Skeletal Muscle Diseases in Animals PDF

CHAPTER 15 Skeletal Muscle tension can cause muscle tearing. Muscles are endowed with an extensive vascular network that can allow entry of bloodborne pathogens, immune complexes, antibodies and toxins, and inflammatory cells. Other routes by which muscle can become dysfunctional are summarized in B...

CHAPTER 15 Skeletal Muscle tension can cause muscle tearing. Muscles are endowed with an extensive vascular network that can allow entry of bloodborne pathogens, immune complexes, antibodies and toxins, and inflammatory cells. Other routes by which muscle can become dysfunctional are summarized in Box 15.6. Some muscular disorders are genetically determined. Inherited or acquired dysfunction of motor neurons or nerves causes muscle injury in the form of atrophy. Toxins or an altered endocrine or electrolyte status can affect muscle, and physiologic damage can be caused by exhaustive or overexuberant exercise. Defense Mechanisms/Barrier Systems Defense mechanisms and barrier systems are summarized in Box 15.7. The thick encircling fascia (epimysium) of many muscles provides some protection from penetrating injuries and from extension of adjacent infection. This fascia can, however, also contribute to injury under circumstances that lead to increased intramuscular pressure causing hypoxia (compartment syndrome). Tissue macrophages are not typically found in normal muscle but are recruited rapidly from circulating monocytes in the vasculature. Macrophages can cross even an intact basal lamina and effectively clear debris from damaged portions of myofibers, allowing for rapid restoration of the myocyte through satellite cell activation. Neutrophils and Box 15.6  Other Causes of Muscle Dysfunction PHYSIOLOGIC Excessive muscle tension causing muscle rupture Exercise-induced damage to myofibers Loss of innervation Loss of blood supply Endocrine and electrolyte abnormalities GENETIC Inborn errors of metabolism Genetic defects of myofiber structural components Developmental defects NUTRITIONAL/TOXIC Deficiency of selenium and/or vitamin E Toxic plants or plant products Feed additives (ionophores) Other toxins (e.g., some snake venoms) Box 15.7  Defense Mechanisms and Barrier Systems of Skeletal Muscle SKIN, SUBCUTIS, AND FASCIA Form structural barriers to protect against external injury VASCULATURE Collateral circulation to protect against ischemia Recruitment of monocytes that become tissue macrophages Recruitment of neutrophils and other inflammatory cells Capillary endothelium resistant to tumor metastasis IMMUNOLOGIC RESPONSES Innate humoral and cellular immunologic responses OTHER Adequate tissue antioxidant concentrations Physiologic adaptation (e.g., hypertrophy, fiber type alteration) Regenerative capacity of myofibers 1007 other inflammatory cells are also recruited from the bloodstream in response to injury or infection. The extensive vascular network of muscle includes extensive collateral circulatory pathways that render muscle relatively resistant to ischemic damage caused by thrombosis or thromboembolism. Despite the high vascular density of muscle, metastasis of neoplasms to muscle is rare. There is evidence that the capillary endothelium of skeletal muscle is inherently resistant to neoplastic cell adhesion and invasion. Diseases Affecting Multiple Species of Domestic Animals Adequate muscle function is essential for the survival of any species. Many domestic animals have been selectively bred for improved musculature for meat production, performance, or appearance. Therefore, muscle disease in animals can have a significant economic impact. In some cases, it is selection pressure imposed by human beings that has resulted in development and perpetuation of various myopathic conditions in animals. It is likely that continued selection for what appears to be a phenotypically desirable trait will lead to the recognition of new genetic mutations and myopathic conditions in the future. It is interesting to compare the effects of muscular disorders that affect human beings and animals. The four-footed stance of animals allows for greater stability, which can allow an animal to remain ambulatory for some time, when a similarly affected person would be confined to a wheelchair. However, disorders that result in recumbency, even if it is transitory, can be devastating in livestock. It is much more difficult to nurse a large animal through a period of recumbency than it would be to nurse a hospitalized human being or small animal. The most common and important muscle disorders of animals are discussed by species because this is the way diseases are considered clinically. The same disease may occur in different species. Details of less common muscle disorders are presented in E-Appendix 15.1. Types of Muscle Disease Classification of muscle diseases based on lesions alone is not very satisfactory, and many classifications are based on cause (e.g., toxic myopathy or nutritional myopathy). An example of such a classification is given in Table 15.2. Myopathic conditions can be inherited or acquired. Inherited disorders can affect muscle metabolism or myofiber structure. Acquired muscle disease in livestock is often associated with nutritional deficiency or with ingestion of myotoxins, whereas acquired muscle disease in the dog is most often caused by immune-mediated inflammatory conditions. Other causes of acquired myopathies include ischemia, infectious agents, hormonal or electrolyte abnormalities, and trauma. There are also many neuropathic conditions that result in denervation atrophy (see section on Dysfunction/Responses to Injury, Alteration in Myofiber Size, Atrophy, Denervation Atrophy). More information on most of the disorders described in this section can also be found under the appropriate species heading or in E-Appendix 15.1. Degenerative Degenerative myopathies are those resulting in segmental or global myofiber necrosis, in which inflammatory cells are not the cause of the myofiber damage. Disturbance of Circulation. Given the numerous capillary anastomoses and rich collateral circulation of skeletal muscle, only disorders that result in occlusion of a major artery or that cause widespread intramuscular vascular damage will result in myofiber necrosis CHAPTER 15 Skeletal Muscle E-Appendix 15.1 Viral Causes of Myositis Porcine encephalomyelitis is caused by a coronavirus of the Enterovirus genus. Besides the destruction of the neurons, which results in paralysis, the virus can also cause multifocal necrosis of myofibers, accompanied by a focal interstitial and perivascular infiltrate of lymphocytes, macrophages, and a few neutrophils. Porcine circovirus type 2 can cause granulomatous necrotizing myositis in pigs. The major lesions of foot-and-mouth disease virus in ruminants and pigs are vesicles in the skin and mucous membranes. In addition, the heart and skeletal muscles can have yellow streaks and pale foci, which microscopically are areas of segmental myofiber necrosis accompanied by an intense lymphocytic and neutrophilic infiltration. Akabane virus (Bunyaviridae family) can produce a nonsuppurative myositis in the bovine fetus. Bluetongue, caused by a virus of the family Reoviridae, is a noncontagious, insect-borne viral disease of sheep that causes vasculitis in a wide array of tissue, particularly the oral mucosa. Gross lesions in muscles are foci of necrosis (infarctions) and hemorrhage. Depending on the age of the lesions, necrosis, calcification, or regeneration may be present. Because of the size of the infarcts, regeneration is usually not possible, and healing is by fibrosis. Parasitic Myositides The larval forms of Ancylostoma caninum migrate somatically, primarily in human beings. After entering the muscles of paratenic hosts, development is arrested. The larvae cause inflammation and myonecrosis. As they continue to migrate, they leave a trail of inflammation and segmental myofiber necrosis. Toxocara canis larvae migrate through numerous tissues of the dog (visceral larval migrans). Some larvae are arrested, and granulomas form around them. These have been found in a wide array of tissue, including kidney, liver, lung, myocardium, and skeletal muscle. The lesion in muscle is a focal granulomatous myositis, with the larvae and granulomas lying between myofibers. Dirofilaria immitis, a nematode normally found in the hearts of dogs and cats, can occasionally involve the external and internal iliac arteries and their branches. Thromboemboli from debris and parasites can cause multiple infarcts in the muscles of the hind limbs (see the section on Disturbance of Circulation). Cysticercus is a larva with a solid caudal portion and a bladderlike proximal portion. It is the intermediate stage in the life cycle of several tapeworms. Taenia solium and Taenia saginata, both tapeworms of human beings, have a cysticercus stage in the pig (Cysticercus cellulosae) and cattle (Cysticercus bovis). These cysticerci preferentially lodge in the most active muscles, especially the heart, masseter, diaphragm, and tongue, where they appear as small white or gray cysts. Histologically, there is displacement of myofibers by the cyst but little myositis; there may be a few lymphocytes, macrophages, and eosinophils around the cyst, which lies in the interstitial tissue, not within the myofiber. With time, the immunologic system of the host kills the cysticercus. C. cellulosae in pigs can become calcified. Cysticercus ovis in the heart and shoulder muscles of sheep and goats is the intermediate stage of Taenia ovis, a tapeworm of dogs. Hepatozoon americanum is a protozoal organism, previously classified as Hepatozoon canis, that infects multiple tissues, including the skeletal muscle of dogs. It is most common in South Africa and the Middle East but also occurs in areas of the United States (primarily Oklahoma and the Gulf Coast area). Young dogs, up to 6 months of age, are most susceptible to infection. The organism is transmitted by ingestion of an infected tick, such as Rhipicephalus sanguineus. Sporozoites invade through the intestinal wall and travel to multiple 1007.e1 tissues, particularly liver and skeletal muscle, where they undergo schizogony. Suppurative to granulomatous inflammation occurs after rupture of schizonts within tissue. Encysted stages, however, do not elicit an inflammatory response. Clinical signs include fever, anorexia, weight loss, body pain, and gait abnormalities. Respiratory signs can also occur. Serum CK activity is often mildly increased. Radiographs often reveal a characteristic periosteal proliferation of long bones similar to that of hypertrophic osteopathy. Diagnosis is made by identification of the organism either within peripheral neutrophils or within affected tissue. In dogs, infection by Trypanosoma cruzi (Chagas’s disease) causes myocarditis with lesser involvement of skeletal muscle. Inflammation consists of lymphocytes admixed with macrophages. Protozoal organisms are typically readily identified in affected tissues. Congenital and Inherited Myopathies Congenital Muscular Hyperplasia (Double Muscling) in Cattle Congenital muscular hyperplasia (double muscling) is seen in several beef breeds, including Charolais, Angus, Belgian blue, Belgian white, South Devon, Santa Gertrudis, and Piedmontese cattle. This disorder is inherited as an autosomal recessive trait with incomplete penetrance. The genetic defect is inactivation of the myostatin gene, which regulates the number and size of myofibers. Affected calves have large, bulky muscles, especially of the shoulder and rump, because of an increased number of otherwise normal fibers. This increased muscle bulk predisposes to dystocia. Body fat deposits and intramuscular fat are reduced to approximately 60% of normal, which is considered desirable in a meat-producing animal. The diagnosis of this disorder is readily made based on typical clinical findings. There is no treatment. Bovine Diaphragmatic Dystrophy A muscular dystrophy affecting diaphragm and respiratory muscles has been recognized in Meuse-Rhine-Yssel cattle in Europe and Holstein cattle in Japan. This disorder appears to be inherited as an autosomal recessive trait. The most common clinical sign is recurrent bloat. Clinical signs appear in adults 2 years of age or older and include loss of condition, decreased rumen activity, and recurrent bloat. Serum activity of muscle enzymes is normal. The