Chapter 66. The Peripheral Nerves & Skeletal Muscle

The peripheral nerves, neuromuscular junction, and skeletal muscle represent the final component of the lower motor neuron unit and are discussed together for that reason. Diseases involving these structures result in muscle weakness. The peripheral nerves also have sensory and autonomic fibers, and—unlike diseases of muscle, which result in motor dysfunction alone—peripheral nerve diseases are manifested by a combination of motor and sensory loss.

Peripheral nerves are composed of axons leading to and from sensory, motor, and autonomic neurons. Each individual axon is surrounded by a myelin sheath of varying thickness. The nerves contain Schwann cells, which form the myelin, and supporting connective tissue (endo-, epi-, and perineurium). The blood supply to peripheral nerves is by small arterioles called the vasa nervorum.

Peripheral Neuropathy

Peripheral neuropathy is a clinical term that denotes nontraumatic disease of the nerves. Most peripheral neuropathies tend to affect the longest fibers first, producing a typical symmetric “glove and stocking” distribution of sensory loss and involvement of the muscles of the hands and feet. Sensory and mixed neuropathies are more common than pure motor neuropathy. Neuropathy affecting autonomic nerves results in autonomic dysfunction.

Two basic pathologic lesions occur in peripheral neuropathy: segmental demyelination and axonal degeneration. Both changes result in failure of nerve conduction. In the case of sensory nerves, the nerve damage results in degenerative changes in the neuron within the sensory nerve root ganglion. When neuronal loss occurs, the lesion is irreversible. There are many causes of peripheral neuropathy (Table 66-1). These are classified by etiology rather than by pathogenesis because pathologic examinations of nerve biopsy material are not routinely performed. Nerve biopsy (sural nerve) is indicated in (1) cases where vasculitis, amyloidosis, granuloma, or inflammation is suspected; and in (2) specialized centers for research into nerve diseases. Identification of fine structural changes in the myelin sheath and axons requires teased nerve preparations and electron microscopy. These techniques are not within the scope of the average pathology laboratory.

Ischemic neuropathy tends to result in asymmetric involvement of a single nerve (mononeuritis) or scattered individual nerves (mononeuritis multiplex).

Guillain-Barré Syndrome (Acute Demyelinating Polyneuritis)

Guillain-Barré syndrome is an uncommon disease believed to be the peripheral nervous system equivalent of experimental allergic encephalomyelitis (Chapter 64: The Central Nervous System: III. Traumatic, Vascular, Degenerative, & Metabolic Diseases). It follows viral infection in a majority of cases, most often with herpesvirus, Epstein-Barr virus, or cytomegalovirus infections; less frequently, it is precipitated by injection of foreign proteins, immunization, or trauma. Well-documented cases were reported following the swine-flu vaccination program of 1976–1977. Subsequent influenza vaccination programs have not been associated with this complication. Experimentally, a similar disease—experimental allergic neuritis—can be induced in animals by injection of peripheral myelin protein P2 with Freund's adjuvant; cytotoxic T lymphocytes develop that have the ability to produce demyelination in tissue culture.

Pathologically, Guillain-Barré syndrome is characterized by acute demyelination of multiple cranial and spinal nerve roots (polyradiculopathy), associated with lymphocytic infiltration of the involved nerves. The cerebrospinal fluid shows a typical change called cell–protein dissociation; the cell count is normal (< 5/μL), but the protein is markedly elevated.

Clinically, Guillain-Barré syndrome has a subacute onset with lower-motor-neuron-type weakness, mainly in the lower extremities (flaccid paraparesis with urinary incontinence). Involvement of the upper extremities and respiratory muscles occurs in severe cases. Sensory impairment is much less than motor impairment, and many patients have no sensory loss. The paralysis progresses for 1–4 weeks and then slowly improves over several months because of the slow regeneration of axons within the restored myelin sheaths. Ninety percent of patients recover completely.

Treatment is supportive. There is evidence that plasma exchange (plasmapheresis) produces a beneficial effect, presumably by removing immunologically active elements from the patient's plasma. Plasmapheresis should be undertaken in severe cases or in the presence of respiratory compromise.

Traumatic Nerve Injuries

Peripheral nerve injuries resulting in transection of the nerve are common. Transection injury is characterized by loss of motor and sensory function in the distribution of the nerve, the severity of which depends on how many nerve fibers within the nerve are interrupted.

