Exertional Rhabdomyolysis and Polysaccharide Storage Myopathy (Tying-Up)

Exertional rhabdomyolysis (ER) is a syndrome of muscle necrosis and cramping associated with exercise, commonly known as 'tying-up' or 'Monday morning disease'. It encompasses a spectrum of myopathies, including sporadic ER (often due to overexertion, electrolyte imbalances, or dietary mismanagement) and recurrent ER (RER) seen in performance horses, as well as polysaccharide storage myopathy (PSSM), a genetic glycogen storage disorder. PSSM is characterized by abnormal accumulation of glycogen and abnormal polysaccharide in skeletal muscle, leading to exercise intolerance, muscle stiffness, and episodes of rhabdomyolysis. The condition is particularly prevalent in Quarter Horses, Draft breeds, and Warmbloods, but can affect any breed. In performance disciplines such as Thoroughbred racing, Standardbred racing, dressage, eventing, and Western pleasure, ER and PSSM are significant causes of lost training days and premature retirement. The disease is a major concern in equine practice, requiring a thorough diagnostic workup and long-term management to prevent recurrence and maintain athletic function.

The etiology of exertional rhabdomyolysis and PSSM is multifactorial. Sporadic ER is often triggered by acute strenuous exercise, especially in unfit horses, or by dietary excesses (high grain, low forage), electrolyte imbalances (particularly potassium, sodium, calcium, and magnesium), and hormonal factors (thyroid dysfunction, stress). Recurrent ER (RER) has a genetic basis in some breeds, with an autosomal dominant inheritance pattern in Thoroughbreds, and is associated with abnormal calcium regulation in muscle cells. PSSM is caused by a mutation in the glycogen synthase 1 (GYS1) gene in many breeds, leading to overactivity of glycogen synthase and excessive glycogen storage. Other causes include viral infections (e.g., equine influenza, EHV-1) that can trigger myositis, and nutritional deficiencies (e.g., selenium/vitamin E deficiency) leading to oxidative muscle damage. In some cases, anhidrosis or heat stress can predispose to ER. The exact trigger for an episode may be a combination of these factors, with exercise serving as the final precipitating event.

Exertional rhabdomyolysis and PSSM are recognized worldwide, with breed and discipline predilections. PSSM is most common in Quarter Horses, Paint Horses, Appaloosas, Draft breeds (Belgian, Percheron, Clydesdale), and Warmbloods. In Quarter Horses, the prevalence of the GYS1 mutation is estimated at 6-10% in some populations, but higher in certain lines. RER is most frequently diagnosed in Thoroughbreds and Standardbreds, particularly in racing and performance disciplines. The condition can occur at any age, but young horses (2-5 years) are often first affected when training begins. Both sexes are affected, but fillies and mares may be overrepresented in some studies. Episodes are more common in horses that are stalled and fed high-concentrate diets, with irregular exercise schedules. The morbidity in affected populations can be high, with up to 5-10% of racing Thoroughbreds experiencing at least one episode. Mortality is rare but can occur due to severe rhabdomyolysis leading to acute renal failure or electrolyte imbalances. The athletic career impact is significant, with many horses requiring prolonged rest and management changes.

The pathophysiology of ER and PSSM involves a cascade of events leading to muscle cell damage and necrosis. In PSSM, the GYS1 mutation results in excessive glycogen synthesis and abnormal polysaccharide accumulation in type 2A and 2B muscle fibers. This abnormal glycogen is resistant to breakdown, leading to energy deficits during exercise and mechanical disruption of myofibrils. In RER, an abnormality in calcium regulation within the sarcoplasmic reticulum leads to uncontrolled muscle contraction and increased energy demand, causing ATP depletion and cell membrane damage. During exercise, the demand for ATP exceeds the muscle's capacity to produce it, leading to activation of proteolytic enzymes, increased intracellular calcium, and mitochondrial dysfunction. This results in rhabdomyolysis, with leakage of muscle enzymes (CK, AST) and myoglobin into the bloodstream. Myoglobinuria can cause acute tubular necrosis and renal failure. Additionally, electrolyte imbalances (hypocalcemia, hypokalemia, hypomagnesemia) can exacerbate muscle excitability and impair relaxation. In severe cases, compartment syndrome and ischemic necrosis can occur, leading to fibrosis and permanent muscle damage.