diaphragm is found to be thickened and pale. Examination of affected muscle indicates a progressive myopathy with severe cytoarchitectural alterations and other chronic myopathic changes, including fibrosis. Scattered necrotic fibers can be found, but this myopathy does not have the characteristic ongoing progressive myofiber necrosis and regeneration of muscular dystrophy. Central corelike lesions are prominent and have been found to contain actin and ubiquitin with immunohistochemical studies. This disorder would be best defined as a progressive inherited myopathy, possibly a myofibrillar myopathy. There is no treatment, and animals producing affected offspring should not be rebred. Ovine Muscular Dystrophy A progressive disorder known as ovine muscular dystrophy is recognized in Merino sheep in Australia. The underlying defect is not known. The disease is inherited as an autosomal recessive trait. Clinical signs of neuromuscular weakness occur as early as 1 month of age and are characterized by a stiff gait and exercise intolerance. Serum concentrations of CK and AST are increased. Because the disease affects only type 1 myofibers, gross lesions are most easily seen in muscles that consist primarily or only of type 1 myofibers (e.g., vastus intermedius). The appearance depends on the age of the animal. Initially the muscle is pale and lacks tone but is close to 1007.e2 SECTION II Pathology of Organ Systems normal size. In the next few years, the muscle becomes firm, more atrophic, and pale gray to almost white as the space formerly occupied by the myofibers is filled with adipocytes and fibrosis. There is atrophy and hypertrophy of the myofibers, along with myopathic features such as internal nuclei and subsarcolemmal masses. Lesions do not have the characteristic ongoing progressive myofiber necrosis and regeneration of muscular dystrophy, and this disorder may be best defined as a progressive inherited myopathy. Diagnosis is based on characteristic clinical and histopathologic findings. There is no treatment for this progressive disorder, and animals producing affected lambs should not be rebred. Other Canine Muscular Dystrophies Defects in sarcoglycan, a protein that is part of the sarcolemmal dystrophin glycoprotein complex, have been found in both male and female dogs of various breeds. Affected dogs exhibit signs of neuromuscular disease by 1 year of age. Serum activities of CK, AST, and ALT are increased. EMG detects abnormal spontaneous activity, including myotonic bursts, and histopathologic findings of multifocal polyphasic necrosis are consistent with muscular dystrophy. X-linked Myotubular Myopathy A rapidly progressive fatal myopathy occurs in Labrador retrievers and Rottweiler dogs. The cause is a mutation in the MTM1 gene resulting in reduction or absence of the enzyme myotubularin. Histopathologic findings are myofiber hypotrophy and cytoarchitectural changes including internal nuclei, perinuclear halos, central aggregates of organelles, and peripheral mitochondrial aggregates. Other Muscular Diseases of Cattle Myopathy of Gelbvieh Cattle A necrotizing myopathy of juvenile Gelbvieh cattle has been recognized. An inherited basis is suspected. Clinical signs include neuromuscular weakness. The characteristic histopathologic change in affected muscles is necrotizing vasculitis that results in myofiber necrosis. The pathogenesis of this disorder is not known; both vitamin E deficiency and immune-mediated disease have been suggested. Pathologic changes are also found in the kidney, dorsal spinal tracts of the spinal cord, and in peripheral nerves. Cardiac lesions can occur but are uncommon. Treatment with vitamin E may be of some benefit. Brown Swiss Cattle Neuronopathy An inherited neuronal degenerative disease designated as a form of spinal muscular atrophy occurs in brown Swiss cattle. Clinical signs of a progressive lower motor neuron weakness appear by 2 to 6 weeks of age. Neuronal degeneration within the ventral gray matter of the spinal cord leads to axonal degeneration of peripheral nerves and denervation atrophy of muscle. The disorder is inherited as an autosomal recessive trait, and pedigree analysis has identified a common ancestor thought to be the founder animal. Animals producing affected calves should not be rebred. Other Breed-Associated Diseases of Dogs Canine Dermatomyositis A condition involving skin and muscle has been described in collies and Shetland sheepdogs, and it has been compared with dermatomyositis of human beings. In human beings, characteristic skin lesions and immune-mediated damage to muscle capillaries occur. In dogs, the dermatopathologic changes are distinctive, but muscle involvement is much less common, and the muscle lesions seen are not always convincingly vascular in nature. In cases studied by the author, occasional muscle inflammation appeared to reflect extension of inflammation from overlying ulcerated skin. Myopathy of Bouvier des Flandres Dogs A progressive degenerative myopathy affecting males and females is recognized in Bouvier des Flandres dogs. Onset of clinical signs of neuromuscular weakness varies from approximately 2 months to 2 years of age. Esophageal and pharyngeal muscles are often most severely affected. Generalized muscle atrophy, weakness, and abnormal gait are typical. Serum activities of CK and AST are often moderately increased. EMG reveals abnormal spontaneous activity (myotonic bursts). Generalized muscle atrophy and megaesophagus are common necropsy findings. Histopathologic changes are generally severe chronic myopathic change with notable cytoarchitectural changes. Multifocal fiber necrosis and regeneration occurs but is not common. Cardiac necrosis and fibrosis can also be seen. Distal Myopathy of Rottweiler Dogs In distal myopathy of Rottweiler dogs, both males and females are affected. Clinical signs of progressive muscle weakness and development of a plantigrade and palmigrade stance are apparent by approximately 2 months of age. This disorder is characterized histologically by severe fiber atrophy and fat infiltration, primarily of distal limb musculature. Myonecrosis and fibrosis are mild. Serum activities of CK and AST can be normal or slightly increased. EMG reveals rare spontaneous activity (fibrillations and positive sharp waves). Decreased serum and muscle carnitine concentrations suggest that this may be a lipid metabolic disorder. Myopathy of English Springer Spaniels A myopathy with involvement of esophageal muscle occurs in English springer spaniel dogs. Affected dogs also have dyserythropoiesis and cardiomegaly. Histologic findings include chronic myopathic change with central linear or granular inclusions within myofibers. Myopathy of Great Danes A progressive myopathy characterized by central “corelike” structures occurs in young Great Dane dogs. Clinical signs are progressive weakness and muscle atrophy. Serum concentration of CK is either normal or only mildly increased. Myoclonus in Wirehaired Miniature Dachshunds A syndrome of sustained muscle contraction (myoclonus), seizures, and early dementia is recognized in related wirehaired miniature dachshunds. Inclusions of PAS-positive, amylase-resistant polyglucosan bodies similar to Lafora bodies described in human beings occur in skeletal muscle and central nervous tissue. Other Breed-Associated Diseases of Cats Feline nemaline myopathy is a congenital disorder described in domestic short-haired cats. Affected cats develop a characteristic progressive gait abnormality and muscle atrophy at an early age. The characteristic pathologic finding of expanded Z-line material (nemaline rods) within skeletal muscle fibers is only apparent in frozen sections or ultrastructurally. The mode of inheritance is not known. An autosomal recessively inherited muscular dystrophy caused by absence of the dystrophin-related protein α-dystroglycan occurs in Devon rex and Sphinx cats. Clinical signs of neuromuscular weakness are apparent beginning at 1 month to 6 months of age. The disease is either slowly progressive or remains static. Megaesophagus is also possible. Muscular dystrophy associated with deficiency of β-sarcoglycan also occurs in cats. Periodic hypokalemic polymyopathy occurs as a genetic disease in Burmese cats. The cause is a single nonsense mutation in the WNK4 gene that codes for lysine-deficient 4 protein kinase, an CHAPTER 15 Skeletal Muscle enzyme in the distal nephron. The mutation is thought to result in a potassium-wasting nephropathy. Myotonia and Pseudomyotonia Equine Species Congenital or early onset myotonia is seen in thoroughbreds, standardbreds, and quarter horses. Various similar disorders, designated as myotonic dystrophy–like or muscular dystrophy–like, are likely to be the same or similar disorders. As with all congenital myotonias, an underlying abnormal ion channel leading to continuous abnormal muscle activity is suspected. But to date the defect and potential for inheritance have not been defined. Affected horses have remarkable exercise intolerance, with stiffness of posture and gait apparent at birth or soon thereafter, and often, remarkably well-defined to hypertrophied muscle groups. Clinical signs of stiffness are most apparent when the animals first begin to move, with some decrease in stiffness with exercise. Serum concentrations of CK and AST are generally normal to only slightly increased. Muscles often show prolonged dimpling after percussion. Concentric needle EMG demonstrates characteristic waxing and waning (“dive bomber”) myotonic bursts. No specific gross lesions are present, other than prominent muscling. On histologic examination, affected muscle fibers vary tremendously in size and shape, with numerous internal nuclei, altered cytoplasmic areas beneath the sarcolemma (sarcoplasmic masses), and other cytoarchitectural alterations such as ring fibers. Scattered fiber necrosis and regeneration may be seen but is not a prominent feature. In chronic cases, affected muscles can develop a variable degree of replacement of myofibers by fat, indicating a previous loss of myofibers. The diagnosis of myotonia is based on characteristic clinical signs in a young horse and can be confirmed by EMG or muscle biopsy. No specific treatment is known at this time. Bovine Species An autosomal recessive disorder causing pseudomyotonia has been described in Chianina and Romagnola cattle, and in one Dutch improved Red and White crossbred bovid. A defect in a gene involved in myofiber calcium homeostasis (the SERCA1 gene). The disorder is characterized by exercise induced muscle contracture. Feline Species The pathogenesis of feline congenital myotonia is not known at this time, although a skeletal muscle ion channel defect is suspected. Cats with congenital myotonia have signs similar to those of cats with X-linked muscular dystrophy, but the muscular hypertrophy is less remarkable. A stiff gait is the most obvious sign. Serum concentrations of CK and AST are normal or only slightly increased. Concentric needle EMG reveals waxing and waning (“dive bomber”) potentials characteristic of myotonia. Other than mild muscular hypertrophy, there are no findings at necropsy. Significant myofiber hypertrophy and increased variation in myofiber diameter are the only histopathologic findings. Dilatation of sarcotubular elements is the characteristic ultrastructural finding. The diagnosis of congenital feline myotonia is based on characteristic clinical findings. At this time, no type of treatment has been attempted. Metabolic Myopathies Acid Maltase Deficiency (Glycogenosis Type II; Pompe’s Disease) Acid maltase deficiency (glycogenosis type II; Pompe’s disease) is a defect that has been described in shorthorn and Brahman cattle and is inherited as an autosomal recessive trait. The enzyme defect 1007.e3 results in blockage of the glycolytic metabolic pathway and in cellular dysfunction, which is most evident in skeletal muscle, Purkinje cells of the heart, and neurons. Myofiber necrosis is thought to be a result of a cellular “energy crisis” (i.e., energy deprivation). Affected shorthorn cattle often show clinical signs of weakness by 3 to 7 months of age and die as a result of respiratory and cardiac failure. Affected shorthorn cattle may also develop relatively normally until 1 to 1½ years of age, at which time weakness and neurologic deficits are evident. Affected Brahman cattle grow poorly and have muscular weakness