17.

Chapter 10 Muscle Pain and Weakness

Manual of Rheumatology and Outpatient Orthopedic Disorders

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Chapter 10 Muscle Pain and Weakness

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J. Robert Polk and Lawrence J. Kagen

Neurologic Causes
	Upper motor neuron diseas
	Lower motor neuron disease
	Nerve root diseas
	Peripheral nerve diseas
	Myoneural junction disease
Myopathic Causes
	Toxin and drug-induced myopathy
	Metabolic myopathies
	Endocrine myopathies
	Muscular dystrophy
	Inflammatory myopathies
	Infectious myositis and myopathy
	Fibromyalgia
	Polymyalgia rheumatica
	Miscellaneous disorders presenting as myopathy
Laboratory Aids to Diagnosis
	Serum chemistries
	Hematologic studies
	Urinary studies
	Provocative studies
	Electromyography and electroneurography
	Muscle biopsy
	Other modalities of imaging or assessing muscle

Muscle pain and weakness are commonly encountered in clinical medicine. Evaluation of a patient with these symptoms and signs begins with a careful history and thorough physical examination. Family history and medication history are important and if possible should be verified personally by the primary physician . Proximal weakness is the usual symptom and sign of myopathy. Muscle pain and tenderness may also be present but are experienced less often than weakness. Syndromes of muscular pain and weakness can be divided into neurologic and myopathic categories.

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Neurologic Causes

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I. Upper motor neuron disease includes brain and brainstem hemorrhages, infarctions, and neoplasms. Some demyelinating diseases may present in this category. Spasticity, increased deep tendon reflexes, pathologic reflexes, sensory abnormalities, and impaired cerebral functions may be noted.

II. Lower motor neuron disease. Brainstem lesions such as progressive bulbar palsy and poliomyelitis may present with weakness but usually have other features, such as cranial nerve dysfunction, that lead to the correct diagnosis. Anterior horn cell lesions can cause muscle weakness. Segmental involvement of muscles , which are flaccid, fasciculations, and loss of deep tendon reflexes are seen. Sensory abnormalities do not occur. Muscle atrophy occurs early.

III. Nerve root disease presents with muscle weakness if the ventral root is involved. Loss of deep tendon reflexes and muscle atrophy also occur. Muscles are hypotonic. Atrophy is less pronounced than in anterior horn cell lesions. Pain and sensory loss may occur with dorsal root dysfunction.

IV. Peripheral nerve disease presents with loss of deep tendon reflexes and hypotonia. Sensory abnormalities may or may not occur. Characteristically, several peripheral nerves are involved simultaneously . Distal weakness occurs early. These diseases can easily be confused with primary myopathies, especially during later stages when a primary myopathy may have features of proximal and distal weakness, muscle atrophy, and loss of deep tendon reflexes.

V. Myoneural junction disease. Myasthenic syndromes resemble myopathies more than neuropathies. Muscle weakness is often more proximal than distal, without early reflex changes or sensory abnormalities. Myasthenia gravis is characterized by increased muscle fatigue with continued exertion. Improvement occurs with rest.

Ocular muscles are frequently involved. An edrophonium test along with electromyography (EMG) can be used to confirm the diagnosis. The Eaton-Lambert syndrome may present with similar features, but repetitive electrical stimulation on EMG causes augmented muscle response at higher frequencies. Drugs that induce a myasthenic syndrome include D-penicillamine and the aminoglycoside antibiotics.

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Myopathic Causes

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The major causes of myopathy are drugs, toxins, metabolic disturbances, inflammatory syndromes, endocrinopathies, infections, and muscle dystrophies.

I. Toxin and drug-induced myopathy

1. Steroid myopathy. The insidious onset of proximal muscle weakness in a patient on steroids should suggest steroid myopathy. Myopathy can occur while a patient is on low or high doses of steroids, frequently after a recent increase in dose.

   The duration of steroid treatment does not correlate with the time of onset. Patients with steroid myopathy frequently have at least two other steroid side effects, such as osteoporosis, cushingoid facies, hyperglycemia, hypertension, or psychiatric disorders. Concomitant hypokalemia is usually not seen. Inflammation is not present.

   1. Laboratory studies. Serum muscle enzymes ”creatine kinase (CK), aldolase, and aspartate aminotransferase (AST, previously known as SGOT) ”are not increased; urinary creatinine excretion, however, is increased.

