Myotonia

Clinical Signs

Myotonia congenita in humans, horses, and goats is usually detected in the first year of life.^45-48 Affected animals commonly have conspicuously well-developed musculature and display mild pelvic limb stiffness. Gait abnormalities are usually most pronounced when exercise begins and frequently diminish as exercise continues. Bilateral bulging (dimpling) of the thigh and rump muscles is often obvious and gives the impression that the animal is very well developed (Fig. 42-3). Stimulation of affected muscles, especially percussion, exacerbates the muscle dimpling below a large area of tight contraction (Fig. 42-4). Affected muscles may remain contracted for up to a minute or more, with subsequent slow relaxation.^37,48,49

Fig. 42-3 Normal muscle mass in an Appaloosa foal (A) and spontaneous myotonic dimpling of semimembranosus muscles in a foal with myotonic dystrophy (B).

Fig. 42-4 Myotonic dimpling of the triceps in a horse with hyperkalemic periodic paralysis.

In goats, myotonia congenita appears to an autosomal dominant mutation in the skeletal muscle chloride channel that has incomplete penetrance.^31,47,50 Affected goats are commonly referred to as “fainting goats.” Signs are usually recognizable by 6 weeks of age and vary from stiffness after rest to marked general rigidity after visual, tactile, or auditory stimulation. Clinical signs remain throughout the animal’s life but are not progressive.⁵¹

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Myotonia congenita does not usually show progression of clinical signs beyond 6 to 12 months of age in horses.³⁷ To date no abnormalities in sarcolemmal chloride conductance have been demonstrated in horses, and an inherited basis has not been established in horses.

Myotonia dystrophica appears to be a separate form of myotonia in horses.^36,37,52 Severe clinical signs of myotonia that progress to marked muscle atrophy and possibly involve a variety of organ systems have been observed in quarter horse, Appaloosa, and Italian-bred foals. Retinal dysplasia, lenticular opacities, and gonadal hypoplasia have been reported in one such quarter horse foal.³⁶ This condition resembles myotonia dystrophica in humans, which is caused by genetic mutations involving either the DMPK gene or the ZNF9 gene.^53,54 In both cases a short segment of DNA is abnormally repeated many times, forming an unstable region in the gene, which alters mRNA processing. The genetic basis of myotonic dystrophy in horses is not yet known.

Prognosis

Prognosis appears to be variable and dependent on the severity of clinical signs. Mildly affected animals may undergo some amelioration of clinical signs with increasing age. In animals that exhibit mild clinical signs, manifestations of the disorder may abate over a period of months to years. The reason(s) for this regression of signs is unknown. Other more severely affected horses may have progression of signs, including atrophy and fibrosis or pseudohypertrophy to the point at which the animal is no longer able to move without great pain and difficulty (Fig. 42-5). Euthanasia of such animals is often warranted.

Fig. 42-5 Marked progressive atrophy of the epaxial and gluteal muscles of a horse with myotonic dystrophy.

Although conclusive evidence regarding the genetic basis of this disorder in horses is still not available, owners of affected horses should be cautioned about the possibility that this disease is heritable.

Hyperkalemic Periodic Paralysis

SHARON J. SPIER

Equine HYPP is caused by an inherited defect in the skeletal muscle sodium channel.^35,58-61 This myopathy manifests as abnormal skeletal muscle membrane excitability leading to episodes of myotonia, or sustained muscle contraction, and paralysis. In humans, numerous muscle membrane channel defects (so-called “channelopathies”) have been characterized, and the molecular basis for disease is well described.⁴⁶ Other reported disorders with suspected membrane defects in horses include myotonic dystrophy and congenital myotonia.^36,48 HYPP was the first equine disease attributed to a specific genetic mutation and detectable through DNA technology.⁶⁰

HYPP is an autosomal dominant trait affecting quarter horses, American Paint horses, Appaloosas, and quarter horse cross-bred animals worldwide. A “syndrome” in related horses was first recognized in the 1980s by breeders and veterinarians and was first reported to be similar to HYPP in humans by Cox at the American Association of Equine Practitioners (AAEP) convention in 1985.⁶¹ In December 2002, this genetic disease was publicly linked to a popular quarter horse sire named Impressive. This prolific sire, born in 1969, has 355,000 offspring registered with the American Quarter Horse Association (AQHA),*and these offspring dominate the halter horse industry. Current estimates indicate that 4% of the quarter horse breed may be affected.⁶² Unfortunately, the gene frequency has not decreased in the past 14 years since genetic testing has been available to breeders, and controversy continues among horse breeders whose stock carry this gene.^† Affected horses appear to have been preferentially selected as breeding stock because of their pronounced muscle development, and there is evidence of selection of HYPP-affected horses as superior halter horses by show judges.⁶³ In 1996 AQHA officially recognized HYPP as a genetic defect or undesirable trait. To increase public awareness of this genetic defect, mandatory testing for HYPP with results designated on the registration certificate began for foals descending from Impressive born after January 1, 1998. In response to requests from the membership, in 2004 the AQHA Stud Book and Registration Committee ruled that foals born in 2007 and later testing homozygous affected for HYPP (H/H) will not be eligible for registration. Breeders opposed to restrictions argue that the disease can be controlled through diet and medication and that these horses are highly successful in the show ring.⁶⁴

Clinical Signs

Clinical signs among horses carrying the same mutation range from none (horses are asymptomatic) to daily muscle fasciculations and weakness. In the majority of horses, intermittent clinical signs begin by 2 to 3 years of age with no apparent abnormalities between episodes.^35,59 Ingestion of diets high in potassium (>1.1%), such as those containing alfalfa hay, molasses, electrolyte supplements, and kelp-based supplements or sudden dietary changes commonly trigger episodes.⁶⁵ Fasting, anesthesia or heavy sedation, trailer rides, and stress may also precipitate clinical signs; however, the onset of signs is often unpredictable and without a definable cause. Other possible precipitating factors that have been noted in humans and horses are exposure to cold, fasting, pregnancy, and concurrent disease and rest after exercise. Exercise per se does not appear to stimulate clinical signs, and serum CK shows no change or only modest increases during episodic fasciculations and weakness.

In most cases clinical episodes begin with a brief period of myotonia, with some horses showing prolapse of the third eyelid. Sweating and muscular fasciculations are observed commonly in the flanks, neck, and shoulders. The muscle fasciculations become more generalized as additional muscle groups are involved. Stimulation and attempts to move may exacerbate muscular tremors. Some horses may develop severe muscle cramping. Muscular weakness during episodes is a common characteristic of HYPP. Horses remain standing during mild attacks. In more severe attacks, clinical signs may progress to apparent weakness with swaying, staggering, dog sitting, or recumbency within a few minutes. Heart and respiratory rates may be elevated, and horses may show manifestations of stress (anxious appearance) yet remain relatively bright and alert during episodes. Affected horses usually respond to noise and painful stimuli during clinical manifestations of the disorder. Episodes last for variable periods, usually from 15 to 60 minutes. Several horses have died during acute episodes.¹ Respiratory distress occurs in some animals as a result of paralysis of upper respiratory muscles, and a tracheostomy may be necessary. In addition, young horses that are homozygous for the HYPP trait have been observed to manifest respiratory stridor and periodically may develop obstruction of the upper respiratory tract. Horses homozygous for HYPP may have dysphagia or respiratory distress, and endoscopic findings include pharyngeal collapse and edema, laryngopalatal dislocation, and laryngeal paralysis.⁶⁶ After the episode subsides, horses regain their feet and appear normal with no apparent or minimal gait abnormalities. Although horses with HYPP appear normal between attacks, electromyographic examination of affected horses reveals abnormal fibrillation potentials, complex repetitive discharges with occasional myotonic potentials, and trains of doublets between episodes.^35,67

Etiology

HYPP results from a point mutation that results in a phenylalanine-leucine substitution in a key part of the voltage-dependent skeletal muscle sodium channel alpha subunit.⁶⁰ In horses with HYPP, the resting membrane potential is closer to firing than in normal horses.⁶⁸ Sodium channels are normally briefly activated during the initial phase of the muscle action potential. The HYPP mutation results in a failure of a subpopulation of sodium channels to inactivate when serum potassium concentrations are increased. As a result, an excessive inward flux of sodium and outward flux of potassium ensues, resulting in persistent depolarization of muscle cells and temporary weakness (Fig. 42-6).

Fig. 42-6 A, Explanation for paralytic attacks in horses with hyperkalemic periodic paralysis (HYPP). B, A horse suffering from an episode of HYPP-associated collapse after exposure to a cool rain shower.

Diagnosis

Descent from the stallion Impressive on the sire's or dam’s side in a horse with episodic muscle tremors, weakness, or collapse is strongly suggestive of HYPP. Quarter horse foals born after 1998 that are offspring of an affected parent have a statement recommending DNA testing for HYPP on the Certificate of Registration. In most cases hyperkalemia (6 to 9 mEq/L), hemoconcentration, and mild hyponatremia occur during clinical manifestations of the disease, with normal acid-base balance.³⁵ Serum potassium concentration returns to normal after the abatement of clinical signs. Some affected horses may have normal serum potassium concentrations during minor episodes of muscle fasciculations.⁵⁹ Differential diagnoses for hyperkalemia include delay before sample centrifugation, hemolysis, acidosis, renal failure, severe rhabdomyolysis, and high-intensity exercise.

Because veterinarians may not be present during acute episodes, the definitive test for identifying HYPP is the demonstration of the base-pair sequence substitution in the abnormal segment of the DNA encoding for the alpha subunit of the sodium channel.⁶⁰ Submission of mane or tail hair with hair root should be made to a licensed laboratory such as the Veterinary Genetics Laboratory at the University of California, Davis (www.vgl.ucdavis.edu).

Treatment

Mild exercise can sometimes abort an episode in mild cases or if horses are just beginning to exhibit clinical signs. Feeding grain or corn syrup to stimulate insulin-mediated movement of potassium across cell membranes may also be helpful. Other treatment options that may abort an episode include intramuscular administration of epinephrine (3 mL of 1:1000 per 500 kg) and administration of acetazolamide (3 mg/kg orally [PO] every 8 to 12 hours). Many horses experience spontaneous recovery from episodes of paralysis and appear normal by the time a veterinarian arrives.

