Myopathies of Systemic Disease

Introduction

When evaluating a child with myopathy, the clinician must not only determine the pattern and extent of muscle weakness but also the cause. In addition to the many primary disorders of muscle, there are many systemic diseases that produce myopathies. These generalized disorders include endocrine abnormalities, renal disorders, infections, medication-related effects, connective tissue diseases, and eosinophilic syndromes. In this chapter, we detail the disorders that may have a significant impact on skeletal muscle function in childhood.

Hyperthyroidism

Thyrotoxic myopathy symptoms are primarily those associated with a chronic proximal myopathy, and patients may complain especially of mild, symmetrical hip flexion weakness. Bulbar or respiratory involvement is rare. Pectoral muscles are more severely affected than the pelvic girdle, and muscle wasting may be noted on examination. Occasionally, distal muscles may also be affected. Despite muscle weakness and wasting in thyrotoxicosis, serum creatine kinase (CK) concentrations are normal or decreased, probably because of increased clearance. Serum myoglobin concentrations are also normal. Findings on muscle biopsy are nonspecific, both by routine histopathology and ultrastructural evaluation. Histochemical staining may demonstrate atrophy of both type I and type II fibers; in some cases, more prominent atrophy of type II fibers is found. Additionally, some studies describe scattered fiber necrosis and inflammatory infiltrates. Patients with thyrotoxic myopathy may respond satisfactorily to antithyroid medications alone and not require additional therapy, such as steroids.

Thyrotoxic periodic paralysis (TPP) is a common cause of sudden-onset muscle weakness in young Asian and Latin American adults that rarely occurs in Caucasians. In North America, TPP occurs in approximately 0.1% to 0.2% of the hyperthyroid population, but is roughly 10-fold more common in Asian populations. Males are more commonly affected than females. Almost all cases occur sporadically, without a history of familial periodic paralysis. Recently, several mutations in KCNJ18 , the gene coding for Kir2.6 (an inwardly rectifying potassium channel), have been shown to be associated with susceptibility to TPP in individuals from the USA, Brazil, and France. Because these mutations were not common in Hong Kong Chinese populations, further studies in Chinese populations demonstrated a new TTP susceptibility locus at 17q24.3, near KCNJ2 (also known as KIR2.1 ). Importantly, Kir2.6 forms functional heterotetramers with Kir2.1.

TPP begins typically in the early morning, often following a day of strenuous exercise; the limbs are primarily involved, and speech is usually spared. TPP clinically resembles idiopathic familial periodic paralysis, except for a greater tendency toward dysrhythmias, cardiac arrest, and respiratory failure. Management includes admission for acute paralysis, cardiac monitoring, correction of hypokalemia, and initiation of antithyroid medication. Episodes of weakness always cease when a euthyroid state is achieved. Short-term use of β-blockers may be indicated. Strenuous exercise and high-carbohydrate diets should be avoided.

A series of four patients with hyperthyroidism due to Graves’ disease described abnormal increases in serum CK concentration that occurred during antithyroid medication treatment. Three of the four patients developed myalgia and muscle cramps. While the cause is not established, a rapid reduction of thyroid hormones in skeletal muscle may produce the muscle symptoms and increased CK level. If myalgias, muscle cramps, or increased CK concentration occurs a few months after the initiation of medical treatment of Graves’ disease, levothyroxine might be added to the regimen rather than discontinuing the antithyroid agents.

Hypothyroidism

Myopathy is a significant complication of hypothyroidism, with an estimated incidence of 30% to 80% among patients with myxedema. In general, the severity of the myopathy parallels the duration and degree of hypothyroidism. Findings in hypothyroid myopathy include muscle pain and cramps, proximal weakness, and slow myotatic reflexes. Serum CK concentration is characteristically increased, and in some cases may be an order of magnitude greater than control levels (i.e. comparable to levels usually associated with muscular dystrophy). With medical treatment for hypothyroidism, CK levels always return to normal. Electromyography (EMG) studies commonly demonstrate myopathic patterns. Magnetic resonance spectroscopy of hypothyroid muscle at rest shows low intracellular pH and delayed glycogen breakdown during exercise. Muscle biopsy specimens from patients with hypothyroid myopathy reveal changes including type I fiber predominance, selective atrophy of type II fibers, and increased numbers of internal nuclei. A fraction of type I fibers may contain core-like structures with reduced nicotinamide adenine dinucleotide reductase activity. Ultrastructural changes include myofilament loss, accumulations of glycogen and lipid, increased vacuoles, abnormal mitochondria, Z-line streaming, dilated sarcoplasmic reticulum, and increased lipofuscin pigment and lysosomes.

