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Neurology_Adams. Cramps are known to increase in frequency under certain conditions and with certain diseases. They are common during pregnancy for reasons not fully understood. Dehydration and excessive sweating predispose to cramping and are a constant threat to athletes. Exertional cramps are elicited more easily than usual in motor system disease, hypothyroidism, and in chronic polyneuropathies. Focal cramping occurs after partial nerve or root injury. For example, the calf muscle on one side is subject to severe recurrent cramps after decompression of the S1 root for lumbar disc disease; in extreme cases, the muscle hypertrophies after long periods of intermittent cramping. Patients undergoing hemodialysis are subject to cramps, which can be suppressed by intravenous hypertonic saline or hypertonic glucose.


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Neurology_Adams. The mechanism of muscle cramping is obscure. Several enzymes have been implicated, controversially but often included among these is myoadenylate. This enzyme, which is present in high concentration in muscle, is thought to function primarily during aerobic exercise and facilitate the regeneration of ATP from ADP through the action of adenylate kinase. However, low levels of this enzyme are not specific, occurring in such unrelated disorders as hypokalemic periodic paralysis and spinal muscular atrophy (see Layzer for details).


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Neurology_Adams. 4 h if necessary, or 300 mg tid for idiopathic diurnal cramping) had been an effective medication but is no longer widely used because of a low risk of ventricular arrhythmia. Some patients, nonetheless, seek relief from the use of quinine water, some brands of which still contain the chemical. Diphenhydramine hydrochloride (Benadryl) 50 mg or procainamide 0.5 to 1.0 g are alternatives. Phenytoin, carbamazepine, and other antiepileptic drugs, and clonazepam may be useful in alleviating repeated daytime cramping. Tetany, Pseudotetany, and Related Cramp Syndromes


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Neurology_Adams. As pointed out earlier, a reduction in ionizable calcium and magnesium is associated with involuntary cramp-like spasms; in their mildest form they appear as distal carpopedal spasms, but they may involve any of the muscles except the extraocular ones. Under these circumstances, stimulation of a muscle through its nerve at high frequencies (15 to 20 times per second) reproduces spasms, and hyperventilation and ischemia increase the tendency. Indeed, the Trousseau sign—carpal spasms with occlusion of the blood supply to the arm—takes advantage of the latter phenomenon. Hypocalcemic tetany is attributable to an unstable depolarization of the axonal membrane of the nerve fiber. This mechanism is affirmed by (1) the sensitivity of nerve to percussion (e.g., tapping over the facial nerve near its foramen of exit induces a facial twitch, or Chvostek sign), (2) fast-frequency doublets and triplets of motor unit potentials in the EMG indicating excessive neural excitability, (3) evocation of


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Neurology_Adams. its foramen of exit induces a facial twitch, or Chvostek sign), (2) fast-frequency doublets and triplets of motor unit potentials in the EMG indicating excessive neural excitability, (3) evocation of spasm by application of a tourniquet to proximal parts of a limb (causing ischemia of segments of nerve beneath the tourniquet), and (4) the associated tingling, prickling paresthesias from excitation of sensory nerve fibers. Hypocalcemia also causes a lesser change in the muscle fibers themselves; hence nerve block does not completely eradicate tetany. We comment here that the Chvostek sign is found in some normal individuals, without obvious explanation.


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Neurology_Adams. The previously described idiopathic benign cramps resemble tetany but without measurable hypocalcemia (pseudotetany). Just as in tetany, in about half of cases of benign cramp, stimulation of nerve at 15 or more times per second produces repetitive discharges. Biopsies have disclosed no abnormalities of the muscle fibers except for a few ringbinden (circumferential bands of myofibrils encircling a normal core of longitudinally oriented myofibrils). Calcium and diazepam are of no therapeutic value, but some patients respond to phenytoin, quinine (no longer widely used because of the risk of arrhythmia), procainamide, or chlorpromazine.


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Neurology_Adams. A familial (autosomal dominant) form of the benign cramp syndrome has been reported; the cramps affected the distal limb muscles, began in childhood and adolescence, and persisted throughout life. Another such family with cramps beginning somewhat later in life and affecting the anterior neck, arm, and abdominal muscles as well as those of the thigh and calf has been described. Also, a familial myalgic-cramp syndrome alluded to early in this chapter has been associated with deletion of part of the dystrophin gene (but with little or no dystrophic weakness). A tendency to cramp and pain has also been noted in a number of the congenital myopathies and in some families with Duchenne and Becker dystrophies.


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Neurology_Adams. Satoyoshi described a group of patients who, in addition to widespread and severe cramping of muscle, developed universal alopecia, amenorrhea, intestinal malabsorption with frequent diarrhea, and some developed epiphyseal destruction and retarded growth. Most Japanese patients he described were younger than 20 years, but the 2 cases we have observed in whites were middle-aged. The serum calcium in these patients is normal, and the EMG shows only high-frequency discharges that are characteristic of cramps. A patient of ours with this condition had decades of chronic diarrhea, alopecia, and continuous, extremely painful calf cramps that had the gross appearance of fasciculations. This triad virtually identifies the disease. The cause of the disorder is obscure but is tentatively presumed to be autoimmune. Glucocorticoids, particularly in high doses over short periods, have been tried with some success; dantrolene has also been used and we had the impression that plasma exchange may


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Neurology_Adams. to be autoimmune. Glucocorticoids, particularly in high doses over short periods, have been tried with some success; dantrolene has also been used and we had the impression that plasma exchange may have been helpful in one case.


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Neurology_Adams. Continuous Muscle Fiber Activity Due to Disorders of Nerve and Distal Axons (See Chap. 46) While the main manifestations of this group of disorders, muscular cramps, would seem to belong in this chapter on muscle diseases, they are, in fact, related to disorders of motor nerves, axons, and their terminal arborizations. For this reason, they appear in Chap. 46 on channelopathies and in Chap. 43, with disorders of the peripheral nerves.


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Neurology_Adams. Many of the muscle diseases described previously are associated with aching and discomfort. These are particularly prominent in conditions that are accompanied by cramp and biochemical contracture (phosphorylase and phosphofructokinase deficiency). Ischemia of muscle—that is, intermittent claudication—is also painful, as is dystonia in some cases. Muscle weakness that imposes persistent abnormal postures on the limbs may cause stretch injury to muscles and tendons. This is observed in a number of the congenital myopathies and dystrophies. In all these conditions, clinical study will usually disclose the source or sources of the pain.


Neurology_Adams

Neurology_Adams. Diffuse muscle pain, which merges with malaise, is a frequent expression of a large variety of systemic infections—for example, influenza, brucellosis, dengue, Colorado tick fever, measles, malaria, relapsing fever, rheumatic fever (in which it was called “growing pains”), salmonellosis, toxoplasmosis, trichinosis, tularemia, and Weil disease. When the pain is intense, especially if it is localized to one side of the lower chest and abdomen, the most likely diagnostic possibility is epidemic myalgia (also designated as pleurodynia, “devil’s grip,” and Bornholm disease caused by Coxsackievirus infection). Poliomyelitis may be accompanied by intense pain at the onset of neurologic involvement, and later the paralyzed muscles may ache. This is true also of the Guillain-Barré syndrome, in which the pain may precede weakness by several days. Little is known about the pathologic basis of the muscular pain in these diseases; it is not a result of muscle inflammation and is probably produced


Neurology_Adams

Neurology_Adams. the pain may precede weakness by several days. Little is known about the pathologic basis of the muscular pain in these diseases; it is not a result of muscle inflammation and is probably produced by circulating cytokines that are common to most systemic infections. Mild muscle pain is a frequent but not a necessary accompaniment of polymyositis and dermatomyositis.


