JPC SYSTEMIC PATHOLOGY
MUSCULOSKELETAL SYSTEM
March 2022
M-M14

Signalment (JPC #1535964): Five-year-old quarter horse mare

 

HISTORY: This mare showed signs of "tying up" after being exercised. She became recumbent and began to pass coffee-colored urine. The mare was euthanatized 8 days after onset of signs. Clinical pathological findings include: BUN-25 (11-27); AST 1250 (160-412); ALT-1750 (no reference interval given); LDH-7200 (112-456).

 

HISTOPATHOLOGIC DESCRIPTION: Skeletal muscle: Multifocally and randomly,  75% of myocytes are characterized by one of the following: markedly swollen with pale, vacuolated sarcoplasm (degeneration); hypereosinophilic and hyalinized with fragmented myofibrils, disruption of the endomysium, loss of cross striations, occasional contraction bands, and nuclear pyknosis or karyolysis (necrosis); or lost with replacement by karyorrhectic debris, moderate numbers of macrophages, and few fibroblasts. Multifocally, few myocytes have nuclear internalization and increased sarcoplasmic basophilia with rowing of nuclei that are large with prominent nucleoli (regeneration), and there is moderate proliferation of satellite cells. Fibrin, edema, moderate numbers of histiocytes, lymphocytes, and plasma cells multifocally infiltrate and expand the perimysium and endomysium.

 

MORPHOLOGIC DIAGNOSIS: Skeletal muscle: Degeneration and necrosis, monophasic, multifocal, random, moderate, with rare myofiber regeneration, and mild histiocytic and lymphoplasmacytic myositis, quarter horse, equine.

 

CONDITION: Equine exertional rhabdomyolysis

 

SYNONYMS: Exertional rhabdomyolysis syndrome (ERS), exertional myopathy, ‘tying-up’, ‘Monday-morning disease’, ‘set fast’, azoturia, black water, paralytic myoglobinuria

 

GENERAL DISCUSSION:

• Sporadic disease of athletic horses worldwide; females appear to be predisposed
• Most often occurs secondary to underlying metabolic abnormalities of muscle rather than poor dietary management and exercise conditioning
  • Most horses with ERS respond to a dietary change to high fat and fiber, low starch and sugar
  • Predisposing conditions may include polysaccharide storage myopathy (M-M20) in many breeds (including quarter horse, Thoroughbred, and other breeds)
  • Electrolyte imbalance, specifically hypokalemia, is considered a possible cause
• Affects type 2 (fast twitch, oxidative) muscle fibers [type 2B (2X) glycolytic and 2A oxidative-glycolytic fibers]; nutritional myopathies involve type 1 oxidative fibers
• Subclinical exertional myopathy apparently common in horses and sporadic cases may represent recurrent disease
• Strong evidence suggests autosomal dominant inheritance
• Previously suggested etiologies no longer implicated (excessive muscle lactate acidosis, equine hypothyroidism, vitamin E/selenium deficiency)

 

PATHOGENESIS:

• Muscle:
  • Inciting cause > loss of integrity of the myocyte cell membrane (type 2, fast twitch, oxidative) > myocyte dysfunction > myocyte death > damaged fiber segments undergo hypercontraction > coagulative necrosis > myoglobin and enzymes released into surrounding tissues > myoglobin enters bloodstream > myoglobinuria > myoglobin-induced acute tubular injury (myoglobinuric nephropathy, U-M20) > renal failure in severe cases
  • Myocyte death results in cellular inability to retain water > swelling within muscle sheath > compartment syndrome perpetuates muscle necrosis
• Kidney (U-M20):
  • Tubular damage > vasoconstriction of preglomerular arterioles via renin-angiotensin system and other mediators (adenosine, thromboxane, endothelin) > decreased GFR
  • Myoglobinemia causes acute tubular necrosis via two pathways:
  • Myoglobin heme group > lipid peroxidation > release iron > epithelial damage
  • Renal ischemia > secondary to shock > chemical mediators of inflammation
  • Tubular blockage (casts) > backpressure > oliguria/anuria > decreased GFR
  • Tubular leakage > interstitial edema > increased interstitial pressure > further tubular collapse and damage

 

TYPICAL CLINICAL FINDINGS:

• Hindlimb weakness and/or pain occurs suddenly
• Variable: Often athletic, heavily muscled, and young (2-5 years old); horses with recurrent episodes of a stiff gait during or immediately after exercise or with sudden onset of weakness, lameness, pain, and reluctance to move; female horses are apparently predisposed
• More severely affected animals may be unable to continue to exercise; muscles (gluteal, femoral, lumbar muscles) are painful, rigid, and swollen, likely due to increased intramuscular pressure from oxidative membrane injury
• Muscle atrophy may occur in some cases

 

TYPICAL GROSS FINDINGS:

• Muscle: Moist, swollen, dark, with dry streaks of pallor
• Kidney: Swollen with dark brown medullary streaks

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Damaged fiber segments generally undergo hypercontraction followed by coagulative necrosis
• Hyalinization, degeneration, and necrosis of myofibers with minimal inflammation
• Contraction band necrosis, regeneration, and fibrosis
• Lesions typically monophasic but may be polyphasic with repeat ERS episodes
• PAS staining should be performed on cases of exertional rhabdomyolysis to assess for evidence of abnormal glycogen due to the incidence of associated polysaccharide storage myopathy (M-M20)
• Calcification / mineralization is NOT a feature
• Cardiac lesions not expected
• Kidney: Swollen proximal convoluted tubular epithelial cells; protein casts with orange pigmented (myoglobin) granules

 

Clinicopathological findings:

• Serum chemistry, moderate to extreme elevations in:
  • Creatine kinase (CK, muscle specific)
  • Alanine aminotransferase (ALT, muscle specific in large animals)
  • Lactate dehydrogenase (LDH, not muscle specific)
  • Aspartate aminotransferase (AST, not muscle specific)
  • Phosphate, due to shift of PO4 from intracellular fluid to extracellular fluid
• Urinalysis:
  • Myoglobinuria: Red-brown urine; does not clear on centrifugation; absence of erythrocytes in sediment; retention of color following addition of saturated ammonium sulfate to the urine; clear normal-colored plasma; no anemia
  • Hematuria: Red, cloudy urine; clears on centrifugation; erythrocytes in sediment; possibly anemia
  • Hemoglobinuria: Red-brown urine; does not clear on centrifugation; absence of erythrocytes in sediment; color clears following addition of saturated ammonium sulfate to the urine; reddish discoloration of plasma; evidence of anemia (hemoglobinemia)
• Decreased serum calcium concentration, likely multifactorial due to:
  • Decreased intake
  • Increased renal loss
  • Increased movement of Ca²⁺ into damaged cells
  • Profuse sweating

 

UltrastructurAL FINDINGS:

• Broadening of the subsarcolemmic space and intermyofibrillar spaces (degeneration) with edema; myofibrillar waving
• Dilated sarcoplasmic reticulum (degeneration)
• Disassociation and disruption of myofilaments (myofibrillolysis)
• Disorganization and streaming of Z bands
• Small, disintegrated mitochondria; large electron-dense deposits within mitochondria

 

DIFFERENTIAL DIAGNOSIS:

• Malignant edema (gas gangrene): Ruminants, horses, and swine very susceptible; rarely carnivores; etiologies include Clostridium septicum, Clostridium perfringens, Clostridium novyi, Clostridium sordelli and Clostridium chauvoei (M-B01); cellulitis > serohemorrhagic myositis, large gaseous and/or edematous areas adjacent to wounds
• Hyperkalemic periodic paralysis (HYPP): Myotonic disorder of quarter horse; often well-muscled; laryngeal muscle dysfunction > laryngospasms; no gross findings or histopathological lesions
• Polysaccharide storage myopathy (PSSM; M-M20): Myopathy of quarter horse and draft-related breeds; abnormal accumulation of intracytoplasmic PAS-positive, amylase-resistant material within type 2A oxidative-glycolytic and type 2B glycolytic fibers; there are two forms of PSSM:
  • Glycogen synthase 1 gene (GYS1) positive-amylase resistant type
  • GYS1 negative animals-amylase sensitive; accumulation of glycogen, glucose-6-phosphate and polysaccharide inclusions; autosomal recessive inheritance suggested
• Ischemic myopathy: Degenerative myopathy secondary to muscle hypoxia after prolonged anesthesia; from systemic hypotension, improper padding, prolonged recumbency; degenerative and/or regenerative changes within affected muscles
• Nutritional myopathy (M-M11): Foals; associated with vitamin E or selenium deficiencies; affects temporal and masseter muscles; bilaterally symmetric atrophy; pale muscles with yellow to white streaks; myocardial lesions with nutritional myopathy, distinguishes from exertional or ischemic myopathy
• Ionophore toxicity (monensin) (M-T01): Cardiac, skeletal muscle necrosis; pale streaks
• Plant toxicity (Cassia occidentalis, coffee weed, box elder weed) (M-T02): Pale areas within the skeletal, cardiac muscle; multifocal areas of necrosis with zero to minimal mineralization
• Protozoal myopathy (Sarcocystis) (M-P04): Common incidental finding in skeletal muscle, cardiac myofibers; lacks inflammatory response, unless cysts rupture