and neurologic disease. Electrocardiographic studies reveal abnormalities of cardiac conduction. Serum concentrations of CK and AST can be increased, with notable increases evident in severely weak animals before death. There may be no obvious changes within the skeletal and cardiac muscle at necropsy, although pale streaks may be evident in those animals undergoing myofiber necrosis before death. No gross pathologic lesions are evident in the nervous system. On histopathologic examination, affected myofibers, cardiac myocytes, and neurons are filled with vacuoles containing glycogen (vacuolar myopathy and neuronopathy), which can be demonstrated by PAS reaction. Glycogen accumulation in skeletal myofibers is segmental, whereas in neurons it is diffuse. Both degeneration and regeneration of skeletal muscle fibers and chronic myopathic change (fiber atrophy, hypertrophy, and internal nuclei) are present. Diagnosis of a glycogenosis can be made based on characteristic clinical and histopathologic findings. Assay of affected tissue for glycolytic enzyme activities is necessary to determine the specific enzyme defect. There is no effective treatment for this disorder, and cattle known to produce affected calves should not be rebred. Myophosphorylase Deficiency (Glycogenosis Type V; McArdle Disease) Myophosphorylase deficiency is an autosomal recessive disorder with glycogen storage similar to acid maltase deficiency but with only skeletal muscle involvement. This disorder has been identified in Charolais cattle. Clinical signs of exercise intolerance and inability to keep up with herd mates are recognized at a relatively early age. If forced to exercise, affected cattle become recumbent for up to 10 minutes. Serum concentrations of CK and AST are often mildly to markedly increased. No specific findings are evident at necropsy. Histopathologic findings in skeletal muscle are similar to those of acid maltase deficiency. Diagnosis can be based on characteristic clinical and histopathologic findings. Affected animals and carriers can be detected after analysis of peripheral blood leukocyte DNA by polymerase chain reaction assay. There is no treatment, and carrier animals should not be used for breeding. A glycogen storage myopathy caused by myophosphorylase deficiency has been identified in sheep in Australia and is similar to the disease in cattle. Phosphofructokinase Deficiency (Glycogenosis Type VII) Phosphofructokinase deficiency (glycogenosis type VII) is an autosomal recessive disorder in dogs caused by a point mutation in the muscle isoenzyme of phosphofructokinase, an important enzyme in the glycolytic pathway. This disorder has been recognized in English springer spaniels and American cocker spaniels. Muscles from older affected dogs can have myopathic changes and inclusions of a PAS-positive, amylase-resistant substance classified as complex polysaccharide. Clinical signs of neuromuscular dysfunction do not occur, however, because skeletal muscle upregulates expression of the liver isoenzyme of phosphofructokinase. Absence of erythrocyte phosphofructokinase results in hemolysis during periods of increased respiratory activity (panting) and resultant mild respiratory alkalosis. 1007.e4 SECTION II Pathology of Organ Systems Feline Glycogenoses Glycogenosis type IV occurs in Norwegian Forest cats because of decreased activity of GBE, resulting in defective carbohydrate metabolism and a generalized glycogen storage disease. The disorder is inherited as an autosomal recessive trait. Affected cats may be stillborn or die within a few hours of birth. Those that survive lack energy and develop muscle tremors and a bunny-hopping pelvic limb gait at approximately 5 months of age. The disease is progressive, resulting in severe generalized muscle atrophy and tetraplegia. Concentric needle EMG reveals abnormal spontaneous activity with normal motor nerve conduction velocities. Serum concentrations of CK and AST are mildly to moderately increased. Muscle atrophy and fibrosis are evident in affected pelvic limb muscles of cats surviving 1 year or longer. The characteristic histopathologic finding is storage of PAS-positive, amylase-resistant material that forms “lakes” within skeletal muscle fibers. Myofiber atrophy is also prominent, and myofiber necrosis and regeneration can be seen. Cardiac myocytes have similar inclusions and undergo necrosis and replacement by fibrosis. Abnormal glycogen storage is also seen within smooth muscle and neurons in the central nervous system. Diagnosis can be suspected on the basis of characteristic clinical and histopathologic findings. Confirmation is based on assay of GBE concentration in blood leukocytes. There is no treatment for this disorder. Similar intramyofiber inclusions of PAS-positive, amylase-resistant inclusions resulting in clinical signs of neuromuscular weakness are found rarely in older cats of mixed breeding, suggesting that there is more than one cause for this finding in cats. Equine Mitochondrial Myopathy A single case of mitochondrial myopathy in a 3-year-old Arabian filly has been reported. Deficiency of mitochondrial respiratory chain complex I was detected. Clinical signs were stiff gait and profound exercise intolerance. Lactic acidosis developed with minimal exercise. Skeletal muscle samples exhibited increased muscle mitochondrial content with bizarre cristae formation on ultrastructural examination. Canine Mitochondrial Myopathies A mitochondrial myopathy has been recognized in Old English sheepdogs. Clinical signs are exercise intolerance leading to episodic weakness and exercise-induced lactic acidosis. A suspected mitochondrial myopathy occurs in Welsh terrier dogs. Involvement of skeletal muscle occurs in Alaskan husky and Australian cattle dogs as part of a mitochondrial encephalomyopathy syndrome. Other Canine Metabolic Myopathies Pyruvate dehydrogenase deficiency occurs in Clumber and Sussex spaniels in the United States and Belgium. Clinical signs are profound exercise intolerance with exercise-induced lactic acidosis. No gross or histopathologic lesions are found in muscle. 1008 SECTION II Pathology of Organ Systems (Box 15.8). Vascular occlusion of a major artery, most often aortoiliac thrombosis, occurs most commonly in cats (thromboembolism) and horses (mural thrombosis). Intramuscular vascular damage occurs in many species, and there are a variety of causes. The basic factor in determining the effect of ischemia on muscle is the differential susceptibility of the various cells forming the muscle as a whole. Myofibers are the most sensitive, satellite cells less sensitive, and fibroblasts the least sensitive to anoxia. Thus, obstruction of the blood supply to an area of muscle leads first to myofiber necrosis, then to the death of satellite cells, and finally to the death of all cells, including the stromal cells. The size of skeletal muscle infarcts depends on the size of the vessel obstructed and the duration of blockage. Because of the numerous anastomoses, blockage of capillaries causes less severe ischemia but can result in segmental myofiber necrosis, which is usually multifocal and if the cause is ongoing, polyphasic, with regenerating and necrotic myofibers. However, when larger arteries are blocked, whole areas of muscle, including the satellite cells, are killed, resulting in a monophasic necrosis and healing by fibrosis. Ischemia can also cause peripheral nerve damage and neuropathy, leading to denervation atrophy of intact myofibers. Table 15.2 Classification of Muscle Disease Classification Cause or Type of Disorder Degenerative Ischemia Nutritional Toxic Exertional Traumatic Bacterial Viral Parasitic Immune-mediated Anatomic defects Muscular dystrophy Congenital myopathy Myotonia Metabolic Malignant hyperthermia Hypothyroidism Hypercortisolism Hypokalemia Hypernatremia Other electrolyte imbalances Peripheral neuropathy Motor neuronopathy Myasthenia gravis Botulism Tick paralysis Primary tumors (rhabdomyoma, rhabdomyosarcoma) Secondary tumors (hemangiosarcoma, fibrosarcoma, infiltrative lipoma, other tumor phenotypes) Metastatic tumors Inflammatory Congenital and/or inherited Endocrine Electrolyte Neuropathic Neuromuscular junction disorders Neoplasia Box 15.8  Causes of Muscle Ischemia Occlusion of a major blood vessel External pressure on a muscle Swelling of a muscle in a nonexpandable compartment (“compartment syndrome”) Vasculitis/vasculopathy Increased intramuscular pressure can occur in a recumbent animal of sufficient weight after a prolonged period of recumbency, because of either disease or general anesthesia. Myofiber necrosis caused by recumbency can occur because of (1) decreased blood flow as a result of compression of major arteries, (2) reperfusion injury causing massive calcium influx into muscle cells when the animal moves or is moved and the compression relieved, (3) increased intramuscular pressure causing compartment syndrome,b or (4) any combination of these factors. Localized myonecrosis caused by recumbency is common in horses, cattle, and pigs; occurs only in large breeds of dogs; and is virtually unheard of in cats. In downer cows, the weight of the body of the animal in sternal recumbency can cause ischemia of the pectoral muscles and of any muscles of the forelimbs or hind limbs that are tucked under the body. Ewes in advanced pregnancy with twins or triplets can develop an ischemic necrosis of the internal abdominal oblique muscle, which can lead to muscle rupture. Plaster casts or bandages that are too tight can put external pressure on muscles, leading to ischemia. The duration of ischemia determines the severity of necrosis and the success of regeneration (see the section on Necrosis and Regeneration). Postanesthetic myopathy is a monophasic, multifocal necrosis. In the downer cow, the lesions are multifocal to locally extensive (Fig. 15.25) and, depending on the duration since the onset of recumbency, can be either monophasic or polyphasic. Any severe insult, whether it be ischemia caused by recumbency or another myodegenerative disorder that causes myonecrosis within a muscle covered by a tight and nonexpansible fascia, can result in ischemic injury because early in the necrosis, there is increased intramuscular pressure. The resulting compromise of blood circulation leads to ischemic myodegeneration, which is known as compartment syndrome. The phenomenon of compartment syndrome is best illustrated in the anterior tibial muscle of human beings after strenuous exercise. This condition is believed to be a consequence of swelling of the anterior tibial muscle, which is surrounded anteriorly by the inelastic anterior fascial sheath and posteriorly by the tibia. Swelling Figure 15.25 Ischemic Necrosis, Downer Cow Syndrome, Pectoral Muscle, Cow. Increased intramuscular pressure during prolonged periods of recumbency has resulted in localized muscle pallor (lighter-colored areas of muscle) from myofiber necrosis secondary to decreased blood flow caused by compression of arteries. (Courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.) bIschemic necrosis of muscle after swelling in a nonexpandable compartment. CHAPTER 15 Skeletal Muscle impedes blood supply, resulting in ischemia. A similar phenomenon occurs in muscles surrounded by tight fascia in animals, particularly horses. Horses that are recumbent because of general anesthesia can develop compartment syndrome affecting gluteal or lateral triceps muscles. Horses can also develop compartment syndrome in gluteal muscles because of exertional rhabdomyolysis and in temporal and masseter muscles because of selenium deficiency. Compartment syndrome is also possible in the temporal and masseter muscles of dogs with masticatory myositis. Damage to intramuscular blood vessels also causes myofiber necrosis. Vasculitis can cause areas of muscle damage (e.g., in horses with immune-mediated purpura hemorrhagica because of Streptococcus equi infection [see Fig. 15.32] and in pigs with erysipelas). Viral diseases that target blood vessels of many organs, such as bluetongue in sheep, can also affect muscle. Exotoxins produced by clostridial organisms cause myositis and severe localized vascular damage, leading to hemorrhage and myofiber necrosis. The familial myopathy of Gelbvieh cattle is characterized by fibrinoid necrosis of intramuscular blood vessels and associated myonecrosis. Nutritional Deficiency. Myofibers are