JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

March 2023

N-T04

 

Signalment (JPC #1757043): Angora goat kid

 

HISTORY: This kid was found in sternal recumbency. During the subsequent two weeks, it was unable to walk or rise but remained alert and continued to eat and drink.  Limb withdrawal reflexes were normal.

 

HISTOPATHOLOGIC DESCRIPTION: Spinal cord: Primarily affecting the medial aspect of the ventral funiculi and to a lesser extent the dorsal aspect of the lateral funiculi there is bilaterally symmetrical, focally extensive vacuolation (spongiosis) of the white matter. Numerous myelin sheaths dilated up to 70 µm in diameter and occasionally contain swollen axons (spheroids), eosinophilic debris, or rarely foamy gitter cells (ellipsoids) (Wallerian degeneration). Scattered motor neurons in the ventral horn of the gray matter are swollen up to 70 µm and contain pale eosinophilic, homogenous central cytoplasm with peripheral dispersion of Nissl substance and eccentrically placed nuclei (central chromatolysis). Occasionally, ventral spinal nerves exhibit Wallerian degeneration with dilated myelin sheaths containing spheroids or gitter cells. 

 

MORPHOLOGIC DIAGNOSIS: Spinal cord, white matter, ventromedial and dorsolateral funiculi; ventral spinal nerve roots: Neuroaxonal degeneration, bilaterally symmetrical, moderate, with ventral horn neuronal chromatolysis, Angora, caprine. 

 

ETIOLOGIC DIAGNOSIS: Nutritional neuroaxonal degeneration

 

CAUSE: Copper deficiency 

 

CONDITION: Enzootic ataxia

 

CONDITION SYNONYMS: Swayback

 

GENERAL DISCUSSION:

• CNS disease of lambs and goat kids due to copper deficiency
• Two syndromes: 
  • Congenital (swayback): primarily lambs, rarely kids; cerebrum, brainstem, and spinal cord lesions; insufficient dietary copper in dam
  • Delayed onset (enzootic ataxia): affects both lambs and kids up to 6 months of age; brainstem and spinal cord lesions
• Copper deficiency may be primary or secondary:
  • Primary: Dietary deficiency; copper deficient soil or forage
  • Secondary: More common; reduced absorption from gut, reduced availability in tissues, or enhanced excretion; unique in ruminants: molybdenum and sulfate limit copper absorption by forming complexes with copper called thiomolybdates; zinc and iron interactions also suspected
• Copper is required for: 
  • Superoxide dismutase – antioxidant activity
  • Cytochrome c oxidase – mitochondrial respiration
  • Dopamine beta-hydroxylase – catecholamine synthesis
  • Tyrosinase – melanin synthesis
  • Ceruloplasmin – protein important in iron homeostasis
  • Hypocuprosis also affects the integument (achromotrichia, straight wool/”steely wool”, skin hypopigmentation, impaired keratinization), musculoskeletal development (osteoporosis), connective tissue integrity, causes iron-deficiency induced anemia, and may cause fatty degeneration of cardiac myocytes, localized weakening of the walls of large elastic arteries (aneurysm), abnormal bone matrix and decreased bone growth and strength (copper co-factor for lysyl oxidase)

 

PATHOGENESIS:  

• Pathogenesis is poorly understood
• Altered function of mitochondrial enzyme cytochrome oxidase may lead to energy failure and subsequent neuronal degeneration, malacia of the cerebral white matter, and Wallerian degeneration in the spinal cord
• Cerebral lesions may result from loss of embryonic cells during brain development or to dysgenesis due to biochemical disturbance
• A mutation in the enzyme copper-zinc superoxide dismutase, observed in humans with familial amyotrophic lateral sclerosis may play a role

 

TYPICAL CLINICAL FINDINGS:  

• Congenital (swayback): Most common in lambs; unable to rise, blind, deaf, swaying, falling, spastic paralysis, and death within first few days of life, occasionally stillborn
• Delayed onset (enzootic ataxia): More common in goat kids; normal at birth; progressive development of motor disturbances including swaying, ataxia, gait deficits, limb paresis, and death within 6 months

 

TYPICAL GROSS FINDINGS:  

• Congenital (swayback): 50% of lambs and rarely kids have bilaterally symmetrical cerebral cortical softening or cavitation 
• Delayed (enzootic ataxia): Few or no gross lesions
• Rarely, cerebellar degeneration in lambs and goat kids; acute cerebral edema in lambs

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• Brainstem and spinal cord lesions are similar in lambs and kids in both congenital and delayed-onset forms
• Spinal cord
  • Gray matter neurons: Loss of Nissl substance (central chromatolysis), eccentric and pyknotic nuclei, eosinophilic fibrillar cytoplasm (neurofilament accumulation), variable necrosis
  • White matter: Bilateral areas of pallor due to degeneration of myelinated axons in the dorsolateral aspect of the lateral funiculi (corresponding to the spinocerebellar tracts) and ventromedial aspect of the ventral funiculi adjacent to the ventral median fissure
• Terminal brainstem: Similar lesions to spinal cord, with scattered distribution
• Cerebellum: Lesions most commonly present in kids and consist of Purkinje cells with central chromatolysis, eccentric and pyknotic nuclei, and variable necrosis, thinning of granular cell layer which may contain ectopic Purkinje cells, hypertrophy of Bergman glial cells and processes (radial fibers), and degeneration in folial white matter
• Cerebrum (swayback): Degeneration of white matter with astrocytosis, minimal degradation of myelin and histiocytic infiltration, cavities lack glial fiber capsule and are spanned by delicate neuronal and astroglial processes, +/- necrosis of grey matter overlying white matter lesions
• Ventral nerve rootlets and peripheral nerves: +/- Wallerian degeneration due to injury of motor neurons in ventral horn  
• Peripheral blood smear: +/- microcytosis