Predisposing factors for ER and PSSM include intrinsic factors such as breed (Quarter Horse, Draft, Thoroughbred), age (young horses in training), sex (females may be more prone), and genetic predisposition (GYS1 mutation, RER family history). Conformational traits such as heavy muscling and a short, thick neck may be associated with PSSM. Extrinsic factors include sudden changes in exercise intensity or duration, prolonged stall confinement with high-energy diets, high grain feeding (especially >50% of diet), inadequate turnout, irregular farriery, and transportation stress. Environmental factors such as hot, humid weather and dehydration can also trigger episodes. In performance horses, overtraining and high-level competition stress are significant contributors. Additionally, concurrent diseases such as hypothyroidism or pituitary pars intermedia dysfunction (PPID) may increase the risk. Management practices that promote glycogen storage, such as feeding large meals of starch, are particularly problematic in PSSM horses.

Clinical signs of ER and PSSM range from mild stiffness to severe recumbency. Early signs include a shortened stride, reluctance to move, and muscle fasciculations, particularly over the gluteal and epaxial muscles. As the condition progresses, horses may exhibit profuse sweating, elevated heart rate (80-120 bpm), and respiratory rate, and signs of pain such as pawing, looking at the flank, and rolling. The horse may adopt a 'sawhorse' stance with stiff, painful muscles. In severe cases, the horse may become recumbent and unable to rise. Urine may appear dark brown or red due to myoglobinuria. On physical examination, muscles are firm and painful on palpation, and the horse may resent movement. In PSSM, signs may be more chronic, with poor performance, muscle atrophy, and a 'camped out' stance. In some cases, episodes are triggered by exercise, but in others, they may occur at rest. The severity can be graded from mild (grade 1) to severe (grade 4) based on clinical signs and CK levels.

Differential diagnoses for ER and PSSM include: 1) Colic (gastrointestinal pain) - horses may show similar signs of abdominal pain, but muscle stiffness and elevated CK are absent; 2) Laminitis - pain in the feet may cause reluctance to move, but digital pulses and hoof testers are positive; 3) Tetanus - muscle rigidity and prolapsed third eyelid are characteristic; 4) Equine motor neuron disease (EMND) - chronic muscle atrophy and weakness, but no acute episodes; 5) Myotonia - muscle stiffness and delayed relaxation, but CK may be normal; 6) Hyperkalemic periodic paralysis (HYPP) - episodes of muscle fasciculations and weakness, but associated with high potassium and specific breed (Quarter Horses); 7) Polysaccharide storage myopathy (PSSM) - can be differentiated by muscle biopsy and genetic testing; 8) Exertional myopathy due to selenium/vitamin E deficiency - responds to supplementation; 9) Atypical myopathy (AM) - associated with sycamore seeds, severe generalized muscle damage, and high mortality; 10) Infectious myositis (e.g., clostridial myositis) - fever, localized swelling, and toxemia. Diagnostic tests such as serum CK, AST, electrolytes, and muscle biopsy are essential to differentiate these conditions.

The diagnostic algorithm for ER and PSSM begins with a thorough history and physical examination. If the horse is showing acute signs, immediate first aid includes rest, sedation, and fluid therapy. Blood samples should be collected for serum CK, AST, electrolytes, and renal parameters. Urine should be assessed for myoglobin. If the horse is stable, a more detailed workup is performed. This includes: 1) Baseline serum CK and AST; if CK is >10,000 U/L, severe rhabdomyolysis is confirmed. 2) Electrolyte panel to identify imbalances. 3) Genetic testing for GYS1 mutation (PSSM) in breeds at risk. 4) Muscle biopsy (from the semimembranosus or gluteal muscle) for histopathology and glycogen staining. 5) Exercise testing to reproduce signs and measure CK response. 6) In recurrent cases, thyroid function tests (T3, T4, TSH) and ACTH to rule out PPID. 7) In cases with atypical signs, further imaging such as ultrasound or MRI may be indicated. The algorithm emphasizes early recognition and treatment to prevent complications.

Laboratory findings in ER and PSSM include markedly elevated serum creatine kinase (CK) and aspartate aminotransferase (AST). CK levels can rise to >10,000 U/L within 6-12 hours of an episode and peak at 24-48 hours, while AST peaks later (48-72 hours) and remains elevated longer. Electrolyte abnormalities may include hypocalcemia, hypokalemia, hypomagnesemia, and hyperphosphatemia. Myoglobinuria is detected by urine dipstick (positive for blood but no red cells on microscopy) or specific tests. In severe cases, renal parameters (BUN, creatinine) may be elevated due to acute kidney injury. In PSSM, baseline CK may be normal or mildly elevated, but exercise testing can show a significant increase. Genetic testing for the GYS1 mutation is definitive for PSSM. Muscle biopsy shows characteristic abnormal polysaccharide inclusions and increased glycogen. In RER, muscle biopsy may show increased variation in fiber size and evidence of muscle damage. Additional tests include serum selenium and vitamin E levels to rule out deficiency. In chronic cases, thyroid hormone levels may be low, but this is often secondary to the myopathy.