In severe cases, administration of calcium gluconate (0.2 to 0.4 mL of a 23% solution per kilogram, diluted in 1 L of 5% dextrose) will often provide immediate improvement. An increase in extracellular calcium concentration raises the muscle membrane threshold potential, which decreases membrane hyperexcitability. To reduce serum potassium, intravenous dextrose (6 mL of a 5% solution per kilogram) alone or combined with sodium bicarbonate (1 to 2 mEq/kg) can be used to enhance intracellular movement of potassium. With severe respiratory obstruction, a tracheostomy may be necessary.

Control

Decreasing dietary potassium and increasing renal losses of potassium are the primary steps taken to prevent HYPP episodes. Feedstuffs to avoid include high-potassium feeds such as alfalfa hay, orchard grass hay, brome hay, soybean meal, sugar molasses, and beet molasses. Optimally, later cuts of timothy or Bermuda grass hay and grains such as oats, corn, wheat, and barley, and beet pulp should be fed in small meals several times a day (Table 42-1). Regular exercise and/or frequent access to a large paddock or yard are also beneficial. Pasture works well for horses with HYPP because the high water content of pasture grass makes it unlikely that horses will consume large amounts of potassium in a short period of time. Ideally, horses with recurrent episodes of HYPP should be fed a balanced diet containing between 0.6% and 1.1% to 1.5% total potassium concentration and meals containing less than 33 g of potassium.^65,69,70 Horses will adapt to diets higher in potassium over a period of 2 weeks and will experience fewer fluctuations in potassium in blood with subsequent decreased frequency of clinical signs.⁶⁹ Because there is wide variation in potassium concentration of forages depending on maturity and soils, it is advisable to have feeds analyzed for potassium concentrations and other nutrients.⁷⁰ The table below contains examples of feeds containing varying concentrations of potassium. Supplement with vitamin E, selenium, salt, and balanced minerals where indicated to meet nutritional requirements. Commercially available complete feeds with a guaranteed K⁺ content may be more convenient for some HYPP horses, especially for owners with few horses.

Table 42-1 Examples of Feed Containing High, Medium, or Low Concentrations of Potassium (K⁺)

DM, Dry matter.

To decrease the frequency of episodes, avoid high-potassium feed; select feed that contains medium to low K⁺. Feeding a balanced ration containing less than 1.5% K⁺ and meals <33 g K⁺ decreases fluctuations of blood K⁺, lowering the frequency of hyperkalemic periodic paralysis symptoms.^12,15,16

For horses with recurrent episodes of muscle fasciculations even with dietary alterations, acetazolamide (2 to 3 mg/kg PO every 8 to 12 hours) or hydrochlorothiazide (0.5 to 1 mg/kg PO every 12 hours) may be helpful. These agents exert their effects through different mechanisms; however, both cause increased renal potassium excretion. In addition, acetazolamide stabilizes blood glucose and potassium by stimulating insulin secretion. Breed registries and other associations may have restrictions on the use of these drugs during competitions, as diuretics may mask prohibited substances.

Prognosis

In most cases HYPP is a manageable disorder, although recurrent bouts may occur and severe episodes can be fatal. Owners of affected horses should be strongly discouraged from breeding these animals for the long-term health of the quarter horse and other breeds. As this is a dominant trait, breeding an affected horse to a normal horse results in a 50% chance of producing a foal with HYPP. All affected horses share the same mutation, regardless of whether or not owners have witnessed signs in their horses.⁷¹ Affected horses are not suitable for young or inexperienced riders. Owners of affected horses should advise veterinarians of HYPP status before anesthesia or procedures requiring heavy sedation, as these circumstances could precipitate an episode of paralysis.

Clinical Signs

Affected horses demonstrate stiffness and cramping in the muscles of locomotion. Pain is a characteristic of the disorder, and affected muscle groups often undergo periodic spasms. In addition, exhausted horses are often dull, depressed, and clinically dehydrated with elevated heart and respiratory rates and persistently elevated body temperature. Common electrolyte abnormalities include hypochloremic metabolic alkalosis with hypokalemia, hypomagnesemia, and low serum ionized calcium concentrations.^73,74,77 Synchronous diaphragmatic flutter (SDF) may be seen in association with cramping.⁷³

Although many of the signs of muscular dysfunction are similar to those of ER, affected horses do not generally develop myoglobinuria.⁷³

Etiology

Factors contributing to cramping are dehydration, electrolyte abnormalities, and disturbances in thermoregulatory and local circulatory function. Whether this disorder is similar to heat cramps seen in human athletes is not known.

Diagnosis

A variety of electrolyte abnormalities occur in affected animals.^73,77 Mild cases are distinguished by the presence of muscle cramps that subside with rest or light exercise in heat-stressed horses. In more severe cases clinical signs of dehydration and shock are often present. Horses with muscle cramping will not have marked elevations in serum CK or AST, nor will they exhibit myoglobinuria. Exhausted horses, however, may progress to develop rhabdomyolysis with marked electrolyte derangements. These horses require immediate treatment.

Treatment

Under most circumstances the mild form of muscle cramping is self-limiting, and the signs abate with rest or light exercise. However, if evidence of other metabolic derangements exists, treatment for these disorders (e.g., plasma volume expansion with oral or intravenous isotonic polyionic fluids, cooling using water and fans) is frequently beneficial to the horse.⁷⁸ Because most horses with this condition are alkalotic, administration of solutions containing sodium bicarbonate is contraindicated. Dietary analysis should be performed to determine the extent of salt and electrolyte supplementation necessary in affected horses. Daily direct addition of 2 oz of sodium chloride and 1 oz of potassium chloride to the feed is recommended for horses with recurrent cramping in addition to electrolyte supplementation before and after endurance rides.

Clinical Signs

The classic sign of SDF is a contraction or twitch in the flank region (unilateral or bilateral) as the diaphragm contracts synchronously with the heart. In severe cases this twitch may produce an audible thumping sound.

The metabolic derangements leading to SDF also may be clinically apparent in some cases. These may include signs of dehydration and volume depletion. Endurance horses with SDF in association with the exhausted horse syndrome may demonstrate dehydration, inappropriate sweating responses, persistently elevated body temperature, depression, anorexia, and aperistalsis.^73,74 In some horses, SDF may be a chronic, recurring problem.⁷⁹

Etiology

A variety of stimuli may result in SDF. These include prolonged exercise, particularly during hot weather; hypocalcemia resulting from lactation, transit, or stress; digestive tract dysfunction; furosemide therapy; trauma; and primary hypoparathyroidism.^79,81 The most consistent metabolic derangement reported in horses with SDF is low serum ionized calcium concentrations, usually associated with hypochloremic metabolic alkalosis.^79,80 Metabolic alkalosis may alter the ratio of free to bound calcium (increasing calcium binding to protein and decreasing ionized calcium), which possibly induces SDF.

SDF occurs in association with atrial depolarization in horses. It has been postulated that fluid, electrolyte, and acid-base derangements may disrupt the normal membrane potential of the phrenic nerve, which passes directly over the atrium, resulting in nerve discharges in response to atrial depolarization.^79,80,82

Treatment

In most cases SDF is a transient event, usually abating when the underlying cause resolves, either spontaneously or in response to treatment.⁷⁹ Most horses undergo rapid remission of signs when given calcium solutions intravenously (IV) as described in the section on hypocalcemia in horses. Although hypomagnesemia is often present with SDF, horses do not respond to magnesium supplementation unless calcium is administered concurrently. Response to therapy is also reflected by improved mental status, return of appetite, and gut motility.⁷⁹

Control

Electrolyte supplementation and some dietary manipulations may help reduce the incidence of SDF in some endurance horses that experience recurrent bouts. Provision of chloride, potassium, and sodium during prolonged exercise may help reduce fluid losses and the metabolic alkalosis that commonly accompanies this form of exercise and frequently occurs in association with SDF. Metabolic alkalosis decreases the amount of free calcium available. Supplementation of calcium and magnesium during endurance rides has been suggested to be helpful in horses prone to SDF.

Alternative approaches involve reduction of dietary calcium in horses prone to SDF for a few days before an endurance ride. It is postulated that this reduction in dietary calcium stimulates the endocrine homeostatic mechanisms and increases osteoclastic activity. In the short term the horse depends less on dietary calcium and is able to mobilize substantial amounts of calcium in response to the demands imposed by the exercise; calcium losses in sweat are overcome by the release of calcium from endogenous storage pools (bone).⁷⁹ Furthermore, horses routinely fed alfalfa hay, which has a relatively high calcium concentration, may be more prone to development of SDF. Limitation of this feedstuff may be indicated in chronically affected horses.

Clinical Signs

Clinical signs are variable and include increased muscle tone; a stiff, stilted gait; rear limb ataxia; muscle fasciculations (especially temporal, masseter, and triceps muscles); trismus; dysphagia; salivation; anxiety; profuse sweating; tachycardia; elevated body temperature; cardiac dysrhythmias; SDF; convulsions; coma; and death.^83,84 Clinical signs may be remarkably similar to some of those seen with tetanus. This disorder may be progressive (in lactating mares in particular) over a 24- to 48-hour period, and some animals die. Clinical signs are related to the magnitude of the serum calcium concentration. Increased excitability is usually the only sign when values are below normal but above 8 mg/dL. Values of 5 to 8 mg/dL usually produce tetanic spasms and incoordination. Concentrations below 5 mg/dL usually result in recumbency and stupor.

Etiology

Loss of calcium in milk, especially in mares that produce large amounts of milk, seems to predispose to this disorder.^83,84 Other factors such as heavily lactating mares grazing lush pastures, hard work, prolonged transport, and ingestion of blister beetles (cantharidin toxicosis) may precipitate attacks.

Diagnosis

Clinical signs often are highly suggestive of hypocalcemia in affected horses. Historic aspects such as lactation, previous prolonged exercise, or transport also may direct the clinician to the suspected diagnosis.⁸³

Definitive diagnosis depends on laboratory demonstration of hypocalcemia, with total calcium concentrations as low as 4 to 6 mg/dL in some cases. In addition, metabolic alkalosis, hypomagnesemia or hypermagnesemia, and hyperphosphatemia or hypophosphatemia have all been found in association with hypocalcemia in horses.⁸³ These alterations may need correction before a return to normal function is seen in some affected animals.