      EMG studies generally are not helpful. Muscle biopsy in patients with Cushing's syndrome has shown predominantly type 2 fiber atrophy, but biopsy in steroid myopathy has yielded conflicting results and has not been helpful.

   2. Treatment is to reduce the steroid dose as much as possible or to discontinue the drug.
2. Hypokalemic myopathy. Any drug or pathologic condition causing hypokalemia can cause muscle weakness. Several drugs have been implicated, some with better substantiation than others; those usually implicated are diuretics and cathartics. Hypokalemia can also exacerbate muscle weakness due to other types of myopathies.
   1. An acute syndrome of muscle pain, tenderness, and weakness of proximal and axial muscles may be seen. More generalized weakness can also occur.

      Serum muscle enzymes are elevated, and muscle biopsy may show vacuolar myopathy, with or without fiber necrosis and regeneration. EMG may show myopathic changes. Reflexes may be depressed or absent.

   2. Chronic hypokalemia can result in a painless proximal or generalized myopathy, also with depressed or absent reflexes. As in the acute syndrome, serum muscle enzymes are elevated, and muscle biopsy shows vacuolar myopathy. Diagnosis is based on demonstration of hypokalemia and identification of the offending drug.
   3. Treatment is restoration of a normal serum potassium level.
3. Alcoholic myopathy. Alcohol has been shown to be a direct hepatotoxin; proof of its muscle toxicity still rests largely on clinical interpretations. Three types of myopathy are caused by alcohol.
   1. Acute. This form presents with cramps and, at times, with fulminant rhabdomyolysis and myoglobinuria, which usually occur together with swelling and tenderness of proximal muscles. Muscle enzymes are markedly elevated. Muscle biopsy shows necrosis and phagocytosis with little regeneration. Recovery occurs with abstinence.
   2. Chronic. This form is least common and may occur even in the absence of a history of the acute clinical variety, described in the preceding section. Proximal muscles are weak, atrophied, and mildly tender. Unless alcoholic neuropathy is also present, distal muscle strength remains intact. Muscle enzymes are moderately elevated, and EMG shows myopathic changes. The lower extremities are affected prominently, with both atrophy and tenderness. Histopathologic findings include fiber necrosis, a mild increase in fibrous tissue , focal fat infiltration, a large variability in muscle fiber size , and regeneration of fibers.
   3. Subclinical. In this form, muscle enzyme elevation occurs without clinical weakness and may be common in confirmed alcoholics. Diagnosis of alcoholic myopathy is based on the standard tests mentioned previously (enzymes, EMG, and muscle biopsy), but it should be remembered that a coexistent peripheral neuropathy caused by nutritional deficiency or another toxin may be present.
4. Drug-induced rhabdomyolysis and myoglobinuria. Features include severe muscle pain with swelling and tenderness, markedly elevated serum muscle enzymes, and gross (dark red-brown) pigmenturia. The urine is positive by dipstick (benzidine or orthotolidine). If hemolysis is suspected, the urine is reddish, the serum is pink, and a low serum haptoglobin is present. Immunoassays and electrophoresis can definitely differentiate hemoglobin and myoglobin and, in doubtful instances, should be performed. Renal failure is the worst consequence of myoglobinemic states. Emphasis from the outset should be placed on maintaining urinary output with furosemide and mannitol, as needed. Other acute laboratory abnormalities are hypocalcemia and hyperkalemia. Several drugs and toxins can induce acute rhabdomyolysis, including cocaine, illicit heroin mixtures, amphetamines, alcohol, some antimalarial drugs, anesthetics, and other drugs that cause hypokalemia. Lipid-lowering agents (e.g., lovastatin and other statins, gemfibrozil) can also produce this syndrome. Other causes of myoglobinuria include McArdle disease, phosphofructokinase (PFK) deficiency, exertion, crush injury, prolonged pressure, injury during surgery, immobilization resulting from neurologic disorders, ischemia, and malignant hyperthermia syndrome.

