Polysaccharide Storage Myopathy: One Important Cause of Exertional Rhabdomyolysis
27 August, 2015
Polysaccharide Storage Myopathy: One Important Cause of Exertional Rhabdomyolysis
Stephanie J. Valberg DVM PhD a, Diplomate ACVIM, James R. Mickelson BS MS PhDb, a Department of Clinical and Population Sciences, b Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Minnesota, St. Paul MN 55108
Acknowledgment: We wish to thank the American Quarter Horse Association for funding research on PSSM
Polysaccharide storage myopathy (PSSM) is a glycogen storage disorder in Quarter Horse-related breeds, warmblood and draft horses that show signs of exertional rhabdomyolysis. A diagnosis should be made by muscle biopsy and identification of abnormal periodic acid Schiff's positive polysaccharide inclusions in muscle fibers. Prevention of tying-up in susceptible horses involves eliminating grain and sweet feed from the ration and adding a fat supplement such as rice bran. In addition, one of the most important factors to prevent rhabdomyolysis in these horses appears to be pasture turn-out and daily exercise. Some laboratories have diagnosed polysaccharide storage myopathy solely on the basis of an apparent increase in muscle glycogen staining. This has unfortunately resulted in the application of the term PSSM to horses of a wide variety of breeds with a variety of symptoms.
Figure 1: A cross- section of skeletal muscle from a horse with polysaccharide storage myopathy. Note the accumulation of aggregates of abnormal PAS positive material in the muscle fibers at the periphery o the muscle fasciles.
Exertional rhabdomyolysis, or tying-up, is a common cause of disability in horses.1-7 Affected horses have a stiff gait, muscle cramping, pain and reluctance to move during or following mild to moderate exercise; however, rhabdomyolysis can occur after endurance rides, transport, and anesthesia. A diagnosis of rhabdomyolysis is usually based on clinical signs and increased serum activities of muscle enzymes such as creatine kinase (CK), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST).1 Although these clinical signs and high CK, LDH and AST indicate an episode of rhabdomyolysis, they do not provide specific information regarding the cause of tying-up. Previously it was assumed that one etiology exists for tying-up and numerous case descriptions of a small number of horses of varying breeds with this syndrome provided conflicting information regarding one specific cause for tying-up. Proposed etiologies include vitamin E and selenium deficiency, electrolyte imbalances, heat exhaustion in endurance horses, hypothyroidism and abnormal calcium regulation.1-5 One reason for the confusion regarding tying-up may well be that there are several causes for muscle pain and cramping in the horse. Only with improved diagnostic procedures will specific etiologies for tying-up in the horse be recognized.
Classification of tying-up: A clinical diagnostic protocol that included, CBC, serum chemistry profile, renal fractional excretion of electrolytes, serum T3 and T4, histochemical and biochemical evaluation of frozen muscle biopsies and pre and 4 hr post-exercise serum CK activity has been applied to over 75 horses with exertional rhabdomyolysis by our laboratory. In general, horses fell into two broad categories, those that tied-up sporadically with no previous history of exercise-related cramping, and those that repeatedly tied-up with exercise. Horses that tied-up sporadically often had a history of a change in the amount or intensity of exercise, a change in the diet, a respiratory tract infection or focal muscle strain. Muscle biopsies revealed no evidence of a previous episode of rhabdomyolysis or metabolic derangements. However, horses with recurrent exertional rhabdomyolysis often developed rhabdomyolysis with light exercise, and had histological evidence of previous episodes of degeneration and regeneration in muscle biopsies. An intrinsic abnormality of muscle function was therefore suggested by the recurrent problems in these horses.