Treatment

Although many animals with mild cases recover without specific treatment, in others this disorder may be life-threatening. Therefore therapy is to be encouraged in most cases. Treatment involves the intravenous administration of calcium solutions such as 20% calcium borogluconate or those recommended for the treatment of parturient paresis in cattle.⁸³ Administration of these solutions at the rate of 250 to 500 mL/500 kg diluted 1:4 with saline or dextrose often results in full recovery, although in some cases it may take several days.⁸³ Relapses do occur. These preparations should be administered slowly in conjunction with close monitoring of the cardiovascular response. Dilution in saline or dextrose before infusion decreases the chance of cardiotoxicity. Normally there is a positive inotropic effect in response to calcium administration.⁸⁵ However, alterations in rate or rhythm provide evidence to suspend the infusion. If no response to an initial infusion occurs, a second dose may be given 15 to 30 minutes later. Most cases respond to this form of therapy, although in some cases in which signs persist, repeated treatments may be necessary.

Clostridial Myonecrosis

STEVEN M. PARISH

STEPHANIE J. VALBERG

Various species of clostridial organisms cause acute myonecrosis in many farm animal species. Infections are characterized by a rapid clinical course, fever, systemic toxemia, and high mortality.^86-88 Clostridial diseases are infectious but not contagious. Specific bacteria associated with clostridial myonecrosis include Clostridium chauvoei (Clostridium welchii), Clostridium septicum, Clostridium sordelli, and occasionally Clostridium novyi type B, Clostridium perfringens type A, and Clostridium carnis. Mixed infections involving several agents are common.⁸⁹ Synonyms for clostridial diseases include blackleg, malignant edema, false blackleg, gas gangrene, and gangrene. Although there may at times be distinct differences among the specific disease syndromes associated with the different clostridial agents, the pathophysiology of these diseases is similar enough to be covered under the general topic of clostridial myonecrosis.

Clinical Signs

Commonly, clostridial myonecrosis is rapidly progressive with the development of tremors, ataxia, dyspnea, recumbency, coma, and death within 12 to 24 hours. Therefore many affected animals may be found prostrate or dead.^86,87 Mortality may approach 100%. Affected animals that are still alive are usually severely depressed, febrile (40° C to 41° C [104° F to 106° F]), tachypneic, anorectic, and lame. These signs are associated with a rapidly developing muscle infection and toxemia. There is usually only one primary site of infection in an affected animal. Any skeletal muscle group in the body can be involved, but most infections affect the limb or trunk muscles. Occasionally muscles such as those around the vulva, tongue, and diaphragm can be involved, or the udder in a cow may be the primary site of sepsis. Areas around recent injections are common sites of myonecrosis in the horse.^88,90 Initially the skin over the area may be swollen, hot, and discolored; however, as the disease progresses the skin over the area may become cool and insensitive with progressive sloughing. Crepitus may be detectable, indicating subcutaneous gas production. If a wound is present, malodorous, serosanguineous fluid may discharge (Fig. 42-7). Aspiration of the swelling often reveals fluid with similar qualities.

Fig. 42-7 Clostridial myositis in the right gluteal muscle after an injection of flunixin meglumine which has progressed to involve the biceps femoris muscle. Fenestrations were created for debridement.

Clostridial myonecrosis generally has characteristic pathologic lesions that are absent in most other conditions, making diagnosis relatively straightforward. Differential diagnoses may include other fulminant disease processes in which there is rapid debilitation or death of the animal.

Acute Rhabdomyolysis

Severe acute generalized rhabdomyolysis has been reported to occur in quarter horses less than 7 years of age.^93,94 Affected horses have evidence of submandibular lymphadenopathy and/or guttural pouch empyema caused by S. equi. Horses develop a stiff gait that progresses rapidly to markedly firm, swollen, painful epaxial and gluteal muscles. In the majority of reported cases, animals became recumbent and unable to rise, and develop unrelenting pain necessitating euthanasia within 24 to 48 hours of hospitalization (Fig. 42-8). Hematologic abnormalities include mature neutrophilia, hyperfibrinogenemia, and marked elevations in CK (115,000 to 587,000 U/L), and AST levels (600 to 14,500 U/L). Titers to the M protein of S. equi are low in affected horses, unless horses are recently vaccinated for strangles. Titers to another protein called myosin binding protein were found to be high in a small number of horses that were tested.⁹³

Fig. 42-8 A horse in severe pain and unable to rise because of acute rhabdomyolysis concurrent with guttural pouch empyema from Streptococcus equi.

At postmortem examination large, pale areas of necrotic muscle are evident in hindlimb and lumbar muscles. The histopathologic lesions are characterized by severe acute myonecrosis with a degree of macrophage infiltration. Sublumbar muscles often show the most severe and chronic necrosis, as indicated by greater macrophage infiltration of myofibers.

Two causes have been proposed. The first possibility is a toxic shock—like reaction arising from profound nonspecific T cell stimulation by streptococcal superantigens with the release of high levels of inflammatory cytokines. An alternative explanation for rhabdomyolysis may be a bacteremia with local multiplication and production of exotoxins or proteases within skeletal muscle. S. equi virulence factors that may account for muscle necrosis include an unidentified cytotoxic protein, several proteases, streptokinase, and streptolysin S.⁹⁵ Although, S. equi has not been cultured in skeletal muscle from horses with rhabdomyolysis, S. equi bacteria have been identified in affected muscle using immunofluorescent stains for both Lancefield group C carbohydrate and S. equi M protein.⁹³ There is currently no evidence that the S. equi involved is an atypical genetic strain of S. equi.⁹⁶

A high mortality rate has been reported in horses receiving intravenous penicillin therapy once clinical signs of strangles and myopathy were well established. It is possible that early recognition of the signs of muscle stiffness in horses with S. equi infections and prompt aggressive treatment may be required for a successful outcome. Although streptococcal species are exquisitely susceptible to β-lactam antibiotics, a mortality rate of 85% has been reported in human group A streptococcal myositis despite penicillin treatment.⁹⁷ An antimicrobial that inhibits protein synthesis, such as rifampin, combined with intravenous penicillin might enhance survival rates in horses with S. equi rhabdomyolysis. In addition, flushing infected guttural pouches and draining abscessed lymph nodes will diminish the bacterial load. Nonsteroidal antiinflammatory drugs (NSAIDs) and possibly high doses of short-acting corticosteroids may assist in diminishing the inflammatory response. Control of unrelenting pain is a major challenge in horses with severe rhabdomyolysis. Constant rate infusion of lidocaine, detomidine, or ketamine may provide better anxiety and pain relief than periodic injections of tranquilizers. Horses should be placed in a deeply bedded stall and moved from side to side every 4 hours if they are unable to rise. Some horses may benefit from a sling if they will bear weight on their hindlimbs when assisted to stand.

Infarctive Purpura Hemorrhagica

STEPHANIE J. VALBERG

Infarctive purpura hemorrhagica (IPH) is a severe form of purpura with a high fatality rate. In one study, prevalence of IPH was 3 of 53 cases of purpura.⁹⁸ Exposure to S. equi within 3 weeks of presentation, vaccination for S. equi, and a concurrent Salmonella infantum infection are reported inciting causes. Titers for serum enzyme-linked immunosorbent assay (ELISA) M protein may be markedly elevated.⁹⁹ The primary presenting complaint is often painful lameness with limb swelling, muscle stiffness, and/or colic. Careful physical examination reveals classic signs of purpura hemorrhagica such as petechia, oral infarctions resembling ulcers, and moderate well-demarcated limb edema; however, in addition, horses with IPH have focal firm intramuscular swellings (Fig. 42-9). Horses with evidence of colic may have markedly decreased borborygmi and hemorrhagic gastric reflux.

Fig. 42-9 Marked swelling of the left adductor muscles of the thigh caused by infarctive purpura hemorrhagica.

Hematologic abnormalities include a leukocytosis characterized by a neutrophilia with a left shift and toxic change, hyperproteinemia, hypoalbuminemia, and marked elevations in CK (47,000 to 280,000 U/L) and AST (960 to 7000 U/L) levels.^94,99 Peritoneal fluid obtained by abdominocentesis may be normal or may have an increased total protein, nucleated cell count, and RBC count if gastrointestinal infarction is present. Ultrasonographic examination of swollen muscle reveals focal hypoechoic lesions within muscle tissue. Biopsies of abnormal muscle show diffuse acute coagulative necrosis, whereas samples from palpably normal muscle tissue show no pathologic abnormalities.

Postmortem findings of horses with IPH include infarction of the skeletal musculature (Fig. 42-10), skin, gastrointestinal tract, pancreas, and lungs and S. equi abscessation of a lymph node. Definitive histopathologic findings include leukocytoclastic vasculitis and acute coagulative necrosis resembling infarction in numerous tissues.⁹⁹ IPH resembles Henoch-Schönlein purpura in humans, which is characterized by infarctive vasculitis of the skin, kidneys, and gastrointestinal tract resulting from IgA immune complex deposition. Immune complexes are present in the sera of horses with PH that appear to primarily be composed of IgM or IgA and streptococcal M protein.¹⁰⁰ Deposition of complement near immune complexes in vessel walls may result in cell membrane destruction, cell death, and vascular occlusion. The distinctive feature of IPH in horses is the extensive infarction of skeletal muscle and consequently marked elevation in serum CK and AST activity.

Fig. 42-10 Numerous infarctions of skeletal muscle caused by infarctive purpura hemorrhagica. (Photo courtesy of Dr. Beth Davis.)

Early recognition of signs and aggressive antibiotic and corticosteroid treatment are essential to combat the high fatality rate with IHP. Treatment of Henoch-Schönlein purpura in humans, including cases with intestinal infarctions, involves high-dose intravenous pulse therapy with methylprednisolone followed by oral corticosteroids plus immunosuppressive agents such as cyclophosphamide and azathioprine. One horse with IPH was successfully treated with penicillin, NSAIDs, and 3 weeks of dexamethasone (0.1 to 0.07 mg/kg) followed by a 10-week tapering course of oral prednisolone (2 mg/kg initially).⁹⁹

Immune-Mediated Polymyositis

STEPHANIE J. VALBERG

Immune-mediated polymyositis (IMM) has recently been reported in horses.^33,101,102 The majority of horses are of quarter horse bloodlines and are either ≤8 years of age or ≥16 years of age. In approximately one third of horses with IMM, a triggering factor appears to have been exposure to S. equi or a respiratory disease. The most prominent clinical sign of IMM in quarter horses is rapid onset of muscle atrophy, particularly affecting the back and croup muscles (Fig. 42-11), accompanied by stiffness and malaise. Atrophy may progress to involve 50% of the horses’ muscle mass within a week and may lead to generalized weakness. Focal symmetric atrophy of cervical muscles has been reported in a pony with IMM.

