Objectives of the Presentation

• Discuss the pathophysiology and management of PSSM, malignant hyperthermia, HYPP, and myosin heavy chain myopathy.
• Discuss the causes and treatment of muscle cramping.
• Discuss the pathophysiology and treatment of clostridial myositis.

Polysaccharide Storage Myopathy (PSSM)

Etiology and Pathophysiology:^1-4

Polysaccharide storage myopathy is the abnormal accumulation of glycogen in muscles.

• Type 1: autosomal dominant missense mutation in glycogen synthase 1 (GYS1) gene
• Drafts, QH (72% PSSM QH), Warmbloods
• Type 2: no GYS1 mutation
• Warmbloods, QH (28% PSSM QH)

Pathophysiology of PSSM1:^1-4

• Gain of function GYS1 mutation leads to higher activity in basal states and when activated by insulin and glucose 6-phosphate
• The 2–4 times increased glycogen concentrations in skeletal muscle that is less branched than normal (not GBED)
• Amylase-resistant polysaccharide accumulates in a small percentage of fast-twitch muscles (e.g., semimembranosus mm)

Risk factors for PSSM1 include: diet high in NSC, exercise <20 minutes at one time, especially if horse rested for several days before exercise, quality of grass, influence of other genes.

Clinical Diagnosis:^1-4

Acute PSSM1 signs in light breeds:

• Begin showing clinical signs 1–14 years old (average 5 years); persistent ↑ CK (>35,000 U/L)
• Occur most commonly at walk and trot, soon after starting exercise; stiff, reluctance to move, firm muscles, may progress to recumbency; sweating, ↑ HR, ↑ RR

Chronic PSSM1 signs in light breeds:

• Range of “poor performance,” lack of energy under saddle, reluctance to move forward, sour attitude toward exercise

PSSM1 clinical signs in drafts:

• Progressive weakness, muscular atrophy, difficulty rising, abnormal limb flexions, fasciculations
• Severe rhabdomyolysis + myoglobinuria with: high-grain diets, exercised irregularly with little turnout, general anesthesia

PSSM2 signs in warmbloods:

• Poor performance without ↑ CK, sore muscles, decreased energy level, unwillingness to perform after 5–10 minutes of exercise, reluctance to engage hindquarters
• Slow onset of muscle atrophy, especially when out of work

PSSM Diagnosis:

• History, clinical signs, ↑ CK and AST (persistent) or exercise test (if resting enzymes normal)
• Muscle biopsy: semimembranosus muscle → amylase-resistant polysaccharide (PSSM1) or granular amylase-sensitive glycogen (PSSM2)
• Gold standard: genetic testing for GYS1 mutation on whole blood or hair root samples

Management:^1-4

PSSM1/PSSM2 QH: horses will stay susceptible but 70% improve with management:

• Rest after ER episode: limit stall confinement (48 h); paddock turnout of gradually increasing size (sedate PRN)
• Daily, regular exercise crucial: start at 5 min in round pen, build by 2 min per day slowly to 30 min over 3 weeks; maximize turnout
• Nutrition: decrease sugar and starch, increase fat
• Forage: <12% NSC at 1.5% body weight
• Concentrate: <15% NSC or ration balancer with added oil (1–2 cups)
• If overweight—skip fat, fast 6 hours before exercise (increases circulating free fatty acids)

PSSM2 Warmbloods:

• No justification for low starch + excess fat; exceptions:
• Equine metabolic syndrome: low starch
• Thin horses: high fat
• Training regimen: long, low warm-up; 3 days of work, 2 days off with lots of turn out

Malignant Hyperthermia (MH)

Malignant hyperthermia is rhabdomyolysis induced by exercise or anesthesia. MH is caused by an autosomal dominant mutation in ryanodine receptor 1 (RYR1) (Ca²⁺ release channel).

Clinical Diagnosis:^1-4

• Intermittent ER, high body temperature, sudden death
• Genetic testing in QH, paints with PSSM difficult to manage; +/- PSSM1 → more severe ER, higher CK post-exercise, less response to diet and exercise management

Treatment and Prevention:^1-4

• Dantrolene, address acidosis, and hyperthermia
• Prevention: dantrolene PO 30–60 min preop to prevent episode
• Intermittent → hard to justify routinely treating before exercise

Hyperkalemic Periodic Paralysis (HYPP)

Etiology and Pathophysiology:^1-4

• Autosomal dominant inherited defect in skeletal muscle dependent Na+ channel → abnormal muscle excitability
• Point mutation of SCN4A gene (phenylalanine/leucin substitution)
• Triggers: high K+ (>1.1%) diet: alfalfa, molasses, electrolytes; fasting, anesthesia, heavy sedation, trailering, stress

Clinical Diagnosis:^1-4

Clinical signs are highly variable—asymptomatic to daily muscle fasciculations and weakness.

