized by vacuolation only, there is an absence of large-scale myelin breakdown or phagocytosis
• Congenital myoclonus: No CNS lesions

 

ADDITIONAL DIAGNOSTIC TESTS:  

 

DIFFERENTIAL DIAGNOSIS:  

• Congenital brain edema: horned Hereford calves in New Zealand unable to stand at birth and have tonic muscle contractions
  • Diffuse myelin vacuolation, hydropic degeneration of astrocytes, increased brain water content; deficiency of myelin
  • Similar condition in polled Hereford calves in the United Kingdom
• Dysmyelination: in utero infection with bovine virus diarrhea virus (pestivirus); hypomyelination of spinal cord
• Neurodegeneration of horned Hereford calves (shaker calf syndrome): Accumulation of neurofilaments within enlarged neurons of central, peripheral and autonomic nervous system 
• Hepatic encephalopathy (N-M17; e.g. chronic hepatic phyto/mycotoxicity): variable neural lesions, often spongy vacuolation of myelin, especially at junction of cerebral cortex and adjacent white matter; Alzheimer type II astroglial cells (especially in horses)
  • Excess ammonium metabolized by astrocytes to glutamine > osmotic changes and cytotoxic edema
• Bovine citrullinemia: neonatal Friesian calves in Australia; inherited error in urea metabolism leading to increased citrulline and ammonia in the blood and subsequent CNS disease (blindness, tremors, seizures, coma, death within a few hours); mild astroglial swelling in cerebral cortex and fatty change in liver
• Transmissible spongioform encephalopathies: Bovine spongiform encephalopathy (N-M09), scrapie (N-M08)

 

COMPARATIVE PATHOLOGY:  

• Dog: 
  • Samoyed pups: Generalized tremor syndrome; fatal; myelin vacuolation throughout CNS
  • Labrador Retriever pups: Tremors, extensor rigidity, dorsal flexion of neck progressing to dysmetria; vacuolation of myelin only in white matter of CNS (and to a mild degree in peripheral nerves) with fibrous astrogliosis 
    • Similar condition in Shetland sheepdogs and Australian cattle dogs termed canine spongiform leukoenephalomyelopathy; lesions in cerebellum and corona radiata; missense mitochondrial DNA mutation in cytochrome b
  • Silky terrier: Myoclonic syndrome (of paravertebral muscles) with myelin vacuolation in the brain and Alzheimer type II astrocytes 
  • Border terrier: Hereditary spongiform leukoencephalomyelopathy
• Spongy myelinopathy of Silver fox (farmed in Norway):  Hereditary; hindlimb ataxia at 2-4 months old; symmetrical vacuolation of myelin in CNS 
• Cat:  Egyptian Mau kittens: Progressive ataxia and hypermetria with vacuolation of both white and gray matter throughout CNS
• African dwarf goats and ragdoll cats: Spongiform CNS myelinopathy reported
• Hedgehogs: Wobbly Hedgehog Syndrome; African and European hedgehogs
  • “Spongy myelinopathy” with widespread CNS involvement
  • Progressive neurologic signs (ataxia à tetrapresis) in hedgehogs <2 yrs
  • Microscopic findings: extensive vacuolization of white matter in cerebrum, cerebellum, brainstem and spinal cord with myelin degeneration and myelin phagocytosis (other spongy myelinopathies do not typically have myelin degeneration with phagocytosis)
    • Typically bilateral and symmetric
    • Myelin degeneration and loss à neuronal/axonal degeneration 

References:  

1. Agnew D, Nofs S, Delaney M, Rothenburger JL. Xenartha, erinacoemorpha, some afrotheria, and phloidota. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier; 2018: 521-522. 
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: Saunders Elsevier; 2016: 342-347.
3. Diaz-Delgado J, Whitley DB, Strots R, et al. The pathology of wobbly hedgehog syndrome. Vet Pathol. 2018; 55(5):711-718. 
4. Miller AD, Porter BF. Nervous system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022: 933.

 

 

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