Fig. 42-11 Symmetric atrophy of the gluteal muscles with immune-mediated myositis. (Photo courtesy of Dr. Beth Davis.)

Hematologic abnormalities are relatively minor in affected horses and are usually restricted to mild to moderate elevations in serum CK and AST activity. However, in some cases serum muscle enzyme activities are normal. Muscle biopsy of epaxial and gluteal muscles shows lymphocyte vasculitis, anguloid atrophy, lymphocyte myofiber infiltration, fiber necrosis with macrophage infiltration and regeneration. Biopsies of semitendinosus or membranous muscles may show some evidence of atrophy and vasculitis, but significant inflammatory infiltrates may be absent in these tissues. The extent of the inflammatory infiltrates in epaxial muscles is such that a diagnosis can often be established from several formalin-fixed Tru-Cut samples.

The lymphocytic infiltrate seen in muscle samples from horses with IMM contains a high CD4:CD8 ratio with no evidence of immunoglobulin G (IgG) binding to myofibers.³³ The reason why specific muscle groups are affected in horses with IMM is unclear.

Horses with concurrent evidence of streptococcal infection should be treated with antibiotics. It is likely prudent to avoid intramuscular injections. Administration of corticosteroids appears to immediately improve signs of malaise and inappetence and prevented further progression of muscle atrophy. Recommended dosages are dexamethasone 0.05 mg/kg for 3 days, followed by prednisolone 1 mg/kg for 7 to 10 days tapered by 100 mg/week over 1 month. Serum CK activity often normalizes after 7 to 10 days. Muscle mass usually gradually recovers over 2 to 3 months. Horses that are not treated with corticosteroids may develop extensive muscle atrophy, but in many cases muscle mass will gradually recover. Recurrence of atrophy in susceptible horses is common and may require reintroduction of corticosteroid therapy. Some horses develop focal residual muscle atrophy.

Epidemiology

The life cycle of the parasite involves two hosts: carnivores as the definitive host and cattle or horses as the intermediate host. Three species of sarcocysts, Sarcocystis cruzi, Sarcocystis hirsuta, and Sarcocystis hominis, are known to infect cattle; canids, felids, and primates are the definitive hosts for these species. Three sarcocyst species have been described in horse muscle: Sarcocystis bertrami, Sarcocystis equicanis, and Sarcocystis fayeri. Dogs have been identified as the definitive host for these equine sarcocyst species. In sheep and goats, Sarcocystis ovicanis and Sarcocystis capracanis have been described, with canids as the definitive host.

The most common mechanism for natural infection in cattle is by ingestion of feeds contaminated with infected carnivore feces. Feedlot workers using feed bunks as toilets may be a source of exposure for feedlot cattle.

NUTRITIONAL AND TOXIC RHABDOMYOLYSIS

Nutritional Myodegeneration

JOHN MAAS

STEPHANIE J. VALBERG

Definition and Etiology

Nutritional myodegeneration (NMD; white muscle disease, stiff lamb disease, nutritional muscular dystrophy) is a peracute to subacute myodegenerative disease of cardiac and skeletal muscle caused by a dietary deficiency of selenium or vitamin E.^115-118 This syndrome occurs in most farm animal species but is most commonly found in young, rapidly growing calves, lambs, kids, and foals, particularly those born to dams that consumed selenium-deficient diets during gestation. The disease has also been reported in yearling and adult cattle and has been suspected in adult horses.

Selenium and vitamin E appear to be synergistic in preventing NMD. However, on the basis of prophylaxis and response to treatment, selenium deficiency appears to be more important.

Clinical Signs

There are two distinct syndromes of NMD: a cardiac form and a skeletal form. The cardiac form is associated with signs of peracute to acute myocardial decompensation, but the skeletal form is associated with skeletal myasthenia and difficulty in ambulation. In both forms the most rapidly growing animals in the herd or flock are affected commonly.

Most cases of NMD are diagnosed during the first year of life. Evidence also suggests that an in utero form of NMD may occur, with affected animals born with myodegeneration or developing myodegeneration soon after birth.

The cardiac form of NMD usually has a sudden onset; it is usually diagnosed in the animal that is either in a state of severe debilitation or dead. The cardiac form often manifests with lesions in the heart, diaphragm, and intercostal muscles. In dead animals there may be evidence of sudden agonal death. In living animals there is usually a rapid onset of depression and respiratory distress. A foamy nasal discharge, possibly bloodstained, is seen often, resulting from pulmonary edema and dyspnea. Profound weakness, recumbency, and a rapid, often irregular heartbeat may be detected. Cardiac murmurs are heard occasionally on auscultation. Rectal temperature is normal usually or may be elevated because of increased muscular work associated with respiratory efforts. Most calves are depressed, with dyspnea, tachypnea, and increased rectal temperature. These cases must be differentiated from pneumonia. The clinical course is frequently short, with death occurring commonly in less than 24 hours despite medical therapy. Occasionally an animal responds to therapy, but such animals often fail to thrive because of residual myocardial damage. Animals with predominantly cardiac signs may also manifest mild skeletal muscle problems associated with NMD.

The skeletal form of NMD frequently has a slower onset characterized by muscular weakness or stiffness. Animals may be recumbent and unable to stand. Those that are able to rise on their own or with assistance show muscle weakness, trembling of limb muscles, or stiffness. Stiffness is more pronounced as fibrosis occurs after an acute attack. Most affected animals are able to remain standing only for short periods. Supporting muscle groups of the frontlimbs and hindlimbs may appear swollen and may be hard and painful on palpation. Commonly affected muscle groups may include the gastrocnemius, semitendinosus, semimembranosus, and biceps femoris and muscles of the lumbar, gluteal, and neck regions. If the diaphragm and intercostal muscles are affected, the animal may show respiratory distress and evidence of increased abdominal effort when breathing. Cardiomyopathy occurs often, along with changes in the diaphragm and intercostal muscles. The muscles of the tongue may be involved, resulting in dysphagia. Dysphagia may be the only sign in some affected animals; foals and lambs are presented in this condition more often than calves. The rectal temperature is normal or moderately elevated, resulting from pain and the release of myoglobin associated with myodegeneration. Some animals exhibit what appears to be abdominal pain with violent thrashing. Heart sounds are normal usually, although the heart rate may be increased; however, myocardial damage and signs consistent with cardiac dysfunction may be present in cases of skeletal NMD. Animals with skeletal NMD often respond favorably to treatment and rest. Improvement is evident after a few days, and within 3 to 5 days animals can often stand and walk.

Differentiation of NMD from other diseases causing sudden death or recumbency is important. Infectious diseases resulting in septicemia, pneumonia, and toxemia may have similar presenting signs. Acute heart failure resulting from cardiac anomalies, cardiotoxic agents such as those found in plants (oleander, cassia, yew, white snakeroot, and gossypol toxicity from cottonseed), and the ionophore antibiotics should also be considered. Other diseases that cause stiffness of gait, weakness, and recumbency with no change in mental status must be differentiated from NMD. Spinal cord compression, cerebellar disease, suppurative and nonsuppurative meningitis or myelitis, polyarthritis, neurotoxins such as organophosphates, tetanus, pelvic fractures, and parasitic myositis all can cause recumbency. Clostridial myositis and traumatic injuries to muscles, long bones, and joints should be considered. Diseases characterized by abdominal pain may resemble NMD, because they may also cause stiffness of gait, weakness, and recumbency.

Clinical Pathology

Significantly elevated CK, AST, and LDH activities occur during the acute phase of myodegeneration. In clinical cases CK levels are in the thousands of international units per liter. In animals recumbent because of a disease other than NMD, CK is elevated only into hundreds of or perhaps a few thousand international units per liter in heavy animals. Progressively decreasing activities of CK can be used as a prognostic indicator of a reduction in the myodegenerative process.

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In foals, other reported abnormal laboratory findings include variable hyperkalemia, hyperphosphatemia, hyponatremia, and hypochloremia.¹¹⁸ Myoglobinuria is found often in foals and yearling cattle with NMD. Myoglobinuria is less common in younger calves. Evidence of dehydration, reflected by elevated serum protein concentrations and hemoconcentration, is common in nonambulatory animals unable to nurse or drink water.

The selenium status of an animal or members of a group can be determined by laboratory analysis of tissue biopsies and whole blood (Table 42-2). Vitamin E status can be determined on serum or plasma samples. In the clinical setting, blood samples are more frequently used. Blood or plasma samples provide information about the circulating levels of selenium and vitamin E, respectively, and are satisfactory for assessing intermediate to long-term nutritional status; however, short-term supplementation or injections can confuse interpretation of circulating levels of selenium or vitamin E. Tissue biopsies and tissue specimens obtained at slaughter and necropsy provide an indication of storage and can also be used to assess herd status and success of supplementation. Whole blood selenium analysis is preferred over plasma and serum.¹¹⁹ Whole blood selenium concentrations ranging from 0.07 to greater than 0.1 ppm (μg/g) are considered normal in large animals. Normal liver concentrations of selenium are 0.9 to 1.75 μg/g of dry matter (DM), 0.9 to 3.5 μg/g DM, and 1.05 to 3.5 μg/g DM for cattle, sheep, and horses, respectively.¹²⁰ Selenium-dependent glutathione peroxidase (GSH-Px) formed in the red cells during erythropoiesis also provides an index of body selenium status. Cross-reacting enzymes, such as glutathione reductase, are not found in erythrocytes. Adequate GSH-Px activities are greater than 30 U/mg of hemoglobin per minute in cattle, 60 to 180 U/mg of hemoglobin per minute in sheep, and 20 to 50 U/mg of hemoglobin per minute in horses. However, GSH-Px reference values are specific only to the laboratory where the analysis is performed and must be validated by comparison with blood selenium concentration. The activity of GSH-Px in RBCs of domestic species remains constant for 4 to 6 days when maintained at 39° F (4° C); after this time significant decreases occur. The critical concentration of vitamin E (α-tocopherol) in plasma is 1.1 to 2 ppm (μg/g) in large animals. Vitamin E deteriorates rapidly in plasma samples. Therefore plasma samples for α-tocopherol analysis need to be put on ice immediately, protected from the light by wrapping in tin foil, and stored (−21° F [−70° C]) if analysis is to be delayed.

