Diseases of Muscle: Introduction
Skeletal, or voluntary, muscle constitutes the principal organ of locomotion, as well as a vast metabolic reservoir. Disposed in more than 600 separate muscles, this tissue makes up as much as 40 percent of the weight of adult human beings. An intricacy of structure and function undoubtedly accounts for its diverse susceptibility to disease, for which reason the main anatomic and clinical facts are provided as an introduction to the muscle diseases.
A single muscle is composed of thousands of muscle fibers that extend for variable distances along its longitudinal axis. Each fiber is a relatively large and complex multinucleated cell varying in length from a few millimeters to several centimeters (34 cm in the human sartorius muscle) and in diameter from 10 to 100 μm. Some fibers span the entire length of the muscle; others are joined end to end by connective tissue. Each muscle fiber is enveloped by an inner plasma membrane (the sarcolemma) and an outer basement membrane. The multiple nuclei of each fiber, which are oriented parallel to its longitudinal axis and may number in the thousands, lie beneath the plasma membrane (sarcolemma); hence they are termed subsarcolemmal, or sarcolemmal nuclei.
The cytoplasm (sarcoplasm) of the cell is abundant, and it contains myofibrils and various organelles such as mitochondria and ribosomes. Each myofibril is enveloped in a membranous net, the sarcoplasmic reticulum (SR; see Fig. 45-2). Extensions of the plasma membrane into the fiber form the transverse tubular system (T tubules), which are extracellular channels of communication with the intracellular sarcoplasmic reticulum. The SR and T tubules are anatomically independent but functionally related membrane systems. The junctional gap between the T tubules and SR is occupied by protein formations that are attached to the SR and are referred to as junctional feet; the latter have been identified as ryanodine receptors and are responsible for the release of calcium from the SR, which is a critical step in exciting the muscle (see Franzini-Armstrong).
The myofibrils themselves are composed of longitudinally oriented interdigitating filaments (myofilaments) of contractile proteins (actin and myosin), additional structural proteins (titin and nebulin), and regulatory proteins (tropomyosin and troponin). The series of biochemical events by which these proteins, under the influence of calcium ions, accomplish the contraction and relaxation of muscle is described in Chap. 45. Droplets of stored fat, glycogen, various proteins, many enzymes, and myoglobin, the latter imparting the red color to muscle, are contained within the sarcoplasm or its organelles.
The individual muscle fibers are surrounded by delicate strands of connective tissue (endomysium), which provide their support and permit unity of action. Capillaries, of which there may be several for each fiber, and nerve fibers lie within the endomysium. Muscle fibers are bound into groups or fascicles by sheets of collagen (perimysium), which also bind together groups of fascicles and surround the entire muscle (epimysium). The latter connective tissue tunics are richly vascularized, different types of muscle having different arrangements of arteries and veins. The muscle fibers are attached at their ends to tendon fibers, which, in turn, connect with the skeleton. By this means, muscle contraction maintains posture and imparts movement.
Other notable characteristics of muscle are its natural mode of contraction, that is, through neural innervation—and the necessity of intact innervation for the maintenance of its normal tone and trophic state. Each muscle fiber receives a nerve twig from a motor nerve cell in the anterior horn of the spinal cord or nucleus of a cranial nerve; the nerve twig joins the muscle fiber at the neuromuscular junction or motor endplate. As was pointed out in Chaps. 3 and 45, groups of muscle fibers with a common innervation from one anterior horn cell constitute the motor unit, which is the basic physiologic unit in all reflex, postural, and voluntary activity.
Embedded in the surface membrane are several types of ion channels that are responsible for maintaining the electrical potential and propagating depolarizing currents across the muscle membrane. Diseases of these channels are discussed in Chap. 50. Also constituting a large part of the membrane is a series of anchoring structural proteins, the nature of which have been thoroughly elucidated in the past few decades. These are described in detail in relation to the muscular dystrophies.
In addition to motor nerve endings, muscle contains several types of sensory endings, all of them mechanoreceptors: Free nerve endings subserve the sensation of deep pressure-pain; Ruffini and pacinian corpuscles are pressure sensors; and the Golgi tendon organs and muscle spindles are tension receptors and participate in the maintenance of muscle tone and reflex activity. The Golgi receptors are located mainly at the myotendon junctions; pacinian corpuscles are localized in the tendon but are also found sparsely in muscle itself. Muscle spindles are specialized groups of small muscle fibers that regulate muscle contraction and relaxation, as described in Chap. 45. All of these receptors are present in highest density in muscles that are involved in fine movements.
Muscles are not equally susceptible to disease, despite the apparent similarity of their structure. In fact, practically no disease affects all muscles in the body and each pathologic entity has a characteristic topography within the musculature. The topographic differences between diseases provide incontrovertible evidence of structural or physiologic differences between muscles that are not presently disclosed by the light or electron microscope, that is, the factors responsible for the selective vulnerability of certain muscles are not known but several hypothetical explanations come to mind. One may relate simply to fiber size; consider, for example, the large diameter and length of the fibers of the glutei and paravertebral muscles in comparison with the smallness of the ocular muscle fibers. The number of fibers composing a motor unit may also be of significance; in the ocular muscles, a motor unit contains only 6 to 10 muscle fibers (some even fewer), but a motor unit of the gastrocnemius contains as many as 1,800 fibers. Also, the eye muscles have a much higher metabolic rate and a richer content of mitochondria than the large trunk muscles. Differences in patterns of vascular supply may permit some muscles to withstand the effects of vascular occlusion better than others. Histochemical studies of skeletal muscles have disclosed that within any 1 muscle, there are subtle metabolic differences between fibers, certain ones (type 1 fibers) being richer in oxidative and poorer in glycolytic enzymes and others (type 2 fibers) having the opposite distribution. The distribution of certain structural proteins may alter the topography of disease expression; for example, the eye muscles do not contain dystrophin, a submembrane protein that is deficient in Duchenne muscular dystrophy, which explains the muscles’ lack of involvement in this disease. The endomysial fibroblasts of eye muscles contain an abundance of glycosaminoglycans, which renders them susceptible to thyroid diseases. Diseases of the neuromuscular junction show a distribution of weakness in relation to the density of these junctions in different muscles. Doubtless other differences will be discovered.
Normal muscle is endowed with a population of embryonic muscle precursor cells, known as satellite cells, and, as a result, it possesses a remarkable capacity to regenerate, a point often forgotten. It has been estimated that enough new muscle can be generated from a piece of normal muscle the size of a pencil eraser to provide normal musculature for a 70-kg adult. However, with complete destruction of the muscle fiber, this regenerative capacity is greatly impaired. Inflammatory and metabolic destructive processes are usually followed by fairly complete restoration of the muscle cells, provided that some part of each fiber has survived and the endomysial sheaths of connective tissue have not been severely disrupted. Unfortunately, many pathologic processes of muscle are chronic and unrelenting. Under such conditions, any regenerative activity fails to keep pace with the disease and the loss of muscle fibers becomes permanent. The bulk of the muscle is then replaced by fat and collagenous connective tissue, typical, for example, of the muscular dystrophies.
The accepted view of the embryogenesis of muscle is that muscle fibers form by fusion of myoblasts soon after the latter differentiate from somatic mesodermal cells. Muscle connective tissue derives from the somatopleural mesoderm. After fusion of the myoblasts, a series of cellular events including the sequential activation of myogenic transcription factors leads to myofibril formation. The newly formed fibers are thin, centrally nucleated tubes (appropriately called myotubes) in which myofilaments begin to be produced from polyribosomes. As myofilaments become organized into myofibrils, the nuclei of the muscle fiber are displaced peripherally to a subsarcolemmal position. Once the nuclei assume a peripheral position, the myofiber is fully formed. The detailed mechanisms whereby myoblasts seek one another, the manner in which each of a series of fused nuclei contributes to the myotube, the formation of actin and myosin fibrils, Z-discs, and the differentiation of a small residue of satellite cells on the surface of the fibers are reviewed by Rubenstein and Kelly.
The mechanisms that determine the number and arrangement of fibers in each muscle are not as well understood. Presumably the myoblasts themselves possess the genetic information that controls the program of development, but within any given species there are wide individual variations that account for obvious differences in the size of muscles and their power of contraction.
The number of fibers assigned to each muscle is probably attained by birth, and growth of muscle thereafter depends mainly on the enlargement of fibers. Although the nervous system and musculature develop independently, muscle fibers continue to grow after birth only when they are active and under the influence of nerve. Measurements of muscle fiber diameters from birth to old age show the growth curve ascending rapidly in the early postnatal years and less rapidly in adolescence, reaching a peak during the third decade. After puberty, growth of muscle is less in females than in males, and such differences are greater in the arm, shoulder, and pelvic muscles than in the leg; growth in ocular muscles is about equal in the 2 sexes. At all ages, disuse of muscle decreases fiber size by as much as 30 percent, and overuse increases the size by about the same amount (work hypertrophy). Normally, type 1 (oxidative enzyme-rich) fibers are slightly smaller than type 2 (phosphorylative enzyme-rich) fibers; the numerical proportions of the 2 fiber types vary in different muscles in accordance with the natural functions of that muscle. The exercising of young animal muscle causes a hypertrophy of high-oxidative type 1 fibers and an increase in the proportion of low-oxidative type 2 fibers; aging muscle lacks this capacity; exercise produces only an increase in the proportion of type 2 fibers (Silbermann et al). No such data are available in humans, but clinical observation suggests that with aging, the capacity of muscle to respond to intense, sustained exercise is diminished.
During late adult life, the number of muscle fibers diminishes and variation in fiber size increases as mentioned in Chap. 29 on aging. The variations are of 2 types: group atrophy, in which clusters of 20 to 30 fibers are all reduced in diameter to about the same extent, and random single-fiber atrophy. Also, muscle cells, like other cells of postmitotic type, are subject to aging changes (lipofuscin accumulation, autophagic vacuolization, enzyme loss) and to death. Group atrophy, present to a slight degree in the gastrocnemii of almost all individuals older than 60 years, represents denervation effect from an aging-related loss of lumbar motor neurons and peripheral nerve fibers. Further comments regarding muscle and aging can be found in the work of Tomlinson and colleagues and in Chap. 29.
Denervation from spinal motor neuron or nerve disease at every age has roughly the same effect; namely, atrophy of muscle fibers (first in random distribution, then in groups) and later, degeneration. Muscle necrosis at all ages excites a regenerative response from sarcolemmal and satellite cells in any intact parts of the fibers. If this occurs repeatedly, the regenerative potential wanes, with ultimate death of the fiber leading to permanent depopulation of fibers with the expected muscle weakness.
Approach to the Patient With Muscle Disease
The number and diversity of diseases of striated muscle greatly exceed the number of symptoms and signs by which they express themselves clinically; thus, different diseases share certain common symptoms and syndromes. To avoid excessive repetition in the description of individual diseases, we discuss here, in one place, the broad clinical manifestations of muscle disease.
The physician is initially put on the track of a myopathic disease by eliciting complaints of muscle weakness or fatigue, pain, limpness or stiffness, spasm, cramp, twitching, or a muscle mass or change in muscle volume. Of these, the symptom of weakness is by far the most frequent and at the same time the most elusive. As remarked in Chap. 24, when speaking of weakness, the patient often means excessive fatigability and poor endurance. Although fatigability in the strict sense of gradually reduced power with ongoing use of a muscle may be a feature of muscle diseases, particularly those affecting the neuromuscular junction such as myasthenia gravis, it is far more frequently a complaint of patients with chronic systemic disease or with anxiety or depression. As stated in Chap. 24, fatigue is an abstruse symptom, always requiring analysis and interpretation. When not attended by manifest reduction in muscle power, it is usually nonmuscular in origin. It may, on medical investigation, prove to be a systemic manifestation of infection, metabolic or endocrine disorder, severe anemia, reduced cardiopulmonary function, or neoplasia. More often, when expressed as a feeling of poor endurance, weariness, and disinclination to undertake or sustain mental and physical activity, it is indicative of neurasthenia, a psychiatric manifestation common to states of chronic anxiety and depression. An elusive syndrome of lifelong exercise intolerance, often accompanied by muscle cramps during exercise, has been traced in a limited number of cases to mutations in the cytochrome b gene of the mitochondrial DNA (Andreu et al), but these are rare. The subject of fatigue as a physiologic phenomenon and as a clinical feature of many psychiatric and medical diseases, including those that are predominantly myopathic, is considered fully in Chap. 24.
Rather than relying on the patient’s report to distinguish between fatigability and weakness, it is more informative to observe the patient during the performance of certain common activities such as walking, climbing stairs, and arising from a sitting, kneeling, squatting, or reclining position or using the arms over the head. Difficulty in performing these tasks signifies weakness rather than fatigue. Sometimes the weakness of a group of muscles becomes manifest only after a period of activity; for example, the feet and legs may “drag” only after the patient has walked a long distance. The physician, upon being told this by the patient, should attempt to conduct the examination under circumstances that duplicate the complaints. Of course, these impairments of muscle function may be caused by a neuropathic or central nervous system (CNS) disturbance rather than of a myopathic one, but usually these conditions can be separated by the basic methods indicated further on in this chapter and in Chaps. 3 and 24.
Reduced strength of muscle contraction—manifest by diminished power of single contractions against resistance (peak power) and during the sustained performance of prolonged or repetitive movements (i.e., endurance)—are the indubitable signs of muscle or neuromuscular disease. In such testing, the physician may encounter difficulty in enlisting the patient’s cooperation. The tentative, hesitant performance of the asthenic or suggestible individual, or the hysteric or malingerer, poses difficulties that can be surmounted by experience and by the techniques described in Chap. 3. In infants and small children, who cannot follow commands, one assesses muscle power by the resistance to passive manipulation or by observing performance while the child is engaged in natural activities. The patient may be reluctant to fully contract the muscles in a painful limb; indeed, pain itself causes a reflex diminution in the power of contraction (algesic paresis). Estimating the strength of isometric contractions that do not require the painful part to be moved is a way around this difficulty.