II. Metabolic myopathies

1. A group of closely related abnormalities are characterized by inborn errors of glycogen metabolism. Distinct enzyme abnormalities cause myopathic symptoms.
   1. Acid maltase deficiency. The infantile form (Pompe's disease) presents a few months after birth with diffuse muscle weakness, severe hypotonia, and cardiomyopathy with congestive heart failure. Death caused by cardiorespiratory failure occurs within 2 years . The adult or late-onset form is caused by a partial deficiency of acid maltase activity. The late-onset form presents in childhood or adult life with gradually progressive limb-girdle weakness. The pelvic girdle muscles are more involved than the shoulder muscles. Clinical heart or liver involvement has not been seen. Respiratory muscle involvement, seen in 25% to 50% of cases, leads to chronic respiratory insufficiency. The late-onset form may be mistaken for polymyositis, limb-girdle dystrophy, or spinal muscular atrophy.
      1. Laboratory studies. Serum CK is increased, and the EMG changes are similar to those of polymyositis. Muscle biopsy shows a vacuolar myopathy. Biochemical assay revealing decreased or absent enzyme activity in muscle confirms the diagnosis. Also useful in diagnosis is decreased urinary excretion of acid maltase.
      2. Treatment. There is no proven effective therapy for either the infantile or late-onset form.
   2. Deficiency of enzymes in the glycolytic pathway
      1. Muscle phosphorylase deficiency (McArdle disease). This inherited deficiency of skeletal muscle phosphorylase is more common than acid maltase deficiency or PFK deficiency; 60 cases have been reported . The female -to-male ratio is 1:4. Childhood symptoms of fatigue are usually overlooked. A characteristic pattern of exercise-induced muscle pains, stiffness, and weakness, which resolves with rest, occurs after puberty. Prolonged exercise results in severe cramps of the exerted muscles. Myoglobinuria and muscle necrosis may occur if exercise is strenuous; however, exercise tolerance may improve after a nonstrenuous warm-up period ( second-wind phenomenon ). As the result of recurrent attacks of myoglobinuria, some patients have a persistent proximal myopathy. The muscle cramps are actually contractions, which may last several hours.
         1. Laboratory studies. Serum CK is increased. Venous lactic acid levels do not rise with the ischemic forearm exercise test (see final the section of this chapter, Laboratory Aids to Diagnosis). Muscle biopsy shows vacuoles that stain with periodic acid “Schiff (PAS) beneath the sarcolemma and scattered necrotic or regenerating muscle fibers.
         2. Treatment. There is no long- term effective treatment.
      2. Muscle phosphofructokinase deficiency results in a syndrome similar to McArdle disease. Easy fatigability occurs during childhood. Later, exercise-induced muscle pain or cramps with myoglobinuria occur. However, unlike those of McArdle disease, exercise-induced symptoms here often include nausea and vomiting. This is an autosomal recessive disease.
         1. Laboratory studies. Serum CK is increased. Venous lactate levels do not rise after the ischemic forearm exercise test. A mild hemolytic anemia occurs when PFK is absent from erythrocytes, which may be helpful diagnostically. Diagnosis is confirmed by the absence of PFK activity on direct measurement in muscle biopsy by biochemical or histochemical methods .
         2. Treatment. No generally effective therapy is available.
      3. Deficiency of other enzymes in the glycolytic pathway also may lead to myopathy with impaired generation of lactate from glucose . These include the following:
         1. Glycogen debrancher.
         2. Phosphoglycerate kinase.
         3. Phosphoglycerate mutase.
         4. Lactate dehydrogenase (M subunit).
2. Disorders of lipid metabolism. Glycogen provides energy for work of short duration, whereas fatty acids provide energy for periods of rest, prolonged low-intensity exercise, and fasting . This knowledge allows prediction of the symptoms of abnormal fatty acid metabolism in muscle.
   1. Carnitine palmityltransferase (CPT) deficiency is inherited as an autosomal recessive disorder with a male preponderance. Patients with CPT deficiency tolerate short periods of exercise normally. However, after prolonged exercise or fasting, muscular pains and myoglobinuria develop. Muscle strength is normal between attacks. There is no second-wind phenomenon.
      1. Laboratory studies. Serum CK is normal at rest but elevated during attacks. There is a normal rise in venous lactate with the ischemic forearm exercise test. Hypertriglyceridemia, which is probably related to the impaired fatty acid utilization of CPT deficiency, may be found. The muscle biopsy specimen may be normal or show intrafiber lipid droplets. A screening test is a 38- hour fast, which will cause an elevation in serum CK.

         Diagnosis is confirmed by biochemical assay of CPT activity in muscle.

