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Normal Skeletal Muscle
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Normal skeletal muscle is composed of fascicles of muscle fibers (myofibrils) that represent the cellular unit. A myofibril is a long, cylindric, multinucleate cell that is the contractile unit of the muscle. Myofibrils are invested by a delicate connective tissue (endomysium) that is continuous with the connective tissue present between the myofibrils (perimysium) and around the whole muscle (epimysium). The connective tissue binds the myofibrils and is continuous at the ends of the muscle with the tendons with which muscles gain attachment to bone.
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Each myofibril has a cell membrane (the sarcolemma) and shows cross-striations because it is made up of regularly alternating bands of different refractility. Difference in refractility is related to the disposition of actin and myosin filaments in the myofibril.
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Human muscle fibers are subdivided into two types on the basis of their staining with the myosin-ATPase reaction at pH 9.4. Type I fibers, which stain lightly, are slow-contracting, fatigue-resistant fibers rich in oxidative enzymes. They function in aerobic conditions using blood glucose as the main energy source (these are the fibers developed in marathon runners). Type II fibers, which stain darkly, are fast-contracting, fatigue-prone fibers rich in glycolytic enzymes. They function in anaerobic conditions using stored glycogen as the main energy source (these are the fibers developed in sprinters). Normal muscle has a random mixture of both fiber types.
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Clinical Features of Muscle Disease
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Causes of muscle weakness include the following:
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Neurologic diseases involving either the upper or lower motor neurons. Lower-motor-neuron paralysis is characterized by muscle atrophy and loss of deep tendon reflexes; it may clinically resemble primary muscle diseases. Upper-motor-neuron paralysis causes spasticity and brisk reflexes without significant muscle atrophy, at least initially.
Failure of neuromuscular transmission.
Disease involving skeletal muscle per se, including myositis, dystrophies, and myopathies.
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Inflammatory lesions of muscle (myositis) are commonly associated with pain and tenderness in the involved muscles. Muscle pain and cramping induced by exercise occur in metabolic diseases associated with defective energy production in muscle. These include glycogen storage disease (most commonly muscle phosphorylase deficiency) and defects in the glycolytic pathway, both of which interfere with glucose utilization.
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Myoglobinuria results from acute muscle destruction (rhabdomyolysis) that may occur with acute toxic, metabolic, infectious, or traumatic muscle disease. Myoglobin is rapidly filtered into the urine, which becomes red. Myoglobinuria must be distinguished from (1) hematuria (the urine contains no erythrocytes in myoglobinuria) and (2) hemoglobinuria (by immunoassay or spectroscopy).
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Diagnosis of Muscle Disease
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The diagnosis of many muscle diseases is based on the distribution of involvement, family studies, and other clinical features.
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Electromyography, which measures action potentials generated in muscles by means of an electrode inserted into the muscle belly, provides useful information regarding muscle function. The action potentials may be generated by voluntary contraction of the muscle or by stimulation of the nerve supply. The latter also permits evaluation of nerve conduction and neuromuscular transmission.
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Serum levels of creatine kinase, aldolase, transaminases, and lactate dehydrogenase become elevated in many muscle diseases, especially the dystrophies and myositis (Table 66-2). Elevations of these enzymes, however, are not specific for muscle diseases, and clinical correlation is essential. Note that muscle atrophy secondary to neuronal lesions does not usually produce elevated enzyme levels. Mild elevation of serum enzyme levels may be present in normal individuals immediately after strenuous exercise.
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Skeletal-muscle biopsy is a highly specialized procedure. The preferred site for biopsy is the gastrocnemius. After removal, the muscle sample should be placed in a special clamp before fixation to prevent contraction. In addition to routine light microscopy, muscle biopsies are examined by special histochemical methods—to assess their enzyme content—as well as by electron microscopy. Such techniques require special processing, and they are done in laboratories equipped for such procedures. Routine light microscopy shows features that permit differentiation of denervation atrophy, muscular dystrophy, and myositis (Figure 66-4).
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Primary Muscle Diseases
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The muscular dystrophies are a group of rare inherited primary muscle diseases characterized by (1) onset in childhood, (2) distinctive distribution of involved muscles, and (3) nonspecific histologic changes (Figure 66-4) in muscle.