Ascertaining the extent and severity of muscle weakness requires a systematic examination of the main groups of muscles. The patient is asked to contract each group with as much force as possible, while the examiner opposes the movement and offers a graded resistance in accordance with the degree of residual power (isokinetic contraction). Alternatively, the patient is asked to produce a maximal contraction and the examiner estimates power by the force needed to overcome or “break” it (isometric contraction or maximum voluntary isometric contraction). If the weakness is unilateral, one has the advantage of being able to compare it with the strength on the normal side. If it is bilateral, the physician must refer to his concept of what constitutes normalcy based on experience in muscle testing. With practice, one can distinguish true weakness from unwillingness to cooperate, feigned or neurasthenic weakness, and inhibition of movement by pain.
To quantitate the degree of weakness, a rating scale may be required. Widely used is the one proposed by the Medical Research Council (MRC) of Great Britain, which recognizes 6 grades of muscle strength as follows:
- 0—Complete paralysis
- 1—Minimal contraction
- 2—Active movement only with gravity eliminated
- 3—Full movement against gravity but cannot offer resistance to manual muscle opposition
- 4—Active movement against gravity and resistance but can be overcome by manual muscle opposition
- 5—Normal strength
Further gradations may be added, specified as 4+ for barely detectable weakness and 4 for easily detected weakness, 3+ and 3, and so on, allowing for 10 grades of power.
The ocular, facial, lingual, pharyngeal, laryngeal, cervical, shoulder, upper arm, lower arm and hand, truncal, pelvic, thigh, and lower leg and foot muscles are examined sequentially. In the case of muscle disease, it is most convenient to test the same muscle from each side. To fully and properly use tools such as the MRC scale and to detect mild weakness, muscles such as the neck flexors and extensors must be tested with the patient in the prone and supine positions. The anatomic significance of each of the actions tested, that is, what roots, nerves, and muscles are involved, can be determined by referring to Table 46-1. A practiced examiner can survey the strength of these muscle groups in 2 to 3 min.
A word of caution is in order: In manually resisting the patient’s attempts to contract the large and powerful trunk and girdle muscles, the examiner may fail to detect slight degrees of weakness, particularly in well-muscled individuals. These muscle groups are best examined by having the patient use the muscle groups for their intended purposes: squat and kneel and then assume the erect posture, arise from and, walk on toes and heels, and lift a heavy object (e.g., Harrison’s Principles of Internal Medicine) over his head. The strength of muscles of the hand can be quantified with a dynamometer; for research purposes, similar but more sophisticated devices exist for other muscle groups (see Fenichel et al). Nonetheless, the examiner should not dismiss the patient’s complaint of weakness simply if it cannot be substantiated by the examination.
In the myasthenic states there is a rapid failure of contraction in the affected muscles during sustained or repetitive activity. For instance, after the patient looks upward at the ceiling for a few minutes, the eyelids progressively droop; closing the eyes and resting the levator palpebrae muscles causes the ptosis to lessen or disappear. Similarly, holding the eyes in a far lateral position will induce diplopia and strabismus. These effects, in combination with restoration of power by the administration of neostigmine or edrophonium, are the most valuable clinical criteria for the diagnosis of myasthenia gravis, as described in Chap. 49.
The opposite of the myasthenic phenomenon, an increment in power with a series of several voluntary contractions is a feature of the Lambert-Eaton myasthenic syndrome, which is associated in approximately 50 percent of cases with small cell carcinoma of the lung. The same increment occurs in botulism. In both instances there is an increase in the amplitude of compound muscle action potentials on the nerve conduction studies obtained following brief exercise (10 to 15 sec), or at high rates of repetitive nerve stimulation (20 to 50 Hz), as described in Chap. 45.
Other abnormalities may be discovered by observing the speed and efficiency of contraction and relaxation during one or a series of maximal actions of a group of muscles. In myxedema, for example, stiffness and slowness of contraction in a muscle such as the quadriceps may be seen on change in posture (contraction myoedema) and by direct percussion of a muscle, and there is an associated prolonged duration of the tendon reflexes. Slowness in relaxation of muscles is another feature of hypothyroidism, accounting for the complaint of uncomfortable tightness of proximal limb muscles. A curious rippling phenomenon in muscles may be the result of several processes and occurs as an inherited autosomal dominant trait. After a period of relaxation, stiffening and rippling occurs in the contracting or stretched muscles.
A prolonged failure of relaxation following contraction of a muscle is characteristic of myotonia, which typifies certain diseases: myotonia congenita, myotonic dystrophy, and paramyotonia congenita. True myotonia, with its prolonged discharge of membrane action potentials, requires strong contraction to elicit, is more evident after a period of relaxation, and tends to disappear with repeated contractions as discussed further in relation to the ion channel disorders in Chap. 50. This persistence of contraction is demonstrable also by tapping a muscle (percussion myotonia), a phenomenon easily distinguished from the electrically silent local bulge (myoedema) induced by tapping the muscle of a myxedematous or cachetic patient and from the brief fascicular contraction that is induced by tapping a normal or partially denervated muscle; the latter is referred to as idiomuscular contraction. In paramyotonia congenita one observes paradoxical myotonia, which refers to an increase in the degree of myotonia during a series of contractions (the reverse of what happens in the usual type of myotonia).
The effect of cold on muscle contraction may also prove informative; either paresis or myotonia, lasting for a few minutes, may be evoked or enhanced by cold. This is most prominent in the paramyotonia of Eulenburg, but it may occur to some degree in all the other myotonic disorders. Also, a cold pack applied to a ptotic eyelid of myasthenia will often reduce the weakness.
Myotonia and myoedema must also be distinguished from the recruitment and spread of involuntary spasm induced by strong and repeated contractions of limb muscles in patients with mild or localized tetanus, with the “stiff man” syndrome and with dystonias of various types. These are not primary muscle phenomena but are neural in origin, a result of an abolition of inhibitory mechanisms and also taken up in Chap. 50.
In practice, the term contracture is applied (somewhat indiscriminately as discussed previously) to all states of fixed muscle shortening. Several distinct types can be recognized. In true physiologic contracture a group of muscles, after a series of strong contractions, remain shortened for many minutes because of failure of the metabolic mechanism necessary for relaxation. In this shortened state, the electromyogram (EMG) remains relatively silent, in contrast to the high-voltage, rapid discharges observed with cramp, tetanus, and tetany. True physiologic contracture occurs in McArdle disease (phosphorylase deficiency), phosphofructokinase deficiency, and possibly in another condition, as yet undefined, where phosphorylase seems to be present. Yet another type of exercise-induced contracture, described originally by Brody, has been attributed by Karpati and coworkers to an autosomal recessive deficiency of calcium adenosine triphosphatase in the sarcoplasmic reticulum in type 2 muscle fibers. True contracture needs to be distinguished from paradoxical myotonia (see earlier) and from cramp, which in certain conditions (dehydration, tetany, pathologic cramp syndrome, amyotrophic lateral sclerosis [ALS]) can also be initiated by one or a series of strong voluntary muscle contractions.
It is appropriate here to comment on pseudocontracture (myostatic or fibrous contracture), for which the term contracture is used in general medicine. This is the common form of muscle and tendon shortening that follows prolonged fixation and inactivity of the normally innervated muscle (as occurs in a broken limb immobilized by a cast or flaccid weakness of a limb that is allowed to remain immobile). Here the shortened state of the muscle and tendons has no clearly established anatomic, physiologic, or chemical basis. Fibrosis of muscle, a state following chronic fiber loss and immobility of muscle, is another cause of muscle shortening. Depending on the predominant position, certain muscles are both weakened and shortened. Flexor fibrous contracture of the arms is a prominent feature of the Emery-Dreifuss form of muscular dystrophy. It also accounts for the rigidity and kyphoscoliosis of the spine, which are so frequently a part of myopathic diseases. The latter state is distinguished from ankylosis by the springy nature of the resistance, coincident with increased tautness of muscle and tendon during passive motion, and from Volkmann contracture, in which there is fibrosis of muscle and surrounding tissues as a result of ischemic injury, usually after a fracture of the elbow.
Arthrogryposis is another form of fibrous contracture that is found in newborns, involving multiple muscle groups; it occurs in association with several diseases that have two features in common: an onset during intrauterine life and an alteration of the neural or muscular apparatus that results in muscular weakness. In other words, contractures and fixity of the limbs in arthrogryposis are the result of reduced mobility of the developing joints, consequent upon muscle weakness during fetal development. Most often the cause is a loss or failure of development of anterior horn cells, as in Werdnig-Hoffman disease, but the abnormality may be in the nerve roots, peripheral nerves, or motor endplates, or in the muscle itself. The rigid spine syndrome (RSS) in children is yet another form of fibrous contracture, presumably the result of an unusual axial muscular dystrophy.
Notably, few of the primary muscle diseases are painful. When pain is prominent and continuous during rest and activity, there will usually be evidence of disease of the peripheral nerves, as in alcoholic–nutritional neuropathy, or of adjacent joints and ligaments (rheumatoid arthritis, polymyalgia rheumatica). Pain localized to a group of muscles is more a feature of torticollis and dystonias. Pain tends not to be prominent in polymyositis and dermatomyositis, but there are exceptions, as commented below. Pain tends to be more definite in polyneuritis, poliomyelitis, and polyarteritis nodosa than it is in polymyositis, various forms of dystrophy, and other myopathies. If pain is present in polymyositis, it usually indicates coincident involvement of connective tissues and joint structures. Hypothyroidism, hypophosphatemia, and hyperparathyroidism are other sources of a myalgic myopathy. Certain drugs produce muscle aches in susceptible individuals. They include the “statin” lipid-lowering drugs, clofibrate, captopril, lithium, colchicine, beta-adrenergic blocking drugs, penicillamine, cimetidine, suxamethonium, and numerous others (see the table contained in the review by Mastaglia and Laing).
There are probably a limited number of mechanisms of muscle pain. Prolonged and sustained contraction gives rise to a deep aching sensation. Contraction under ischemic conditions—as when the circulation is occluded by a tourniquet or from atherosclerotic vascular disease—induces pain; the pain of intermittent claudication is presumably of this type and is not accompanied by cramp. It was postulated that lactic acid or some other metabolite accumulates in muscles and activates pain receptors, but there is also evidence to the contrary. The delayed pain, swelling, and tenderness that occur after sustained exercise of unconditioned muscles are evidently a result of fiber necrosis (Armstrong).
Muscle biopsy infrequently reveals the cause of these painful syndromes, but it may be undertaken in cases of suspected metabolic or dystrophic muscle disease. In their retrospective series, Filosto and colleagues determined that the biopsy was most likely to be helpful if there was exercise-induced muscle pain and the creatine kinase (CK) concentration was greatly elevated; even then two-thirds of the entire group had either normal or nonspecific findings on the biopsy.
Having listed all these causes of proximal pains, all physicians are aware that arthritic and mundane musculoskeletal complaints are more common causes of discomfort.
Benign fasciculations, a common finding in otherwise normal individuals, can be identified by the lack of muscular weakness and atrophy and by the small-size muscle fascicles involved and repetitive appearance in only or regions. The recurrent twitches of the eyelid or muscles of the thumb experienced by most normal persons are often referred to inaccurately as “live flesh” or myokymia but are benign fasciculations of this type. Individuals with truly benign fasciculations have normal EMGs (i.e., they have no fibrillations) as demonstrated in a large series of such patients studied and followed for many years by Blexrud and colleagues. Myokymia is a less common condition, in which there are repeated twitchings and rippling of a muscle at rest.
Muscle cramps, despite their common occurrence, are a poorly understood phenomenon. They occur at rest or with movement (action cramps), and they are frequently reported in motor system disease, tetany, dehydration after excessive sweating and salt loss, metabolic disorders (uremia and hemodialysis, hypocalcemia, hypothyroidism, and hypomagnesemia), and certain muscle diseases (e.g., rare cases of Becker muscular dystrophy and congenital myopathies). Gospe and colleagues reported a familial (X-linked recessive) type of myalgia and cramps associated with a deletion of the first third of the dystrophin gene, which is the one implicated in Duchenne dystrophy; strangely, there was no weakness or evidence of dystrophy. Lifelong, severe cramping of undetermined type has also been seen in a few families. The dramatic Satoyoshi syndrome is characterized by continuous, painful leg cramps, alopecia universalis, and diarrhea.
Far more frequent than all these types of cramping, and experienced at one time or another by most normal persons, is the benign form (idiopathic cramp syndrome) in which no other neuromuscular disturbance can be found. Most often benign cramps occur at night and affect the muscles of the calf and foot, but they may occur at any time and involve any muscle group. Some patients state that cramps are more frequent when the legs are cold and daytime activity has been excessive. In others, the cramps are provoked by the abrupt stretching of muscles, are very painful, and tend to wax and wane before they disappear. The EMG counterpart is a high-frequency discharge. Although of no pathologic significance, the cramps in extreme cases are so persistent and readily provoked by innocuous movements as to be disabling. Cramps of all types need to be distinguished from sensations of cramp without muscle spasm. The latter is a dysesthetic phenomenon in certain polyneuropathies. The disorders that simulate cramps, such as stiff-man syndrome and other forms of continuous muscle fiber activity that have various bases, is discussed in Chap. 50.
Contrasted to cramp is the already described physiologic contracture, observed in McArdle disease and related metabolic myopathies, in which increasing muscle shortening and pain gradually develop during muscular activity. Unlike cramping, it does not occur at rest, the pain is less intense, and the EMG of the contracted muscle at the time is relatively silent. Continuous spasm intensified by the action of muscles and with no demonstrable disorder at a neuromuscular level is a common manifestation of localized tetanus and also follows the bite of the black widow spider. There may also be difficulty distinguishing cramps and spasms from the early stages of a dystonic illness.