• Episodes of 15–60 minutes progressing through stages
• Initially: brief episode of myotonia (+/- prolapse 3rd eyelid), sweating, muscle fasciculations (flank, neck, shoulders); stimulation, attempts to move → more severe muscle cramping; tachycardia and tachypnea
• Severe episode: severe generalized muscle cramping, fasciculations → severe weakness; swaying, staggering, dog-sitting, recumbency (still conscious); paralysis of upper respiratory muscles → respiratory distress → death

Diagnostic testing:

• Transient hyperK (6–9 mEq/L); more likely if sample obtained during or immediately after episode
• Genetic testing (20–30 mane or tail hairs with roots)

Treatment:^1-4

• Light exercise (hand-walking) at beginning of crisis; feeding grain and corn syrup (stimulate insulin-mediated K+ movement into cells)
• Initial medical treatment: epinephrine (3 ml 1:1000/horse) IM → facilitate intracellular K+ movement
• Severe cases: calcium gluconate to decrease membrane hyperexcitability, dextrose to enhance intracellular potassium movement

Control:^1-4

• Decrease dietary K+: total dietary K<1.1% or 33 g/day
• Avoid alfalfa, orchard grass, molasses
• Pasture turnout ideal: high H₂O content
• Regular exercise
• Increase renal loss of K+: acetazolamide, hydrochlorothiazide

Prognosis:^1-4

• Manageable disease—but recurrent episodes occur, and severe episodes may be fatal
• Discourage owner from breeding affected horse
• Horses not suited for young inexperienced riders

Myosin Heavy Chain Myopathy

Etiology and Pathophysiology:^4-6

• MYH1 gene mutation for protein in type 2X fibers (fastest contracting muscle fibers)
• 7% of QH; highest in reining, working cow, halter (16–24% carriers)
• Initial presentation may be either atrophy or rhabdomyolysis, or atrophy may follow rhabdomyolysis

Immune-Mediated Myositis (IMM):^4-6

• Triggers reported in ~40% cases; recent infectious disease exposure to S. equi, S. zoo, respiratory viruses; vaccination with influenza, EHV-4, S. equi
• Horses ≤8 years or ≥17 years
• Clinical signs: rapid, symmetric atrophy of lumbar and gluteal muscles—up to 40% loss of muscle mass within 48 hours, may persist for months
• Also: depression, loss of appetite, stiffness
• Treatment: corticosteroids mainstay of treatment
• Dexamethasone 0.05 mg/kg for 3 days
• Then prednisolone 1 mg/kg for 7–10 days, tapered by 100 mg/week over 1 month
• Antibiotics if infection present (based on CBC)
• Prognosis:
• 20% heterozygotes (My/N) develop rapid atrophy; typically resolve without long-term issues
• 80% homozygotes (My/My) develop more severe and recurrent atrophy—less likely to recover

Non-Exertional Rhabdomyolysis:^4-6

• Generally young horses (<3 years)
• Clinical signs: muscle pain, stiffness, recumbency, reluctance to stand up, firm muscles; myoglobinuria common; 35% develop subsequent muscle atrophy (typical of IMM)
• CK >50,000 U/L; AST >100,000 U/L; perform PCR for S. equi
• Treatment as for SER; also includes: dantrolene, corticosteroids (see IMM), antibiotics if infection present (based on CBC)
• Management: recurrent episodes in ~50% → minimize exposure to infectious agents, avoid immunostimulants (EqStim)
• Only most necessary vaccines, spaced out 4–6 weeks, smallest number of vaccines/syringe possible; flu/rhino—common trigger; ideally use I.N. flu (Flu Avert I.N., Merck); strangles vaccination (even I.N.) is contraindicated
• Guarded prognosis if unable to rise after lying down

Muscle Cramping

Synchronous Diaphragmatic Flutter:^1,2

• Dehydrated or exhausted horses (prolonged exercise, hypoCa, trailering, stress) with electrolyte abnormalities
• Fluid/electrolyte imbalances disrupts membrane potential of phrenic nerve → fires with atrial depolarization → diaphragm contracts → “thumps”
• Treatment: correct Ca²⁺ and other electrolytes (IVF + Ca²⁺ gluconate)
• Control: supplement K+/Na+/Cl- during prolonged exercise

