Clinical

The prevalence of hypoKPP is approximately 1 per 100,000. Episodes of limb weakness accompanied by hypokalemia usually begin during adolescence. Attacks usually occur in the morning and are often triggered either by the ingestion of a carbohydrate load and high salt intake the previous night, or by rest following strenuous exercise. Generalized muscle weakness and reduced or absent tendon reflexes are characteristic. Heralding the weakness may be sensory changes, fatigue, or a feeling of heaviness or aching in the legs or back. During paralysis, level of consciousness and sensation are preserved. Paralysis either spares the facial and respiratory muscles or causes only mild weakness, making medical intervention rarely necessary. The frequency, length, and severity of attacks vary. Although attacks may occur several times a week, they more often occur at intervals of weeks or months. Attack durations vary from minutes to days, typically lasting several hours. Occasionally the attacks are sufficiently brief to cause difficulty in documenting the accompanying hypokalemia. Patients usually recover full strength, although mild weakness may persist for several days or (more rarely) be permanent. The prophylactic use of acetazolamide usually prevents the acute attack. A progressive permanent myopathy may develop later in life.

Pathophysiology

In up to 70% of cases, the responsible mutation has been linked to a gene encoding a VGCC on chromosome 1q (Venance et al., 2006). The gene, CACNA1S, encodes the α₁-subunit of the dihydropyridine-sensitive L-type VGCC found in skeletal muscle. This channel functions as the voltage sensor of the ryanodine receptor and plays an important role in excitation-contraction coupling in skeletal muscle. Four mutations in the S4 segments are responsible for voltage sensitivity. Two mutations, one involving arginine-to-histidine substitutions within the highly conserved S4 segments of DII and DIV (Arg-528-His and Arg-1239-His) account for most cases. The others involve arginine-to-glycine substitutions at the same locations.

Some 10% to 20% of families with hypoKPP have mutations in the gene encoding the α-subunit of the skeletal muscle voltage-gated sodium channel (SCN4A) on chromosome 17q. This is the same channel implicated in hyperKPP and other disorders described later (see Fig. 64.1). Evidence suggests that this sodium channel–associated syndrome is phenotypically different from the more common CACNA1S form. A proposed separate clinical entity, hypoKPP2, may be distinguishable from hypoKPP associated with CACNA1S by the presence of myalgias following paralytic attacks, and the presence of tubular aggregates instead of vacuoles in the muscle biopsy. In some patients, acetazolamide worsens symptoms (Bendahhou et al., 2001; Sternberg et al., 2001). In a large retrospective series, hypoKPP2 was associated with an older age of onset and shorter duration of attacks than classical hypoKPP (Miller et al., 2004).

Whether involving SCN4A or CACNA1S, virtually all mutations causing hypoKPP involve an S4 voltage-sensor domain. In the case of the sodium channel, these mutations allow a leak current to pass through the “gating pore” at resting membrane potentials, bypassing the central channel pore and leading to inappropriate muscle fiber depolarization and consequent channel inactivation and action potential failure (Sokolov et al., 2007). Speculation exists that this phenomenon may also occur in mutated VGCCs.

Diagnosis

An accurate medical history is essential for the diagnosis because observation of attacks is unusual, and patients are often normal between attacks. Characteristic features of hypoKPP that distinguish it from hyperKPP are that paralytic attacks are less frequent, longer lasting, precipitated by a carbohydrate load, and often begin during sleep (Table 64.2). Potassium concentrations are usually low during an attack, although concentrations less than 2 mM should suggest a secondary form of periodic paralysis. Electrocardiogram (ECG) changes such as increased PR and QT intervals, T-wave flattening, and prominent U waves suggest an underlying hypokalemia. Provocative testing can be dangerous and is not routine. Test performance requires a hospitalized setting with continuous cardiac monitoring and should be performed only in patients without cardiac or renal disease. After giving an oral glucose load (2-5 mg/kg up to a maximum of 100 g) without or, less commonly, with subcutaneous insulin (0.1 U/kg), perform serial examinations of strength while monitoring serum glucose and potassium concentrations. Other diagnostic tests include electromyography (EMG), which may show decreased compound muscle action potential amplitudes during attacks compared with interictal values. Muscle histology reveals nonspecific myopathic changes of tubular aggregates or vacuoles within fibers. Genetic testing should render muscle biopsy and provocative testing obsolete for diagnosis.