particularly sensitive to nutritional deficiencies that result in the loss of antioxidant defense mechanisms. Nutritional myopathies are most common in livestock, including cattle, horses, sheep, and goats (Table 15.3). Although nutritional myopathy of livestock is often referred to as selenium/vitamin E deficiency, in the vast majority of cases, deficiency of selenium is the cause of myofiber degeneration. The trace mineral selenium is a vital component of the glutathione peroxidase system, which helps to protect cells from oxidative injury. The high oxygen requirement combined with contractile activity makes striated muscle, both skeletal and cardiac, particularly sensitive to oxidative injury. Neonatal animals, which rely on stores of selenium accumulated during gestation, are most frequently affected. Affected muscle is pale as a result of necrosis (see Fig. 15.39), thus the common name white muscle disease. As should be evident from the previous discussion, a gross observation of pale muscle is not specific for necrosis caused by nutritional deficiency; therefore, the term nutritional myopathy is much preferred. Toxic Myopathies. Livestock are the animals most prone to develop a degenerative myopathy from the ingestion of a toxin (see Table 15.3). Myotoxins can be present in plants in pastures or hay Table 15.3 Nutritional and Toxic Myopathies Disorder Nutritional myopathy Ionophore toxicity Plant toxicity Pasture-associated myopathy (Uni­ ted Kingdom, midwestern United States) Species Affected Horses, cattle, sheep, goats, camelids, pigs Horses, cattle, sheep, goats, pigs Horses, cattle, sheep, goats, pigs Horses Cause Selenium or (less commonly) vitamin E deficiency Monensin, other ionophores used as feed additives Cassia occidentalis, Senna obtusifolia, other toxic plants; gossypol in cotton­ seed products Box elder tree (Acer negundo) toxicity 1009 and in plants or plant products in processed feed. Examples of toxic plants and plant products include Cassia (coffee senna), Karwinskia (coyotillo), Eupatorium (white snakeroot), Acer negundo (box elder tree) seeds, and gossypol present in cottonseed. Clinical signs are weakness, often leading to recumbency, and are accompanied by a moderate to severe increase in serum muscle enzyme concentrations. Gross and histologic findings of multifocal necrosis that can be either monophasic or polyphasic are typical. Diagnosis is based on identification of causative plants within feed, pasture, or stomach contents or, when available, detection of toxic compounds in stomach content or liver. Ionophore antibiotics, such as monensin, lasalocid, maduramicin, and narasin, are often added to ruminant feeds to enhance growth. Ionophores form lipid-soluble dipolar reversible complexes with cations and allow movement of cations across cell membranes, often against the concentration gradient. This causes a disruption of ionic equilibrium that can be detrimental, especially to excitable tissue such as the nervous system, heart, and skeletal muscle. Ionophore toxicity results in calcium overload and death of skeletal (see Figs. 15.11, B, and 15.33) and cardiac muscle. Most domestic ruminants are tolerant of moderate ionophore levels, but toxicity occurs at very high levels. Most cases of ionophore toxicity involve the ingestion of monensin. The LD50 (the dose at which 50% of animals die) of monensin in cattle is 50 to 80 mg/kg, and the LD50 for sheep and goats is 12 to 24 mg/kg. Horses are exquisitely sensitive to ionophores and even very low levels are toxic, with an LD50 for monensin of only 2 to 3 mg/kg of body weight. Exertional Myopathies. The ionic and physical events associated with myofiber contraction can, under certain circumstances, predispose a myofiber to necrosis. Exercise-induced myonecrosis, which can be massive, can occur because of simple overexertion. This outcome is well known in the capture and restraint of nondomesticated species, a syndrome known as capture myopathy. More often, however, exercise-induced myofiber damage occurs in animals with preexisting conditions such as selenium deficiency, muscular dystrophy, severe electrolyte depletion, or glycogen storage disease. The term exertional rhabdomyolysis (also known as exertional myopathy, azoturia, setfast, blackwater, Monday morning disease, and tying up) has long been applied to a syndrome recognized in horses (see Fig. 15.35). Only recently have underlying myopathic conditions been identified as the most common predisposing cause of equine exertional rhabdomyolysis (see Diseases of Horses). A similar disorder affects working dogs such as racing sled dogs and greyhounds, the cause of which is still unclear. Trauma. External trauma to muscle includes crush injury, lacerations and surgical incisions, tearing caused by excessive stretching or exercise, burns, gunshot and arrow wounds, and certain injections. Some of these result in complete or partial rupture of a large muscle. The diaphragm is the most common muscle to rupture and in dogs and cats is most often the result of a sudden increase in intraabdominal pressure, such as from being hit by a car. In horses, diaphragmatic rupture is thought to occur most often during falls in which the pressure of the abdominal viscera causes diaphragmatic damage. A partial rupture of a muscle results in a tear in the fascial sheath, through which the muscle can herniate during contraction. In racing greyhounds, spontaneous rupture of muscles, such as the longissimus, quadriceps, biceps femoris, gracilis, triceps brachii, and gastrocnemius, can occur during strenuous exercise. In horses, damage to the origin of the gastrocnemius muscle has been linked to overexertion during exercise or while struggling to rise. Tearing of muscle fibers occurs in the adductor muscles of the hind limbs of 1010 SECTION II Pathology of Organ Systems cattle doing the “splits” (sudden bilateral abduction) on a slippery floor. Because there is often extensive disruption of the myofibers’ basal laminae, most of the healing is accomplished by fibrosis. If muscle trauma is accompanied by fractures of bones and the animal moves the limb, further trauma by laceration by sharp bone fragments can result. Unusual Lesions Resulting from Muscle Trauma Information on this topic is available at www.expertconsult.com. Inflammatory Myopathies (Myositis, Myositides [Plural]) In addition to the misnomer “myositis ossificans,” the term myositis has been inappropriately applied to various other veterinary disorders, such as exertional and nutritional myopathy, in the horse. These two disorders are degenerative myopathies, not inflammatory myopathies. It is vital to distinguish between a true myositis and a degenerative myopathy in which there is a secondary inflammatory response. In the normal response to the myofiber necrosis, the necrotic segment is infiltrated by macrophages recruited from the circulating monocyte population (see Figs. 15.12, B, and 15.13, A), which phagocytose the cellular debris. Severe acute necrotizing myopathy may also be accompanied by a certain degree of infiltrating lymphocytes, plasma cells, neutrophils, and eosinophils. Cytokines released from damaged muscle fibers are likely to recruit a variety of inflammatory cells under various circumstances, but these cells are not involved in causing the muscle cell damage. True myositis occurs only when inflammatory cells are directly responsible for initiating and maintaining myofiber injury and when inflammation is directed at the myofibers and not at the stroma. In some cases, it may take careful evaluation of the overall tissue changes, an understanding of the probable underlying cause, and years of experience with muscle pathology to differentiate a florid cellular response with macrophages on a “cleanup” mission from true inflammation. Lymphocytic myositis must also be distinguished from lymphoma involving skeletal muscle (see the section on Neoplasia). Bacterial. Bacterial infections of muscle are not uncommon, particularly in livestock (Table 15.4). Bacteria can cause suppurative and necrotizing, suppurative and fibrosing, hemorrhagic, or granulomatous lesions. Bacterial infection can be introduced by direct penetration (wounds or injections), hematogenously, or by spread from an adjacent cellulitis, fasciitis, tendonitis, arthritis, or osteomyelitis (see the section on Portals of Entry/Pathways of Spread). Table 15.4 Bacterial Causes of Myositis and Neuromuscular Junction Disease Infectious Agent Species Affected Clostridium spp. causing myositis (e.g., C. septicum, C. chauvoei, C. sordellii, C. novyi) Clostridium botulinum causing neuromuscular junction disease Pyogenic bacteria causing myositis (e.g., Trueperella [Arcanobacterium] pyogenes, Corynebacterium pseudotuberculosis) Bacteria causing fibrosing and granulomatous myositis (e.g., Actinomyces bovis, Actinobacillus lignieresii) Horses, cattle, sheep, goats, pigs Horses, cattle, sheep, goats, dogs Horses, cattle, sheep, goats, pigs, cats Cattle, sheep, goats, pigs Various clostridial species, particularly Clostridium perfringens, Clostridium chauvoei, Clostridium septicum, and Clostridium novyi, can elaborate toxins that damage myofibers and intramuscular vasculature, resulting in hemorrhagic myonecrosis (see Figs. 15.31 and 15.37). Toxemia is typical and often lethal. Clostridial myositis is most common in cattle and horses. Clostridial myositis has also been called gas gangrene and malignant edema in horses and blackleg in cattle. Pyogenic bacteria introduced into a muscle usually cause localized suppuration and myofiber necrosis. This may resolve completely or become localized to form an abscess. In some cases, the infection can spread down the fascial planes (see Fig. 15.24). For example, a nonsterile intramuscular injection into the gluteal muscles of cattle can cause an infection that extends down the fascial planes of the muscles of the femur and tibia and erupts to the surface through a sinus proximal to the tarsus. Although the majority of inflammation involves fascial planes, some bacteria extend into and cause necrosis of adjacent muscle fasciculi. Streptococcus zooepidemicus (horses), Trueperella (Arcanobacterium) pyogenes (cattle and sheep), and Corynebacterium pseudotuberculosis (horses, sheep, and goats) are common causes of muscle abscesses. After bite wounds from other cats, cats can develop cellulitis caused by Pasteurella multocida that extends into the adjacent muscle. Bacteria causing single or multiple granulomas (focal or multifocal granulomatous myositis) are relatively uncommon. Most such lesions are caused by tuberculosis (Mycobacterium bovis), usually in cattle and pigs, but this disease is rare in North America. Chronic fibrosing nodular myositis of the tongue musculature in cattle is the result of infection with Actinobacillus lignieresii (wooden tongue) or Actinomyces bovis (the agent causing lumpy jaw). A similar lesion caused by Staphylococcus aureus is known as botryomycosis and is most commonly seen in horses and pigs. It is most often wound related and can occur at a variety of sites. Histologically, actinobacillosis, actinomycosis, and botryomycosis are similar in that the lesions are encapsulated inflammatory lesions containing a central focus of “radiating clubs” of amorphous eosinophilic material associated with bacteria and neutrophils (Splendore-Hoeppli reaction). Neutrophils admixed with macrophages (pyogranulomatous inflammation) can also be seen. Gram-stained tissue can be used to differentiate between the clusters of Gram-positive cocci in Staphylococcus infection, the Gram-positive bacilli causing actinomycosis (Actinomyces bovis), and the Gram-negative bacilli causing actinobacillosis (Actinobacillus lignieresii). Viral. Relatively few of these are recognized in veterinary medicine. Spontaneous ones are listed in Table 15.5. Gross lesions may or may not be visible and, if present, are small, poorly defined foci or streaks. Muscle lesions induced by viruses are either infarcts secondary to a vasculitis, as seen in bluetongue in sheep, or multifocal necrosis, presumably because of a direct effect of the virus on the myofibers. Table 15.5 Viral Myopathies RNA VIRUSES Disease Family Causal Agent Porcine encephalomyelitis Porcine circovirus Foot-and-mouth disease Bluetongue Akabane disease Picornaviridae Circoviridae Picornaviridae Reoviridae Bunyaviridae Enterovirus Circovirus type 2 Aphthovirus Orbivirus