Chapter 50. The Myotonias, Periodic Paralyses, Cramps, Spasms, and States of Persistent Muscle Fiber Activity

This chapter considers a category of disorders that is characterized by disturbances of the electrical excitability of the skeletal muscle membrane. Although the main manifestations are episodes of generalized paralysis and myotonia, there are many others. Another related group of diseases are unified by spontaneous and persistent muscle fiber activity and these are addressed in a later part of this chapter. The myotonias have been historically categorized as a special group of muscle diseases unified by the clinical sign of myotonia and were aligned in older classifications with the muscular dystrophies. This view was based on myotonia as it was understood in the classic form of myotonic dystrophy, a subject discussed in Chap. 48. Similarly, before fundamental knowledge of their mechanism was revealed, the periodic paralyses (better called episodic paralysis) were considered to be metabolic diseases of muscle. However, it has become evident that most diseases that feature prominent myotonia and the processes that cause episodic muscular paralysis are neither degenerative nor dystrophic. Clinical and electrophysiologic studies show that myotonia is an elemental feature of many nondystrophic conditions, foremost among them are the hyperkalemic form of periodic paralysis and myotonia congenita. Most of these diseases are caused by mutations in genes that code for chloride, sodium, calcium, or potassium ion channels in the muscle membrane, and they are referred to as ion channel diseases, or as "channelopathies" (see Ryan and Ptácek). Within this group there are also instances of muscle conditions that display no myotonia but only periodic paralysis.

Given that these are disorders of muscle membrane excitability, it is not surprising that the primary defects are in voltage-dependent ion channels. By analogy, it was anticipated that ion channelopathies would be implicated in two other categories of disease in which there is altered membrane excitability, namely the epilepsies and certain cardiac arrhythmias and indeed, this has proven to be the case (see discussion in Chap. 16 on the epilepsies). In the process, several new forms of nondystrophic myotonia have been defined. Molecular studies, notably those of Rüdel, Lehmann-Horn (2004), and Ricker and their associates, identified the fundamental defects in the myotonias and episodic paralyses and clarified their relationships. The biology of the ion channels and their disease-related mutations are reviewed by Hanna and colleagues, by Cannon, and by Heatwole and colleagues.

Table 50-1 summarizes the main features of the ion channel diseases affecting muscle and the individual members of the group are described as follows.

Myotonia Congenita (Thomsen Disease)

This is an uncommon disease of skeletal muscle that begins in early life and is characterized by myotonia, muscular hypertrophy, nonprogressive course, and dominant inheritance. It is distinctly different from myotonic dystrophy, which is characterized by a progressive degeneration of muscle fibers and has a different genetic basis. Thomsen disease is caused by one of several inherited molecular defects in the voltage-dependent chloride channel gene (CLCN1), as first demonstrated by Jentsch and associates (see Koch et al). It is interesting that most mutations behave as dominant traits, whereas others have either a dominant or recessive pattern of inheritance (see Table 50-1). The physiologic mechanism whereby these mutations alter ion fluxes across the muscle membrane and cause myotonia is described further on.

History

The disorder was first brought to the attention of the medical profession in 1876 by Julius Thomsen, a Danish physician who himself suffered from the disease, as did 20 members of his family over 4 generations. His designation of ataxia muscularis was not correct, but his description left no doubt as to the nature of the condition in that it featured "tonic cramps in voluntary muscles associated with an inherited psychical indisposition." The latter aspect of the condition was not borne out by subsequent studies and is now thought to be his erroneous speculation as to causality. In 1881, Strümpell assigned the name myotonia congenita to the disease and in 1883, Westphal referred to it as Thomsen's disease. Erb provided the first description of its pathology and called attention to two additional unique features: muscular hyperexcitability and hypertrophy. In 1923, Nissen, Thomsen's great-nephew, extended the original genealogy to 35 cases in 7 generations, and in 1948, Thomasen updated the subject in a monograph that is still a useful clinical reference.

Clinical Features

Myotonia, a tonic spasm of muscle after forceful voluntary contraction, stands as the cardinal feature and is best represented in this disease. As emphasized in Chap. 45, this phenomenon reflects electrical hyperexcitability of the muscle membrane. It is most pronounced after a period of inactivity. Repeated contractions "wear it out," so to speak, and the later movements in a series become more swift and effective. Rarely, the converse is observed—where only the later movements of a series induce myotonia (myotonia paradoxica); usually this is a feature of another condition, cold-induced paramyotonia congenita (see further on). Unlike cramp, the myotonic spasm is painless but after prolonged activity, nocturnal myalgia (a pinching-aching sensation in the overactive muscles) may develop and prove distressing. Close observation reveals a softness of the muscles during rest and the initial contraction appears not to be significantly slowed.

The disease as mentioned above is usually inherited as a dominant trait so that most often, other members of the family have been affected. Its congenital nature may be evident even in the crib, where the infant's eyes are noted to open slowly after it has been crying or sneezing and its legs are conspicuously stiff as the child tries to take its first steps. In other cases, the myotonia becomes evident only later in the first or second decade. The muscles are generously proportioned and may become hypertrophied but seldom to the degree observed in the recessive form of the disease described further on.

Despite their muscular appearance, these patients are inept in athletic pursuits as a result of the myotonia. When severe, myotonia affects all skeletal muscles but is especially prominent in the lower limbs. Attempts to walk and run are impeded to the extent that the patient stumbles and falls. Other limb and trunk muscles are also thrown into spasm, as are those of the face and upper limbs. One of the characteristic features is grip myotonia in which the patient is unable to release a handshake and must slowly open the fingers one at a time. Occasionally a sudden noise or fright may cause generalized stiffness and falling. Small, gentle movements such as blinking or elicitation of a tendon reflex do not initiate myotonia, whereas strong closure of the eyelids, as in a sneeze, sets up a spasm that may prevent complete opening of the eyes for many seconds. Spasms of extraocular muscles occur in some instances, leading to strabismus. If the patient has not spoken for a time, there is sometimes a striking dysarthria. Arising at night, the patient cannot walk without first moving the legs for a few minutes. After a period of rest, the patient may have difficulty in arising from a chair or climbing stairs. Loosening of one set of muscles after a succession of contractions does not prevent the appearance of myotonia in another area, nor in the same ones if used in another pattern of movement. Smooth and cardiac muscles are not affected and intelligence is normal. Lacking also are the narrow face, frontal balding, cataracts, and endocrine changes typical of myotonic dystrophy that is discussed in Chap. 48. Myotonia that is evident in infancy is far more likely to represent myotonia congenita than myotonic dystrophy, in which myotonia rarely has its onset in the first few years of life.

Myotonia can also be induced in most cases by tapping a muscle belly with a percussion hammer (percussion myotonia). Unlike the lump or ridge produced in hypothyroid or cachectic muscle (myoedema), the myotonic contraction involves an entire fasciculus or an entire muscle and, unlike the phenomenon of idiomuscular irritability (contraction of a fascicle in response to striking the muscle), it persists for several seconds. If tapped, the tongue shows a similar reaction. An electrical stimulus delivered to the motor point in a muscle induces a prolonged contraction (Erb myotonic reaction). In Thomsen disease, as in virtually all forms of myotonia, the stiffness is somewhat exaggerated in cold. On a cold day, affected individuals may have a prolonged grimace with closed eyes after a sneeze. We encountered two brothers with this disorder who described diving into a cool swimming pool on a hot summer day and having to lie nearly motionless at the bottom of the pool for several seconds until the muscle stiffness abated enough to allow them to swim to the top. However, as mentioned, prominent cold-induced myotonia, is more characteristic of paramyotonia congenita (see later).

Biopsy reveals no abnormality other than enlargement of muscle fibers, and this change occurs only in hypertrophied muscles. As often happens in fibers of increased volume, central nucleation is somewhat more frequent than it is in normal muscle. The large fibers contain increased numbers of normally structured myofibrils. In well-fixed biopsy material examined under the electron microscope, Schroeder and Adams discerned no significant morphologic changes.

Myotonia levior was the name applied by DeJong to a dominantly inherited form of myotonia congenita in which the symptoms are milder and of later onset than those of Thomsen disease. In 2 patients of a myotonia levior family, Lehmann-Horn and coworkers (1995) identified a mutation of the same chloride ion channel (CLCN1) that is implicated in Thomsen's disease. Thus it appears that myotonia levior is simply a mild form of Thomsen disease.

Diagnosis

In patients who complain of spasms, cramping, and stiffness, myotonia must be distinguished from several of the disorders of persistent muscle activity described in Chap. 48. None of these disorders displays percussion myotonia or the typical electromyogram (EMG) abnormality of myotonic discharge. The only possible exceptions are the Schwartz-Jampel syndrome of hereditary stiffness combined with short stature and muscle hypertrophy, and stiff-man syndrome which are discussed in Chap. 48.