Table 64.2 Clinical Features of the Periodic Paralyses and Nondystrophic Myotonias

Thyrotoxic periodic paralysis may be clinically indistinguishable from hypoKPP, except that it is not familial and serum potassium levels are often lower than in familial hypoKPP (<2.5). Some cases may be associated with a mutation in KCNJ18, the gene encoding a novel inwardly rectifying potassium channel (Ryan et al., 2010). All patients with hypoKPP require screening for hyperthyroidism, as the treatment—correction of the thyroid disorder—differs from that outlined later for idiopathic hypoKPP. Exclude other secondary forms of hypokalemic paralysis when serum potassium concentrations remain low between attacks. Renal, adrenal, and gastrointestinal causes of persistent hypokalemia are common, and thiazide diuretic use or licorice (glycyrrhizic acid) intoxication are considerations.

Treatment

An effective holistic approach to treatment includes lifestyle modifications and acute and chronic pharmacological intervention. Dietary modification to avoid high carbohydrate loads and refraining from excessive exertion helps prevent attacks. Oral potassium (5-10 g load) reverses paralysis during an acute attack. Prophylactic use of acetazolamide (Table 64.3) decreases the frequency and severity of attacks. Dichlorphenamide is another carbonic anhydrase inhibitor that effectively prevents attacks, as demonstrated in a randomized clinical trial (Tawil et al., 2000) where the average dose was 100 mg daily. More potent than acetazolamide, dichlorphenamide may be useful when efficacy of the former begins to fail. Many believe, without supporting evidence, that reducing the frequency of paralytic attacks provides protection against the development of myopathy. As insight into molecular pathophysiology expands, new treatment possibilities—and a new understanding of old treatments—seem likely (Matthews and Hanna, 2010).

Table 64.3 Acetazolamide

Clinical

Characteristic of this disorder is episodic weakness precipitated by hyperkalemia. Although the weakness is generally milder than in hypoKPP, it can be sufficiently severe in hyperKPP to cause flaccid quadriparesis. As in hypoKPP, respiratory and ocular muscles are unaffected and consciousness is preserved. Frequency of attacks varies from several per day to several per year. Attacks are usually brief, lasting 15 to 60 minutes, but may last up to days. Unlike hypoKPP, myotonia is present between attacks. Onset is usually in infancy or childhood, and characteristic attacks occur by adolescence. Triggers include rest after vigorous exercise, foods high in potassium, stress, and fatigue. Despite its name, hyperKPP is often associated with a normal serum potassium concentration during an attack (see following Diagnosis section). Most patients experience a subacute onset, and some describe paresthesias or a sensation of muscle tension prior to attacks. In these situations, mild exercise may abort or lessen the severity of the attack. Mild weakness may persist afterward, and the later development of a progressive myopathy is common.

Pathophysiology

HyperKPP is as an autosomal dominant disorder, with some sporadic cases. The disorder links to SCN4A, the same gene responsible for a minority of hypoKPP cases. Among several identified missense mutations, four account for about two-thirds of cases (see Fig. 64.1). Functional expression of naturally occurring mutations demonstrated a decrease in the voltage threshold of channel activation or abnormally prolonged channel opening or both (Bendahhou et al., 2002; Hayward et al., 1999), effectively increasing the depolarizing inward current. If sustained long enough, this would lead to inactivation of the sodium channels, transitory cellular inexcitability, and weakness.

Diagnosis

Despite advances in defining the underlying genetic mutations, a thorough medical and family history and physical examination remain the best diagnostic tools. Furthermore, genetic testing is not generally available, and the high number of causative sodium channel mutations makes widespread use of genetic testing unlikely in the near future. Serum potassium is normal between attacks and even during many attacks. Unlike hypoKPP, potassium administration may precipitate an attack. In the absence of provocative testing, the basis for diagnosis is the clinical presentation. Myotonia is present in many patients between attacks, either spontaneously or after muscle percussion, and failure to produce myotonia discriminates hypoKPP from hyperKPP (see Table 64.2). Take care not to confuse subjective muscle stiffness with objective changes. Peaked T waves on ECG suggest hyperkalemia and are an aid to diagnosis. As in hypoKPP, serum creatine kinase concentrations may be normal or elevated. Electrodiagnostic studies are useful for demonstrating subclinical myotonic discharges, not seen in hypoKPP. Nonspecific findings such as fibrillation potentials and small polyphasic motor unit potentials occur during late stages of disease.