Akabane virus CHAPTER 15 Skeletal Muscle An abnormal response to localized muscle trauma is thought to be a possible underlying cause of two uncommon reactions of muscle: myositis ossificans and musculoaponeurotic fibromatosis. The term myositis ossificans is a misnomer because the lesion does not involve inflammation, but it is considered acceptable in common usage. Myositis ossificans is a focal lesion usually confined to a single muscle and has been seen in horses, dogs, and human beings. The lesion is essentially a focal zone of fibrosis with osseous metaplasia, often with a zonal pattern. The central zone contains proliferating undifferentiated cells and fibroblasts; the middle one, osteoblasts depositing osteoid and immature bone; and the outer one, trabecular bone, which may be being remodeled 1010.e1 by osteoclasts. These lesions can cause pain and lameness, which are often cured by surgical excision. A connective tissue disorder in cats, fibrodysplasia ossificans progressiva, has been inappropriately called myositis ossificans. Musculoaponeurotic fibromatosis has so far been described only in horses and human beings. It is a progressive intramuscular fibromatosis that has also been called a desmoid tumor. Musculoaponeurotic fibromatosis is not, however, considered to be a true neoplastic process. Progressive dissecting intramuscular fibrosis accompanied by myofiber atrophy are the characteristic features. In most cases, the extent of intramuscular involvement makes surgical excision impossible, although wide excision of early lesions has proved to be curative. CHAPTER 15 Skeletal Muscle Parasitic. Parasitic infections of the skeletal muscles of domestic animals are not uncommon and include protozoal organisms and nematodes. The most important ones are listed in Table 15.6 and are discussed under the appropriate species heading. Most parasitic diseases have little pathologic or economic importance, with the exceptions of Neospora caninum, Hepatozoon americanum, and Trypanosoma cruzi in dogs and Trichinella spiralis in pigs. As the name Sarcocystis suggests, intramyofiber protozoal cysts caused by Sarcocystis spp. are a common finding. This protozoal organism is a stage in the life cycle of an intestinal coccidium of carnivores that uses birds, reptiles, rodents, pigs, and herbivores as an intermediate host. Ingestion of oocysts by an intermediate host releases sporozoites that penetrate through the intestinal wall, enter blood vessels, and are hematogenously disseminated and invade tissue, including muscle. This parasite rarely causes clinical disease and is therefore most often considered an incidental finding. Sarcocystis infection of muscle is seen most often in horses, cattle, and small ruminants and occasionally in cats. Because they are intracellular, cysts are protected from the host’s defense mechanisms; thus, there is no inflammatory response (Fig. 15.26; also see Fig. 15.40, B). 1011 the cause of myofiber injury. Although cytotoxic T lymphocytes are the effector cells causing myofiber damage, the inflammatory infiltrate is a mixture of lymphocyte types. The characteristic histologic pattern of immune-mediated myositis is an interstitial and perivascular lymphocytic infiltration (Fig. 15.27, A; see also Fig. 15.47), often with invasion of intact myofibers by lymphocytes (Fig. 15.27, B). A variety of forms of immune-mediated myositis occur in the dog and can be localized to specific muscles, presumably because of unique myosin isoforms within those muscles. These are listed in Table 15.7. Acquired myasthenia gravis is also an immune-mediated disease and is included in this table for completeness, but this is a disorder causing damage to the neuromuscular junction rather than to myofibers. In cats, feline immunodeficiency virus (FIV) infection is a cause of immune-mediated myositis. In horses, lesions consistent Immune Mediated. Immunologically induced myositis, not associated with vascular injury, has been recognized primarily in the dog. Rarely, immune-mediated myositis occurs in cats and horses. Infiltrating lymphocytes, most often cytotoxic T lymphocytes, are Table 15.6 Parasitic Myopathies Infectious Agent Type of Agent Sarcocystis spp. Protozoan Trichinella spiralis Neospora caninum Trypanosoma cruzi Cysticercus spp. Nematode Protozoan Protozoan Cestode (larval form) Nematode Nematode larval migrans Hepatozoon americanum Protozoan Species Affected A Horses, cattle, sheep, goats, camelids, pigs Pigs Dogs, fetal cattle Dogs Cattle, sheep, goats, pigs Dogs Dogs B Figure 15.27 Immune-Mediated Myositis, Canine Polymyositis, Skeletal Muscle, Transverse Sections, Dog. A, There is a dense interstitial infiltrate of primarily mononuclear inflammatory cells. Frozen section, hematoxylin and eosin (H&E) stain. B, Note the interstitial infiltrate of mononuclear inflammatory cells and mononuclear cells that have invaded intact myofibers causing myofiber necrosis. Frozen section, modified Gomori’s trichrome stain. (A and B courtesy Dr. B.J. Cooper, College of Veterinary Medicine, Oregon State ­University.) Table 15.7 Figure 15.26 Sarcocystosis, Skeletal Muscle, Longitudinal Section, Cow. The horizontally elongate encysted intramyofiber protozoan (dark purple structure) is characteristic of Sarcocystis spp. There is no associated inflammation. These parasites are common in the muscles of many species of domestic animals and are usually an incidental finding. Formalin fixation, hematoxylin and eosin (H&E) stain. (Courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.) Immune-Mediated Muscle Disorders Disorder Species Affected Purpura hemorrhagica Viral-associated Polymyositis Masticatory myositis Extraocular muscle myositis Acquired myasthenia gravis Horses Horses, cats Dogs, horses (rare) Dogs Dogs Dogs, cats 1012 SECTION II Pathology of Organ Systems with immune-mediated myositis are occasionally found after exposure to Streptococcus equi ssp. equi or infection with equine influenza virus. Note that small perivascular and interstitial infiltrates of lymphocytes, with no apparent myofiber damage, are a frequent incidental finding in equine muscle. Immune-mediated vasculitis resulting in muscle injury occurs in horses and is known as purpura hemorrhagica. Purpura hemorrhagica has been classically associated with Streptococcus equi ssp. equi, but other bacteria, such as Corynebacterium pseudotuberculosis, can also cause purpura hemorrhagica. Congenital and Inherited Disorders Muscle is subject to numerous hereditary, congenital, and neonatal defects (E-Box 15.1; also see E-Table 1.2). Muscular disorders that are apparent at birth are congenital, but they may or may not be inherited. Inherited disorders can manifest at birth or soon thereafter, or they may not be apparent for many years. Molecular biologic studies and development of molecular genetic tests have greatly enhanced our understanding of several muscular disorders of animals and the ability to detect affected and carrier animals. Anatomic Defects. Anatomic defects in skeletal muscle are apparent at birth or soon thereafter. These defects can be either genetic or acquired and result from either abnormal in utero muscle development or abnormal innervation. Innervation Defects. Congenital defects in the lower motor neuron system, involving motor neurons or peripheral nerves, result in severe alteration of myofiber development. Denervation occurring in fetal and neonatal animals can result in very complex muscle lesions because of the importance of innervation in myofiber development and maturation. Depending on the nature of the nervous system defect, muscular lesions can reflect failure of innervation, denervation of previously innervated fibers, or a combination of both. The most common example of this is arthrogryposis in cattle and sheep in which in utero infection or toxin ingestion causes nervous system lesions that lead to failure of innervation or to denervation of skeletal muscle. In addition, a disorder thought to have a genetic basis has been reported in black Angus cattle and results in failure of innervation of skeletal muscle. Failure of innervation or severe denervation injury in utero most often results in failure of the myofibers to develop and their subsequent replacement by adipose tissue (fatty infiltration). This outcome can be severe in affected muscle and may be the basis for some cases of congenital muscular steatosis in livestock (see Figs. 15.9, D, and 15.23). Genetic Defects. Congenital muscular hyperplasia (double muscling) is a genetic disease causing a congenital anatomic skeletal muscle defect (increased number of myofibers) in cattle, dogs, and children. This disorder is caused by defects in the myostatin gene, which controls in utero muscle development. There is more information on this disease in E-Appendix 15.1. With continued selective breeding and advancement in molecular biologic techniques, it is likely that other genetic defects affecting muscle structure may occur or be recognized. Failure of Normal Development. In addition to failure of myofiber maturation caused by innervation defects, inherent myofibrillar developmental defects can occur. This is exemplified by myofibrillar hypoplasia causing splay leg in neonatal pigs. A similar condition has been reported in a calf. Congenital defects in the diaphragmatic muscle (diaphragmatic hernia) can occur in all species but are most well documented in dogs and rabbits. A genetic basis with a multifactorial inheritance is suspected. Clinical signs of respiratory distress caused by herniation of abdominal viscera into the thoracic cavity generally occur at or soon after birth. Defects in the left dorsolateral and central portions of the diaphragm because of failure of closure of the left pleuroperitoneal canal are most common. Muscular Dystrophy. The term muscular dystrophy has been grossly misused in the veterinary literature. According to the definition used for human beings, muscular dystrophy should be applied only to inherited, progressive, degenerative primary diseases of the myofiber characterized histologically by ongoing myofiber necrosis and regeneration (polyphasic necrosis). Several types of muscular dystrophy occur in human beings and animals. The enormous recent advances in genetic and molecular characterization of muscle diseases have resulted in defining their exact genetic defects, such as those in the dystrophin gene responsible for Duchenne’s muscular dystrophy and trinucleotide repeat sequences in myotonic dystrophy, and in the reclassification of others. Similarly, reevaluation of some inherited disorders previously classified as muscular dystrophy, such as muscular dystrophy in sheep and cattle, suggests that they would be better classified as progressive congenital myopathies. Congenital Myopathies. Those inherited disorders of muscle that do not qualify as anatomic defects, muscular dystrophy, myotonia, or a metabolic myopathy are classified as congenital myopathies. These include structural defects leading to abnormal myofiber cytoarchitecture. In some cases, the defective gene is known, whereas the cause of others remains undetermined. Myotonia (Channelopathies). Myotonia is defined as the inability of skeletal muscle fibers to relax, resulting in spasmodic contraction. Various inherited myotonic conditions have been recognized in human beings and animals for many years. Only recently has the basis for many of these myopathies been determined. Most have been found to be related to inherited defects resulting in abnormal ion channel function. Maintenance of ionic equilibrium and control of the ionic fluxes of excitable tissue, such as muscle, are critical to normal muscle functioning. A variety of sarcolemmal ion channels exist that control fluxes of ions such as sodium, potassium, chloride, and calcium. Defective sodium or chloride channels most often result in myotonia. Metabolic Myopathies. Inherited disorders of muscle metabolism (see E-Box 15.1) are characterized by reduced muscle cell energy production. Clinical signs include exercise intolerance, exercise-induced muscle cramps, and rhabdomyolysis (acute segmental myofiber necrosis). Metabolic defects can involve glycogen metabolism, fatty acid metabolism, or mitochondrial function. Metabolic disorders often cause increased blood lactate after exercise. Inheritance patterns vary. Glycolytic, glycogenolytic, and nonmitochondrial DNA–encoded enzyme