Uncertainty in diagnosis arises in patients who have only myotonia in early life and later prove to have classic (type 1) myotonic dystrophy or who notice myotonia in adulthood with mild proximal weakness and are found to have type 2 myotonic dystrophy (see later). The myotonia in myotonic dystrophy is usually mild and in several families that we have followed, some degree of weakness and the typical facies of myotonic dystrophy could be appreciated even in early childhood. This is not the case in the less-frequent type 2 myotonic dystrophy in which there are no dysmorphic features (also called proximal myotonic myopathy [PROMM]; see Chap. 48 and further on). In paramyotonia congenita there is also myotonia of early onset, but, again, it tends to be mild, involving mainly the orbicularis oculi, levator palpebrae, and tongue; the diagnosis of paramyotonia is seldom in doubt because of the worsening with continued activity and prominent cold-induced episodes of myotonia and paralysis.

In patients with very large muscles, one must consider not only myotonia congenita but also familial hyperdevelopment, hypothyroid myopathy, the Bruck-de Lange syndrome (congenital hypertrophy of muscles, mental retardation, and extrapyramidal movement disorder), Becker myotonia (see later), Duchenne dystrophy, and most of all, hypertrophic myopathy (hypertrophia musculorum vera); this last disease is of interest because the aberrant protein (myostatin) and gene defect have been characterized. Muscle hypertrophy is not, of course, a feature of myotonic dystrophy. The demonstration of myotonia by percussion and EMG study usually resolves the problem, although in exceptional cases of Thomsen disease, the persistence of contraction may be difficult to demonstrate. In hypothyroidism, the EMG may show bizarre high-frequency (pseudomyotonic) discharges; however, true myotonia does not occur, myoedema is prominent, and, along with other signs of thyroid deficiency, there is slowing of contraction and relaxation of tendon reflexes not seen in myotonia congenita.

Treatment

Quinine is effective in reducing myotonia but is now used infrequently because of the (low) risk of causing torsade de pointes. Procainamide, 250 to 500 mg qid, and mexiletine, 100 to 300 mg tid, are beneficial in relieving the myotonia. Phenytoin, 100 mg tid, is useful in some cases. The cardiac antiarrhythmic drug tocainide (1,200 mg daily) has also proved effective, but it sometimes causes agranulocytosis and is no longer recommended.

Generalized Myotonia (Becker Disease)

This is a second form of myotonia congenita, inherited as an autosomal recessive trait. Like the dominant Thomsen form, it is caused by an allelic mutation of the gene encoding the chloride ion channel of the muscle fiber membrane. The clinical features of the dominant and recessive types are similar except that myotonia in the recessive type does not become manifest until 10 to 14 years of age, or even later, and tends to be more severe in the dominantly inherited variety. The myotonia appears first in the lower limbs and spreads to the trunk, arms, and face. Hypertrophy is invariably present. There may be associated mild distal weakness and atrophy; this was found in the forearms in 28 percent of Becker's 148 patients and in the sternocleidomastoids in 19 percent. Dorsiflexion of the feet was limited and fibrous contractures were common. Weakness may also be present in the proximal leg and arm muscles. The most troublesome aspect of the disease is the transient weakness that follows initial muscle contraction after a period of inactivity. Progression of the disease continues to about 30 years of age, and according to Sun and Streib, the course of the illness thereafter remains unchanged. In contrast to Thomsen disease, the creatine kinase (CK) may be elevated. Testicular atrophy, cardiac abnormality, frontal baldness, and cataracts—the features that characterize myotonic dystrophy—are conspicuously absent.

The main diseases in this category are hyperkalemic periodic paralysis and paramyotonia congenita. The derivative disorders normokalemic periodic paralysis, acetazolamide-responsive myotonia, myotonia fluctuans, and myotonia permanens are variants of hyperkalemic periodic paralysis. All of them are caused by mutations in the gene encoding the alpha subunit of the membrane-bound voltage-gated sodium channel in skeletal muscle (SCN4A).

Hyperkalemic Periodic Paralysis

The essential features of this disease are episodic generalized weakness of fairly rapid onset and a rise in serum potassium during attacks. Weakness appearing after a period of rest that follows exercise is particularly characteristic. This type of periodic paralysis was first described and distinguished from the more common (hypokalemic) form by Tyler and colleagues in 1951. Five years later, Gamstorp described two additional families with the disorder and named it adynamia episodica hereditaria. As further examples were reported, it was noted that in many of them there were minor degrees of myotonia, which brought the condition into relation with paramyotonia congenita (see further on). Hyperkalemic periodic paralysis is associated with a defect in the alpha subunit of the sodium channel gene (Fontaine et al, 1990). It is now appreciated that there are distinct variants of hyperkalemic periodic paralysis that are genetically distinct. All are associated with membrane hyperexcitability because of delays in sodium channel inactivation following membrane depolarization, as discussed later.

Clinical Manifestations

The pattern of inheritance is autosomal dominant as noted, with an onset usually in infancy and childhood. Characteristically, attacks of weakness occur before breakfast and later in the day, particularly when resting following exercise. In the latter case, the weakness appears after 20 to 30 min of becoming sedentary. The patient notes difficulty that begins in the legs, thighs, and lower back and spreads to the hands, forearms, and shoulders over minutes or more. Only in the severest attacks are the neck and cranial muscles involved; respiratory muscles are usually spared. As the muscles become inexcitable, tendon reflexes are diminished or lost. Attacks usually last 15 to 60 min, and recovery can be hastened by mild exercise. After an attack, mild weakness may persist for a day or two. In severe cases, the attacks may occur every day; during late adolescence and the adult years, when the patient becomes more sedentary, the attacks may diminish and even cease entirely. In certain muscle groups, if myotonia coexists, it is difficult to separate the effects of weakness from those of myotonia. Indeed, when an attack of paresis is prevented by continuous movement, firm, painful lumps may form in the calf muscles. Usually, however, the presence of myotonia can only be detected electromyographically. Some patients with repeated attacks may be left with a permanent weakness and wasting of the proximal limb muscles.

During the attack of weakness serum K rises, often, but not always, up to 5 to 6 mmol/L. This is associated with increased amplitude of T waves in the electrocardiogram (ECG) and a fall in the serum Na level (because of entry of Na into muscle). With increased urinary excretion of K, the serum K falls and the attack terminates. Between attacks serum K is usually normal or only slightly elevated.

The attacks of paralysis are virtually alike in all clinical variants of the disease. In the paramyotonic form discussed below, the attacks are associated with paradoxical myotonia (myotonia induced by exercise and also by cold).

The provocative test, undertaken under careful supervision when the patient is functioning normally, consists of the oral administration of 2 g of KCl in a sugar-free liquid repeated every 2 h for 4 doses, if that many are necessary to provoke an attack. The test is given in the fasting state, ideally just after exercise. The weakness typically has a latency of 1 to 2 h after the administration of K. The patient must be carefully monitored by ECG and frequent serum estimations of serum potassium. The test should never be undertaken in the presence of an attack of weakness, or when there is reduced renal function, or in those with diabetes requiring insulin.

The treatment of this syndrome is the same as that for paramyotonia congenita, described further on.

Normokalemic Periodic Paralysis

This form of episodic paralysis resembles the hyperkalemic form in practically all respects except that serum potassium does not increase out of the normal range, even during the most severe attacks. However, some patients with normokalemic periodic paralysis are sensitive to potassium loading (Poskanzer and Kerr); other kindreds are not (Meyers et al). The disorder is also transmitted as an autosomal dominant trait and the basic defect has proved to stem from the same mutation as that of hyperkalemic periodic paralysis of which it may be considered a variant.

Paramyotonia Congenita (Eulenburg Disease)

In this disease, attacks of periodic paralysis are associated with myotonia, which may be paradoxical in type—that is, developing during exercise and worsening as the exercise continues. In addition, a widespread myotonia, often coupled with weakness, is induced by exposure to cold. In some patients, the myotonia can be elicited even in a warm environment. The weakness may be diffuse, as in hyperkalemic periodic paralysis, or limited to the part of the body that is cooled. As commented in the earlier sections, cold exaggerates many types of myotonia to some extent, but this property is most characteristic of paramyotonia and it is in this condition that cold-induced weakness persists for up to several hours once started, even after the body is rewarmed. Percussion myotonia can be evoked in the tongue and thenar eminence. According to Haass and colleagues, myotonia that is constantly present in a warm environment diminishes with repeated contraction, whereas myotonia induced by cold increases with repeated contraction (paradoxical myotonia).

Like hyperkalemic periodic paralysis, paramyotonia congenita is transmitted in an autosomal dominant manner and both diseases have been linked to the same gene (SCN4A), which encodes the alpha subunit of the muscle membrane sodium channel; the two mutations are allelic.

