Exertional Rhabdomyolysis: Not Just Tying-Up Anymore

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Originally published on TheHorse.com

Few things are scarier than watching a horse sweating, trembling, and twisting in pain during an episode of tying-up. Researchers have worked tirelessly to better understand this disorder and its cause, and they're continually uncovering ways to manage it.

Stephanie Valberg, DVM, PhD, Dipl. ACVIM, ACVSMR, professor at and director of the University of Minnesota (UM) Equine Center in St. Paul, chronicled her work in unraveling the causes of tying-up, or exertional rhabdomyolysis (ER), during the Frank J. Milne State-of-the-Art Lecture at the 2012 American Association of Equine Practitioners Convention, held Dec. 1-5 in Anaheim, Calif. In doing so, she also became the first female to deliver this prestigious lecture.

In her presentation Valberg covered everything from late 19th century observations about this condition to recent discoveries that could reveal the cause of one type of rhabdomyolysis--seasonal pasture myopathy

History

Valberg said that even back in the late 19th century, horsemen and veterinarians had described ER in draft horses, calling it azoturia. One account from 1883 described the disorder's clinical signs as "sweating and trembling, scarcely able to turn in the stall, the muscles of the back and loins in a state of spasm, tail quite stiff," she said. At this point in history, veterinarians also recognized that ER most commonly occurred after periods of hard work, followed by a layup, she added. For this reason, the disorder was colloquially termed "holiday disease" or "Monday morning disease."

In the 19th and early 20th centuries, Valberg said, veterinarians commonly saw ER in carriage horses and reported mortality rates as high as 50%. Still, its cause remained unclear.

Starting in the early 20th century, veterinarians began looking more closely at the disease and searching for answers. Valberg relayed that some key findings from this period included recognizing another type of ER in lighter-breed horses; confirming that ER was a muscle disease that resulted in myoglobinuria (in which myoglobin, a type of muscle cell protein, appears in the urine because of muscle cell damage); and successfully reproducing ER in draft horses by feeding them 3 kg of molasses during rest and before exercise, among others.

"A gradual recognition of the complexity of ER that affected a wide variety of equine breeds arose from these studies," she said.

By the late 20th century, she said, an "explosion" of research advances in related human medical conditions allowed researchers--including her--to gain a "more sophisticated" understanding of ER.

Furthering Research

To help the audience understand ER and its various manifestations, Valberg first gave the audience an in-depth review of muscle fiber components and how they work. This knowledge was made possible by the mid-1970s adaptation of the percutaneous muscle biopsy technique (whereby the veterinarian takes a sample of organ tissue for examination by maneuvering a biopsy needle through the skin and into the organ of interest) for equine use by Lindholm and Snow, she said.

Scientists began establishing neuromuscular diagnostic laboratories that evaluated veterinary samples, and Valberg said these "formed the cornerstone" for further understanding equine muscular disorders. The University of California, Davis, led the way with its lab in the 1970s, and two others eventually opened in the United States (including the UM Neuromuscular Diagnostic Laboratory, which Valberg currently directs). Valberg said the formation of such laboratories allowed:

• Practitioners to submit biopsies as well as their clinical observations for future reference;
• Researchers to collect hundreds of samples and cases with which to evaluate and identify disease patterns;
• Researchers to bank biochemical and DNA samples, which they used to evaluate the pathophysiology (the functional changes that accompany a condition) of disease subsets; and
• The formation of a "research hub," where interested parties could collaborate on understanding equine muscle diseases.

Additionally, Valberg explained how the development of genetic tools helped further ER research and provided a better understanding of the disorder's heritability. Researchers first suggested ER was a heritable trait back in the 1950s and 1960s, based on research performed on human neuromuscular diseases. Moving forward, scientists examined a possible genetic basis for ER in Standardbred horses in the mid-1990s, and Valberg and colleagues from UM evaluated heritability in Quarter Horses and Thoroughbreds in the late 1990s. Results of these pedigree analysis-based studies suggested a genetic basis, but they didn't prove that the disorder was familial (runs in bloodlines).