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Polymyalgia Rheumatica (See Chap. 10)

Neurology_Adams. Polymyalgia Rheumatica (See Chap. 10)


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Neurology_Adams. The major consideration in elderly and middle-aged patients with pain in proximal muscles of the limbs is polymyalgia rheumatica. This subject is mentioned briefly in other sections of this book in relation to back and extremity pain (see Chap. 10) and to temporal arteritis, to which it is closely connected (see Chap. 9). The muscular soreness may be diffuse or asymmetrical, particularly in the proximal arms and shoulders. Every movement is reported as stiff and painful. The periarticular tissues and their muscular attachments are affected primarily and may be tender, but this is difficult to interpret, because tenderness in these regions may be found in healthy individuals. The sedimentation rate is elevated in the majority of patients, and a 48-h trial of prednisone, by completely alleviating muscle pain, confirms the diagnosis. In the context of muscle pain, systemic symptoms such as weight loss, headache, and fatigue, as well as mild anemia, are particularly suggestive of


Neurology_Adams

Neurology_Adams. alleviating muscle pain, confirms the diagnosis. In the context of muscle pain, systemic symptoms such as weight loss, headache, and fatigue, as well as mild anemia, are particularly suggestive of polymyalgia rheumatica.


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Neurology_Adams. This would appear, by definition, to represent an inflammation or other affection of the fibrous tissues of the muscles, fascia, and aponeuroses. Unfortunately, the pathologic basis of this state remains obscure. Only some clinical facts can be stated. During the first movements after a period of inactivity, a muscle or group of muscles may become painful and tender, particularly after exposure to cold, dampness, or minor trauma, but often for no reason that can be discerned. One looks in vain for signs of tendinous, muscular, or arthritic disease. The neck and shoulders are the most common sites. Tender areas, up to several centimeters in diameter, can be palpated within the muscles (“fibrositic nodules” by experts), and active contraction or passive stretching of the involved muscles increases the pain—points said to be of diagnostic value, but disputed. Often, symptoms such as mental and physical fatigue, insomnia, and headache are associated and raise the suspicion of an anxiety


Neurology_Adams

Neurology_Adams. the pain—points said to be of diagnostic value, but disputed. Often, symptoms such as mental and physical fatigue, insomnia, and headache are associated and raise the suspicion of an anxiety state or depression. In a few instances the condition clears up in a few weeks; local heat and massage and local injections of anesthetics or steroids are found to give comfort while symptoms are present, but most often it becomes a chronic condition.


Neurology_Adams

Neurology_Adams. The chronic form of fibromyalgia presents far greater problems, usually disabling the patient and causing a change in accustomed habits and employment as discussed in Chap. 10. It has become one of the prime diagnoses made by rheumatologists and physiatrists, but the patient may first come to the attention of a neurologist. Most definitions of the syndrome have been circular or somewhat arbitrary. Those now in general use are similar to the one proposed by a committee of the American College of Rheumatology. The basis for diagnosis is the presence of widespread pain, including focal areas of pain (trigger points) that can be produced by 4 kg of digital pressure in 11 of 18 typical locations over muscles, tendons, or bone—these are concentrated around the shoulders and paraspinal regions—and there is no requirement for the presence of the several common systemic complaints that accompany the illness in most patients (fatigue, difficulty concentrating, sleeping difficulty, or anxiety).


Neurology_Adams

Neurology_Adams. there is no requirement for the presence of the several common systemic complaints that accompany the illness in most patients (fatigue, difficulty concentrating, sleeping difficulty, or anxiety). In the past, similar pains were associated with cases of irritable bowel or irritable bladder syndromes, dysmenorrhea, chronic headache, and cold intolerance. Depending on how broad a definition one allows for the widespread pain and painful trigger points, most or all patients in our experience manifest many of the same complaints as those with the chronic fatigue syndrome, which is discussed in Chap. 24. Writers on the subject, however, have pointed out that in the majority of patients, formal assessment by modern criteria fails to confirm the presence of depression, and that when depression coexists with the muscular complaints, the two are discordant temporally and in severity. While we acknowledge that antidepressants often give disappointing results and that in our practice there have


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Neurology_Adams. with the muscular complaints, the two are discordant temporally and in severity. While we acknowledge that antidepressants often give disappointing results and that in our practice there have been a number of patients with fibromyalgia who appeared to be psychologically sound and lacked depression, they have been the exceptions. The literature eschews the use of corticosteroids for treatment of the pain, but we have had occasion to see patients whose symptoms were relieved when these medications were used for other purposes.


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Neurology_Adams. Fibromyalgia remains a problematic illness, defined largely by a pattern of pain that justifies its name. Despite attempts to objectify the physical symptoms, psychiatric factors should not be overlooked. This condition is a favorite illness with physiotherapists, who claim that their physical measures are helpful, as they may well be. Rarely, a similar syndrome is the forerunner of what proves, after some days, with the onset of neurologic signs, to be a radiculitis, brachial neuritis, or outbreak of herpes zoster.


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Neurology_Adams. An impressive polymyalgia follows excessive exercise. Often, the patient observes that aching pain occurs not at the time of activity but some hours or even a day or two later, resembling the discomfort following the excessive use of unconditioned muscles. The muscles are sore and there is an intolerance of exercise and physical exertion. The serum CK concentration is mildly to moderately elevated. This is a natural phenomenon and is self-limiting. When such a state persists indefinitely and a program of conditioning exercises does not alleviate the pain, it represents a special category of disease. In a few instances an increased sedimentation rate or other laboratory aids may clarify the diagnosis, and muscle biopsy may reveal a nonspecific interstitial nodular myositis or the giant cell arteritis associated with polymyalgia rheumatica. Whether or not patients on lipid-lowering statin medications are particularly susceptible to this problem is not clear. A few individuals go on to


Neurology_Adams

Neurology_Adams. arteritis associated with polymyalgia rheumatica. Whether or not patients on lipid-lowering statin medications are particularly susceptible to this problem is not clear. A few individuals go on to have the features of the previously described fibromyalgic syndrome. However, this cluster of symptoms most often occurs without explanation, and one can only suspect an obscure infection or a subtle aberration of muscle metabolism, presently impossible to demonstrate. Reference has been made in the literature to the controversial finding of a myoadenylate deaminase deficiency in some of these cases. There is also a group of patients who have idiopathic leg pain during rest after activity. Some families afflicted in this way are forced to live a sedentary existence. The condition does not respond to analgesics. In 2 cases, a deficiency of calcium ATPase was found and reportedly alleviated by a calcium channel blocker such as verapamil, 120 mg (Walton). It must be distinguished from the


Neurology_Adams

Neurology_Adams. to analgesics. In 2 cases, a deficiency of calcium ATPase was found and reportedly alleviated by a calcium channel blocker such as verapamil, 120 mg (Walton). It must be distinguished from the syndromes of painful legs and moving toes, and from the restless leg syndrome discussed in Chap. 18.


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Neurology_Adams. Before dismissing vague muscle aches as an excessive somatic concern, hypothyroidism, hyperparathyroidism, and renal tubular acidosis, hypophosphatemia, hypoglycemia, and the intrinsic phosphorylase or phosphofructokinase defects should be considered. Patients with these latter diseases often complain of soreness, stiffness, and lameness after strenuous muscular effort. The most valuable screening tests are the sedimentation rate and serum CK concentration. Some patients probably have an obscure metabolic myopathy, presently undiagnosable. In every reported series, such as that of Serratrice and coworkers, half of the cases with diffuse myalgia are of this uncertain type. This coincides with, or is more optimistic than, our own experience. Masses may be found in one or many muscles in a variety of clinical settings, and the clinical findings in each one have a different significance.