Laboratory Findings

In both hyperkalemic periodic paralysis and paramyotonia congenita, the serum K is usually above the normal range during bouts of weakness, but paralysis has been observed at levels of 5 mEq/L and lower. Each patient appears to have a critical level of serum K, which, if exceeded, will be associated with weakness. (This has led some authors to term the periodic paralysis as potassium dependent.) The administration of KCl, raising serum K to above 7 mEq/L, a level that has no effect on normal individuals, invariably induces an attack. As mentioned earlier, the ECG must be monitored during such provocative testing. The EMG shows myotonic discharge in all muscles, even at normal temperatures. The CK may be elevated.

In vitro studies of muscle from patients with cold-induced stiffness and weakness have shown that as temperature is reduced, the muscle membrane is progressively depolarized to the point where the fibers are inexcitable (Lehmann-Horn et al, 1987). A sodium channel blocker (tetrodotoxin) prevents the cold-induced depolarization. In patients with paramyotonia, but not in those with hyperkalemic periodic paralysis, Subramony and colleagues observed a diminution of the compound muscle action potential in response to the cooling of muscle, largely settling the argument as to whether the two syndromes (hyperkalemic paralysis and paramyotonia) are the same or different.

Some patients with paramyotonia, like those with certain other forms of periodic paralysis, may in later life slowly develop a myopathy that causes persistent weakness. In some cases this is sufficiently severe that it mimics the pattern of late-onset limb-girdle muscular dystrophy. However, in the case of paramyotonia there are relatively few histologic changes, primarily vacuoles in some of the muscle fibers and minimal evidence of myofiber degeneration.

Treatment

Most patients with hyperkalemic periodic paralysis and its variants benefit from prophylactic use of the carbonic anhydrase inhibitor acetazolamide, 125 to 250 mg bid or tid (paradoxically, as it has a tendency to produce potassium retention). Acetazolamide reduces the frequency of attacks and may provide some relief from myotonia. There are no controlled studies of acetazolamide in these disorders, but a trial of the related carbonic anhydrase inhibitor dichlorphenamide demonstrated a reduced frequency of paralytic spells in both hyper- and hypokalemic forms of periodic paralysis (Tawil et al). However, in some patients the attacks of hyperkalemic paralysis and of paramyotonia congenita are too infrequent, too brief, or too mild to require continuous treatment.

The administration of diuretics such as hydrochlorothiazide (0.5 g daily), keeping the serum K below 5 mEq/L, also prevents attacks but risks inducing dangerous degrees of hypokalemia. When the myotonia is more troublesome than the weakness, mexiletine 200 mg tid is perhaps the best alternative, because it prevents both cold- and exercise-induced myotonia but it does not influence frequency of acute attacks. Some additional benefit may be gained by adding inhaled beta-adrenergic agonists such as albuterol or salbutamol. Some studies suggest that one agent in this class, clenbuterol, may have a direct effect in blocking the sodium channel, independent of its activation of adrenergic receptors. Procainamide or the lidocaine derivative tocainide, in doses of 400 to 1,200 mg daily, is also useful for the myotonia (tocainide carries a small risk of agranulocytosis).

For the treatment of an acute and severe episode, intravenous calcium gluconate (1 to 2 g) often restores power. If after a few minutes this treatment is unsuccessful, intravenous glucose or glucose and insulin and hydrochlorothiazide should be tried so as to reduce the serum potassium concentration.

Other Sodium Channel Disorders

Several other clinical presentations of hereditary periodic paralysis have been linked to mutations of the gene encoding the alpha subunit of the skeletal muscle sodium channel and probably represent variants of the disease. One of these, described by Ricker and colleagues, has been designated myotonia fluctuans, because muscle stiffness fluctuated in severity from day to day. In other respects the clinical features resemble those of myotonia congenita, including provocation of attacks of myotonia by exercise. The muscle stiffness is only slightly sensitive to cold but is markedly aggravated by the ingestion of potassium and, interestingly, never progresses to muscular weakness or paralysis. Myotonia permanens is the name given to a severe, persistent myotonia and marked hypertrophy of muscles, particularly of the neck and shoulders. The EMG discloses continuous muscle activity. This disease was discovered in the course of genotyping a patient who earlier had been reported by Spaans and associates as an example of "myogenic" Schwartz-Jampel syndrome, but it affects the same channel as in hyperkalemic periodic paralysis.

Trudell and colleagues studied 14 patients from a large kindred with autosomal dominant myotonia, the main feature of which was periodic worsening of myotonia accompanied by muscle pain and stiffness, most severe in the face and hands. The symptoms were enhanced by cold (suggesting paramyotonia) and severe stiffness and palpable rigidity followed within 15 min of the ingestion of potassium but neither of these measures provoked muscle weakness. Muscle biopsy disclosed a normal ratio of types 1, 2A, and 2B fibers, further distinguishing this disorder from typical myotonia congenita, where 2B fibers may be reduced in number. All patients in this family who were treated with the carbonic anhydrase inhibitor acetazolamide had a dramatic resolution of symptoms within 24 h, hence the name acetazolamide-responsive myotonia. This disorder has been linked to the same molecular alteration of the sodium channel gene as occurs in hyperkalemic periodic paralysis (Ptácek et al, 1994b).

Rosenfeld and coworkers described yet another form of painful congenital myotonia attributable to a novel mutation in the sodium channel alpha-subunit gene (SCN4A). Affected members of this family experienced debilitating pain, particularly severe in the intercostal muscles. Also, the pain was resistant to treatment with acetazolamide and other antimyotonic drugs (mexiletine and tocainamide) and could not be provoked by ingestion of potassium-rich foods, differing in these ways from the patients described by Trudell and Ptácek (1994a) and their associates.

Finally, in regard to disorders of the sodium channel, it should be mentioned that the marine toxins (ciguatoxin, tetrodotoxin, saxitoxin), discussed in Chap. 43, produce their effects on the peripheral and central nerves by blocking sodium channels, but have little obvious effect on muscle function.

Pathophysiology of Myotonia and Hyperkalemic Periodic Paralysis (See also Chap. 45)

In both myotonia congenita and hyperkalemic paralysis, the absence of major morphologic changes and the prominence of the myotonic phenomenon in individual muscle fibers is consistent with a disorder of the sodium channel. This is also compatible with the observation that myotonia persists after the administration of curare, thereby exonerating neural input as the source of myofiber hyperexcitability.

The electromyographic pattern of a myotonic muscle reveals highly characteristic discharges that persist following the cessation of voluntary contraction. The tension of the myotonic muscle fibers is slow to diminish as a result of these greatly prolonged trains of muscle action potentials (see Fig. 45-8). Some of these afterdischarge potentials are the size of fibrillations, but others are as large as normal motor units. Thus myotonia can be distinguished electrophysiologically from contracture (e.g., that encountered in McArdle disease, in which the muscle is electrically silent). In experiments conducted in the 1940s, Denny-Brown and Foley, stimulating single muscle fibers directly, found that myotonic discharges could be elicited only by a volley of stimuli and not by a single stimulus. They also noted that the series of myotonic potentials progressively diminished in size. Percussion elicits myotonia by imparting a brief but relatively intense repetitive excitation of the muscle membrane.

The biophysical basis of myotonia is now well understood in terms of the functioning of chloride and sodium channels in the muscle membrane and internal structures. The correspondence between mathematical models of the electrical properties of the membrane and the clinical features of the myotonic and periodic paralyses is quite remarkable. During the normal action potential in all neural and muscular tissue, membrane depolarization is terminated by two events: the depolarization-induced inactivation of the sodium channel (which ends the inward sodium current) and the subsequent action of the outward potassium current. In muscle, the termination of an action potential requires an additional factor. Because of its large size, excitation of the muscle fiber involves depolarization that propagates not only along the cell surface but also radially into the center of the muscle cell through the transverse tubules (T tubules). The tubules are very narrow structures whose internal spaces are in continuity with the extracellular space. When the repolarizing outward potassium current is activated, potassium ions flood into the tubules from the muscle cytoplasm. By itself, this tubular K accumulation would depolarize the muscle membrane and prolong excitation. Normally, this does not occur because there is a large opposing chloride conductance in the tubules that counteracts the influence of potassium accumulation.

The first clues to the importance of the chloride channel in this electrical stabilizing process were obtained by Bryant who performed in vitro studies of myotonic goat muscle and found a reduced chloride conductance in the transverse tubular system. Subsequent studies of muscle from patients with myotonia congenita by Lipicky and Bryant (1971) demonstrated a similarly low chloride conductance. That a mutation in a muscle chloride channel could produce myotonia was confirmed in a mouse model by Jentsch and Steinmeyer and colleagues (see Koch et al), who subsequently also described the first human chloride channel (CLCN1) mutations.