Some of the additional genetic research approaches scientists now employ and discoveries they've made with these tools include:

• Breeding trials: Valberg relayed that the American Quarter Horse Association and the Morris Animal Foundation provided funding to cover time-consuming, expensive trials for investigating ER in both Quarter Horses and Thoroughbreds. Both trials proved successful in confirming a genetic basis.
• Candidate gene studies: Valberg explained that candidate gene trials--which involve sequencing a gene located in a chromosome region that scientists suspect is involved in the expression of a trait--were the first real genetic tests used to evaluate ER. "This approach was first used by Dr. Sharon Spier (DVM, PhD, Dipl. ACVIM) to identify the genetic basis for hyperkalemic periodic paralysis (HYPP) in Quarter Horses," she said, and researcher Monica Aleman, MVZ, PhD, Dipl. ACVIM, also used it to confirm that a specific gene could cause ER. Valberg noted that one common challenge associated with this investigation method is sequencing the wrong candidate gene(s).
• Genome-Wide Association Mapping and Sequencing: This broader approach to studying traits' or disorders' genetic components involves identifying genetic markers closely associated with chromosomes containing the affected gene. Once researchers have identified an "affected" region, they can evaluate genes using the candidate gene approach. Valberg said researchers used this method to identify the genetic mutation that causes polysaccharide storage myopathy (PSSM) in Quarter Horses.
• Linkage Analysis: According to Valberg, linkage analysis requires multi-generation pedigrees with many full- or half-sibling offspring. Researchers analyze a subset of these animals' DNA for association with the trait or disorder. "This approach was used in Thoroughbred horses where samples were collected through breeder cooperation and from a breeding trial," Valberg explained. The researchers used linkage analysis to exclude potential candidate genes as they looked to find the cause of recurrent exertional rhabdomyolysis (RER, more on this disorder in a moment) in Thoroughbreds.
• Single Nucleotide Polymorphism Chips: Finally, Valberg discussed this method made possible by the 2008 whole-genome sequence of the Thoroughbred mare Twilight. She explained that because of the vast number of genes identified during the genome sequence, researchers created a "denser set of polymorphic markers," which they can now use to identify genes associated with specific traits and disorders. "The UM research group identified a region on equine chromosome 16 that was significantly associated with ER in Thoroughbreds" using this technique, she said.

Evaluating ER Horses

Different ER types require different treatment approaches, so it's important to get a clear diagnosis before heading down a treatment path. Valberg described the best ways for veterinarians to clinically evaluate horses with ER--regardless of the root cause--based on what researchers have learned:

• Obtain a detailed history. "A detailed history is the foundation for evaluating ER because the disorder can be intermittent in nature and not evident on physical examination," she explained. She recommended recording information about the horse's muscle tone and mass, gaits, pain level, any exercise intolerance, and weakness when signs appear. She also recommended gathering information on factors that might prompt ER episodes, including the horse's temperament and diet, among others.
• Perform a full physical exam. She recommended veterinarians first evaluate the horse's muscle mass and symmetry from afar, then proceed with palpation (to assess muscle tone and detect heat, swelling, and fasciculations [twitching]); a lameness examination (as lameness can exacerbate ER, and some lamenesses can cause muscle pain to worsen); a neurologic examination (to rule out neurologic causes); and possibly an ultrasonographic exam (to identify areas of muscle trauma).
• Take blood samples for laboratory tests. Most ER horses have elevated blood serum creatine kinase (CK) and aspartate transaminase (AST), Valberg said, noting that AST levels rise and fall more slowly than CK levels. In cases of severe ER veterinarians should look for additional factors including hyponatremia (low blood sodium levels), hypochloremia (low blood chloride levels), hypocalcemia (low blood calcium levels), hyperkalemia (elevated blood potassium levels), and hyperphosphatemia (elevated blood phosphorus levels).
• Perform an exercise response test. Valberg relayed that these tests are useful when veterinarians examine horses with a history of ER but normal blood test results. She explained that with exercise response tests, veterinarians take blood samples before and four to six hours after a light exercise. "A normal response is less than a three- to fourfold increase from basal CK, four to six hours after the exercise test," she said. Elevated CK levels could indicate ER.
• Collect and evaluate a muscle biopsy. A muscle biopsy provides veterinarians with extensive information regarding ER horses. Valberg said veterinarians can use one of two techniques to collect the biopsy: an open surgical technique or the percutaneous technique described above. The former technique, she said, is more commonly used in the field and includes excising a half-inch cube of muscle from the back of a horse's hind end. Biopsies are then sent to a laboratory for evaluation. After samples arrive at the laboratory, theyare closely evaluated for abnormalities.