A potassium-loading test provokes an attack but is not usually necessary and can be dangerous. Patients are placed on cardiac monitors following exercise and are given an oral potassium load of 1 mEq/kg (4-10 g KCl) in a fasting state. Weakness generally ensues 20 to 60 minutes later, and the accompanying rise in potassium occurs as a second peak 90 to 180 minutes after administration. Concomitant EMG shows decreasing amplitude of the compound muscle action potential.

Treatment

The goal of therapy is to abort the acute attacks and prevent future attacks. Acute attacks are often sufficiently brief and mild so as not to require acute intervention. In more severe attacks, aim treatment at lowering extracellular potassium levels. Mild exercise or eating a high sugar load (juice or a candy bar) may suffice, as insulin drives extracellular potassium into cells. Thiazide diuretics and inhaled β-adrenergic agonists are similarly helpful, and intravenous calcium gluconate may be useful when weakness is very severe. To prevent attacks, a diet low in potassium and high in carbohydrates may obviate the need for prophylactic drug therapy. Oral dichlorphenamide was useful for prophylaxis in one randomized controlled trial (Tawil et al., 2000). Acetazolamide (see Table 64.3) and thiazide diuretics are useful as well. Successful prophylaxis may decrease the later onset of myopathy, although direct proof of this hypothesis is lacking. Finally, myotonic symptoms are troublesome in some patients; based on the underlying pathophysiology, sodium channel blockers would seem an effective therapy, and mexiletine is commonly used for this purpose.

Clinical

The characteristic features of paramyotonia congenita (PMC) are paradoxical myotonia, cold-induced myotonia, and weakness after prolonged cold exposure. Unlike classic myotonia that shows a warm-up phenomenon (see following section on Myotonia Congenita), patients with PMC often show exacerbation of myotonia after repeated muscle contraction. Symptoms are present at birth and usually remain unchanged throughout life. Myotonia affects all skeletal muscles, although the facial muscles, especially the orbicularis oris, and muscles of the neck and hands are the most common sites of myotonia in the winter. The onset of weakness is often during the day, lasts several hours, and is exacerbated by cold, stress, and rest after exercise. Many patients are asymptomatic when warm. However, cold-induced stiffness may persist for hours even after the body warms, and percussion myotonia is present even when the patient is otherwise asymptomatic.

Pathophysiology

The cause of PMC is point mutations in the SCN4A gene on chromosome 17q, the same gene mutated in hyperKPP, potassium-aggravated myotonia, and less commonly, in hypoKPP. Mutations of the gene, which include substitutions at T1313 on the DIII to DIV linker and at R1448 on the DIV-S4 segment, cause defects in sodium channel deactivation and fast inactivation. The resting membrane potential rises from −80 up to −40 mV when intact muscle fibers cool. Mild depolarization results in repetitive discharges (myotonia), whereas greater depolarization results in sodium channel inactivation and muscle inexcitability (weakness).

Diagnosis

A family history of exercise- and cold-induced myotonia strongly supports the diagnosis of PMC. However, take care to differentiate subjective and objective changes in response to cold. When asked to close their eyes forcefully and repeatedly, affected individuals exhibit progressive difficulty with relaxation and are eventually unable to open their eyes. Serum potassium concentration may be high, low, or normal during attacks, and serum creatine kinase concentrations may be elevated 5 to 10 times normal. Electrodiagnostic studies are useful in establishing the diagnosis. EMG reveals fibrillation-like potentials and myotonic discharges that muscle percussion, needle movement, and muscle cooling accentuate. Muscle cooling elicits an initial increase in myotonia, then a progressive decrease in myotonia followed by a decrease in compound muscle action potential amplitude that correlates respectively with muscle stiffness and weakness. A reduction in isometric force of 50% or more and a prolongation of the relaxation time by several seconds after muscle cooling support the diagnosis. Muscle pathology shows only nonspecific changes, and biopsy is unnecessary.

Treatment

Symptoms are generally mild and infrequent. Direct treatment, when required, at either myotonia or weakness or both. Sodium channel blockers such as mexiletine are sometimes effective in reducing the frequency and severity of myotonia. Patients with weakness often respond to agents used to treat hyperKPP (e.g., thiazides, acetazolamide). A single case report suggests the possible use of pyridostigmine (Khadilkar et al., 2010). Cold avoidance reduces the frequency of attacks.