Altered structure and function of muscle are not accurately revealed by palpation. Of course, the difference between the firm, hypertrophied muscle of a well-conditioned athlete and the slack muscle of a sedentary person is as apparent to the palpating fingers as to the eye, as is also the persistent contraction in tetanus, cramp, contracture, fibrosis, and extrapyramidal rigidity. The muscles in dystrophy are said to have a “doughy” or “elastic” feel, but we find this difficult to judge. In the Pompe type of glycogen storage disease, attention may be attracted to the musculature by an unnatural firmness and increase in bulk. The swollen, edematous, weak muscles in acute rhabdomyolysis with myoglobinuria or severe polymyositis may feel taut and firm but are usually not tender. Areas of tenderness in muscles that otherwise function normally, a state called myogelosis, have been attributed to fibrositis or fibromyositis, but their nature has not been divulged by biopsy.
In almost all the diseases under consideration, some muscles are affected and others spared, each disease displaying its own pattern. Restated, the topography or distribution of weakness tends to be alike in all patients with the same disease. The pattern of weakness is as important a diagnostic attribute of muscular disease as for the various diseases of the peripheral nervous system discussed in Chap. 46, but the configurations differ in important ways. As a general rule, muscle diseases are identified by a predominantly proximal weakness that is symmetric.
The following patterns of muscle involvement constitute a core of essential clinical knowledge in this field. Subacute and chronic evolution of weakness is distinguished in each category from more acute causes.
Primary diseases of muscle do not involve the pupil, and in most instances their effects are bilateral. In lesions of the third, fourth, or sixth cranial nerves, a neural origin is disclosed by the pattern of ocular muscle palsies, abnormalities of the pupil, or both. When weakness of the orbicularis oculi (muscles of eye closure) is added to weakness of eye opening (levator palpebrae; ptosis), it nearly always signifies myasthenia gravis and occasionally, a rare primary disease of muscle (progressive external ophthalmoplegia [PEO]). Other causes of subacute and chronic development of relatively pure weakness of the muscles of eye movement are oculopharyngeal dystrophy, and exophthalmic (hyperthyroid) ophthalmopathy. In PEO, the muscles, including the levators of the eyelids, become paralyzed almost symmetrically over a period of years. In most cases, this disorder is a form of mitochondrial myopathy. Oculopharyngeal dystrophy involves primarily the levators of the eyelids and, to a lesser extent, other eye muscles and pharyngeal-upper esophageal striated muscles. It begins in middle or late adult life and later, and—like PEO—tends only decades later to involve girdle and proximal limb muscles.
There are several other less common chronic myopathies in which external ophthalmoplegia is associated with involvement of other muscles or organs, namely, the congenital ophthalmoplegia of the Goldenhar-Gorlin syndrome (see Aleksic et al); the Kearns-Sayre syndrome (retinitis pigmentosa, heart block, short stature, generalized weakness, and ovarian hypoplasia); other congenital myotubular and mitochondrial myopathies; and nuclear ophthalmoplegia with bifacial weakness (Möbius syndrome). Rarely, eye muscle weakness may occur at a late stage in a few other dystrophies and ptosis has a wider diagnostic range that includes myotonic dystrophy. Although not a regular feature of the disease, ophthalmoparesis can occur in the Lambert-Eaton myasthenic syndrome.
Ptosis is variable in all of these conditions. When present in infantile myopathic disease, it is frequently a marker of the congenital myasthenic syndromes. Trichinosis is a rare cause, associated also with periorbital edema.
Varying degrees of bifacial weakness are observed in myasthenia gravis, usually conjoined with ptosis and ocular palsies. On occasion, weakness of facial muscles may be combined with myasthenic weakness of the masseters and other bulbar muscles without involvement of ocular muscles. Facial weakness and ptosis are features of myotonic dystrophy. More severe or complete facial palsy occurs in facioscapulohumeral dystrophy, sometimes presenting several years before weakness of the shoulder girdle muscles. Bifacial weakness is also a feature of certain congenital myopathies (centronuclear, nemaline), Kennedy type of degenerative bulbospinal motor neuron disease, and the Möbius syndrome of the absence of the facial nuclei (in combination with abducens palsies).
Advanced scleroderma, Parkinson disease, or a pseudobulbar state can immobilize the face to the point of simulating myopathic or neuropathic paralysis, but always in a context that makes the cause obvious.
Bulbar (Oropharyngeal) Palsy Presenting as Dysphonia, Dysarthria, and Dysphagia With or Without Weakness of Jaw or Facial Muscles
Myasthenia gravis is the most frequent cause of this syndrome and must also be considered whenever a patient presents with the solitary finding of a hanging jaw or fatigue of the jaw while eating or talking; usually, however, ptosis and ocular palsies are conjoined. Dysphagia and dysphonia may be early and prominent signs of polymyositis, as well as inclusion body myositis (IBM), and may appear in patients with myotonic dystrophy, because of upper esophageal atonia.
Combinations of these palsies are not typically of muscular or neuromuscular origin but instead are observed as an acute syndrome in botulism, in brainstem stroke, and at the outset of Guillain-Barré syndrome. Diphtheria and bulbar poliomyelitis are now rare diseases that may present in this way. Progressive bulbar palsy (motor neuron disease) may be the basis of this syndrome (see Chap. 39); the last of these diagnoses is most obvious when the tongue is withered and twitching. Syringobulbia, basilar invagination of the skull, and certain types of Chiari malformation may reproduce some of the findings of bulbar palsy by involving the lower cranial nerves. Rare cases of progressive aphonia include the X-linked Kennedy syndrome of bulbospinal atrophy.
Cervical Palsy Presenting With Inability to Hold the Head Erect or to Lift the Head from the Pillow (“Hanging, or Dropped, Head” Syndrome, “Camptocormia”)
This is caused by weakness of the posterior neck muscles and of the sternocleidomastoids and other anterior neck muscles. In advanced forms of this syndrome, the head may hang with chin on chest unless the patient holds it up with the hands. There may be difficulty differentiating the condition from a dystonic anterocollis; in the latter there is palpable tonic spasm of the sternomastoid and posterior neck muscles. A pattern of neck and spine extensor weakness also occurs in advanced Parkinson disease. A common error in all these cases is to attribute the problem to structural disease of the cervical spine.
This topographic pattern occurs most often in idiopathic polymyositis and IBM, in which cases it is often combined with mild dysphagia, dysphonia, and weakness of girdle muscles. The same symptom may be a feature of motor neuron disease and is infrequently the presenting feature of that process. Myasthenic patients commonly complain of an inability to hold up their heads late in the day; both flexors and extensors of the neck are found to be weak. Occasionally, this pattern of weakness is observed in patients with nemaline rod myopathy. Cases of hanging head have appeared many years after local radiation of the neck and thorax for Hodgkin disease as described by Rowin and colleagues and with syringomyelia (Nalini and Ravishankar).
There is, in addition, a poorly characterized local myopathic process isolated to the cervical paraspinal muscles, which has no distinguishing histopathologic or histochemical features but has accounted for many of the cases of neck extensor weakness that we have encountered. The condition is observed in elderly persons, in some series mainly men, but our experience has included as many women. There is severe but relatively nonprogressive weakness of the neck extensors and only mild weakness of shoulder girdle and proximal arm muscles. Katz and colleagues have suggested the designation “isolated neck extensor myopathy” in preference to dropped head syndrome. What has been referred to as a bent spinesyndrome (for which the term camptocormia is also used) is probably the same entity and may follow after years of the condition affecting the neck, or it may surface independently. These conditions of cervical weakness are reviewed by Umapathi and colleagues and by Azher and Jankovic. Several recent series have suggested that mutations in RYR1 that encodes for ryanodine receptor may be a common cause of late onset axial myopathy and neck extensor weakness-bent spine syndrome (Løseth et al). Mutations in RYR1 are more commonly associated with the central core congenital myopathy or malignant hyperthermia as noted in a later section.
The major types of progressive muscular dystrophies, when advanced, usually affect the anterior neck muscles severely. Syringomyelia, spinal accessory neuropathy, some form of meningoradiculitis, and loss of anterior horn cells in conjunction with systemic lymphoma or carcinoma may differentially paralyze the various neck muscles.
Usually the diaphragm, chest, and trunk muscles are affected in association with shoulder and proximal limb muscles, but occasionally, isolated weakness of the respiratory muscles is the initial or the dominant manifestation of a muscle disease. Dyspnea and diminished vital capacity first bring the patient to the pulmonary clinic. The main causes are motor neuron disease, myasthenia gravis and less often because of their rarity, glycogen storage disease (acid maltase deficiency—Pompe disease), mitochondrial myopathies, and nemaline myopathy. Polymyositis may cause respiratory weakness, but pulmonary difficulty is more often the result of interstitial lung disease. Unilateral paralysis of the diaphragm may result from compression of the phrenic nerve in the thorax by tumor or aortic aneurysm; an idiopathic or postinfectious variety may be related to brachial plexitis (see Chap. 46). The diaphragm and accessory muscles may be severely affected in some types of muscular dystrophies, but usually in association with pelvocrural and shoulder muscle weakness. Nocturnal dyspnea, sleep apnea, and respiratory arrest may occur, particularly in myasthenics and in patients with glycogen storage myopathies, and respiratory failure may threaten life in severe myasthenia gravis, Guillain-Barré syndrome, and poliomyelitis.
As a general observation, in the acute neuromuscular paralyses, the cervical and shoulder muscles and the diaphragm, all of which share a common innervation, show a similar degree of weakness. Asking the patient to count aloud on 1 maximal breath can help detect diaphragmatic weakness (counting to 20 equates with a vital capacity of approximately 2 L). Paradoxical inward movement of the abdomen with inspiration is another sign of diaphragm weakness. Disorders of breathing and ventilation are discussed in Chaps. 26 and 46 in relation to its most dramatic presentation in the Guillain-Barré syndrome.
Weakness, atrophy, and fasciculations of the hands, arms, and shoulders characterize the common form of motor neuron disease, ALS. Primary diseases of muscle hardly ever weaken these parts disproportionately. A diffuse weakness of both arms and the shoulder muscles may occur in the early stages of Guillain-Barré syndrome, paraneoplastic neuropathy, and amyloid polyneuropathy, in special forms of immunoglobulin (Ig) M-related paraproteinemic, or in inflammatory polyneuropathy (e.g., brachial neuritis) and porphyric polyneuropathy. A lesion affecting the central portion of the spinal cord in the cervical region produces this same pattern, but in that case there is an associated loss of pain and thermal sensation in the upper limbs and shoulders, signs that exclude disease of muscle.
Proximal Limb-Girdle Palsies Presenting as Inability to Raise the Arms or to Arise From a Squatting, Kneeling, or Sitting Position
This is the common pattern of a number of myopathies. Polymyositis, IBM, dermatomyositis, and the muscular dystrophies most often manifest themselves in this fashion. The endocrine and the acquired metabolic myopathies (e.g., Cushing disease, hyperthyroidism, and steroid or statin administration) are other typical causes. Proximal limb weakness is a feature of myasthenia but almost always after the development of ocular or pharyngeal involvement. The childhood Duchenne, Becker, and limb-girdle types of dystrophies tend first to affect the muscles of the pelvic girdle, gluteal region, and thighs, resulting in a lumbar lordosis and protuberant abdomen, a waddling gait, and difficulty in arising from the floor and climbing stairs without the assistance of the arms. Climbing up by placing the hands on the thighs (Gower sign) is particularly characteristic of the dystrophies. Facioscapulohumeral dystrophy affects the muscles of the face and shoulder girdles foremost, and it is manifest by incomplete eye closure, inability to whistle and to raise the arms above the head, winging of the scapulae, and thinness of the upper arms with preserved forearm bulk (“Popeye” effect). Certain early or mild forms of dystrophy may selectively involve only the peroneal and scapular muscles. In milder forms of polymyositis, weakness may be limited to the neck muscles or to the shoulder or pelvic girdles.
A number of other diseases of muscle may express themselves by a disproportionate weakness of girdle and proximal limb musculature. An intrinsic metabolic myopathy, such as the adult form of acid maltase deficiency and the familial types of periodic paralysis, may affect only this region. The congenital myopathies (central core, nemaline, myotubular) cause a relatively nonprogressive weakness of girdle muscles more than distal ones. Proximal muscles are occasionally implicated in spinal muscular atrophy or late onset type and in Kennedy bulbospinal atrophy.
Bicrural Palsy Presenting as Lower Leg Weakness With Inability to Walk on the Heels and Toes, or as Paralysis of All Leg Muscles
With the exception of certain distinctive distal types of muscular dystrophies, this pattern, usually due to weakness of peroneal, anterior tibial, and thigh muscles, is usually not a result of myopathy. Symmetrical weakness of the lower legs is more often caused by polyneuropathy. In cases of total leg and thigh weakness, one first considers a spinal cord disease. Motor neuron disease may begin in the legs, asymmetrically and distally as a rule, and affect them disproportionately to other parts of the body. Thus the differential diagnosis of distal or generalized leg weakness involves more diseases than are involved in the restricted paralyses of other parts of the body.
Isolated quadriceps femoris weakness may be the expression of several diseases. In adults, the most common cause is IBM (where it may be unilateral or asymmetrical) or, a restricted form of Becker muscular dystrophy. In thyrotoxic and steroid myopathies, the major effects are on the quadriceps muscles. If unilateral or bilateral with loss of patellar reflex and sensation over the inner leg, this condition is most often the result of a femoral neuropathy, as occurs from diabetes, or of an upper lumbosacral plexus lesion. Injuries to the hip and knee cause rapid disuse atrophy of the quadriceps muscles. A painful condition of infarction of the muscle on 1 side is seen in diabetic patients.
Distal Bilateral Limb Palsies Presenting as Foot-Drop with Steppage Gait (With or Without Pes Cavus), Weakness of All Lower Leg Muscles, and Later Wrist-Drop and Weakness of Hands
The principal cause of this syndrome is a familial polyneuropathy, mainly of the Charcot-Marie-Tooth type (see Chap. 46); the course is over decades. Chronic nonfamilial polyneuropathies, particularly paraproteinemic and inflammatory ones with motor conduction block and exceptionally, some forms of familial progressive muscular atrophy and distal types of progressive muscular dystrophy, and sarcoid myopathy may also present in this way. In myotonic dystrophy, there may be weakness of the leg muscles as well as the forearms, sternocleidomastoids, face, and eyes. With these exceptions, the generalization that girdle weakness without sensory changes is indicative of myopathy and that distal weakness is indicative of neuropathy is clinically useful.