Further classification of horses with recurrent exertional rhabdomyolysis was possible on the basis of the histological appearance of the muscle biopsies. Many of the Thoroughbred, Standardbred and Arabian horses with recurrent exertional rhabdomyolysis had muscle biopsies characterized by numerous mature muscle fibers with centrally located nuclei and moderately dark periodic acid Schiff's staining (PAS) for muscle glycogen. In contrast, a number of Quarter Horses, draft and warmbloods had muscle fibers with subsarcolemmal vacuoles, dark PAS staining and most notably abnormal complex polysaccharide accumulation in muscle fibers. The term polysaccharide storage myopathy (PSSM) was given to this one specific subset of horses with recurrent rhabdomyolysis based on the presence of abnormal complex polysaccharide in skeletal muscle.6 The purpose of this article is to describe the clinical signs, etiology, treatment and prevention of PSSM, one important cause of exertional rhabdomyolysis in the horse.
Unlike many nervous racehorses with exertional rhabdomyolysis, horses with PSSM often have a calm demeanor. Episodes are usually first observed when 2-4 yr old horses are put into training but may occur in weanling halter horses on high grain diets. Rest for days-weeks before exercise is a common triggering factor. The frequency of episodes can vary widely from once or twice a year to every exercise session. In its mildest form, horses develop a tucked-up abdomen, fasciculations in the flank region and a camped-out coach horse stance after 10-30 minutes of exercise. If exercise is continued, horses will sweat profusely, exhibit fore or hindlimb gait asymmetry, hind limb stiffness and reluctance to move. Some horses will paw or roll when returned to their stall and in severe cases this may resemble colic. Myoglobinuria may occur with severe episodes and a few horses have become recumbent and died or been euthanized. Exercise intolerance at higher speeds and resentment of exercise may be the primary complaint in horses with PSSM.
Serum activities of CK, LDH and AST are increased and range according to the severity of the episode from a few thousand to >200,000 U/L. Unlike other forms of rhabdomyolysis, if PSSM horses are stall rested after an initial clinical episode, serum CK may remain increased or even rise due to subsequent subclinical episodes.
Diagnosis of PSSM
Muscle biopsy: A definitive diagnosis of PSSM is based on the results of a muscle biopsy. Muscle biopsy is indicated in horses with repeated episodes of rhabdomyolysis that do not respond to standard therapies such as rest, altered training schedule and the addition of electrolytes, vitamin E and selenium to the diet. In most field situations an open surgical biopsy technique is most feasible. The semimembranosus muscle is often biopsied using the open technique because of the ease of this approach, the lack of a highly visible scar, and the high prevalence of abnormal polysaccharide in this muscle. Horses are sedated, the tail is wrapped and, following subcutaneous anesthesia, a 2" incision is made through skin and fascia 6" distal and medial to the tuber ischei. Subsequently, a 1.5"x 1.5"x 1/2" sample of semimembranosus muscle is removed. The tissue is handled gently and placed on gauze moistened with 0.9% saline and shipped on icepacks or dry ice overnight to a laboratory specialized in equine muscle disorders. The fascia is closed using absorbable sutures and skin closed using intracuticular sutures to prevent rubbing and contamination by fecal material. The advantages of frozen rather than formalin-fixed muscle sections are that PAS positive inclusions are readily observed and distinguishable from normal glycogen, and that numerous other stains can be performed to characterize the biopsy. In addition, muscle samples shipped on dry ice can be used for biochemical analysis of glycogen concentrations. Most neurological examinations in human medicine include evaluation of frozen muscle biopsies to characterize suspected myopathies or distal neuropathies.
