JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

January 2023

N-M24

 

Signalment (JPC #2414304): 11-year-old male standardbred horse

 

HISTORY: This horse had a three-week history of weight loss but with good appetite, trembling, increased periods of time in sternal recumbency, and abnormal stance.

 

HISTOPATHOLOGIC DESCRIPTION: Spinal cord: Within the ventral horns numerous neuronal cell bodies are swollen and rounded with loss of Nissl substance and pale, eosinophilic cytoplasm (chromatolysis). Nuclei are often faded with dispersed chromatin (karyolysis) or are rarely karyorrhectic (neuronal necrosis); occasionally necrotic neurons are surrounded by small aggregates of glial cells (satellitosis). Within the white matter funiculi, few random myelin sheaths are dilated and contain either clear space, swollen, eosinophilic axons (spheroids), or cellular debris and gitter cells with foamy cytoplasm (ellipsoids or digestion chambers); on longitudinal section the dilated myelin sheaths coalesce in linear arrangements.  

 

MORPHOLOGIC DIAGNOSIS: Spinal cord, ventral motor neurons: Degeneration, multifocal, moderate, with multifocal mild axonal degeneration, standardbred, equine.

 

ETIOLOGIC DIAGNOSIS: Idiopathic motor neuron degeneration

 

CONDITION: Equine motor neuron disease (EMND)

 

GENERAL DISCUSSION: 

• Acquired neuromuscular disease of horses characterized by degeneration of type I lower motor neurons in the ventral horns of the spinal cord and in brain stem nuclei that manifests as weakness, atrophy of type I myofibers, weight loss, and muscle fasciculation
• Horses lacking access to green feeds high in vitamin E for long periods of time (generally >1 year) are at risk
• The progression can slow or stop but the horse will be left with permanent disabilities;  most horses are euthanized because of the clinical signs

 

PATHOGENESIS:

• Multifactorial disease
• Major contributing/predisposing factor: Diet deficient in vitamin E (α-tocopherol) > decreased antioxidant capacity > accumulation of free radicals > oxidative damage to the somatic ventral motor neuron cells
• Increased rate of glucose metabolism may contribute, due to increased vitamin E use within the cell secondary to mitochondrial oxidative phosphorylation

 

TYPICAL CLINICAL FINDINGS:

• Rapid and progressive muscle wasting and atrophy, weakness, muscle fasciculations, and weight loss 
• Characteristic stance with feet positioned well under the body and lowered head; frequent shifting of weight from limb to limb
• Pigmentary retinopathy: Ophthalmoscopic exam reveals a mosaic pattern of pigment deposition in the tapetal zone coupled with a horizontal band of pigment at the junction of the tapetum and nontapetum; corresponds with histologic changes

 

TYPICAL GROSS FINDINGS:  

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Degeneration and loss of motor neurons in spinal cord ventral horns and in some brainstem nuclei (trigeminal, facial, hypoglossal, and the nucleus ambiguus)

• Motor neurons are swollen, chromatolytic and contain karyolytic nuclei
• Eosinophilic cytoplasmic inclusions are often present in the perikarya
• Wallerian degeneration is generally seen in the axons of affected lower motor neurons 
• Neurons and endothelial cells often contain abundant lipofuscin

• Skeletal muscle: Histologic findings in skeletal muscle are characteristic of denervation atrophy

• Angular atrophied fibers with preferential atrophy of type 1, high-oxidative fibers especially of postural muscles

• Eye:  Pigmentary retinopathy:  Accumulation of dark brown/black to yellow brown pigment (ceroid-lipofuscin) in the retinal pigmented epithelium (RPE) and retina (similar to lesions in hunting dogs with chronic vitamin E deficiency), and congestion of the RPE

• Outer segments of peripheral photoreceptors contain an unusually high proportion of polyunsaturated fatty acids in their lipids making them extremely susceptible to autooxidative damage

 

ULTRASTRUCTURAL FINDINGS:

• Affected neurons contain bundles of neurofilaments filling the perikaryon
• Focal aggregates of membranous vesicles correspond in location and size to eosinophilic inclusions seen in light microscopy

 

ADDITIONAL DIAGNOSTIC TESTS:

• Low serum and skeletal concentration of a-tocopherol (vitamin E) (<1 mg/mL)
• Antemortem diagnosis:  Surgical biopsy of muscle and immunohistochemistry showing unique preferential atrophy of type 1 myofibers (due to selective injury of type 1 motor neurons)

• Enzyme histochemical stains used to determine myofiber types: 

• Most useful stain for fiber typing is myosin ATPase with variation in acid and alkali lability; type I myofibers stain darkly with ATPase stain with acidic preincubation and stain lightly with alkaline preincubation, vice versa for type II myofibers
• Additional stains for mitochondrial oxidative activity: NADH-tetrazolium reductase (NADH-TR) and succinate dehydrogenase (SDH)