Clinical

Inheritance of myotonia congenita (MC) is either as an autosomal dominant (Thomsen disease) or recessive (Becker myotonia) trait. The main feature is myotonia or delayed muscle relaxation after contraction. Forceful movement abruptly initiated after several minutes of rest causes the most pronounced myotonic stiffness. The myotonia of MC displays a warm-up phenomenon in which the myotonia decreases or vanishes completely when repeating the same movement several times, in contrast to the myotonia seen in patients with PMC. The onset of Thomsen myotonia is often within the first decade, whereas the onset of Becker myotonia is generally at 10 to 14 years of age. Although myotonia can affect all skeletal muscles, it is especially prominent in the legs, where it is occasionally severe enough to impede a patient’s ability to walk or run. In rare cases, sudden noise causes sufficient generalized stiffness to make the patient fall to the ground and remain rigid for several seconds. The recessive and dominant forms share many similarities, but some clinical features help distinguish the two. In general, patients with recessive disease experience transitory bouts of weakness after periods of disuse and may develop progressive myopathy (Kornblum et al., 2010); in addition, muscle hypertrophy and disease severity are greater than in the dominant form. Becker myotonia is more common than Thomsen disease.

Pathophysiology

Electrical instability of the sarcolemma leads to muscle stiffness by causing repetitive electric discharges of affected muscle fibers. Early in vivo studies in myotonic goats revealed greatly diminished sarcolemmal chloride conductance in affected muscle fibers. This causes a depolarization of the sarcolemmal membrane and muscle hyperexcitability. Genetic linkage analysis for both recessive and dominant forms of MC pointed to a locus on chromosome 7q, where the responsible gene, CLCN1, encodes the major skeletal muscle chloride channel. More than 70 mutations have been identified within CLCN1, and interestingly, some of these mutations are recognized to cause both dominant and recessive forms (Zhang et al., 2000). Examination of the functional effects of several myotonia-causing CLCN1 mutations in heterologous expression systems reveal effects on channel gating, usually resulting in a decreased chloride conductance (Zhang et al., 2000).

Diagnosis

Tapping the belly of a muscle with a percussion hammer can elicit myotonia that lasts for several seconds. Myotonia is a nonspecific sign found in several other diseases including myotonic dystrophy 1, myotonic dystrophy 2 (proximal myotonic myopathy), PMC, and hyperKPP (see earlier section). Cardiac abnormalities, cataracts, skeletal deformities, and glucose intolerance are not components of MC, and their presence should suggest one of the dystrophic myotonias. Muscle strength and tendon reflexes are normal, but patients commonly display muscle hypertrophy, often giving these patients an athletic appearance. The finding of decremental compound muscle action potential amplitudes with muscle cooling on EMG distinguishes PMC from MC. EMG in MC typically reveals bursts of repetitive action potentials with amplitude (10 µV to 1 mV) and frequency (50-150 Hz) modulation, so-called dive-bombers, in the EMG loudspeaker. Biopsy is usually nonspecific, showing enlarged fibers in hypertrophied muscle, increased numbers of internalized nuclei, and decreased type 2B fibers.

Treatment

Many patients experience only mild symptoms and do not require treatment. For those with more severe myotonia, sodium channel blocking agents remain the mainstay of treatment. Mexiletine is the most commonly used and was shown effective in treating myotonia in a randomized placebo-controlled study. Other sodium channel blockers such as tocainide, phenytoin, procainamide, and quinine exhibit variable degrees of efficacy.

Clinical

Potassium-aggravated myotonia (PAM) is a rare autosomal dominant disorder with clinical features similar to MC, except that the myotonia fluctuates and worsens with potassium administration. Distinguishing PAM from other nondystrophic myopathies is important because PAM patients respond to carbonic anhydrase inhibitors. Episodic weakness and progressive myopathy do not occur. Symptom severity varies, with some patients experiencing only mild fluctuating stiffness, and others a more protracted painful myotonia. PAM now encompasses the conditions previously known as myotonia fluctuans, myotonia permanens, and acetazolamide-sensitive myotonia. Exercise or rest after exercise, potassium loads, and depolarizing neuromuscular blocking agents aggravate myotonia, whereas cold exposure has no effect. Prominent myotonia of the orbicularis oculi and painful myotonia suggest the diagnosis.