 

COMPARATIVE PATHOLOGY:

• Exertional rhabdomyolysis: Dogs, nonhuman primates, cattle
  • Canine exertional rhabdomyolysis: Racing greyhounds and racing sled dogs
    • Racing greyhounds: Proposed predisposing factors include an excitable nature, lack of physical fitness, hot and humid conditions, and overexertion of physically fit dogs; gross lesions typically absent; histopathologic findings include acute degenerative changes found in susceptible muscles (longissimus, quadriceps, and biceps femoris muscles)
    • Racing sled dogs: Sudden death may occur during racing; gross lesions not often seen
  • Capture myopathy (CM): Massive muscle injury caused by overexertion (i.e. exertional rhabdomyolysis) associated with restraint and/or transportation; reported in wild animals, marine mammals; resembles exertional rhabdomyolysis; circulating catecholamines may play a role; clinical signs include dyspnea, weakness, muscle tremors or muscle rigidity, hyperthermia, collapse, and often death
  • Multifocal, monophasic skeletal muscle lesions; prominent muscle edema, indistinct pale streaks and hemorrhagic streaking of skeletal muscle
  • All cervid species are susceptible
  • A great concern surrounding translocation of rhinoceros
  • Common in macropods
  • Reported in chondrichthyans
  • Malignant hyperthermia (pigs, dogs, humans, horses):
  • Genetic defect of the calcium-release channel (ryanodine receptor – ryr1) of skeletal muscle sarcoplasmic reticulum
  • Autosomal dominant condition EXCEPT in pig (autosomal recessive)
  • Halothane anesthesia may precipitate condition
  • In pigs, also termed porcine stress syndrome or hertztod; affects lean, heavily muscled pig breeds

 

REFERENCES:

1. Alexander AB, Hanley CS, Duncan MC, Ulmer K, Padilla LR. Management of acute renal failure with delayed hypercalcemia secondary to sarcocystis neurona-induced myositis and rhabdomyolysis in a California sea lion (Zalophus californianus). J Zoo Wildl Med. 2015; 46(3):652-656.
2. Aleman M, Nieto JE, Magdesian KG. Malignant hyperthermia associated with ryanodine receptor 1 (C7360G) mutation in horses. J Vet Intern Med. 2009; 23:329-334.
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4. Duncan M. Perissodactyls. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier. 2018:437-438.
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6. Higgins D, Rose K, Spratt D. Monotremes and Marsupials. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier. 2018:460.
7. Howerth EW, Neneth NM, Ryser-Degiorgis MP. Cervidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier. 2018:151.
8. McCue ME, Armién AG, Lucio M, Mickelson JR, Valberg SJ. Comparative skeletal muscle histopathologic and ultrastructural features in two forms of polysaccharide storage myopathy in horses. Vet Pathol. 2009; 46(6): 1281-1291.
9. Quist EM, Dougherty JJ, Chaffin MK, Porter BF. Diagnostic exercise: Equine rhabdomyolysis. Vet Pathol. 2011; 48(6): E52-E58.
10. Valentine BA: Skeletal muscle. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017: 917, 925, 938-939.
11. Yazwinski M, Milizio JG, Wakshlag JJ. Assessment of serum myokines and markers of inflammation associated with exercise in endurance racing sled dogs. J Vet Intern Med. 2013; 27(2): 371-376.
12. Stedman NL, Garner MM. Chondrichthyes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier. 2018:1006.
13. Stockham SL, Scott MA. Fundamentals of veterinary clinical pathology, 2^nd Ames, IA:Blackwell Publishing.2008:437, 466, 610, 618.

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