Generalized or Universal Paralysis: Limb (but Usually Not Cranial) Muscles, Involved Either in Attacks or as a Chronic Persistent, Progressive Deterioration
When acute in onset and episodic, this syndrome is usually a manifestation of familial or acquired hypokalemic or hyperkalemic periodic paralysis. One variety of the hypokalemic type is associated with hyperthyroidism, another with hyperaldosteronism. Attacks of porphyric neuropathy and of Refsum disease with generalized weakness have an episodic nature. Widespread paresis (rather than paralysis) that has an acute onset and lasts many weeks is at times a feature of a severe form of idiopathic or parasitic (trichinosis) polymyositis and, rarely, of the toxic effects of certain pharmaceutical agents, particularly those used to treat hypercholesterolemia. Idiopathic polymyositis and, rarely, IBM may involve all limb and trunk muscles, but usually spare the facial and ocular muscles, whereas the weakness in trichinosis is mainly in the ocular and lingual muscles. In infants and young children, a chronic and persistent generalized weakness of all muscles, except those of the eyes, always raises the question of Werdnig-Hoffman spinal muscular atrophy or, if milder in degree and relatively nonprogressive, of one of the congenital myopathies or polyneuropathies. In these diseases of infancy, paucity of movement, hypotonia, and retardation of motor development may be more obvious than weakness, and there is arthrogryposis at birth.
This is usually neuropathic, less often spinal or myopathic. Muscle disease does not need to be considered except in certain instances of pressure-ischemic necrosis of muscle as a result of local pressure or infarction, as in monoplegic alcoholic myopathy or in diabetic muscle infarction. The weakness of IBM has a preference for certain sites, specifically parts of the quadriceps, or of the forearm muscles, particularly the long finger flexors (flexor digitorum profundus), and also therefore enters into consideration.
From this exposition of the topographic aspects of weakness, one can appreciate that each neuromuscular disease exhibits a predilection for particular groups of muscles. Apart from these patterns that suggest certain possibilities of disease and exclude others, diagnosis depends on the age of the patient at the time of onset and tempo of progression, the coexistence of medical disorders, certain laboratory findings (serum concentrations of muscle enzymes, EMG, and biopsy findings), and genetic determinants.
The symptoms and signs of muscle disease are considered in this chapter mainly in connection with the age of the patient at the time of onset, their mode of evolution, and the presence or absence of familial occurrence. Because many muscle diseases are hereditary, a careful family history is important. The pattern of inheritance has diagnostic significance and, if genetic counseling or prenatal diagnosis is a consideration, a detailed genealogic tree becomes essential. When historical data are insufficient, it is often necessary to examine siblings and parents of the proband. The molecular genetics and other genetic aspects of the heritable muscle diseases, subjects of intense interest in recent years, are discussed at appropriate points in the chapter.
In summary, the clinical recognition of myopathic diseases is facilitated by a prior knowledge of a few topographic syndromes, the age of the patient at the onset of the illness, a familial occurrence of the same or similar illnesses, and of the medical setting in which weakness evolves. Diagnostic accuracy is aided by the intelligent use of the laboratory examinations discussed in Chap. 45, particularly the muscle enzymes, EMG, and muscle biopsy.
The Infectious Myopathies
The discovery that striated skeletal muscle and that cardiac muscle could be the sole targets of a number of infectious agents came about during the era of the development of microbiology and occupied the attention of many prominent clinicians, including Osler. As these diseases were being characterized, however, a number of other inflammatory states affecting muscle were found for which there was no infectious cause. Later, an autoimmune mechanism was postulated, but even today this is not securely established. This group of idiopathic inflammatory myopathies figures so prominently in clinical myology that we devote a separate section to the subject. First, the infections of muscle are described.
Included here are trichinosis, toxoplasmosis, parasitic and fungal infections, and a number of viral infections. The related but unclassifiable entity of sarcoid myopathy is addressed in a later section of this chapter.
This parasitic disease is caused by the nematode Trichinella spiralis. Its general features are discussed in Chap. 32. Regarding the myopathic aspect of the illness, the authors have been most impressed with the ocular muscle weakness, which results in strabismus and diplopia; with weakness of the tongue, resulting in dysarthria; and with weakness of the masseter and pharyngeal muscles, which interferes with chewing and swallowing. Any weakness of limb muscles is usually mild and more severe proximally than distally. However, the diaphragm may be involved, as well as the myocardium. The affected muscles are slightly swollen and tender in the acute stage of the disease. Often, there is conjunctival, orbital, and facial edema, sometimes accompanied by subconjunctival and subungual splinter hemorrhages. As the trichinae become encysted over a period of a few weeks, the symptoms subside and recovery is complete. Many, perhaps the majority, of infected patients are asymptomatic throughout the invasive period, and as much as 1 to 3 percent of the population in certain regions of the country will be found at autopsy to have calcified trichinella cysts in their muscles with no history of parasitic illness. Heavy infestations have been known to end fatally, usually from cardiac and diaphragmatic involvement. In these more massive infections, the brain also may be involved, probably by emboli that arise in the heart from an associated myocarditis.
Clinically, one should suspect the disease in a patient who presents with a puffy face and tender muscles. Eosinophilia is practically always present in the peripheral blood (>700 cells/mm3), although the sedimentation rate is often normal. The CK level is moderately elevated. A skin test using Trichinella antigen is available, but it is unreliable. The enzyme-linked immunosorbent assay (ELISA) blood test is more accurate, but it becomes positive only after 1 or 2 weeks of illness. Biopsy of almost any muscle (usually the deltoid or gastrocnemius), regardless of whether it is painful or tender, is probably the most reliable confirmatory test. More than 500 mg of muscle may be required to demonstrate larvae, but smaller specimens will almost invariably show an inflammatory myopathy. Muscle fibers undergo segmental necrosis, and the interstitial inflammatory infiltrates contain a predominance of eosinophils. This accounts for the edema, pain, and tenderness of heavily infested muscles. The capsules of the larvae gradually thicken in the first month of the infection and then calcify. The EMG may exhibit profuse fibrillation potentials, a phenomenon attributed on theoretical grounds to the disconnection of segments of muscle fibers from their motor endplates (Gross and Ochoa).
No treatment is required in most cases. In patients with severe weakness and pain, a combination of thiabendazole, 25 to 50 mg/kg daily in divided doses for 5 to 10 days, and prednisone, 40 to 60 mg/d, is recommended. Albendazole, in a single oral dose of 400 mg daily, is equally effective but is not available in the United States except by special request (from Smith Kline Beecham). Recovery, as mentioned, is complete as a rule, except in rare patients with cerebral infarcts. Other aspects of this parasitic infestation are discussed in Chap. 32.
This is an acute or subacute systemic infection caused by the encephalitozoon Toxoplasma gondii. Most Toxoplasma infections in immunocompetent patients, which occur in up to 10 to 30 percent of the population, are asymptomatic, but there may be fever and varying degrees of involvement of the skin, lymph nodes, retina, myocardium, liver, brain, and muscle. In one such case studied by our colleagues, Toxoplasma organisms and pseudocysts were detected in skeletal muscle (Kass et al); wherever a parasitic pseudocyst had ruptured, there was focal inflammation. Some muscle fibers had undergone segmental necrosis, but this was not prominent (one contained the organism), accounting for the relative paucity of muscle symptoms. With the emergence of AIDS, many more toxoplasmic infections of the brain, but also including those of skeletal muscle, were seen (Gherardi et al). However, physicians who see many cases of AIDS have indicated to us that a primary AIDS myopathy and treatment-related muscle diseases are more common (see later). Again, in this population, brain infestation with Toxoplasma is many times more common than is myositis. The subject of AIDS and toxoplasmic infection is discussed in greater detail in Chap. 32.
The myopathy, which occurs with variable fever, lymphopenia, and failure of other organs, consists of weakness, wasting, myalgia, and elevated CK levels. Presumably, the immunocompromised patient is unable to respond to protozoan infections, allowing latent infections to be reactivated. Sulfadiazine in combination with pyrimethamine or trisulfapyrimidine, which act synergistically against the toxoplasmic trophozoites, improves the muscle symptoms and reduces serum CK. Folic acid is given in addition.
Echinococcosis, cysticercosis, trypanosomiasis (Chagas disease), sparganosis, toxocariasis, and actinomycosis have all been known to affect skeletal muscle on occasion, but the major symptoms relate more to involvement of other organs. Only cysticercosis may first claim the attention of the clinical myologist because of a dramatic pseudohypertrophy of thigh and calf muscles. Hydatids infest the paravertebral and lumbar girdle muscles in 5 percent of cases and may lead to their enlargement. Coenurosis and sparganosis are causes of movable lumps in the rectus abdominis, thigh, calf, and pectoralis muscles. Protozoan infections of muscle—microsporidiosis, African and American trypanosomiasis—which occurred only rarely until a decade ago, are now being observed in immunodeficient (HIV-infected) individuals in endemic areas. The reader who seeks more details may refer to the chapter on parasitic myositis by Banker (2004).
HIV and human T-lymphotropic (or leukemia) virus type I (HTLV-I) are increasingly common causes of viral myositis (Engel and Emslie-Smith). Moreover, as discussed further on, zidovudine (ZVD), a drug included in many regimens to treat HIV infections, may itself induce a myopathy with myalgia and weakness that is, at times, indistinguishable from HIV myopathy (Dalakas et al).
An inflammatory, and presumed infectious, myopathy may develop early in the course of HIV infection but is rarely the initial manifestation. The pattern is like that of idiopathic polymyositis with painless weakness of the girdle and proximal limb muscles. Reflexes are diminished in most cases, but this is difficult to interpret in view of the high incidence of concomitant polyneuropathy. Serum CK is elevated, and the EMG shows an active myopathy with fibrillations, brief polyphasic motor units, and complex repetitive discharges.
The myopathologic changes in AIDS are also like those of idiopathic polymyositis described further on. Additionally, in some cases electron microscopy discloses the presence of nemaline (rod) bodies within type 1 fibers, similar to those observed in the congenital form of nemaline myopathy discussed further on. As implied earlier, the pathogenesis of the AIDS myopathy has not been firmly established as there is scant evidence of a direct viral infection of the muscle fibers. An immune basis has been suggested in view of a response to corticosteroids, plasma exchange, and gamma globulin, comparable to the beneficial effects in the idiopathic variety of polymyositis. Corticosteroids in doses similar to those used in the treatment of idiopathic polymyositis are effective in ameliorating the weakness, but they entail special risks in immunocompromised patients.
The clinical features of putative ZVD-induced myopathy are much the same as those of HIV myopathy except that moderate pain is said to be characteristic of the drug-induced variety. The myopathy has been attributed to the mitochondrial toxicity of the drug, which may account for the presence of “ragged red” fibers in biopsy specimens. The onset of symptoms appears to be related to the sustained administration of high doses of the drug (1,200 mg daily for a year or longer). Cessation or reduction in dosage of the drug diminishes the muscular discomfort within weeks, but strength recovers more slowly.
A myopathy caused by HTLV-I infection also simulates polymyositis in its clinical and histologic features. The illness occurs most often in endemic areas but is less common than the myelopathy that is associated with the virus.
Distinguished from the HIV- and ZVD-related inflammatory myopathies is the severe generalized muscle wasting that characterizes advanced, cachectic AIDS. Muscle enzymes are normal and strength is affected little, especially considering the loss of muscle bulk. Histologically, there is atrophy of type 2 fibers. The pathogenesis of this cachectic syndrome is uncertain; it has been attributed to a multiplicity of systemic factors, including circulating catabolic cytokines, just as in other wasting syndromes such as cancer.
In most patients with pleurodynia (epidemic myalgia, Bornholm disease), muscle biopsies disclose no abnormalities and there is no clear explanation of the pain. However, group B Coxsackie virus has been isolated from striated muscle of a few patients with this disorder. A necrotizing myositis has been suspected in a number of patients with influenza; under the electron microscope, some muscle fibers contain structures with the features of influenza virions. Malaise, myalgia, and slight weakness and stiffness were the clinical manifestations. Because of the myalgia, it is difficult to know how much of the weakness is only apparent. Recovery has been complete within a few weeks. In 1 patient with generalized myalgia and myoglobinuria, the influenza virus was isolated from muscle (Gamboa et al). These observations suggest that the intense muscle pain in certain viral illnesses might be the result of a direct viral infection of muscle. However, there are many cases of influenzal myalgia, mainly of the calves and thighs, such as those reported by Lundberg and by Antony and coworkers, in which it was not possible to establish that there was a muscular disorder at all. In the condition described as epidemic neuromyasthenia (benign myalgic encephalomyelitis, Icelandic disease), in which influenza-like symptoms were combined with severe pain and weakness of muscles, a viral cause was postulated, but an organism was never isolated. The illness has been absorbed into the large and indistinct category of chronic fatigue syndrome (discussed in Chap. 24).
Despite these ambiguities, viral myositis is an established entity in myopathology. Echo 9, adenovirus 21, herpes simplex, Epstein-Barr virus, coxsackievirus, and Mycoplasma pneumoniae have all been cited by Mastaglia and Ojeda and by others as causes of sporadic myositis with rhabdomyolysis. In these infections the nonmyopathic aspects of the disease usually predominate; in some of them, the evidence of invasion of muscle has not been fully substantiated, as in many instances a nonspecific (Zenker-type) degeneration could have explained the muscle findings. The existence of a postinfectious type of polymyositis is also unsettled.
Immune-Inflammatory Myopathies (Polymyositis, Dermatomyositis, Inclusion Body Myositis, Necrotizing Myopathy)
These are common diseases that affect primarily the striated muscle and skin and sometimes connective tissues. The term used to describe the disease reflects the tissues involved. If the inflammatory changes are restricted clinically to the striated muscles, the disease is called polymyositis (PM); if, in addition, the skin is involved, it is called dermatomyositis (DM), although the two diseases are now understood to be immunopathologically distinct. Either may be associated with a connective tissue disorder, in which case the designation is PM or DM with rheumatoid arthritis, rheumatic fever, lupus erythematosus, scleroderma, Sjögren syndrome, or mixed connective tissue disease, as the case may be. There is also an important but inconsistent relationship of these myositides and systemic carcinoma, as discussed further on.