As indicated, an essential event for normal repolarization of an excitable membrane is the rapid inactivation of the inward sodium current. This process of rapid, complete sodium channel inactivation is impaired by the sodium channel mutations implicated in hyperkalemic periodic paralysis. The mutations cause imperfect inactivation of the channel and lead to aberrant and early reopenings. Repolarization is then incomplete, rendering the muscle cell more readily re-excited; it is this hyperexcitability that causes the myotonia of hyperkalemic periodic paralysis. The problem becomes self-reinforcing because, as the membrane fails to repolarize fully, its electrolytic inactivation becomes increasingly less effective. If this process is not aborted, the result is such excessive depolarization that the muscle cell ultimately becomes unexcitable—a state that corresponds to the paralytic phase of hyperkalemic periodic paralysis. These features are evident in hyperkalemic muscle in vitro (Cannon) and can be recapitulated in computer simulations of aberrant channels. Presumably, over several hours, a variety of compensatory mechanisms (e.g., activation of Na-K adenosine triphosphatase [ATPase] pumps) restores the baseline excitability of the muscle membrane.

Hypokalemic Periodic Paralysis

This is the best-known form of periodic paralysis. The history of the disease is difficult to trace, but the first unmistakable account was probably that of Hartwig in 1874, followed by the accounts of Westphal (1885) and Oppenheim (1891). Goldflam (in 1895) first called attention to the remarkable vacuolization of the muscle fibers that is characteristic of the process. In 1937, Aitken and associates described the occurrence of low serum potassium during attacks of paralysis and reversal of the paralysis by the administration of potassium, thus setting the stage for subsequent differentiation from the hyperkalemic forms of periodic paralysis. For English-speaking readers, Talbott's monograph serves as the best historical review of the subject and includes all cases that had been reported prior to 1941; the more contemporary reviews by Layzer and by Lehmann-Horn and their associates (2004) bring the subject largely up-to-date.

The usual pattern of inheritance is autosomal dominant with reduced penetrance in women (male-to-female ratio of 3 or 4:1). Fontaine and coworkers (1990, 1994) localized the mutation to a region containing the gene that encodes the alpha subunit of the calcium channel of skeletal muscle and the gene has now been determined. The subunit, which is part of the dihydropyridine receptor complex, is located in the transverse tubular system. This region is believed to act both as a voltage sensor that controls calcium release from the sarcoplasmic reticulum, thus mediating muscle excitation–contraction coupling, and as a calcium-conducting pore. How precisely the reduced calcium channel function relates to hypokalemia-induced attacks of muscle weakness is not fully known. Approximately 10 percent of cases, however, are due to a mutation in the earlier discussed sodium channel, SCN4A.

Clinical Manifestations

In our experience, this disease has become clinically apparent after adolescence and has been much more severe in males. We note, however, that in Talbott's review of 152 cases, there were 40 in which symptoms began before the tenth year of life and 92 before the sixteenth year. The typical attack comes on during the second half of the night or the early morning hours, after a day of unusually strenuous exercise; a meal rich in carbohydrates favors its development. Excessive hunger or thirst, dry mouth, palpitation, sweating, diarrhea, nervousness, and a sense of weariness or fatigue are mentioned as prodromata but do not necessarily precede an attack. Usually, the patient awakens to discover a mild or severe weakness of the limbs. However, diurnal attacks also occur, especially after a nap that follows a large meal. The attack evolves over minutes to several hours; at its peak, it may render the patient so helpless as to be unable to call for assistance. Once established, the weakness lasts a few hours if mild or several days if severe.

The distribution of the paralysis varies. Limbs are affected earlier and often more severely than trunk muscles, and proximal muscles are possibly more susceptible than distal ones. The legs are often weakened before the arms, but exceptionally the order is reversed. The muscles most likely to escape are those of the eyes, face, tongue, pharynx, larynx, diaphragm, and sphincters, but on occasion even these may be involved. When the attack is at its peak, tendon reflexes are reduced or abolished and cutaneous reflexes may also disappear. As the attack subsides, strength generally returns first to the muscles that were last to be affected. Headache, exhaustion, diuresis, and occasionally diarrhea may follow the attack. Myotonia is not seen; indeed, clinical or EMG evidence of myotonia essentially excludes the diagnosis of hypokalemic periodic paralysis.

Attacks of paralysis tend to occur every few weeks and tend to lessen in frequency with advancing age. Rarely, death may occur from respiratory paralysis or derangements of the conducting system of the heart. Mainly, such fatal cases were reported in the era before modern intensive care.

Atypical forms include weakness of one limb or certain groups of muscles, bibrachial palsy (inability to lift one's arms or to comb one's hair), and transient weakness during accustomed activities such as walking. Some of our patients had a talipes deformity from early life. During middle adult life, a number of patients have developed a severe, slowly progressive proximal myopathy, with vacuolated and degenerated fibers and myopathic action potentials, in some instances long after attacks of periodic paralysis had ceased.

Laboratory Findings

The attacks are accompanied by reduction in serum K levels, as low as 1.8 mEq/L, but usually at levels that would not be associated with muscle weakness in normal subjects. The fall in serum K is associated with little or no increase in urinary K excretion. Presumably, large quantities of K enter the muscle fibers during an attack but this explanation may not be complete. Some episodes occur with near-normal levels of K, and weakness persists for a time after the serum level has been restored. The serum K levels return to normal during recovery. Although the shifts in K are of undoubted importance in the pathogenesis of muscle weakness, the marked sensitivity to small reductions of serum K suggests that other factors are operative and that the fall in K may be a secondary phenomenon.

As in hyperkalemic paralysis, the muscular weakness in this disease is associated with a decrease in the amplitude, and eventual loss, of muscle action potentials and there is failure of excitation by supramaximal stimulation of peripheral nerve or by strong voluntary effort. A decline in strength precedes the loss of motor unit potentials and the failure of propagation of action potentials over the surface of the fiber. The polarization potentials of muscle fibers measured by intracellular recordings are initially normal despite the failure of impulse propagation by the sarcolemma. One would expect the muscle fiber to be hyperpolarized as K moves into it, but it actually becomes depolarized. Rüdel and associates attribute the latter change to an increased Na conductance. The ECG changes also begin at levels of K that are slightly below normal (about 3 mEq/L); they consist of prolonged PR, QRS, and QT intervals and flattening of T waves.

Diagnosis at a time when the patient is normal may be facilitated by provocative tests. With the patient carefully monitored, including the use of ECG, the oral administration of 50 to 100 g of glucose or loading with 2 g of NaCl every hour for 7 doses, followed by vigorous exercise, brings on an attack, which then can be terminated by 2 to 4 g of oral KCl (the opposite of what pertains in hyperkalemic periodic paralysis).

Pathologic Changes

The muscle fibers are uniformly somewhat large but the most striking change, particularly in the late degenerative phases of the disease, is vacuolization of the sarcoplasm. The myofibrils are separated by round or oval vacuoles containing clear fluid, presumably water, and a few periodic acid-Schiff (PAS)-positive granules. There are pathologic changes in myofibrils and mitochondria as well, and focal increases in muscle glycogen. Isolated muscle fibers may undergo segmental degeneration. Electron microscopic studies have shown that the vacuoles arise as a result of proliferation and degeneration of membranous organelles within the sarcoplasmic reticulum and transverse tubules (A.G. Engel).

Treatment

A low-sodium diet (less than 160 mEq/d), avoidance of large meals and of exposure to cold, and acetazolamide 250 mg tid may be helpful in preventing attacks. That acetazolamide reduces attacks is somewhat surprising as it is kaluretic, but it may work through the production of acidosis; a few patients have worsened with the drug. Patients who are unresponsive to acetazolamide may be treated with the more potent carbonic anhydrase inhibitor, dichlorphenamide, 50 to 150 mg/d, or with the potassium-sparing diuretics spironolactone or triamterene (both in doses of 25 to 100 mg/d), but caution must then be exercised with the simultaneous administration of oral potassium supplements. The daily administration of 5 to 10 g of KCl orally in an unsweetened aqueous solution prevents attacks in many patients and apparently, this program can be maintained indefinitely. If this approach fails, a low-carbohydrate, low-salt, high-K diet combined with a slow-release K preparation may be effective.

For an acute attack, 0.25 mEq KCl/kg should be given orally or, if this is not tolerated, some other K salt may be tried. This dose may be insufficient and if there is no improvement in 1 or 2 h, KCl may have to be given intravenously: 0.05 to 0.1 mEq/kg initially in a bolus at a safe rate, followed by 20 to 40 mEq KCl in 5 percent mannitol, avoiding glucose or NaCl as the carrier solution. For the late-progressive polymyopathy that follows many severe attacks of periodic paralysis, Dalakas and Engel report successful restoration of strength by the long-term administration of dichlorphenamide. Regular exercise (not too strenuous) to keep the patient fit is desirable.

