In this chapter, we describe the pathophysiology, clinical presentation, laboratory findings, and treatment of the nondystrophic myotonias and periodic paralyses (Table 31-1).

There are several inherited myopathic disorders associated with clinical or electrical myotonia in which muscle is not dystrophic.^1–5 These disorders are caused by mutations in various ion channels, and are thus referred to here as muscle channelopathies. Mutations in the chloride channel cause myotonia congenita (MC). The sodium channelopathies include potassium-sensitive (hyperkalemic) periodic paralysis (HyperKPP), paramyotonia congenita (PMC), potassium-aggravated myotonias (PAM) (e.g., myotonia fluctuans, myotonia permanens, and acetazolamide-responsive myotonia), and familial hypokalemic periodic paralysis type 2 (HypoKPP2). HyperKPP and PMC are usually associated with episodes of transient generalized or focal weakness. Hypokalemic periodic paralysis type 1 (HypoKPP1) is not associated with myotonia clinically or electrically and is caused by mutations of muscle dihydropyridine (DHP) receptor (a type of calcium channel). Andersen–Tawil syndrome (ATS) is another rare form of hereditary periodic paralysis of which some forms are due to mutations in a potassium channel.

Electrophysiological studies, in particular the short- and long-exercise tests (SETs and LETs), also described in Chapter 2, can be useful in distinguishing subtypes of muscle channelopathy and thus deserve special comment (Tables 32-1,32-2).^1–9 The SET is performed by having the patient isometrically exercise a muscle (e.g., abductor digiti minimi) for 10 seconds, followed by measurement of compound muscle action potential (CMAP) amplitudes immediately after exercise and every 10 seconds thereafter up to 60 seconds. Fournier et al. modified the test by having the SET repeated twice more with a rest period of 60 seconds between trials. In addition, the SET should be done at room temperature and then with cooling of the muscle. In normal individuals, immediately after short exercise, there is a mild increase in the CMAP amplitudes compared to baseline (mean 4–5%, range −28% to +27%) with the amplitudes returning to baseline within 10 seconds.^8,9 If the SET is performed after cooling the limb (e.g., with an ice pack), the CMAP amplitudes decrease (−25% to −65%), but the durations of the CMAPs increase.

The LET is performed by having the patient isometrically exercise a muscle (e.g., abductor digiti minimi) for 5 minutes (with 3–4 seconds of rest every 30–45 seconds), while CMAP amplitudes are recorded every minute during the exercise period, immediately after cessation of exercise, then every minute for 5 minutes, and finally every 5 minutes for 40–45 minutes. In normal people, CMAP amplitudes only slightly decrease after the exercise period (range −16 to +5%), and the amplitudes then return to normal within the next 30–60 seconds and remain so during the next 40–50 minutes.^8,9

Changes in CMAP amplitudes with the SET separates muscle channelopathies into five patterns (Table 32-2; Fig. 32-1).⁸ The first three patterns help distinguish the nondystrophic myotonias, particularly when performed at room temperature and then in cold, while Patterns IV and V are useful in diagnosing periodic paralysis in combination with the LET.^6,8,9

MYOTONIA CONGENITA

Clinical Features

The autosomal-dominant form of MC, or Thomsen disease, often presents in the first few years of life.^{1–4,10–16} Affected infants may have difficulty opening their eyes after crying. Stiffness in the legs upon arising and taking the first few steps may lead to tripping and falling. As patients become older, their muscle stiffness may become more noticeable in the arms. Myotonia of muscles of mastication may result in difficulties in chewing and swallowing. As with most forms of myotonia, the stiffness in the muscles eases with repeated contractions, the so-called warm-up phenomena. Thus, although an affected individual may have initial stiffness in their legs when they begin to walk, within a short time ambulation becomes easier. After rest, the same stereotypical pattern of stiffness returns on initiation of physical activity. The myotonia can worsen with cold similar to that seen in PMC.¹⁷ The severity of the myotonia can fluctuate and is variable even within affected family members. The stiffness may worsen during pregnancy. Of note, people with MC usually do not typically complain of muscle pain with their stiffness. In contrast to the myotonic dystrophies, there are no systemic disorders (e.g., cataracts, endocrinopathies, cardiopathy, ventilatory muscle weakness) associated with MC or increased mortality. However, some individuals present later in life with stiffness and proximal weakness and resemble myotonic dystrophy type 2 (DM2) or proximal myotonic myopathy (PROMM).^4,17 There may be an increased risk of malignant hyperthermia (MH) with anesthetic agents.