      2. Treatment. Therapy consists of eating regular meals and avoiding prolonged exertion. A diet high in carbohydrates and low in fats is effective in reducing the incidence of acute attacks.
   2. Carnitine deficiency occurs in two forms, an isolated myopathy or a systemic disorder.
      1. Isolated muscle carnitine deficiency is characterized by childhood onset of a slowly progressive limb-girdle weakness. Facial and pharyngeal muscles may be involved. Deep tendon reflexes are decreased or absent.
         1. Laboratory studies. Serum CK is moderately increased. EMG reveals a myopathic pattern. Serum carnitine levels are normal or slightly decreased. Muscle biopsy shows prominent intrafiber lipid droplets, especially in type 1 fibers. Carnitine levels in muscle are reduced to one-tenth to one-fifth of normal.
         2. Treatment. Preferred long-term treatment is oral administration of carnitine with a medium-chain triglyceride diet. Prednisone is effective but not desirable as long-term treatment.
      2. Systemic carnitine deficiency presents with myopathy and hepatic insufficiency. Hepatic encephalopathy and attacks of lactic acidosis occur. Death usually occurs by age 20.
         1. Laboratory studies. Patients uniformly have decreased levels of serum carnitine. Carnitine deficiency states are often associated with other primary metabolic defects.
         2. Treatment with oral carnitine has resulted in improved strength and normalization of hepatic function in some cases.
3. Disorders associated with abnormal serum potassium. These interrelated syndromes of muscular weakness are associated with either hypokalemia or hyperkalemia. The exact pathogenetic role of potassium in these disorders is largely unknown.
   1. Familial periodic paralysis. An autosomal dominant disease, this disorder is characterized by attacks of intense weakness of limb muscles that progress to complete paralysis. Attacks begin in adolescence or early adulthood and occur less frequently with age. There is marked hypotonia and absent-to-decreased tendon reflexes during attacks. Strenuous exercise or a high intake of carbohydrates may precipitate attacks. Chronic myopathy may occur after repeated attacks.
      1. Laboratory studies. Serum CK is elevated and serum potassium is low during attacks. Muscle biopsy shows vacuolar changes.
      2. Differential diagnosis. Hyperaldosteronism and hyperthyroidism with periodic paralysis may mimic the syndrome. The use of diuretics or cathartics may also cause similar symptoms.
      3. Treatment is with oral potassium (2 to 8 g of potassium chloride until the attack resolves) or intravenous potassium (50 mEq over several hours).
   2. Adynamia episodica hereditaria (Gamstorp's disease). This autosomal dominant disease is characterized by attacks of weakness or paralysis of skeletal muscle, similar to those of familial periodic paralysis. The onset is between ages 5 and 10 years. The disease is most active during the adolescent years, after which it subsides. Attacks are precipitated by prolonged exertion or by administration of 2 to 5 g of potassium chloride.
      1. Laboratory studies. During attacks, the serum potassium is elevated, although high normal values have been noted. Between attacks, the patient is asymptomatic and serum potassium is normal, although persistent weakness may last for several days after an attack. Serum CK is elevated.
      2. Treatment with potassium-lowering agents, such as 50 to 100 mg of hydrochlorothiazide PO daily, is effective in preventing attacks.
4. Deficiency of myoadenylate deaminase. Deficiency of this enzyme has been associated with post-exertional cramps and myalgia. It has been suggested that impairment in the function of adenylate deaminase may lead to reduced entry of adenine nucleotides into the purine nucleotide cycle during exercise and that this may be responsible for the observed abnormalities.
5. Mitochondrial myopathies. Abnormalities in mitochondrial genetics can produce a variety of myopathic disorders, from ophthalmologic states to myopathies associated with encephalopathy and lactic acidoses. In addition, mitochondrial dysfunction can be manifested in different phenotypes affecting skeletal and cardiac muscle, the nervous system, and the kidneys. Diagnosis can be approached by family history, which may demonstrate a pattern of maternal inheritance; microscopy of biopsied tissue demonstrating structural abnormalities of mitochondria (e.g., subsarcolemmal aggregates in myofibers, the so-called ragged red fibers); and biochemical studies demonstrating abnormalities in components of oxidative phosphorylation, such as cytochrome oxidase.

III. Endocrine myopathies

1. Hypothyroid myopathy. The most commonly recognized endocrine myopathy occurs as a feature of hypothyroidism; it may antedate the diagnosis of hypothyroidism by several months. Symptoms and signs of this entity range from mild aches and pains, muscle cramps, and proximal weakness to apparent muscle hypertrophy and the mounding phenomenon, or myoedema (a transient focal ridging of muscle in response to percussing or pinching the muscle). In the usual form, proximal weakness may be observed, although atrophy is rare.

   Hypertrophic muscles may exhibit myotonia-like contractions that are electrically silent on EMG.