Secondary Kalemic Periodic Paralyses

In addition to the hereditary kalemic paralyses described earlier, transitory episodes of weakness are associated with a number of acquired derangements of potassium metabolism (mainly hypokalemia); these include thyrotoxicosis, aldosteronism, 17α-hydroxylase deficiency (Yazaki et al), barium poisoning (Lewi and Bar-Khayim), glycyrrhizic acid ingestion (a substance in licorice that has mineralocorticoid activity), and abuse of thyroid hormone (Layzer). Other forms of secondary hypokalemic weakness have been observed in patients suffering from chronic renal and adrenal insufficiency or disorders caused by a loss of potassium, as occurs with excessive use of diuretics or laxatives (the most common cause in practice). (Renal failure with hyperkalemia can also induce considerable weakness.)

Thyrotoxicosis with Periodic Paralysis

This is a special form of secondary hypokalemic periodic paralysis and occurs mainly in young adult males (despite the higher incidence of thyrotoxicosis in women), with a strong predilection for those of Japanese and Chinese origin (Pothiwala). In Japan, Okinaka and associates found that 8.9 percent of males with thyrotoxicosis had periodic paralysis, but this was the case in only 0.4 percent of females; in China, the corresponding figures were 13.0 and 0.17 percent (McFadzean and Yeung). The paralytic disorder is unrelated to the severity of the hyperthyroidism. In patients with the familial forms of periodic paralysis, the induction of hyperthyroidism is said not to increase the frequency or intensity of attacks. Therefore, it seems likely that thyrotoxicosis has unmasked another type of hereditary periodic paralysis, although a familial occurrence in the thyrotoxic cases is exceptional. Clinically, the attacks of paralysis are much the same as those of familial hypokalemic type except for a greater liability to cardiac irregularity. As in the familial form, the paralyzed muscles are electrically inexcitable. Potassium chloride restores power in paralytic attacks, and treatment of the hyperthyroidism prevents their recurrence (see "Myasthenia Gravis With Hyperthyroidism" in Chap. 49).

Hypokalemic Weakness in Primary Aldosteronism (Conn Syndrome)

Hypokalemic weakness because of hypersecretion of the major adrenal mineralocorticoid aldosterone was first described by Conn and associates in 1955. In primary aldosteronism, the cause of the hypersecretion is in the adrenal gland itself, usually an adrenal cortical adenoma, less often adrenal cortical hyperplasia. Although the disorder is uncommon (occurring in approximately 1 percent of unselected hypertensive patients), its recognition is essential for effective treatment. Persistent aldosteronism is frequently associated with hypernatremia, polyuria, and alkalosis, which predispose to attacks of tetany as well as to hypokalemic weakness. Conn and associates (1964), in an analysis of 145 patients with primary aldosteronism, found that persistent muscular weakness was a major complaint in 73 percent; intermittent attacks of paralysis occurred in 21 percent; and tetany in another 21 percent. These manifestations were much more frequent in women than in men, in contrast to the preponderance of men among patients with hypokalemic periodic paralysis of familial type. Rarely, as already noted, primary aldosteronism is produced by the chronic ingestion of licorice; this is due to its content of glycyrrhizic acid, a potent mineralocorticoid (Conn et al, 1968).

The muscle fibers of patients with primary aldosteronism show necrosis and vacuolation. Ultrastructurally, the necrotic areas are characterized by dissolution of myofilaments with degenerative vacuoles; nonnecrotic fibers contain membrane-bound vacuoles and show dilatation of the sarcoplasmic reticulum and abnormalities of the transverse tubular system, suggesting that vulnerability of the latter structures may be responsible for the muscle fiber necrosis (Atsumi et al).

Malignant Hyperthermia

This dramatic syndrome is observed during general anesthesia in susceptible individuals, some of whom clearly have a channelopathy. It is characterized by rapidly rising body temperature, extreme muscular rigidity, and a high mortality rate. Since the original report by Denborough and Lovell in 1960, as larger experience was gained with this entity, it proved in some cases to be a metabolic myopathy inherited as a dominant trait, rendering the individual vulnerable to any volatile anesthetic agent, particularly halothane, and to the muscle relaxant succinylcholine. The fundamental cause in a large proportion of cases is an aberration in a component of the ryanodine calcium channel. Malignant hyperthermia has been estimated to occur approximately once in the course of every 50,000 administrations of general anesthesia.

The full clinical picture is striking but anesthesiologists have become adept at detecting its earliest stages and aborting the process. As halothane or a similar inhalational anesthesia is induced, or succinylcholine is given for muscular relaxation, the jaw muscles unexpectedly become tense rather than relaxed and soon rigidity extends to all of the muscles. Thereafter, the body temperature rises to 42°C or 43°C and there is tachypnea and tachycardia. Blood pH may fall to 7 or below. There may be gross myoglobinuria and serum CK reaches extraordinarily high levels. Circulatory collapse and death may ensue in approximately 10 percent of cases, or the patient may survive with gradual recovery. In some cases there is the same sequence of events (increased temperature and acidosis) without muscular spasm. In cases of early death, the muscle may appear normal by light microscopy. With survival for several days, samples of muscle reveal scattered segmental necrosis and phagocytosis of sarcoplasm without inflammation. Patients with a particular congenital myopathy (central core myopathy), and those with King-Denborough syndrome mentioned later, have a propensity to malignant hyperthermia as noted in Chap. 48.

Pathophysiology and Etiology

The pathogenesis of malignant hyperthermia has been the subject of numerous investigations. During the rigor phase, oxygen consumption in muscle increases threefold and serum lactate, 15- to 20-fold. Muscle from most affected individuals is abnormally sensitive to caffeine, which induces contracture in vitro. It has been postulated that halothane acts in a manner similar to caffeine—that is, to release calcium from the sarcoplasmic reticulum and prevent its reaccumulation, thus interfering with relaxation of the muscle. The essential physiologic change is one of increased intracellular calcium.

Insight into the disease has been gained from a breed of pigs, inbred for muscular development, in which muscle spasm (true contracture) and hyperthermia follow the administration of anesthetic agents. These swine have an inherited defect in the ryanodine receptor, a protein component of the calcium channel of the sarcoplasm that is sensitive to both caffeine and ryanodine. However, one of several similar defects in ryanodine is found in somewhat fewer than 20 percent of people with the susceptibility to malignant hypothermia. It is presumed that other yet unidentified allelic mutations of this receptor protein or another that controls the structure of the calcium channel account for the remainder of cases. The cause of the high fever is unknown; it is probably caused by the muscle spasm, but an effect of the anesthetic on heat-regulating centers has not been excluded.

Clues as to which patients are at risk for this condition come from several sources. Other members of the family may have difficulties or have died during anesthesia. Some susceptible individuals exhibit myopathic and musculoskeletal abnormalities (Isaacs and Barlow). One such dysmorphic constellation consists of short stature, ptosis, strabismus, highly arched palate, dislocated patellae, and kyphoscoliosis, which have been present in several families (King-Denborough syndrome). As mentioned just above and in Chap. 48 on the congenital myopathies, central core (sometimes called multicore) myopathy is frequently complicated by malignant hyperthermia. This is understandable insofar as both disorders have been linked to the gene encoding the ryanodine receptor; the two diseases are a result of allelic variations (Quane et al). It has been pointed out that another rare muscle disease (Evans myopathy, named after the affected family) may also be a predisposing condition. It is inherited as an autosomal trait and may be asymptomatic until the anesthetic reaction but some patients have wasting of the distal thigh muscles and an elevation of serum CK concentration (see Harriman et al).

Diagnostic Testing

Various tests for susceptibility to malignant hyperthermia have undergone phases of popularity. The only currently valid one involves in vitro exposure of a muscle biopsy specimen to halothane and to caffeine and the detection of muscle contracture with both agents. This is performed only in a few centers, which are listed at http://www.mhaus.org. The review by Denborough may be consulted for further details on the testing and clinical aspects of the disease.

Treatment

This consists of discontinuation of anesthesia at the first hint of masseter spasm or rise of temperature. The intravenous administration of dantrolene, which inhibits the release of calcium from the sarcoplasmic reticulum, may be lifesaving. An infusion of 1 mg/kg is given initially and increased slowly until symptoms subside, the total dosage not exceeding 10 mg/kg. Other measures should include body cooling, intravenous hydration, sodium bicarbonate infusion to correct acidosis, and mechanical hyperventilation to decrease acidosis. Thereafter, halothane and other volatile anesthetic agents and succinylcholine should be avoided in such individuals and surgical procedures, if necessary, should be done with other agents, such as propofol, nitrous oxide, fentanyl, thiopental (or other barbiturate), or local anesthesia. Intravenous dantrolene (2.5 mg/kg given slowly 1 h prior to anesthesia) prevents the syndrome, but this is not a preferred option in patients with the disorder.