On examination, affected individuals usually appear extremely muscular (e.g., Herculean). Muscle strength is usually normal, but some patients develop mild proximal weakness. Action myotonia can be elicited by having the patient make a strong grip and then try to relax their fingers, or by having patients forcefully close their eyes and then try to open them. One sees delayed relaxation, which improves with repeated activity due to the warm-up phenomena discussed above. In addition, myotonia can be demonstrated by percussing a muscle (e.g., the thenar eminence) with a reflex hammer (percussion myotonia).

Becker described the features of the autosomal recessive form of MC which bears his name. The clinical features of the autosomal recessive and dominant forms of MC are similar, but there are some differences.^{1–4,10,11,14,15} The autosomal recessive or Becker type of MC usually presents between 4 and 12 years of age, somewhat later than that seen in the autosomal-dominant form, however, the severity of weakness is typically worse.^1,2,13 Transient muscle weakness, particularly in the distal arms, may occur following a severe bout of myotonia. On examination, muscle bulk is usually increased. Mild fixed weakness is apparent in proximal muscles of the arms and legs as well as in the neck. Systemic complications are not seen, though there is an increased risk of MH.

Laboratory Features

Skeletal muscle MRI is usually not that helpful as it may¹⁸ or may not¹⁹ demonstrate signal abnormalities, which if present are nonspecific. Serum creatine kinase (CK) is normal or only slightly elevated. Routine motor and sensory nerve conduction studies (NCS) are normal. On repetitive nerve stimulation, a decrement may be appreciated when a prolonged train of stimuli are delivered at 10 Hz or more. In such cases, the CMAP amplitudes may decrease to 65% of normal and even large degrees of decrement can occur with stimulation at higher rates.^6,20

The SET is associated with a decrease in CMAP amplitude immediately after exercise that returns to baseline after 20–40 seconds, in 48–80% of individuals with MC, (Fig. 32-1B).^2,4,7,9 The reduction in the CMAP amplitude decreases with repeated trials of short exercise, corresponding to the clinical warm-up phenomena. Fournier et al.⁷ called this Pattern II (Table 32-2). A greater than 40% decrement of SET is specific for MC.^4,9 More accurately though, it is the autosomal recessive cases that usually have the reduction in CMAP amplitudes, while the autosomal-dominant cases typically are not associated with significant change in amplitude.^3,8,9 Performing the SET in a cooled limb in patients with autosomal-dominant MC may result in a drop in amplitude that improves with repeated short exercise (e.g., a conversion from normal to Pattern II with cold). In contrast, there is usually no significant difference in the results of the short exercise performed at room temperature, in comparison to cold in individuals with autosomal recessive MC (they remain with Pattern II).^4,8 Overall, Fournier Pattern II is seen in over 60% of autosomal recessive MC, but less than 30% of autosomal-dominant MC.^4,8 In addition, postexercise repetitive discharges or myotonic potentials (PEMPs) are seen in about one-third of MC patients after short exercise.⁷ These PEMPs disappear within 10–30 seconds after exercise. The LET is usually normal, but 10–30% of patients with MC (usually AR-MC) have a and initial transient decrement greater than normal (Fig. 32-2).^7,9,21

On needle electromyography (EMG), myotonic discharges are evident at rest and during volitional activity. Cooling a limb does not lead to exacerbation of the clinical or electrical myotonia or development of weakness, unlike that seen in PMC.²² It may be difficult to appreciate motor unit action potential (MUAP) as the myotonic discharges obscure the voluntary MUAPs, but morphology and recruitment are usually normal. However, short duration, small amplitude MUAPs may occasionally be appreciated in weak muscles. Single fiber EMG reveals normal fiber density but slightly increased jitter.

