Myopathies: Disorders of Skeletal Muscle

Myopathies: Disorders of Skeletal Muscle

Curtis W. Dewey & Lauren R. Talarico

Introduction8, 36, 40, 44, 61, 102, 141, 179, 214, 232, 301, 315

Skeletal muscle is the effector organ for the somatic motor nervous system. In general, clinical signs of skeletal muscle dysfunction include weakness with preservation of sensory function—e.g. nociception (deep pain perception), proprioception—muscle atrophy, and muscle pain (myalgia). In some diseases, muscle hypertrophy is present rather than atrophy. Also, myalgia is not a feature of some myopathies.

Skeletal muscle is composed of multinucleated cells termed “myofibers” that are arranged in bundles called “fascicles.” Each myofiber is innervated by an axonal process of a motor neuron at a specialized area of the sarcolemma (muscle cell plasma membrane) called the endplate (see Chapter 19). The myofibers contain the contractile apparatus, which comprises interlocking myofilaments (actin, myosin, troponin, tropomyosin). Muscle contraction occurs when calcium is released from the sarcoplasmic reticulum (the myofiber endoplasmic reticulum) following sodium influx into the myofiber (depolarization). Adenosine triphosphate (ATP) is required for the coordinated contraction and relaxation of the muscle fiber. A muscle enzyme called creatine kinase (CK) is required to immediately replenish ATP from adenosine diphosphate (ADP) by cleaving a high-energy phosphate group from the compound phosphocreatine, also found in the myofiber.

There are two main types of myofibers, differentiated upon the intensity of histochemical staining at different pHs (Fig. 18.1) with the ATPase reaction (muscle biopsy samples). Type I fibers are “slow-twitch” (relatively high levels of oxidative enzymes and lipid, low glycogen content) fibers and type II fibers are “fast-twitch” (relatively high levels of glycogen, lesser amounts of oxidative enzymes and lipid) fibers. A uniquely staining fiber type is also found only in masticatory muscle, called type IIM. One motor neuron will innervate a number of myofibers within a fascicle, and the fiber types of those myofibers will all be the same. The motor neuron and the myofibers it innervates comprise what is called a motor unit. The motor neuron dictates the fiber type of the myofibers of its motor unit. The myofibers of a single motor unit are normally scattered through a fascicle, giving a “checkerboard” appearance to the stained biopsy sample.


Figure 18.1 Cryosections from the vastus lateralis muscle reacted with myofibrillar ATPase at pH 9.8 shows type I fibers stained lightly and type II fibers stained dark. Type II fiber atrophy is present, consistent with an endocrine disorder such as hypothyroidism, or Cushing’s syndrome. (G. Diane Shelton, University of California, La Jolla, CA, 2014. Reproduced with permission from G. Diane Shelton.)

In some cases, it will be difficult to clinically discern a myopathy from a neuropathy or neuromuscular junction disorder. A diagnosis of myopathy is based upon neurologic examination findings as well as specific diagnostic tests. Typical diagnostic tests to pursue when a myopathy is suspected include serum CK measurement (elevations suggest muscle damage), and electrodiagnostics (remember that electromyographic [EMG] abnormalities can be seen with neuropathies and myopathies). However, these tests may yield abnormal results for reasons unrelated to neuromuscular disease. In particular, CK activity may be elevated in anorexic cats. Historical information, examination findings, and a decrease in CK activity with nutritional support may be used to help differentiate this elevation from that seen in neuromuscular disease. Muscle and/or nerve biopsies can be very helpful in elucidating the cause of a peripheral nervous system disorder. In addition to the ATPase reaction, there is a barrage of histochemical stains and reactions that can be applied to cryosections of properly frozen muscle biopsies to help characterize the nature of the muscle disorder (Fig. 18.2 to Fig. 18.9). A summary of myopathies of dogs and cats is shown in Table 18.1.

Table 18.1 Myopathies of dogs and cats.

Degenerative/Developmental Metabolic Inflammatory/Infectious Ischemic Traumatic
Muscular dystrophy
Centronuclear myopathy
Exercise intolerance and collapse of Labrador Retrievers
Distal myopathy of Rottweilers
Myotonia congenita
Fibrotic myopathy
Nemaline myopathy
Myositis ossificans (fibrodysplasia ossificans progressiva)
Pharyngeal/esophageal dysfunction of Bouviers
Polysystemic disorder of English Springer Spaniels
Cricopharyngeal achalasia
Episodic muscle hypertonicity (“cramp”)
Myokymia and neuromyotonia
Hypokalemic myopathy
Hyperkalemic periodic paralysis
Hyperadrenocorticoid (Cushing’s) myopathy
Hypothyroid myopathy
Malignant hyperthermia
Exertional myopathy
Lipid storage/mitochondrial myopathies
Glycogen storage disorders (glycogenoses)
Masticatory myositis
Extraocular myositis
Laryngeal/pharyngeal myositis
Autoimmune polymyositis
Feline hyperesthesia syndrome
Infectious myositis
Ischemic neuromyopathy Infraspinatus contracture
Iliopsoas muscle injury
Quadriceps contracture
Coccygeal muscle injury

Fig. 18.2 is of hematoxylin and eosin (H&E) stained muscle cryosections showing a large pale staining necrotic fiber. H&E staining is used for the evaluation of general morphology. Fig. 18.3 is of modified Gömöri trichrome stained cryosections showing a prominent intramuscular nerve branch. Myelin stains pink with this stain. The modified Gömöri trichrome stain is a good general morphological stain, highlights intramuscular nerve branches and stains nemaline rods, and identifies ragged red-like fibers.


Figure 18.2 Hematoxylin and eosin stain muscle cryosections. (G Diane Shelton, University of California, La Jolla, CA, 2014. Reproduced with permission from G Diane Shelton.)


Figure 18.3 Modified Gömöri trichrome stained cryosections. (G Diane Shelton, University of California, La Jolla, CA, 2014. Reproduced with permission from G Diane Shelton.)

Fig. 18.4 shows staining with periodic acid-Schiff highlights glycogen or polysaccharide deposits that would suggest a glycogen or polysaccharide storage disorder. Note the figure has a glycogen deposit within a muscle fiber that is stained dark purple. Fig. 18.5 is of a nicotinamide adenine dinucleotide reductase reaction that identifies mitochondrial accumulations and tubular aggregates. In this muscle section, dark-blue reactions are present under the sarcolemma and extend into the sarcoplasm, consistent with lobulated fibers.


Figure 18.4 Staining with periodic acid-Schiff. (G Diane Shelton, University of California, La Jolla, CA, 2014. Reproduced with permission from G Diane Shelton.)


Figure 18.5 Nicotinamide adenine dinucleotide reductase reaction. (G Diane Shelton, University of California, La Jolla, CA, 2014. Reproduced with permission from G Diane Shelton.)

Fig. 18.6 demonstrates the oil red O stain that localizes the presence of lipid droplets composed of neutral triglycerides within muscle fibers supporting a metabolic myopathy which may be mitochondrial in origin, or resulting from a defect in fatty acid oxidation or carnitine metabolism. Fig. 18.7 shows how cryosections react with esterase to highlight large numbers of macrophages in a necrotizing myopathy. Esterase stains lysosomal accumulations in macrophages and also in degenerating muscle fibers. Fig. 18.8 shows the cryosection reaction highlighting the motor endplates. The acid phosphatase reaction also highlights increased lysosomal activity in macrophages and within muscle fibers (Fig. 18.9; note in this cryosection the red stained areas within macrophages).