defects are generally inherited in an autosomal recessive manner. Defects involving mitochondrial DNA–encoded enzymes are inherited through the dam because all mitochondria are contributed by the oocyte. The pathways of glycolysis and glycogenolysis are complex, involving a cascade of enzymatic reactions. Deficiency of a glycolytic or glycogenolytic enzyme leads to accumulation of glycogen and in some cases glycogen-related proteoglycans. There are many different types of glycogen storage diseases, and their categorization is dependent on which enzyme is deficient. Of the types of glycogenoses recognized in human beings, five types (II, III, IV, V, and VII) cause glycogen accumulation in muscle. Of the glycogenoses affecting muscle, only types II (acid maltase deficiency), IV (glycogen branching enzyme [GBE] deficiency), V (myophosphorylase deficiency), and VII (phosphofructokinase deficiency) have so far CHAPTER 15 Skeletal Muscle E-Box 15.1  Confirmed or Suspected Inherited Myopathies and Neuromuscular Junction Diseases in Animals  rthrogryposis A Autosomal recessive myopathies, species and breed specific Carnitine deficiency Centronuclear myopathy Congenital myasthenia gravis Congenital pseudomyotonia Glycogen storage disease Hereditary spinal muscular atrophy Hyperkalemic periodic paralysis Malignant hyperthermia Mitochondrial myopathy Muscular dystrophy Myasthenia gravis Myostatic defect (double muscling) Myotonia congenita Myotubular myopathy Periodic hypokalemic polymyopathy 1012.e1 CHAPTER 15 Skeletal Muscle been recognized in animals. Storage diseases in which glycogen accumulates in muscle have been described in horses, cattle, sheep, dogs, and cats. Inherited lipid storage myopathies have not yet been described in animals, although dogs appear to have a predilection for development of neuromuscular weakness because of acquired lipid storage myopathy with concurrent reduction in skeletal muscle carnitine activity. Mitochondrial myopathies are rarely recognized in animals, perhaps because of the difficulty in confirming mitochondrial defects. A few such disorders have been described in dogs, and a mitochondrial myopathy has been reported in one Arabian horse. Mitochondrial disorders may affect only muscle, or muscle involvement may be part of an encephalomyopathic condition. Malignant Hyperthermia. Malignant hyperthermia (MH) is a condition characterized by unregulated release of calcium from the sarcoplasmic reticulum, leading to excessive myofiber contraction that generates heat, resulting in a severe increase in body temperature. MH is often fatal. In human beings, pigs, horses, and dogs, a congenital defect in the sarcoplasmic reticulum calcium-release channel, the ryanodine receptor, causes dysregulation of excitationcontraction coupling leading to MH. Episodes in affected individuals can be triggered by general anesthetic agents, especially halothane, or by stress, thus the name porcine stress syndrome for the disorder in pigs (see Fig. 15.42). An MH-like condition can also occur because of other myopathic conditions, especially those that result in uncoupling of mitochondrial oxidative phosphorylation from the electron transport chain. Inherently uncoupled mitochondria within brown fat are the physiologic basis for production of heat during breakdown of this fat in neonates, and pathologically uncoupled or loosely coupled mitochondria, in muscle as a result of an underlying myopathy, release energy as heat. Gross and microscopic lesions are described in the section on Diseases of Pigs, Congenital and Inherited Myopathies, Malignant Hyperthermia. Endocrine and Electrolyte Abnormalities Various endocrinologic abnormalities can result in myopathic conditions (Table 15.8). The most common are hypercortisolism and hypothyroidism in dogs. In horses, pituitary hyperfunction resulting in Cushing’s disease also causes muscle disease. In most cases of endocrine myopathy, the end result is myofiber atrophy, particularly of type 2 fibers. A unique syndrome of muscle hypertrophy and pseudomyotonia occurs in dogs associated with hypercortisolism. Endocrine myopathies can also be complicated by the fact that endocrinopathy can also cause pathologic changes in peripheral nerves, leading to a mixture of myopathic (type 2 fiber atrophy) and neuropathic changes (denervation atrophy and alteration in fibertype pattern) within muscle. Denervation followed by reinnervation Table 15.8 Myopathies Caused by Endocrine and Electrolyte Abnormalities Disorder Species Affected Hypothyroidism Hypercortisolism Hypokalemia Hypophosphatemia Hypernatremia Hypocalcemia Hypothalamic/pituitary dysfunction Dogs Dogs Cattle, cats Cattle Cats Cattle Horses 1013 leading to fiber-type grouping can be seen in dogs with chronic hypercortisolism (see Fig. 15.18, B) and hypothyroidism. Normal electrolyte status is vital to normal skeletal muscle function. Hypocalcemia, hypokalemia, hypernatremia, and hypophosphatemia can cause profound skeletal muscle weakness, sometimes associated with myofiber necrosis, in various species. Neuropathic and Neuromuscular Junction Disorders Dysfunction of the lower motor neurons, peripheral nerves, or neuromuscular junction can have profound effects on muscle function. Neuropathic Disorders. There are many peripheral nerve disorders and a few motor neuron disorders that can lead to denervation atrophy of muscle in animals. These can be inherited or acquired. Long nerves, such as the sciatic and left recurrent laryngeal nerves, appear to be particularly sensitive to development of acquired neuropathy. Many of the peripheral nerve disorders of animals are discussed in Chapter 14, Nervous System. Characteristic features of denervation atrophy are described in the section on Dysfunction/ Responses to Injury, Alterations in Myofiber Size, Atrophy. Neuromuscular Junction Disorders. The neuromuscular junction is a modification of the postsynaptic myofiber membrane. At the neuromuscular junction, the membrane is folded to increase surface area and is studded with specialized ion channels known as acetylcholine receptors. After arrival of an action potential at the distal end of a motor nerve, the terminal axons release acetylcholine, which diffuses across the synaptic space to bind to the acetylcholine receptors. Binding opens these channels, leading to sodium influx, which initiates the skeletal muscle action potential that culminates in muscle contraction. Acetylcholine is rapidly degraded by acetylcholinesterase released from the postsynaptic membrane, which prevents continued stimulation and thus contraction of the muscle fiber. Disorders that impair the ability of nerve impulses to travel across the neuromuscular junction have profound effects on skeletal muscle function. Technically, however, the myofibers are still innervated, so denervation atrophy does not occur, and no light microscopic abnormalities in the muscle or nerve are present. Various neurotoxins (i.e., in snake and spider venom and in curare-containing plants) and drugs can affect the neuromuscular junction, but the most common neuromuscular junction diseases affecting animals are myasthenia gravis, botulism, and tick paralysis. Myasthenia Gravis. Myasthenia gravis can be either acquired or congenital. Acquired myasthenia gravis is an immune-mediated disorder caused by circulating autoantibodies against skeletal muscle acetylcholine receptors (Fig. 15.28). Binding of these antibodies to the acetylcholine receptor on the postsynaptic membrane leads to a severe decrease in the number of functional receptors. The mechanisms by which antibodies damage these receptors are (1) direct damage to the neuromuscular junction, which may be visible with electron microscopy as simplification of the folding of the membrane, and (2) formation of cross-linked antibodies leading to receptor internalization. Sufficient functional acetylcholine receptors are present to initially allow normal neuromuscular transmission, but if there is sustained muscular activity the decrease in the number of available receptors leads to progressive weakness and collapse. Therefore, acquired myasthenia gravis results in episodic collapse, and repetitive nerve stimulation causes a characteristic rapid decrease in amplitude of the muscle compound motor action potential. Diagnosis of myasthenia gravis can also be made after intravenous injection of cholinesterase inhibitors such as edrophonium chloride (Tensilon, ICN Pharmaceuticals, Costa Mesa, CA) in collapsed animals. The reduction in cholinesterase activity leads 1014 SECTION II Pathology of Organ Systems Normal Myasthenia gravis Synaptic vesicle with acetylcholine Acetylcholine bound to the receptor Autoantibody Muscle Acetylcholinesterase Autoantibody against the acetylcholine Muscle associated with the receptor leads to receptor damage that end plate acetylcholine receptor prevents binding of acetylcholine Figure 15.28 Pathogenesis of Acquired (Immune-Mediated) Myasthenia Gravis. Myoneural junction in normal muscle (left panel). When acetylcholine binds to acetylcholine receptors, a signal from the receptor opens ligand-gated sodium channels in the muscle cell membrane leading to contraction. Myoneural junction in myasthenia gravis (right panel). Autoantibody directed against acetylcholine receptors causes receptor injury and blocks the binding of acetylcholine to the receptor, resulting in episodic weakness and collapse. to more active acetylcholine being available within the synapse and rapid, although transient, restoration of skeletal muscle contraction. Detection of autoantibodies to acetylcholine receptors in the blood confirms the diagnosis of acquired myasthenia gravis. The origin of the autoantibodies causing myasthenia gravis is not always known, but there is a strong link between thymic abnormalities and development of myasthenia gravis in both human beings and animals. Specialized cells within the thymic medulla, known as myoid cells, express skeletal muscle proteins, including those of the acetylcholine receptor. It is thought that these cells participate in development of self-tolerance. Abnormalities of the thymus, most commonly thymoma in animals and thymic follicular hyperplasia in human beings, can lead to loss of self-tolerance to acetylcholine receptors. In such cases, removal of the abnormal thymus can result in restoration of normal neuromuscular junction activity. When thymic abnormalities are not present, treatment with long-acting anticholinesterase agents and in some cases immunosuppressive agents, such as corticosteroids, is necessary. Congenital myasthenia gravis is an inherited disorder that is much less common than acquired myasthenia gravis. To date it has been described only in human beings, dogs, and cats. Animals with congenital myasthenia gravis are born with defective neuromuscular junctions that often have a decreased membrane surface area, best visualized with electron microscopy, and as a consequence an inherently reduced acetylcholine receptor density. Such animals may be normal at birth because there are sufficient functional acetylcholine receptors to support muscle contraction in a neonate. However, with rapid postnatal growth, clinical signs of profound, sustained, and progressive weakness occur as a consequence of insufficient functional receptors to support the function of growing muscles. Botulism. Botulism is a neuromuscular disorder caused by the exotoxin of the bacterium Clostridium botulinum. Botulinum toxin is considered one of the deadliest of the known toxins. Botulism is characterized by profound generalized flaccid paralysis. Seven serologically distinct but structurally similar forms of botulinum toxin are designated A, B, C, D, E, F, and G. Sensitivity to these toxin Box 15.9  Portals of Entry—Equine Botulism Gastrointestinal colonization of ingesta: Foals up to 6 months of age Ingestion of preformed botulinum toxin: Adults, usually from rodent carcasses in hay or concentrated feed, or environmental contamination Wound contamination: Adults, deep wounds, uncommon types varies among different species. Dogs are most sensitive to type C toxin, ruminants to types C and D, and horses to types B and C. Botulinum toxin consists of a light chain and a heavy chain linked by a disulfide bond. Binding of botulinum toxin to receptors on the presynaptic terminals of peripheral nerves is followed by endocytosis of the toxin. Within the endocytotic