Molecular Genetics and Pathogenesis

Both the autosomal-dominant form (Thomsen) and recessive form (Becker) of MC are caused by mutations in the muscle chloride channel gene (CLCN1) on chromosome 7q35 (Fig. 32-3).^1,5,23–25 Of note, there is a so-called painful variant of MC that resembles the Thomsen and Becker forms, except patients with this disorder more frequently complain of myalgias. This painful variant of MC is usually caused by mutations in the muscle sodium channel gene, SCN4A, (discussed later). Structurally, the chloride ion channel is a homotetramer with each subunit encoded by the CLCN1 gene.²⁴ The function of the chloride ion channel is to maintain the high resting membrane conductance in muscle fibers.²⁶ Mutations of the CLCN1 gene are associated with reduced chloride conductance. Because chloride ions are responsible for 70% of the skeletal muscle resting membrane potential, reduced chloride conductance leads to a decrease in the rate of muscle membrane repolarization. Thus, sodium channels are able to recover from inactivation faster. As a result of the muscle membrane being in a state of depolarization, recurrent firings of action potentials or myotonic discharges occur.²⁶

Treatment

Many individuals with MC do not require medical treatment. However, when the myotonia is severe and impairs function, treatment with antiarrhythmic or antiepileptic medications (e.g., mexiletine, phenytoin, carbamazepine) that interfere with the muscle sodium channel can be beneficial. In this regard, a randomized, placebo-controlled trial demonstrated that mexiletine (200 mg three times daily) reduced muscle stiffness.²⁷ We have also found mexiletine diminishing the transient exacerbations of weakness that can accompany the myotonia. Prior to starting mexiletine, we obtain a baseline electrocardiogram (EKG) as the drug can prolong the QT interval. If the EKG reveals a significant abnormality, we obtain a cardiology consultation before beginning mexiletine. Light-headedness, diarrhea, and dyspepsia are dose-limiting side effects of mexiletine. Dantrolene, which blocks the release of calcium from the sarcoplasmic reticulum, may reduce myotonia as well, but is usually avoided because of side effects.

SODIUM CHANNELOPATHIES

The sodium channelopathies include HyperKPP, PMC, the PAMs (e.g., myotonia fluctuans, myotonia permanens, and acetazolamide responsive myotonia)^{1–5,28–45} and familial HypoKPP2^1,32–34 They are myopathies that share some similar clinical and laboratory features but have differences (Table 32-1). These disorders are inherited in an autosomal-dominant fashion. They are all caused by missense mutations in the pore-forming subunit of the voltage-gated skeletal-muscle sodium channel Na_V1.4 (encoded by the SCN4A gene that is located on chromosome 17q23–25) (Fig. 32-4).^{1,5,28,30–37} For the most part, each missense mutation in SCN4A is consistently associated with one of the four allelic sodium channel disorders, suggesting the presence of separate classes of functional defects. However, some variability exists and the distinction is often blurred between PMC and HyperKPP, even in affected members of the same family.

POTASSIUM-SENSITIVE OR HYPERKALEMIC PERIODIC PARALYSIS (ADYNAMIA EPISODICA HEREDITARIA)

Clinical Features

Potassium-sensitive periodic paralysis or hyperkalemic periodic paralysis (HyperKPP) is an autosomal-dominant disorder with a high degree of penetrance.^{12,30,36–38,46–56} A recent large study in England revealed the prevalence to be 0.17 per 100,000.⁵ HyperKPP manifests in three forms: (1) without myotonia, (2) with clinical or electrical myotonia, or (3) associated with paramyotonia. The course of the attacks of weakness is similar in each form, except that cooling triggers weakness in those with paramyotonia. Clinical myotonia is often mild, and can be elicited in the face (e.g., eyelids), tongue, forearm (e.g., finger extensors), and the thenar eminence with percussion or activity. The myotonia eases with repetitive activity, except in individuals with paramyotonia who exhibit paradoxical myotonia in which muscle stiffness is induced or worsened by exercise and cold temperature.

Most affected individuals become initially symptomatic with attacks of weakness in the first decade of life. These attacks usually develop in the morning, although can occur at any time, and are often precipitated by rest following exercise, intake of potassium rich food, fasting, and even by stress. The weakness can be mild or severe, with the latter more commonly occurring after strenuous physical activity. People may note paresthesia and achiness in the muscles prior to the development of weakness. The thigh and calf muscles are often affected and weakness may progress to other muscle groups. However, the weakness can also be focal. In contrast to HypoKPP, generalized flaccid paralysis is uncommon. Rarely, the bulbar and ventilatory muscles are affected. The sphincter muscles are unaffected during attacks.

The duration of weakness attacks is usually less than 2 hours, although mild weakness can persist for a few days. The frequency of attacks is highly variable, ranging from several times a day to less than once a year. In addition, there is great variation of attack severity and frequency within and between families. The frequency of paretic attacks often decreases with age. Sustained mild exercise after a period of strenuous activity may postpone or prevent weakness from developing in the exercising muscles, while resting muscle groups become weak. Following a bout of weakness, it is not uncommon for pain to be experienced in the affected muscles up to several days. During attacks, the reflexes are diminished or absent, while sensation remains normal. Between the attacks, sensation and muscle stretch reflexes are normal and lid lag or eyelid myotonia may be the only clinical signs present. Not infrequently, affected individuals develop fixed or slowly progressive weakness, independent of the episodic attacks, usually involving the more proximal muscles.