Figure 18.6 Oil red O stain. (G Diane Shelton, University of California, La Jolla, CA, 2014. Reproduced with permission from G Diane Shelton.)


Figure 18.7 Cryosections reacting with esterase. (G Diane Shelton, University of California, La Jolla, CA, 2014. Reproduced with permission from G Diane Shelton.)


Figure 18.8 Cryosections reacting with esterase highlight the dark reddish brown stained motor endplates.


Figure 18.9 Acid phosphatase reaction. (G Diane Shelton, University of California, La Jolla, CA, 2014. Reproduced with permission from G Diane Shelton.)

The immunoreagent Staphylococcal protein A-horseradish peroxidase identifies circulating serum antibodies that bind to the sarcolemma, to myofibers, to muscle nuclei in cases with anti-nuclear antibodies and to motor endplates in cases of myasthenia gravis following incubation of muscle cryosections with patient serum (Fig. 18.10). In the figure, distinct sarcolemmal labeling can be seen that is consistent with antibodies against an unidentified sarcolemmal protein(s) in a dog with polymyositis.


Figure 18.10 Immunoreagent Staphylococcal protein A-horseradish peroxidase. (G Diane Shelton, University of California, La Jolla, CA, 2014. Reproduced with permission from G Diane Shelton.)

Disorders of skeletal muscle in dogs and cats

  1. Degenerative/developmental

    1. Muscular dystrophy (MD)8, 15, 27, 53, 57, 58, 62, 64, 69, 71, 81, 83, 85, 95, 105, 110, 111, 118, 130, 148, 155, 156, 164, 165, 169, 176, 177, 179–181, 186, 190, 201, 235, 241, 245–248, 254, 258, 262, 288, 293, 295, 297, 301, 303–305, 310, 314, 333, 334, 337, 338, 346, 349, 354, 355, 357, 360, 365

      1. The term “muscular dystrophy” refers to a wide variety of inherited myopathies with specific defects of skeletal muscle proteins. The most common form of MD in both humans and animals is associated with the sarcolemmal protein dystrophin. Dystrophin is located on the X-chromosome and thus is an X-linked disorder (X-linked muscular dystrophy, or XLMD). Dystrophin is thought to have an important structural role for myofibers and may also serve a vital role in cellular homeostasis, possibly as a regulator of intracellular calcium transport.

        X-linked dystrophin-deficient muscular dystrophies in dogs and cats are believed to be the veterinary analogs of Duchenne and Becker muscular dystrophy of humans, and have been described in various dog breeds (Golden Retriever, Rottweiler, German Shorthaired Pointer, Irish Terrier, Samoyed, Belgian Shepherd (Groenendael), Miniature Schnauzer, Rat Terrier, Wire-haired Fox Terrier, Samoyed, Brittany Spaniel, Japanese Spitz, Weimaraner, Labrador Retriever, Old English Sheepdog, Grand Basset Griffon Vendéen, Corgi) and cats (domestic shorthair, Siamese, Maine Coon). Specific gene mutations have been defined in Golden Retrievers, German Shorthaired Pointers, Cavalier King Charles Spaniels, Japanese Spitz dogs and Rottweilers. Progressive muscle atrophy predominates in dogs (although some muscle groups tend to hypertrophy), whereas muscle hypertrophy is the hallmark of XLMD in cats. The pathologic change in affected muscle is characterized histologically by variation in myofiber size (including both degenerating and regenerating myofibers), with necrosis and mineralization of myofibers (Fig. 18.11). A number of dystrophin-associated proteins (e.g. sarcoglycans, dystroglycans), as well as laminins (basement membrane proteins) may also be deficient in other forms of MD.


        Figure 18.11 H&E (A) and alizarin red (B) stained muscle biopsy specimens from a dog with Duchenne muscular dystrophy. In A, a wide variation in muscle fiber size can be appreciated, and in B, there is evidence of intracellular calcium accumulation. (G. Diane Shelton, University of California, La Jolla, CA, 2014. Reproduced with permission from G. Diane Shelton.)

      2. Dystrophin-deficient muscular dystrophy is best described in the Golden Retriever. Marked elevations in serum CK activity detected during the first few weeks of life are a hallmark of this disease. Clinical signs of partial trismus and a “bunny-hopping” gait may be appreciated as early as 6 wks of age in male puppies. Although MD is largely restricted to males, it has been reported in female dogs. Additionally, female carriers of dystrophin mutations often show elevations in their serum CK activities, without significant clinical disease. In affected dogs signs typically progress over 3–6 mos, after which time the disease often stabilizes. Common clinical signs include progressive muscle atrophy of the limbs, head, and trunk, exercise intolerance, a stilted gait, plantigrade stance (with associated tarsal joint contracture), excessive salivation (pharyngeal dysfunction), weak bark (dysphonia), kyphosis that progresses to lordosis, and hypertrophy of the muscles of the base of the tongue. Proximal limb muscles, particularly the cranial sartorius muscle, may undergo hypertrophy in some dogs. Dysphagia and exercise-induced myalgia may present as sole clinical findings initially, prior to the onset of generalized weakness. Hiatal hernia and gastroesophageal reflux can be seen clinically, secondary to diaphragmatic and esophageal dystrophy, respectively. Spinal reflexes are normal initially but may become decreased due to muscle fibrosis. Inhalation pneumonia from pharyngeal/esophageal dysfunction and heart failure due to cardiomyopathy have also been reported. Uncommonly, some puppies display a more fulminant form of MD, and die within 10 days of birth.

        There appears to be considerable variation in time of disease onset and severity of clinical signs in cats with XLMD. Although affected cats may exhibit characteristic signs, such as a “bunny-hopping” pelvic limb gait in the first months of life, they may also have mild or inapparent clinical signs of myopathy until approximately 2 yrs of age. Progressive “stiffness” in gait and muscle hypertrophy are prominent features of MD in cats, in contrast to the weakness and atrophy characteristic of the canine disorder. Stress may induce open-mouthed breathing and/or syncopal episodes in cats with MD, presumably due to a combination of cardiac and respiratory muscle involvement. A form of MD associated with laminin alpha 2 deficiency (normal dystrophin) has been described in two young female cats (Siamese and domestic shorthair). These cats exhibited progressive muscle atrophy and weakness, beginning in the pelvic limbs, at approximately 5–6 mos of age. Spinal reflexes were depressed to absent. Both cats progressed to nonambulatory status over 6–12 mos.