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Types of Muscular Dystrophy
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Duchenne Muscular Dystrophy
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Duchenne muscular dystrophy (pseudohypertrophic muscular dystrophy) is the most common entity within this group. It is inherited as an X-linked recessive trait. Females carry the abnormal gene and transmit it on average to 50% of their male offspring, who manifest the disease. The disease is due to the absence of a gene located on the short arm of the X chromosome at the Xp21 site. This results in the absence of the gene product dystrophin in skeletal muscle, a consistent finding in Duchenne's disease. Dystrophin is a membrane-associated structural protein that serves as a strut to maintain muscle fiber integrity during contraction. Identification of the female carriers is now possible.
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Affected males are normal at birth and manifest the disease in early childhood. The disease progresses rapidly, with most children functionally disabled within a few years. Death commonly occurs by the end of the second decade.
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Muscle weakness is symmetric and first affects the muscles of the pelvic girdle. This causes difficulty in getting up from a seated position: the child pushes up with the hands to compensate for pelvic girdle weakness. Walking becomes progressively more difficult, with a typical waddling gait leading to a disability so severe as to confine the child to a wheelchair within a few years. A few patients with Duchenne muscular dystrophy also have reduced intelligence and myocardial involvement. Death commonly results from involvement of respiratory muscles.
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A typical feature of Duchenne muscular dystrophy is that the affected muscles appear larger than normal in the early stages. This is most easily seen in the calf muscles. Enlargement of muscle is caused by increased fat content (pseudohypertrophy); the myofibrils themselves show the randomly alternating muscle fiber atrophy and hypertrophy that characterizes all muscular dystrophies (Figure 66-4).
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Other Muscular Dystrophies
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Many other types of muscular dystrophy are recognized and characterized according to the distribution of initial muscle weakness and observed inheritance patterns (Table 66-3). Different entities have onset at different ages and different rates of progression of disease. Most are less severe than Duchenne muscular dystrophy. All are characterized by muscle weakness and atrophy, and histologic changes on muscle biopsy are identical. Becker's muscular dystrophy results from a deficiency of the same dystrophin gene whose absence causes Duchenne's disease. The dystrophin deficiency in Becker's disease results in milder disease manifesting in adult life.
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One exception to these rules is myotonic dystrophy, which is characterized not by muscle weakness but by failure of relaxation of muscle after voluntary contraction. Onset is usually in adult life, and progression is very slow. Patients with myotonic dystrophy also may have cataracts, gonadal atrophy, mental retardation, abnormal insulin metabolism, and cardiac arrhythmias.
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Congenital Myopathies
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Congenital myopathies are a group of very rare primary muscle diseases characterized by (1) onset at birth or in early infancy, with muscle weakness and decreased muscle tone (floppy infant syndrome); (2) a very slowly progressive or nonprogressive course, with long survival being the rule; and (3) specific histologic changes on muscle biopsy that characterize individual entities within the group (Table 66-4). Most are inherited.
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Many acquired diseases are associated with muscle weakness without causing histologic changes in the involved muscle. Common diseases causing acquired myopathies are thyrotoxicosis, hypercortisolism (Cushing's syndrome), acromegaly, and malignant neoplasia, in the last of which myopathy occurs as a paraneoplastic syndrome. Hypocalcemia associated with osteomalacia and abnormal potassium metabolism associated with familial periodic paralysis also cause myopathy.
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Inflammation of Muscle (Myositis)
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A large number of infectious agents affect muscle, leading to myositis (Table 66-5). In trichinosis, muscle involvement characterized by severe muscle pain and swelling is the dominant clinical manifestation in the acute phase. Bornholm disease is a coxsackievirus infection of chest-wall muscles characterized by severe chest pain aggravated by breathing. Skeletal muscle involvement also occurs in exotoxic bacterial infections. In diphtheria, there is necrosis of muscle with inflammation. Muscle pain (myalgia) is a common clinical accompaniment of many viral infections, typhoid fever, and leptospirosis.