Imaging modalities are not routinely used for the diagnosis of ER and PSSM, but they can be helpful in certain situations. Ultrasonography of the affected muscles may show areas of increased echogenicity due to edema and necrosis, but this is nonspecific. In chronic PSSM, ultrasound may reveal muscle atrophy and fatty infiltration. Magnetic resonance imaging (MRI) can provide detailed images of muscle structure and may show areas of inflammation, fibrosis, or fatty replacement, but it is expensive and not widely available. Scintigraphy (bone scan) can detect areas of increased uptake in muscles due to inflammation, but it is also nonspecific. In cases where the diagnosis is uncertain, muscle biopsy remains the gold standard. Imaging is more useful for ruling out other causes of lameness or colic, such as radiography for fractures or ultrasound for abdominal pain. In horses with concurrent laminitis, radiographs of the feet are indicated to assess rotation and sinking.

Cytology and histopathology are crucial for the definitive diagnosis of PSSM and to differentiate it from other myopathies. Muscle biopsy is typically taken from the semimembranosus or semitendinosus muscle under local anesthesia. Histopathological examination with periodic acid-Schiff (PAS) staining reveals abnormal accumulation of glycogen and the presence of amylase-resistant polysaccharide inclusions in type 2 fibers. These inclusions are characteristic of PSSM. In RER, histopathology may show increased fiber size variation, central nuclei, and evidence of muscle fiber necrosis and regeneration. Immunohistochemistry can be used to assess the expression of proteins involved in calcium regulation. In cases of atypical myopathy, histopathology shows severe lipid accumulation in muscle fibers. Cytology of muscle aspirates is less commonly used but may show necrotic debris and inflammatory cells. In addition, blood smears may show hemoconcentration and leukocytosis in severe cases. Muscle biopsy is also useful to monitor the response to treatment and to assess the severity of muscle damage.

Treatment of ER and PSSM involves both acute management and long-term therapy. Acute episodes require immediate rest and sedation with acepromazine (0.02-0.04 mg/kg IV) or detomidine (0.01-0.02 mg/kg IV) to reduce anxiety and muscle spasms. Intravenous fluid therapy is essential to promote diuresis and prevent myoglobinuric nephropathy. Polyionic isotonic fluids (e.g., lactated Ringer's solution) are administered at a rate of 10-20 mL/kg/h initially, then adjusted based on urine output and hydration status. In severe cases, mannitol (0.25-1 g/kg IV over 20-30 minutes) may be used to enhance diuresis. Non-steroidal anti-inflammatory drugs (NSAIDs) such as flunixin meglumine (1.1 mg/kg IV) or phenylbutazone (4.4 mg/kg IV) are given to reduce pain and inflammation. Muscle relaxants such as methocarbamol (20-40 mg/kg IV) may be used. In cases with severe electrolyte imbalances, specific supplementation is provided. For PSSM, long-term management includes a low-starch, high-fat diet (e.g., fat supplementation with vegetable oil at 0.5-1 cup/day), regular daily exercise, and avoidance of high-grain meals. For RER, management focuses on reducing stress, providing a consistent exercise schedule, and ensuring adequate electrolyte balance. In some cases, dantrolene (2-4 mg/kg PO) may be used prophylactically before exercise. In chronic cases, dietary supplements such as vitamin E (5000 IU/day) and selenium (1-2 mg/day) are recommended.

The prognosis for ER and PSSM varies depending on the underlying cause and the severity of the episode. For sporadic ER, the prognosis is generally good if treated promptly and the inciting cause is corrected. Most horses recover within a few days to weeks, and return to athletic function is possible with appropriate management. For recurrent ER (RER), the prognosis is guarded, as episodes may recur despite treatment. However, with strict management, many horses can continue to perform at a high level. For PSSM, the prognosis is fair to good with proper dietary and exercise management. Horses with PSSM can often lead active lives, but they may require lifelong dietary restrictions and regular exercise. Severe episodes of rhabdomyolysis can lead to complications such as acute renal failure, which carries a poor prognosis. Negative prognostic indicators include persistent myoglobinuria, severe electrolyte imbalances, and the development of laminitis. In horses with PSSM, the presence of the GYS1 mutation does not necessarily predict the severity of clinical signs, but early diagnosis and management improve outcomes.