Exhaustion in Endurance Horses:^1,2

• Endurance/3-day event horse performing prolonged work (2+ hours) in hot humid environment → work beyond exhaustion deplete glycogen, H₂O, electrolytes
• Syndrome includes: “thumps,” ileus (colic signs), +/- rhabdomyolysis, multiple organ failure, death
• Bloodwork: hypoCl metabolic alkalosis with hypoK, hypoNa, hypoMg, low iCa²⁺
• Treatment: enteral or IV fluids, cooling with water and fans
• Prevention: daily salt (same as SER); 1 oz salt + 1 oz lite salt/h exercise syringed as slurry

Clostridial Myositis

Etiology and Pathophysiology:^1,2

• Clostridium species: C. perfringens type A—α toxin; mortality 20%, treat aggressively; C. septicum, C. chauvoei, C. sporogenes—high fatality
• Spores enter through GI tract → dormant in liver, muscle; IM injection, trauma → tissue devitalized forming anaerobic environment → vegetative form and exponential growth → toxin release
• IM flunixin meglumine, phenylbutazone, ivermectin commonly implicated

Clinical Diagnostics:^1,2

• Clinical signs:
• Local: around recent injection site → swelling, heat, pain, crepitus; progresses to cool, insensitive tissue with sloughing
• Malodorous, serosanguinous fluid, “cooked” muscle appearance
• Systemic depression, fever, toxemia; may progress to multiorgan failure, intravascular hemolytic crisis, recumbency, death within 12–24 h
• Ultrasound → gas, tissue edema
• Aspirates → gram-positive rods; culture: aerobic and anaerobic

Treatment:^1,2

• Aggressive antimicrobial and surgical management
• Antibiotics with anaerobic activity: penicillin G, metronidazole, oxytetracycline
• Surgical: debridement and fenestration → get O₂ in tissues
• Supportive: fluids, NSAIDs, aggressive pain management (acetaminophen, gabapentin, butorphanol, lidocaine), nutritional support

Prognosis:^1,2

• Dependent on organism: C. perfringens ~80% survival; up to 100% mortality with C. chauvoei and C. septicum in case reports despite early intervention

Summary Including Five Key “Take Home” Points

1.  Polysaccharide storage myopathy type 1 is due to a genetic mutation and results in accumulation of amylase-resistant glycogen in muscles. Management focuses on diet and daily exercise to prevent repeated episodes.

2.  Polysaccharide storage myopathy type 2 is not due to a genetic mutation. In warmbloods, PSSM2 presents as poor performance without increased CK, and management focuses on proper warm-up and lots of turn-out between days of exercise.

3.  Hyperkalemic periodic paralysis triggers include high potassium diet, anesthesia, and stress. There are a wide range of clinical signs associated with episodes. Management focuses on decreasing dietary potassium by avoiding alfalfa hay and molasses.

4.  Myosin heavy chain myopathy may result in immune-mediated myositis or non-exertional rhabdomyolysis. Infectious diseases are important triggers for IMM, and treatment requires tapering doses of corticosteroids.

5.  Clostridial myositis caused by C. perfringens has the best prognosis but requires prompt surgical and pharmaceutical intervention.

References/Suggested Reading

1.  Valberg SJ, Spier SJ, Parish SM, Murphy M, Carlson GP. Diseases of Muscle. In: Smith BP, Van Metre DC, Pusterla N, eds. Large Animal Internal Medicine. 6th ed. Elsevier; 2020:1421–1455.

2.  Valberg SJ. Disorders of the musculoskeletal system. In: Reed SM, Bayly WM, Sellon DC, eds. Equine Internal Medicine. 4th ed. Elsevier; 2018:542–579.

3.  Valberg SJ. Muscling in on the cause of tying-up. In: AAEP Proceedings. 2012:85–123.

4.  Valberg SJ. Genetics of equine muscle disease. Vet Clin North Am Equine Pract. 2020;36(2):353–378.

5.  Gianino GM, Valberg SJ, Perumbakkam S, et al. Prevalence of the E321G MYH1 variant for immune-mediated myositis and nonexertional rhabdomyolysis in performance subgroups of American Quarter Horses. J Vet Intern Med. 2019;33(2):897–901. doi: 10.1111/jvim.15393.

6.  Valberg SJ, Henry ML, Perumbakkam S, Gardner KL, Finno CJ. An E321G MYH1 mutation is strongly associated with nonexertional rhabdomyolysis in Quarter Horses. J Vet Intern Med. 2018;32(5):1718–1725. doi: 10.1111/jvim.15299.