Hypothyroidism affects muscle by impacting glycogenolysis (with reduced acid maltase activity) and mitochondrial oxidation. In patients with subclinical hypothyroidism (elevated circulating thyroid-stimulating hormone levels in the face of normal free thyroid hormone levels), incremental, submaximal exercise results in venous lactate values that are significantly higher than in controls; blood pyruvate concentrations are not elevated. These results suggest that there is in vivo functional impairment of mitochondrial function in patients with subclinical hypothyroidism. Rarely, hypothyroid myopathy may be associated with exercise-induced myalgias and recurrent rhabdomyolysis (the latter being supported by increased serum CK level and muscle fiber necrosis on biopsy). Exercise-induced myalgia may be an early symptom of hypothyroid myopathy.

Moderate to severe hypothyroidism during infancy can produce myopathy in association with multiple other features, resulting in the Kocher-Debré-Sémélaigne syndrome. Examination findings may include coarse facial features; protruding tongue; hoarse cry; persistence of an open fontanelle; abdominal distention; umbilical hernia; and cool, mottled, or dry skin (see Case Example 36.1 ). Marked hypertrophy of calf, thigh, deltoid, and forearm muscles gives a “herculean” appearance; involved muscles have a firm consistency and are prominently weak. Myotatic reflexes may display delayed relaxation. Immediate treatment of hypothyroidism in infancy is critical to limit cognitive and developmental deficits.

Case Example 36.1

S.R. is a 2.5-year-old girl who was brought to the clinic with a history of motor and language delay. She was born at 42 weeks’ gestation with Apgar scores of 9 and 9. Her mother reported the child had mild feeding difficulties as a newborn, and the baby had an especially hoarse cry. More recently, the girl has appeared apathetic, clumsy, and slow. On examination, the patient had coarse facial features; a large, protruding tongue; and prominent abdominal distention (with an umbilical hernia; Figure 36.1A and B ). Her anterior fontanelle was open and readily palpable. Her skin was very dry and cool ( Figure 36.1C ). Multiple muscles appeared hypertrophied and were firm on palpation; these included the deltoid, thigh, and calf muscles. She had difficulty rising from a seated position, and had an unsteady, waddling gait. Myotatic reflexes were abnormal with delayed relaxation. Thyroid function studies revealed that total T ₄ , T ₃ , and free thyroxine were all depressed, while thyroid-stimulating hormone level was markedly elevated. These laboratory findings confirmed the suspicion of primary hypothyroidism. Her muscle weakness improved remarkably with thyroxine replacement, and her pseudoathletic appearance gradually softened ( Figure 36.1D and E ). She was enrolled in an early intervention program.

The term Hoffman’s syndrome refers to the rare association of hypothyroidism with increased muscle volume/hypertrophy, weakness, and slowness of movement in adolescents and adults. Muscle atrophy is much more common in older patients with hypothyroidism than with hypertrophy. While hypertrophy in Hoffman’s syndrome resembles the pseudohypertrophy of muscular dystrophy, it occurs in the setting of normal serum aspartate aminotransferase levels and responds briskly to thyroid therapy.