Neuroleptic Malignant Syndrome

This state, in which hyperthermia occurs as an idiosyncratic reaction to neuroleptic drugs, is also accompanied by widespread myonecrosis. It shares some features with malignant hyperthermia but is a distinct entity, as discussed in Chap. 43.

The discovery of several types of seizure disorders based on inherited defects of the potassium channel has elicited considerable interest and only recently was it appreciated that one form of periodic paralysis, Andersen disease, is associated with the voltage-gated potassium channel.

Andersen Disease

Andersen and coworkers first drew attention to a distinct form of potassium-sensitive periodic paralysis characterized by the triad of periodic potassium-sensitive weakness, ventricular dysrhythmias with long QT syndrome, and dysmorphic features (micrognathia, short stature, scaphocephaly, hypertelorism, broad nose, low-set ears, and short index fingers). From a study of 5 kindreds, Sansone and colleagues have pointed out that attacks of paralysis can be associated with hypo-, normo-, or hyperkalemia, and that a prolonged QT interval is an integral feature of the disease (and sometimes the only sign in a given family). Plaster and colleagues demonstrated that most cases of Andersen disease are a consequence of dominant-negative mutations in the gene KCNJ2 that encodes a type of K channel. In vitro studies indicate that the mutation impairs the ability of preformed channels to migrate to the membrane surface and also impedes the current-carrying capacity of the potassium channel system. This defect would be expected to impair repolarization of the muscle membrane, thereby making both skeletal and cardiac muscle hyperexcitable.

Morvan Fibrillary Chorea (Chorée Fibrillaire)

This oddly named disease is included in this chapter because an abnormality of voltage-gated potassium channels (VGKC) or circulating antibodies against the channel has been discovered in many patients. It is characterized by continuous muscle fiber activity sometimes referred to as "neuromyotonia" and therefore may also be considered among similar disorders of constant muscle activity that are discussed further in the chapter. Hyperhidrosis, weight loss, insomnia, and hallucinations may occur, and most cases so far described have ended fatally in a matter of months (Serratrice and Azulay). Plasma exchange reversed the syndrome in the case described by Ligouri and colleagues. Some cases have an associated thymoma and its removal may be curative. Weak oligoclonal bands are sometimes found in the spinal fluid. Whether the antibodies are responsible for the cerebral symptoms is unknown, but the connection is plausible.

An interesting category of disease has emerged as being caused by antibodies to the voltage-gated potassium channel (Thieben et al), sometimes parallel to an idiopathic or paraneoplastic "limbic" encephalitis, which is described in Chap. 31.

In addition to the above disorders, various seizure syndromes (see Chap. 16) and a category of spinocerebellar ataxias are also attributable to mutations of ion channels and are addressed in other sections of the book. Also mentioned here for completeness are several diseases that result from secondary dysfunction of these same ion channels. Most of these conditions are acquired and autoimmune in nature, for example, the Lambert-Eaton myasthenic syndrome that results from an autoimmune attack on calcium channels (see Chap. 49), the Isaac syndrome that results from an autoimmune attack on potassium channels, producing neuromyotonia (see Chap. 45), anti-voltage-gated potassium channel and anti-NMDA encephalitis (see Chap. 31), and erythromelalgia that implicates a sodium channel (see Chap. 11). Thus, ion channels, being ubiquitous in all excitable tissues, might be expected to produce a large variety of diseases that affect central and peripheral nervous structures. Despite this, each of the genetic and acquired processes has remarkably specific features that are pertinent only to the channel as expressed in a single tissue.

Muscle Contracture, Pseudomyotonia, Tetanus, and Related States

Many of these states were discussed in Chap. 48 on diseases of muscle. They are reintroduced here in relation to specific diseases with which they are associated.

Physiologic Contracture Caused by Phosphorylase Deficiency (McArdle Disease) and Phosphofructokinase Deficiency (Tarui Disease)

Contractures are examples of an entirely different type of painful shortening and hardness of muscle. In both these diseases, an otherwise healthy child, adolescent, or adult begins to complain of weakness and stiffness and sometimes pain on using the limbs. Muscle contraction and relaxation are normal when the patient is in repose, but strenuous activity, especially under conditions of ischemia, causes the muscles to shorten gradually, because of a failure of relaxation. The contracted muscles in these disorders—unlike muscles in cramp, continuous muscular activity syndromes, or myotonia and other involuntary spasms—no longer use energy for which reason they are almost silent electrically in the EMG. This condition is spoken of as physiologic contracture. McArdle and Tarui diseases are discussed more fully in a later section.

Pseudomyotonia

This phenomenon is observed in hypothyroidism, where the muscle fibers contract and relax slowly, a response readily demonstrated in the tendon reflexes, particularly the Achilles reflex. The muscles are large and subject to myoedema. When contracted, they may show waves of slow contraction. The basis of this disorder appears to be slowness in the reaccumulation of calcium ions in the endoplasmic reticulum and in the disengagement of actin and myosin filaments. The EMG may show afterpotentials following voluntary contraction, but they do not resemble the typical waning discharges ("myotonic runs") of true myotonia.

A closely related syndrome, wherein painless contracture is induced by exercise, has been described by Lambert and Goldstein, and by Brody. Muscle contraction is normal but the relaxation phase becomes increasingly slow during exercise. Lambert and Goldstein referred to it as an unusual type of myotonia, and Brody, as a decrease of "relaxing factor"; the slow relaxation has also been attributed to a decreased uptake of calcium by the sarcoplasmic reticulum. In some cases, the disease is transmitted as a recessive trait with a mutation that impairs the function of a sarcoplasmic reticular calcium adenosine triphosphatase (ATPase). In other instances, the disease is transmitted as a dominant trait that is not genetically linked to calcium ATPase. This latter process may be more closely aligned with the muscular dystrophies and is mentioned in Chap. 48 under that heading.

Tetanus (See "Tetanus" in Chap. 43)

This toxic disorder is characterized by persistent spasms of skeletal muscles, owing to the effect of the tetanus toxin on spinal neurons (Renshaw and other cells), the natural function of which is to inhibit the motor neurons. As the condition develops, activities that normally excite the neurons (i.e., voluntary contraction and startle from visual and auditory stimulation) all evoke involuntary spasms. Sleep tends to quiet them, and they are suppressed by spinal anesthesia and curare. The EMG shows the expected interference pattern of muscle action potentials. Once the muscle is involved in persistent contraction, it is said that the shortened state is not abolished by procaine block or severance of nerve (in animals), but this type of myostatic contracture has not been demonstrated in humans.

The effect of tetanus toxin on the spinal inhibitory neurons is analogous to that of strychnine. There is also an action of the toxin at the neuromuscular junction, which has been more difficult to evaluate in the face of its powerful central action. Having injected this toxin locally in animals, Price and associates demonstrated its localization at motor endplates. It binds with ganglioside in the axon membrane and is transported by retrograde flow to the spinal cord, where it induces local tetanus effects. Neurons that innervate slow-twitch type 1 muscle fibers are more sensitive than those supplying fast-twitch type 2 fibers. Presynaptic vesicles increase in number, acetylcholine (ACh) is blocked, and terminal axon injury may paralyze muscle fibers. Fibrillation potentials and axonal sprouting follow. The similarities to stiff man syndrome are mentioned further on.

Black Widow Spider Bite

The toxin produced by this spider within a few minutes of the bite leads to a striking syndrome of cramps and spasms and then a painful rigidity of abdominal, trunk, and leg muscles. The spasms are followed by weakness. There is also vasoconstriction, hypertension, and autonomic hyperactivity. If death does not occur in the first 24 to 48 h, recovery is complete.

The spider venom has a presynaptic localization and rapidly releases quanta of ACh. The vesicles became depleted. There is some evidence that the venom prevents endocytosis of the vesicles by inserting itself into the presynaptic membranes, causing a disturbance of ionic conductance channels (Swift).

Treatment consists of calcium gluconate infusions and diazepine. Intravenous magnesium sulfate also helps to reduce the release of ACh and control the convulsions that sometimes occur. There is antiserum that is available in regions where such envenomation is frequent; it shortens the illness considerably.

Metal or other type of poisoning may simulate an inherently relapsing polyneuropathy.