   1. Laboratory studies. Serum CK is often markedly elevated. A variety of EMG changes have been noticed, most of which indicate a myopathic process. Muscle biopsy may show focal necrosis, regeneration, and vacuolization of fibers, but findings are usually normal. Fiber size is quite variable. Sarcolemma nuclei are numerous , enlarged, and centrally placed. Mucoprotein deposits occur in one-third of patients. Histochemical staining has shown a decrease in type 2 fibers that is directly proportional to disease severity and serum CK levels. CK levels are not increased in hypopituitarism, and a myopathy has not been reported with hypopituitarism; nonetheless, in a patient with hypothyroidism, hypopituitarism should be considered .
   2. Treatment of hypothyroidism is thyroid hormone replacement. With proper therapy, serum CK levels return to normal over several months.
2. Thyrotoxic myopathy. The manifestations of this disorder range from complaints of diffuse weakness, easy fatigability, and mild atrophy to severe proximal muscle weakness with pronounced atrophy. Laryngeal and pharyngeal muscles are not involved. Serum muscle enzymes are not elevated, even in the severe form; creatinuria, however, is present. EMG may show myopathic changes. Muscle biopsy may reveal only small fiber size or atrophy of fibers with replacement of fat and lymphocyte infiltrates. (Less common myopathies in association with hyperthyroidism are exophthalmic ophthalmoplegia, thyrotoxic periodic paralysis, and the association of Graves' disease in 5% of patients with myasthenia gravis).
3. Acromegalic myopathy. Proximal muscle weakness and easy fatigability occur in up to 50% of patients with acromegaly. Myalgia and cramps may occur in a few patients. Muscle mass, however, is increased. Serum CK and aldolase are usually normal but may be slightly elevated. EMG shows myopathic findings. Muscle biopsy shows no consistent pattern, but there is some evidence that type 2 fiber hypertrophy may occur. With treatment of the pituitary tumor, strength recovers gradually over months or years.

IV. Muscular dystrophy. This group of primary muscle diseases is characterized by degeneration of muscle fibers, which occurs on a genetic basis. Although there is no specific treatment for these disorders, it is important to distinguish them from treatable forms of myopathy. Genetic counseling is suggested for patients and their families.

1. Duchenne's pseudohypertrophic muscular dystrophy. The onset of this sex-linked disease is usually in early childhood. Pelvic-girdle involvement, manifested by frequent falls , difficulty in climbing stairs, difficulty in rising from the floor, and a peculiar gait, is characteristic. The onset is insidious, and progression is slow. Gradually, the trunk and shoulder muscles become involved, causing the patient to require a wheelchair by age 12. Patients usually die in their twenties of either pulmonary infection or the cardiomyopathy associated with the disease.
   1. Physical examination early in the disease reveals enlarged, firm (pseudohypertrophic), but weak calves and sometimes quadriceps and deltoids. Facial and distal muscles usually retain normal strength.
   2. Laboratory studies. Serum muscle enzymes are increased. Creatinuria is present. Muscle biopsy shows fiber size variation and fat infiltration, depending on the stage of the disease. Dystrophin, a normal muscle protein bound to the sacrolemma, is absent. EMG reveals low-amplitude potentials of short duration. Electrocardiographic abnormalities, such as a prolonged PR interval, slurred QRS complex, ST-segment depression or elevation, and usually right bundle-branch block, are seen late in the disease. Female carriers may have mild abnormalities of serum CK, muscle biopsy, and EMG but are clinically asymptomatic.
2. Becker's muscular dystrophy is similar to the Duchenne form but milder, with later manifestations of disability. It is also an X-linked dystrophinopathy, with reduced synthesis of dystrophin.
3. Fascioscapulohumeral dystrophy is an autosomal dominant disease that affects female and male subjects equally. The usual age of onset is between 9 and 20 years, although adult onset has been recognized. The symptoms vary in severity; thus, diagnosis may be difficult. Shoulder-girdle weakness and winged scapulae are usually the first findings. Facial muscles are involved and may be the first muscles affected in some patients. The face is flattened, and the mouth moves asymmetrically , unable to pucker or whistle . Axial and pelvic muscles may become involved late in the disease; however, distal muscles are usually spared. Cardiac disease is rare, and patients usually live a normal life span. Serum muscle enzymes may be elevated slightly, and elevated urinary creatine is common.
4. Limb-girdle dystrophy is inherited in an autosomal recessive form and affects female and male subjects equally. Its onset occurs during the second or third decades. Shoulder- or pelvic-girdle muscles are involved first, with gradual progression to other muscle sites over years, although facial muscles are spared. Cardiac disease resulting from limb-girdle dystrophy is rare.
   1. Laboratory studies. Serum muscle enzymes are slightly elevated, and creatinuria is present. Muscle biopsy shows fibrous and fatty replacement with necrosis of single fibers. Sarcolemmal nuclei are increased in number, forming chains centrally in the fibers. These changes may also be seen in Duchenne's dystrophy and fascioscapulohumeral dystrophy.