Pathophysiology

PAM links to chromosome 17q, where mutations in the SCN4A gene cause the disease. This sodium channel is the same one implicated in hyperKPP, PMC, and the sodium channel subtype of hypoKPP (see earlier discussion and Fig. 64.1). Functional expression studies reveal that the disease-causing mutations lead to a large persistent sodium current secondary to an increased rate of recovery from inactivation and an increased frequency of late channel openings (Wu et al., 2001). The cause of myotonia is this enhanced inward current, which leads to prolonged depolarization and subsequent membrane hyperexcitability.

Diagnosis

Diagnosis is clinical because screening for the mutated gene is not widely available. Distinguishing PAM from other episodic nondystrophic myotonias may be difficult. Unlike hyperKPP and PMC, PAM patients do not experience weakness. Another distinction between PAM and PMC is the lack of response to muscle cooling, either clinically or on EMG. Furthermore, the myotonia with PAM improves with carbonic anhydrase inhibitors, whereas mexiletine is more effective in alleviating the myotonia in MC and PMC.

Treatment

Carbonic anhydrase inhibitors markedly reduce the severity and frequency of attacks of myotonia. Acetazolamide is most commonly used (see Table 64.3).

Clinical

Andersen-Tawil syndrome (ATS) is a rare autosomal dominant disorder characterized by the triad of periodic paralysis, cardiac arrhythmias, and dysmorphic features (including hypertelorism, micrognathia, low-set ears, high-arched or cleft palate, short stature, and clinodactyly) (Yoon et al., 2006a). The periodic paralysis, often triggered by rest after exercise, prolonged rest, and stress, is often the presenting symptom and can be hypo-, normo-, or hyperkalemic. The cardiac phenotype, often discovered later, includes prolonged QT intervals, but bidirectional ventricular tachycardia is common. Despite the known association of cardiac arrhythmias in rare periodic paralysis patients, ATS was only recognized as a separate entity in 1971. In families segregating an ATS allele, the phenotypic expressivity can vary greatly. Patients can manifest one, two, or three features of the triad, and the severity of any one feature can be extremely variable. Rare individuals are asymptomatic disease-gene carriers. Finally, ATS patients may exhibit neurocognitive deficits in executive function and abstract reasoning (Yoon et al., 2006b).

Pathophysiology

Mutations in the KCNJ2 gene on chromosome 17q account for approximately two-thirds of ATS probands. KCNJ2 encodes a widely expressed inwardly rectifying potassium channel (Plaster et al., 2001). Interestingly, among all identified probands, about 50% have an autosomal dominant disorder, and identification of sporadic cases with de novo mutations is common. The mechanisms of channel dysfunction are heterogeneous, including impaired phospholipid binding, pore function, or protein trafficking. Because VGKCs are tetrameric complexes, many (if not all) of the mutations are dominant negative.

Diagnosis

Previous studies that took into account the variable penetrance of ATS classified individuals as affected if two of three criteria were met: paroxysmal weakness, prolonged QT interval with or without ventricular dysrhythmias, or characteristic dysmorphic features (Yoon et al., 2006a). ATS should be included in the differential diagnosis of any individual with documented long-QT syndrome, even in the absence of periodic paralysis or dysmorphism. Some family members of patients with the full clinical triad show only prolonged QT intervals. Similarly, perform ECG on all patients with suspected periodic paralysis for careful measurement of the QT interval.

Often the diagnosis of ATS is established when an individual with paroxysmal weakness presents during an acute phase with ECG abnormalities. However, one often overlooks the diagnosis because the cardiac abnormalities, as with periodic muscle weakness, can be transitory and missed on routine ECG. A Holter monitor can capture episodic dysrhythmias or longer tracings for QT-interval analysis when ATS is suspected and the standard ECG is normal. Cardiac monitoring under provocative maneuvers such as tilt-table testing or graded exercise protocols may allow dysrhythmias to surface and should be utilized when the diagnosis of ATS is highly suggested but prior cardiac evaluation is unremarkable.

Creatine kinase concentrations are often normal during episodes of weakness but are occasionally elevated. Depending on the particular mutation, potassium concentrations during an attack are usually low but can be high or normal. Provocative testing in any case of periodic paralysis may be risky, and hypokalemic challenges in ATS may be particularly dangerous because of the potential to exacerbate preexisting QT prolongation and trigger life-threatening ventricular arrhythmias.