States of Persistent Muscle Activity

This is an interrelated group of clinical states, all characterized by some degree of regional continuous muscular activity that in some cases cannot be fully differentiated from one another. From a clinical perspective we have found it is useful to categorize them in groups that are caused by (1) hyperexcitability of the peripheral motor nerves (fasciculations and myokymia), (2) centrally mediated hyperexcitability of motor output (Isaacs syndrome, stiff man syndrome), and (3) nonmyotonic hyperexcitability of muscle (rippling muscle disease, Schwartz-Jampel syndrome).

Hyperexcitability of Peripheral Nerve

This comprises a set of disorders in which peripheral motor nerve activity is augmented such that there are excessive, sometimes sustained contractions of the motor unit. Its mildest manifestation is benign fasciculation. In more severe form the manifestations include neuromyotonia, Isaacs disease, and a disease of potassium-gated ion channels (Morvan disease, or Morvan fibrillary chorea discussed below) that may also involve the brain. These processes are not generally familial and several lines of investigation suggest an acquired autoimmune nature (Newsom-Davis). For example, all but benign fasciculations are associated more often than might be expected with other autoimmune diseases such as myasthenia gravis and some respond to autoimmune therapies such as plasmapheresis, the patient's serum possesses antibodies to either voltage-gated potassium channels as mentioned or, less frequently, to nicotinic acetylcholine (ACh) receptors (Vernino and Lennon).

Benign Fasciculations

A few random fasciculations in the muscles of the calf, small muscles of the hand or of the face, or elsewhere are seen in most normal individuals. They are of little significance but can be a source of worry to physicians and patients who have read that fasciculations are an early sign of amyotrophic lateral sclerosis. A simple clinical rule is that fasciculations in relaxed muscle are not indicative of motor system disease unless there is associated weakness, atrophy, or reflex change.

Healthy individuals experience intermittent twitching of a muscle (or even part of a muscle), such as one of the muscles of the thenar eminence, eyelids, calves, or orbicularis oculi. They may continue for days. Electromyographically, benign fasciculations tend to be more constant in location and more frequent and rhythmic than the ominous fasciculations of amyotrophic lateral sclerosis but such distinctions are not entirely reliable. Quantitative study of the motor unit size may be helpful in these circumstances by demonstrating normally modeled units in the benign form and abnormally large units because of reinnervation in the case of motor neuron disease.

Occasionally, benign fasciculations are widespread and may last for months or even years. In several of our patients they have recurred in bouts separated by months and lasting several weeks. No reflex changes, sensory loss, nerve conduction, EMG abnormality (other than fasciculations), or increase in serum muscle enzymes is found. Low energy and fatigability in some of these patients may suggest an endogenous depressive illness yet the fasciculations are not explained by this mechanism. Patients commonly report a sense that the muscles affected by the twitching are weak but this cannot be confirmed by testing and several of our patients, curiously most of whom have been physicians, complained of equally troubling migratory zones of paresthesias. Pain of aching or burning type may increase after activity and cease during rest. Fatigue and a sense of weakness are frequent complaints. We suspect that this fasciculatory state reflects a disease of the terminal motor nerves, for a few of our patients have shown slowing of distal latencies, and Cöers and associates have found degeneration and regeneration of motor nerve terminals in similar cases. However, most such cases are of benign nature and settle down in a matter of weeks or months. In the cases reported by Hudson and colleagues, the condition, even after years, did not progress to spinal muscular atrophy, polyneuropathy, or amyotrophic lateral sclerosis. This conforms to our experience and to that reported from the Mayo Clinic where 121 patients with benign fasciculations, followed in some cases for more than 30 years, showed no progression of symptoms and did not acquire motor neuron disease or neuropathy (Blexrud et al). It should be acknowledged, however, that there are infrequent patients with seemingly benign fasciculations in whom the EMG shows some abnormal features (e.g., rare fibrillations) in numerous muscles and who later develop the other features of motor neuron disease. Carbamazepine, and to a lesser extent phenytoin, has been helpful in reducing the fasciculations and sensations of weakness in a proportion of cases and numerous other medications have been reportedly helpful.

Cramp-Fasciculation Syndrome

This is probably a variant of the above-described benign entity in which fasciculations are conjoined with cramps, stiffness, and systemic features such as exercise intolerance, fatigability, and muscle aches. Although affected individuals may be to some degree disabled by these symptoms, the prognosis is good. The salient finding on physiologic studies is that stimulation of peripheral nerves results in sustained muscle firing due to prolonged trains of action potentials in the distal motor nerve. This phenomenon may be brought out in special electrophysiologic testing, as described by Tahmoush and colleagues. In effect, this is a mild form of neuromyotonia, which is described further on. In a small number of patients with cramp-fasciculation syndrome it is possible to demonstrate the presence of autoantibodies directed against voltage-gated axonal potassium channels. Carbamazepine or gabapentin may be beneficial.

There are, in addition to these benign states, several syndromes of abnormal muscle activity. The main ones are myokymia, a state of successive contractions of motor units imparting an almost continuous undulation or rippling of the overlying body surface, and several syndromes of continuous muscle fiber activity described below.

Myokymia

This state of abnormal rippling muscle activity may be generalized or limited to one part of the body such as the muscles of the shoulders or of the lower extremities. It is observed most often with demyelination of peripheral nerve following injury, and thus it is neuropathic in nature. The common underlying conditions are multiple sclerosis or Guillain-Barré syndrome affecting the facial nerve and radiation damage to the brachial or lumbar plexus. In the EMG, myokymic discharges consist of repetitive firing of one motor unit, firing at 5 to 60 Hz and recurring regularly at 0.2- to 10-s intervals. The driving impulses arise in the most peripheral parts of the axon of chronically damaged nerves. In some patients cramping is associated, and those muscles about to cramp may twitch or show premonitory spontaneous rippling contractions; the cramping may be associated with sweating. Thus, myokymia, fasciculation, and cramping seem to be related but not clinically identical conditions.

Continuous Muscle Fiber Activity (Isaacs Syndrome)

The relation of myokymia to the state called continuous muscle fiber activity is ambiguous. Sporadically in the neurologic literature there have been descriptions of patients whose muscles at some point begin to "work" continuously (see Isaacs). Terms such as neuromyotonia and widespread myokymia with delayed muscle relaxation are additional names that have been applied to what is essentially the same condition. At the moment, there is little reason to distinguish one from another except in gradations of severity. In each case the excessive and spontaneous activity can be attributed to hyperexcitability of terminal parts of motor nerve fiber, possibly as a result of a partial loss of motor innervation and compensatory collateral sprouting of surviving axons (Cöers et al; Valli et al). Twitching, spasms, and rippling of muscles (myokymia) are evident, the latter being the main clinical sign. In advanced cases there is generalized muscle stiffness and a sense of weakness. Complaints of muscle aching are usual, but severe myalgia is uncommon. The tendon reflexes may be reduced or abolished. Any muscle group may be affected. The stiffness and slowness of movement make walking laborious ("armadillo" syndrome); in extreme cases, all voluntary movement is blocked. The muscle activity persists throughout sleep. The continuous visible and painful cramps of the above-described Satoyoshi disease may be difficult to distinguish from myokymia clinically, but they represent a different phenomenon.

General and spinal anesthesia do not always suppress the muscular activity but curare does; nerve block usually has no effect or may reduce the activity, as in the case described by Lütschg and colleagues. The EMG findings are much the same as those described earlier.

Special types of myokymia arise in childhood or adult life, sometimes in association either with a polyneuropathy or rarely with an inherited type of episodic ataxia that is variably responsive to acetazolamide or remits spontaneously (see Chap. 5). An inherited form of continuous muscle fiber activity has been traced to a mutation of the peripheral nerve K channel (Gutmann and Gutmann). In addition to the association with polyneuropathy, a state of continuous muscular activity has also been described in association with lung cancer and thymoma in which cases an immune mechanism has been inferred (see reviews by Thompson and by Newsom-Davis and Mills and the discussion of paraneoplastic syndromes in Chap. 31).

Treatment

Phenytoin or carbamazepine often abolish the continuous muscular activity and cause a return of reflexes. Acetazolamide has been helpful in other cases (Celebisoy et al). Many of the idiopathic cases will improve spontaneously after several years, however, plasma exchange may be tried if the symptoms are intractable.

Centrally Mediated Motor Hyperexcitability and Stiff Man (Stiff Person) Syndrome

This is a condition of persistent and intense spasms, particularly of the proximal lower limbs and lumbar paraspinal muscles. It was originally described by Moersch and Woltman in 1956 as stiff man syndrome. Since then, many examples have been reported all over the world and the term stiff person syndrome has been used to indicate its occurrence in both women and men. For lack of a better place in the book to discuss it, it is included here with other processes that cause muscular spasms and cramps.