Table 42-2 Deficient, Marginal, and Normal Concentrations of Whole Blood Selenium and Glutathione Peroxidase Activities in Sheep and Cattle ^67,71

Pathophysiology

The effects of selenium and vitamin E deficiency have been postulated to result, at least in part, from the destruction of cell membranes and proteins leading to a loss of cellular integrity.^115,121 Selenium, which has been shown to be an essential component of at least five selenoproteins¹²² (three glutathione peroxidase enzymes, a deiodinase in liver and kidney that converts T₄ to T₃, and selenoprotein-P, a plasma protein of unknown function), and vitamin E (α-tocopherol) serve as biologic antioxidants. During normal cellular metabolism highly reactive forms of oxygen (free radicals) are produced. These include hydrogen peroxide, hydroperoxides, lipoperoxides, superoxide, various hydroxy radicals, and singlet oxygen. Vitamin E is active within the cell membrane as a lipid-soluble antioxidant that scavenges free radicals that otherwise might react with unsaturated fatty acids to form lipid hydroperoxides. In contrast, GSH-Px destroys hydrogen peroxide and lipoperoxides that have already been formed and converts them to H₂O or relatively harmless alcohols. Other enzymes such as catalase and superoxide dismutase are also involved in this protective process.

Apparently important interrelationships exist among the selenium and vitamin E status of the animal, the level of polyunsaturated fatty acids (PUFAs) in the diet,^115,121 and NMD, particularly in ruminants.¹¹⁵ PUFAs of dietary origin can undergo peroxidation to hydroperoxides, forming toxic free radicals. During active growing periods pasture grasses and plants contain high concentrations of linolenic acid, a PUFA. Under normal conditions the rumen is thought to be important in saturating dietary unsaturated fatty acids. However, concentrations of PUFAs in the plasma often increase in calves recently turned out to pasture, possibly enhancing the chance of free radical formation and tissue damage. This indicates that the capacity of the various protective mechanisms can be overwhelmed by dietary factors such as high levels of PUFAs. It is not surprising that selenium- or vitamin E—deficient animals may be at a greatly increased risk of tissue oxidative damage when exposed to such diets. However, the potential for induction of NMD by this process should not be overemphasized, because calves on a milk diet may be severely affected.

The precise interrelationships among selenium, vitamin E, other metabolic factors, and triggering mechanisms in NMD are not fully understood because many animals deficient in selenium or vitamin E have no evidence of muscle disease. In certain situations deficiencies of both selenium and vitamin E are necessary for disease to occur. In other animals NMD can occur when a deficiency of only one of the agents is present and levels of the other are normal in blood and tissues.

Epidemiology

NMD occurs in all farm animals and is seen most commonly in young, rapidly growing calves, lambs, kids, and foals. The occurrence of NMD in very young animals usually reflects a deficiency in their dams during a substantial portion, if not all, of the gestation period. The selenium and GSH-Px values of neonatal calves tend to be similar to those of their dams.^123,124

Marginally to severely selenium-deficient areas occur throughout a large portion of the United States and other countries of the world.^115,125 Forages and grains produced in the northeastern and eastern seaboards and northwestern regions of the United States are particularly deficient because of low soil levels of selenium. Acid soils and those originating from igneous (volcanic) rock are often selenium deficient, as are those having high sulfur content or soils treated with sulfur-containing fertilizers. Sulfur inhibits selenium uptake by plants and absorption by animals. Different forages in a specific area will also vary in their selenium content. Legumes take up less selenium than do grasses. Also, forage selenium concentrations are lowest during periods of rapid growth such as in the spring and during times of highest rainfall.

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Vitamin E deficiency occurs most commonly when animals are fed poor-quality hay, straw, or root crops. Grain treated with propionic acid and having high moisture content is commonly vitamin E deficient. Storage of grain crops for extended periods results in marked decreases in their vitamin E content. Calves fed milk replacers that contain fish oil, linseed oil, soybean oil, or corn oil, all of which increase the dietary levels of unsaturated fatty acids, require increased dietary supplementation of vitamin E to avoid deficiency. In contrast, cereal grains, green growing pastures, and properly prepared hay usually have adequate vitamin E.

In young ruminants the majority of cases of NMD occur in calves 2 to 4 months of age during the spring and summer months in association with exercise when at pasture, although congenital and perinatal cases do occur. Histologic lesions consistent with NMD have also been seen in late-term aborted fetuses.¹²⁰ These findings are suggestive of an in utero form of NMD in large animals. Yearling cattle housed during the winter, fed diets high in grain with high moisture content, and then turned out in the spring may also be affected. Lambs born in confinement and turned out to pasture at 1 to 3 weeks of age frequently develop signs of NMD. Stresses such as transport, herding, and driving may also precipitate signs of NMD. In horses, NMD generally occurs during the first year of life, with most cases observed from birth to weaning.^116,126

Necropsy Findings

Bilaterally symmetric myodegeneration is a consistent finding in NMD. Skeletal muscle degeneration is characterized by pale discoloration and a dry appearance of affected muscle, white streaks in muscle bundles, calcification, and intramuscular edema (Fig. 42-12). The white streaks seen in muscle bundles represent bands of coagulation necrosis or, in chronic cases in which insults may have occurred weeks before, may represent fibrosis and calcification. Affected muscle bundles are often adjacent to apparently normal or minimally affected muscle. The color of normal muscle in young calves is pale because of reduced myoglobin concentrations; therefore close inspection and histologic examination are necessary in cases of suspected NMD. Cardiac muscle undergoes changes similar to those of skeletal muscle. In calves the left ventricle and septum are most frequently involved (Fig. 42-13), but in lambs both ventricles are usually involved. Myocardial degeneration usually extends through the full thickness of the ventricular wall.

Fig. 42-12 White streaks within diffusely pale skeletal muscle caused by nutritional myodegeneration.

Fig. 42-13 Pale areas of muscle necrosis in the myocardium of a calf with nutritional myodegeneration.

Histologically, affected muscle fibers may be hypercontracted and fragmented with some mineralization of muscle fibers and others undergoing macrophage infiltration. In yearling cattle, type I muscle cells are more frequently affected.

Treatment and Prognosis

In the cardiac form of NMD myocardial damage is often extensive and incompatible with life. Only rarely is treatment successful. In contrast, the skeletal form of NMD is more generally amenable to treatment, although the prognosis for clinical recovery from the skeletal form of NMD is guarded and often depends on whether secondary complications such as respiratory disease develop. In all cases of NMD, therapy should involve specific supplementation with selenium and vitamin E and general supportive care.

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Alleviation of selenium-responsive NMD requires the use of injectable selenium products. These are available with selenium concentrations varying from 1 mg of selenium per milliliter to 5 mg/mL, with all products containing 50 mg/mL (68 IU) of vitamin E as DL-α-tocopheryl acetate. The label dose for selenium is 0.055 to 0.067 mg/kg (2.5 to 3 mg/45 kg) of body weight given intramuscularly or subcutaneously. Dosage of these injectable products should not be greatly increased above the label dosage to prevent an inadvertent selenium toxicosis. However, when using the vitamin E and selenium combinations, the amount of vitamin E in these combination products is present as a preservative for the solution and is therefore insufficient for vitamin E supplementation. Injectable vitamin E products are now available that contain 300 IU of vitamin E per milliliter as D-α-tocopherol* and 500 IU of vitamin E per milliliter as D-α-tocopherol.^† Administration of these products increases the tissue and/or plasma level of vitamin E activity for approximately 3 weeks in farm animals. The bioavailability of vitamin E from injectable products is dependent on the form of vitamin E (the alcohol form, D-α-tocopherol, being the most active) and the amount and quality of the solution emulsifier used. Bioavailability data on injectable vitamin E products should receive careful clinical consideration. Oral supplementation is the general approach to provide additional dietary levels of vitamin E. Recommended levels of supplementation for calves range from 15 to 60 mg of DL-α-tocopheryl acetate per kilogram of dry feed.¹²⁵ For horses a daily supplement of 600 to 1800 mg of DL-α-tocopheryl acetate has been recommended.¹²⁶ Oral α-tocopherol is now available for all species and contains 500 IU of vitamin E per milliliter.^‡ The recommended dose of this product is 1 to 3 IU/lb of body weight. Studies with injectable selenium show that absorption and distribution occur rapidly.¹²⁷ It is thought that incorporation of selenium into heart, skeletal muscle, and other tissues may be very rapid and could account for the rapid improvement in clinical signs seen in reversible cases. The discovery of four new selenoproteins may help explain these clinical observations.¹²² This improvement can occur even though blood GSH-Px activity rises slowly because of the delay caused by erythropoiesis and release of red cells from the bone marrow.¹²⁷ However, platelet GSH-Px activity rises within hours and may be a more accurate reflection of changes in muscle and other tissues.

Supportive therapy may include administration of antibiotics to help combat secondary pneumonia and infected decubital lesions that are common in recumbent patients. Provision of adequate energy intake and attention to the fluid and electrolyte balance are of critical importance if recovery is to be successful.

Prevention and Control

The prevention and control of NMD are achieved through supplementation of selenium and vitamin E. Although selenium deficiency is implicated more commonly in most NMD syndromes, attempts to ensure adequate provision of selenium and vitamin E should be undertaken. Under current U.S. federal regulations, selenium can be incorporated into the total ration of ruminants and other species to a level of 0.3 parts per million (ppm). In salt and mineral mixtures formulated for free-choice feeding, selenium can be incorporated at 90 ppm for sheep and 120 ppm for cattle. In certain areas or in herds, levels as high as 200 ppm selenium in salt and mineral mixtures may be necessary to maintain adequate selenium levels in the animals. Federal regulations limit the intake of supplemental selenium by sheep to 0.7 mg/head/day and by cattle to 3 mg/head/day. The use in ruminants of ruminoreticular boluses, which release a precise amount of selenium daily, has been commonplace in many countries of the world; however, under current U.S. Food and Drug Administration (FDA) guidelines these products are not available in the United States. These slow-release boluses can replace supplementation by salt mixtures or by injections and are extremely valuable in extensive grazing systems. Alternatively, individual animals can be supplemented by periodic (30- to 60-day intervals) injections of selenium and vitamin E preparations to help maintain body concentrations and assist in transplacental transfer of selenium to the fetus.