Parathyroid Disease

Hypoparathyroidism can be caused by altered parathyroid gland function, surgical resection of parathyroid glands, infiltrative diseases, and irradiation. The clinical features of hypoparathyroidism are linked to hypocalcemia. At the neuromuscular junction, hypocalcemia is associated with hyperexcitability and may result in laryngospasm, tetany, muscle cramps, and carpopedal spasm. Myopathy with increased serum CK has been reported in patients with hypoparathyroidism, but is not common; there appears to be an inverse relationship between serum calcium and serum CK. The etiology of CK elevation in hypoparathyroidism with myopathy is unclear, but could be related to hypocalcemia-induced changes in the sarcolemma, or less likely tetani. Muscle biopsy findings in such cases have been unremarkable or nonspecific; type II fiber atrophy, focal myofibrillar degeneration, and perinuclear accumulation of mitochondria have been reported. Some patients with myopathy have been reported to have a concurrent rash (face, legs).

The pathogenesis of primary hyperparathyroid myopathies is thought to be a combination of altered energy metabolism/utilization and parathyroid-induced muscle breakdown. Phosphorus and calcium levels do not correlate with the severity of neuromuscular symptoms in hyperparathyroidism, CK levels are only slightly elevated or normal, and muscle biopsies typically show only nonspecific findings. Ischemic calcific myopathy has been reported as a complication of azotemic hyperparathyroidism, but is rare. If surgical management is not pursued, cinacalcet therapy can normalize serum calcium levels and promote resolution of muscle weakness over weeks to months.

Cushing’s Syndrome

The diagnosis of Cushing’s myopathy should be considered in patients with proximal muscle weakness, myopathic EMG, and normal serum CK and aspartate aminotransferase levels. EMG findings in myopathy of Cushing’s syndrome share features seen in inflammatory myopathies and include low-amplitude, short-duration motor unit potentials that are recruited in increased numbers with minimal effort. Some patients may also have abnormal insertional activity, with brief runs of positive waves or fibrillation potentials. Atrophy of type II muscle fibers on biopsy analysis may offer a clue to the diagnosis, although such a finding is nonspecific. Type II fiber atrophy is also found in exogenous steroid myopathy, as well as the endocrine myopathies of thyrotoxicosis, myxedema, and osteomalacia. Nonspecific ultrastructural findings include excessive glycogen accumulation, myofilament loss, large mitochondria, and excess lipofuscin.

Once hypercortisolism is suspected, the diagnosis is further supported by increased morning serum cortisol levels, increased 24-hour urinary free cortisol levels, and the failure of suppression of endogenous cortisol with dexamethasone. Several months after definitive treatment (e.g. excision of an adrenal adenoma), muscle strength increases, blood pressure normalizes, and excess weight decreases.

Uremia

Muscle weakness in uremia is prominent in the lower extremities, especially the proximal muscles. Biopsy studies show moderate muscle fiber atrophy, especially type II fibers. Ultrastructurally, severe yet nonspecific degenerative changes are found. Multiple factors have been implicated in the myopathy of chronic renal failure: (1) abnormalities in vitamin D metabolism; (2) various uremic toxins; (3) excess parathyroid hormone; (4) malnutrition and reduced energy uptake; (5) carnitine depletion and impaired energy uptake; (6) abnormalities in cellular energetics; (7) impaired protein synthesis and amino acid metabolism; (8) hypophosphatemia and diminished intracellular phosphorus stores; and (9) impaired biochemical integrity of the sarcolemma.

Osteomalacia

Osteomalacia is known to be associated with symmetrical weakness and wasting of the proximal limb muscles, especially the legs. Myotatic reflexes and sensation are intact. The serum alkaline phosphatase level is always elevated, but CK level is often normal; muscle biopsy may prove unremarkable. With appropriate treatment, such as the administration of vitamin D, the weakness is reversible. Because neuromuscular abnormalities may precede osteoarticular findings in some infants with vitamin D-deficiency rickets, osteomalacia should be considered in young children with muscle weakness.

Hypokalemia

Paralytic myopathy is a recognized feature of primary aldosteronism, with a high incidence reported among Asian populations. Patients with myopathy have low serum potassium levels, and the greater the degree of hypokalemia, the more severe the muscle weakness. Limb muscles are most commonly involved, but facial and neck muscles may also be affected. An associated feature may be hypertension, related to the marked sodium retention associated with the disorder. Mechanistically, hypokalemia results in transient membrane depolarization and consequently renders muscle fibers electrically unexcitable. In addition, hypokalemia can cause a cellular energy crisis because potassium is required to maintain intracellular muscle energy stores through phosphorylation of creatine and adenosine diphosphate.

