January 2017



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 vacuolation of myelin within the cerebellar white matter characterized by clear, round to oval vacuoles which vary from 30-100 um in diameter (status spongiosis).  Vacuolation rarely extends into the deep granular layer of the cerebellar cortex.  There is diffuse mild gliosis in the white matter and rare gitter cells. 


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


CONDITION:  Hereditary neuraxial edema


SYNONYM:  Maple syrup urine disease (MSUD)



·       Hereditary neuraxial edemaincludes two discrete neurologic syndromes:

o   Branched-chain ketoacid dehydrogenase deficiency(BCKAD):  Affects 2-4 day old Hereford, polled Hereford and polled shorthorn calves

§  Autosomal recessive

§  Also reported in a herd of Gelvieh-cross cattle in Nebraska

o   Inherited congenital myoclonus:  Affects polled Hereford calves at birth



·       BCKAD: Genetic mutation àdeficiency of mitochondrial branched-chain a-ketoacid dehydrogenase àunable to degrade the essential branched-chain amino acids valine, isoleucine and leucine (these are normally digested and the amino acids are used in various metabolic processes)à toxic accumulation of ketoacids (ketoisovaleric, keto-b-methylvaleric, ketoisocaproic, respectively) àoxidative decarboxylation of alpha-ketoacids à formation of a toxic metabolite à vacuolar change and splitting of myelin lamellae

·       Inherited congenital myoclonusLack of glycinergic receptors on spinal inhibitory neurons (analogous to strychnine poisoning)



·       BCKAD: 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 of burned sugar due to an isoleucine derivative resembling maple syrup

·       Inherited congenital myoclonus signs: Lateral recumbency, severe myoclonic muscle spasms, hypersensitivity, coxofemoral fractures; absence of significant CNS signs



·       BCKAD:  Lesions range from none to swollen brain with flat cerebral gyri

·       Congenital myoclonus:  Coxofemoral joint trauma, cartilage erosion



·       BCKAD:  Status spongiosus - severe vacuolar change of white matter myelin (most pronounced in  large myelinated tracts) involving cerebellar folia and nuclei, reticular formation, pons, medulla, and basal nuclei, corona radiata, deep cerebral cortex; some extension into gray matter; spinal white matter usually not affected

o   This condition is characterized by vacuolation only, there is an absence of large scale myelin breakdown or phagocytosis

·       Congenital myoclonus:  No CNS lesions



·       In BCKAD plasma, urine, CSF, and tissues have high concentrations of branched-chain amino acids and alpha-ketoacids



·       BCKAD (i.e. spongiform myelinopathy): Separation of myelin lamellae at intraperiod line; no associated degenerative or reactive changes



·       Congenital brain edema:  Horned Hereford calves in New Zealand unable to stand at birth and have tonic muscle contractions

o   Myelin vacuolation, hydropic degeneration of astrocytes, increased brain water content

o   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 (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)

o   Excess ammonium metabolized by astrocytes to glutamine > osmotic changes and cytotoxic edema

·       Bovine citrullinemia: Another disease due to problems with amino acid metabolism; 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

·       Other toxins:

o   Hexachlorophene toxicosis: Topical antiseptic, occasionally given orally to prevent Fasciola hepatica infection

o   Halogenated salicylanilide toxicosis: Anihelmintics used in sheep and goats

o   Stypandra toxicosis: Australian “blindgrass;” toxic principal is sypandrol

o   Tylecodon wallichii: Cause of krimpsiekte- small ruminant neurotoxicosis in South Africa; toxin is cotyledoside

o   Helichrysum spp toxicosi.: Australia and South Africa; hepatic encephalopathy

o   Diplodia maydis toxicity: Mycotoxin in Africa and Argentina

o   Copper toxicity in sheep: Massive myelin vacuolation

o   Bromethalin toxicosis: Relatively popular rodenticide that causes acute fluid retention in the CNS and marked vacuolation of the white matter (as seen with this entity)

§  No glial response, no swollen axons or spheroids

·       Transmissible spongioform encephalopathies: Bovine spongioform encephalopathy, scrapie



·       Dog:

o   Samoyed pups:  Generalized tremor syndrome; fatal; myelin vacuolation throughout CNS

o   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, Australian cattle dogs termed canine spongiform leukoenephalomyelopathy; lesions in cerebellum and corona radiata; missense mitochondrial DNA mutation in cytochrome b

o   Saluki:  Seizures, behavior change, affects the gray and white matter

o   Silky terrier:  Myoclonic syndrome (of paravertebral muscles)  with myelin vacuolation and Alzheimer type II astrocytes

·       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

·       Africian dwarf goats and ragdoll cats:  Spongiform CNS myelinopathy also reported



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: Saunders Elsevier; 2016: 342-347.

2.      O’Toole D, Montgomery DL, Steadman L, O’Rourke B, Russell W, Dennis J. Status spongiosus of white matter in newborn Gelbvieh-cross calves. J Vet Diagn Invest. 2005;17(6):546-553.

3.      Summers BA, Cummings JF, de Lahunta A. Veterinary Neuropathology. St. Louis, MO: Mosby-Year Book Inc.; 1995: 295-299.

4.      Miller AD, Zachary JF. Nervous system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017: 848.

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