The onset is insidious, usually in middle life. No genetic predisposition is known. At first the stiffness and spasms are intermittent, then gradually they become more or less continuously active in the proximal leg and axial trunk muscles and increasingly painful. The spasms impart a robotic appearance to walking and an exaggerated lumbar lordosis. Attempts to move an affected part passively yield an almost rock-like immobility, perceptibly different from spasticity, paratonia, or extrapyramidal rigidity. Muscles of respiration and swallowing and those of the face may be involved in advanced cases, but trismus, a common feature of tetanus, does not occur. We have observed brief periods of cyanosis and respiratory arrest during episodes of intense spasm, and one of our patients died during such an episode. The eye muscles are rarely affected.

As the illness progresses, any noise or other sensory stimulus or attempted passive or voluntary movement may precipitate painful spasms of all the involved musculature. The tendon reflexes are normal if they can be tested. The affected muscles, particularly the lumbar paraspinals and glutei, are extremely taut when palpated and eventually they become hypertrophied. It is this axial spasm that is most characteristic of the disease and gives rise to a characteristic lumbar lordosis. We have experience with one unusual instance of this disease that caused the obverse, namely, flexion spasm of the abdominal musculature with a bent-over camptocormia.

A similar stiffness of one limb ("stiff limb" syndrome) has been differentiated from the generalized variety by Barker and colleagues and others (see Saiz et al; Brown et al), but most of the localized cases have antibodies to glutamic acid decarboxylase, as described below. The limited form of the condition begins in one leg and spreads to its opposite, but remains isolated to the lower extremities, similar to localized tetanus.

A central origin of the muscle spasms is indicated by their disappearance during sleep, during general anesthesia, and with proximal nerve block. The electrophysiologic features differ from those of myokymia and continuous muscle fiber activity syndrome in that the EMG in stiff man syndrome consists entirely of activated but normally configured motor units, with no evidence of distal motor nerve disturbance.

Of interest is the finding that about two-thirds of the cases of stiff man syndrome display circulating autoantibodies that are reactive with glutamic acid decarboxylase (GAD), the synthesizing enzyme for gamma-aminobutyric acid (GABA; Solimena et al). On several occasions the test for this antibody has become positive after samples taken over 2 years were negative. An antibody to the glycine receptor (GlyR) has been identified in a subset of patients with stiff man syndrome with anti-GAD antibodies (McKeon and colleagues). The GlyR antibody, mainly expressed in the brain stem and spinal cord, has also been associated with progressive encephalomyelitis with rigidity and myoclonus, but appears to be highly specific for stiff man syndrome in patients who have anti-GAD antibodies.

Reduced spinal GABA presumably creates an imbalance between the spinal inhibitory (gabanergic) input and the excitatory input to alpha motor neurons. This interpretation is supported by the fact that the spasms worsen under the influence of drugs that enhance aminergic activity, thereby facilitating long-latency spinal reflexes, or that inhibit catecholaminergic or gabanergic transmitters. An autoimmune mechanism is further suggested by the high incidence of insulin-dependent diabetes (present eventually in almost all the cases under our care) with detectable antibodies to islet cells; a few patients have thyroiditis, pernicious anemia, or immune-mediated vitiligo.

There are rare paraneoplastic varieties of stiff man syndrome, mostly accompanying breast cancer and associated in some cases with circulating antibodies directed against amphiphysin or gephyrin, proteins associated with synaptic GABA receptors. Some of the cases related to the antiamphiphysin antibodies also display more conventional types of paraneoplastic neurologic disorder such as encephalopathy or opsoclonus (see Chap. 31).

The stiff man syndrome must be distinguished from tetanus (see "Tetanus" in Chap. 43 and further on), Isaacs syndrome, and the rare syndrome of subacute myoclonic spinal neuronitis, described in Chaps. 33 and 44. In both the stiff man syndrome and myoclonic spinal neuronitis, the intense spasms and stiffness of muscles are a result of disinhibition of interneurons in the gray matter of the spinal cord.

The syndromes of continuous muscle activity are usually distinguishable clinically and electromyographically from extrapyramidal and corticospinal abnormalities such as dystonia, dyskinesia, and rigidity, although early phases of axial dystonic disorders and stiff man syndrome have similarities.

Treatment

In the stiff man syndrome, diazepam in doses of up to 50 to 250 mg/d, increased gradually, is most effective; clonazepam, vigabatrin, or baclofen is sometimes effective as well. In keeping with the presumed autoimmune mechanism of most cases, plasma exchange, high-dose corticosteroids, or intravenous gamma globulin are helpful in some patients, albeit for only several weeks or months before another infusion is required. Several of our patients have required intravenous gamma globulin for several years at intervals of 6 to 12 weeks but nevertheless became disabled if the dose of diazepam was reduced below 100 mg/d. A small randomized trial of intravenous immune globulin conducted by Dalakas and colleagues has demonstrated the efficacy of this treatment; in their study, the benefits varied in duration from 6 weeks to 1 year. The typical dose is 0.4 mg/kg daily for 4 or 5 consecutive days. Immunosuppression with rituximab is being used increasingly, on the basis of numerous case reports and small series but a small randomized trial has been negative.

Congenital Neonatal Rigidity

A "stiff infant" syndrome, observed by Dudley and colleagues in four families of mixed heritage, probably should be included in this general category. The condition came to medical attention because of respiratory distress as the result of a generalized muscular rigidity beginning at about 2 months of age. The rigidity spread slowly from cervical muscles to those of the trunk and limbs, and, as it persisted, slight hypertrophy developed. The use of respiratory aid and a feeding gastrostomy enabled the infants to survive. The rigidity slowly diminished in the second year of life. The clinical course was unlike that of tetanus. In fatal cases there were zones of fiber loss, with fibrosis in skeletal and cardiac muscles, and a greater than normal variation in fiber size. Altered Z lines were observed with electron microscope in some fibers.

Primary Hyperexcitability of Muscle

At least three varieties of primary muscle disorder are known, not myotonic in nature, that produce continuous muscle activity. The first described below is because of a defect in the muscle membrane; the second has been found to be a disease of the extracellular matrix of muscle. The third disorder, Brody disease, is only mentioned here for completeness as it is quite rare, even in comparison to the other unusual disorders in this section.

"Rippling Muscle Disease"

Ricker and Burns and their associates described a rare familial disorder (autosomal dominant) in which muscles display an unusual sensitivity to stretch, manifest by rippling waves of muscle contraction. Percussion of muscles yields a pronounced and painful local mounding. The activation is a type of myokymia. Similar familial and sporadic cases have been traced to a defect in caveolin, a protein otherwise implicated in one of the muscular dystrophies (Vorgerd). An autoimmune process was implicated in some other cases (Ashok Muley and Day). The EMG discloses neither myotonic discharges nor the action potentials of cramp, indicating that the basic abnormality is in the muscle membrane.

Schwartz-Jampel Syndrome

A syndrome characterized by continuous muscle fiber activity with stiffness and blepharospasm, accompanied by obvious dysmorphic features (dwarfism, pinched face with low-set ears, blepharophimosis, high-arched palate, receding chin, diffuse metaphyseal and epiphyseal bone dysplasia with flattened vertebrae), was described by Schwartz and Jampel in 1962. It has been reported under other names including myotonic chondrodystrophy. There may be percussion myotonia. Intelligence is usually preserved. The stiff muscles disturb gait most obviously.

The muscle stiffness is the result of frequent, almost continuous muscle activity with a combination of normal motor units and high-frequency discharges and afterdischarges similar to those seen in Isaacs syndrome. The discharges can be demonstrated to arise from muscle fibers themselves as the activity is not obliterated by curare. Agents such as procainamide, which block sodium channels in muscle, inhibit the discharges, just as they do in some other myotonic disorders. However, Spaans and associates, who have reviewed the clinical, EMG, and histologic features of 30 cases of this syndrome, report a diminished chloride conductance by the sarcolemma, which can be suppressed by procainamide or even better by mexiletine.

The disorder is usually inherited as an autosomal recessive trait that is caused by mutations in perlecan, a heparin-sulfate proteoglycan that is bound to the basement membranes of skeletal muscle and cartilage. Loss of function of the protein perturbs the organization of the basement membrane leading to an altered clustering of ACh esterase and abnormal expression of ion channels. Electron microscopic studies of muscle have yielded inconsistent findings: dilated T system, Z-band streaming, and dilatation of mitochondria; in addition, in the patient reported by Fariello and colleagues, muscle biopsy disclosed signs of denervation (group atrophy). In the latter case, treatment with procainamide, phenytoin, diazepam, and barbiturates was ineffective.

The condition, described by Aberfeld and coworkers, of two siblings in whom myotonia was combined with dwarfism, diffuse bone disease, and unusual ocular and facial abnormalities, and thought by them to represent a unique disorder, is probably a variant of the Schwartz-Jampel syndrome.