Histochemistry: The hallmark feature of PSSM is the presence, in horses with clinical signs of rhabdomyolysis or exercise intolerance, of PAS positive inclusions in scattered fast twitch muscle fibers (figure 1). Unlike normal glycogen, many of these PAS positive inclusions are resistant to digestion with amylase, and electron microscopy reveals that they consist of both filamentous material as well as beta glycogen particles . Other histological features that may or may not be evident include increased staining for normal glycogen, rimmed vacuoles, subsarcolemmal vacuoles, necrotic muscles fibers, centrofasicular atrophy and regeneration. Using this criteria, PSSM can be seen in particular Quarter Horse blood-lines, warmbloods and draft horses. No complex polysaccharide was found in the Standardbred, Thoroughbred, Arabian and other breeds of horses evaluated for exertional rhabdomyolysis. Some laboratories have based a diagnosis of PSSM solely on qualitative histochemical stains for high muscle glycogen without abnormal polysaccharide being present.10 Since muscle glycogen concentrations are influenced by diet, stage of training and numerous other factors, basing a diagnosis of PSSM on dark PAS staining of muscle section without abnormal PAS positive inclusions would classify a wide variety of horses with and without a specific myopathy as having PSSM. As such, this definition of PSSM seems too broad and would not represent one specific genetic defect.
Biochemistry: Muscle glycogen concentrations were measured in 71 horses with exertional rhabdomyolysis including both horses that had exertional rhabdomyolysis and no complex polysaccharide as well as those with complex polysaccharide in muscle (figure 2). Mild elevations in muscle glycogen were apparent in the racehorses and Arabians with exertional rhabdomyolysis and no abnormal polysaccharide accumulation. These horses did not appear to have a glycogen storage disorder and further studies have implicated abnormal intracellular calcium regulation as the likely cause of rhabdomyolysis in these breeds. 7-9 In contrast, muscle glycogen concentrations were markedly elevated in horses with PSSM compared to other horses with recurrent rhabdomyolysis and control horses (figure 2).
Exercise testing: A 15 min. exercise test at a trot on a longe-line has proven to be very useful for screening horses for exertional rhabdomyolysis. This test is often sufficient to produce subclinical rhabdomyolysis in PSSM horses. On average, a 1000 U/L or greater increase in CK 4-6 hours post-exercise may be observed in PSSM but not healthy horses. Severely affected horses may have persistent elevations in serum CK even after weeks of stall rest.
Polysaccharide storage myopathy has been identified in Quarter Horses, American Paint Horses, Appaloosas, Quarter Horse crosses, warmbloods, and drafts or draft crosses using the criteria of abnormal polysaccharide storage. 6, 11-13 The age range for PSSM is between 8 months and 19 years of age with females being over represented. Pedigree analysis of Quarter Horses, American Paint Horses and Appaloosa horses with PSSM support a familial basis for this condition.13 Line breeding of these breeds to two popular related stallions may be responsible for the increasing incidence for this condition. The nature of PSSM in draft horses and warmbloods is not, as yet, as well documented as in Quarter Horses, and it is unclear at present whether this represents the same heritable trait as suggested for Quarter Horses. 12
Muscle glycogen concentrations in horses with PSSM are 1.5 to 4 times those reported for normal horses or for other breeds of horses with exertional rhabdomyolysis (figure 2). 6,14 This finding together with the abnormal polysaccharide present in skeletal muscle classify this disorder as a glycogen storage disease or "glycogenosis." Glycogenoses could either result from impaired utilization and breakdown of glycogen by tissues or abnormal, increased glycogen synthesis. Studies of the glycogenolytic capacity of skeletal muscle of Quarter Horses with PSSM have not revealed any abnormalities and in fact during anaerobic exercise, PSSM horses have higher glycogen utilization rates than healthy horses.14 As such the metabolic defect responsible for marked glycogen accumulation appears to be due to abnormal regulation and stimulation of glycogen synthesis. Glycogen is synthesized by the combined activity of glycogen synthase which adds straight 1,4 glucose linkages, and branching enzyme which adds a 1,6 glucose branch after every seventh glucose molecule to form a tree-like structure. In horses with PSSM both normal glycogen as well as a filamentous material resembling long straight chains of glucose are present. Preliminary results of glucose tolerance tests suggest that horses with PSSM have significantly higher rates of glucose uptake into muscle than normal horses (personal observation) supporting an abnormality in glycogen synthesis. To date, the precise etiology of PSSM in horses remains unknown.