      Some forms of this disorder are secondary to a genetic lack of production of dystrophin-associated glycoproteins.

5. Myotonic dystrophy. Myotonia is an inability to relax a muscle normally after contraction. It may be elicited by grasping with the hand or by directly percussing muscle groups, such as those of the forearm or tongue, or the thumb adductors.

   Myotonic dystrophy is an inherited disease that begins early in adult life. It is manifested by distal muscle weakness and atrophy. Deep tendon reflexes are reduced. Ptosis may be present, and closure of the eyelids is also weak. Atrophy of the temporalis and sternocleidomastoid muscles is severe. Other clinical features include early frontal alopecia, cataracts, blepharitis, conjunctivitis, and testicular atrophy. Mental retardation may occur. Dystrophic cardiac disease occurs late. The disease can be quite variable, and some patients and affected family members may manifest only one or two features.

   1. Laboratory studies. EMG reveals myopathic changes and characteristic afterpotentials of myotonia. Serum muscle enzymes are usually normal, and creatinuria is rare. Histopathologic features are similar to those of other dystrophies; however, there may be prominent rows of sarcolemmal nuclei, spirals of myofibrils, and areas of clear sarcoplasm, devoid of myofibrils. Type 1 fiber atrophy is present. Peripheral nerves and anterior horn cells are normal. This disease is associated with an expanded cytosine-thymine-guanine (CTG) repeating motif in the noncoding region of the myotonin protein kinase gene.
   2. Treatment. Quinine in a dose of 300 to 600 mg PO q6h can relieve the myotonia; however, there is no known cure. Supportive therapy and physical therapy may prolong mobility and prevent contractures.
6. Congenital myopathies are rare inherited diseases that begin during infancy. Progression may be quite insidious. Diagnosis rests on muscle biopsy.

V. Inflammatory myopathies. This group of myopathies is characterized by inflammation of unknown etiology within the muscles.

1. For full discussions of idiopathic polymyositis, dermatomyositis, myositis of other rheumatic diseases, and myositis associated with carcinoma , see Chapter 27.
2. Sarcoid myopathy. Muscle biopsies in small numbers of sarcoid patients without symptoms of muscle pain or weakness have revealed noncaseating granulomas typical of the disease. The occurrence of asymptomatic muscle involvement has clouded the issue of whether a true sarcoid myopathy exists. Nonetheless, there are sarcoid patients with symptomatic muscle involvement. Muscle pain and tenderness are most often seen in acute sarcoidosis with erythema nodosum. Symmetric proximal muscle weakness can be seen in chronic sarcoid (see Chapter 51).
   1. Laboratory studies. EMG shows a nonspecific myopathic pattern. Muscle biopsy shows noncaseating granulomas, surrounding lymphocytic infiltrates, muscle fiber necrosis, and fiber regeneration.
   2. Differential diagnosis. Similar granulomatous reactions have been seen in various malignancies, leprosy, syphilis, tuberculosis, Crohn's disease, drug reactions , and several fungal infections.
   3. Treatment. Administration of 20 to 40 mg of prednisone daily has been effective in about half of patients.

VI. Infectious myositis and myopathy. Several microorganisms have been implicated in the onset of myositis. Both diffuse and proximal myopathies have been reported. This group of myopathies is to be distinguished from the isolated muscle involvement seen in tropical pyomyositis, streptococcal myositis, and clostridial myonecrosis.