      3. A diagnosis of MD is based upon signalment, characteristic clinical findings, marked serum CK elevations (often over 10,000 Units/L), bizarre high-frequency discharges on electromyograph, and muscle biopsy results (myofiber degeneration/regeneration with or without mineralization). Overall, the degree of elevation of CK in affected dogs does not correlate to the severity of their clinical signs. Serum CK levels in female dogs with MD have been less dramatically elevated compared with most males with the disorder. Cats with dystrophin-deficient muscular dystrophy frequently show myotonic discharges and fibrillation potentials on EMG evaluation, particularly in the proximal appendicular muscles. Motor nerve conduction studies remain normal. A lack or absence of dystrophin can be demonstrated immunocytochemically on a muscle biopsy specimen or by western blot analysis. Occasionally, dystrophin-associated proteins and laminins may also be deficient, with or without obvious lack of muscle dystrophin. Muscles of affected Golden Retrievers undergo fibrosis earlier than in other affected breeds, a process that appears to be cytokine-driven.

        Golden Retrievers with MD may show consistent abnormalities on thoracic and pelvic radiographs. Diaphragmatic asymmetry, with an undulating pattern and either left crural flattening or ventral displacement, may be seen on thoracic radiographs, and can be accompanied by a hiatal hernia. Characteristic pelvic radiographic abnormalities include narrowing of the body of the ilia, ventral deviation of the tuber ischii, elongation of the obturator foramina, and lateral elongation of the wings of the ilia. The pelvis is overall tilted vertically, narrowed, and elongated. These pelvic changes may be secondary to myopathy-induced contractures resulting in bone remodeling and appear to be specific to the form of MD seen in Golden Retrievers. Cats with MD may develop marked diaphragmatic hypertrophy, with megaesophagus seen secondary to esophageal stricture.

      4. There is no definitive treatment for and of the muscular dystrophies. Some patients may have an unexplained positive response when treated with glucocorticoids. Golden Retrievers with this disorder treated with daily prednisone therapy experience a combination of functional improvement but histopathologic deterioration. Growth hormone has been used clinically in human patients to decrease the severity of Duchenne muscular dystrophy. Additionally, lower IGF-1 concentrations (used as a measure of growth hormone) have been related to more severe forms of MD in Golden Retriever dogs. However, supplementation of growth hormone in such dogs has not yet been evaluated. There is active research concerning gene therapy for this myopathy, and preliminary studies have shown improvements in mobility and muscle function in dystrophic dogs using multiple gene therapy protocols. Pharmacologic upregulation of utrophin production (a paralogue of dystrophin) shows promise as a potential treatment for Duchenne muscular dystrophy and possibly the canine XLMD. However, continued research is needed before such treatments become available for clinical use. Stem cell therapy for dogs and humans with MD is also under investigation. The severity of dysfunction is variable, so the prognosis is guarded to poor. Clinical signs tend to progress more slowly after 6 mos of age in patients that survive that long.

    2. Centronuclear myopathies (CNM)2, 5, 8, 22, 30, 31, 35, 65, 100, 104, 112, 122, 179, 184, 189, 203, 212, 213, 215, 216, 217, 218, 297, 303, 328

      1. Centronuclear myopathies are a group of congenital myopathies with characteristic histopathologic abnormalities affecting mainly type II myofibers. These abnormalities include central or internal location of myonuclei (often in areas devoid of myofibrils), central areas of mitochondrial aggregation, and type II fiber atrophy. The appearance of subsarcolemmal ring-like structures (“necklace fibers”) has also been reported. In dogs, a causative genetic mutation has been identified for Labrador Retrievers (PTPLA gene) and Great Danes (BIN1 gene) with CNM. These recessively inherited myopathies were previously termed Labrador Retriever myopathy and inherited myopathy of Great Danes, respectively; the Great Dane disorder had been described previously as a core myopathy, which is now known to be incorrect. A similar condition was reported in a Border Collie, although a specific genetic mutation was not identified in this dog. An X-linked form of CNM, specifically named myotubular myopathy, has been reported in young Labrador Retrievers with onset at weeks of age. This is a very severe disease and usually results in early euthanasia or death. X-linked myotubular myopathy is caused by a mutation in the gene that codes for the protein myotubularin. A similar X-linked myotubular myopathy with a confirmed mutation in the MTM1 gene has recently been identified in Rottweiler puppies (Dr. Shelton, unpublished data).
      2. The age of onset as well as the severity and range of clinical signs are variable. For CNM of Labrador Retrievers, age of onset of clinical signs may range between 6 wks and 7 mos, but most dogs manifest obvious clinical signs of disease at about 3–4 mos of age. A short, stilted gait with “bunny-hopping” in the pelvic limbs is often observed. Some dogs display ventroflexion of the neck and arching of the back (kyphosis; Fig. 18.12). Abnormal joint posture—such as carpal hyperextension and valgus, splaying of the digits, and a “cow-hocked” pelvic limb stance—may also be apparent. Tendon reflexes are usually reduced or absent (especially patellar and triceps reflexes). Variable degrees of muscle atrophy, especially of the proximal limbs and head, develop as the disease progresses. Epaxial (paraspinal) musculature may also become atrophied. Weakness is often exacerbated by stress, excitement, exercise, and cold weather. A few dogs with this disorder have developed megaesophagus. The condition typically stabilizes by 6–12 mos of age. The time of onset of clinical signs in Great Danes with CNM has ranged from 6 mos to 3 yrs in age in reported cases, although the majority present as older puppies (median age of 7 mos). Clinical signs may initially be mild and are often slowly progressive. These can include generalized muscle weakness that worsens with exercise, progressive muscular atrophy, a short-strided gait, “bunny-hopping,” and tremors while standing. Depressed spinal reflexes have been reported in a small subset of affected dogs.

        Figure 18.12 Characteristic posture of a dog with Labrador Retriever myopathy.

      3. Diagnosis of CNM in Labradors and Great Danes is confirmed by genetic testing. In addition to supportive clinical features of CNM, EMG findings are often abnormal. Serum CK levels may be normal or slightly elevated. In the Border Collie with CNM, EMG findings were abnormal, but CK levels were within reference range.
      4. There is no specific treatment for this disorder. However, some dogs with CNM have improved with a combination of L-carnitine, coenzyme Q and B vitamins. In general, Labrador Retrievers with CNM are only mildly disabled, so the patient’s lifespan is often normal. Exposure to cold and stressful environments should be avoided. The Border Collie with CNM was reported to have normal exercise tolerance 14 mos after diagnosis. CNM of Great Danes appears to be more severe than the disorder in Labrador Retrievers. The majority of affected Great Danes appear to progress in their clinical signs and require euthanasia within months of the initial diagnosis (median survival time of 4 mos in one report). However, a subset of dogs with milder manifestations of the disease has been described, having a median survival time of 27 mos (range of 10 to 55 mos).