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Inflammation of muscle is common in several autoimmune diseases. In polymyositis (often associated with skin involvement—dermatomyositis), inflammation of muscles is the dominant clinical manifestation (see Chapter 68: Diseases of Joints & Connective Tissue). In other autoimmune diseases and in sarcoidosis, muscle involvement occurs as part of a general systemic illness. In myasthenia gravis, focal collections of lymphocytes (lymphorrhages) may be seen in muscle; they have little connection with the pathogenesis of the disease.
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Myositis may also occur after high-dosage radiation (most commonly in treatment of cancer), ischemia, and when muscle is infiltrated by malignant neoplasms. A specific form of myositis called myositis ossificans is characterized by bone formation in the involved muscle. This usually appears as a hard mass in the muscle that may be mistaken for a neoplasm.
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Disorders of Neuromuscular Transmission
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Myasthenia gravis is one of the more common muscle diseases, affecting 1:40,000 persons in the United States. The most common age at onset is 20–40 years. There is a female preponderance when the disease occurs under the age of 40 years.
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Myasthenia gravis is a clinical syndrome resulting from failure of neuromuscular transmission due to blockage and destruction of acetylcholine receptors by autoantibody (Figure 66-5). Myasthenia gravis is therefore an organ-specific autoimmune disease.
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Antiacetylcholine-receptor antibody is present in the serum of almost all patients. It is an IgG antibody and may cross the placenta in pregnancy, causing neonatal myasthenia in the newborn.
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The reason for the production of antiacetylcholinereceptor autoantibody is unknown. Thymectomy often improves the condition. It is believed that the thymus plays a role in the etiology of myasthenia gravis, either acting as a source of cross-reactive antigen (the thymic myoid cells bear acetylcholine receptors on their surface) or being involved in the production of helper T cells that influence production of the autoantibody. The thymus is not the source of the antibody, which is produced by the peripheral lymphoid tissue.
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Patients with myasthenia frequently have other autoantibodies in their blood. The commonest of these is antistriated-muscle antibody, which reacts with skeletal muscle fibers away from the motor end plate. This autoantibody also cross-reacts with myoid cells in the thymus.
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Specific morphologic abnormalities are not seen on gross examination or light microscopy. Focal collections of lymphocytes (lymphorrhages) may be seen in affected muscle. Immunohistochemistry demonstrates the presence of IgG and complement components on the motor end plate. Electron microscopy shows damage to the motor end plate with loss of the normally complex folds.
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Thymic abnormalities are seen in many patients with myasthenia gravis. These include thymic hyperplasia (presence of reactive lymphoid follicles in an adult thymus) in 65% and thymomas in 10%.
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Clinical Features & Diagnosis
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Myasthenia gravis is characterized by muscle weakness that is typically aggravated by repeated contraction. Muscles with the smallest motor units are affected first, the most typical clinical presentation being weakness of ocular muscles (causing bilateral ptosis, or drooping of the eyelid, and diplopia, or double vision). Twenty percent of patients with myasthenia have only ocular involvement (ocular myasthenia). In others, the disease progresses to include facial muscles, limb girdle muscles, and respiratory muscles (generalized myasthenia). Progression is variable but usually slow, with respiratory muscle involvement occurring 5–20 years after onset. Untreated, 40% of patients with myasthenia gravis will die of their disease within 10 years.
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The clinical diagnosis of myasthenia gravis may be confirmed by therapeutic testing, electromyography, and serologic testing: (1) Edrophonium (Tensilon) is a short-acting anticholinesterase drug that produces immediate improvement in muscle weakness when administered intravenously; (2) Electromyography shows a progressive decline in amplitude of muscle action potentials in patients with myasthenia gravis when the muscle is subjected to repeated voluntary contraction; (3) Serum assay for antiacetylcholine-receptor antibody is an excellent test, being positive in 80% of patients with myasthenia gravis. It is highly specific, with a positive test being diagnostic of the disease. The titer of antibody does not correlate with disease severity.
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Anticholinesterases, which increase the acetylcholine levels at the motor end plate and compensate for the receptor blockage, represent the mainstay of treatment. In crisis situations, the use of high-dosage corticosteroids and plasma exchange, both of which reduce antibody activity, have proved effective.