Treatment and Prevention
Treatment: Horses with acute evidence of muscle cramping and pain frequently become more comfortable after administration of acetylpromazine. If evidence of dehydration is present, intravenous fluids are indicated prior to administration of acetylpromazine and flunixin meglumine. Horses with severe rhabdomyolysis and myoglobinuria may also benefit from intravenous DMSO.
Prevention: Prevention of further episodes of rhabdomyolysis is often successful when the diet and training regime is altered. The goal of this treatment is to provide minimal calories in the form of blood glucose and to prevent excessive glycogen storage by increasing utilization of glucose and glycogen through daily exercise. Principles include establishing regular routines, gradually increasing daily exercise and providing a low soluble carbohydrate, high fat diet.
Exercise: Horses with PSSM benefit from daily turn-out and as little stall rest as possible. Within a few days of an acute episode, exercise on a longe-line can begin but it should be minimal (e.g. 2-5 min of trotting) with the addition of a few extra minutes of trotting every few days. After 3-4 weeks, horses can usually trot for 30 minutes without difficulty on the longe-line at which time work under saddle can begin. Any change in intensity or duration of exercise should be gradual. Treadmill studies show that regular daily exercise is necessary to decrease exercise-induced elevations in serum CK and that these changes will not occur with dietary changes alone (personal observation). PSSM horses benefit most from regular daily exercise with turn-out especially if they can not be ridden daily.
Diet: Episodes of rhabdomyolysis appear to be minimized in horses with PSSM by decreasing the soluble carbohydrate such as grain, sweet feed, molasses in the diet.18 High quality grass hay or half oat/half alfalfa hay combined with a balanced vitamin, mineral and electrolyte mix should form the basis of the diet. If additional calories are necessary, they can be provided in the form of a fat supplement. Rice bran, a 20% fat supplement, is palatable for most horses and 0.5 to 3 kg/day is well tolerated. i,ii Treadmill studies of the metabolic response to exercise showed a decrease in muscle glycogen concentrations following 6 weeks on a rice bran diet i and combined with training a decrease in lactate accumulation (personal observation). Commercially available soy bean/rice bran fat supplements are other alternative fat sources. iii Since these sources are high in phosphorus, it is recommended that the balanced mineral mix also sold by the manufacturers be fed with these fat supplements. Corn-oil is another alternative fat source that can be fed at 1-4 cups/day mixed with alfalfa cubes if horses find this diet palatable. Horses with PSSM should be fed the minimum amount of calories to supply their energy needs. Dietary change alone without changes in training are often not sufficient to prevent rhabdomyolysis.
Most horses with PSSM have competed successfully as pleasure horses, hunters and dressage horses with minimal recurrence of clinical signs. This is particularly true of cross-breds with rhabdomyolysis. A small number of horses are severely affected by PSSM and although improvement is seen with this therapy, they continue to have episodes and may remain exercise intolerant. Typically, these horses have very high muscle glycogen concentrations in their biopsy (>1000 mmol/kg dry weight) and abnormal polysaccharide in 15 % or more of their muscle fibers. Many owners have retired these mares to breeding which seems likely to propagate the trait to subsequent generations.
Polysaccharide storage myopathy, a glycogenosis, represents one of many different causes of exertional rhabdomyolysis in horses. Some confusion regarding the diagnosis of this condition has developed based on the necessary criteria for a positive diagnosis. If abnormal complex polysaccharide is used as a diagnostic criterion, PSSM is commonly found in Quarter Horse related-breeds, warmbloods and draft horses with signs of rhabdomyolysis. Whether the biochemical basis for this disorder in all of these breeds is the same is currently not known. Clinical signs usually follow light exercise and include gait asymmetry, stiffness, stretching out and reluctance to move due to painful muscle cramping. Preventing recurrent episodes of rhabdomyolysis involves decreasing the amount of soluble carbohydrates in the diet, adding a fat supplement, and most importantly providing regular daily exercise.