Laboratory Features

Skeletal muscle MRI scans may reveal nonspecific signal abnormalities in thigh and calf muscles.¹⁸ Serum CK levels are usually mildly elevated. In between the attacks, serum potassium levels are within normal limits. Increase in serum potassium levels (usually to 5–6 mEq/L) are associated with attacks of weakness, though serum levels may remain within normal limits. Serum sodium levels can fall during episodes of weakness. During attacks, there is increased urinary excretion of potassium that can actually result in transient hypokalemia at the end of an attack. On EKG, the hyperkalemia can result in increased amplitudes of the precordial T waves.

Secondary causes of hyperkalemia can cause generalized weakness and must be excluded particularly in individuals with no family history (Table 32-3). Usually the serum potassium levels are greater than 7 mEq/L. Patients with secondary causes of hyperkalemic do not exhibit clinical or electrical myotonia. While provocative testing such as potassium challenge has been performed in the past when the diagnosis is unclear, there are obvious risks of such testing. The availability of commercial genetic testing and features on electrophysiological testing obviate the need for such provocative testing.

Routine motor and sensory NCS are normal between attacks of weakness.^53–56 However, during an attack of weakness, the CMAP amplitudes may be reduced in affected muscles. As previously mentioned, the SET and LET can be useful in distinguishing subtypes of channelopathies.^7–9 With the SET test, some patients with HyperKPP, depending on the exact mutation (e.g., T704M), have abnormal increased CMAP amplitudes that persist for a longer period of time than normal individuals.^7,9 Further, repetition of short exercise amplifies the increase in CMAP amplitudes. With the LET, during the exercise period and immediately afterwards, there is an initial increase in CMAP amplitudes from baseline that is followed by a progressive decline in the amplitudes over the next 40–50 minutes. Brief exercise (e.g., 10 seconds) during this paretic phase may induce an increment in the CMAP amplitudes (Fig. 32-5).⁷ This constellation of findings on SET and LET is termed Fournier Pattern IV.

Needle EMG reveals variable findings. Myotonic discharges are found in 50–75% of affected individuals, though clinical myotonia is apparent in less than 20%.^7,57 In patients with myotonia, examination of the muscle between attacks of weakness reveals an increase in insertional activity, in the form of fibrillation potentials and positive sharp waves, in addition to myotonic discharges. These abnormal discharges reflect the hyperexcitability or instability of the muscle membrane and are not due to denervation. Reducing the limb temperature may exacerbate the runs of myotonic discharges. Analysis of MUAP parameters may reveal a slight increase in small amplitude, short duration, polyphasic potentials. In people with HyperKPP without myotonia, the insertional and spontaneous activity is normal between attacks of weakness. During an attack of weakness, the MUAPs decrease in duration and amplitude and may disappear altogether in plegic muscles.

Histopathology

Muscle biopsy in patients with HyperKPP frequently reveals nonrimmed vacuoles.^12,58,59

Molecular Genetics and Pathogenesis

Potassium sensitive periodic paralysis is caused by mutations in the α-subunit of the voltage-dependent sodium channel gene (SCN4A) (Fig. 32-4).^{5,13,38,41,60–62}

Treatment

Attack frequency may be reduced with a low-potassium, high-carbohydrate diet and avoidance of fasting, strenuous activity, and cold. Mild, short-lasting attacks of weakness usually do not require treatment. Sometimes a simple ingestion of simple carbohydrates (e.g., fruit juices, glucose-containing candies) decreases the serum potassium level by increasing insulin secretion and may improve strength. Beta-adrenergic agonists (e.g., metaproterenol, albuterol, salbutamol) also may increase strength but one needs to take care in regard to associated cardiac arrhythmias. Beta-adrenergic medications may have their effect through the sodium–potassium pump. Only in severe attacks of weakness is treatment with intravenous glucose, insulin, or calcium carbonate warranted. Prophylactic use of acetazolamide (125–1000 mg per day), chlorothiazide (250–1000 mg per day), or dichlorphenamide (50–150 mg per day) may be beneficial in reducing the frequency of attacks and perhaps the myotonia, though dichlorphenamide is no longer commercially available.^16,29,36 Mexiletine may be useful in managing myotonia when it is bothersome.