Neurology_Adams

Neurology_Adams. Masses may be found in one or many muscles in a variety of clinical settings, and the clinical findings in each one have a different significance. Muscle or tendinous rupture is usually caused by a violent strain attended by an audible snap and then a bulge, which appears when the muscle contracts. A very focal weakening in contractile power and mild discomfort are usually noted by the patient. The biceps brachii and soleus muscles are most often affected. Treatment is by surgical repair; if that is delayed, little can be done for the condition. Hemorrhage into muscle may occur as a consequence of trauma, as a complication of the use of anticoagulants, in hematologic diseases, in severe myotonia, or after a minor trauma to a patient with Zenker degeneration of muscle who is convalescing from typhoid fever or some other infection. Runners may acquire painful localized hematomas in leg muscles.


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Neurology_Adams. Tumors of muscle include desmoid tumor (a benign massive growth of fibrous tissue observed most often in parturient women and after surgery), rhabdomyosarcoma (a highly malignant tumor with strong liability to local recurrence and metastasis), liposarcoma, and angioma. Large neurofibromas or neurofibrosarcomas beneath large muscles such as the hamstring may be difficult to differentiate by physical examination or MRI from masses within the muscle. Pseudotumorous growths, sometimes massive, may follow injury to a muscle. Interlacing regenerating muscle fibers and fibroblasts compose the mass. Excision of the entire muscle had been undertaken in several cases in the belief that the growth was a rhabdomyosarcoma, whereas it is actually a benign reaction to trauma (Kakulas and Adams). Metastasis to muscle occurs, most often lymphomatous in our experience.


Neurology_Adams

Neurology_Adams. Thrombosis of arteries or, more often, of veins causes congestion and infarction of muscle. A special type of muscle infarction occurs in patients with complicated and poorly controlled diabetes mellitus (Banker and Chester). Usually it involves the anterior thigh, and occasionally other muscles of the lower limb. The symptoms are the sudden onset of pain and swelling of the thigh, with or without the formation of a tender, palpable mass. Recurrent infarction of the same or opposite thigh is characteristic. The stereotypical clinical picture and the striking MRI appearance obviate the need for diagnostic muscle biopsy. Extensive infarction of muscle is due to the occlusion of many medium-sized muscular arteries and arterioles, most likely the result of embolization of atheromatous material from eroded plaques in the aorta or iliac arteries. Recognition of this complication and immobilization of the limb are of prime practical importance, as muscle biopsy and early ambulation may cause


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Neurology_Adams. from eroded plaques in the aorta or iliac arteries. Recognition of this complication and immobilization of the limb are of prime practical importance, as muscle biopsy and early ambulation may cause serious hemorrhage into the infarcted tissue.


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Neurology_Adams. The pretibial, or compartment syndrome, also well recognized, follows direct trauma or excessive activity (marching, exercising of unconditioned muscles) or ischemic infarction due to arterial occlusion. There is swelling of the extensor hallucis longus, extensor digitorum longus, and anterior tibial muscles. Being tightly enclosed by the bones and pretibial fascia, the swelling leads to ischemic necrosis and myoglobinuria. Permanent weakness of this group of muscles can be prevented by incising the pretibial fascia and thereby decompressing the affected muscles. A similar compartment syndrome can occur in the forearm. This condition involves the deposition of bone within the substance of a muscle. Two types are recognized. One is a localized form that appears in a single muscle or group of muscles after trauma, and the other is a progressive, widespread ossifying process, entirely unrelated to trauma, in many muscles of the body.


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Neurology_Adams. Localized (traumatic) myositis ossificans After a muscle tear, a single blow to the muscle, or repeated minor trauma, a painful area develops in the muscle. It is gradually replaced by a mass of cartilaginous consistency, and within 4 to 7 weeks a solid mass of bone can be felt and seen in CT or radiographs. This most frequently happens in vigorous adult men. The inner thigh muscles (in those who ride horses) and to a lesser extent the pectoralis major and biceps brachii are the most frequent locations. The mass tends to subside after several months if the patient desists from the activity that produced the trauma.


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Neurology_Adams. Generalized myositis ossificans This disease, first described by Munchmeyer in 1869, has since been referred to by his name or as myositis ossificans progressiva. It is rare, although Lutwak, in 1964, was able to collect 264 cases from the literature. The cause is unknown, but the disease is probably inherited as an autosomal dominant trait. It consists of widespread bone formation along the fascial planes of muscles and has its onset in infancy and childhood in 90 percent of cases. Biopsies of indurated swellings have revealed extensive proliferation of interstitial connective tissue in which little inflammatory cell reaction is found. Within a few weeks, the connective tissue becomes less cellular and retracts, compressing the adjacent muscle fibers. Osteoid and cartilage formation occur at a later stage, developing in the connective tissue and enclosing relatively intact muscle fibers.


Neurology_Adams

Neurology_Adams. Nearly 75 percent of all reported cases have been associated with congenital anomalies, the most frequent of which is a failure of development of the great toes or thumbs and less often, other digits. Less frequently, there is hypogenitalism, deafness, and an absence of upper incisors. The first symptom is often a firm swelling and tenderness in a paravertebral or cervical muscle. There is, in addition, a mild discomfort during muscle contraction, and the overlying skin may be reddened and slightly swollen. Trauma may be recalled as the initiating factor, but as the months pass, other muscles not injured in any recognizable way become similarly involved. At first, radiographs reveal no important changes, but within 6 to 12 months, calcium deposits are observed, and one can feel stony-hard masses within the muscles. As the disease advances, limitation of movement and deformities become increasingly evident. Calcified bridges between adjacent muscles and across joints lead to rigidity


Neurology_Adams

Neurology_Adams. masses within the muscles. As the disease advances, limitation of movement and deformities become increasingly evident. Calcified bridges between adjacent muscles and across joints lead to rigidity of the spine, jaw, and limbs; scoliosis; and limited expansion of the thorax. Ultimately, the patient is virtually “changed to stone.” A genetic basis for one type, fibrodysplasia ossificans progressiva, has been determined.


Neurology_Adams

Neurology_Adams. The principal problem in diagnosis is to differentiate generalized myositis ossificans from calcinosis universalis. The latter usually occurs in relation to scleroderma or polymyositis and is characterized by calcium deposits in the skin, subcutaneous tissues, and connective tissue sheaths around the muscles; in myositis ossificans, there is actual bone formation within the muscles. The pathologic data are often too meager to justify this sharp distinction. The prolonged ingestion of large doses of vitamin D may also result in the deposition of masses of calcium salts around muscles, joints, and subcutaneous tissue. Calcific deposits, perhaps true ossification, may occur in the soft tissues around the hips and knees of paraplegics and rarely following a hemiplegia (“paralytic myositis ossificans”) or other causes of prolonged immobilization such as casting.


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Neurology_Adams. Myositis ossificans may undergo spontaneous remissions and may stabilize for many years, during which the patient is capable of adequate function. In other cases, progression leads to marked debilitation and respiratory embarrassment, the final illness often being a terminal pneumonia or other infection. The molecular basis for myositis ossificans is unknown, but it has been suggested that one causative defect is the overexpression of bone morphogenic protein. In mice, the forced expression of this protein induces heterotopic bone formation. It is likely that the primary problem arises either because of inappropriate expression of one element of the protein or of excessive binding between signaling proteins and their receptors.


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Neurology_Adams. The administration of a diphosphonate (ethane-1- hydroxy-1,1-diphosphate [EHDP], 10 to 20 mg/kg orally), a compound that inhibits the deposition of calcium phosphate, has been said to cause regression of new swellings and to prevent calcification. Some of the calcium deposits in calcinosis universalis have receded in response to prednisone, and because of the unclear relationship of this disease to generalized myositis ossificans, it is probably advisable to try this form of therapy as well. Excision of bony deposits may be undertaken if it is certain that they are the cause of particular disabilities. Adams RD: Thayer lectures: I. Principles of myopathology: II. Principles of clinical myology. Johns Hopkins Med J 131:24, 1972. Adams RD, Kakulas BA, Samaha FA: A myopathy with cellular inclusions. Trans Am Neurol Assoc 90:213, 1965.