    3. Exercise-induced intolerance and collapse (EIC) Labrador Retrievers107

      1. A congenital, autosomal recessive inherited disease seen in young adult, field trial Labrador Retrievers. Exercise-induced intolerance and collapse is characterized by episodic limb weakness followed by ataxia and collapse occurring 5–20 min after intense exercise. Dogs are normal between episodes and recovery is typically very rapid. Occasionally, death can occur. Spinal reflexes, specifically the patellar reflex during a collapse episode, are often absent and hyporeflexia/areflexia can progress to the thoracic limbs.
      2. A mutation in the dynamin 1 (DNM1) gene, specifically Arg256Leu, has been associated with EIC in Labradors. DNM1 belongs to an enzyme complex responsible for catalyzing hydrolysis of guanosine triphosphate (GTP), leading to conformation changes in other proteins needed for cellular homeostasis. DNM1 is responsible for endocytosis and neurotransmission during prolonged periods of stimulation, such as strenuous exercise. Clinical disease typically occurs in dogs which are homozygous recessive for the DNM1 mutation; however, heterozygous and dogs negative for DNM1 mutation can also be affected. The frequency of the DNM1 mutation in Labradors ranges from 17 to 38%. The homozygous DNM1 genotype frequency between conformation show, field trial/hunting, and pet/service dogs ranges from 1.8 to 13.6%. In a study of 211 dogs with clinical signs referable to EIC and confirmed DNM1 mutation, 33 dogs (15.6%) were heterozygous or lacked the Arg256Leu DNM1 mutation. Dogs homozygous for the DNM1 mutation are young (median age 12 mos old) when they experience their first collapse episode. Heterozygous dogs or those lacking the mutation are typically older (median age 23 mos) and can have a wide variety of characteristics of collapse not consistent with a particular disease.
      3. EIC has historically been a clinical diagnosis of exclusion, ruling out all other causes for exercise intolerance in a young adult, athletic dog. Affected dogs do not show cardiovascular, orthopedic, or neurologic abnormalities. All diagnostic tests and physical exam parameters are normal between episodes. Hyperthermia and elevated plasma lactate levels are commonly seen at the onset collapse, although an elevation in body temperature of up to 3° Celsius may be found in normal dogs of this breed following intensive exercise. Additionally, affected dogs show a change in their lactate/pyruvate ratio, while this should not be seen in normal dogs.
      4. A commercially available DNA test for the Arg256Leu DNM1 gene mutation is now available to diagnosis EIC-affected dogs.
      5. There is no curative treatment for this disease. Most affected dogs make suitable pets and should refrain from intense exercises such as running, chasing balls or toys, and hunting and field trial events.

    4. Distal myopathy of Rottweilers82, 136, 210, 234

      1. A presumably inherited myopathic disorder that preferentially involves distal appendicular muscles was described in four young Rottweiler dogs. Two of the four dogs were siblings, and one of the remaining two dogs evaluated had two reportedly similarly affected siblings (not evaluated clinically). The etiology of this disease is unknown. Distal myopathy of Rottweilers appears to be similar to distal myopathy of humans, a broad category of autosomally inherited myopathies that primarily affect distal appendicular muscles.

      2. The age at which the dogs were evaluated was between 4 and 7 mos, but all dogs had exhibited an abnormal gait and posture within the first several weeks of life. Characteristic clinical signs of dysfunction include a palmigrade and plantigrade stance (Fig. 18.13), splayed digits in the forelimbs (Fig. 18.14), generalized weakness, and exercise intolerance.


        Figure 18.13 Characteristic posture of a Rottweiler with distal myopathy. (Courtesy of Dr. Stephen Hanson.)


        Figure 18.14 Splaying of the digits, characteristic of Rottweiler distal myopathy. (Hanson et al., 1998. Reproduced with permission from Wiley.)136

      3. Diagnosis is based primarily on signalment, characteristic clinical features, and abnormal muscle biopsy histopathology results. CK levels were normal in one dog and only mildly elevated in the two others in which it was measured. EMG was performed in two of the four dogs. In one dog, rare fibrillation and positive sharp waves were identified. No EMG abnormalities were identified in the other dog. Both dogs had decreased amplitude of interosseous compound muscle action potentials, elicited during motor nerve conduction velocity testing. Plasma carnitine levels were decreased in all four dogs. Muscle carnitine levels were below normal levels in three dogs, and in the low–normal range in the remaining dog. Dystrophin immunocytochemical staining was normal in the two dogs for which this test was performed.
      4. At present, the prognosis for this myopathy appears to be poor. All four dogs were euthanized, three due to the severity of the disease and one due to an unrelated behavioral disorder. This latter dog’s clinical signs appeared to improve somewhat with oral carnitine supplementation, but did not deteriorate after carnitine withdrawal. The clinical significance of low plasma and muscle carnitine levels in this disorder is unknown but is felt to be a secondary, rather than a causative, phenomenon. The potential efficacy/inefficacy of carnitine supplementation for this myopathy remains to be determined.

    5. Myotonia congenita3, 8, 26, 28, 35, 37, 76, 96, 103, 129, 146, 147, 150, 178, 179, 183, 224, 225, 272, 285, 286, 297, 311, 314, 329, 331, 335, 343, 344, 345, 351, 358, 367, 368

      1. This disorder is believed to be inherited as an autosomal recessive trait in Chow Chow dogs and Miniature Schnauzers. Other breeds reported with a similar condition include the Staffordshire Terrier, Rhodesian Ridgeback, Great Dane, West Highland White Terrier, Samoyed cross, Australian Cattle dog, and Labrador Retriever. Myotonia congenita has also been described in six domestic shorthaired kittens. The four kittens in one report were from separate litters, but the queens of those litters were related. The discerning clinical feature of this disorder is sustained muscle contraction after cessation of voluntary movement. Failure of muscle relaxation is believed to be due to abnormal sarcolemmal chloride conductance. The decreased chloride conductance leads to hyperexcitability of the muscle membrane. Subsequent accumulation of potassium ions in the T-tubule system is responsible for sustained muscle contraction following initial depolarization. Abnormal sarcolemmal chloride channels, due to an autosomally inherited genetic defect, have been demonstrated as the cause of myotonia congenita in the Miniature Schnauzer. There are several forms of myotonia congenita in humans, some of which are due to abnormal sodium conductance across the sarcolemma.

      2. Clinical signs are usually appreciated when affected puppies and kittens begin to ambulate. Affected animals typically appear worse after a period of rest. Cold temperatures also tend to cause exacerbation of clinical signs. The gait is stiff and tends to improve or even normalize with activity. The pelvic limbs are often more severely affected than the thoracic limbs; in canine myotonia, they may be advanced simultaneously in a “bunny-hopping” fashion. It may be difficult for affected dogs to flex the stifle joints. The thoracic limbs are often held abducted while ambulating, due to a decreased ability to flex the proximal limb joints. Myotonic patients may have difficulty rising from a sternal position. Myotonic kittens tend to snag their claws when walking on carpet. When myotonic kittens are startled, they may hyperextend all four limbs and fall into lateral recumbency for approximately 10 sec. Startling in these kittens may also result in bilateral prolapse of the nictitans, blepharospasm (due to spasm of the orbicularis oculi muscles), flattening of the ears, and retraction of the lips.

        Generalized muscle hypertrophy (especially proximal appendicular and neck muscles and the tongue in dogs, gastrocnemius muscles most prominent in cats) is often appreciated and percussing the muscle may leave an indentation, referred to as a “myotonic dimple” (Fig. 18.15). Some patients will exhibit dysphagia and respiratory problems (e.g. stridor) because of sustained contraction of pharyngeal and laryngeal musculature, respectively. Affected kittens may exhibit signs of dysphonia, characterized by a hoarse meow and quiet purr. Unusual physical characteristics apparent in all of a group of related myotonic Schnauzers were prognathism (shortened mandible) and medially displaced canine teeth.


        Figure 18.15 Myotonic dimpling in the caudal thigh musculature of a myotonia congenita patient. (Dr. G Kortz, 2014. Reproduced with permission from Dr. G Kortz.)