PARAMYOTONIA CONGENITA (EULENBURG DISEASE)

Clinical Features

PMC is an autosomal-dominant disorder with high penetrance that is allelic to potassium-sensitive periodic paralysis, which probably explains why many patients have clinical features of both disorders (paralysis periodica paramyotonia).^{1–4,12,29,30,50,63–67} The name derives from the “para”-doxical reaction to exercise. In contrast to the warm-up phenomena observed in other myotonic syndromes, repeated exercise worsens the muscle stiffness in patients with PMC. Paramyotonia, particularly of the eyelids, is typically evident in most affected individuals. Myotonia is also exacerbated by exercise or cold exposure. A cold-induced attack of weakness can last for several hours even after return to a warm environment. Weakness can also be induced in some cases by potassium intake. Further attacks of weakness can be focal or generalized attacks of weakness.

Symptoms and signs of PMC usually manifest within the first decade of life. During a crying spell, infants may be noted to have difficulty opening their eyes secondary to the “exercise”-induced myotonia of the orbicularis oculi muscles. While percussion myotonia may be demonstrated, it is usually not prominent. Some people complain of mild muscle pain, but myalgias are usually not as prominent as that seen in patients with DM2/PROMM which PMC can resemble. In addition, fixed, progressive weakness muscle weakness of proximal or distal muscles can develop over time.

Laboratory Features

Serum CK levels are usually mildly to moderately elevated. Serum potassium levels may be normal or elevated in some patients during an attack of paralysis. Skeletal muscle MRI scans may reveal nonspecific signal abnormalities.¹⁸

Routine sensory and motor NCS are normal between attacks of weakness.⁶³ Prolonged repetitive stimulation at rates exceeding 5 Hz or repetitive stimulation following a minute or more of exercise can induce a decrement in the CMAP in some patients.^20,63 The SET may demonstrate several distinctive abnormalities (Tables 32-1,32-2).^4,7–9 Immediately after 10 seconds of exercise, repetitive after-discharges may be seen on recorded CMAPs evoked by a single supramaximal stimulus (PEMPs) (Fig. 32-6). Subsequent stimuli are associated with reduction of these PEMPs. Also, there is decrement in the amplitudes of the main CMAP waveforms compared to baseline with repeated stimuli following the short exercise in some patients. We repeat the SET with a 10-second break in between epochs to increase the yield of finding abnormalities. Upon repetition of the short exercise, even in those patients who do not show any CMAP decline after the first trial, one may see marked reduction of CMAP amplitudes by the third trial (Fig. 32-1A). In some patients, there is also a gradual decrease in PEMPs. This so-called Fournier Pattern I is seen in approximately 90% of patients with PMC caused by a T1313M mutation in the SCN4A gene (Tables 32-1,32-2).^4,7,9 Fournier et al. reported patients with R1448C also had Pattern I, but other series reported no decrement on SET in individuals with this mutation.^4,7,9 This pattern is for the most part distinct from that seen in MC and DM2, which PMC may clinical resemble. Individuals with PMC mutations caused by Q270K mutations in the SCN4A gene may have SET that resemble those seen in MC (Fournier Pattern II).⁸ To further increase the yield, the SET should be repeated after the extremity has been cooled.^4,8,9 Cooling may bring out further abnormalities (even more marked reduction in amplitudes that worsen with repetition of short exercises than seen when the SET is performed at room temperature). Upon cooling, the SET in patients with Q270M mutations may convert to Fournier Pattern I that is more typical of PMC. With the LET, the CMAP amplitudes are markedly reduced during and following the exercise compared to baseline.^4,7,9,22,63 The amplitudes remain reduced for prolonged periods, sometimes exceeding an hour.

EMG reveals normal MUAPs though they are often difficult to appreciate with the background of diffuse myotonic discharges.^4,7,65 In patients with PMC and periodic paralysis, local cooling of the muscle results in dense fibrillation potentials and the gradual reduction in MUAP activity. As the muscle becomes flaccid, the myotonic discharges abate and complete electrical silence is observed. In contrast, in patients with pure PMC without periodic paralysis, local cooling of the muscle results in increased myotonic discharges, but MUAP morphology and recruitment remain normal and the muscle strength remains normal. Single fiber EMG reveals a slight increase in jitter and fiber density.⁶⁶

Histopathology