Once veterinarians determine a diagnosis for a specific ER type, they can make recommendations on how to best control these disorders.

Sporadic ER

Sporadic ER can occur in horses of any breed, age, or sex, Valberg said, and veterinarians typically see it in horses with "adequate" performance histories. Several issues can cause sporadic ER, she said, including:

• Muscle trauma--When horses sustain muscle injury (commonly the muscles in the back and rump) via focused or generalized trauma or from struggling when cast, they often experience clinical signs similar to ER.
• Overexertion--Increasing exercise intensity without properlyconditioning a horse is a common cause of ER, Valberg said, adding that overexertion has been blamed for roughly 81% of ER cases in polo ponies in the United States.
• Exhaustion--Valberg said that exhaustion causes ER most commonly in endurance horses and racehorses, and signs include weakness, ataxia (incoordination), rapid breathing, muscle twitching, sweating, and collapse. These horses often have elevated body temperatures and CK levels.
• Dietary and electrolyte Imbalances--She explained that unbalanced diets--specifically those high in nonstructural carbohydrates and low in forage--can prompt ER episodes, along with electrolyte imbalances.

Valberg suggested veterinarians manage horses with sporadic ER similar to how they would initially manage acute episodes: resting the horse, allowing paddock access so he can self-exercise (which can minimize the chances of the horse suffering another episode), and performing weekly serum CK checks. If horses cannot be turned out, Valberg recommended hand walking them for a few minutes at a time to start and gradually increasing to longer spans.

She also recommended ensuring vitamins and minerals are balanced in the horse's diet; providing a salt block or supplementing feed rations with one to three tablespoons of salt per day can help the horse maintain proper sodium levels. And although it hasn't been proven scientifically, anecdotal reports indicate selenium and vitamin E supplementation can help prevent ER episodes."Once serum CK returns to normal, training can be resumed gradually," she said, recommending that owners start the horse with less than 20 minutes of exercise per day and gradually increase the effort.

Chronic ER

In addition to sporadic ER, researchers have identified several types of chronic ER that affect different types of horses.

Recurrent exertional rhabdomyolysis (RER)--Most commonly identified in Thoroughbreds and Standardbreds, RER is caused by an abnormality in the regulation of muscle contraction and relaxation, researchers believe, and it is often triggered by a excitement. Valberg noted that in both Thoroughbreds and Standardbreds, RER shows up most commonly after low-intensity work and, in the former breed, more commonly after works when the rider holds the horse back, not allowing him to gallop freely.

Valberg said RER can be found in roughly 4.9% of Thoroughbred racehorses in the United States, 5.4% of Thoroughbreds in Australia; 6.7% of Thoroughbred racehorses in the U.K.; and 6.4% of Standardbred racehorses in Sweden.

Researchers have shown that RER is more prevalent in females than males and more common in nervous horses than calm horses. Additionally, she noted that Thoroughbreds consuming more than 2.5 kilograms (about 5.5 pounds) of grain per day are more likely to develop RER than horses consuming less concentrate.

Valberg said veterinarians diagnose RER based on clinical signs and the presence of risk factors associated with the disease, and they often look at serum CK and AST levels to confirm muscle degeneration in these horses. There is no genetic test for this disorder as of yet, she relayed.

Finally, Valberg described steps for managing horses with RER:

• Keep at-risk horses in a quiet environment and in a routine to help reduce stress;
• Exercise affected or at-risk horses daily, and choose workouts that keep them as relaxed and quiet as possible;
• Consider placing affected horses on a high-fat, low-starch diet, which still provides them with adequate calories for their work but reduces the amount of muscle damage sustained during exercise; and
• Ensure horses consume 30 to 50 grams of salt daily, either via top dressing on feeds or a salt block, and consider electrolyte supplementation when conditions are hot and humid.

Veterinarians can consider prescribing dantrolene, a medication that slows calcium release from muscle storage sites. It can be helpful for managing RER if given 60 to 90 minutes before exercise.

Valberg added that hormone therapies to suppress estrus could help mares prone to RER during their heat cycles, and some complementary therapies--such a massage and stretching--performed by experienced professionals could help promote muscle relaxation in affected horses.