      3. Diagnosis is based upon signalment, characteristic clinical signs, and electrodiagnostic findings (EMG abnormalities). CK levels are often either normal or only mildly elevated, and changes on muscle biopsy are usually mild and nonspecific (e.g. variation in myofiber size). Muscle biopsy results may contribute to the diagnosis, but may not be worth the risk of anesthesia in these patients. Anesthesia may be both difficult and dangerous due to stenosis of the laryngeal glottis. Also, people with myotonia are predisposed to anesthetic-induced malignant hyperthermia. The characteristic finding on EMG is bizarre high-frequency discharges that wax and wane (Fig. 18.16). These discharges are frequently referred to as “dive-bomber sounds,” due to their waxing and waning nature. Others have likened their sound to a motorcycle engine. Myotonic discharges have also been reported on EMG evaluations of heterozygote (carrier) Miniature Schnauzers, although the length of these discharges is shorter than is seen in homozygote dogs of this breed. Lastly, polymerase chain reaction-based DNA tests have recently been reported for screening Australian Cattle dogs and Miniature Schnauzers for myotonia congenita.

        Figure 18.16 EMG tracing of a dog with myotonia.

      4. There is some evidence that using membrane-stabilizing agents may be helpful in relieving clinical signs in myotonic dogs. Procainamide is thought to be more effective than phenytoin or quinidine. Other drugs that have been used to treat myotonia in dogs include carbamazepine, tocainide, nifedipine, and mexiletine hydrochloride. Environmental modification alone is recommended to control clinical signs in myotonic cats. These kittens tend to be well managed without drug therapy, and drugs typically used to control canine myotonia have unacceptable toxicity risks in cats. Myotonia congenita is not considered a progressive disease, and clinical signs of dysfunction tend to stabilize between 6–12 mos of age. In general, most dogs and cats with myotonia congenita are not severely disabled, and therefore the prognosis for long-term survival is favorable. The prognosis for sustained improvement of clinical signs of myotonia is guarded, however.

    6. Fibrotic myopathy (gracilis/semitendinosus myopathy)39, 74, 196, 197, 198, 199, 200, 202, 297

      1. This is an idiopathic disorder characterized by replacement of muscle tissue with dense fibrous connective tissue. It occurs most commonly in dogs, especially adult male German Shepherd dogs (approximately 81% of reported cases). Other breeds reported with fibrotic myopathy include Belgian Shepherd, Boxer, Old English Sheepdog, Doberman Pinscher, Saint Bernard, and Bobtail. It has been reported in one cat. The gracilis muscle is most often affected (86% of cases), but the semitendinosus muscle may also be affected either alone or concurrently. Involvement of the supraspinatus and quadriceps muscles has been reported, but this is rare. The fibrotic gracilis/semitendinosus muscle produces a tethering effect, interfering with coxofemoral joint abduction, as well as stifle and hock joint extension. The pathogenesis is unknown. Autoimmune myopathy, neuropathy, isolated muscle trauma, repeated microtrauma, and vascular compromise have all been suggested as possible etiologies.

      2. Age of onset of dysfunction ranges from 8 mos to 9 yrs (mean, 5 yrs). Clinical signs are usually limited to apparently nonpainful pelvic limb lameness, which is more obvious at a trot than at a walk. In most cases, the lameness has an insidious onset and progresses over weeks to months before reaching a plateau. Occasionally, acute onset of lameness is reported. Bilateral involvement occurs in approximately 26% of cases. When both pelvic limbs are affected, the degree of dysfunction may not be symmetric; also, one limb may be affected initially, the other becoming dysfunctional at a later date. Although classically considered a nonpainful disorder, one study found that a painful response could be elicited from the majority of affected dogs with hip abduction and/or digital pressure applied to the distal aspect of the fibrotic muscle. The fibrous muscle prevents full extension of the pelvic limb during ambulation. The lameness in the affected limb is characterized by internal rotation of the stifle and external rotation of the hock as the limb is advanced (Fig. 18.17). The foot performs a “flipping” motion at the end of each stride. The resultant gait is often described as “jerky” or “goose stepping.” Affected muscle tissue may be visibly abnormal and the distal myotendinous area is often firm and hypertrophied when palpated (Fig. 18.18).


        Figure 18.17 Typical pelvic limb gait of a dog with fibrotic myopathy.


        Figure 18.18 Bilateral fibrosis of the gracilis muscles in a dog with fibrotic myopathy.

      3. Diagnosis is based primarily upon signalment and characteristic clinical findings. Increased thickness may be appreciated in affected muscles with both radiographs and ultrasonography. CK values are typically normal or slightly elevated. EMG often fails to record any abnormal electrical activity. There are reports of both increased EMG activity and lack of normal insertional activity. Muscle biopsy reveals dense collagenous connective tissue.
      4. Medical therapies for fibrotic myopathy (e.g. corticosteroids, penicillamine, colchicine) have been ineffective. Various surgical procedures (e.g. tenotomy, Z-plasty, excision of affected muscle) have met with poor long-term success. Improvement in gait post surgery is often substantial but transient, lasting only a few months. If the abnormal gait is not severely limiting the patient’s lifestyle, no treatment is recommended.

    7. Nemaline myopathy75, 77, 88, 185, 204, 231, 292, 303, 308, 309

      1. Nemaline myopathy is a rare, presumably inherited disorder described in young related cats. Congenital nemaline myopathy has also been reported in two dogs, a 10-mo-old Border Collie, and an 11-yr-old Schipperke. Nemaline rods were also observed in muscle biopsy specimens from a dog with hyperadrenocorticoid myopathy and a dog with hypothyroid myopathy. Finally, nemaline rods have been reported as incidental findings in muscle biopsies of dogs with neuromuscular disease. The presence of nemaline rods in a muscle biopsy is not necessarily specific for nemaline myopathy.

        A diagnosis of nemaline myopathy should be suspected when there are numerous nemaline rods present in the absence of any other cause for a myopathy. The pathogenesis of nemaline myopathy is unknown, but special stains of muscle biopsy specimens reveal rod-shaped inclusions within myofibers (nemaline rods). In human nemaline myopathy, these rods have been shown to be composed of cytoskeletal proteins identical to those found in the Z-band area of the contractile filament apparatus. A myofiber cytoskeletal protein abnormality is suspected. Accumulations of tubulin-positive crystalline inclusions, and dystrophin and spectrin proteins in addition to nemaline rods, have been reported in cats as well. A myofibrillar myopathy showing accumulations of alpha-actin (Z-disc material) and desmin within the myofiber has been reported in an Australian Shepherd dog.