Oral supplementation for horses at 1 mg of selenium per day increases blood selenium concentrations above levels known to be associated with NMD.¹²⁸ Supplementation of pregnant mares is advised in areas known to be selenium deficient; however, only limited selenium may cross the placenta.¹¹⁷ Supplementation during lactation increases the levels of selenium in milk and thus provides a potential means of selenium supplementation in foals; however, evidence in cattle indicates that this increased level of selenium in milk may not meet nutrient requirements.^123-125

Regardless of the method of supplementation, periodic blood (or tissue) sampling of animals at risk is recommended to ensure desired levels of selenium. In high-risk areas, samples should be taken every 60 to 90 days to determine selenium status in susceptible animals and every 6 to 12 months to monitor supplementation. On the basis of these assessments, adjustments to the rate or extent of selenium supplementation may be made.

Feeding animals properly prepared and stored hay and grain or allowing them access to high-quality green forage should ensure adequate vitamin E intake.

Toxic Causes of Rhabdomyolysis

MICHAEL MURPHY

STEPHANIE J. VALBERG

Ingestion of toxic substances in feed or forage is a common cause of toxic rhabdomyolysis.

Toxic Plants

Gossypol is of greatest significance in swine. Monogastrics, including young calves, should not ingest feed containing more than 200 ppm of gossypol. Mature ruminants may tolerate 20 g of gossypol per day. This normally amounts to 5 to 6 lb of whole cottonseed per head per day.¹²⁹ Two common forage toxins that cause myonecrosis are Cassia species and tremetone-containing plants. Cassia obtusifolia (sicklepod) is prevalent in the southeastern United States, and ingestion of seeds by swine, ruminants, or horses may cause a degenerative myopathy and cardiomyopathy with evidence of myofiber atrophy, segmental necrosis, and mitochondrial disruption.¹³⁰ White snakeroot (Eupatorium rugosum) grows in shaded areas of the eastern and central United States,¹³¹ and rayless goldenrod (Isocoma wrightii) is common in the Southwest on open pastures. These tremetone-containing plants can cause a fatal cardiomyopathy and severe skeletal muscle degeneration in horses when ingested at 0.5% to 2% of body weight.^132,133 Other grazing livestock are likely to be affected by ingestion of these plants at 2% of body weight. Tremetone remains active in hay and in the stalks of the dead plants on pasture, so both the fresh and the dried form of the plants should be kept from livestock.¹³⁴ Microsomal activation of the toxin in the liver may be necessary for toxic effects.¹³²

Atypical Myopathy

A highly fatal myopathy that occurs in large numbers of horses on pasture during cold wet conditions occurs in the fall in Europe and the midwestern United States.^135-139 Terms such as atypical myopathy, atypical myoglobinuria, and pasture myopathy have been used to describe this syndrome. Affected horses are usually kept on pasture for more than 12 hours per day without snow cover when minimum daily temperatures range from 29° F to 56° F and weather is often inclement. Clinical signs develop acutely and include muscular weakness, sweating, fasciculations, stiffness, tachycardia, tachypnea, recumbency, and, when urine is observed, myoglobinuria. The most notable change in serum biochemistry is a marked increase in serum CK and AST activity. Serum troponin I concentrations may be high, indicating cardiomyopathy. Postmortem findings include extensive necrosis in postural and respiratory muscles and, in 50% or more of cases, myocardium (Fig. 42-14). Serum vitamin and selenium as well as urine tremetone concentrations are normal. Frozen sections of myocardium, intercostal, diaphragm, or deep postural muscles show marked intracellular lipid accumulation in oxidative fibers (oil red O stain). A few horses have survived with aggressive fluid therapy, antioxidant, and antiinflammatory treatment including dimethyl sulfoxide (DMSO), vitamin E, vitamin C, and NSAIDs.¹³⁵ The cause of pasture myopathy is suspected to be an ingested or enterically produced toxin (e.g., bacterial toxin, mycotoxin, or phytotoxin that disrupts lipid metabolism).¹³⁸ Soil-borne ionophores or clostridial toxins have been suggested as possible causes.¹³⁹

Fig. 42-14 The lower muscle group shows severe compartmental muscle necrosis resulting in total pallor and friable muscle tissue. In comparison the upper muscle group is normal in color and grossly unaffected.

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IONOPHORES

Ionophores are commonly added to feeds for their growth promotion and coccidiostat properties. Species differences in sensitivity to ionophores and the variety of ionophores on the market have led to several cases of ionophore-induced toxicosis. Rhabdomyolysis and cardiomyopathies are common sequelae to ionophore toxicosis. Experimental studies have indicated that LD₅₀ values for monensin are 2 to 3, 12, 17, 26, and 21 to 36, for horses, sheep, pigs, goats, and cattle, respectively. Feed concentrations of 100 g/ton and 400 g/ton have been fatal to sheep and cattle, respectively.^129,140 Newborn calves given 100 mg of lasalocid three times daily for treatment of cryptosporidiosis experience muscle necrosis.¹⁴¹ Other ionophores include naracin, salinomycin, and laidlomycin. Ionophores are quickly eliminated from the body after exposure.

CHEMICAL TOXINS

Several chemical agents have been associated with muscle necrosis on rare occasions. Parenteral products, insecticides, and feed contaminants have been implicated. Muscle necrosis has been reported in cattle and pigs that received injections of lidocaine, diazepam, digoxin, levamisole, nitroclofene, pentazocine, thiazinamium, chloramphenicol, and oxytetracycline and in horses after injectable ivermectin administration. One of 70 horses poisoned with blister beetles developed muscle necrosis.^87,142 Animals with organophosphate toxicosis, particularly from parathion, may develop muscle necrosis.^143-145 Several miniature horses being fed a complete feed containing tetrachlorvinphos, a feed-through fly control agent, were reported to develop chronic myonecrosis involving masseter, tongue, neck, respiratory muscles, and postural muscles and occasionally cardiac muscle.¹⁴⁶ Affected horses showed signs of lethargy, dysphagia, fasciculations, tachypnea, and tachycardia. Muscle tissue showed evidence of chronic myonecrosis as well as lipid accumulation. Myonecrosis was attributed to acetylcholine accumulation at muscarinic and nicotinic sites, producing oxidant stress. Low selenium concentrations may contribute to the toxicosis.

TRAUMATIC RHABDOMYOLYSIS

Localized Myopathy-Neuropathy

Clinical Signs

Localized myopathy usually occurs in muscles that are in contact with a hard surface during anesthesia or those in which arterial blood supply is compromised through positional occlusion. Commonly affected muscles include triceps, deltoid, masseter, hindlimb extensors, or, if the horse has been in dorsal recumbency, the hindlimb adductor and gluteal muscles.^148-150 Injury also may occur to nerves in these areas, resulting in temporary radial, peroneal, or femoral nerve paralysis (Fig. 42-15). Clinical signs may be apparent on recovery or may be delayed for periods of up to 30 to 60 minutes after the horse has recovered from anesthesia. Affected muscles may be swollen, hot, and painful on deep palpation; and the horse is often reluctant to bear weight on the affected limb. Myasthenia (weakness) of affected muscles is common, particularly with peripheral nerve involvement. In some horses this condition may limit the animal’s ability to stand for some time after anesthesia. The loss of muscle strength, particularly when involving adductor muscles, can contribute to orthopedic injury during repeated attempts to rise. Many horses with mild to moderate muscle injury recover over a period of hours to days even if untreated.¹⁴⁸

Fig. 42-15 Postanesthetic myoneuropathy showing paralysis of the right femoral and peroneal nerves.

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Etiology

A variety of factors acting alone or in combination have been suggested to contribute to this disorder. The most important factors include ischemia and hypoperfusion as a result of prolonged immobility, muscle compression, systemic hypotension, and hypoxia.^148-152 There is increased lactate efflux from dependent muscles during anesthesia in horses that develop a myopathy, supporting the contention that these muscles experience compromised perfusion.^151,152 Halothane anesthesia has a greater propensity than isoflurane to compromise tissue oxygen delivery even in nondependent muscles.¹⁵⁰ If mean arterial pressure is allowed to fall below 55 to 65 mm Hg for several hours during inhalation anesthesia, particularly if mechanical ventilation is not used, the incidence of postanesthetic myopathy increases substantially.¹⁵²

Diagnosis

Diagnosis is based on a history of anesthesia or prolonged recumbency, clinical signs, and possibly clinical pathology examinations. Laboratory findings include elevations in serum CK and subsequently serum AST and serum LDH activities. Elevations in CK levels of thousands to tens of thousands of international units per liter are commonly demonstrated in horses with moderate forms of the myopathy.

Treatment

Horses demonstrating only minor localized manifestations of the myopathy usually have an uncomplicated recovery with little or no treatment.¹⁴⁸ Supportive care, including the use of antiinflammatory drugs, DMSO, and dantrolene sodium 2 to 4 mg/kg PO, often is sufficient in mild to moderate cases.¹⁵³ Significant muscle atrophy may develop over the ensuing 3 to 4 weeks but usually will resolve within 2 to 3 months. Treatment of more severe cases is outlined under generalized reactions.

Control

Correct positioning and judicious use of padding and water- or air-filled mattresses can reduce dependent muscle pressure up to 50%, thereby aiding in the reduction of this disorder. In addition, through elevation of the upper limb during anesthesia, the pressure on the lower limbs is significantly reduced. Pulling the lower forelimb forward also markedly reduces pressure in the dependent triceps muscle. When the horse is in dorsal recumbency, padding under the shoulders and hips is absolutely imperative.

Maintaining anesthesia at the lightest plane possible for a specific surgical procedure is beneficial in prophylaxis. Similarly, if possible, maintaining systemic mean arterial blood pressure above 80 to 85 mm Hg during anesthesia is advisable. The use of inotropic agents such as dobutamine during anesthesia has been useful in reducing the occurrence of anesthetic myopathies. Administration of dantrolene sodium (2 to 4 mg/kg PO) 1 hour before induction of anesthesia may result in a reduction in the incidence of this myopathy in some susceptible horses.