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Neurology_Adams. Adams RD, Kakulas BA, Samaha FA: A myopathy with cellular inclusions. Trans Am Neurol Assoc 90:213, 1965. Aleksic S, Budzilovich C, Choy A: Congenital ophthalmoplegia in oculoauriculovertebral dysplasia hemifacial microsomia (Golden-har-Gorlin syndrome). Neurology 26:638, 1976. Amato AA, Griggs RC: Unicorns, dragons, polymyositis, and other mythological beasts. Neurology 61:288, 2003. Amato AA, Gronseth GS, Jackson CE, et al: Inclusion body myositis: Clinical and pathological boundaries. Ann Neurol 40:581, 1996. Amato AA, Russell J: Neuromuscular Disease. New York, McGraw-Hill, 2008. Amato AA, Sivakumar K, Goyal N, et al: Treatment of sporadic inclusion body myositis with bimagrumab. Neurology 83:2239, 2014. Andreu AL, Hanna MG, Reichman H, et al: Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N Engl J Med 341:1037, 1999. Antony JH, Procopis PG, Ouvrier RA: Benign acute childhood myositis. Neurology 29:1068, 1979.


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Neurology_Adams. Antony JH, Procopis PG, Ouvrier RA: Benign acute childhood myositis. Neurology 29:1068, 1979. Armstrong RB: Mechanisms of exercise-induced, delayed onset muscular soreness: A brief review. Med Sci Sports Exerc 16:529, 1984. Awerbuch GI, Nigro MA, Wishnow R: Beevor’s sign and facioscapulohumeral dystrophy. Arch Neurol 47:1208, 1990. Azher SN, Jankovic J: Camptocormia. Pathogenesis, classification, and response to therapy. Neurology 65:355, 2005. Banker BQ: Congenital deformities, in Engel AG, Franzini- Armstrong C (eds): Myology, 3rd ed. New York, McGraw-Hill, 2004, pp 1931–1962. Banker BQ: Dermatomyositis of childhood: Ultrastructural alterations of muscle and intramuscular blood vessels. J Neuropathol Exp Neurol 34:46, 1975. Banker BQ: Other inflammatory myopathies, in Engel AG, Franzini-Armstrong C (eds): Myology, 2nd ed. New York, McGraw-Hill, 1994, pp 1461–1486.


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Neurology_Adams. Banker BQ: Other inflammatory myopathies, in Engel AG, Franzini-Armstrong C (eds): Myology, 2nd ed. New York, McGraw-Hill, 1994, pp 1461–1486. Banker BQ: Parasitic myositis, in Engel AG, Franzini-Armstrong C (eds): Myology, 3rd ed. New York, McGraw-Hill, 2004, pp 1419–1444. Banker BQ, Chester CS: Infarction of thigh muscle in the diabetic patient. Neurology 23:667, 1973. Banker BQ, Victor M: Dermatomyositis (systemic angiopathy) of childhood. Medicine (Baltimore) 45:261, 1966. Banker BQ, Victor M, Adams RD: Arthrogryposis multiplex due to congenital muscular dystrophy. Brain 80:319, 1957. Barbeau A: The syndrome of hereditary late onset ptosis and dysphagia in French Canada, in Kuhn EE (ed): Progressive Muskeldystrophies, Myotonie, Myasthenie. New York, Springer-Verlag, 1966. Barohn RJ, Amato AA, Sahenk Z, et al: Inclusion body myositis: Explanation for poor response to immunosuppressive therapy. Neurology 45:1302, 1995.


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Neurology_Adams. Barohn RJ, Amato AA, Sahenk Z, et al: Inclusion body myositis: Explanation for poor response to immunosuppressive therapy. Neurology 45:1302, 1995. Barohn RJ, Jackson CE, Rogers SJ, et al: Prolonged paralysis due to non-depolarizing neuromuscular blocking agents and corticosteroids. Muscle Nerve 17:647, 1994. Bassez G, Authier FJ, Lechat-Zakman E, et al: Inflammatory myopathy with abundant macrophages (IMAM). A condition sharing similarities with cytophagic histiocytic panniculitis and distinct from macrophagic myofasciitis. J Neuropathol Exp Neurol 62:464, 2003. Batten FE, Gibb HP: Myotonia atrophica. Brain 32:187, 1909. Becker PE, Keiner F: Eine neue X-chromosomale muskeldystrophie. Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr 193:427, 1955. Ben Hamida M, Fardeau M, Attia N: Severe childhood muscular dystrophy affecting both sexes and frequent in Tunisia. Muscle Nerve 6:469, 1983.


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Neurology_Adams. Ben Hamida M, Fardeau M, Attia N: Severe childhood muscular dystrophy affecting both sexes and frequent in Tunisia. Muscle Nerve 6:469, 1983. Bethlem J, Arts WF, Dingemans KP: Common origin of rods, cores, miniature cores, and focal loss of cross-striations. Arch Neurol 35:555, 1978. Bethlem J, van Wijngaarden GK: Benign myopathy with autosomal dominant inheritance: A report on three pedigrees. Brain 99:91, 1976. Blau HM: Cell therapies for muscular dystrophy. N Engl J Med 359:1403, 2008. Blexrud MD, Windebank AJ, Daube JR: Long-term follow-up of 121 patients with benign fasciculations. Ann Neurol 34:622, 1993. Braakhekke JP, De Bruin MI, Stegeman DF, et al: The second wind phenomenon in McArdle’s disease. Brain 109:1087, 1986. Brody I: Muscle contracture induced by exercise: A syndrome attributable to decreased relaxing factor. N Engl J Med 281:187, 1969.


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Neurology_Adams. Brody I: Muscle contracture induced by exercise: A syndrome attributable to decreased relaxing factor. N Engl J Med 281:187, 1969. Brouwer R, Hensgstman GJD, Egberts WV, et al: Autoantibody profiles in the sera of European patients with myositis. Ann Rheum Dis 60:116, 2001. Buchbinder R, Hill CL: Malignancy in patients with inflammatory myopathy. Curr Rheumatol Rep 4:415, 2002. Bushby KMD: Making sense of the limb girdle muscular dystrophies. Brain 122:1403, 1999. Byers TJ, Neumann PE, Beggs AH, Kunkel LM: ELISA quantitation of dystrophin for the diagnosis of Duchenne and Becker muscular dystrophies. Neurology 42:570, 1992. Chahin N, Selcen D, Engel AG: Sporadic late onset nemaline myopathy. Neurology 65:1158, 2005. Cori GT, Cori CF: Glucose-6-phosphatase of the liver in glycogen storage disease. J Biol Chem 199:661, 1952. Cros D, Harnden P, Pouget J, et al: Peripheral neuropathy in myotonic dystrophy: A nerve biopsy study. Ann Neurol 23:470, 1988.


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Neurology_Adams. Victor M, Hayes R, Adams RD: Oculopharyngeal muscular dystrophy: A familial disease of late life characterized by dysphagia and progressive ptosis of the eyelids. N Engl J Med 267:1267, 1962. Vignos PJ: Physical models of rehabilitation in neuromuscular disease. Muscle Nerve 6:323, 1983. Vissing J, Haller RG: The effect of oral sucrose on exercise tolerance in patients with McArdle’s disease. N Engl J Med 349:2503, 2003. Walton JN: The idiopathic inflammatory myopathies and their treatment. J Neurol Neurosurg Psychiatry 54:285, 1991. Walton JN, Adams RD: Polymyositis. London, Livingstone, 1958. Walton JN, Karpati G, Hilton-Jones D (eds): Disorders of Voluntary Muscle, 6th ed. Edinburgh, UK, Churchill Livingstone, 1994. Walton JN, Nattrass FS: On the classification, natural history and treatment of myopathies. Brain 77:169, 1954. Welander L: Myopathia distalis tarda hereditaria. Acta Med Scand 141(Suppl 265):1, 1951.