 

ULTRASTRUCTURE FINDINGS:  

• Chromatolytic neurons have depletion of ribosomes and aggregates of enlarged, mitochondria, and abundant fascicles of neurofilaments 
• Primary axonal degeneration with secondary loss of myelin

 

ADDITIONAL DIAGNOSTIC TESTS:  

• Plasma, serum, or tissue (liver, CNS) concentration of copper; concentrations below 25-150 ppm in goat livers (wet weight) is considered deficient
• Microcytic hypochromic anemia that is nonresponsive to iron supplementation
• Luxol fast blue (highlights myelin), Cresyl violet (highlights Nissl substance)

 

DIFFERENTIAL DIAGNOSIS:  

• Bluetongue (Reoviridae, Orbivirus): Infection of dam results in cerebral anomalies in lambs including porencephaly
• Border disease (Flaviviridae, Pestivirus): Infection of dam causes CNS abnormalities of lambs or goats, including hypomyelination, porencephaly-hydranencephaly, cerebellar hypoplasia, microencephaly and decreased diameter of the spinal cord
• Cache Valley Fever (Bunyaviridae, Bunyavirus): Infection results in hydranencephaly, microencephaly, cerebellar hypoplasia, and absence of the ventral horn neurons in the spinal cord of lambs
• Akabane (Bunyaviridae, Bunyavirus): Infection results in porencephaly, hydranencephaly, and ventral horn degeneration in spinal cord of various ruminant species in Japan, Australia, Israel
• Rift Valley Fever (Bunyaviridae, Phlebovirus), hydranencephaly in lambs in Africa

 

COMPARATIVE PATHOLOGY:  

• Ruminants: 
  1. Cattle: Primary copper deficiency results in unthriftiness, poor hair coat (achromotrichia), loss of milk production, and anemia in adult cattle; poor growth and long bone fractures in calves; secondary copper deficiency is similar except anemia occurs less frequently and diarrhea (“peat scours”) occurs more frequently
  2. Sheep: “Steely wool”, osteoporosis, hypopigmentation of black wool
  3. Young adult red deer: Syndrome and lesions similar to enzootic ataxia with progressively stiff gait, swaying, and recumbency that leads to death; spinal cord demyelination and midbrain neuronal degeneration; osteochondrosis, poor hair coat
  4. White-tailed deer and tule elk: Antler malformations  
  5. Tibetan gazelles: Unsteady gait disease in free ranging animals exhibiting pica, dyskinesia, and ataxic gait due to secondary copper deficiency
  6. Free-range Swedish Moose: Älvsborg (wasting) syndrome suspected to be primarily due to starvation/malnutrition; typically associated with dietary imbalances including low copper with high molybdenum; gross features include emaciation with serous atrophy of fat, fragile skin, achromotrichia, cataract and corneal opacity, edematous abomasum and heart, splenic atrophy, and osteoporosis; diagnosed based on gross findings, low hepatic copper levels, and lack of other underlying disease
• Swine: Piglets may exhibit Wallerian degeneration in the brain stem and spinal cord white matter with no neuronal changes; skeletal abnormalities leading to fractures; elastin formation abnormalities in the aorta and pulmonary arteries leading to aneurism that may rupture with secondary hemothorax or hemoabdomen
• Captive born Cheetahs: Fatal myelopathy, age 2.5 months -12 years; rapid onset ataxia and paresis, more severe in hind limbs; bilaterally symmetric spinal cord white matter tract degeneration +/- gliosis and degeneration of Purkinje and granular cells; pathogenesis unknown but copper deficiency suspected
• Old and New World Camelids: Hyperextension of metacarpophalangeal or metatarsophalangeal joint may be due to copper deficiency in conjunction with excess zinc
• Tapiers: Secondary copper deficiency associated with stillbirth and light haircoat
• Dogs: Normocytic normochromic anemia under experimental conditions  
• Avian species: 
  1. Dissecting aneurism; suspected secondary to copper deficiency due to low hepatic copper levels in affected birds; proposed pathogenesis is reduced strength of elastin and collagen fibers due to lysyl oxidase impairment (copper-dependent enzyme); most commonly reported in turkeys, fewer ostriches, and an emu 
  2. Tibial dyschondroplasia reported in turkeys, chickens, and ducks; defective vascularization of cartilage resulting in inappropriately mineralized core of cartilage extending from distal articular surface into distal diaphysis; etiologies include copper deficiency, specific toxins, excessive dietary cysteine, and acidosis
• Humans: Approximately 20% of affected individuals with familial amyotrophic lateral sclerosis exhibit copper-zinc superoxide dismutase gain of function mutation; accumulation of neurofilament in brainstem and ventral horn neurons with degeneration of corticospinal fiber tracts (versus spinocerebellar in small ruminants); classified as late onset motor neuron disease 

 

REFERENCES:  

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