LOCAL MUSCLE STRAIN

STEPHANIE J. VALBERG

Clinical Signs

Classically, horses develop a stiff, stilted gait, with excessive sweating and a high respiratory rate during or after exercise (Fig. 42-16). Most commonly, signs are seen after only 15 to 30 minutes of light exercise. After exercise, horses may stretch out as if to urinate, become extremely reluctant to move their hindquarters, and in severe cases show signs of colic or become recumbent.^15,171 Attempts to move more severely affected animals may result in extreme pain, obvious anxiety, and possible exacerbation of the condition. Firm painful muscles may be palpated over the back and hindlimbs. Scintigraphic evaluation of horses with rhabdomyolysis after exercise shows symmetric damage to the gluteal, semitendinosus, and semimembranosus muscles.²² Myoglobinuria is a classic feature of more severely affected horses.^171,172 Endurance horses often show other signs of exhaustion including a rapid heart rate, dehydration, hyperthermia, SDF, and collapse.⁷³

Fig. 42-16 Exertional rhabdomyolysis in a horse showing signs of pain, stiffness, sweating, and elevated respiratory rate.

Etiology

Several factors appear to precipitate episodes of ER. Some successful athletic horses may experience one or two isolated episodes of rhabdomyolysis during their lifetime, suggesting that environmental influences play an important role in sporadic cases.^173-177 Other horses may have chronic episodes of rhabdomyolysis that compromise their ability to compete. An inherent muscle dysfunction precipitated by certain triggering factors likely contributes to rhabdomyolysis in these horses.^14,178,179 ER is a syndrome that has many causes. To identify the cause in individual horses it may be helpful to initially subdivide cases into those with no intrinsic muscle abnormality (extrinsic or sporadic form) and those with a suspected intrinsic abnormality of muscle function (intrinsic or chronic form). Causes for sporadic and chronic exercise-induced muscle damage are listed in Box 42-1.

Sporadic Exertional Rhabdomyolysis

Most cases of ER can be diagnosed on the basis of the animal’s history and clinical signs. Confirmation of rhabdomyolysis requires determination of abnormally elevated serum CK, serum AST, or serum LDH. Serum CK is often in the tens to hundreds of thousands of international units per liter, and AST in the thousands to tens of thousands.^9,171 The degree of elevation in enzymes reflects the time lapse between rhabdomyolysis and obtaining a blood sample, as well as the extent of myonecrosis. Myoglobinuria is a common finding in severely affected horses.

Treatment

Treatment of ER is directed at relieving anxiety and muscle pain and replacing fluid and electrolyte losses. Tranquilizers such as acepromazine (0.04 to 0.07 mg/kg), xylazine (0.4 to 1 mg/kg), or detomidine (0.02 to 0.04 mcg/kg) combined with butorphanol (0.01 to 0.04 mg/kg) provide excellent sedation and analgesia. For horses with extreme pain and distress, a constant rate infusion of detomidine, lidocaine, or butorphanol may provide additional pain relief. NSAIDs such as ketoprofen (2.2 mg/kg), phenylbutazone (2.2 to 4.4 mg/kg) or flunixin meglumine (1.1 mg/kg) are frequently used to relieve pain but should be used with caution in dehydrated animals. Intravenous or intragastric DMSO (as a <20% solution) is used as an antioxidant, antiinflammatory, and osmotic diuretic for severely affected horses. Methylprednisolone succinate (2 to 4 mg/kg IV) has been advocated in the acute stage by some veterinarians if horses are recumbent. Muscle relaxants such as methocarbamol (5 to 22 mg/kg IV, slowly) seem to produce variable results, possibly depending on the dose used. The administration of Dantrium (dantrolene sodium) (2 to 4 mg/kg PO) in severely affected horses may decrease muscle contractures and possibly prevent further muscle necrosis. The dose can be repeated every 4 to 6 hours if necessary. Overdosing produces muscle weakness.

Severe rhabdomyolysis can lead to renal compromise owing to the ischemic and the combined nephrotoxic effects of myoglobinuria, dehydration, and NSAIDs. In mildly dehydrated horses, provision of free-choice electrolytes and water or administration of fluids via a nasogastric tube may be adequate. Horses with moderate to severe dehydration require intravenous administration of balanced polyionic electrolyte solutions. Hyperkalemia can occur with severe rhabdomyolysis, necessitating the use of isotonic sodium chloride. If hypocalcaemia is present, then supplementing intravenous fluids with 100 to 200 mL of 24% calcium borogluconate is recommended, but serum calcium should not exceed a low-normal range. Affected animals are usually alkalotic, making bicarbonate therapy inappropriate. In severely affected animals, regular monitoring of serum creatinine is advised to assess the extent of renal damage.

Horses with rhabdomyolysis should be stall rested on a hay diet for a few days. Small paddock turnout in a quiet area for a few hours twice a day is then helpful. Horses may be hand walked at this time, but more than 5 to 10 minutes at a time may induce another episode of rhabdomyolysis. For horses with sporadic forms of tying-up, rest with regular access to a paddock should continue until serum muscle enzyme concentrations are normal. For chronic cases of tying-up, this much rest may not be appropriate. Training should be resumed gradually, and a regular exercise schedule that matches the degree of exertion to the horse's underlying state of training should be established. Endurance horses should be supplemented with electrolytes and water during an endurance ride and monitored particularly closely during hot, humid conditions.

Prevention

Because the inciting cause is usually temporary in sporadic cases, most horses respond to a few weeks of rest, dietary adjustments, and a gradual increase in training. The diet should be adjusted to include high-quality grass hay (or less than 50% alfalfa hay) and the minimum amount of soluble carbohydrate necessary (grains, sweet feed, molasses). A ration balancer containing protein, vitamins, and minerals should be added if necessary. If more than 3 to 5 kg of grain per day is necessary to maintain body weight, the addition of a fat source such as vegetable oil, rice bran, or a complete high-fat, low-starch feed should be considered. The horse should receive on a daily basis an electrolyte supplement that contains at least 1 oz of sodium chloride. A vitamin E and selenium supplement may be necessary in areas with low soil selenium. In addition, myriad treatments are commercially available that are guaranteed to cure tying-up in horses. Many of these have yet to be scientifically tested for efficacy. Skeletal muscle shows remarkable ability to regenerate after injury. After ER complete repair of muscle tissue is possible within 4 to 8 weeks.

Chronic Exertional Rhabdomyolysis

Many horses have repeated episodes of rhabdomyolysis with minimal exercise, even when the dietary and training recommendations for sporadic ER are followed. Forms of chronic ER are seen in many breeds of horses including quarter horses, American Paint horses, Appaloosas, thoroughbreds, Arabians, standardbreds, Morgans, draft breeds, and warmbloods. Current research suggests that many of these horses are susceptible to rhabdomyolysis because of an inherent disorder in muscle function.^179,195 Rhabdomyolysis in such horses occurs as a result of specific environmental circumstances that trigger muscle necrosis in genetically susceptible animals. Two heritable causes of chronic ER have recently been identified, but there may be several others that are yet unidentified. These include a glycogen storage disorder called polysaccharide storage myopathy and a disorder of muscle contractility called recurrent exertional rhabdomyolysis.^14,26,196 Distinguishing among the various forms of chronic ER requires a thorough history, dietary evaluation, physical examination, determination of serum and urine electrolyte concentrations, assessment of serum vitamin E and whole blood selenium concentrations, and histologic evaluation of muscle biopsies using special stains.

Polysaccharide Storage Myopathy

A subset of horses with chronic ER includes horses found to have a glycogen storage disorder characterized by the accumulation of glycogen and an abnormal polysaccharide in their muscle.¹⁹⁶ To date, quarter horses, Paint horses, Appaloosas, Morgans, draft horses, draft cross-breds, warmbloods, and a few thoroughbred and Arabian horses have been identified as having PSSM.^197-201

Diagnosis

A definitive diagnosis of PSSM can be made only by evaluation of a muscle biopsy sample.¹⁹⁶ Supportive evidence of PSSM in quarter horses includes clinical signs of ER, persistent elevations in serum CK and AST activities, and a minimum threefold elevation in CK activity 4 hours after an exercise test consisting of a maximum of 15 minutes of lunging at a walk and trot.¹⁹³ Supportive evidence in draft and warmblood breeds includes exercise intolerance, muscle atrophy, weakness, and some gait abnormalities without necessarily finding elevations in muscle enzymes.^161,201,202

A muscle biopsy of any locomotor muscle that provides a 2-cm × 1-cm block of tissue for evaluation is often sufficient for analysis. The site most easily sampled in the field using an open surgical approach is the semimembranosus or semitendinosus muscle. Clinics that can rapidly process muscle for frozen sections often use a modified Bergstrom biopsy instrument inserted into the gluteal muscle through a 1-cm incision. A diagnosis can be made irrespective of diet and proximity of sampling to recent episodes of rhabdomyolysis. The characteristic features in histologic sections include the presence of subsarcolemmal vacuoles, increased staining for amylase-sensitive glycogen in periodic acid—Schiff (PAS) stain, and the presence of amylase-resistant PAS-positive abnormal polysaccharide inclusions in skeletal muscle fibers (Fig. 42-17).^25,196 Laboratories that use the acronym EPSM process formalin-fixed muscle tissue; the diagnostic criteria used in such laboratories may be those described previously, but in addition these laboratories allow the sole criteria for diagnosis to be increased staining for amylase-sensitive glycogen or the presence of PAS-positive sarcoplasmic masses.¹⁹⁸ A much wider spectrum of breeds is diagnosed with PSSM using these criteria, and the specificity for diagnosis is decreased.

Fig. 42-17 Periodic acid—Schiff stain for glycogen in a gluteal biopsy from a horse with polysaccharide storage myopathy showing aggregates of intensely staining abnormal polysaccharide in some fibers.

POLYSACCHARIDE STORAGE MYOPATHY IN QUARTER HORSE—RELATED BREEDS

A survey of 164 quarter horses used mainly for breeding or ranch work found that 6% of these horses had PSSM based on identifying amylase-resistant abnormal polysaccharide in skeletal muscle biopsies.²⁰³ These horses were kept on pasture, fed very little grain, and showed no clinical signs of a myopathy. In contrast, 50% of muscle biopsy samples from quarter horse—related breeds submitted to the Neuromuscular Diagnostic Laboratory at the University of Minnesota because of signs of a neuromuscular disorder are diagnosed with PSSM.¹⁹⁷ PSSM appears to be a common cause of neuromuscular disease in quarter horse—related breeds, however, under certain environmental conditions clinical signs may be inapparent.