vesicle of the terminal nerve, the disulfide bond is cleaved, and the released light chain is translocated into the axonal cytoplasm (see Fig. 4.27). Botulinum toxin light chains are metalloproteinases. Numerous proteins are involved in the release of acetylcholine from presynaptic vesicles, and botulinum toxin blocks release of acetylcholine by irreversible enzymatic cleavage of one or more of these proteins. Different forms of botulinum toxin affect different proteins, but the end result is the same. Active neuromuscular junctions are the most sensitive, which has led to the use of low concentrations of locally injected botulinum toxin as a treatment for localized muscular disorders resulting in spasm. C. botulinum spores are commonly present in the gastrointestinal tract of animals and in the soil. Under favorable anaerobic and alkalinic conditions, these spores become active, with resultant toxin production. Botulism can occur because of ingestion of preformed toxin, such as in feed contaminated by dead rodents or soil-borne organisms, or from toxin produced by C. botulinum organisms within the gastrointestinal tract or superficial wounds (Box 15.9). Dogs and cats are the species most likely to ingest dead rodents containing botulinum toxin and are resistant to developing botulism. In veterinary medicine, horses are the most sensitive to botulinum toxin. Death of horses, most often the result of respiratory muscle paralysis, can result from exposure to only very small amounts of botulinum toxin. The damage to presynaptic axon terminals is irreversible, and CHAPTER 15 Skeletal Muscle 1015 recovery from botulism occurs only after terminal axon sprouting and reestablishment of new functioning synapses. Tick Paralysis. Dermacentor and Ixodes ticks can elaborate a toxin that also blocks release of acetylcholine from axon terminals. Tick paralysis is seen most often in dogs and children. Recovery after tick removal can be rapid (within 24 to 48 hours), indicating that the mechanism of toxin action in tick paralysis does not result in irreversible presynaptic damage and thus is different from that of botulinum toxin. Neoplasia Neoplasms involving skeletal muscle are most often those that arise within the muscle or its supporting structures or that invade muscle from adjacent tissue. Neoplasms metastatic to muscle are rare. Primary Muscle Tumors. Tumors with striated muscle differentiation are thought to arise from intramuscular pluripotential stem cells rather than from satellite cells. These tumors are uncommon and are either benign (rhabdomyoma) or malignant (rhabdomyosarcoma [Fig. 15.29]). Primary intramuscular tumors can also arise from fibrous tissue, vasculature, or neural elements. The most common tumor to arise from muscle-supporting structures is hemangiosarcoma. Rhabdomyoma and Rhabdomyosarcoma. Tumors of striated muscle that occur at sites other than within muscle are rhabdomyomas of the heart or lung and botryoid rhabdomyosarcomas of the urinary bladder; these are not discussed in this section. Rhabdomyoma and rhabdomyosarcoma arising within skeletal muscle are most common in the dog, followed by the horse and cat. Morphologic variants include round cell, spindle cell, and mixed round and spindle cell, reflecting the developmental stages of skeletal muscle. Historically, diagnosis of tumors of skeletal muscle has relied on identification of cross-striations indicative of sarcomeric differentiation. Cross-striations are most often seen in elongated multinucleate cells known as strap cells (Fig. 15.29, C) and in ovoid cells known as racquet cells. They are most easily recognized after staining with phosphotungstic acid hematoxylin (PTAH) stain, but the search for cross-striations can be extremely frustrating and often unrewarding. These days, the diagnosis of tumors of skeletal muscle origin relies primarily on results of immunohistochemical examination using antibodies for muscle-specific proteins. Muscle actin and desmin are expressed by smooth and skeletal muscle tumors, but myoglobin, sarcomeric actin, myogenin, and MyoD1 are specific for skeletal muscle. Evidence of muscle differentiation, such as primitive myofilaments and Z-band structures, can also be detected by electron microscopy. Rhabdomyoma is most often a round cell tumor and occurs most commonly in the larynx of adult dogs. The youngest reported age is 2 years. Tumors are generally smooth and nodular, pink, and unencapsulated. Histologic features are closely packed, plump round cells that have central euchromatic nuclei, generally with a single prominent nucleus, and abundant vacuolated to granular eosinophilic cytoplasm. A small number of multinucleate and elongate strap cells can also be seen. Mitoses are rare, and evidence of invasion is uncommon. Similar to the situation in human beings, rhabdomyosarcomas in animals most often occur at a young age and are most common in the neck or oral cavity, especially in the tongue. These tumors are pink and fleshy, and they often have prominent local invasion. The most common and most distinctive form of rhabdomyosarcoma in animals is embryonal rhabdomyosarcoma, composed of primitive round cells with prominent euchromatic nuclei, a single prominent nucleolus, and either indistinct or prominent eosinophilic cytoplasm (“rhabdomyoblasts”; see Fig. 15.29, A and B). Rhabdomyosarcoma A B C Figure 15.29 Rhabdomyosarcoma. A, Skeletal muscle, cat. An admixture of small round basophilic cells with a lesser number of larger round cells with prominent eosinophilic cytoplasm is characteristic of embryonal rhabdomyosarcoma. Nuclei are central and euchromatic, most often with a single large nucleolus. Hematoxylin and eosin (H&E) stain. B, Immunostaining reaction of the same rhabdomyosarcoma as depicted in A, showing intense cytoplasmic expression of desmin in many tumor cells, indicative of muscle origin (skeletal, cardiac, or smooth). These cells also express myoglobin and sarcomeric actin (not shown), which differentiates skeletal muscle tumors from smooth muscle tumors. Immunoperoxidase reaction for desmin. C, Botryoid rhabdomyosarcoma, urinary bladder, large-breed dog. Cross-striations, characteristic of a well-differentiated rhabdomyosarcoma, are present in the elongated multinucleate tumor cells. H&E stain. (Courtesy Dr. B.A. Valentine, College of Veterinary Medicine, Oregon State University.) can also contain elongate multinucleate strap cells (see Fig. 15.29, C) and ovoid racquet cells. Cellular and nuclear pleomorphism is common, as is mitotic activity. These tumors are locally invasive and frequently metastasize, although too few cases have been studied to document any pattern of metastasis. Hemangiosarcoma. Malignant vascular neoplasms (hemangiosarcoma) arising within muscle are most common in the horse and 1016 SECTION II Pathology of Organ Systems occurrence of hyperkalemic periodic paralysis (HYPP), in which a muscle mutation results in visually appealing increased muscle bulk and definition. Unfortunately, as noted in the discussion of HYPP later, such mutations do not often result in improved muscle function. Bacterial and Parasitic Myopathies Infection by various bacterial organisms and clostridial toxins can cause myopathy in the horse. Protozoa (Sarcocystis spp.) are common incidental findings in equine muscle, but Sarcocystis-induced muscle damage resulting in clinical signs of muscle disease is rare. Clostridial Myositis (Malignant Edema; Gas Gangrene) Figure 15.30 Intramuscular Hemangiosarcoma, Dorsal Paravertebral Muscle, Horse. The muscle is expanded and replaced by a mass containing multiple irregular zones of hemorrhage. (Courtesy Dr. P.L Habecker, University of Pennsylvania School of Veterinary Medicine.) dog (Fig. 15.30). Clinical signs include swelling within a muscle, often with associated lameness. Cytologic preparations frequently reveal only peripheral blood, which is suggestive of a hematoma. Pathologic diagnosis can be difficult if multiple sites within the lesion are not sampled, because the amount of hemorrhage often far exceeds the area composed of proliferating neoplastic endothelial cells. Intramuscular hemangiosarcoma has a high incidence of metastasis, often to the lungs. Other Tumors Involving Skeletal Muscle. A variant of lipoma, known as infiltrative lipoma, is often located in skeletal muscle. Characteristic gross pathologic and histopathologic findings are mature adipocytes invading skeletal muscle. This tumor is most common in the dog but has also been reported in young horses. Wide excision is the treatment of choice because this tumor recurs as a result of local invasion, but it does not metastasize. Infiltration of skeletal muscle by neoplastic lymphocytes is not uncommon. Neoplastic lymphocytic infiltrates surround myofibers and can cause myofiber atrophy. These cells do not invade myofibers, however, and myonecrosis is rare. This helps to distinguish intramuscular lymphoma from lymphocytic myositis. Careful examination of infiltrating neoplastic cells typically reveals a relatively monomorphic population of lymphocytes, which may be atypical in appearance. Immunohistochemistry to confirm a single infiltrating cell type is also useful. Vaccine-associated sarcoma in the muscle of the cat can arise within an intramuscular vaccination site or extend into underlying skeletal muscle from a subcutaneous injection site. Occasionally, mast cell tumors and carcinomas exhibit prominent skeletal muscle invasion. Melanoma arising in the skin of older gray horses often metastasizes to muscle fascia and may exhibit some extension into the muscle itself. Intramuscular metastasis of tumors is rare (see the section on Defense Mechanisms/Barrier Systems). Intramuscular metastasis of carcinoma, particularly prostatic, and of hemangiosarcoma can occur in dogs. When carcinomas with areas of sclerosis involve muscle, either by extension or by metastasis, the muscle basement membrane of adjacent myofibers is typically destroyed, often resulting in bizarre multinucleate cells representing attempts at muscle regeneration (see Fig. 15.15). These bizarre cells should not be misidentified as tumor cells. Diseases of Horses There is perhaps no other domestic animal species for which optimal muscle development and function is so critical as the horse. Selective breeding for better muscling has occurred in virtually all horse and pony breeds. The ability of such selection pressure to perpetuate equine muscle mutations is exemplified by the relatively recent Clostridial myositis in the horse is an often fatal disorder caused by infection by various toxin-producing clostridial species, which are large Gram-positive anaerobic bacilli. Clostridium septicum is the most common cause of clostridial myositis in horses, but Clostridium perfringens types A to E, Clostridium chauvoei, Clostridium novyi, Paeniclostridium sordellii, and Clostridium fallax can also cause infection. Infection can involve more than one clostridial species. Clostridium spp. are ubiquitous organisms that form spores within the soil and within the gastrointestinal tract. Unlike cattle, in which nonpenetrating trauma can cause muscle bruising and anaerobic conditions that activate clostridial spores already in the muscle, clostridial myositis in horses is virtually always secondary to a penetrating wound. Most often, this is an injection site of a nonantibiotic substance, but infection of sites of puncture wounds and of perivascular leakage of irritants in intravenously administered compounds is also possible. It is also possible that clostridial bacteria entering the blood from an injured gastrointestinal tract can colonize damaged muscle. This is one possible explanation for the frequent occurrence of signs of colic before development of clostridial myositis at the site of intramuscular injection of medications such as flunixin meglumine that cause localized muscle damage. Under anaerobic conditions, clostridia proliferate and produce toxins that damage blood vessels, resulting in hemorrhage and edema, and cause necrosis of adjacent muscle fibers. Clinical signs are acute onset of heat, swelling, and pain within a muscle group and adjacent fascia, with concurrent fever, depression, dehydration, and anorexia. If sufficient muscle necrosis is present, serum CK and AST concentrations may be mildly to moderately increased. Death from toxemia and/or septicemia often occurs within 48 hours. Affected