      2. The reported cats had an acute onset of clinical signs between 6 and 18 mos of age. Clinical signs included weakness, a rapid and crouched hypermetric gait, muscle tremors, hyporeflexia, muscle atrophy, and reluctance to move. Only the muscle atrophy appeared to be progressive. Both congenital canine nemaline myopathy cases had slowly progressive clinical signs that included exercise intolerance, and reluctance to stand and walk. The Border Collie displayed tremors in all limbs, muscle atrophy, and absence of patellar reflexes. Additional clinical signs of dysfunction in the Schipperke included a stiff gait, spontaneous limb jerking, and decreased withdrawal reflexes in all four limbs. The endocrine myopathy cases had clinical signs of dysfunction typical for their respective myopathic disorders.
      3. Diagnosis is based upon signalment, clinical signs, and demonstration of nemaline rods on muscle biopsy samples. CK levels were only mildly elevated in the reported cats and EMG evaluation was normal. Similarly, the CK level of one of the congenital canine cases was normal; the other was slightly elevated. EMG changes in these two dogs were mild.
      4. Although only the muscle atrophy was progressive, the reported cats continued to lose condition and became inappetent. All the cats were eventually euthanized. The disorder in the reported dogs was slowly progressive over several years. There is no known treatment for nemaline myopathy and the prognosis for recovery is poor.

    8. Dancing Doberman disease

      This is an idiopathic syndrome in adult Doberman Pinschers that has characteristics of both a neuropathy and a myopathy. It is discussed in more detail in Chapter 17.

    9. Myositis ossificans (fibrodysplasia ossificans progressiva)7, 39, 75, 161, 204

      1. This is a rare idiopathic disorder of dogs and cats in which proliferation of fibrovascular tissue within muscle occurs, with secondary calcification and ossification. Intermuscular mineralization has also been reported. It is not known whether this disease represents a primary muscle disorder or is an abnormality of connective tissue adjacent to muscle (e.g. tendons, fascia) that leads to a secondary myopathy. Calcinosis circumscripta within lingual muscle has also been reported, secondary to a nutritional myopathy and idiopathic calcinosis.
      2. This disorder typically affects young adult to middle-aged animals of both sexes. Clinical signs include progressive weakness and stiffness of gait, enlargement of proximal limb muscles, and myalgia. Focal, firm swellings may be evident on muscle palpation.
      3. Diagnosis is based primarily upon signalment, clinical signs, and radiographic evidence of mineralized/ossified densities (usually multiple) within muscle tissue. CK levels are typically elevated, and EMG evaluation reveals abnormal potentials. Histopathologically, fibrosis, myofiber necrosis and phagocytosis, and areas of calcification/ossification may be seen.
      4. Since this tends to be a progressive disease, the prognosis is considered guarded to poor. However, focal lesions may regress or respond favorably to surgical excision.

    10. Pharyngeal/esophageal dysfunction of Bouviers46, 247

      1. A myopathy primarily affecting pharyngeal and esophageal musculature has been described in 24 Bouvier des Flandres dogs from the Netherlands. The pathogenesis of this disorder is unknown, but muscle histopathology revealed abnormalities similar to those observed in dystrophin-related muscular dystrophy (DRMD). It has been suggested that this disorder may be the canine analog of oculopharyngeal muscular dystrophy in humans. Although suspected to be a heritable trait, the mode of transmission is unknown. Four adult female Bouviers with generalized muscle weakness and megaesophagus were described in the United States. These dogs also had histopathologic changes on muscle biopsies consistent with DRMD. It is unknown whether these dogs had a variation of the same disorder as the group in the Netherlands.
      2. Both males and females were affected, with an age range of presentation from 6 mos to 9 yrs of age. The predominant clinical sign of dysfunction was dysphagia. Seven of the 24 dogs with dysphagia also exhibited regurgitation. Regurgitation was the predominant clinical feature in three dogs.
      3. Tentative diagnosis of this myopathy was based upon historical and clinical signs, as well as abnormal pharyngeal and esophageal movement on fluoroscopic examination. Only seven dogs had radiographically obvious air accumulation in the esophagus. In 20 dogs in which serum CK levels were evaluated, seven dogs had normal values, and CK levels were elevated in 13 dogs. EMG abnormalities of the pharyngeal and/or esophageal musculature were found in all but one dog examined. A histopathologic evaluation of pharyngeal/esophageal muscles from affected dogs revealed changes characteristic of DRMD. In two dogs, these characteristic abnormalities were also apparent in temporalis, masseter, and laryngeal musculature.
      4. There is no known effective treatment for this disorder. Four dogs with dysphagia underwent cricopharyngeal myotomy. One of these dogs improved, but the other three died of aspiration pneumonia within two days of surgery. The majority of the affected dogs were euthanized due to continued dysphagia. The prognosis for dogs with this disorder appears to be poor.

    11. Polysystemic disorder of English Springer Spaniels149

      1. Three related young English Springer Spaniels have been described with the combination of polymyopathy, dyserythropoiesis, and cardiac abnormalities. The etiology of this polysystemic disorder is unknown, but is suspected to be a heritable variant of MD.
      2. All three dogs developed clinical signs of dysfunction within the first 6 mos of life, and all were considered small for their age. One dog occasionally regurgitated, and the other two had decreased gag reflexes. Slowly progressive temporalis muscle atrophy developed in all dogs, with subsequent partial trismus. To a lesser degree, pelvic limb muscle atrophy occurred over time. One dog exhibited a stiff gait, most notable in the pelvic limbs, often “bunny-hopping” when ambulating. Exercise intolerance was not a notable feature in any of the three dogs.
      3. Diagnosis of this disorder was based upon both antemortem and necropsy evidence of concurrent polymyopathy, dyserythropoietic anemia (erythrocytes with abnormal morphology, including blast forms), and various cardiac abnormalities (e.g. right ventricular enlargement, enlargement of conus arteriosus, ascending aorta enlargement, ventricular premature complexes). Varying degrees of megaesophagus and abnormal esophageal motility were evident on thoracic radiographs and fluoroscopic evaluation, respectively. Serum CK levels were normal in one dog and slightly elevated in another. EMG abnormalities were not evident in the one dog in which electrodiagnostics were pursued. Abnormal muscle pathology in affected dogs included marked fiber size variation and fiber splitting.
      4. There is no known effective therapy for this disorder and the prognosis for recovery is poor. All three dogs were euthanized.

    12. Cricopharyngeal achalasia52, 120, 188, 211, 233, 251, 277, 281, 298, 350, 352

      1. This is an uncommon and enigmatic disorder of young dogs. It is characterized by a failure to relax the cricopharyngeus muscle during the oropharyngeal phase of swallowing. The underlying reason for the lack of cricopharyngeus relaxation is unknown. Suggested etiologies include myopathy, neuropathy (affecting the glossopharyngeal nerve and the pharyngeal branch of the vagus nerve), junctionopathy, and central nervous system, or CNS, (brain-stem) lesion. Cricopharyngeal achalasia associated with hypothyroidism has been reported in one dog. A full recovery was seen following thyroid hormone supplementation, suggesting a possible role of hypothyroidism in the development of cricopharyngeal achalasia in this case.
      2. Numerous dog breeds have been reported with cricopharyngeal achalasia. Spaniel breeds appear to be overrepresented in the literature; there is one report of cricopharyngeal achalasia occurring in Cocker Spaniel littermates. Clinical signs of dysfunction are usually evident at the time of weaning and remain static, unless aspiration pneumonia develops. Dysphagia is the hallmark clinical sign of dysfunction. Other characteristic clinical signs include regurgitation (typically immediately following attempted swallowing), nasal reflux of ingested food, coughing, and either weight loss or failure to gain weight. Dogs with this disorder may be more able to swallow liquids than solids, but ingesting liquids may lead to more nasal reflux than solids.
      3. Diagnosis of cricopharyngeal achalasia is based primarily upon history, signalment, and characteristic clinical features, as well as ruling out other causes of dysphagia and regurgitation (e.g. idiopathic megaesophagus, myasthenia gravis, vascular ring anomalies). Radiographs of the pharyngeal area and thorax should be obtained to rule out pharyngeal foreign bodies and megaesophagus, respectively. Also, the presence or absence of aspiration pneumonia can be ascertained by thoracic radiographs. Crucial to diagnosis is evaluation of swallowing using contrast fluoroscopy (Fig. 18.19). This radiographic evaluation should confirm failure of cricopharyngeal relaxation during the swallowing reflex. Endoscopic evaluation of the pharyngeal area will be normal, and there is typically no appreciable impediment to passing the scope through the pharyngeal region.