Genetics

Although in general the prevalence of PSSM is 6% of quarter horses, on some breeding farms the prevalence can be as high as 42%.²⁰³ This suggests that PSSM may be inherited within particular bloodlines. A familial basis for PSSM has been suggested from pedigree analysis and by limited breeding trials at the University of Minnesota.^195,204 Although pedigree analysis initially supported an autosomal recessive pattern of inheritance, identification of PSSM in quarter horse crosses indicates that a dominant mode of inheritance is more likely.

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Clinical Signs

The average age of onset of clinical signs of PSSM is 5 years in quarter horses, and ranges from 1 to 14 years of age.¹⁷⁸ There is no significant temperament, body type, or gender predilection for PSSM. Approximately 40% of owners believe there is a seasonal incidence to the development of clinical signs. The most common trigger for clinical signs of PSSM is less than 20 minutes of exercise at a walk and trot, particularly if the horse has been rested for several days before exercise. Signs of ER include firm painful muscles, stiffness, fasciculations, sweating, weakness, and reluctance to move. The hindquarters are frequently most affected, but back muscles, abdomen, and forelimb muscles may also be involved. During exercise, horses may stop and posture as if to urinate, perhaps as a means to alleviate muscle cramping (Fig. 42-18). Signs of pain can be particularly severe, with 30% of horses exhibiting muscle pain for more than 2 hours and approximately 10% of cases becoming recumbent. Less common signs of PSSM in quarter horses include gait abnormalities, mild colic, and muscle wasting.

Fig. 42-18 Typical stance of a horse with PSSM after 10 minutes of walking and trotting. Note the tucked-up abdomen and camped-out stance, which were concurrent with firm muscles, fasciculations in the flank, and elevated serum creatine kinase activity.

Quarter horses frequently exhibit elevations of serum CK and AST in association with clinical signs. The median CK and AST levels for all PSSM quarter horses with muscle biopsy samples submitted to the Neuromuscular Diagnostic Laboratory at the University of Minnesota were 2809 and 1792 U/L, respectively. Persistent elevation in CK activity, despite an extended period of rest, is a common observation in PSSM quarter horses.¹⁵

Pathophysiology

Muscle glycogen concentrations in PSSM horses are often one and a half to four times normal, and glucose-6-P concentrations are up to 10 times normal.¹¹⁵ Glycogen accumulation in PSSM horses is not the result of an inability to metabolize glycogen but rather of increased synthesis of glycogen. There appear to be at least two linked biochemical abnormalities associated with PSSM. The first abnormality is expressed as enhanced sensitivity to insulin in quarter horses with PSSM horses as determined by intravenous or oral glucose tolerance tests as well as euglycemic hyperinsulinemic clamping.^208,209 In association with high dietary starch intake, this enhanced insulin sensitivity may increase uptake of glucose into skeletal muscle and the subsequent formation of glycogen. Draft horses have not been found to have heightened insulin sensitivity. The second biochemical abnormality in horses with PSSM is associated with abnormal regulation of glycogen synthase, resulting in persistent glycogen synthesis. Abnormal polysaccharide formed in PSSM skeletal muscle is less highly branched than normal glycogen and may reflect an imbalance in the heightened activity of glycogen synthase relative to the less tightly regulated glycogen branching enzyme. Abnormal polysaccharide is also occasionally found in the heart of PSSM horses but has not been identified in the liver.

The development of rhabdomyolysis in PSSM horses is not directly associated with heightened insulin sensitivity.²¹⁰ If PSSM horses are treated with dexamethasone, their insulin sensitivity can be reduced to well within the normal range; however, they still develop rhabdomyolysis. Rather, muscle necrosis with exercise appears to be associated with a separate but potentially linked biochemical abnormality in energy metabolism. During submaximal exercise, muscle fibers in PSSM horses do not generate adequate energy for muscle contraction, as evidenced by the degradation of adenine nucleotides in individual muscle fibers.²¹¹ It is likely that PSSM is caused by a defect in a pathway that controls both the flux of substrates such as glucose into the cell, as well as the flux of substrates such as glycogen and free fatty acids through metabolic pathways during aerobic exercise.

Treatment and Prevention

Horses diagnosed with PSSM will always have an underlying predilection for muscle soreness. The best that can be done is to manage horses to minimize clinical signs. With adherence to diet and exercise recommendations, at least 80% of horses show notable improvement in clinical signs, and many return to acceptable levels of performance.^178,212 There is, however, a wide range in the severity of clinical signs shown by horses with PSSM; horses with severe or recurrent clinical signs will require more stringent adherence to diet and exercise recommendations in order to regain muscle function.

Treatment of horses with acute rhabdomyolysis is similar to that described for sporadic ER except that PSSM horses should not be confined to a stall for more than 48 hours. They should be provided turnout in paddocks of gradually increasing size once stiffness has subsided. Hand walking horses recovering from an episode of PSSM for more than 5 to 10 minutes at time may trigger another episode of rhabdomyolysis.

Recurrent Exertional Rhabdomyolysis

Recurrent episodes of muscle stiffness, sweating, muscle contractures, and reluctance to move occur commonly in racing thoroughbreds, standardbreds, and Arabian horses. Many of these horses likely have tying-up as a result of a defect in the regulation of muscle contraction termed recurrent exertional rhabdomyolysis (RER).

Epidemiology and Genetics

Most studies show that approximately 5% of thoroughbred horses develop signs of muscle pain and cramping during a racing or polo season.^{173,176,177,214} Approximately 75% of thoroughbred racehorses with RER have at least four episodes of rhabdomyolysis and 25% have more than 10 episodes in a 4-month racing season.²¹⁴ One predisposing factor for RER appears to be inheritance of susceptibility to developing exercise-induced episodes of rhabdomyolysis.^179,215 Analysis of pedigrees of thoroughbred horses from across the United States suggests that RER is an autosomal dominant trait. Furthermore, subsequent breeding trials confirm that the abnormal contracture test is inherited in an autosomal dominant fashion.¹⁷⁹

Predisposing environmental factors that trigger rhabdomyolysis in susceptible horses include gender, temperament, diet, exercise duration and intensity, excitement, and lameness.^176,214 Females are most commonly affected by RER (67% female; 33% male), particularly those that are 2 years old and in race training.²¹⁴ Nervous horses are five times more likely to develop RER, and horses with lameness are four times more likely to tie up. Susceptible horses receiving more than 5 kg of sweet feed are more likely to develop rhabdomyolysis than those receiving 2.5 kg of sweet feed per day.^189,190

Diagnosis

RER affects a specific subset of thoroughbred and likely standardbred and Arabian horses with intermittent episodes of exercise-induced rhabdomyolysis. These horses have increased numbers of centrally located nuclei in muscle biopsy samples and normal muscle glycogen staining (see Fig. 42-8).¹⁴ In addition, RER is characterized by abnormal sensitivity of intact muscle bundles to contractures induced by caffeine or halothane in the muscle bath.^26,28,216 Although studies of muscle contraction indicate similarities to MH in swine, biochemical studies of isolated muscle cell membranes have not identified a similar defect in the function of the calcium-release channel in horses with RER.¹⁵⁶ Many thoroughbreds with RER have developed rhabdomyolysis under halothane anesthesia.^162,217

Clinical Signs

Episodes often occur in horses once they become fit and are frequently associated with excitement at the time of exercise. In thoroughbreds, rhabdomyolysis occurs most frequently during training when horses are held to a slow gallop.²¹⁴ In standardbreds, rhabdomyolysis often occurs 15 to 30 minutes into slow jogging.⁹ A history of poor performance and elevated serum AST and CK may be the only presenting complaints in some horses. Older thoroughbreds used as riding horses may have very intermittent episodes of rhabdomyolysis associated with lay-ups of fit horses or with the steeplechase in 3-day events. Muscle stiffness and reluctance to collect may be present on a continual basis between episodes in some of these older horses. Arabian horses often develop clinical signs with little exertion, frequently in association with excitement.

Prevention

RER appears to be an inherited disorder that is expressed when horses are subjected to the stress and rigors of training, particularly at a young age. Prevention of further episodes of RER in susceptible horses includes adhering to standardized daily routines and providing an environment that minimizes stress. This should include desensitizing horses to stressful situations, moving the stall to a quiet area of the barn, performing regular turnout, and so on. Daily exercise is essential, whether in the form of turnout, longing, or riding.

In the past, horses have been box-stall rested for several weeks after an episode of RER. It is my opinion that this is counterproductive and increases the likelihood that the horse will develop RER when put back into training. The initial muscle pain usually subsides within 24 hours of acute RER, and daily turnout in a small paddock can be provided at this time. Subsequently a gradual return to performance is recommended once serum CK is close to normal range.

The diet should be adjusted to include a balanced vitamin and mineral supplement, high-quality hay, and a minimum of carbohydrates (<2.5 kg) such as grain and sweet feed. Additional dietary fat supplements are helpful to maintain weight in nervous horses without providing excessive carbohydrates. In hard keepers or horses in heavy work, corn oil and rice bran added to the diet may not be adequate to maintain weight. In such cases new commercial feeds that are low in starch and high in fiber, designed for horses with RER, are helpful to maintain weight but avoid rhabdomyolysis.¹⁹⁰ The use of low doses of acepromazine tranquilizers (e.g., a dosage rate of approximately 0.005 to 0.01 mg/kg) 30 minutes before exercise in excitable horses is believed to help some horses.

Dantrolene 2 to 4 mg/kg PO given 1 hour before exercise in fasted horses is effective in preventing RER.^153,218 Dantrolene decreases the release of calcium from the sarcoplasmic reticulum during contraction. Phenytoin has also been advocated as a treatment for horses with RER. Doses are adjusted in horses to maintain serum levels of 8 to 10 μ/mL. Initial dosages begin at 6 to 8 mg/kg PO for 3 to 5 days. Doses can be increased by 1-mg/kg increments every 3 days until rhabdomyolysis is prevented but should be cut back if horses appear drowsy.²¹⁶ If possible, serum phenytoin concentrations should be assessed regularly at the initiation of treatment. Phenytoin acts on a number of ion channels within muscle and nerves including sodium and calcium channels. Unfortunately, long-term treatment with dantrolene or phenytoin is expensive, and efficacy has not been established.