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).