Both diseases have been known since the nineteenth century. Polymyositis was first described by Wagner in 1863 and 1887, and DM was established as an entity by Unverricht in a series of articles written from 1887 to 1891. A modern classification introduced in the monograph of Walton and Adams included categories associated with neoplasia and with connective tissue diseases. References to the original articles and a survey of the literature since that time can be found in the monograph of Kakulas and Adams and in the chapters on the PM and DM syndromes by Engel and colleagues.
It is emphasized further on that there is disagreement regarding the frequency of PM as an independent entity. Amato and Griggs have expressed the opinion that many cases so classified are a result of DM, an immune necrotizing myopathy commented on below, or IBM, or are related to an underlying connective tissue disease. Even other cases are examples of muscular dystrophy with secondary inflammatory changes. The main point of controversy has been the proposal they favor, that isolated PM is rare and overdiagnosed (see van der Muelen et al).
Inflammatory myopathy coexists with numerous systemic diseases as discussed, and some authors consider it to be a syndrome rather than a disease. The current authors continue to see a few well-studied and convincingly documented cases of “classic” PM that are unassociated with other disease.
Recently added to the traditional group of inflammatory myopathies is an increasingly recognized immune-mediated necrotizing myopathy (IMNM); instances of myopathy that were previously classified as either dermato- or polymyositis are now recognized as being the result of antibodies to anti-signal recognition particle (SRP), and some cases of necrotizing myopathy that are due to statins are similarly caused by antibodies directed at HMGCoA reductase, and not a direct toxic effect of the medication. This process emphasizes that clinicians should conduct a careful evaluation before concluding that a patient has idiopathic polymyositis.
This is an idiopathic subacute or chronic and symmetrical weakness of proximal limb and trunk muscles without dermatitis. The onset is usually insidious and the course progressive over a period of several weeks or months. It may develop at almost any age and in either sex; however, the majority of patients are 30 to 60 years of age, and a smaller group shows a peak incidence at 15 years of age; women predominate in all age groups. A febrile illness or benign infection may precede the weakness, but in most patients the first symptoms develop in the absence of these or other apparent initiating events.
The usual mode of onset is with mainly painless weakness of the proximal limb muscles, especially of the hips and thighs and to a lesser extent the shoulder girdle and neck muscles. Often, the patient cannot easily determine the time of onset of weakness. Certain actions—such as arising from a deep or low chair or from a squatting or kneeling position, climbing or descending stairs, walking, putting an object on a high shelf, or combing the hair—become increasingly difficult. Pain of an aching variety in the buttocks, calves, or shoulders is experienced by approximately 15 percent of patients, and it may indicate a combination of PM and rheumatoid arthritis, tendonitis, or other connective tissue disorder.
When the patient is first seen, many of the muscles of the trunk, shoulders, hips, upper arms, and thighs are usually involved. The posterior and anterior neck muscles (the head may loll) and the pharyngeal, striated esophageal, and laryngeal muscles (dysphagia and dysphonia) may be involved as well. In restricted forms of the disease, only the neck or paraspinal muscles (camptocormia) may be implicated. Ocular muscles are not affected in PM, but there are rare instances of combined PM and myasthenia gravis. The facial, tongue, and jaw muscles are only occasionally affected, and the distal muscles, namely the forearm, hand, leg, and foot are spared in 75 percent of cases. The respiratory muscles are weakened to a minor degree and in only an exceptional case is there dyspnea, the cause of which is revealed only by an intercostal muscle biopsy (Thomas and Lancaster). Occasionally, the early symptoms predominate in one proximal limb before becoming generalized. As emphasized further on, onset after age 50 years, normal CK, or aberrant patterns of weakness, such as early wrist or finger flexor, quadriceps, or ankle dorsiflexor involvement, are indicative of IBM.
The muscles are usually not tender, and atrophy and reduction in tendon reflexes, although sometimes present, are far less pronounced than they are in patients with chronic denervation atrophy, IBM, or Lambert-Eaton myasthenic syndrome (the last of these is discussed in Chap. 49). As the weeks and months pass, the weakness and muscle atrophy progress unless treatment is initiated. Without physical therapy, fibrous contracture of muscles eventually develops. Some elderly individuals with a particularly chronic form of the disease may present with severe atrophy and fibrosis of muscles; the response to treatment in such cases is poor.
In both PM and DM, there may be involvement of organs other than muscle. In a surprising number of our cases of PM (and DM), cardiac abnormalities have been observed and in a small proportion of these, sudden death has occurred. The cardiac manifestations have taken the form of relatively minor electrocardiographic (ECG) changes, but several patients have had arrhythmias with clinical consequences. Among the fatal cases, about half have shown necrosis of myocardial fibers at autopsy, usually with only modest inflammatory changes. Interstitial lung disease is another known association in a few cases; its frequency ranges from 5 to 47 percent in different series (see further on under “Laboratory Diagnosis of PM and DM”), but the lower figure is probably correct. Exceptionally, there is a low-grade fever, especially if joint pain coexists.
The presentation of muscle weakness is similar to that of polymyositis, but the denominative feature is a rash. Most often, the skin changes precede the muscle syndrome and take the form of a localized or diffuse erythema, maculopapular eruption, scaling eczematoid dermatitis, or exfoliative dermatitis. Sometimes, skin and muscle changes evolve together over a period of 3 weeks or less. A characteristic form of the skin lesions are patches of a scaly roughness over the extensor surfaces of joints (elbows, knuckles, and knees) with varying degrees of pink-purple coloration. Red, raised papules may be present over exposed surfaces such as the elbows, knuckles, and distal and proximal interphalangeal joints (Gottron papules); these are particularly prominent in DM of childhood. Also typical is a lilac-colored (heliotrope) change in the skin over the eyelids, on the bridge of the nose, on the cheeks, and over the forehead; it may have a scaly component. Itching may be a troublesome symptom in regions of the other skin eruptions. A predominance of rash over the neck and upper shoulders has been termed the V sign, while rash over the shoulders and upper arms, the shawl sign. This distribution suggests that the skin changes reflect heightened photosensitivity (a feature shared with pellagra). Periorbital and perioral edema are additional findings but mainly in fulminant cases. Skin changes may be transient and in some instances are restricted to 1 or more patches of dermatitis; they are difficult to appreciate in dark-skinned individuals. Evanescent and restricted skin manifestations are emphasized because they are frequently overlooked and provide clues to diagnosis. In the healing stage, the skin lesions leave whitened atrophic scars with a flat, scaly base.
In contrast to PM, DM affects children and adults about equally. Among adults, DM is more frequent in females whereas in childhood, males and females are affected equally.
Other physical signs include periarticular and subcutaneous calcifications that are common in the childhood form. Signs of associated connective tissue disease are more frequent than in pure PM (see further on). The Raynaud phenomenon has been reported in nearly one-third of the patients and a similar number have dilated or thrombosed nail fold capillaries. Whether this signifies the presence of a systemic autoimmune tissue disease has not been clarified. Others subsequently develop a mild form of scleroderma, and an associated esophageal weakness is demonstrated by fluoroscopy in up to 30 percent of all patients. The superior constrictors of the pharynx may be involved, but cinefluoroscopy may be necessary to demonstrate the abnormality.
At one time this was a controversial subject and in some respects it remains so because of widely varying incidences of concurrence between systemic malignancy with PM and DM (see Engel et al and Buchbinder and Hill). In the large series reported by Sigurgeirsson and colleagues, 9 percent of 396 patients with PM were found to have carcinoma, either at the time of diagnosis of the muscle disease or within 5 years. DeVere and Bradley reported that 29 percent of their overall group of DM patients had an associated carcinoma; this figure rose to 40 percent if the patient was older than 40 years, and to 66 percent if the patient was both male and older than 40 years. This, however, is higher than reported in most other series. The relationship between myositis and malignancy is not understood; nonetheless, the connection appears valid, even if of uncertain frequency.
The neoplastic processes linked most often with myositis are lung and colon cancer in men and breast and ovarian cancer in women; however, tumors have been reported in nearly every organ of the body. In about half the cases, myositis antedates the clinical manifestations of the malignancy, sometimes by 1 to 2 years, a duration that then brings the association into question. The morbidity and mortality of patients with this combination is usually determined by the nature of the underlying tumor and its response to therapy. Occasionally, excision of the tumor is attended by remission of the myositis, but information on this point comes mostly from sporadic reports.
Idiopathic myositis occurs in children, but less frequently than in adults. Some cases tend to be relatively benign but otherwise do not differ from the syndrome in adults. More frequently, there is a distinctive illness, described by Banker and Victor, which differs in some respects from the usual adult form of the disease. In these children and adolescents, there is greater involvement of blood vessels in the connective tissue of multiple organs, as well as in skin and muscle. This childhood form of DM begins, as a rule, with typical skin changes accompanied by anorexia and fatigue. Erythematous discoloration of the upper eyelids (the previously noted heliotrope rash), frequently with facial edema, is another characteristic early sign. The erythema spreads to involve the periorbital regions, nose, malar areas, and upper lip as well as the skin over the knuckles, elbows, and knees. Cuticular overgrowth, subungual telangiectasia, and ulceration of the fingertips may be found. Capillary prominence in the nail beds and avascular regions in the cuticle are said to be characteristic but need to be sought with a magnifying lens or ophthalmoscope (these signs are also seen in the “CREST” [calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, telangiectasia] form of scleroderma).
Symptoms of weakness, stiffness, and pain in the muscles usually follow but may precede the skin manifestations. The weakness is generalized but always more severe in the muscles of the shoulders and hips and proximal portions of the limbs. A tiptoe gait, the result of fibrous contractures of flexors of the ankles, is a common late abnormality. Tendon reflexes are depressed or abolished, but only commensurate with the degree of muscle weakness. Intermittent low-grade fever, substernal and abdominal pain (like that of peptic ulcer), melena, and hematemesis from bowel infarction may occur, the result of an accompanying systemic vasculitis.
The mode of progression of DM of childhood, like that of the adult form, is variable. In fulminant cases, the weakness appears rapidly, involving all the muscles including those of chewing, swallowing, talking, and breathing and leading to total incapacitation. Perforation of the gastrointestinal tract from bowel infarction may be the immediate cause of death, as it has been in two of our patients. In others, there is slow progression or arrest of the disease and, in a small number, there is a remission of weakness. Flexion contractures at the elbows, hips, knees, and ankles and subcutaneous calcification and ulceration of the overlying skin, with extrusion of calcific debris are manifestations in the late, untreated stages of the disease.
In both PM and DM, the inflammatory changes are often not confined to muscle but are associated with systemic autoimmune diseases such as rheumatoid arthritis, scleroderma, lupus erythematosus, or combinations thereof (mixed connective tissue disease); the same muscle changes are associated less often with the Sjögren syndrome. Conversely, in the aforementioned immune diseases, inflammatory muscle changes are frequently found but in only a limited number of muscles and often asymptomatically. The incidence of these “crossover” or overlap cases cannot be stated with certainty. A true necrotizing–inflammatory myopathy has been reported in up to 8 percent of cases of lupus erythematosus (far higher than in our experience), and an even smaller proportion of cases of systemic sclerosis, rheumatoid arthritis, and Sjögren syndrome. The treatment of rheumatoid arthritis with d-penicillamine increases the incidence of, or perhaps independently precipitates, a myositis.
Also notable is the sporadic concurrence of myositis with other autoimmune diseases such as myasthenia gravis and Hashimoto thyroiditis and less often, with a monoclonal paraprotein in the blood; it is not clear whether these are coincidental, but it is likely that they reflect an underlying genetic propensity to autoimmune disease.
In the overlap syndromes that incorporate autoimmune disease and myositis, there is usually greater muscular weakness and atrophy than can be accounted for by the muscle changes alone. Inasmuch as arthritis or periarticular inflammation may limit motion because of pain, result in disuse atrophy, and also at times cause a vasculitic polyneuropathy, the interpretation of diminished strength in these autoimmune diseases is not simple. Malaise, aches, and pains are common and attributable mostly to the systemic disease. Sometimes the diagnosis of myositis must depend on muscle biopsy, EMG findings, and measurements of muscle enzymes in the serum. In these complicated cases, myositis may accompany the connective tissue disease or occur many years later.
It is worth noting that PM may occur during pregnancy and that rarely the fetus is affected (most often the fetus and neonate are normal) with elevated CK levels for months postpartum (Messina et al).
In the majority of patients, serum levels of CK and other muscle enzymes, such as aldolase, are elevated. Serum CK levels tends to be higher in PM than in DM because of the widespread single-fiber necrosis in the former (as described in the following section on pathologic changes). However, in DM, if there are infarcts in muscle, CK levels will be moderately elevated as well. The sedimentation rate is normal or mildly elevated in both diseases.
It has been appreciated that some cases of PM and DM are associated with autoantibodies in the blood. Some of these are undoubtedly nonspecific markers of an autoimmune or inflammatory state, but others may be of pathogenetic significance or are markers for syndromes with multiorgan damage that extends beyond muscle. Tests for circulating rheumatoid factor or antinuclear antibody (ANA) are positive in fewer than half of cases. A high titer of ANA, in conjunction with elevated antiribonuclear antibodies, suggests the coexistence of systemic lupus or mixed connective tissue disease. It must be emphasized, however, that absent or low-titer ANA and a normal sedimentation rate do not exclude the diagnosis of PM, a fact that limits their diagnostic usefulness. Other antibodies can be found on occasion that are directed against constituents of a nucleolar protein complex (PM-Scl) and ribonucleoproteins (Ro/SS-A and La/SS-B).