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Neurology_Adams. Welander L: Myopathia distalis tarda hereditaria. Acta Med Scand 141(Suppl 265):1, 1951. Whitaker JN, Engel WK: Vascular deposits of immunoglobulin and complement in idiopathic inflammatory myopathy. N Engl J Med 286:333, 1972. Wintzen AR, Bots GTH, DeBakker HM, et al: Dysphagia in inclusion body myositis. J Neurol Neurosurg Psychiatry 51:1542, 1988. Wohlfart G, Fex J, Eliasson S: Hereditary proximal spinal muscle atrophy simulating progressive muscular dystrophy. Acta Psychiatr Neurol Scand 30:395, 1955.


Neurology_Adams

Neurology_Adams. Wohlfart G, Fex J, Eliasson S: Hereditary proximal spinal muscle atrophy simulating progressive muscular dystrophy. Acta Psychiatr Neurol Scand 30:395, 1955. Figure 45-1. Schematic of the major subcellular components of a myofibril. The transverse (T) system, which is an invagination of the plasma membrane of the cell, surrounds the myofibril midway between the Z lines and the center of the A bands; the T system is approximated to, but apparently not continuous with, dilated elements (terminal cisternae) of the sarcoplasmic reticulum on either side. Thus, each sarcomere (the repeating Z-line-to-Z-line unit) contains two “triads,” each composed of a pair of terminal cisternae on each side of the T tubule. (From Peter, by permission.)


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Neurology_Adams. Figure 45-2. The molecular organization of the dystrophin-glycoprotein complex in the membrane and sarcolemma and endoplasmic reticulum-Golgi apparatus. These proteins are related to Duchenne, limb-girdle, Miyoshi, and certain congenital dystrophies. Details in text. Figure 45-3. Expanded schematic of the nuclear and contractile proteins of the muscle. These proteins are referable to Emery-Dreifuss dystrophy and a number of the distal and the congenital dystrophies, as well as several of the limb-girdle dystrophies. Details in text. Chapter 45 Diseases of Muscle Disorders of the Neuromuscular Junction, Myotonias, and Persistent Muscle Fiber Activity


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Neurology_Adams. Chapter 45 Diseases of Muscle Disorders of the Neuromuscular Junction, Myotonias, and Persistent Muscle Fiber Activity These disorders are discussed together because they cause weakness or changes in salience of the musculature but are not strictly speaking disease of muscle, instead having their origins in problems with the terminal motor axons or neuromuscular junction, the ends of the line in motor transmission, so to speak. Their pathophysiology and clinical features sometimes overlap with immune mechanisms that underlie a number of them. In most ways, however, they stand apart from each other but are most efficiently described together here.


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Neurology_Adams. Included under this category is a group of diseases, the most important of which is myasthenia gravis. Most of these disorders exhibit the characteristic and striking features of fluctuating weakness and fatigability of muscle. Some degree of weakness is usually present at all times but it is made worse by activity. The weakness and fatigability reflect physiologic abnormalities of the neuromuscular junction that are demonstrated by clinical signs and by special electrophysiologic testing. As an aid to understanding the diseases discussed in this chapter, the reader should consult the discussion of the structure and function of the neuromuscular synapse given in Chap. 2.


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Neurology_Adams. The cardinal feature of myasthenia gravis, usually referred to simply as myasthenia, is fluctuating weakness of voluntary (skeletal) muscles, particularly those innervated by motor nuclei of the brainstem, that is, ocular, masticatory, facial, deglutitional, and lingual. Manifest weakening during continued activity, quick restoration of power with rest, and dramatic improvement in strength following the administration of anticholinesterase drugs such as neostigmine are the other notable characteristics. Myasthenia is an immune disease in which circulating antibodies against components of the motor postsynaptic membrane and subsequent structural changes in that membrane explain virtually all the features of the disease.


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Neurology_Adams. Historical note Several students of medical history affirm that Willis, in 1672, gave an account of a disease that could be none other than myasthenia gravis. Others give credit to Wilks (1877) for the first description and for having noted that the medulla was free of disease, in distinction to other types of bulbar paralyses. The first reasonably complete accounts were those of Erb (1878), who characterized the disease as a bulbar palsy without an anatomic lesion, and of Goldflam (1893); for many years thereafter, the disorder was referred to as the Erb-Goldflam syndrome. Jolly (1895) was the first to use the name myasthenia gravis, to which he added the term pseudoparalytica to indicate the lack of structural changes at autopsy. Also it was Jolly who demonstrated that myasthenic weakness could be reproduced in affected patients by repeated faradic stimulation of the motor nerve and that the “fatigued” muscle would still respond to direct galvanic stimulation of its membrane.


Neurology_Adams

Neurology_Adams. weakness could be reproduced in affected patients by repeated faradic stimulation of the motor nerve and that the “fatigued” muscle would still respond to direct galvanic stimulation of its membrane. Interestingly, he suggested the use of physostigmine as a form of treatment but there the matter rested until Reman, in 1932, and Walker, in 1934, demonstrated the therapeutic value of the drug. The relationship between myasthenia gravis and tumors of the thymus gland was first noted by Laquer and Weigert in 1901, and in 1949, Castleman and Norris gave the first detailed account of the pathologic changes in the gland.


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Neurology_Adams. In 1905, Buzzard published a careful clinicopathologic analysis of the disease, commenting on both the thymic abnormalities and the infiltrations of lymphocytes (called lymphorrhages) in muscle. In 1973 and subsequently, the autoimmune nature of myasthenia gravis was established through a series of investigations by Patrick and Lindstrom, Fambrough, Lennon, and A.G. Engel (1977) and their colleagues (see in the following text). These and other references to the historical features of the disease can be found in the reviews by Viets and by Kakulas and Adams; A.G. Engel’s monograph (1999) is an excellent comprehensive reference.


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Neurology_Adams. The clear demonstration of an immunologic mechanism operative at the neuromuscular junction was the most significant development in our understanding of myasthenia gravis. Patrick and Lindstrom discovered that repeated immunization of rabbits with AChR protein obtained from the electric eel caused a muscular weakness (contrary to what is stated in some books, their discovery was not accidental). Lennon and colleagues recognized this model as being similar to that of myasthenia gravis. Soon thereafter, Fambrough and coworkers demonstrated that the basic defect in myasthenia gravis was a marked reduction in the number of ACh receptors on the postsynaptic membrane of the neuromuscular junction. These observations were followed by the creation of an experimental model of the disease and the demonstration that experimentally induced myasthenia had clinical, pharmacologic, and electrophysiologic properties identical with those of human myasthenia gravis (Engel et al, 1976). It was also


Neurology_Adams

Neurology_Adams. demonstration that experimentally induced myasthenia had clinical, pharmacologic, and electrophysiologic properties identical with those of human myasthenia gravis (Engel et al, 1976). It was also shown that humoral antibodies directed against protein components of AChR could transfer the myasthenic weakness to normal animals, and that the weakness as well as the physiologic abnormalities could be reversed by the administration of anticholinesterase drugs. Thus, the accumulated evidence satisfied the criteria for the diagnosis of an autoantibody-mediated disorder (Drachman, 1990).


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Neurology_Adams. Epidemiology Certain epidemiologic features of the disease are of clinical interest. Its prevalence is variously estimated to be from 43 to 84 per million persons and the annual incidence rate is approximately 1 per 300,000. The disease may begin at any age, but onset in the first decade is relatively rare (only 10 percent of cases begin in children younger than 10 years of age). The peak age of first symptoms is between 20 and 30 years in women and between 50 and 60 years in men. Under the age of 40, females are affected two to three times as often as males whereas in later life, the incidence in males is higher (3:2). Of patients with thymomas, the majority is older (50 to 60 years) and males predominate.