muscle and adjacent fascia are swollen and often hemorrhagic, with edema, suppurative inflammation, and necrosis; gas may also be present (Fig. 15.31). Vasculitis is not seen. Gram-positive bacilli characteristic of Clostridium spp. are generally demonstrable within affected tissue. The diagnosis can be made with reasonable certainty based on typical historic, gross pathologic, cytologic, and histopathologic findings. Clostridium spp. can also be identified by culture under anaerobic conditions or by a fluorescent antibody test. Treatment must be initiated rapidly and includes surgical incisions into affected muscle to allow drainage and oxygenation, antibiotic therapy, and supportive care. Corynebacterium pseudotuberculosis (Pigeon Fever) Intramuscular abscesses caused by Corynebacterium pseudotuberculosis occur almost exclusively in horses in arid regions of the western United States and Brazil. C. pseudotuberculosis is a Gram-positive pleomorphic facultative anaerobic bacillus present within the soil. It can enter muscle via penetrating wounds, including injection sites. The biotype most common in horses is different from that which affects sheep and goats because it is unable to reduce nitrates to nitrites. The high lipid content of the bacterial cell wall contributes CHAPTER 15 Skeletal Muscle A * 1017 Figure 15.32 Intramuscular Vasculitis, Purpura Hemorrhagica, Skeletal Muscle, Transverse Section, Horse. In the wall of the blood vessel (arrow) is a band of circumferential fibrinoid necrosis containing nuclear debris. Many of the adjacent myofibers are necrotic (center to lower right areas). Some of these myofibers are fragmented, and a small number contain fine basophilic deposits of mineral. Formalin fixation, hematoxylin and eosin (H&E) stain. (Courtesy Dr. B.A. Valentine, College of Veterinary Medicine, Oregon State University.) * * B Figure 15.31 Clostridial Myositis, Malignant Edema, Horse. A, Clostridium septicum is the most common cause of clostridial myositis in horses. Affected muscle (shown here) and adjacent fascia (not shown here) are swollen and often hemorrhagic. B, Interstitial edema, hemorrhage, and inflammatory cells surround numerous swollen and fragmented necrotic myofibers (asterisks). Formalin fixation, hematoxylin and eosin (H&E) stain. (Courtesy Dr. B.A. Valentine, College of Veterinary Medicine, Oregon State University.) to the survival of C. pseudotuberculosis within macrophages. Bacterial exotoxins, such as phospholipase D, contribute to vascular damage and inhibition of neutrophil function. Equine infections occur most frequently during the fall and early winter, and a higher incidence of the disease is often seen after rainy winters. Infections are most common in the pectoral musculature, but other locations are possible. Affected muscles are swollen and edematous and contain variably sized zones of localized suppurative inflammation. Fever is common. The causative agent is readily isolated from affected tissue and can be seen in aspirates from intramuscular abscesses. Treatment is generally curative and includes antibiotic therapy and establishment of drainage of abscesses. Rarely, infection with C. pseudotuberculosis in horses leads to immune-mediated vasculitis (purpura hemorrhagica; see the next section). Streptococcal-Associated Myopathies Two distinct degenerative myopathies are associated with infection or exposure of the horse to Streptococcus equi ssp. equi. One, known as purpura hemorrhagica, has been recognized for many years. The other, known as streptococcal-associated rhabdomyolysis and muscle atrophy, has only recently been recognized. Purpura Hemorrhagica. In this disease, muscle damage is not caused by the direct infection of the muscles but, rather, by an immune response to the bacterial pathogen. Streptococcus equi is the most common cause of purpura hemorrhagica in horses, but C. pseudotuberculosis and possibly other bacteria can also cause purpura hemorrhagica. In cases caused by S. equi, circulating immune complexes composed of immunoglobulin A (IgA) antibodies and streptococcal M antigen deposit in the walls of small vessels. This leads to vasculitis and vascular wall necrosis (Fig. 15.32), with resultant hemorrhage and infarction of myofibers. It is also possible that antibodies to streptococcal M protein cross-react with skeletal and cardiac muscle myosins to cause direct injury. Signs of myopathy often accompany systemic signs of poststreptococcal purpura in horses (i.e., depression, fever, dependent edema, petechiae or ecchymoses, leukocytosis, increased serum fibrinogen, and anemia), but myopathy can also be the primary presenting disease process. Affected horses are weak, may have a short-strided gait, and can become recumbent. Myoglobinuria and very high increases in serum concentrations of CK and AST are common. Multiple muscles are involved (as opposed to the locally extensive lesion of clostridial myositis), and affected muscles contain multifocal to locally extensive hemorrhage and edema that dissects between necrotic muscle fibers and muscle fasciculi. Gross pathologic findings are similar to those seen in clostridial myositis (see Fig. 15.31, A), but lesions do not contain gas bubbles. Vascular injury (leukocytoclastic vasculitis and fibrinoid necrosis of blood vessels; see Fig. 15.32) is seen on microscopic examination and is the diagnostic feature. Diagnosis is based on a history of exposure of the horse to S. equi and the typical clinical, clinicopathologic, and histopathologic findings. Because this is an immune-complex disorder, histopathology, cytology, and bacterial cultures of affected muscle do not reveal S. equi. This bacterium or other causative bacteria may be cultured from other affected tissues, especially lymph nodes or guttural pouch. A high serum titer to S. equi M protein is strongly supportive of a diagnosis of streptococcal-associated purpura hemorrhagica. Treatment includes corticosteroid therapy and supportive care, but horses frequently succumb to other sequelae of systemic vasculitis, such as gastrointestinal infarcts. Streptococcal-Associated Rhabdomyolysis and Muscle Atrophy. A syndrome of severe acute rhabdomyolysis resulting in profound rapidly progressive generalized loss of muscle mass has also been seen in horses with clinical infection by S. equi or in horses that 1018 SECTION II Pathology of Organ Systems have been exposed to this bacterium but that did not develop obvious clinical signs of infection. This syndrome occurs most frequently in young to young adult quarter horses, but young horses of other breeds can also be affected. Clinically recognizable muscle atrophy is often most evident in paraspinal and gluteal muscles. Some cases have microscopic evidence of concurrent equine polysaccharide storage myopathy (see the section on Diseases of Horses, Inherited or Congenital Myopathies and Myotonic Disorders), which may be a predisposing factor. In others, nonsuppurative perivascular and interstitial inflammation has been detected, and the proposed mechanism is immune-mediated damage caused by cross-reaction of streptococcal antibodies with muscle proteins. Affected horses do not show typical signs of purpura hemorrhagica but often have very high serum concentrations of CK (often greater than 100,000 units per liter) and AST (often greater than 10,000 units per liter). Affected horses may respond to corticosteroid therapy. Most recover, but recurrence after subsequent exposure to S. equi is possible. Protozoal Myopathy Protozoa (Sarcocystis spp.) are common incidental findings in equine skeletal and cardiac muscles. Because the protozoa are in cysts within the myofiber itself and thus are protected from the body’s surveillance, there is no inflammatory response. Massive infection by Sarcocystis fayeri is suspected of causing a degenerative myopathy in horses, but this is rare. Rarely, localized thickening of the tongue has been found in horses with granulomatous myositis, the result of Sarcocystis organisms within tongue musculature. The cause of the intense inflammation apparently incited by protozoa in these rare cases is unknown. Ear Tick–Associated Muscle Spasms Episodic muscle spasms of various muscle groups can occur in horses with ear ticks (Otobius megnini). The mechanism is not known. Dimpling of affected muscles after percussion can be seen, but myotonic discharges are not found with electromyography (EMG). Treatment for ear ticks results in rapid recovery. Nutritional and Toxic Myopathies Nutritional deficiency, most often of selenium, and various toxins are relatively common causes of degenerative myopathy in the horse. Nutritional Myopathy Foals (most commonly up to 2 weeks of age) and young adult horses are most susceptible to nutritional myopathy because of a deficiency of the antioxidants selenium or (less commonly) vitamin E. In severely selenium-deficient areas, such as the Pacific Northwest, selenium deficiency myopathy can occur in horses of any age. Normally the selenium present in the soil is taken up by growing plants. In many areas, the soil is selenium deficient, and selenium supplements to the animal’s ration must be provided. Vitamin E deficiency occurs in horses that eat marginal- to poor-quality grass hay and have little or no access to pasture and no supplemental vitamin E. Oxidative injury to actively contracting muscle fibers occurs as a result of a lack of antioxidant activity. Affected foals are most likely to be those born to selenium-deficient mares. Foals have generalized weakness, which may be present at birth or become apparent soon after birth. Affected foals may become recumbent but are generally bright and alert. They often continue to suckle if bottle fed, but weakness of the tongue and pharyngeal muscles can lead to weak suckling. Affected adult horses are most often stabled horses fed only selenium-deficient hay, with clinical disease being seen most commonly in the late winter or early spring. In the Pacific Northwest, selenium deficiency myopathy can occur in adult horses fed only pasture or hay, and it can occur at any time of year. Affected adult horses often show preferential involvement of the temporal and masseter muscles (the condition is sometimes inappropriately termed maxillary myositis or masseter myositis) with swelling and stiffness of these muscles and impaired mastication. Involvement of pharyngeal muscle results in dysphagia and involvement of the tongue results in impaired prehension of food, which can be mistaken for botulism. In more chronic cases, bilaterally symmetric atrophy of the masseter muscles may be evident, which can be mistaken for atrophy secondary to protozoal myeloencephalitis. Careful examination of these horses often reveals generalized weakness, evident as a stiff, short-strided gait. Severely affected horses can have an acute onset of recumbency that mimics neurologic disease. Serum concentrations of CK and AST are generally mildly to moderately increased, although extremely high concentrations can be seen in severely affected foals and horses. Concentric needle EMG of affected muscles results in abnormal spontaneous activity (positive sharp waves, fibrillations, and myotonic bursts). Muscles of affected horses appear pale (hence the common name, white muscle disease), often in a patchy distribution (see Fig. 15.39). The most severely affected muscles are those that have the highest workload (e.g., cervical muscles in foals used during suckling and “bumping” the udder, proximal limb muscles, tongue, and masticatory muscles). The gross appearance depends on the extent of the necrosis and the stage. In early stages, yellow and white streaks are present, and later pale, chalk white streaks often appear. Horses with impaired swallowing can have cranioventral aspiration pneumonia. Severely selenium-deficient foals and horses also have pale areas of necrosis within the myocardium, especially the left ventricular wall and septum, which are areas that have a high workload. The stage of the necrosis depends on the age of the lesions. In foals with severe, acute myopathy leading to death or euthanasia, lesions are at the stage of massive muscle necrosis and mineralization with minimal macrophage infiltration (monophasic). In animals that have lived longer (i.e., subacute cases), the lesions are polyphasic, and active necrosis, macrophage infiltration, and regeneration are present. Although type 1 fib