The degree of hypokalemia found in patients with primary aldosteronism is in part related to sodium intake. The restriction of sodium leads to potassium retention and improves hypokalemic manifestations, while sodium excess promotes renal potassium wastage and can produce profound hypokalemia. In Taiwan, average daily salt intake is greater than 14 grams. One may therefore propose that the higher incidences of thyrotoxic hypokalemic periodic paralysis and aldosterone hypokalemic paralysis reported among the Asian population are dietary rather than ethnic or genetically induced.

Although hypokalemic periodic paralysis and hypokalemic myopathy may both present with paralysis, they are distinct diseases. Hypokalemic periodic paralysis is caused by mutations in the dihydropyridine receptor. In hypokalemic periodic paralysis, skeletal muscle is overloaded with glycogen and rhabdomyolysis is absent. On the other hand, in hypokalemic myopathy, muscle glycogen is initially absent, necrosis is prominent, muscle-derived enzyme levels are elevated, and recovery requires a prolonged course of potassium supplementation. Hypokalemic myopathy may occur as a result of injudicious use of diuretics, laxatives, treatment with mineralocorticoids, amphotericin B, and lithium, and also in compulsive licorice eaters. Laxative and diuretic abuse can be prominent in patients with anorexia nervosa. The periodic paralyses are described in Chapter 38 .

Hypernatremia

Marked hypernatremia may be seen in the setting of hypothalamic lesions, which produce a defective thirst drive and impaired antidiuretic hormone levels. In addition to altered states of consciousness, such as lethargy and delirium, hypernatremia may also be associated with tenderness and weakness of proximal muscles. EMG results are consistent with a myopathic pattern. After correction of serum sodium, muscle tenderness and weakness disappear, CK values are restored to a normal range, and EMG findings become unremarkable. The mechanism of muscle weakness in hypernatremia has not been established, but may be caused by a depletion of intracellular energy stores (e.g. reduced adenosine triphosphate because of overactive Na-K pump consumption).

Primary Hyperparathyroidism

This disorder may present as a clinical syndrome of easy fatigability and muscle weakness, especially involving the proximal leg muscles. Other common features include glucose intolerance and insulin resistance. Myotatic reflexes are preserved or hyperactive. Patients may also exhibit tremors of the tongue, minor sensory defects, and abnormalities of phonation, gait, station, and mentation. EMG findings are mixed, with some patients showing action potentials of abnormally short duration and low amplitude whereas others show high-amplitude, long-duration polyphasic potentials. Atrophy of both type I and type II fibers is seen on muscle biopsy. As a rule, serum CK and transaminase levels are normal. In addition to the deleterious effects of the associated hypercalcemia, parathyroid hormone itself in abnormally high concentrations may be toxic to muscle fibers.

Human Immunodeficiency Virus

Human immunodeficiency virus (HIV) myopathy may be present early in HIV infection, but more commonly complicates full-blown acquired immunodeficiency syndrome. HIV myopathy occurs almost exclusively in adults. HIV myopathy begins with the subacute onset of proximal, symmetrical muscle weakness that may be associated with wasting of the legs more often than the arms. Myalgias can be seen, and serum CK level is increased as much as 10 to 15 times normal. EMG findings include spontaneous activity with fibrillations and positive sharp waves, and brief, low-amplitude, polyphasic units. Nerve conduction studies are either normal or may suggest a mild, axonal sensory neuropathy. The muscle biopsy shows inflammatory cells, chiefly lymphocytes and macrophages, in a perivascular, endomysial, or perimysial distribution, surrounding healthy muscle fibers; degenerating and necrotic muscle fibers may also be present. There is an increase in connective tissue in more severe cases. Rarely, scattered cytoplasmic bodies and nemaline (rod) bodies can be seen. If some angulated fibers are also present, there may be a coexisting axonal neuropathy. Ultrastructurally, there is disorganization of the myofibrillar structure and macrophages, lymphocytes, and plasma cells.