Neurology_Adams

Neurology_Adams. Familial occurrence of myasthenia is known, but it is rare. Many such cases prove to have one of the genetically determined myasthenic syndromes and not the acquired autoimmune form of disease (see further on). More common is a family history of one of the autoimmune diseases enumerated earlier. For example, in the series reported by Kerzin-Storrar and associates 30 percent had a maternal relative with a connective tissue disease, suggesting that myasthenia gravis patients inherit a susceptibility to autoimmune disease. Two of our patients have sisters with lupus. There have also been reports of the concurrence of myasthenia and multiple sclerosis, but this association is less certain. There is an increased representation of HLA-B8 and -DR3 haplotypes, as occurs in other autoimmune diseases, which are discussed further on.


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Neurology_Adams. HLA-B8 and -DR3 haplotypes, as occurs in other autoimmune diseases, which are discussed further on. Myasthenia gravis, as the name implies, formerly had a grave prognosis, perhaps less so today but still associated with considerable morbidity. As mentioned, repeated or persistent activity of a muscle group exhausts contractile power, leading to a progressive paresis, and rest restores strength, at least partially. These features, concentrated in the palpebral, ocular, and the oro-facial-lingual muscles are the identifying attributes of the disease and their demonstration is usually enough to establish the diagnosis on clinical grounds.


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Neurology_Adams. The special vulnerability of the neuromuscular junctions in certain muscles gives myasthenia its highly characteristic clinical appearance. Usually the eyelids and the muscles of eye movement, and somewhat less often, of the face, jaws, throat, and neck, are the first to be affected. Infrequently, the initial complaint is referable to the limbs or to breathing. Specifically, weakness of the levator palpebrae or extraocular muscles is the initial manifestation of the disease in about half the cases, and these muscles are involved eventually in more than 90 percent. Ocular palsies and ptosis are usually accompanied by weakness of eye closure, a combination that is virtually always indicative of the disease although it may be observed in certain muscular dystrophies. Diplopia is quite common in myasthenia, but it does not correspond to the innervatory pattern of a nerve; instead, it is the result of asymmetrical weakness of several muscles in both eyes. As the disease advances, it


Neurology_Adams

Neurology_Adams. common in myasthenia, but it does not correspond to the innervatory pattern of a nerve; instead, it is the result of asymmetrical weakness of several muscles in both eyes. As the disease advances, it spreads insidiously from the cranial to the limb and axial muscles, but there are instances of fairly rapid development, sometimes initiated by an infection, usually respiratory. In rare cases, the distal extremity muscles may be involved, such as the “myasthenic hand” described by Janssen and colleagues. Symptoms may first appear during pregnancy or, more commonly, during puerperium or in response to paralytic drugs used during general anesthesia.


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Neurology_Adams. In addition to special circulating autoantibodies, inflammatory thymic abnormalities of several types are closely connected with the disease, as elaborated further on, and weakness may begin months or years before or after removal of a thymoma.


Neurology_Adams

Neurology_Adams. Particular ocular signs are highly characteristic of myasthenia. For example, sustained upgaze (for 30 or more seconds) will usually induce or exaggerate ptosis and may uncover myasthenic ocular motor weakness, thereby marking it as “fatigable.” Another characteristic sign, not as frequently elicitable as fatigable ptosis, was described by Cogan and is a twitching of the upper eyelid that appears a moment after the patient moves the eyes from a downward to the primary position (“lid-twitch” sign). Or, after sustained upward gaze, one or more twitches may be observed upon closure of the eyelids or during horizontal movements of the eyes. Repeated ocular versions when tracking a target or by an optokinetic stimulus may disclose progressive paresis of the muscles that carry out these movements. Unilateral painless ptosis without either ophthalmoplegia or pupillary abnormality in an adult will most often prove to be due to myasthenia. Usually, there is subtle ptosis of the other eye that


Neurology_Adams

Neurology_Adams. Unilateral painless ptosis without either ophthalmoplegia or pupillary abnormality in an adult will most often prove to be due to myasthenia. Usually, there is subtle ptosis of the other eye that can be revealed by manually elevating the more affected eyelid. Attempts by the patient to overcome ptosis may impart a staring expression of the opposite eye. Bright sunlight is said to aggravate the ocular signs and cold to improve them. The application of an ice pack over the eye often relieves the ptosis for a brief period.


Neurology_Adams

Neurology_Adams. Muscles of facial expression, mastication, swallowing, and speech are affected in 80 percent of patients at some time in the illness, and in 5 to 10 percent, these are the first or only muscles to be involved. Less frequent is early involvement of the flexors and extensors of the neck, muscles of the shoulder girdle, and flexors of the hips. (This pattern may be associated with a special autoantibody as will be discussed later.) Of the trunk muscles, the erector spinae are the most frequently affected. In the most advanced cases, all muscles are weakened, including the diaphragmatic, abdominal, and intercostal, and even the external (skeletal muscle) sphincters of the bladder and bowel. As the disease progresses, the involvement of any group of muscles closely parallels their degree of weakness early in the disease. The clinical rule also holds that the proximal muscles are far more vulnerable than distal ones, as they are in most other forms of myopathy.


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Neurology_Adams. Another characteristic and understandable feature of myasthenic weakness is its tendency to increase as the day wears on or with repeated use of an affected muscle group but curiously, patients seldom volunteer this information. A few patients report paradoxical worsening on awakening, especially if they have not taken medication during the night but a larger proportion of patients are close to asymptomatic after a night’s rest. In general terms, therefore, myasthenia gravis may be conceived as a fluctuating and fatigable oculofaciobulbar palsy.


Neurology_Adams

Neurology_Adams. Other features result from the topography and fatigability of the disease. The natural smile becomes transformed into a snarl; the jaw may sag, so that it must be propped up by the patient’s hand; chewing tough food may be difficult and the patient may have to terminate a meal because of inability to masticate and swallow. It may be more difficult to eat after talking, and the voice fades and becomes nasal after sustained conversation. Women may complain of inability to fix their hair or makeup because of fatigue of the shoulders, or of difficulty in applying lipstick because they are unable to purse and roll their lips. Weakness of the neck muscles causes fatigue in holding up the head. In cases with generalized weakness, there is difficulty in retaining flatus because of weakness of the external rectal sphincter.


Neurology_Adams

Neurology_Adams. A peculiarity of myasthenic muscle contraction that may be observed occasionally is a sudden lapse of sustained posture or interruption of movement resulting in a kind of irregular tremor, similar to that of normal muscle nearing the point of exhaustion. A dynamometer demonstrates the rapidly waning power of contraction of a series of hand grips, and repetitive stimulation of a motor nerve at slow rates while recording muscle action potentials shows the same decremental strength in a quantitative fashion (see Fig. 2-15A and in the following text).


Neurology_Adams

Neurology_Adams. Weakened muscles in myasthenia gravis undergo atrophy to only a minimal degree or not at all. Tendon reflexes are seldom altered. Even repeated tapping of a tendon does not usually tax muscles to the point where contraction fails. Smooth and cardiac muscles are not involved and other neural functions are preserved. Weakened muscles, especially those of the eyes and back of the neck, may ache, but pain is seldom an important complaint. Paresthesias of the face, hands, and thighs are reported infrequently but are not accompanied by demonstrable sensory loss. The tongue may display one central and two lateral longitudinal furrows (trident tongue), as pointed out originally by Buzzard; the tongue may be atrophic in the MuSK (muscle-specific tyrosine kinase) form of disease.


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Neurology_Adams. Patients with MuSK antibody, mostly women, have a special clinical syndrome of prominent oculobulbar weakness (Scuderi et al), or severe disease characterized by respiratory crises (see also Evoli et al). Others have reported a different pattern of mainly neck and proximal weakness that simulates a myopathy. Many of these patients are inadequately responsive to anticholinesterase treatment. Clinical grading To facilitate clinical staging of therapy and prognosis, the classification introduced by Osserman remains useful; it can be found in his monograph cited in the references and in previous editions of this book. This system has been replaced by a scheme suggested by a task force of the Myasthenia Gravis foundation (see Jaretzki et al) as reproduced here.