Of greater interest are the findings that perhaps 20 percent of patients with PM and DM have antibodies against various cellular components of muscle, in particular, antibodies directed against cytoplasmic transfer ribonucleic acid (tRNA) synthetases (anti-Jo1), or against the tRNA itself. These are fairly specific to PM and, less frequently, to DM; they are found when the myositis is coupled with an expanded illness that involves other organs or connective tissues. The clinical disorders associated with these antibodies usually combine myositis with (1) interstitial lung disease but also (2) arthritis, (3) Raynaud syndrome, and (4) thickening of the skin of the hands (“mechanic’s hands”). Following from the designation of the main type of antibody, these have been termed synthetase syndromes. Furthermore, an unexpectedly high proportion of cases of PM and DM show myositis-specific antibodies that are directed against a cytoplasmic ribonucleoprotein complex (SRP), or against a protein complex that is a nuclear helicase (Mi-2). The former is found in approximately 10 percent of cases of PM, and of DM (and with inclusion body myopathy; see further on), and in some series has carried a heightened risk of cardiac muscle inflammatory involvement. Although these various autoantibodies, with the possible exception of anti-Jo1, have not been especially useful as primary diagnostic tools, they do have a role in refining diagnosis. For example, a positive Jo1 antibody, although too uncommon to use as a screening test, precludes the diagnosis of inclusion body myopathy (which has been associated with a different set of autoantibodies as discussed further on) and its presence raises concern about the later development of interstitial lung disease. The presence of these antibodies also underscores the role for the humoral immune system in the pathogenesis of PM and raises opportunities for investigation discussed as follows.
Myoglobinuria can be detected in the majority of patients with most forms of myositis, particularly a necrotizing form, provided that a sensitive immunoassay procedure is used, but this test is not routinely performed.
The EMG is quite helpful in diagnosis but has been normal in a small proportion of our patients, even when many muscles are sampled. A typical “myopathic pattern is disclosed,” that is, many abnormally brief action potentials of low voltage in addition to numerous fibrillation potentials, trains of positive sharp waves, occasional polyphasic units, and myotonic activity—all but the brief potentials possibly reflecting irritability of the muscle membranes (see Chap. 45). These findings are most apparent in weak muscles and are almost always seen when proximal weakness is well developed but they also may be observed in clinically unaffected areas. Indolent and chronic cases in which fibrosis of muscle and wasting have supervened may show polyphasic units that simulate denervation–reinnervation changes, juxtaposed with myopathic motor units. The EMG is also helpful in choosing a muscle for biopsy sampling but care must be taken not to obtain tissue from precisely the same site as a recent EMG needle insertion as a spurious histopathologic appearance of muscle damage may be obtained in this region (see the following text). Our approach has been to perform the needle EMG examination on one side of the body and biopsies on the other side.
As stated earlier, the ECG is abnormal in some cases and this finding may suggest the need for vigilance regarding cardiac symptoms and arrhythmias.
The results of magnetic resonance imaging (MRI) of muscle have been interesting and may aid the clinician in that abnormalities in T1, T2 and STIR signal intensity define regions of increased water content and inflammation and spectroscopic studies demonstrate regional deficits in energy production. Although MRI cannot at this time replace a biopsy for diagnosis, it can refine the distribution of lesions and aid in targeting the muscle biopsy, as well as provide a useful index of the efficacy of drug therapy. In some cases, MRI can distinguish IBM from either PM or metabolic muscle disease (see Lodi et al and also Dion et al).
Because of the scattered distribution of inflammatory lesions and destructive changes, only part (or none) of the complex of pathologic changes may be divulged in any single biopsy specimen. Because of this limitation, more than one site of biopsy or multiple samples through one incision is advisable.
The principal changes in idiopathic PM consist of widespread destruction of segments of muscle fibers with an inflammatory reaction, that is, phagocytosis of muscle fibers by mononuclear cells and infiltration with a varying number of lymphocytes and lesser numbers of other mononuclear and plasma cells. Evidence of regenerative activity of muscle, mainly in the form of proliferating sarcolemmal nuclei, basophilic (RNA-rich) sarcoplasm, and new myofibrils, is evident in damaged regions. Many of the residual muscle fibers are small, with increased numbers of sarcolemmal nuclei. Some of the small fibers are found in clusters, the result of splitting of regenerating fibers. Either the degeneration of muscle fibers or an infiltration of inflammatory cells may predominate in any given biopsy specimen, although both types of changes are in evidence at autopsy.
In a single section from a biopsy sample, there may be only necrosis and phagocytosis of individual muscle fibers without infiltrates of inflammatory cells, or the reverse may be observed. However, in serial sections, muscle necrosis is shown to be adjacent to inflammatory infiltrates. Repeated attacks of a necrotizing myositis exhaust the regenerative potential of the muscles so that fiber loss, fibrosis, and residual thin and large fibers in haphazard arrangement may eventually impart a dystrophic appearance. For all these reasons, the pathologic picture can be correctly interpreted only in relation to clinical and other laboratory data. Guidelines for the interpretation of the muscle biopsy reflecting these comments, a critical step in correct diagnosis of the inflammatory myopathies, are given in the review by Dalakas and Hohlfeld.
In DM, there are several other distinctive histopathologic changes. In contrast to the evident necrosis of single fibers of PM, DM is characterized by perifascicular muscle fiber atrophy (referring to changes at the periphery of a fascicle, for reasons noted below). Moreover, the inflammatory infiltrates in DM predominate in the perimysial connective tissue, whereas in PM they are scattered throughout the muscle and are most prominent in relation to the muscle fiber membrane and the endomysium. The muscle lesions in dermatomyositis of childhood are similar to those of the adult form, only greatly accentuated. In a biopsy sample, the diagnosis can be inferred from the perifascicular pattern of degeneration and atrophy of muscle fibers.
Even more distinctive of DM are microvascular changes in muscle. Endothelial alterations (tubular aggregates in the endothelial cytoplasm) and occlusion of vessels by fibrin thrombi may be appreciated, with associated zones of infarction. The same vascular changes underlie the lesions in the connective tissue of skin, subcutaneous tissue, and gastrointestinal tract when they are present. The perifascicular muscle fiber atrophy had in the past been attributed to an ischemic process set up by capillary occlusion, but recent evidence suggests otherwise (see Greenberg and Amato).
PM and DM are idiopathic. All attempts to isolate an infective agent have been unsuccessful. Several electron microscopists observed virus-like particles in muscle fibers, but a causative role has not been proved. A polymyositic illness has not been induced in animals by injections of affected muscle as it has in models of several other inflammatory neurologic conditions. Nevertheless, the notion that an autoimmune mechanism is operative in PM and DM is supported by the association of these disorders with a number of the more clearly established autoimmune diseases enumerated earlier in this chapter. Further evidence of an autoimmune nature is given by the presence of specific autoantibodies in nearly half of cases, as also described earlier.
Immunopathologic studies have partially substantiated an autoimmune mechanism and suggested that PM and DM can be distinguished from one another on the basis of their immunopathologic characteristics. In DM, immune complexes, IgG, IgM, complement (C3), and membrane-attack complexes are deposited in the walls of venules and arterioles, indicating that the immune response is directed primarily against intramuscular blood vessels (Whitaker and Engel; Kissel et al). Such a response is lacking in PM (and in IBM, discussed further on). Engel and Arahata have demonstrated a difference between the two disorders on the basis of the subsets and locations of lymphocytes that make up the intramuscular inflammatory aggregates. However, the deposition of these complexes may be a secondary event as our colleagues Greenberg and Amato propose. In PM, there are a large number of activated T cells, mainly of the CD8 class, whereas B cells are sparse. Moreover, T cells, accompanied by macrophages, enclose and invade nonnecrotic muscle fibers. In DM, very few fibers are affected in this manner, and the percentage of B cells at all sites is significantly higher than it is in PM. Engel and Arahata interpreted these differences as indicating that the effector response in DM is predominantly humoral, whereas in PM the response is composed of cytotoxic T cells, clones of which have been sensitized to a yet undefined antigen on the muscle fiber.
Most clinicians agree that corticosteroids (prednisone, 1 mg/kg, as a single daily dose orally, or intravenously) are a reasonable first line of therapy for both PM and DM. The response to treatment is monitored by careful testing of strength and measurement of CK (not by following the erythrocyte sedimentation rate [ESR]). In patients who respond, the serum CK decreases before the weakness subsides; with relapse, the serum CK rises before weakness returns. Once the CK level normalizes and strength improves, typically several weeks or longer, the dosage may be reduced gradually—by no more than 5 mg every 2 weeks—toward 20 mg daily. It is then appropriate to attempt to control the disease with an alternate-day schedule with double this amount (i.e., prednisone, 40 mg every other day) so as to reduce the side effects of the drug. After cautious reduction of prednisone over a period of 6 months to 1 year or longer, the patient can usually be maintained on doses of 7.5 to 20 mg daily, with the aim of eventual discontinuation of the drug. Corticosteroids should not be discontinued prematurely, for the relapse that may follow is often more difficult to treat than the original illness.
In acute and particularly severe cases, treatment may be facilitated by the use initially of high-dose methylprednisolone (1 g infused over 2 h each day for 3 to 5 days). This form of treatment should be regarded as a temporary measure until oral prednisone becomes effective.
Alternatively, or sometimes in tandem with this approach, intravenous immunoglobulin (IVIg) or plasma exchanges may be instituted. In patients with DM who respond poorly to corticosteroids and other immunosuppressants or are severely affected early on, the addition of IVIg infusions often proves helpful, although several courses of treatment at monthly intervals may be required to achieve sustained improvement. In several controlled studies of small numbers of patients with DM, practically all showed improvement in muscle strength and in skin changes, and a reduction in CK concentration (see Dalakas; Mastaglia et al). PM has also been reported to respond favorably to treatment with IVIg, but the evidence is less certain. Further controlled studies are required to corroborate these reports and to establish, in both PM and DM, the optimal doses and modes of administration. It is noteworthy from our experience that IVIg has seldom been effective in PM or DM when used alone or as initial therapy. The proper use of these treatments in crossover cases with connective tissue disease has not been established.
Some patients who cannot tolerate, or are refractory to, prednisone may respond favorably to oral azathioprine with care being taken to avoid severe leukopenia. Methotrexate is currently favored by many groups over azathioprine as an adjunct to steroids (5 to 10 mg/week in 3 divided oral doses, increased by 2.5 mg/week, to a total dose of 20 mg weekly). Methotrexate or azathioprine should generally be given along with the lowest effective doses (15 to 25 mg) of prednisone. Although 1 study failed to show efficacy (Oddis et al), in cases that have been refractory to corticosteroids and methotrexate, we and our colleagues have had success rituximab intravenously, 750 mg/m2, repeated in 2 weeks and sometimes required every 6 to 18 months. Some clinicians favor, from the beginning, a combination of prednisone in low dosage and one of these immunosuppressant drugs, and this approach is generally necessary when myocarditis or interstitial pneumonitis is coupled with DM. Mycophenolate mofetil has also been introduced and has allowed a reduction in steroid dose within several months in both PM and DM, according to a number of anecdotal reports, but has not proven clearly effective in a randomized trial; the reasons for this failure are being actively discussed and we have not abandoned its use. Cyclosporine has also been used in recalcitrant cases; it has few advantages over other immunosuppressant drugs and has a number of potentially serious side effects, including nephrotoxicity. Cyclophosphamide, which is a useful drug in the treatment of Wegener granulomatosis, polyarteritis, and other vasculitides, is said to be of lesser value in PM, but it may be useful in refractory cases and has perhaps the highest toxicity of the immunosuppressive medications that are used for inflammatory myopathies; we no longer use it with any regularity.
Except for patients with malignancy, the prognosis in adult PM and DM is generally favorable. Only a small proportion of patients with PM succumb to the disease and then usually from a secondary pulmonary complication or from myocarditis as already mentioned. Several of our patients have had severe aspiration pneumonias as a result of their dysphagia. The period of activity of disease varies considerably but is typically 2 to 3 years in both the child and adult. As indicated earlier, the majority improves with corticosteroid therapy, but many are left with varying degrees of weakness of the shoulders and hips. Approximately 20 percent of our patients have recovered completely after steroid therapy and long-term remissions have been achieved after withdrawal of medication in about an equal number. The extent of recovery is roughly proportional to the acuteness and severity of the disease and the duration of symptoms prior to institution of therapy. Patients with acute or subacute PM in whom treatment is begun soon after the onset of symptoms have the best prognosis. In the series collected by DeVere and Bradley, in which patients were treated early, there was remission in more than 50 percent of cases, whereas Riddoch and Morgan-Hughes reported a far lower rate in patients who were treated more than 2 years after onset of the disease. Those patients who have come to our attention after a long period of proximal weakness and with substantial muscle atrophy have not recovered completely, although some improvement occurred over years.
Even in patients who have a coexistent malignancy, muscle weakness may lessen and serum enzyme levels decline in response to corticosteroid therapy, but weakness returns after a few months and may then be resistant to further treatment. As already stated, if the tumor is successfully removed, muscle symptoms may remit, but even this experience has not been uniform.
The overall mortality after several years of illness had in the past approximated 15 percent, being higher in childhood DM, in PM with connective tissue diseases, and, of course, when a malignancy is found. Recent figures give more optimistic results.
Inclusion body myositis (IBM) is the third major form of inflammatory myopathy and, depending on the care taken with histologic diagnosis, is the most common inflammatory myopathy in patients older than 50 years. Its defining features, intracytoplasmic and intranuclear inclusions, were first described in 1965 by Adams and colleagues, who also drew attention to a number of clinical attributes now considered characteristic. By 1994, only 240 sporadic cases had been recorded in the medical literature (Mikol and Engel), but the diagnosis is now made so frequently that this low number almost certainly reflects the misidentification of IBM as PM in the past. Garlepp and Mastaglia concluded that more than one-third of cases of inflammatory myopathy, especially in men, are IBM. Moreover, the majority of myopathies in patients over 50 years, not attributable to medication toxicity, are due to IBM. A set of clinical and pathologic diagnostic criteria for the disease have been proposed by Griggs and coworkers and are useful for research purposes. A source of confusion has been the entirely separate entity of inclusion body myopathy, a largely hereditary, pauci-inflammatory process, and displays a different pattern of weakness from IBM. The myositis, as alluded to earlier, predominates in males (in a ratio of 3:1) and has its onset in middle or late adult life. Diabetes, any one of a variety of autoimmune diseases, and a relatively mild polyneuropathy are associated in approximately 20 percent of sporadic cases of IBM, but associations with malignancy or systemic autoimmune disease have not been established.