• Ocular manifestations aid in diagnosis

 

DIFFERENTIAL DIAGNOSIS:

• Equine degenerative myeloencephalopathy (N-M07) and cervical stenotic myelopathy (N-M02)

• Present clinically as ataxia and paresis; younger horses; slightly different anatomic locations affected
• Affects white matter; simultaneous involvement in multiple cord segments of ascending and descending tracts
• Vitamin E deficiency may also play a role

• Protozoal encephalomyelitis (Sarcocystis neurona, N-P01)

• Typically necrotizing; may cause focal or multifocal degeneration of motor neurons and degeneration of brain and spinal cord white matter
• May see merozoites and schizonts
• Resulting LMN weakness is localized and often asymmetric

• Rabies (N-V06)

• May initially present with signs suggestive of lower motor neuron disease however other neurologic signs will follow due to the diffuse, rapid spread of the lesion

• Equine herpesvirus type 1 encephalomyelopathy

• Vasculitis within the brain, spinal cord, leptomeninges, and spinal ganglia

• Lead intoxication (N-T05)

• Generalized peripheral neuropathy resulting in muscle atrophy and weakness

• Equine dysautonomia (grass sickness)

• Characterized by degenerative changes in neurons of the autonomic system
• Recorded in Northern Europe (UK) in grazing horses
• Recent study (Piccinelli, Vet Pathol. 2019) identified cytology of the cranial cervical ganglion as a reliable rapid postmortem diagnostic tool to identify neuronal degeneration, especially with May-Grunwald Giemsa stain

 

COMPARATIVE PATHOLOGY: Motor neuron degenerative conditions in other animals:

Canine: 

• Hereditary spinal muscular atrophy (HCSMA): autosomal dominant disease of Brittany spaniels; a similar condition exists in Rottweilers
  • 3 phenotypes: chronic, intermediate, and accelerated 
  • Accelerated phenotype resembles Werdnig-Hoffman disease in children
  • Neuropathology: varying degrees of degenerative change in spinal motor neurons focused on intumescences; similar changes are present in hypoglossal and trigeminal motor nuclei
  • Results in symmetrical denervation atrophy of pectoral, pelvic, tongue, and masseter muscles
  • Neurons are swollen and contain large argetophilic swellings at the proximal segments of axons near affected cell bodies
• Neuronal abiotrophy in Swedish Lapland dogs: characterized by denervation muscle atrophy
  • degeneration of spinal motor neurons is only in the lateral aspects of intumescences, and in spinal ganglia and Purkinje cells
• Motor neuron disease in English pointers: autosomal recessive; severe distal degeneration of peripheral motor neurons and muscle degeneration
  • Spinal motor neurons are filled with cytoplasmic lipid inclusions
• Focal asymmetrical spinal motor neuron degeneration in German shepherd dogs: affects the cervical spinal cord intumescence and leads to denervation muscle atrophy of thoracic limb muscles
• Progressive lower motor neuron disease has been reported in various breeds including sheepdog, collie, pug, dachshund, fox terrier, Doberman, Saluki

Feline: Inherited motor neuron disease in domestic cats

Bovine: Bovine spinal muscular atrophy (SMA) described in Brown Swiss, Hereford (“shaker calf syndrome”), and Holstein-Fresian with varying phenotypes

Porcine: lower motor neuron disease with neurofilamentous accumulation has been described in Hampshire and Yorkshire breeds

Humans:  

• Amyotrophic lateral sclerosis (ALS) is the most common progressive motor neuron disease in humans 

• Neuron degeneration in ALS involves both upper and lower motor neurons
• EMND differs from classical ALS in that upper motor neuron pyramidal tracts are not involved   

• EMND more closely resembles progressive spinal muscle atrophy (PSMA), a variant of ALS

 

References:

1. 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; 2016:330-332.
2. Cooper BJ and Valentine BA. Muscle and Tendon.   In: Maxie MG ed. Jubb, Kennedy,and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier; 2016:169-175.
3. Finno CJ, Kaese HJ, Miller AD, et al. Pigment retinopathy in warmblood horses with equine degenerative myeloencephalopathy and equine motor neuron disease. Vet Ophthalmol. 2017;20(4):304-309.
4. Miller AD, Porter BF. Nervous system. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:963-964, 990.
5. Piccinelli C, Jago R, and Milne E. Ganglion cytology: A novel rapid method for the diagnosis of equine dysautonomia. Vet Pathol. Vol 56(2):244-247. 
6. Vandevelde M, Higgins R, Oevermann A. Veterinary Neuropathology: Essentials of Theory and Practice. St. Louis, MO: Wiley-Blackwell; 2012:159-162.

 

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