        Figure 18.19 Fluoroscopic image of a dog with cricopharyngeal achalasia before (A) and after (B) cricopharyngeal myotomy. Prior to surgery, very little of the contrast bolus passed through the upper esophageal sphincter. (Ladlow and Hardie, 2000.)188

      4. Treatment of cricopharyngeal achalasia is myotomy or myectomy of the cricopharyngeus muscle. This surgical therapy is highly effective for this disorder. However, if the diagnosis is incorrect, cricopharyngeal myotomy/myectomy may not only be of no therapeutic value but also lead to life-threatening aspiration pneumonia. Lastly, inappropriate or insufficient treatment of aspiration pneumonia and/or malnutrition preoperatively in animals with cricopharyngeal achalasia frequently worsens postoperative outcome.

        The authors have treated one case of cricopharyngeal achalasia with therapeutic Botox injections. The abnormal cricopharyngeal musculature was identified with an EMG. The Botox was injected into the abnormal muscle and repeated 3 wks later. This procedure was both therapeutic and used to prognosticate this patient’s overall success with a permanent myectomy. This patient showed clinical improvement after this procedure and went on to have a permanent myectomy performed.

    13. Episodic muscle hypertonicity (“cramp”)6, 106, 145, 166, 220, 221, 222, 223, 249, 282, 294, 318, 343, 361, 362, 363

      This uncommon disorder, initially reported in the Scottish Terrier breed (“Scotty cramp”), is characterized by episodic muscle hypertonicity. The episodes are of variable frequency and severity and are induced by stress, exercise, and excitement. The disease appears to be inherited as an autosomal recessive trait in Scottish Terriers. Although the pathogenesis is not completely understood, clinical manifestations of this disorder may be due to a functional deficiency of serotonin in the CNS. Drugs that potentiate CNS serotonergic effects (e.g. acepromazine) alleviate clinical signs, whereas those that decrease CNS serotonergic effects (e.g. amphetamine) either worsen or induce clinical signs. Similar conditions have been described in a number of different breeds. These and other movement disorders are covered in more detail in Chapter 10.

    14. Myokymia and neuromyotonia109, 131, 132, 266, 336, 347, 366

      This category of disease (especially myokymia) is often discussed with tremor and movement disorders, but it is probably more accurately categorized as a neuropathy (see Chapter 17). It is discussed in this chapter because the manifestations of the disorder appear clinically more like a myopathy than a neuropathy. It is also briefly discussed in Chapter 10. The underlying pathophysiological cause for the intermittent and excessive muscle contraction characteristic of myokymia/neuromyotonia is thought to be hyperexcitability of motor axons; in humans, this hyperexcitability is thought to be due to abnormalities of voltage-gated potassium channels (VGKC) in these nerves, which is often due to an autoimmune process. In addition to autoimmune disorders of VGKC, there are some heritable disorders of these ion channels; for example, the disorder known as episodic ataxia with myokymia is due to a point mutation in the VGKC gene (KNA1). Whether acquired (autoimmune) or inherited, the VGKC involved in this disorder are fast potassium channels, also referred to as delayed rectifier channels, whose function is necessary for the cessation of depolarization as well as repolarization of the axon. If these channels are dysfunctional and/or decreased in density, prolongation of depolarization will allow more calcium to enter (calcium channels will remain open), with a subsequent excessive release of acetylcholine transmitter quanta into the synaptic cleft. This, along with delayed repolarization, will lead to excessive and repetitive muscle contraction. Confusion regarding this clinical phenomenon is likely perpetuated both by an unnecessary number of descriptive terms as well as the vast array of primary disorders that can lead to the manifestation of this type of muscular activity. The terms “myokymia” and “neuromyotonia” probably refer to the same class of disorders, differing solely in the frequency (in Hz) of the episodic involuntary muscle fiber contraction that characterizes the disease syndrome. The term myokymia, which is derived from the Greek word kyma (which means “wave”), is probably the most descriptive term for the vermicular (“worm-like”), rippling, or undulating motion of the skin (most notably on the proximal limbs) caused by the spontaneous intermittent contraction of subcutaneous musculature. Myokymic discharges are characteristically bursts of single motor unit action potentials that have a frequency of 5–150 Hz. Neuromyotonic discharges are described as similar episodic discharges of higher frequency (150–300 Hz, often with a waning amplitude), which are believed to be more likely than myokymic discharges to culminate in generalized contractions of large muscle groups (e.g. limb musculature). These intermittent bursts of motor unit action potentials occur as doublets, triplets, or multiplets on EMG examination, and sound (over the loudspeaker) like soldiers marching. These muscle fiber discharges persist during sleep and when the patients are under general anesthesia. The terms myokymia and neuromyotonia likely refer to different stages of severity of the same clinical condition. According to some sources, myokymia is considered a clinical manifestation of the overall disease syndrome of neuromyotonia. In other words, the umbrella term for the disorder is neuromyotonia, which includes the phenomenon of myokymia. Since the majority of reported cases in the veterinary literature describe patients that displayed myokymia and then rapidly progressed to generalized muscle contraction and collapse, this is probably the correct use of the terminology. In addition to these terms, neuromyokymia, continuous muscle fiber activity (CMFA), continuous motor unit activity (CMUA), neurotonia, pseudomyotonia, and episodic nonpostural repetitive myoclonus have been proposed. The list of disorders in humans that have been associated with concurrent myokymia and neuromyotonia is extensive and includes several autoimmune or suspected autoimmune disorders; it includes caudal fossa tumors, Guillain–Barré syndrome, multiple sclerosis, radiation-induced plexopathy, timber rattlesnake envenomation, chronic inflammatory demyelinating polyneuropathy (CIDP), thymoma, lymphoma, plasmacytoma, small-cell lung carcinoma, Hashimoto’s thyroiditis, Addison’s disease, rheumatoid arthritis, and acquired myasthenia gravis. The disorder has also been associated with penicillamine treatment. In addition to the multitude of terms already mentioned, the terms Isaacs’ syndrome, Mertens’ syndrome, Isaac–Mertens’ syndrome, and Morvan’s syndrome (also includes signs of encephalopathy) all refer to myokymia/neuromyotonia due to autoimmune response against VGKC.