1. Trichinosis is caused by the nematode Trichinella spiralis. It is transmitted by ingestion of uncooked or poorly cooked pork or bear meat. Within 2 days of ingestion of the cysts, diarrhea, nausea, abdominal pain, and fever occur. By the end of the first week, patients may have fever , periorbital edema, conjunctivitis, muscle pain and tenderness, and an erythematous maculopapular rash. Muscle weakness may be mild but is often quite severe. Muscle invasion may last 6 weeks. Myocarditis and encephalitis may occur during this stage of illness . The most commonly invaded muscles are those of the diaphragm, eye, tongue, shoulder, and calf.
   1. Laboratory studies. Biopsy of the deltoid or gastrocnemius muscle should be performed during the third or fourth week of illness. Pressing the tissue between glass slides will reveal the uncalcified larvae. Calcified cysts represent former infection. The muscle shows a severe myositis with neutrophilic, eosinophilic, and lymphocytic infiltrates. Fiber degeneration and necrosis are present. Serum muscle enzymes are characteristically elevated. By the end of the second week, a 15% to 50% eosinophilia is present. Serologic tests become positive by the end of the third week.
   2. Treatment is with 25 mg of thiabendazole per kilogram twice daily for 7 days. Patients with myocarditis, encephalitis, or severe hypersensitivity manifestations should be treated with 40 mg of prednisone daily during thiabendazole administration.
2. Toxoplasmosis. Toxoplasma gondii has been proved to cause myositis in an occasional patient. A recent case report of a patient with polymyositis and cerebellar ataxia is an example of this problem. The patient had severe muscle cramps, coarse fasciculations, and no weakness or muscle tenderness. Serum CK was markedly elevated. EMG indicated a chronic peripheral neuropathy. Muscle biopsy showed chronic interstitial myositis, fiber necrosis, and encysted T. gondii. Toxoplasma organisms were grown in mice injected with a suspension of the muscle biopsy.

   Serologic evidence of Toxoplasma infection in patients with polymyositis consists of elevated complement-fixation titers, positive findings on Sabin-Feldman dye tests, and specific immunoglobulin M antibodies in a subgroup of patients. Most rheumatologists do not routinely order these tests. However, some patients with positive serologies defined early in the disease course did respond to antibiotic therapy for toxoplasmosis.

3. Viral myositis. A number of different viruses may cause an illness similar to polymyositis. Often, a prodromal illness is caused by the virus. It is unclear whether the myositis is a post-infectious immune phenomenon or a true infection of muscle. Virus-like particles have been found in muscle in some cases. Biopsy shows myositis with fiber necrosis and regeneration. Myoglobinuria may occur, especially with influenza and herpes group myositis. Viruses implicated are hepatitis B and C virus, echovirus, coxsackie virus, herpes simplex virus, and influenza virus. Late atrophy of muscles may occur. In addition, muscle biopsy findings at times may be normal. Human immunodeficiency virus (HIV) and medications such as zidovudine (AZT) can be responsible for severe myopathy as well as a syndrome indistinguishable from polymyositis.
4. Miscellaneous infections causing myopathy. It should be noted that numerous other microorganisms have been implicated as etiologic agents in myositis. Some have occurred only in immunocompromised patients. Agents found include Candida tropicalis, Mycoplasma pneumoniae, Trypanosoma cruzi, and Echinococcus alveolaris.

VII. Fibromyalgia presents as variable muscle pain and multiple tender points with normal muscle strength. The sedimentation rate and muscle enzymes are normal. It is a diagnosis of exclusion. (See Chapter 49 for a full discussion.)

VIII. Polymyalgia rheumatica presents in patients over 50 with proximal soreness and stiffness and constitutional symptoms. It may be associated with temporal arteritis. The Westergren sedimentation rate is elevated to over 50 mm/h in most patients, and many are anemic. (See Chapter 26 for a full discussion.)

IX. Miscellaneous disorders presenting as myopathy. The following disorders may present with muscle pain:

1. Primary amyloidosis.
2. Stiff-man syndrome.
3. Cervical and lumbar spondylosis.
4. Parkinson's disease.

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Laboratory Aids to Diagnosis

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I. Serum chemistries. As a result of the association of hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypomagnesemia, and hypophosphatemia with muscle weakness, tetany, and sometimes cramps, it is prudent to obtain serum chemistry values if clinical suspicion so indicates.

Muscle enzymes commonly measured are CK, aldolase, lactic dehydrogenase (LDH), and AST. CK is probably the most reliable indicator of muscle damage because skeletal muscle, compared with other tissues, contains relatively more of it. However, heart, brain, and smooth muscle also contain CK. Strenuous physical exertion as well as intramuscular injections may increase CK and cause elevated values for a week. Serum myoglobin is elevated in polymyositis in essentially all patients with active disease. However, this test is only performed in the setting of red urine or renal compromise. An immunoassay should be performed to detect myoglobinemia. Plasma cortisol, growth hormone, thyroid-stimulating hormone (TSH), and thyroxine values are indicated if one of the endocrine myopathies is suspected. CK may also be elevated in amyotrophic lateral sclerosis.