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Neurology_Adams. Others, for example, Compston and colleagues, have proposed a classification based on a constellation of the age of onset, presence or absence of thymoma, antibody level against acetylcholine receptor (AChR), and association with human leukocyte antigen (HLA) haplotypes. Their system is as follows: (1) myasthenia gravis with thymoma—no sex or HLA association, high AChR antibody titer; (2) onset before age 40, no thymoma—female preponderance and an increased association with HLA A1, B8, and DRW3 antigens; (3) onset after age 40, no thymoma—male preponderance, increased association with HLA A3, B7, and DRW2 antigens, low AChR antibody titer. The last group includes a proportion of older men with purely ocular symptoms (formerly Osserman type I). Classifications such as these are meant to capture certain types and contexts of myasthenia more than to convey the severity of illness.


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Neurology_Adams. The course of the illness is extremely variable. Rapid spread from one muscle group to another occurs in some, but in others the disease remains unchanged for years before progressing or there is no progression. Remissions may take place without explanation, usually in the first years of illness, but these happen in less than half the cases and seldom last longer than a month or two. If the disease remits for a year or longer and then recurs, it then tends to be steadily progressive. Relapse may also be occasioned by the same events that in some cases preceded the onset of the illness, especially infections.


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Neurology_Adams. In Simpson’s opinion, and this coincides with our observations, the danger of death from generalized myasthenia gravis is greatest in the first year after onset of the disease. A second period of danger in progressive cases is from 4 to 7 years after onset. After this time, the disease tends to stabilize and the risk of severe relapse diminishes. Fatalities relate mainly to the respiratory complications of pneumonia and aspiration. The mortality rate in the first years of illness, formerly in excess of 30 percent, is now less than 5 percent and with appropriate therapy virtually all patients lead normal lives.


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Neurology_Adams. An aspect of interest is the timing and frequency of conversion from ocular and restricted oropharyngeal patterns of weakness to more widespread involvement including the diaphragm. Bever and coworkers have confirmed the general impression that an increasing duration of purely ocular myasthenia is associated with a decreasing risk of late generalization of weakness. In a retrospective study of 108 patients, these authors found that only 15 percent of the observed instances of generalization occurred more than 2 years after isolated ocular manifestations.


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Neurology_Adams. A later age at onset was also associated with a higher incidence of fatal respiratory crises. In general, patients whose disease begins at a younger age run a more benign course. Grob and colleagues, who recorded the course of an astonishing 1,036 patients for a mean duration of 12 years, found that the clinical manifestations remained confined to the extraocular muscles and orbicularis oculi in 16 percent. Their data further indicated that localized ocular myasthenia present for only a month was associated with a 60 percent likelihood that the disease would generalize, but in those cases that remained restricted for more than a year, only 16 percent became generalized. In contrast, of 37 consecutive cases carefully studied by Weinberg et al with only ocular signs, 17 had more widespread weakness within a period of 6 years. Also informative in Grob’s series was that in 67 percent the disease attained its maximum severity within a year of onset, and in 83 percent, within 3 years. It


Neurology_Adams

Neurology_Adams. weakness within a period of 6 years. Also informative in Grob’s series was that in 67 percent the disease attained its maximum severity within a year of onset, and in 83 percent, within 3 years. It has been stated that the progression of symptoms is more rapid in male than in female patients.


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Neurology_Adams. It is not widely recognized that isolated muscle groups may occasionally remain permanently weak even when the ocular and generalized weakness has resolved. The muscles most often affected in this way are the anterior tibialis, triceps, and portions of the face. The long-term outlook for children with myasthenia is better than it is for adults, and their life expectancy is only slightly reduced. Rodriguez and colleagues followed a group of 149 children for an average of 17 years; 85 of them had thymectomies, one of the main treatments for myasthenia as discussed further on. Approximately 30 percent of the nonthymectomized and 40 percent of the thymectomized patients underwent remission and were free of symptoms, usually in the first 3 years of illness. Those children with bulbar symptoms and no ocular or generalized weakness had the most favorable outcome.


Neurology_Adams

Neurology_Adams. A nonneoplastic lymphofollicular hyperplasia of the thymic medulla occurs in 65 percent or more of cases of myasthenia and thymic tumors occur in 10 to 15 percent. Thymomas with malignant characteristics may spread locally in the mediastinum and to regional lymph nodes but they rarely metastasize beyond these structures; when they do, the lungs and liver are usually affected. It should be emphasized that thymic enlargement and tumors may be missed in plain films of the chest and should be sought by CT with contrast.


Neurology_Adams

Neurology_Adams. A striking degree of hyperplasia of the medulla of the thymus characterized by lymphoid follicles with active germinal centers is found in the majority of cases. Hyperplasia is even more frequent in younger patients in the third and fourth decades. The cells in the centers of the follicles are histiocytes surrounded by helper T lymphocytes, B lymphocytes, and plasma cells; immunoglobulin G (IgG) is elaborated in the germinal follicles. These resemble the cellular reaction observed in the thyroid tissue of Hashimoto thyroiditis. Because the latter disease has been reproduced in animals by injecting extracts of thyroid with Freund adjuvants, it had long ago been suggested that the so-called thymitis of myasthenia gravis is the result of a similar autoimmune sensitization but the inciting events for this process are entirely unknown. Immunosuppression with steroids causes involution of the thymus.


Neurology_Adams

Neurology_Adams. With regard to thymic tumors, two forms have been described: one composed of histiocytic cells like the reticulum cells in the center of the follicles, and the other predominantly lymphocytic and considered to be lymphosarcomatous. Some of the tumors have a high proportion of spindle-shaped cells. Overlapping types have been common. Thymic tumors may be unattended by myasthenia, though myasthenia has eventually developed in all of the cases under our observation, sometimes 15 to 20 years after the tumor was removed surgically. According to Bril and colleagues, the severity of myasthenic symptoms is no different in patients with thymoma than it is from that in patients without a tumor, but our impression has been that patients with tumors, particularly children, often have a peculiar clinical course. For example, we have observed unexpected sudden remissions and severe relapses, as well as resistance to medications.


Neurology_Adams

Neurology_Adams. Many contemporary studies, including more than 40 autopsies at our hospitals, have confirmed Erb’s original contention that myasthenia gravis is a disease without a central nervous system lesion. The brain and spinal cord are normal unless damaged by hypoxia and hypotension from cardiorespiratory failure. Furthermore, the muscle fibers are generally intact, although in fatal cases with extensive paralysis, isolated fibers of esophageal, diaphragmatic, and eye muscles may undergo segmental necrosis with variable regeneration (Russell). Scattered aggregates of lymphocytes (lymphorrhages) are also observed, as originally noted by Buzzard, but none of these changes in muscle explains the widespread and severe weakness.


Neurology_Adams

Neurology_Adams. The main ultrastructural alterations occur in the motor endplate. These changes, elegantly demonstrated by A.G. Engel and associates (1976, 1977, 1987), consist of a reduction and simplification in the surface area of the postsynaptic membrane (sparse, shallow, abnormally wide, or absent secondary synaptic clefts) and a widening of the synaptic cleft (Fig. 46-1). The number and size of the presynaptic vesicles and their quanta of acetylcholine (ACh) are normal. The observation of regenerating axons near the junction, the many simplified junctions, and the absence of nerve terminals supplying some postsynaptic regions suggested to Engel and coworkers (1976, 1977, 1987) that there was an active process of degeneration and repair of the neuromuscular junction, particularly of the postsynaptic side.