Malignant Hyperthermia (MH)--Valberg touched on MH briefly. This dangerous condition is caused by a mutation of the RYR1 gene affects less than 1% of Quarter Horses and Paints. General anesthesia drugs can trigger MH-associated rhabdomyolysis (often characterized by a high fever, metabolic failure, and death under general anesthesia), she said, and it the condition is difficult to control via diet and exercise. She said it's important to consider genetic testing if a horse's family members have or are suspected of having the disease.

Valberg recommended treating affected horses with the drug dantrolene 30 to 60 minutes prior to inducing anesthesia, but she cautioned that cardiac arrest is difficult to prevent once rhabdomyolysis begins.

PSSM Types 1 and 2--Next, Valberg discussed PSSM, which veterinarians have seen in several different breeds since its discovery in 1992. A discovery in 2008 related to the mutation of the glycogen synthase 1 (GYS1) gene prompted researchers to split affected horses into one of two categories: those with the mutation (termed PSSM1) and those with similar clinical signs but without the mutation (PSSM2).

Researchers estimate that 6-10% of Quarter Horses have PSSM1, along with 6-8% of Paints and Appaloosas and about 36 to 54% of Belgians and Percherons, said Valberg. Among Warmbloods PSSM1 is less prevalent. She added that veterinarians haven't tied PSSM1 to any particular temperament, body type, or gender..

While some PSSM1 horses don't show many clinical signs, others' muscles become stiff after exercise for as brief as 20 minutes or less. She said signs typically develop while the horse is walking or trotting, especially if he has had days off prior to exercise.

In light-breed horses, other signs of acute PSSM1 include tucking the abdomen up, muscle twitching in the flank, generalized muscle stiffness, sweating, reluctance to move, and muscle contractions. Additional signs of chronic disease include lack of energy under saddle, reluctance to move, stopping and stretching out (as if to urinate), a poor attitude when exercised, chronic back pain, not rounding over jumps, and pain or twitching on back muscle palpation.

Most draft horses affected by PSSM1 don't display outward clinical signs. However, these animals can develop acute onset rhabdomyolysis when they are put under general anesthesia, consume high-grain or -starch diets, or are exercised irregularly, especially without turnout.

Since PSSM1 involves a genetic mutation, the gold standard diagnostic test is a genetic test, Valberg said. Veterinarians can also use clinical signs, consistently elevated serum CK and AST levels, and muscle biopsies as adjunct diagnostics.

Less is known about PSSM2, Valberg said, "because as it turns out, previous research on PSSM has largely involved horses with type 1 PSSM." Researchers have identified PSSM2 in several breeds, including Quarter Horses, Paints, Appaloosas, Morgan Horses, Warmbloods (Dutch Warmbloods having the highest prevalence among Warmblood breeds), Standardbreds, Thoroughbreds, and Arabians. Its cause remains unclear.

Acute clinical signs are similar among PSSM1 and PSSM2 horses, she said, although chronic signs differ. Horses with PSSM2 often show signs related to poor performance, including undiagnosed gait abnormalities, sore muscles, decreased energy level after five to 10 minutes of work, firm and painful back and hindquarter muscles, reluctance to collect and/or engage the hind end, poor rounding over fences, and slow-onset atrophy (muscle wasting).

Veterinarians must diagnose PSSM2 with a biopsy because researchers haven't yet identified a genetic mutation in affected horses.

Management recommendations for both PSSM types are based largely on a strict diet and exercise program. "With adherence to both diet and exercise recommendations, at least 70% of horses show notable improvement in clinical signs and many return to acceptable levels of performance," Valberg said.

Diets for PSSM horses should be low in starch and sugar and high in fat; this reduces the amount of glucose these horses produce and increases the amount of free fatty acids to aid in muscle metabolism and lower insulin concentrations, Valberg said.

Based on recent research, Valberg suggested making the following considerations when planning a diet for a PSSM horse:

• Select a hay comprised of 12% nonstructural carbohydrates or less to help keep plasma insulin concentrations stable (NSCs, the easily digestible carbohydrates, include simple sugars and fructans); insulin encourages additional glycogen production, she noted, which leads to problems in PSSM horses;
• Ensure PSSM horses consume additional fat to aid oxidation in skeletal muscles. Common fat sources include vegetable oils (such as corn, canola, or flaxseed; this type of fat is very digestible and very energy dense, she noted), rice bran, and animal-based fat (such as lard and fish oil); and
• Consider feeding a commercially available low-starch, high-fat concentrate feed if fat supplements aren't working out (Valberg noted they can be messy to deal with, unpalatable for some horses, and difficult to keep fresh in hot temperatures). She said these feeds are typically comprised of 10-15% fat by weight and contain less than 20% NSC by weight. Nonstructural carbohydrate content is not consistently listed on feed tags, so she recommended contacting manufacturers for this information.