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Thymectomy produces variable remission of the symptoms of myasthenia in many patients. The improvement is most pronounced in young women with recent onset of myasthenia and thymic hyperplasia. The improvement is least in patients with thymoma. The reason for remission of myasthenia after thymectomy is unknown.
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Other Causes of Neuromuscular Transmission Failure
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Myasthenic Syndrome (Eaton-Lambert Syndrome)
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Myasthenic syndrome is a paraneoplastic syndrome associated with cancer, particularly small-cell carcinoma of the lung. Very rarely, myasthenic syndrome occurs in patients without cancer.
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Myasthenic syndrome is the result of an abnormality of acetylcholine release by nerve endings at the motor end plate caused by an autoantibody directed against calcium channels on the motor nerve terminals. It is characterized clinically by weakness of muscles in a distribution similar to that of myasthenia gravis, with early involvement of ocular muscles. The muscle weakness is not aggravated by effort and on electromyography shows progressive increase of amplitude of action potentials upon repeated contraction (an effect opposite to that seen in myasthenia gravis).
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The exotoxin of Clostridium botulinum in minute doses blocks release of acetylcholine at the motor end plate. Generalized muscle weakness rapidly leads to respiratory paralysis and death.
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Ticks of the genus Dermacentor—Dermacentor andersoni, the Rocky Mountain wood tick, and Dermacentor variabilis, the American dog tick—secrete a toxin that inhibits acetylcholine release. Removal of the tick is curative.
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Aminoglycosides in high dosage, especially in the presence of renal dysfunction, inhibit acetylcholine release and cause muscle weakness. These antimicrobial drugs should be avoided in patients with myasthenia gravis.
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Neoplasms of Skeletal Muscle
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Benign Neoplasms (Rhabdomyoma)
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Benign neoplasms of skeletal muscle (rhabdomyoma) are extremely uncommon. Cardiac rhabdomyoma occurs rarely in patients with tuberous sclerosis (see Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases).
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Malignant Neoplasms (Rhabdomyosarcoma)
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Rhabdomyosarcoma is an uncommon soft tissue sarcoma. Three histologic subtypes are recognized:
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Embryonal rhabdomyosarcoma is the most common type, especially in children under 10 years of age. It presents as a rapidly growing neoplasm involving the soft tissues of the extremities, retroperitoneum, orbit, nasal cavity, and a variety of organs. It is extremely infiltrative and tends to metastasize via the bloodstream at an early stage. A special variant of embryonal rhabdomyosarcoma occurring in the vagina in very young girls is known as sarcoma botryoides. This tumor appears as an enlarging mass that protrudes from the vagina, having the appearance of a bunch of grapes. Histologically, embryonal rhabdomyosarcoma is highly cellular, being composed of small round and oval cells with primitive hyperchromatic nuclei, scanty cytoplasm, and a high mitotic rate. Skeletal muscle differentiation can be demonstrated by (1) the presence of scattered cells with abundant pink cytoplasm (strap cells) that show cross-striations; (2) the presence of irregular Z bands on electron microscopy; and (3) the presence of muscle proteins such as myoglobin, myosin, actin, and desmin as shown by immunohistochemical studies. Sarcoma botryoides is composed of similar cells but shows areas of low cellularity with myxomatous change in the stroma and a characteristic layer of small primitive cells beneath the vaginal epithelium (cambium layer). Aggressive chemotherapy has greatly improved survival of children with embryonal rhabdomyosarcoma.
Alveolar rhabdomyosarcoma is less common and occurs in the age group from 10 to 30 years. Patients often present with a mass around the shoulder or pelvis. The tumor is characterized by an alveolar arrangement of the small, primitive neoplastic skeletal muscle cells. Like embryonal rhabdomyosarcoma, it is rapidly growing and highly malignant. The response to chemotherapy is less satisfactory than in the embryonal type.
Pleomorphic rhabdomyosarcoma is an uncommon neoplasm of soft tissue that mainly affects the extremities and retroperitoneum in elderly patients. It is highly malignant and resistant to chemotherapy.