      Myokymia and neuromyotonia have been reported in eight dogs and one cat. The dogs included three Jack Russell Terriers, two Yorkshire Terriers, a Border Collie, a Cocker Spaniel, and a mixed-breed dog. The one feline report was a 6-yr-old domestic shorthaired cat. With the exception of one dog with facial myokymia (6-mo-old Cocker Spaniel, age at onset of 4 mos) who had occasional involvement of the left shoulder musculature, all of the other reported cases exhibited neuromyotonia with more generalized muscle stiffness, in addition to myokymia. Of the neuromyotonia cases, the cat was the least severely affected, remaining ambulatory despite the involuntary muscle contractions. With the exception of one Border Collie with an age at onset of 2 yrs, the other dogs with neuromyotonia had a very young age at onset of disease (2–11 mos). These dogs all had a similar clinical presentation, in which the excessive muscular contraction culminated in collapse. In all cases, the dogs were fully conscious during the collapsing episodes. The episodes in these dogs were typically triggered by stress, excitement, or exercise and lasted for several minutes to several hours. Between episodes, the dogs returned to normal, or their pre-episode condition (see comments below on the Jack Russell Terriers). Episodes were heralded in three dogs by intense facial rubbing, similar to what has been reported in hypocalcemic dogs. Common to all of these reported cases of myokymia/neuromyotonia was moderate to severe hyperthermia during the episodes. In two cases, death during an episode was attributed to hyperthermia. Another common feature was persistence of spontaneous muscle contraction during sleep and general anesthesia. All three reported Jack Russell Terriers exhibited generalized ataxia in addition to the myokymia/neuromyotonia episodes. Whether this finding represents concurrent hereditary ataxia or a condition similar to human episodic ataxia with myokymia is unknown. Two of the Jack Russell Terriers also exhibited mild cyanosis during episodes.

      As with humans with myokymia/neuromyotonia, the diagnosis rests primarily on characteristic clinical features of the disease along with demonstrating the characteristic EMG abnormalities (i.e. episodic bursts of spontaneous muscle activity of specific frequencies). Other characteristic supportive features include serum elevations of ALT, AST, and CK concentrations. Muscle/nerve biopsy results in humans may be normal or indicative of axonal degeneration and/or demyelination. Muscle histopathology was normal in the four dogs for which it was performed. The Jack Russell Terriers had evidence of axonal degeneration and demyelination of peripheral nerves, with very mild muscle changes. One Yorkshire Terrier had normal muscle biopsy results. The cat had evidence of myofiber necrosis and regeneration, and intramuscular nerve branches were normal. Although none of the veterinary cases had an obvious underlying disorder for which the myokymia/neuromyotonia was considered a secondary or associated phenomenon, this should be addressed in such cases, based on what is known in the human literature on the subject. Unlike the scenario in human medicine, there is no assay for circulating anti-VGKC antibodies for dogs or cats (to diagnose autoimmune causes for myokymia/neuromyotonia), and no canine or feline hereditary mutations for the VGKC gene have been identified.

      A variety of drugs have been effective in treating human myokymia/neuromyotonia, including procainamide, phenytoin, carbamazepine, acetazolamide, mexiletine, and gabapentin. These drugs have membrane-stabilizing properties and may also be of some benefit for veterinary cases of myokymia/neuromyotonia. In people with underlying autoimmune disorders, immunosuppressive drugs are used in addition to membrane-stabilizing agents. The cat responded favorably to oral phenytoin, and one Yorkshire Terrier responded well to procainamide. Two other dogs had transient responses to such therapy. The Border Collie responded for several months to oral mexiletine, and then reverted to the previous frequency of episodes. One Jack Russell Terrier responded to oral procainamide, but died during an episode in the second month of treatment. Four dogs either died during an episode (two dogs) or were euthanized due to disease severity (two dogs), suggesting at least a guarded prognosis for this disorder. However, more experience with this disease, especially with treatment options recommended for people with the disorder (only one of the deceased dogs was treated with one of these drug options), will be necessary before an accurate estimate for prognosis can be formulated for myokymia/neuromyotonia in dogs and cats.

  2. Metabolic

    1. Hypokalemic myopathy29, 35, 38, 91, 92, 93, 151, 163, 174, 195, 229, 297, 324

      1. A relatively common myopathy associated with low extracellular potassium levels is encountered in cats. Most of these cats have chronic renal dysfunction with subsequent potassium loss through the urine. Other conditions associated with hypokalemic myopathy in cats include hyperthyroidism, dietary potassium deficiency, hyperaldosteronism (Conn’s syndrome), fluid overadministration, chronic vomiting/diarrhea, and overuse of potassium-wasting diuretics. There is also a suspected hereditary condition of unknown pathogenesis in Burmese kittens with periodic hypokalemia and signs of myopathy. This is a suspected autosomal recessive condition. It may be similar to hypokalemic periodic paralysis of people. Hypokalemia leads to hyperpolarization of the sarcolemma resting membrane potential, making it refractory to depolarization and subsequent contraction.
      2. Most cats with this condition are older and have evidence of renal dysfunction. The Burmese kittens with intermittent hypokalemia and myopathy ranged between 2 and 6 mos of age. Clinical signs are typically acute in onset and include neck ventroflexion (Fig. 18.20), myalgia, reluctance to ambulate, and a stiff, stilted gait. With severe hypokalemia, respiratory paralysis and rhabdomyolysis can occur.

        Figure 18.20 Cat with cervical weakness demonstrating cervical ventroflexion.

      3. Diagnosis is based upon signalment, historical and clinical findings, as well as supportive evidence of a myopathy in a cat with hypokalemia. An abdominal ultrasound is recommended to rule out an underlying adrenal tumor supporting Conn’s disease and to evaluate renal status. The potassium level in affected cats is less than 3.5 mEq/L, and often is less than 3.0 mEq/L. CK levels are usually moderately to markedly elevated. EMG evaluation typically reveals abnormal activity such as fibrillation potentials, positive sharp waves, and bizarre high-frequency potentials. Muscle biopsy samples often reveal no or very mild abnormalities. Resolution of clinical signs with potassium supplementation also supports the diagnosis.

      4. Treatment of this condition is oral potassium gluconate at an initial dose of 5–8 mEq/kg/day, divided into two doses. Normal potassium levels are often achieved within 1–3 days with this therapy. Maintenance therapy of 2–4 mEq/day is usually sufficient after achieving normal serum potassium levels. Potassium administration via intravenous fluids is usually counterproductive, because the dilutional and diuretic aspects of fluid administration actually further lower the potassium level.

        In life-threatening hypokalemia, concentrated intravenous potassium solutions can be administered at a rate of 0.4 mEq/kg/hr. However, this is potentially dangerous and can lead to fatal cardiac arrhythmias without close monitoring of the serum potassium level and the electrocardiogram. An alternative is a dopamine infusion of 0.5 mg/kg/min. This may cause a transient increase in serum potassium, and allow time for oral potassium supplementation. The prognosis for this condition with proper therapy is generally favorable. Most cats exhibit obvious improvement within 1–3 days of potassium supplementation, although complete recovery may take several weeks.

    2. Hyperkalemic periodic paralysis (HPP)38, 91, 162, 174, 297

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Apr 7, 2020 | Posted by in SMALL ANIMAL | Comments Off on Myopathies: Disorders of Skeletal Muscle

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