The illness is more variable but generally more focal in presentation than is PM and DM. It is characterized by a steadily progressive, painless muscular weakness and modest atrophy, which is usually distal in the arms and both proximal and distal in the legs. In approximately 20 percent of cases, the disease begins with focal weakness of the quadriceps, finger or wrist flexors, or lower leg muscles on one or both sides, and gradually spreads to other muscle groups after many months or years. Selective weakness of the flexor pollicis longus is a particularly characteristic pattern of involvement, and isolated quadriceps weakness or neck extensor weakness should also bring the diagnosis to mind, although IBM is not the exclusive cause of these patterns. In most patients, the deltoids are spared and the thumb flexors are weak, the opposite pattern to PM and DM. The tendon reflexes are normal initially but diminish in about half the patients, especially the knee jerks, as the disease progresses. Interestingly, the knee jerks may be depressed or lost even without much in the way of quadriceps weakness; this is not the case in PM, in which the reflexes are spared until the muscle is extremely weak. These clinical features are well displayed in the series reported by Amato and colleagues. Dysphagia is common (Wintzen et al). Selective or asymmetric involvement of distal muscles, when it occurs, erroneously suggests the diagnosis of motor neuron disease (the reflexes are not, however, enhanced as they are in ALS).
The CK is normal or slightly elevated, generally showing lower levels than in cases of PM with comparable amounts of weakness. EMG abnormalities are much like those found in PM, as discussed earlier. In addition, a small proportion of IBM patients display a more typically neuropathic EMG pattern, mainly with long-duration polyphasic potentials because of the chronicity of the disease, in the distal limb muscles. However, the EMG changes tend to be restricted to weakened muscles, a distinction from ALS.
The diagnosis depends on the clinical features and is supported by the muscle biopsy. There are structural abnormalities of muscle fibers and inflammatory changes. The latter are identical to but usually of lesser severity than those observed in idiopathic PM. (The infiltrating cells are mainly T cells of the CD8 type.) The denominative finding is of intracytoplasmic, subsarcolemmal vacuoles and eosinophilic inclusions in both the cytoplasm and nuclei of degenerating muscle fibers. The vacuoles contain, and are rimmed by, basophilic granular material “rimmed vacuoles. Special stains, particularly Gomori trichrome on frozen sections, and extensive inspection of biopsy specimens are required to disclose the rimmed vacuoles, for they are infrequent, widely dispersed, and easily overlooked. The inclusions may be congophilic, and may stain for TDP-43, p62, SM1-31, and, particularly, beta amyloid. As noted in subsequent sections similar inclusions are found in a number of other muscle diseases and are not in and of themselves diagnostic, especially without the destructive and mildly inflammatory changes of IBM. Moreover, the clinical context of these other diseases usually causes little difficulty in identifying the inclusions as ancillary and minor abnormalities on the biopsy.
Of clinical utility has been the recent introduction of testing for the earlier mentioned cytosolic antibodies (anti-cN1; NT5C1A) that are found in two-thirds of patients with IBM. They appear to be specific and assist in particular by differentiating this disease from the other inflammatory myopathies and in its detection when there is an unusual pattern of weakness that is not typically of an inflammatory myopathy. Testing other antibodies such as anti-Jo is probably suited to confirming cases that have the elements of a larger syndrome that includes, for example, interstitial lung disease.
Ultrastructural studies show that the protein inclusions accumulate at or near foci of abnormal tubulofilamentous structures in both the nuclei and cytoplasm. The nature of these diverse changes is obscure. The tubulofilamentous inclusions suggested to earlier investigators a viral origin, but an agent has never been isolated and serologic studies have failed to substantiate an infectious causation.
IBM has not responded in any consistent fashion to treatment with corticosteroids or other immunosuppressive drugs. Indeed, the disease should be suspected in recalcitrant cases of apparent PM. The level of CK and the degree of leukocyte infiltration of muscle often diminish with corticosteroid treatment despite a lack of clinical improvement. On this basis, Barohn and coworkers suggested that the inflammatory response is not a primary cause of muscle destruction. In a few cases there has been brief improvement in response to IVIg, especially in weakened muscles involved in swallowing, but the gains have been unsustained and serial histopathologic examinations have detected no change. Two controlled trials have failed to show a benefit of IVIg. Plasma exchange and leukocytapheresis have also been tried, with generally discouraging results.
The disease in most patients is relentlessly progressive over many years, sometimes very slowly, and no method of treatment has so far altered the long-term prognosis. Sometimes, the process remains fairly restricted in scope or severity for up to a decade, thereby creating less disability than in cases that become generalized.
The main issue here is differentiation from inclusion body myopathy, a subject introduced in the next section. The specific problem of determining which patients with DM or PM should have an extensive evaluation for a systemic malignancy and for connective tissue disease has been partially settled. We have adopted the practice of careful inspection of the chest radiograph, routine blood tests and stool examination for blood for all patients, and of undertaking a more extensive evaluation in patients older than 55 years and in smokers of any age. The evaluation of patients over 55 and smokers includes chest and abdominal computed tomographic (CT) scans, colonoscopy, pelvic ultrasound, cancer antigen (CA)-125, carcinoembryonic antigen (CEA), as well as other tests. In patients with recent weight loss, anorexia, or other symptoms suggestive of malignancy, we have included upper endoscopy and resorted to a body positron emission tomography scanning.
In addition to these main issues of distinguishing PM and DM from IBM, currently aided by antibody testing for the latter, we call attention to the following problems that we have encountered in connection with diagnosis:
The patient with proximal muscle weakness is incorrectly diagnosed as having progressive muscular dystrophy (actually, the opposite pertains more often). Points in favor of myositis are (1) lack of family history (although many dystrophies have recessive inheritance); (2) older age at onset; (3) rapid evolution of weakness; (4) evidence, past or present, of other connective tissue diseases; (5) high serum CK values (again, can be high in certain dystrophies; (6) marked degeneration and regeneration in muscle biopsy; and, finally, if there is still doubt, (7) unmistakable improvement with corticosteroid therapy.
The patient with a systemic autoimmune disease (rheumatoid arthritis, scleroderma, lupus erythematosus, Sjögren syndrome) is suspected of having PM in addition. Pain in these conditions prevents strong exertion (algesic pseudoparesis). Points against the coexistence of myositis are (1) the inability to document weakness out of proportion to muscle atrophy and the presence of pain on passive movement of the limbs; (2) normal EMG; (3) normal serum CK; and (4) normal muscle biopsy except possibly for areas of infiltration of chronic inflammatory cells in the endomysial and perimysial connective tissue (interstitial myositis).
When muscle pain is a prominent feature, polymyalgia rheumatica must be differentiated. This latter syndrome is characterized by pain, stiffness, and tenderness in the muscles of the neck, shoulders, and arms, and sometimes of the hips and thighs; even passive motion of the limbs causes pain because of the periarticular locus of this disease. A high sedimentation rate, usually above 65 mm/h, is a diagnostic feature, but more typically the value is close to 100 mm/h, levels higher than in myositis. Biopsy of the temporal artery frequently discloses a giant cell arteritis. CK levels—and, of course, muscle biopsy—are normal. Rapid disappearance of pain with administration of small doses of prednisone is also diagnostic of polymyalgia rheumatica (see Chap. 11).
The patient has restricted muscle weakness. Weakness or paralysis of the posterior neck muscles, with inability to hold up the head, restricted bilateral quadriceps weakness, and other limited pelvocrural palsies are examples. Most often, the head-hanging or head-lolling syndrome proves to be caused by PM, and the other syndromes are caused by restricted forms of dystrophy or by motor neuron disease. IBM is the main alternative consideration in cases of neck or quadriceps weakness, particularly if the latter weakness is asymmetric; muscle enzymes in the serum are normal or slightly elevated. EMG and biopsy are helpful in diagnosis.
The patient has diffuse myalgia and fatigability. Most such patients have proved to be depressed and only rarely to have a myopathy. A few will be found to be caused by a toxic myopathy, particularly from one of the statin class of drugs. Hypothyroidism, McArdle disease, hyperparathyroidism, steroid myopathy, adrenal insufficiency, and early rheumatoid arthritis must be excluded by appropriate studies. Features that virtually exclude a myositis are (1) lack of reduced peak power of contraction and (2) normal EMG, serum enzymes, and muscle biopsy.
Trichinosis, toxoplasmosis, HIV, and other infectious causes of myositis can simulate acute immune myositis as described in the early parts of this chapter. Occasionally, the diagnosis of sarcoidosis is made from the muscle biopsy, but the myopathic features (weakness and pain) tend to be minor.
There are a large number of unrelated myositides and rare forms of focal myositis or relatively minor changes in muscle that occur in the course of inflammatory diseases of blood vessels or systemic infections and, curiously, with certain tumors such as thymoma. Most of these do not warrant extensive consideration and are described in detail in monographs devoted to muscle disease (see Banker). We are uncertain how to place the newly described and undoubtedly rare entity of myositis with abundant macrophage infiltration and aluminum hydroxide crystalline deposits. A type of fasciitis that is characterized by pronounced infiltration of macrophages has been related to vaccinations that contain the aluminum compound, but the myositis does not seem to be related to this aforementioned entity (see Bassez et al).
Three inflammatory myopathic diseases, however, are distinctive and of interest to neurologists: (1) eosinophilic myositis, fasciitis, and myalgia syndrome, (2) orbital myositis, and (3) sarcoidosis of muscle.
This term has been applied to 4 overlapping clinical entities: (1) eosinophilic fasciitis, (2) eosinophilic monomyositis (sometimes multiplex), (3) eosinophilic PM, and (4) the eosinophilia-myalgia syndrome.
This condition, mistakable for PM, was reported by Shulman in 1974. He described 2 men with a scleroderma-like appearance of the skin and flexion contractures at the knees and elbows associated with hyperglobulinemia, elevated sedimentation rate, and eosinophilia. Biopsy revealed greatly thickened fascia, extending from the subcutaneous tissue to the muscle and infiltrated with plasma cells, lymphocytes, and many eosinophils; the muscle itself appeared normal and the skin lacked the characteristic histologic changes of scleroderma. One of Shulman’s patients recovered in response to prednisone.
The many reports that followed have substantiated and amplified Shulman’s original description. The disease predominates in men in a ratio of 2:1. Symptoms appear between the ages of 30 and 60 years and are often precipitated by heavy exercise (Michet et al). There may be low-grade fever and myalgia followed by the subacute development of diffuse cutaneous thickening and limitation of movement of small and large joints. In some patients, proximal muscle weakness and eosinophilic infiltration of muscle can be demonstrated (Michet et al). Repeated examinations of the blood disclose an eosinophilia in most but not all patients. The disease usually remits spontaneously or responds well to corticosteroids. A small number relapse and do not respond to treatment and some have developed aplastic anemia and lympho- or myeloproliferative disease.
Painful swelling of a calf muscle or, less frequently, some other muscle has been the chief characteristic of this disorder. Biopsy discloses inflammatory necrosis and edema of the interstitial tissues; the infiltrates contain large but variable numbers of eosinophils. The disorder was typified by 1 of our patients, a young woman who developed such an inflammatory mass first in 1 calf and, 3 months later, in the other. The response to prednisone was dramatic; the swelling and pain subsided in 2 to 3 weeks and her power of contraction was then normal. When the connective tissue and muscle are both damaged, a chaotic regeneration of fibroblasts and myoblasts may result, forming a pseudotumorous mass that may persist indefinitely.
Layzer and associates described an eosinophilic disorder that they classified as “subacute polymyositis.” Their patients were adults in whom predominantly proximal weakness evolved over several weeks. The features of the muscle disorder were typical of PM except that the inflammatory infiltration was predominantly eosinophilic and the muscles were swollen and painful. Moreover, the muscle disorder was part of a widespread systemic illness typical of the hypereosinophilic syndrome. The systemic manifestations included a striking eosinophilia (20 to 55 percent of the white blood cells), cardiac involvement (conduction disturbances and congestive failure), vascular disorder (Raynaud phenomenon, subungual hemorrhages), pulmonary infiltrates, strokes, anemia, neuropathy, and hypergammaglobulinemia. There was a favorable response to corticosteroids in 2 patients, but in a third the outcome was fatal in 9 months. Layzer and coworkers noted that a lack of necrotizing arteritis distinguished this process from polyarteritis nodosa and Churg-Strauss disease. No infective agent was isolated. An allergic mechanism seems possible, and in the present authors’ view one cannot exclude an angiitis as a cause of the muscle lesions.
The last two of these previously mentioned syndromes (eosinophilic monomyositis and polymyositis) have overlapping features as shown by Stark’s cases, in which a monomyositis was accompanied by several of the systemic features described by Layzer and colleagues. An uncertain proportion of cases are attributable to mutations in CAPN3, the gene for calpain-3 (Krahn et al). Moreover, some cases of eosinophilic polymyositis without systemic features have been found to be limb-girdle muscular dystrophy 2A, also due to a calpain mutation (i.e., both are considered to be “calpainopathies”). Patients with the dystrophic process, who also have a peripheral eosinophilia, probably have eosinophilic myositis.
Beginning in 1980, sporadic reports documented a lingering systemic illness characterized by severe generalized myalgia and eosinophilia of the peripheral blood following the ingestion of contaminated L-tryptophan. In late 1989 and early 1990, an outbreak occurred of this eosinophilia-myalgia syndrome, as the illness came to be called. More than 1,200 cases were reported to the Centers for Disease Control and Prevention (Medsger) and we examined several of them. The outbreak was ultimately traced to the use of nonprescription L-tryptophan tablets used as a sleep aid supplied by a single manufacturer and contaminated by ethylidene-bis-tryptophan and methyltetrahydro-beta-carboline-carboxylic acid, both close chemical relatives of L-tryptophan (Mayeno et al, 1990, 1992).
