JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

January 2023

N-M04

 

Slide A: Signalment (JPC #1895035): Male German shepherd dog

 

HISTORY: This dog developed an abnormal gait and had proprioceptive deficits and a progressive loss of motor nerve function.

 

HISTOPATHOLOGIC DESCRIPTION: Spinal cord: Multifocally, all white matter funiculi and spinal nerves contain numerous dilated myelin sheaths, up to 50 µm in diameter, that are often arranged in linear chains in longitudinal sections of the spinal cord. These dilated myelin sheaths frequently lack axons and contain cellular debris and occasional gitter cells (ellipsoids) (axonal degeneration). Multifocally, there are scattered reactive astrocytes characterized by large nuclei with finely stippled chromatin and a scant amount of amphophilic, fibrillar cytoplasm. The dura is focally expanded by an island of maturing woven bone surrounding a central marrow cavity that contains adipose tissue and scant hematopoietic elements (osseous metaplasia).

 

MORPHOLOGIC DIAGNOSIS: 1. Spinal cord, white matter; spinal nerves: Myelin sheath dilation and axonal loss, multifocal, moderate, with ellipsoids, German shepherd dog, canine. 

2.  Spinal cord, dura mater: Osseous metaplasia, focal, mild.

 

ETIOLOGIC DIAGNOSIS: Hereditary myelopathy

 

CONDITION: Degenerative myelopathy 

 

CONDITION SYNONYMS: German shepherd myelopathy, progressive myelopathy, chronic degenerative radiculomyelopathy

 

Slide B: Signalment (JPC #2082443): Tissue from a 3-month-old female Afghan hound.

 

HISTORY: This dog presented 7 days prior to necropsy with a 2-day history of progressive hindlimb weakness, hyperreflexia, and rigid paraplegia. The panniculus reflex was absent. No lesions were seen on radiographs.

 

HISTOPATHOLOGIC DESCRIPTION: Spinal cord: Multifocally affecting all funiculi, most severely in the dorsal and ventral funiculi adjacent to midline and the ventral median fissure, there is marked bilaterally symmetrical liquefactive necrosis characterized by rarefaction, loss of tissue architecture, and replacement by fragmented and clumped eosinophilic cellular and necrotic debris admixed with many large, microvacuolated macrophages (gitter cells). Within necrotic foci, there are increased numbers of prominent, ectatic, large and small caliber vessels (redundant vessels), that are multifocally surrounded by clear space (edema) and wispy eosinophilic glial strands. In less affected areas surrounding necrotic foci, there are frequent dilated myelin sheaths up to 40 µm in diameter, which occasionally contain either swollen axons (spheroids) or gitter cells or cellular debris (ellipsoids), as well as low numbers of hypertrophic astrocytes with abundant cytoplasm (gemistocytes).

 

MORPHOLOGIC DIAGNOSIS: Spinal cord, white matter: Liquefactive necrosis, bilaterally symmetrical, multifocal, marked (dorsal and ventral funiculi) to moderate (lateral funiculi), with marked myelin sheath dilation and redundant vessels, Afghan hound, canine.

 

ETIOLOGIC DIAGNOSIS: Hereditary myelopathy

 

CONDITION: Inherited necrotizing myelopathy of Afghan hounds 

 

SYNONYMS: Myelomalacia in Afghan hounds; hereditary myelopathy with myelinolysis in Afghan hounds

 

GENERAL DISCUSSION:

German shepherd degenerative myelopathy:

• A common, slowly progressive, idiopathic, degenerative myelopathy of aging German shepherds and other large dogs usually over 8 years of age

• Also reported in Rhodesian ridgebacks, Pembroke Welsh corgies, boxers, Chesapeake Bay retrievers, Siberian huskies, Bernese mountain dogs

Afghan hound necrotizing myelopathy:

• Acute, rapidly progressive, necrotizing, symmetrical spinal cord disease of young (3-12 month old) Afghan hounds recognized since the early 1960s

• Also reported in miniature poodles and Kooikerhondje dogs

• Initially described as acute necrotizing myelomalacia; subsequent studies show florid myelinolysis and cavitation, sparing axon (leukodystrophy)
• Myelin degenerates around apparently normal axons with no inflammation

 

PATHOGENESIS:  

• Unknown 
• German shepherd myelopathy: may be associated with immunodeficiency and also thought to have a genetic determination 

• In some breeds, a transitional mutation in superoxide dismutase 1 (SOD-1) has been demonstrated
• In other studies, an altered immune-mediated response has been suggested as a cause of the neurodegeneration

• Afghan hound necrotizing myelopathy:
• Presumed to be metabolic or enzymatic defect involving myelin
• Evidence suggests a simple autosomal recessive pattern of inheritance

 

TYPICAL CLINICAL FINDINGS:

German shepherd myelopathy:

• Affected dogs usually 5-8+ years of age and older
• Insidious onset, prolonged course, progressive ataxia and muscle weakness localized to thoracolumbar spinal cord; thoracic limbs spared
• Initial loss of proprioception progressing to paw-dragging, crossing of limbs, hypertonia, hypermetric hind limbs, signs may be asymmetric
• General wasting (disuse atrophy) of caudal thoracic and lumbosacral muscles
• 10-15% of cases have loss of patellar reflexes and degeneration in femoral nerves
• Increased protein in CSF when collected from the lumbar subarachnoid space but normal when collected from the cisternal subarachnoid space

Afghan hound necrotizing myelopathy:

• Present around 6 months of age (range 3-13 months) 
• Rapidly progressive, caudal ataxia progresses to paraplegia in few days (commonly 7-10 days), followed by phrenic paralysis (diaphragmatic failure)
• Stiff thoracic limbs, truncal weakness, ataxia of pelvic limbs, bunny-hopping gait, spastic paraparesis 
• Increased spinal reflexes and tone, pelvic limb hypoalgesia 
• CSF may have normal to high protein levels

 

TYPICAL GROSS FINDINGS:  

German shepherd myelopathy:

Afghan hound necrotizing myelopathy:

• Gray discoloration and extreme softening of all funiculi (leukomyelomalacia), occasionally resulting in cavitation
• Principle locus is thoracic spinal cord; rarefaction tapers cranially to the midcervical region often involving only the dorsal and/or ventral funiculus and caudally to about L5 and involving the ventral funiculus

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

German shepherd myelopathy:

• Ballooning and degeneration of myelin sheaths accompanied by axonal degeneration and loss in thoracic spinal cord, diffuse or multifocal; lesions throughout the spinal cord but most intense in thoracic region and dorsal spinal nerve roots

• Specifically dorsolateral and ventromedial funiculi, cerebellar peduncles, and occasionally brainstem (trapezoid body and olivary nuclei); occasionally in peripheral nerves

• Changes include vacuolation, axonal and myelin sheath degeneration and loss of superficial (subpial) and deep fibers in both ascending and descending pathways, gliosis, and increased numbers of small blood vessels
• Can affect all funiculi, typically bilateral but not necessarily symmetrical 

Afghan hound necrotizing myelopathy:

• Dominant change is myelin vacuolation followed by myelinolysis
• Bilaterally symmetric pattern in ventral, lateral, and dorsal funiculi
• Most extensive throughout thoracic segment
• Mild lesions are characterized by loosely arranged white matter with vacuolated myelin sheaths
• Severe lesions are characterized by severe cribriform change, depletion of neuroglial structures, redundant vessels, and numerous gitter cells
• Axons are commonly spared
• Involvement of gray matter is uncommon

 

ULTRASTRUCTURAL FINDINGS:

Afghan hound necrotizing myelopathy:

• Earlier lesions have intact myelin sheaths that are split at the intraperiod line
• Cavitated areas contain demyelinated fibers that are supported by the processes of reactive astrocytes

 

ADDITIONAL DIAGNOSTIC TESTS:  

 

DIFFERENTIAL DIAGNOSIS:

German shepherd myelopathy:

• Causes of Wallerian degeneration: trauma, intervertebral disc disease (N-M27), lumbosacral disease, stenosis, or fibrocartilaginous emboli (N-M03)
• Giant axonal neuropathy of German shepherds: A distal axonopathy; ~15-months old; paraparesis, ataxia, megaesophagus; inherited autosomal recessive

• Giant clumps of neurofilaments accumulate at distal ends of long axons in spinal cord with degeneration of terminal ends > appears as argentophilic axonal swellings in ascending fasiculus gracilis and dorsal spinocerebellar tracts, as well as the peripheral CNS

Afghan hound necrotizing myelopathy:

 

COMPARATIVE PATHOLOGY:

• Canine degenerative myelopathy, Welsh corgi: Clinically and pathologically similar to human amyotrophic lateral sclerosis, superoxide dismutase 1 (SOD1) mutation 
• Demyelinating myelopathy in miniature poodles: Rare idiopathic demyelination of the brain stem and spinal cord in puppies
• Equine (N-M07): Degenerative myelopathy with myelin loss, astrocytosis, primarily dorsal funiculi but may be diffuse, onset birth to 2 years; similar presentation in Mongolian wild (Przewaski) horses potentially related to hypovitaminosis E
• Bovine: Progressive degenerative myelopathy (Weaver syndrome) in brown Swiss cattle characterized by axonal degeneration in funiculi and medulla white matter and Purkinje cell degeneration; onset usually from 5 to 8 months
• Cat: Myelopathy similar to that seen in the German shepherd dog
• Rat: Paraparesis associated with myeloradiculopathy in senescent rats; 2 years or older, paraplegic and wasting of pelvic limbs, all funiculi affected, most severe in cranial thoracic segments

 

References:  

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10. Tanaka Y, Watanabe K, Miller AD, Matsumoto K, Kobayashi Y. Cholesterol granuloma associated with degenerative neuropathy in the cauda equina of a dog. J Vet Diagn Invest. 2022;34(6):1010-1014. 
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