Recovery from a nerve injury depends on several factors, most importantly whether the continuity of the nerve sheath of the damaged axon is maintained. Where the nerve sheath is not disrupted, complete recovery is the rule. This takes a period of several weeks because the axon and myelin sheath distal to the point of injury undergo wallerian degeneration and then regenerate slowly (1–2 cm per week) from the proximal end. In such nerve injuries, return of effective function depends on the degree of secondary degeneration that occurs in the end organ (motor end plate, muscle, sensory receptor, etc), which in turn depends on the time taken for reinnervation to occur.

More serious nerve injuries, which are much more common, are associated with transection of the nerve sheath as well as the axon. In most cases, the entire nerve trunk is severed. Wallerian degeneration occurs distally, with degeneration of axons and demyelination. The Schwann cells at the proximal end of the severed nerve fibers proliferate rapidly, and in some cases this process reestablishes continuity with the distal nerve sheath. Recovery of function is dependent on the number of nerve sheaths that reestablish continuity and permit axonal recovery. This depends mainly on the accuracy of apposition of the severed nerve ends. Effective functional recovery requires that the axon reestablish its original innervation. With complete transection of a mixed sensory and motor nerve, the chances of this occurring are slight.

The complications of nerve transection include (1) failure of return of function; (2) return of abnormal function, due to establishment of incorrect innervation, eg, proximal sensory fiber growing down a distal motor axon; and (3) development of a mass at the severed nerve end composed of proliferating Schwann cells—these resemble neurofibromas histologically and are called traumatic neuromas.

Neoplasms of Peripheral Nerves

Neoplasms of peripheral nerves are common. They may occur in any nerve and may be classified anatomically as (1) neoplasms within the skull or spinal canal; (2) neoplasms that involve both the spinal canal and the paraspinal soft tissue (termed dumbbell tumors because of their shape—2 large masses connected by a narrow mass within the intervertebral foramen); (3) neoplasms arising in large nerve trunks in extraspinal or extracranial soft tissues; and (4) neoplasms in small peripheral nerve filaments that appear as soft tissue masses without obvious connections to nerves.

In all of these anatomic sites, neural tumors fall into 3 groups: (1) schwannoma, (2) neurofibroma, and (3) malignant peripheral nerve sheath tumor—a type of sarcoma also called malignant schwannoma or neurofibrosarcoma. Most neural neoplasms occur as sporadic lesions. In a small number of cases, multiple neural neoplasms occur as part of the familial generalized neurofibromatosis syndrome of von Recklinghausen (see Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases).

Schwannoma (Neurilemmoma)

(Figure 66-1)

Schwannoma is a slowly growing benign neoplasm that commonly occurs in relation to large nerve trunks. Sensory cranial nerves (eighth and fifth nerve schwannoma) and the sensory root of spinal nerves are common locations. In the extra-axial soft tissues, they most commonly occur in the posterior mediastinum, the retroperitoneum, the head and neck, and the extremities. Schwannomas are usually solitary; multiple schwannomas may be associated with von Recklinghausen's neurofibromatosis.

Clinically, schwannomas present as a mass lesion, usually causing compression of surrounding structures. Compression of the nerve of origin causes irritative and paralytic symptoms—eg, acoustic schwannoma results in tinnitus followed by nerve deafness. Pain in the distribution of affected sensory nerves is a common finding.

On gross examination, schwannomas appear as encapsulated masses that compress the nerve of origin, which is frequently splayed out on one side of the mass. There is usually a plane of cleavage separating the nerve from the mass that may permit the tumor to be removed surgically without sacrificing the nerve. Areas of hemorrhage and cystic change are seen commonly in schwannomas; rarely, the neoplasm is composed predominantly of a cyst.

Histologic examination shows the tumor to be composed of Schwann cells arranged in one or both of two distinct patterns (Figure 66-2). The Antoni A pattern is characterized by highly cellular, compact, spindle-shaped cells arranged in short bundles or fascicles. Palisade arrangement of nuclei (nuclei of a fascicle of cells arranged one below the other) and Verocay bodies (structures formed by two rows of palisaded nuclei separated by an oval mass of pink cytoplasm) are characteristic histologic features. The Antoni B pattern is a loose, haphazard arrangement of Schwann cells in a richly myxomatous stroma. Large vascular spaces with hyalinized walls are a common feature. Nuclear pleomorphism and atypia, sometimes marked, may be present. Mitotic figures may also be present. Neither cytologic atypia nor mitotic activity indicates malignancy. Immunohistochemical studies show the presence of S100 protein in the Schwann cells.

The malignant potential of schwannomas is very low.

Neurofibroma

(Figure 66-1)

Neurofibroma is a slowly growing benign neoplasm that occurs (1) in relation to large nerve trunks and (2) in peripheral tissues such as skin, where it arises from very small nerves. Neurofibroma most commonly occurs as a solitary neoplasm. In patients with von Recklinghausen's disease, there are multiple neurofibromas in the skin and viscera (Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases).

Clinically, neurofibroma presents as a soft tissue mass. It is commonly associated with pain.

On gross examination, neurofibromas of large nerves appear as an expansion of the affected nerve (Figure 66-3). The mass is firm and rubbery, not demarcated from the nerve, and cannot be removed surgically without sacrificing the nerve. Cystic degeneration is common.

Histologic examination shows a varied spindle cell population composed of Schwann cells and fibroblasts. Cellularity is variable, and myxomatous change is commonly present in the stroma. Nuclear atypia and pleomorphism may be observed without indicating that the neoplasm is malignant. The presence of mitotic activity in a neurofibroma indicates a strong likelihood of malignant biologic potential. Immunohistochemical studies show the presence of S100 protein; this is a reliable method of confirming the histologic diagnosis of both schwannoma and neurofibroma. Neurofibroma carries a low but significant risk of malignant transformation. Risk of malignancy is greatest in patients with von Recklinghausen's disease.

Malignant Peripheral-Nerve-Sheath Tumor

The term malignant peripheral-nerve-sheath tumor is applied to all malignant neural neoplasms and is synonymous with malignant schwannoma and neurofibrosarcoma. Most such tumors occur de novo; a few complicate preexisting neurofibromas, particularly in patients with von Recklinghausen's disease.

Malignant peripheral-nerve-sheath tumors appear clinically as soft tissue neoplasms. Any location may be affected; most common are the extremities and retroperitoneum. The rate of growth varies, being slow in low-grade neoplasms and rapid in high-grade ones. The tumors are diffusely infiltrative, frequently invading surrounding structures. Many patients have evidence of metastatic disease at the time of presentation. The most common site of metastasis is the lung.

Grossly, malignant peripheral-nerve-sheath tumors are fleshy masses, frequently large and showing extensive infiltration. Areas of necrosis and hemorrhage are common. Microscopically, they are highly cellular spindle cell sarcomas with marked cytologic atypia and pleomorphism and a high mitotic rate. The diagnosis of malignant peripheral-nerve-sheath tumor may be made when (1) a sarcoma has its origin from a large peripheral nerve, (2) a sarcoma of appropriate histologic type occurs in a patient with von Recklinghausen's disease, (3) S100 protein is demonstrated in the tumor cells, or (4) electron microscopy demonstrate features typical of Schwann cells. Less than 50% of malignant peripheral-nerve-sheath tumors stain positively for S100 protein.

Normal Skeletal Muscle

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.

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.

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.

Clinical Features of Muscle Disease

Muscle Weakness

Causes of muscle weakness include the following:

1. 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.

2. Failure of neuromuscular transmission.

3. Disease involving skeletal muscle per se, including myositis, dystrophies, and myopathies.

Muscle Pain

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.

Myoglobinuria

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).

Diagnosis of Muscle Disease

Clinical Examination

The diagnosis of many muscle diseases is based on the distribution of involvement, family studies, and other clinical features.

Electromyography

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.

Serum Enzyme Levels

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.

Muscle Biopsy

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).

Primary Muscle Diseases

Muscular Dystrophies

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.

Types of Muscular Dystrophy

(Table 66-3)

Duchenne Muscular Dystrophy

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.

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.

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.

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).

Other Muscular Dystrophies

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.

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.

Congenital Myopathies

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.

Acquired Myopathies

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.

Inflammation of Muscle (Myositis)

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.

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.

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.

Disorders of Neuromuscular Transmission

Myasthenia Gravis

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.

Etiology

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.

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.

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.

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.

Pathology

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.

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%.

Clinical Features & Diagnosis

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.

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.

Treatment

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.

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.

Other Causes of Neuromuscular Transmission Failure

Myasthenic Syndrome (Eaton-Lambert Syndrome)

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.

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).

Botulism

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.

Tick Paralysis

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.

Aminoglycoside Drugs

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.

Neoplasms of Skeletal Muscle

Benign Neoplasms (Rhabdomyoma)

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).

Malignant Neoplasms (Rhabdomyosarcoma)

Rhabdomyosarcoma is an uncommon soft tissue sarcoma. Three histologic subtypes are recognized:

1. 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.

2. 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.

3. 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.