II. Hematologic studies. The erythrocyte sedimentation rate (ESR) may be elevated in inflammatory myopathy. It is useful for following patients but is not a specific test for any myopathy. Atypical lymphocytosis may occur in viral illness or toxoplasmosis. Eosinophilia may occur in infections and polymyositis. Cold agglutinins may indicate Mycoplasma infection.

III. Urinary studies. Steroid myopathy and some muscular dystrophies may be associated with elevated creatine-creatinine urinary excretion ratios with normal muscle enzymes:

% creatinuria = creatine (mg/24 hr)/creatine (mg/24 hr) + creatine (mg/24 hr) — 100

This ratio should be calculated on at least two 24-hour urine collections, as day-to-day variability may occur. A ratio above 6% in adults is elevated. Urinary studies for heavy metals may be useful if a peripheral neuropathy is suspected. Myoglobinuria occurs in several diseases of muscle. Both hemoglobin and myoglobin give positive reactions to orthotolidine and benzidine. Immunoassay and electrophoresis techniques can measure myoglobin. The ammonium sulfate test has often proved unreliable or difficult to interpret. Excretion of acid maltase is decreased in acid maltase deficiency.

IV. Provocative studies

The ischemic forearm exercise test is of value in detecting deficiencies of enzymes of glycolysis. The test is performed with the patient at rest and fasting. After a baseline venous lactate level has been obtained through an indwelling catheter, a blood pressure cuff on the upper arm is inflated above systolic pressure. The patient exercises this arm for 1 minute to produce lactic acid. Sufficient work can be generated by compressing another blood pressure cuff at a rate of one stroke per second; a rise in the mercury column can then be observed. After 1 minute of exercise, the cuff is deflated and serial lactate levels are obtained at 1, 2, 3, and 5 minutes after work. Patients with enzyme deficiency will not show the expected rise in venous lactate. However, decreased lactate production is also seen following alcohol ingestion. In addition to decreased lactate production, a progressive contracture of forearm muscle that is electrically silent on EMG may develop in patients with myophosphorylase deficiency. Assay of these samples for ammonia can be used as a screening test for myoadenylate deficiency.

V. Electromyography and electroneurography

1. Nerve conduction velocities are an informative way to detect peripheral neuropathies. Diseases such as infectious polyneuritis (Landry-Guillain-Barr syndrome), Charcot-Marie-Tooth disease, and several others characteristically are associated with a slowed nerve conduction velocity.
2. EMG abnormalities are helpful in the diagnosis of polymyositis, myasthenia gravis, myotonic dystrophy, Eaton-Lambert syndrome, and McArdle disease. Characteristic findings in polymyositis are mentioned in Chapter 27. Note, however, that trichinosis and several muscular dystrophies may cause a myopathic EMG pattern similar to that of polymyositis. In myasthenia gravis, repetitive stimulation gives a characteristic decremental response, which is opposite to the pattern seen in Eaton-Lambert syndrome. In myotonic dystrophy, electrical silence after a brief voluntary contraction does not occur; instead, there is a burst of electrical activity that subsides in minutes. In McArdle disease, the muscular cramping that occurs is electrically silent.

VI. Muscle biopsy is of major diagnostic value in inflammatory muscle disease, steroid myopathy, muscular dystrophy, and infectious myositis. It is also valuable in the diagnosis of myopathy associated with various connective tissue diseases, including vasculitis. The site for a muscle biopsy should be the deltoid or quadriceps in most cases. EMG abnormalities identify areas of pathology. A biopsy specimen of the muscle contralateral to that subjected to EMG should be taken to detect artifacts that may have been produced by EMG needles . The muscle chosen for biopsy should not be atrophied or severely weak.

VII. Other modalities of imaging or assessing muscle, such as magnetic resonance imaging and ultrasound , can also provide valuable information regarding extent and activity of disease.

Bibliography

Lane RJM, ed. Handbook of muscle disease. New York: Marcel Dekker, 1996.

Griggs RC, Mandell JR, Miller RG. Evaluation and treatment of myopathies. Philadelphia: FA Davis Co, 1995.

Engel AG, Francini-Armstrong C. Myology: basic and clinical. New York: McGraw-Hill, 1994.

Walton J, Karpati G, Hilton-Jones D. Disorders of voluntary muscle. New York: Churchill Livingstone, 1994.

Books@Ovid
Copyright 2000 by Lippincott Williams & Wilkins
Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders