1 Equine Muscle Disorders

Equine Muscle Disorders

• Equine muscle disorders include:
  • Polysaccharide Storage Myopathy (PSSM)
  • Glycogen Branching Enzyme Deficiency (GBED)
  • Recurrent Exertional Rhabdomyolysis (RER)

Blood Work Values

• The blood work values are as follows:
  • Glucose: 210 mg/dL
  • BUN: 21 U/L
  • Creatinine: 1.9 U/L
  • Sodium: 142 mmol/L
  • Chloride: 99 mmol/L
  • Potassium: 3.5 mmol/L
  • Aspartate transaminase: 278 U/L
  • Creatine phosphokinase: 39,000 U/L
  • GGT: 14 U/L

Learning Objectives

• Enrollees will discover the pathogenesis of various forms of equine muscle disease.
• Enrollees will be able to identify breed predilections for various disorders.
• Enrollees will learn to perform examinations for suspect myopathy, specific to the disease.
• Example: Differentiating examination for Quarter Horse with PSSM vs. foal with GBED.
• Enrollees will gain information about disease manifestation based on breed, standard of care, therapy, and prognosis.

Lecture Outline

• Topics in the lecture:
  • Polysaccharide Storage Myopathy (PSSM):
    • Quarter Horse
    • Draft breeds (Belgian/Percheron)
    • Warmblood
  • Glycogen branching enzyme deficiency (GBED):
    • Quarter Horse foals
  • Recurrent exertional rhabdomyolysis
    • Thoroughbred and Standardbred
  • Clinical management of rhabdomyolysis:
    • Pain management
    • Diuresis
    • Exercise as permitted

Exertional Rhabdomyolysis

• Terminology:
  • Tying up
  • Monday morning disease
  • Azoturia
• PSSM is associated with:
  • Quarter Horses
    • Polysaccharide storage myopathy (PSSM)
    • Malignant hyperthermia (MH)
  • Draft Horses
  • Warmbloods
• RER is associated with Thoroughbreds

Polysaccharide Storage Myopathy (PSSM)

• PSSM is defined by unregulated glycogen synthesis and production.
• Type II PSSM primarily affects fast-twitch muscle fibers.
• Tying up is a common symptom of PSSM, resulting in:
  • Pain
  • Stiffness
  • Firm musculature
  • Sweating
• Genetic testing identifies two types of PSSM:
  • Type 1: Glycogen synthase I (GYSI) mutation
  • Type 2: No mutation, but still experience tying up episodes
• Quarter Horses and similar breeds show:
  • 1.5 times higher glycogen levels in skeletal muscle
  • Amylase-resistant inclusions
  • Familial autosomal dominant trait

PSSM Type I vs Type II

• Type I PSSM (PSSM 1):
  • Recurrent tying up.
  • Muscle biopsy histopathology shows tissue changes consistent with PSSM.
  • DNA testing reveals mutations in the glycogen synthase gene (GYS1).
• Type II PSSM (PSSM 2):
  • Recurrent tying up.
  • Muscle biopsy histopathology reveals tissue changes consistent with PSSM.
  • DNA shows there is no GYS1 mutation.
  • The cause is another problem.

Myofibrillar Myopathy (MFM)

• MFM is a recently identified disorder in horses presenting with exercise intolerance and intermittent ER.
• MFM-affected horses have cytoplasmic aggregates of the cytoskeletal protein desmin.
• MFM has cytoplasmic aggregates of glycogen similar to PSSM 2.
• MFM may be an extreme form of PSSM 2.

PSSM Pathophysiology

• Pathophysiology includes:
  • Elevated creatine (phospho)kinase (CK)
  • Elevated aspartate aminotransferase (AST)
  • A 3X elevation in CK/AST after 15 minutes of exercise is presumptive
  • 80% of cases show exercise intolerance and gait abnormalities.

PSSM and Pathogenesis

• A mutation of Glycogen Synthase (GYS1) includes:
  • Arginine to histidine mutation at codon 309
• Increased enzyme activity results in the gain of function mutation.
• Increased sensitivity to insulin includes:
  • Increased glucose uptake and muscle cells
  • Dexamethasone induces IR and can still have tying up episodes

Exercise Testing for PSSM

• It is a 15 minute exercise test.
• Aids in the identification of 80% of horses with PSSM.
• There is an increase in CK activity 4-6 hours after exercise.
• Example results:
  • Pre-exercise: 310 U/L
  • Post-exercise: 1,599 U/L

Malignant Hyperthermia

• It is a severe pharmacogenetic state.
• It is induced by volatile anesthetics, depolarizing anesthetics, and stress.
• There is a Ryanodine receptor gene mutation called RyR1 gene mutation.

Equine Malignant Hyperthermia (MH)

• The Ryanodine receptor mutation = RyR1 mutation.
  • This is caused by: C7360G => R2454G amino acid mutation.
• Results in excessive release of calcium into the myoplasm.
• Causes heat, hypercapnia, and lactic acidosis, possibly death.
• Quarter Horses are susceptible.
• MH can be triggered by halogenated anesthetics, stress, exercise, breeding, or other myopathies.

PSSM and MH

• PSSM and MH may occur concurrently.
• Blood or hair roots are needed for DNA testing.
• When PSSM and MH are present together, the patient has a more severe form of muscle disease.
• The exertional rhabdomyolysis can be so severe that the horse may not survive the episode.
• There are high muscle enzymes due to PSSM.
• There is an elevated temperature due to MH.

PSSM Diagnosis

• Diagnosed with muscle biopsy at Equine Muscle Lab
• Take a 2 X 1 cm block of tissue from:
  • Semimembranosus
  • Semitendinosus
• Subsarcolemmal vacuoles are inspected.
• It is tested for Amylase-resistant PAS positive polysaccharide.

PSSM and Young Horses

• DNA testing for GYSI is most appropriate.
  • It has a high sensitivity.
• If amylase resistant polysaccharide is the method used, testing may be negative due to low sensitivity.
• Abnormal glycogen accumulation takes time, so morphologic changes may not be present.

Breed Effects and PSSM

• 1251 horses were evaluated UM NDL.
• 40% of suspect cases are PSSM
• The following breeds are cases:
  • Quarter Horse at 63%
  • Draft breed at 12%
    • Belgian and Percheron
  • Warmblood at 9%
• McCue et al., EVJ 2006

PSSM: Breed and Environment

• QH on pasture = 6% disease if:
  • There is no grain.
  • There are no clinical signs.
• QH in stall / on grain is a 50% clinical disease.
• "Environment and diet play a role!": McCue et al, JVIM, 2006

PSSM Clinical Signs

• Range in age from 1-14 years, average is 5 years.
• Non-seasonal onset
• No gender, temperament, or body type predilection.
• Short exercise (
  • Particularly after rest / lay up
• Muscle pain and stiffness, and sweating.
  • Characterized by stretching out to urinate
• Gait, colic, muscle wasting

Tying Up and Exertional Rhabdomyolysis

• Incidental instances are once in their life, never again
• PSSM positive cases can be determined through histopathology.
  • GYS 1 mutation
    • Type 1 PSSM
  • GYS 1 and RYR 1 (MH) mutation
    • Type 1 PSSM
  • Other, GYS 1 - negative: to be identified
    • Type II PSSM
      • Mild to moderate
      • Severe
      • MFM
• RER:
  • To be identified.

PSSM and Draft Horses

• Original testing was done and 54% of drafts tested were PSSM-I positive.
• Belgians and Percheron and crosses are a factor.
• Belgians alone reported to be 36%.
• Firshman et al., JAVMA, 2005

PSSM Presentation in Draft Horses

• Variable presenting complaint!
• Possible no or few clinical signs
• Possibility so severe to result in recumbency
• Post-anesthetic issues and complications
• Weakness
• Difficulty rising
• There may be normal muscle enzymes.
• There are typically normal vitamin E and selenium levels.

PSSM Draft Breeds

• High muscle glycogen content
• 1.8 fold is compared with healthy horses
• There is no increase in insulin sensitivity
• It May not be identical disorders in QH and Draft breeds.

Shivers

• Can affect Draft horses
  • The Belgian can be affected.
• Can affect Warmbloods
• This is Not PSSM
• It is a Chronic movement disorder
• Found in Tall, male horses
• Indicated by Elevation of pelvic limbs, particularly with backing or stress
• It Generally begins < 7 years, progressive disorder

PSSM Warmbloods

• NDL Minnesota studies have noted a 19-33% PSSM rate.
• Of Warmbloods biopsied, some presented Poor performance and Few (15%) full blown Tied up cases.
• PSSM is associated with GYS1 in Warmbloods - Johlig, Valberg et al EVJ 2011

PSSM General Management

• Conduct Routine exercise as much as possible:
  • Regular riding and regular turnout / living outdoors
• When following episode of tying up complete, conduct approxiamtely a 1-2 days of stall rest
  • Then turnout, with minimal concentrate (grain)
• Prolonged rest = persistent elevation of CK
• Do not recommend forced hand walking and sedation for excitable horses
• It is recommened to conduct turnout so a horse can control their own level of activity.

Recovery from of Acute PSSM Disease

• Conduct Turn out
• Modify diet and give time for acclimation
• The Duration and gradual increase of exercise is important.

PSSM Training Program

• Careful exercise enhances oxidative capacity of muscle.
• There is Typically low oxidative capacity in QH
  • Gradual and routine exercise will improve condition -Provide fat as an alternative energy substrate (non-carbohydrate form of energy).

PSSM Diet

• Reduce dietary carbohydrate intake.
• Provide fat as an alternate energy source
• Diet change with low carbohydrate and high fat only shown to help QH w/ PSSM patients
• Recommend: Diet should be Starch 10% of daily DE
• It is recommended Increase fat to >/= 13% of daily DE.
• With diet and exercise, It takes 3 weeks - 4 months to see changes.
• Recommend DIET AND EXERCISE is the best therapy

Overall PSSM Points

• PSSM can affect a variety of breeds.
• A clinical disease is most commonly associated with exertional rhabdomyolysis.
• Suspect QH, related, and previously identified breeds should be tested for GYS1 (QH RyR1) mutations.
• Environmental management can reduce chance for episodes.
• Full blown exertional rhabdomyolysis may require fluid therapy and pain management.

Glycogen Branching Enzyme Deficiency (GBED)

• GBED is a Glycogen storage disorder primarily seen in QH and Paint foals

• The inheritance is Autosomal recessive

• Mutation leads to non-functional Glycogen Branching Enzyme (GBE) synthesis

• GBED has been present since 1940, with cases including King P234 and Zantanon

• If N is the normal and G is the GBED allele:

  • N/G x N/G = 25% N/N normal; 50% N/G; 25% G/G = Lethal -N/G x N = 50% N/N normal; 50% N/G N G N G N 25% N/N 25% N/G N 50% N/N 50% N/G G 25% N/G 25% G/G

• This is a Autosomal Recessive trait

• 9% QH and Paints are carriers

• Abortion during late gestation

• Abortion or death in first 60 days

GBED: Pathologic Features

• Muscle biopsy histopathology and Abnormal PAS staining
• Genetic testing is most accurate
• Tested at UC Davis using http://www.vgl.ucdavis.edu/service/horse/index.html
• Mane or tail hairs WITH roots are needed

GBED Presentation

• Clinical presentation: -Weakness - Hypothermia - Flexural deformities

GBED Progression and Hematology

• Disease progression:
  • Hypoglycemia and Respiratory failure is seen.
  • Hallmark feature: Hypercarbia (with high PaCO2 levels)
  • Requires a Ventilator for support
  • Invariably fatal condition
• Hematology:
  • Leukopenia is a common feature
    • Leukopenia ~4,000 cells / uL
  • Moderate elevation of:
    • Creatine Kinase (CK)
    • Aspartate transaminase (AST)
    • Gamma glutamyl transferase (GGT)
  • +/- hypoglycemia
    • Pronounced and severe with advanced disease.

GBED: Pathogenesis

• Glycogen synthesis: branched and energy dense molecule
• Without glycogen all tissues become energy deprived
• Glycogen synthase
  • Straight chain alpha 1,4 glycosidic linkages
• Glycogen branching enzyme
  • Branches of glucose alpha 1,6 linkages
  • Without proper branching the carbohydrate molecule is not stored properly and is not functional to the host.

Recurrent Exertional Rhabdomyolysis (RER)

• It occurs in the Race horses:
  • Primarily Thoroughbreds and Standardbreds
• Nervous fillies are more at risk
• Is detected in the early in the course of exercise at 10-15-min into exercise warm up
• Clinical signs are similar to other forms of exertional rhabdomyolysis.
• RER is NOT equal to PSSM

RER: Clinical Signs

• Clinical signs can include:
  • Stiff painful muscles and Muscle fasciculations -Myoglobinuria
  • Have Significant elevation of CK and AST 4-6 hours after exercise

RER: Pathophysiology

• Not lactic acidosis or electrolyte imbalance but Abnormal excitation-contraction coupling
• It is due to to Abnormal intracellular Ca++ regulation resulting in ↑ myoplasmic Ca++ - Prolonged relaxation of muscle

RER: Diagnosis

• Diagnosis Through Muscle Biopsy:
  • Check for necrosis, regeneration, centrally-located myonuclei
• Biochemical Testing (Gold Standard tests): -Halothane and Caffeine sensitivities that are Similar to malignant hyperthermia.
  • Note that Specialized instruments and personnel = not routinely available

RER: Management

• Provide Stall rest for 1-2 days,
• Then standard turnout: CAREFULLY and provide Daily turnout for 2 weeks to the individual
• Administer mild sedative if anxious.
  • Use Acepromazine
• Use Dantrolene to inhibit calcium release from sarcoplasmic reticulum
• Use Phenytoin to alters Na+ and Ca++ channels to help manage RER episodes
  • Also use: a Low carb high fat diet.

Clinical Management Tying Up

• Clinical Management of acute tying up is regardless of inciting cause through -Manage with Fluids, Analgesics and Muscle Relaxants -Severe muscle pain - use severe muscle pain, Fasciculations, and Sweating. -Restrict movement / Exercise

Acute Tying Up

• Analgesic
  • Xylazine and Detomidine
• Treat with Muscle relaxation
  • Methocarbamol 15-25 mg/kg IV, slowly Q8-12h
  • Danrolene for MH horses using 4 mg/kg PO q 4-8 hours
• Fluid therapy
  • NSAIDs- monitor hydration status and use Butorphanol

Acute Tying Up: Clinical Management

• Provide the following:
  • Intravenous fluids, 40-60 L isotonic fluids
  • Maintain renal blood flow and Improve muscle blood flow
  • Continue for 1-2 days until urine is clear
    • Conduct Creatinine and Creatine phosphokinase testing.
  • Monitor renal function. -Prognosis: generally favorable

Summary: Equine Extertional Rhabdomyolysis

• Equine Extertional Rhabdomyolysis include the following components: -PSSM- recurring tying, prevalent in QH, warmblood, and certain draft breeds, results from excessive glycogen, autosomal trait. -GBED - specific to QH and related breeds , abortion/neonatal death, evident as neonatal foals, autosoma recessive, can be fatal, enzymes increased . -RER- evident in thoroughbred and racehorses, often impacts fractious females causing performance limiting issue,.
• For clinical management, conduct: -Maintain hydration. -Provide comfort by reliving pain. -Diuresis if applicable should address myoglobinuria..
• Diet, exercise must improve clinical management.