Follow-up care for ER and PSSM is essential to prevent recurrence and monitor recovery. After an acute episode, serum CK and AST should be monitored every 24-48 hours until they return to normal. The horse should be rested for at least 7-14 days, with gradual return to exercise. A structured rehabilitation program should be implemented, starting with hand-walking and progressing to light lunging and then ridden work. For PSSM, dietary changes should be implemented immediately, and the horse should be exercised daily, even if only for 20-30 minutes. Regular veterinary rechecks are recommended every 3-6 months to assess muscle enzyme levels and adjust management. In horses with recurrent episodes, a muscle biopsy may be repeated to evaluate the response to treatment. Additionally, farriery should be maintained to ensure proper hoof balance, as lameness can exacerbate muscle strain. Owners should be educated on the signs of an impending episode and the importance of early intervention. In breeding animals, genetic testing should be considered to inform breeding decisions.

Clinical pearls: 1) Always measure serum CK in any horse with acute muscle stiffness or reluctance to move; a CK >10,000 U/L confirms rhabdomyolysis. 2) In PSSM, a low-starch, high-fat diet is the cornerstone of management; fat supplementation can be increased gradually to avoid digestive upset. 3) Regular daily exercise is crucial for PSSM horses; even on rest days, hand-walking is beneficial. 4) In RER, reducing stress and maintaining a consistent routine is key; consider using a calming supplement or magnesium. 5) Always check urine color for myoglobinuria; if present, aggressive fluid therapy is needed to prevent renal failure. Pitfalls: 1) Do not administer corticosteroids in acute ER, as they may worsen muscle damage. 2) Avoid using acepromazine in stallions, as it can cause penile prolapse. 3) Do not overlook concurrent conditions such as laminitis or colic, which may mimic ER. 4) In PSSM, do not feed high-starch meals, even small amounts, as they can trigger episodes. 5) Do not assume that a horse with a single episode of ER has PSSM; a thorough workup is needed to identify the underlying cause.

Current drug protocols for ER and PSSM are based on Plumb's Veterinary Drug Handbook and ACVIM guidelines. For acute episodes: 1) Acepromazine (0.02-0.04 mg/kg IV) for sedation and vasodilation. 2) Detomidine (0.01-0.02 mg/kg IV) for analgesia and sedation. 3) Flunixin meglumine (1.1 mg/kg IV) or phenylbutazone (4.4 mg/kg IV) for pain and inflammation. 4) Methocarbamol (20-40 mg/kg IV) as a muscle relaxant. 5) Intravenous fluids: Lactated Ringer's solution at 10-20 mL/kg/h, with potassium chloride (20-40 mEq/L) if hypokalemia is present. 6) In severe cases, mannitol (0.25-1 g/kg IV over 20-30 minutes) to promote diuresis. 7) For myoglobinuria, consider sodium bicarbonate (1-2 mEq/kg IV) to alkalinize urine, but use with caution. For long-term management: 1) For PSSM, dietary fat supplementation (vegetable oil 0.5-1 cup/day) and a low-starch diet. 2) Vitamin E (5000 IU/day PO) and selenium (1-2 mg/day PO) as antioxidants. 3) For RER, dantrolene (2-4 mg/kg PO) 1-2 hours before exercise. 4) Magnesium supplementation (e.g., magnesium oxide 10-20 g/day PO) may help reduce muscle excitability. 5) In horses with PPID, pergolide (0.002 mg/kg PO) may be indicated. 6) For chronic pain, gabapentin (5-10 mg/kg PO) may be used. Always monitor renal function and electrolytes during treatment.

Landmark studies have advanced our understanding of ER and PSSM. The discovery of the GYS1 mutation in 2008 by McCue et al. revolutionized the diagnosis of PSSM, allowing for genetic testing. A study by Valberg et al. (1992) first described PSSM as a distinct myopathy in Quarter Horses. Subsequent research has characterized the histopathological features and the response to dietary management. In RER, studies have identified an autosomal dominant inheritance in Thoroughbreds and have explored the role of calcium regulation. A randomized controlled trial by Ribeiro et al. (2015) demonstrated that a low-starch, high-fat diet significantly reduced episodes of ER in PSSM horses. Another study by McKenzie et al. (2003) showed that regular exercise is beneficial in managing PSSM. ACVIM consensus statements on equine myopathies provide guidelines for diagnosis and treatment. Meta-analyses have highlighted the importance of early recognition and aggressive fluid therapy in preventing renal failure. Overall, the evidence supports a multimodal approach to management, including dietary modification, exercise, and pharmacological intervention.