Neurology_Adams

Neurology_Adams. Although not directly relevant to myasthenia, it is of interest that a number of curious neurologic disorders occur in association with thymoma. Among our own patients were 2 with “limbic encephalitis” with memory loss and confusion that could not be differentiated from the paraneoplastic variety of encephalitis (see Chap. 30), 1 case of midbrain encephalitis, 1 of Morvan’s fibrillary chorea (see further on), and 1 of aplastic anemia. Some of these neurologic processes are associated with antibodies directed against voltage-gated potassium channels (VGKC). Such cases appear in the literature, and all are considered to have a humoral immune basis.


Neurology_Adams

Neurology_Adams. Of biologic and even greater clinical importance is the coexistence of myasthenia gravis and other autoimmune diseases. Thyrotoxicosis with periodic paralysis (5 percent of myasthenic patients), lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, mixed connective tissue disease, anticardiolipin antibody, and (curiously) polymyositis have all been associated with myasthenia more often than can be explained by chance. A proportion of young women with myasthenia have moderately elevated titers of antinuclear antibody without the clinical manifestations of systemic lupus.


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Neurology_Adams. The present view, well founded, is that myasthenic weakness and fatigue are a result of the failure of effective neuromuscular transmission on the postsynaptic side. The greatly reduced number of receptors and the competitive activity of anti-AChR antibodies (see later) produce postsynaptic potentials of insufficient amplitude to discharge some muscle fibers. Blocked transmission at many endplates results in a reduction in the contractile power of the muscle. This deficiency is reflected first in the ocular and cranial muscles that are both the most continuously active and have the fewest AChRs per motor unit. Fatigue is understandable as the result of the normal decline in the amount of ACh released with each successive impulse.


Neurology_Adams

Neurology_Adams. Antibodies to AChR protein are present in more than 85 percent of patients with generalized myasthenia and in 60 percent of those with ocular myasthenia (Newsom-Davis). The presence of receptor antibodies has proved to be a reasonably sensitive and reliable test of the disease, as discussed later. The manner in which the antibodies that are directed against proteins in the intracellular compartment (such as anti-MuSK discussed later) causes weakness is not known. Neuromuscular transmission is therefore impaired in several ways: (1) the antibodies block the binding of ACh to the AChR; (2) serum IgG from myasthenic patients has been shown to induce an increase in the degradation rate of AChR. This may be the result of the capacity of antibodies to cross-link the receptors; (3) antibodies cause a complement-mediated destruction of the postsynaptic folds (Engel and Arahata).


Neurology_Adams

Neurology_Adams. Although the evidence that an autoimmune mechanism is responsible for the functional disorder of muscle in myasthenia gravis is incontrovertible, the source of the autoimmune response has not been established. Because most patients with myasthenia have thymic abnormalities and a salutary response to thymectomy, it is logical to implicate the lymphoid reaction in this gland in the pathogenesis of the disease. Both T and B cells from the myasthenic thymus are particularly responsive to the AChR, more so than analogous cells from peripheral blood. Moreover, the thymus contains “myoid” cells (resembling striated muscle) that bear surface AChR. It is not known with certainty that thymic myoid cells are the source of immunologic stimulation in myasthenia gravis. The most obvious objection is that such cells are even more abundant in the normal than in the myasthenic thymus (according to Schluep et al). Another suggested pathogenesis, yet unconfirmed, is that a virus with a tropism for


Neurology_Adams

Neurology_Adams. is that such cells are even more abundant in the normal than in the myasthenic thymus (according to Schluep et al). Another suggested pathogenesis, yet unconfirmed, is that a virus with a tropism for thymic cells might alter such cells and induce antibody formation. A viral infection might at the same time have a potential for oncogenesis, accounting for thymic tumors, but this is all speculative. Scadding and associates have suggested a different mode of thymic involvement; they have shown that thymic lymphocytes from patients with myasthenia gravis can synthesize anti-AChR antibody, both in culture and spontaneously.


Neurology_Adams

Neurology_Adams. In patients who present with a changeable, specifically fatigable, diplopia or ptosis and the typical myasthenic facies—unequally drooping eyelids, relatively immobile mouth turned down at the corners, a smile that looks more like a snarl, a hanging jaw supported by the hand—the diagnosis can hardly be overlooked. However, only a few patients display this fully developed syndrome. Ptosis, diplopia, difficulty in speaking or swallowing, or weakness of the limbs is at first mild and inconstant and may be mistaken for a cerebrovascular disease. However, the finding that sustained activity of small cranial muscles results in weakness (e.g., increasing droop of eyelids while looking at the ceiling or diplopia when fixating in lateral or vertical gaze or reading for 2 to 3 min) and that contraction improves after a brief rest is virtually diagnostic, even in the early stages of the disease. Any other affected group of muscles may be tested in similar fashion. The characteristic ocular signs


Neurology_Adams

Neurology_Adams. improves after a brief rest is virtually diagnostic, even in the early stages of the disease. Any other affected group of muscles may be tested in similar fashion. The characteristic ocular signs have already been described. For confirmation, the measurement of specific antibody (anti-AChR), electromyography, and certain pharmacologic tests described below are necessary. Several special clinical problems and associated conditions are summarized further on.


Neurology_Adams

Neurology_Adams. Electrophysiologic testing Characteristic of myasthenia is a rapid reduction in the amplitude of compound muscle action potentials during a series of repetitive stimulations of a peripheral nerve at a rate of 3 per second (decrementing response as shown in Fig. 2-15A). Reversal of this response by neostigmine or edrophonium has been a reliable confirmatory finding in most cases. A decremental response to stimulation can usually be obtained most often from the proximal limb muscles followed by the facial and, to a lesser extent, the hand muscles, which may or may not be clinically weak. During a progressive phase of the disease or during corticosteroid therapy, a slight initial incrementing response may be obtained, not to be confused with the marked incrementing response after voluntary contraction that characterizes the Lambert-Eaton syndrome (see further on).


Neurology_Adams

Neurology_Adams. Single-fiber electromyography (EMG) represents an even more sensitive method of detecting the defect in neuromuscular transmission. This technique demonstrates an inconstancy of the normally invariant interval between the firing of muscle fibers connected to the same motor unit (“jitter”—see “Single-Fiber Electromyography” in Chap. 2) or complete blocking of successive discharges from single muscle fibers belonging to the same motor unit. The test requires a great deal of cooperation from the patient and that contraction of a muscle be sustained at just the right amplitude in order to isolate single muscle fibers from the same unit. It is also possible to detect such pairs of fibers by electrical stimulation of a nerve. Nerve conduction velocities and distal motor latencies are normal unless there is a coincident polyneuropathy.


Neurology_Adams

Neurology_Adams. Neostigmine test Almost as valuable as electrophysiologic testing is testing with the cholinesterase inhibitors neostigmine and in the past, edrophonium a more rapidly acting agent. These drugs prolong and exaggerate the effects of ACh in the synapse and thereby produce an increment in muscle power in the patient with myasthenia. Edrophonium is variably available in the United States at the time of this writing but neostigmine affords a longer time for observation, as noted in the next paragraph. The tests are performed in the following manner. After the estimation of strength in a cranial (usually the levator palpebrae or an extraocular muscle) or limb muscle (by dynamometry), or vital capacity, neostigmine is injected intramuscularly in a dose of 1.5 mg. Atropine sulfate (0.8 mg) is generally given several minutes in advance to counteract the unpleasant muscarinic effects of neostigmine (salivation, sweating bronchorrhea, borborygmi, bowel cramps and, sometimes, diarrhea).


Neurology_Adams

Neurology_Adams. is generally given several minutes in advance to counteract the unpleasant muscarinic effects of neostigmine (salivation, sweating bronchorrhea, borborygmi, bowel cramps and, sometimes, diarrhea). Neostigmine may alternatively be given intravenously in a dose of 0.5 mg, but its effect is often too brief to be as useful. After intramuscular injection of neostigmine, objective improvement occurs within 10 to 15 min, reaches its peak at 20 min, and lasts up to 1 h, allowing for careful verification of the neurologic improvement. Many neurologists perform this test twice, once with an injection of saline as a control.