Dealing with overweight PSSM horses can be particularly challenging, so Valberg offered two management suggestions:

• Rather than supply additional fat to the diet, fast overweight horses for six hours pre-exercise. This has been shown to elevate free fatty acid levels in the blood plasma, which has a similar effect to feeding extra fat; or
• Find forage with a very low (around 4%) NSC concentration and provide additional calories via fat and concentrate supplementation.

It's advisable to work with your veterinarian on choosing feed for an overweight PSSM horse to ensure his diet is balanced.

The other key aspect of managing PSSM horses is providing exercise, Valberg said, noting that neither management approach alone will effectively control the disorder. After a horse suffers a rhabdomyolysis episode, veterinarians typically recommend limiting total stall rest time to 48 hours or less, then turning the horse out to promote free exercise, which has been proven beneficial in the long term. She cautioned that excitable horses might need mild sedation prior to turnout to prevent excessive galloping. Limit hand walking to five to 10 minutes immediately after an ER episode, she said, as even this short amount of exercise could trigger another episode.

Prior to beginning an exercise regimen, Valberg suggested giving the horse two weeks to adjust to the turnout and diet change. Then begin quiet, relaxed ground work that including lots of stretching in a long and low frame; often owners accomplish this using a longe line or a round pen. Begin with about four minutes of walking and trotting and add two minutes daily until the horse is working for the desired duration, she said.

Valberg said it usually takes about three weeks to build up to under saddle work, and she encouraged adding two minutes of collection or canter after the relaxed warm-up period. Build the horse back up to the desired level of work slowly if no additional ER episodes occur, she said.

Seasonal Pasture Myopathy

Finally Valberg touched on seasonal pasture myopathy, which researchers first described in Minnesota in the late 1990s. This type of rhabdomyolysis is most common in pasture-kept horses in the fall. Affected horses can either die suddenly or exhibit profuse sweating, muscle fasciculation, weakness, urine discoloration, reluctance to move, recumbency (inability to stand), difficulty breathing, and death after 12-72 hours.

Valberg and colleagues recently identified seeds from the box elder tree, seen here, as a cause of seasonal pasture myopathy.

Photo courtesy Stephanie Valberg, DVM, PhD

When pathologists conducted necropsy examinations on several affected horses, they noticed a backlog of fat metabolites in affected horses' blood (acylcarnitines) and urine (glycine conjugates), along with high fat accumulation in the muscles, she said.

Until recently veterinarians had been unable to determine what causes the disorder, so they were unable to offer any treatment options and/or preventive suggestions. However, after much investigation and many hours of walking pastures that affected horses inhabited, Valberg identified the box elder tree as common denominator in all of the pastures. After additional laboratory work she confirmed that box elder seeds contain an amino acid called hypoglycin A, which is also found in a related fruit known to cause severe illness in humans.

In subsequent tests researchers found the conjugated form of hypoglycin A metabolite methylenecyclopropylacetic acid (MCPA), known to be toxic in other species, in affected horses' serum and urine. The results of the study that identified MCPA as a cause have been accepted for publication in the Equine Veterinary Journal.

She also noted that a similar disease found in Europe--termed equine atypical myopathy--is likely caused by the compound found in a related seed from the European sycamore tree. She and Swiss and Belgian researchers identified these in pastures housing affected horses.

The good news about this disease, she relayed, is that it's completely preventable by removing horses from pastures containing box elder or European sycamore trees.

Take-Home Message

"It's not just tying-up anymore," Valberg said in closing. The term "tying-up" now encompasses myopathies including metabolic disorders, calcium regulation deficits, and more.

"It's been a remarkable and wonderful journey being able to piece these things together," she concluded.

Disclaimer: Seek the advice of a qualified veterinarian before proceeding with any diagnosis, treatment, or therapy.

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