The onset of the muscular illness was relatively acute, with fatigue, low-grade fever, and eosinophilia (>1,000 cells/mm3). Muscle pain and tenderness, cramps, weakness, paresthesias of the extremities, and induration of the skin were the main clinical features. A severe axonal neuropathy with slow and incomplete recovery was associated in some cases. Biopsies of the skin fascia, muscle, and peripheral nerve disclosed a microangiopathy and an inflammatory reaction in connective tissue structures; changes like those observed in scleroderma, eosinophilic fasciitis, and in the toxic oil syndrome. The latter syndrome, caused by the ingestion of contaminated rapeseed oil, occurred in an outbreak in Spain in 1981 and gave rise to a constellation of clinical and pathologic changes that were essentially identical to those caused by contaminated l-tryptophan (Ricoy et al; see also Chap. 46). The two toxins are also closely linked chemically and there have been other more limited outbreaks of the toxic neuropathy, usually from adulterated cooking oil.
The cutaneous lesions and eosinophilia of this syndrome responded to treatment with prednisone and other immunosuppressive drugs, but other symptoms persisted. Severe axonal neuropathy in our patients improved incompletely over several years, leaving one chair-bound with severe distal atrophic weakness after 15 years. Although no longer a problem that is likely to be seen by physicians, it serves as a model for future peculiar myopathic syndromes from adulterated drugs that otherwise would seem innocuous.
Among the many cases of orbital inflammatory disease (pseudotumor of the orbit and Tolosa-Hunt syndrome, as described in Chap. 14), there is a small group in whom the inflammatory process appears to be localized to the extraocular muscles. To this group, the term acute orbital myositis has been applied. The abrupt onset of orbital pain that is made worse by eye motion, redness of the conjunctiva adjacent to the muscle insertions, diplopia caused by restrictions of ocular movements, lid edema, and mild proptosis are the main clinical features and, admittedly, the distinctions from orbital pseudotumor are not clear. It may spread from one orbit to the other. The ESR is usually elevated and the patient may feel generally unwell, but only rarely can the ocular disorder be related to a systemic autoimmune disease or any other specific systemic disease. CT and MRI have proved to be particularly useful in demonstrating the swollen ocular muscles or muscle, and in separating orbital myositis from the other remitting inflammatory orbital and retroorbital conditions (Dua et al). As a rule, acute orbital myositis resolves spontaneously in a matter of a few weeks, although it may recur in the same or the opposite eye. Administration of steroids appears to hasten recovery.
There are undoubted examples of muscle involvement in patients with sarcoidosis, but they seem to be less frequent and less certain than would appear from the medical literature. In some cases, sarcoid myopathy becomes evident as a slowly progressive, occasionally fulminant, painless proximal or distal weakness. The CK levels are elevated. Muscle biopsy discloses numerous noncaseating granulomas. However, such lesions may also be found in patients with sarcoidosis who have no weakness. Treatment with moderate doses of corticosteroids (prednisone, 25 to 50 mg daily) is usually effective in symptomatic cases, but an additional immunosuppressive agent, such as cyclosporine, may have to be instituted if improvement is not evident in several weeks.
Much more puzzling have been cases of myopathy with the clinical features of idiopathic polymyositis and the presence of noncaseating granulomas in the muscle biopsy but with no evidence of sarcoidosis of the nervous system, lungs, bone, skin, or lymph nodes. Such cases call into question the validity of a muscle granuloma as a criterion of sarcoidosis, but the matter cannot be settled until we have a better definitions and etiology for sarcoidosis. These cases are presently classified as granulomatous myositis and, if limited to one or a small group of muscles, localized nodular myositis (Cumming et al). In a syndrome described by Namba and colleagues, this type of myositis was combined with myasthenia gravis, myocarditis, and thyroiditis. The muscle process has, on a few occasions, also been associated with Crohn disease. Electron microscopy has disclosed muscle fiber invasion by lymphocytes, suggesting a cell-mediated immune reaction. Very rarely, a granulomatous myositis may complicate tuberculosis or syphilis.
The Muscular Dystrophies
INHERITANCE TYPE | GENE OR CHROMOSOME | ONSET DECADE | CK ELEVATION | REGIONS AFFECTED |
|---|---|---|---|---|
X-linked recessive | ||||
Duchenne/Becker | Dystrophin | 1st | 10–50 × | Proximal, then distal muscles |
Cardiac muscle | ||||
Emery-Dreifuss | Emerin | 2nd–3rd | 5 × | Proximal muscles, joint contractures; cardiac arrhythmias |
Scapuloperoneal | FHL1 | Scapular-peroneal | ||
Autosomal dominant | ||||
LGMD 1A | Myotilin | 3rd–4th | 2 × | Distal greater than proximal weakness, vocal cords, pharynx; allelic with myofibrillar myopathy |
LGMD 1B | Lamin A/C | 1st–2nd | 3–5 × | Resembles Emery-Dreifuss disease |
Proximal muscles and heart, joint contractures | ||||
LGMD 1C | Caveolin-3 | 1st | 4–25 × | Proximal muscles |
LGMD 1D | 6p | 3rd–5th | 2–4 × | Proximal muscles; cardiomyopathy |
LGMD 1E | Desmin | 1st | Nl | Proximal muscles |
Autosomal recessive | ||||
LGMD 2A | Calpain-3 | 1st–2nd | 3–15 × | Proximal and distal muscles |
LGMD 2B | Dysferlin | 2nd–3rd | 10–50 × | Proximal and distal muscles |
Allelic to Miyoshi myopathy | ||||
LGMD 2C–F | α, β, γ, δ-sarcoglycans | 1st–3rd | 5–40 × | Phenotype of Becker dystrophy |
LGMD 2G | Telethonin | 2nd | 3–17 × | Proximal greater than distal muscles |
LGMD 2H | TRIM32 | 1st–3rd | 2–25 × | Proximal greater than distal muscles |
LGMD 2I | FKRP | 1st–3rd | 10–30 × | Proximal greater than distal muscles |
FKRP defects also cause CMD | ||||
LGMD 2J | Titin | 1st–3rd | 2 × | Proximal and sometimes distal muscles |
LGMD 2M | POMGNT1* | Birth | Mutations also associated with muscle-eye-brain diseases |
TYPE | GENE OR CHROMOSOME | ONSET DECADE | CK ELEVATION | REGIONS AFFECTED |
|---|---|---|---|---|
Myotonic dystrophy (DM1) | Expanded intronic CTG repeat in myotonin kinase | 1st–2nd | 1–2 × | Distal weakness, myotonia, cataracts |
Testicular atrophy, balding, cardiac arrhythmias | ||||
Proximal myotonic myopathy (DM2) | Expanded intronic CCTG repeat in zinc finger protein | 1st–2nd | 1–2 × | Resembles myotonic dystrophy with prominent proximal muscle weakness but no infancy onset; less facial weakness |
Facioscapulohumeral dystrophy | Multigene dysregulation at 4q telomere | 1st–4th | 1–2 × | Facial, scapular, anterior tibial muscles |
Hearing loss, ocular telangiectasias | ||||
Oculopharyngeal dystrophy | Exonic GCG expansion (alanine) in poly-A binding protein | 6th–7th | 1–2 × | Oculopharyngeal and levator palpebrae muscles |
Bethlem myopathy | Collagen VI, subunits α 1-3 | 1st–3rd | 1–4 × | Proximal weakness |
Contractures in fingers, elbows, knees | ||||
May present as CMD | ||||
Myofibrillar myopathy | Myotilin, desmin, αβ-crystallin | 2nd–4th | 1–5 × | Allelic with LGMD-1A |
INHERITANCE DISORDER | GENE OR PROTEIN DEFICIENCY | ONSET DECADE | CK ELEVATION | REGIONS AFFECTED |
|---|---|---|---|---|
Autosomal recessive | ||||
Miyoshi myopathy | Dysferlin | 2nd–3rd | 10–50 × | Begins in gastrocnemius muscles, rarely, in anterior tibial muscles |
Identical genetic defects may cause LGMD-2B | ||||
Involves multiple muscle groups, spares heart | ||||
Nonaka myopathy with rimmed vacuoles (familial IBM) | GNE kinase–epimerase | 2nd–3rd | 3–10 × | Distal more than proximal weakness |
UDP-N-acetylglucosamine-2-epimerase/N-mannosamine kinase | ||||
Quadriceps sparing | ||||
Spares heart | ||||
Autosomal dominant | ||||
Welander distal dystrophy | Unknown | 4th–5th | 2–3 × | Weakness begins in hands |
Slow progression | ||||
Spares cardiac muscle | ||||
Tibial muscular dystrophy | Titin | 4th–8th | 2–4 × | Onset in tibial distribution |
No cardiac involvement | ||||
Scapuloperoneal dystrophy | X-linked (see Table 48-1) | 3rd–6th | 2–10 × | Scapuloperoneal weakness |
Hyaline bodies in muscle | ||||
Early onset of foot-drop | ||||
Desmin myopathy | Desmin | 3rd–4th | 2–3 × | Onset of distal weakness, slowly progressive |
Cardiac arrhythmias (sometimes fatal) | ||||
Gower-Laing | MYHC-1 (MYH7) | 2nd–3rd | 3 × | Anterior tibial (early foot-drop) |
Markesbery-Griggs | ZASP | 2nd–3rd | 2 × | Anterior tibial Cardiomyopathy common |
The muscular dystrophies are a group of progressive hereditary degenerative diseases of skeletal muscles. The intensity of the degenerative changes in muscle and the cellular response and nature of the regenerative changes distinguish the dystrophies histologically from other diseases of muscle and also have implications regarding their pathogenesis. The category of more benign and relatively nonprogressive myopathies—each named from its special histopathologic appearance, such as central core, nemaline, mitochondrial, and centronuclear diseases—present greater difficulty in classification. Like the dystrophies, they are primarily diseases of muscle and are often heredofamilial in nature, but they are placed in a separate category because of a nonprogressive or slowly progressive course and their distinctive histochemical and ultrastructural features.
The current clinical classification of the muscular dystrophies is based mainly on the distribution of the dominant muscle weakness; however, several of the classical types have retained their eponymic designations: Duchenne, Becker, Emery-Dreifuss, Landouzy-Dejerine, Miyoshi, Welander, Fazio-Londe, and Bethlem are among the ones that still have utility in shorthand. To these are added myotonic dystrophy and a group of so-called congenital muscular dystrophies, usually severe in degree.
The extraordinary depth of information regarding the molecular nature of the dystrophies is one of the most gratifying developments of modern neuroscience. The majority of the dystrophies are caused by changes in structural elements of the muscle cell, mainly in its membrane, but other important mechanisms also are being identified, such as altered messenger RNA (mRNA). In keeping with the outlook expressed throughout the book, we adhere to a clinical orientation in describing the muscular dystrophies but make clear that treatment in the future could be determined based on understanding of molecular mechanisms. Each of the muscular dystrophies is described in accordance with this scheme.
The differentiation of dystrophic diseases of muscle from those secondary to neuronal degeneration was an achievement of neurologists of the second half of the nineteenth century. Isolated cases of muscular dystrophy had been described earlier, but no distinction was made between neuropathic and myopathic disease. In 1855, the French neurologist Duchenne described the progressive muscular atrophy of childhood that now bears his name. However, it was not until the second edition of his monograph in 1861 that the “hypertrophic paraplegia of infancy” was recognized as a distinct syndrome. By 1868 he was able to write a comprehensive description of 13 cases and recognized that the disease was muscular in origin and restricted to males. Gowers in 1879 gave a masterful account of 21 personally observed cases and called attention to the characteristic way in which such patients arose from the floor (Gowers sign). Erb, in 1891, crystallized the clinical and histologic concept of a group of diseases caused by primary degeneration of muscle, which he named muscular dystrophies. The first descriptions of facioscapulohumeral dystrophy were published by Landouzy and Déjerine in 1894; of progressive ocular myopathy by Fuchs in 1890; of myotonic dystrophy by Steinert and by Batten and Gibb in 1909; of distal dystrophy by Gowers in 1888, Milhorat and Wolff in 1943, Welander in 1951, and Miyoshi and colleagues in 1986; and of oculopharyngeal dystrophy by Victor and associates in 1962. References to these and other writings of historical importance can be found in the works of Kakulas and Adams, of Walton and colleagues, and of Engel and Franzini-Armstrong, and most recently of Amato and Russell.
In the more recent history of the dystrophies, the most notable event was the discovery by Kunkel, in 1986, of the dystrophin gene and its protein product. Since then there has been an extraordinary accumulation of molecular-genetic, ultrastructural, and biochemical information about the muscular dystrophies, which has greatly broadened our understanding of their mechanisms. It has also clarified a number of uncertainties as to their clinical presentations and has necessitated a revision of an older classification.
This is the most frequent and best known of the early-onset muscular dystrophies. It begins in early childhood and runs a relatively rapid, progressive course. The incidence is in the range of 13 to 33 per 100,000 yearly or about 1 in 3,300 live male births. There is a strong familial liability as the disease is transmitted as an X-linked recessive trait, occurring almost exclusively in males. However, careful examination of the mothers of affected boys shows slight muscle involvement in as many as half of them, as pointed out by Roses and coworkers (a frequency higher than in our limited experience). Approximately 30 percent of patients have no family history of the disease and these represent spontaneous mutations.
Rarely, a severe proximal Duchenne-type muscular dystrophy occurs in young girls. This may have several explanations. The female may have only 1 X chromosome, as occurs in the Turner (XO) syndrome, and that chromosome carries the Duchenne gene, or the Lyon principle may be operative; that is, there is inactivation of the unaffected paternal X chromosome allowing expression of the mutated Duchenne protein from the maternal chromosome in a large proportion of embryonic cells (mosaicism). It so happens that most childhood dystrophies in girls prove to be of an entirely different type that is caused by an autosomal recessive mutation causing a limb-girdle dystrophy as discussed further on.
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Chapter 28. Normal Development and Deviations in Development of the Nervous System
Chapter 50. The Myotonias, Periodic Paralyses, Cramps, Spasms, and States of Persistent Muscle Fiber Activity
Chapter 38. Developmental Diseases of the Nervous System
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