Other factors may contribute to muscle disease in HIV infection. Although rare, infection of skeletal muscle with opportunistic organisms can occur in the course of disseminated infection in older patients. Such organisms include Cryptococcus neoformans , Toxoplasma gondii , Mycobacterium avium-intracellulare , and Mycobacterium tuberculosis . Further myotoxic factors include vitamin deficiencies; induction of type II fiber atrophy due to disuse, prolonged immobilization, or muscle wasting related to bacterial toxins and systemic sepsis; and myotoxicity from the assortment of drugs used to treat underlying illnesses. Increased levels of cachexin and tumor necrosis factor are found in patients with acquired immunodeficiency syndrome and may contribute to muscle wasting syndrome by interfering with aspects of lipid metabolism. HIV wasting syndrome, then, in most cases is not a true myopathy, but probably is due to metabolic or nutritional factors, or both.

Pyomyositis is the most common myopathy in children who are HIV positive. Findings suggestive of pyomyositis include low-grade fever (even without leukocytosis), localized pain and swelling in a large muscle group, and elevated creatine kinase level. An enhancing lesion, often with a fluid density, may be demonstrated by ultrasound, magnetic resonance imaging, or computed tomography scan with contrast. Staphylococcus aureus is implicated, or more rarely gram-negative organisms; a single case of an 11-year-old boy with perinatally acquired HIV and pyomyositis due to Streptococcus agalactiae has been reported. Risk factors for pyomyositis include exercise-induced trauma, underlying muscle abnormalities, or hematogenous spread of a bacterial infection; HIV-associated defects of neutrophil function may contribute to the disease.

Zidovudine (AZT) is capable of inducing a myopathy with depletion of mitochondrial DNA, secondary to its mitochondrial toxicity. AZT inhibits γ-DNA polymerase, which is found solely in the mitochondrial matrix, and produces termination of DNA strands. AZT myopathy may occur in as many as 30% of adults treated with long-term (>1 year), high-dose (>1200 mg daily) AZT. The clinical features of AZT myopathy include proximal muscle weakness; myalgias, especially in the calves and thighs, that are often exacerbated with exercise; and elevated serum CK levels (that may also worsen with exercise). EMG studies demonstrate myopathic units like those observed in HIV myopathy. Because AZT myopathy is clinically similar to HIV myopathy, the only clinical method of differentiating between them is to stop AZT and monitor for clinical improvement. Such improvement includes decreased muscle pain, increased strength, and reduced serum CK levels. On biopsy, the most prominent characteristic of AZT myopathy is the presence of “ragged-red” fibers on trichrome-stained preparations, indicating abnormalities in muscle mitochondria. Electron microscopy studies have confirmed that abnormal mitochondria are present and show further that they are ubiquitous, even in areas appearing normal by light microscopy. Following the discontinuation of AZT, these muscle changes are partially or fully reversible.

Lyme Disease

Lyme disease, caused by Borrelia burgdorferi , is the most common vector-borne disease in the United States. The clinical features of Lyme disease in children are similar to those in adults; however, the long-term complications of the illness in the pediatric population appear to be more rare. Lyme disease is commonly associated with muscle stiffness and nonspecific myalgia early in its course; less often, myositis is noted, which is characteristically localized and may occur concomitant with or up to a year after erythema migrans lesions. Myositis is demonstrated by EMG or biopsy typically near an involved joint or localized neuropathy. Although myopathic patterns by electromyography can be found, they are not mandatory for the diagnosis; neuropathic patterns are secondary to Borrelia -associated neuropathy. Histopathologic examination reveals features of interstitial myositis or focal nodular myositis, with a cellular infiltrate that is predominantly T cells (CD4+>CD8+). B cells are relatively rarely noted. Muscle fiber degeneration is minimal. Although not successfully cultured from muscle, Borrelia spirochetes are detected in biopsy specimens by silver or immunogold-silver staining. Positive PCR analysis of fluid from involved muscle tissue at biopsy can provide additional diagnostic support. Nuclear medicine imaging (gallium 67 uptake) may be useful in documenting potential areas of localized myositis in Lyme disease. With appropriate antibiotic therapy, a good clinical response is expected.