Periodic Paralyses

Background

The heterogeneous group of muscle diseases known as periodic paralyses (PP) is characterized by episodes of flaccid muscle weakness occurring at irregular intervals. Most of the conditions are hereditary and are more episodic than periodic. They can be divided conveniently into primary and secondary disorders.

General characteristics of primary PP include the following: (1) they are hereditary; (2) most are associated with alteration in serum potassium levels; (3) myotonia sometimes coexists; and (4) both myotonia and PP result from defective ion channels.

• References

Pathophysiology

A clinically useful classification of primary periodic paralyses, shown in Table 1, includes hypokalemic, hyperkalemic, and paramyotonic forms.

Table 1. Primary Periodic Paralysis (modified from Jurkat-Rott and Lehmann-Horn^[1] )

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The physiologic basis of flaccid weakness is inexcitability of the muscle membrane (ie, sarcolemma). Alteration of serum potassium level is not the principal defect in primary PP; the altered potassium metabolism is a result of the PP. In primary and thyrotoxic PP, flaccid paralysis occurs with relatively small changes in the serum potassium level, whereas in secondary PP, serum potassium levels are markedly abnormal.

No single mechanism is responsible for this group of disorders. Thus, they are heterogeneous but share some common traits. The weakness usually is generalized but may be localized. Cranial musculature and respiratory muscles usually are spared. Stretch reflexes are either absent or diminished during the attacks. The muscle fibers are electrically inexcitable during the attacks. Muscle strength is normal between attacks but, after a few years, some degree of fixed weakness develops in certain types of PP (especially primary PP). All forms of primary PP (except Becker myotonia congenita [MC]) are either autosomal dominant inherited or sporadic (most likely arising from point mutations).

Voltage-sensitive ion channels closely regulate generation of action potentials (brief and reversible alterations of the voltage of cellular membranes). These are selectively and variably permeable ion channels. Energy-dependent ion transporters maintain concentration gradients. During the generation of action potentials, sodium ions move across the membrane through voltage-gated ion channels. The resting muscle fiber membrane is polarized primarily by the movement of chloride through chloride channels and is repolarized by movement of potassium. Sodium, chloride, and calcium channelopathies, as a group, are associated with myotonia and PP. The functional subunits of sodium, calcium, and potassium channels are homologous. Sodium channelopathies are better understood than calcium or chloride channelopathies. All forms of familial PP show the final mechanistic pathway involving aberrant depolarization, inactivating sodium channels, and muscle fiber inexcitability.

Discussion in this article primarily addresses the sodium, calcium, and potassium channelopathies as well as secondary forms of PP. Chloride channelopathies are not associated with episodic weakness and are discussed in more detail in the articles on myotonic disorders.

Summary of channel dysfunction in various types of PP

With HyperPP fast channel inactivation, mutations are usually situated in the inner parts of transmembrane segments or in the intracellular loops affecting the docking sites for the fast inactivating particle, thus impairing fast channel inactivation leading to persistent Na⁺ current.

With HypoPP hyperpolarization-activated cation leak counteracting K⁺ -rectifying current, mutations cause outermost arginine or lysine substitution.

With NormoPP depolarization-activated cation leak, mutations are in deeper locations of voltage sensor of domain II at codon R675.^{[1, 2]}

Ion channel dysfunction is usually well compensated with normal excitation, and additional triggers are often necessary to produce muscle inexcitability owing to sustained membrane depolarization.

Glucose and potassium intake has the opposite effects in these disorders. In HyperPP, potassium intake triggers the attack, whereas glucose ameliorates it. In contrast, glucose provokes hypokalemic attacks and potassium is the treatment for the attack.^[2]

Note the image below.

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Mutations in periodic paralysis.

Muscle sodium channel gene

The sodium channel has an alpha subunit and a beta subunit. The alpha subunit of the sodium channel is a 260-kd glycoprotein comprising about 1800-2000 amino acids. This channel is highly conserved evolutionarily from Drosophila to human. It has 4 homologous domains (I-IV) that fold to form a central pore, each with 225-325 amino acids. Each domain consists of 6 hydrophobic segments (S1-S6) traversing the cell membrane. The main functions of the channel include voltage-sensitive gating, inactivation, and ion selectivity. The extracellular loop between S5 and S6 dips into the plasma membrane and participates in the formation of the pore. The S4 segment contains positively charged amino acids at every third position and functions as a voltage sensor. Conformation changes may occur during depolarization, resulting in activation and inactivation of the channel. The cellular loop between domain III-S6 and domain IV-S1 acts as an inactivating gate.

The sodium channel has 2 gates (activation and inactivation) and can exist in 3 states. At rest with the membrane polarized, the activation gate is closed and the inactivation gate is opened. With depolarization, the activation gate opens, allowing sodium ions to pass through the ion channel and also exposing a docking site for the inactivation gate. With continued depolarization, the inactivation gate closes, blocking the entry of sodium into the cell and causing the channel to enter the fast-inactivation state. This inactivation of the channel allows the membrane to become repolarized, resulting in a return to the resting state with the activation gate closed and the inactivation gate opened. Two inactivation processes occur in mammalian skeletal muscle: Fast inactivation involves terminating the action potential and acts on a millisecond time scale. Slow inactivation takes seconds to minutes and can regulate the population of excitable sodium channels.

Sodium channel mutations that disrupt fast and slow inactivation are usually associated with a phenotype of HyperPP and myotonia, where as mutations that enhance slow or fast inactivation producing loss of sodium channel function cause HypoPP.

Mutations of the sodium channel gene (SCN4A) have several general features. Most of the mutations are in the "inactivating" linker between repeats III and IV, in the "voltage-sensing" segment S4 of repeat IV or at the inner membrane where they could impair the docking site for the inactivation gate. The clinical phenotype differs by specific amino acid substitution and, while some overlap may occur between hyperkalemic PP, paramyotonia congenita (PC), and potassium-aggravated myotonias (PAM), the 3 phenotypes are generally distinct (as described below). Nearly all mutant channels have impaired fast-inactivation of sodium current. Most patients are sensitive to systemic potassium or to cold temperature.

Two populations of channels exist, mutant and wild-type; the impaired fast-inactivation results in prolonged depolarization of the mutant muscle fiber membranes and can explain the 2 cardinal symptoms of these disorders, myotonia and weakness. In hyperkalemic PP, a gain of function occurs in mutant channel gating, resulting in an increased sodium current excessively depolarizing the affected muscle. Mild depolarization (5-10 mV) of the myofiber membrane, which may be caused by increased extracellular potassium concentrations, results in the mutant channels being maintained in the noninactivated mode. The persistent inward sodium current causes repetitive firing of the wild-type sodium channels, which is perceived as stiffness (ie, myotonia).

If a more severe depolarization (20-30 mV) is present, both normal and abnormal channels are fixed in a state of inactivation, causing weakness or paralysis. Thus, subtle differences in severity of membrane depolarization may make the difference between myotonia and paralysis. Temperature sensitivity is a hallmark of PC. Cold exacerbates myotonia and induces weakness. A number of mutations are associated with this condition, 3 of them at the same site (1448) in the S4 segment. These mutations replace arginine with other amino acids and neutralize this highly conserved S4 positive charge. Mutations of these residues are the most common cause of PC. Some of the possible mechanisms responsible for temperature sensitivity include the following:

• Temperature may differentially affect the conformational change in the mutant channel.
• Lower temperatures may stabilize the mutant channels in an abnormal state.
• Mutations may alter the sensitivity of the channel to other cellular processes, such as phosphorylation or second messengers.

Most cases of hyperkalemic PP are due to 2 mutations in SCN4A, T704M, and M1592V. Mutations in the sodium channel, especially at residues 1448 and 1313, are responsible for paramyotonia congenita. A small proportion of hypokalemic periodic paralysis cases are associated with mutations at codons 669 and 672 (HypoPP2). In HypoPP2, sodium channel mutations enhance inactivation to produce a net loss of function defect.

Normokalemic PP resembles both HyperPP (potassium sensitivity) and HypoPP (duration of attacks) and is caused by SCN4A mutations at a deeper location of voltage sensor DII at codon 675. R675 mutations differ from HypoPP in that these mutations result in depolarization-activated gating pore generating ω-current with reversed voltage dependence as this site is exposed to extracellular sites at stronger depolarization.^[3]

Calcium channel gene

The calcium channel gene (CACNL1A3) is a complex of 5 subunits (alpha-1, alpha-2, beta, gamma, and delta). The skeletal muscle dihydropyridine (DHP) receptor is located primarily in the transverse tubular membrane. The alpha-1 subunit has binding sites for DHP drugs and conducts the slow L-type calcium current. It also participates in excitation-contraction (EC) coupling and acts as a voltage sensor through its linkage with the ryanodine receptor of sarcoplasmic reticulum (ie, calcium release channel). Any changes in the membrane potential are linked to intracellular calcium release, enabling EC coupling. Point mutations in DHP receptor/calcium channel alpha-1 subunit cause hypokalemic PP (HypoPP1). Two mutations of CACNA1S gene, R528H and R1239H, are responsible for most cases of hypokalemic PP.

The physiological basis of disease is still not understood, but is more likely due to a failure of excitation rather than a failure of EC coupling. However, hypokalemia-induced depolarization may reduce calcium release, affecting the voltage control of the channel directly or indirectly through inactivation of the sodium channel. Insulin and adrenaline may act in a similar manner. Mutations of the calcium channel gene have some similarities to SCN4A mutations. Mutations modify channel inactivation but not voltage-dependent activation. Recordings from myotube cultures from affected patients revealed a 30% reduction in the DHP-sensitive L-type calcium current. Channels are inactivated at low membrane potentials.

Calcium channel mutations cause a loss of function manifested as a reduced current density and slower inactivation. How this inactivation is related to hypokalemia-induced attacks is not understood. At least in R528H mutation, a possible secondary channelopathy occurs, tied to a reduction in the ATP-sensitive potassium current from altered calcium homeostasis. The lower currents associated with CACNL1A3 mutations could slightly alter intracellular calcium homeostasis, which could affect the properties and expression of K⁺ channels, particularly KATP (ATP-sensitive potassium channel) belonging to inward rectifier class of channels. Insulin also acts in HypoPP by reducing this inward rectifier K⁺ current.

Voltage sensor charge loss accounts for most cases of HypoPP. Sodium and calcium channels have homologous pore-forming alfa subunits. Point mutations in CACNL1A3 and SCN4A affect argentine residues in the S4 voltage sensors of these channels. Arginine mutations in S4 segments are responsible for 90% of HypoPP cases.^[4]

Voltage sensor charge loss accounts for most cases of HypoPP. Sodium and calcium channels have homologous pore-forming α subunits. Almost all of the mutations in Cav1.1 (HypoPP-1) and Nav1.4 (HypoPP-2) neutralize a positively charged amino acid in one of the outermost arginines or lysines of voltage sensors. The Nav1.4 mutations are most commonly situated in the voltage sensors of I, II, and III repeats, causing a cation leak.

Substitution of outermost arginine with a smaller amino acid such as glycine opens a conductive pathway at hyperpolarized potential, resulting in an inward cation current (cation leak or ω current to distinguish from (ω-) through ion–conducting pore, is a hyperpolarization-activated current of monovalent cations through S4 gating pore counteracting rectifying K⁺ currents) depolarizing or destabilizing the resting potential.

S4 segment moves outward during depolarization closing the conductive pathway. Muscle fibers with severe voltage sensor mutations are depolarized not only during hypokalemia but also at potassium levels in the normal range, explaining interictal and permanent weakness. Severe myopathy with fatty replacement of muscle tissue is commonly found in patients with Cav1.1 R1239H (DIV mutations).^[1]

Glucocorticosteroids cause HypoPP by stimulating Na⁺ K⁺ ATPase mediated by insulin and amylin.^[5]

Potassium channel gene

Inward rectification is an important property of Kir channels. Rectification involves voltage-dependent conduction-pore blockage of pore with polyamines and Mg⁺⁺ during depolarization, and this blockage is removed during potential gradient during hyperpolarization. Potassium channel mutations are seen in Andersen-Tawil syndrome and thyrotoxic PP.

The triad of dysmorphic features, periodic paralysis, and cardiac arrhythmias characterizes Andersen-Tawil syndrome. This syndrome is associated with mutations in the KCNJ2 gene.^[6] The KCNJ2 gene encodes the inward-rectifying potassium channel Kir2.1. Potassium channel mutations in KCNE3 are reported to cause hypokalemic PP, but this has not been substantiated.

Mutations in Kir2.6 cause susceptibility to thyrotoxic PP. Episodic weakness seen in thyrotoxic PP is similar to that seen in HypoPP and Andersen-Tawil syndrome. This disorder is most prevalent in Asians and Latin American men. Thyrotoxic PP is a genetic disorder unmasked by thyrotoxicosis. Kir2.6 is primarily expressed in skeletal muscle. Triiodothyronine enhances KCNJ18 transcription, which may drive enhanced expression of Kir2.6. PKC is activated during thyrotoxicosis because of increased PIP2 turnover and Kir channels directly interact with PIP2 during normal gating. In Andersen-Tawil syndrome, there is decreased PIP2 affinity. In thyrotoxic PP, none of the mutations alters Kir2.6 rectification.^[7]

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Epidemiology

Frequency

The frequencies of hyperkalemic periodic paralysis, paramyotonia congenita (PC), and potassium-aggravated myotonias (PAM) are not known. Hypokalemic periodic paralysis has a prevalence of 1 case per 100,000 population.

Thyrotoxic PP is most common in males (85%) of Asian descent with a frequency of approximately 2%.

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History

All periodic paralyses (PPs) are characterized by episodic weakness. Strength is normal between attacks. Fixed weakness may develop later in some forms. Most patients with primary PP develop symptoms before the third decade.^[8]

Hyperkalemic periodic paralyses

• Age at onset is younger than 10 years. Patients usually describe a sense of heaviness or stiffness in the muscles. Weakness starts in the thighs and calves, which then spreads to arms and neck. Proximal weakness predominates; distal muscles may become involved after vigorous exercise.
• In children, a myotonic lid lag (lagging of upper eyelid on downward gaze) may be the earliest symptom. Complete paralysis is rare and some residual mobility remains. Respiratory muscle involvement is rare. The attacks last less than 4 hours and in the majority of cases, less than 1 hour. Sphincters are not involved; any bowel and bladder dysfunction is due to abdominal muscle weakness.
• Weakness occurs during rest after a period of strenuous exercise or during fasting. It also may be provoked by potassium, cold, ethanol, or stress. It may be relieved by mild prolonged exercise or carbohydrate intake. Patients also may report muscle pains and paresthesias. Between attacks, clinical and electrical myotonia is present in the majority of patients. Some families have no myotonia. Clinically apparent myotonia is seen less than 20% of patients, but electrical myotonia may be found in 50-75%. Interictal weakness, if present, is not as severe as in hypokalemic PP.

Hypokalemic periodic paralyses

• This can be divided into HypoPP1 (calcium channel mutation) and HypoPP2 (sodium channel mutation).
• Severe cases present in early childhood and mild cases may present as late as the third decade. A majority of cases present before age 16 years. Weakness may range from slight transient weakness of an isolated muscle group to severe generalized weakness. Severe attacks begin in the morning, often with strenuous exercise or a high carbohydrate meal on the preceding day. Sometimes, the time between premonitory symptoms to full-blown attack is in order of minutes. Attacks may also be provoked by stress, including infections, menstruation, lack of sleep, and certain medications (eg, beta-agonists, insulin, corticosteroids). Patients wake up with severe symmetrical weakness, often with truncal involvement.^[9]
• Mild attacks are frequent and involve only a particular group of muscles, and may be unilateral, partial, or monomelic. This may affect predominantly legs; sometimes, extensor muscles are affected more than flexors. Duration varies from a few hours to almost 8 days but seldom exceeds 72 hours. The attacks are intermittent and infrequent in the beginning but may increase in frequency until attacks occur almost daily. The frequency starts diminishing by age 30 years; it rarely occurs after age 50 years.
• Urinary output is decreased during the attack because water accumulates intracellularly in muscles. In HypoPP1 patients, the age of onset is earlier (10 y), the symptoms lasts longer (20 h), and the fixed proximal weakness is more frequent (about 70%), compared with HypoPP2 patients (16 y, 1 h, none).
• Permanent muscle weakness may be seen later in the course of the disease and may become severe. Hypertrophy of the calves has been observed. Proximal muscle wasting, rather than hypertrophy, may be seen in patients with permanent weakness.
• HypoPP2 differs from HypoPP1 by (1) late onset, (2) tubular aggregates in muscle biopsy (vacuolar myopathy in HypoPP1), (3) aggravation by acetazolamide in HypoPP2.

Paramyotonia congenita

• In this autosomal dominant inherited disorder, myotonia worsens with activity (paradoxical myotonia) or cold temperatures.
• Symptoms are most pronounced in the face, tongue, and hand muscles with lesser involvement of lower limb.
• Muscle hypertrophy may be seen in 30% of patients.
• Myotonia lasts for seconds to minutes, but weakness may persist for hours and sometimes days. Frequency of paralytic attacks declines with age.
• Permanent and severe myopathy is more frequent in patients with periodic paralysis.
• Episodic weakness also may develop after exercise or cold temperatures and usually lasts only a few minutes, but may last as long as days.
• Potassium loading usually worsens the symptoms, but in some cases, lowering the serum potassium level precipitates the attacks.

Thyrotoxic periodic paralyses

• Thyrotoxicosis periodic paralyses (TPP) are the most common secondary hypokalemic PP. TPP is most common in adults aged 20-40 years. Hyperinsulinemia, a carbohydrate load, and exercise are important in precipitating paralytic attacks. Weakness is proximal and, if severe, may involve respiratory or bulbar muscles. Attacks last hours to days.^{[10, 11]}
• The prevalence of TPP in patients with thyrotoxicosis is estimated to be 0.1-0.2% in Caucasians and 13-14% in Chinese. Ninety-five percent of TPP cases are sporadic. As TPP is more common in Asians, a genetic predisposition is strongly suspected. Familial clustering of TPP indicates unmasking of an inherited disease (which is sporadic) by thyrotoxicosis. A mutation in KCNE3 potassium channel gene was identified in one series.^[12]

Andersen-Tawil syndrome

• Andersen-Tawil syndrome is characterized by variable expression of the triad of dysmorphic features, periodic paralysis, and cardiac arrhythmias. Patients may have short stature, hypertelorism, low-set ears, micrognathia, fifth finger clinodactyly, and scoliosis. Episodic weakness lasting a few hours to several days may arise spontaneously but usually follows physical activity. The periodic paralysis is not associated with myotonia.
• Prolonged QT interval and ventricular arrhythmias are the most common cardiac manifestations. Other ECG abnormalities include PVCs, ventricular bigeminy, supraventricular and ventricular tachycardias, prominent U waves, and torsades de pointes. Bidirectional ventricular tachycardia, which is characterized by beat-to-beat alternating QRS axis polarity, is unique to a subset of patients. Patients may be completely asymptomatic. Patients may experience palpitations, syncopal episodes, and cardiac arrest. Sudden cardiac death is less frequent in ATS when compared with the other long QT syndromes.
• Andersen-Tawil syndrome should always be considered in any patient with periodic paralysis as facial dysmorphism may be subtle and cardiac symptoms are not always present in spite of an abnormal ECG.

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Physical

Most of the patients with a periodic paralysis (PP) have similar clinical features, which are as follows:

• Interictal lid lag and eyelid myotonia - May be the only clinical signs in hyperkalemic PP
• Normal sensation
• Fixed proximal weakness - May develop in patients with either hyperkalemic or hypokalemic PP
• Diminished stretch reflexes during attacks

Table 2. Distinguishing Features Among the Common Forms of Periodic Paralyses

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• References

Laboratory Studies

Hypokalemic periodic paralyses

Serum potassium level decreases during attacks but not necessarily below normal. Creatine phosphokinase (CPK) level rises during attacks. In a recent study, transtubular potassium concentration gradient (TTKG) and potassium-creatinine ratio (K/C) distinguished primary hypokalemic PP from secondary PP resulting from a large deficit of potassium. Values of more than 3.0 mmol/mmol (TTKG) and 2.5 mmol/mmol (PCR) indicated secondary hypokalemic PP.

A random urine potassium-creatinine ratio (K/C) of less than 1.5 is indicative of poor intake, gastrointestinal loss, and potassium shift into the cells. If hypokalemia is associated with paralysis, one should consider hyperthyroidism or familial or sporadic periodic paralysis.

Some of the medical conditions associated with hypokalemia are included in the table below (modified from Assadi 2008^[13] ).

Table 5. Medical Conditions Associated With Hypokalemia

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ECG may show sinus bradycardia and evidence of hypokalemia (flattening of T waves, U waves in leads II, V ₂ , V ₃ , and V ₄ , and ST-segment depression).

Hyperkalemic periodic paralyses

Serum potassium level may increase to as high as 5-6 mEq/L. Sometimes, it may be at the upper limit of normal, and it seldom reaches cardiotoxic levels. Serum sodium level may fall as potassium level rises. This results from sodium entry into the muscle. Water also moves in this direction, causing hemoconcentration and further hyperkalemia. Hyperregulation may occur at the end of an attack, causing hypokalemia. Water diuresis, creatinuria, and an increase in CPK level also may occur at the end of an attack.

ECG may show tall T waves.

Table 6. Diagnostic Studies of Hypokalemic and Hyperkalemic Periodic Paralyses

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• References

Other Tests

Electrodiagnosis and provocative testing can be performed for periodic paralysis.

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Electrodiagnosis

Nerve conduction studies

The compound muscle action potential (CMAP) amplitude declines during the paralytic attack, more so in hypokalemic periodic paralysis. Sensory nerve conduction study findings are normal in most patients with periodic paralyses. Nerve conduction findings may be abnormal when the patient has peripheral neuropathy associated with thyrotoxicosis.

Repetitive nerve stimulation in hyperkalemic periodic paralysis may show a decrement in CMAP (accentuated by cooling) that is steadily progressive without tendency to recover as in myasthenia gravis. The amount of decrement is variable and increases with increased frequency of stimulation. In some patients, it is seen only with stimulation greater than 25 Hz.^[14]

Muscle cooling

Cooling of muscle to 20°C leads to force reduction and prolonged twitch-relaxation in PC and hyperkalemic periodic paralyses. Muscle paralysis is prolonged and persistent even after rewarming.

As the muscle depolarizes at different temperatures in different patients, a muscle temperature of 20-25°C is preferable. This is best achieved by immersing the whole arm in ice water. This alone causes weakness in many patients.

Short periods of exercise (2-3 1-second short exercises) enhance the weakness and result in a very small CMAP.^[14]

Exercise test in periodic paralyses

This is one of the most informative diagnostic tests for periodic paralyses. The test is based on 2 previously described observations: that CMAP amplitude is low in the muscle weakened by periodic paralyses and the weakness can be induced by exercise. Recording electrodes are placed over the hypothenar muscle and a CMAP is obtained by giving supramaximal stimuli. The stimuli are repeated every 30-60 seconds for a period of 2-3 minutes, until a stable baseline amplitude is obtained. Two kinds of exercise tests can be performed.

A short exercise test is one in which the muscle is contracted strongly in isometric conditions for 10-12 seconds. CMAPs are obtained 2 seconds immediately after exercise an then every 10 seconds for 50 seconds. In hyperkalemic periodic paralyses patients carrying T704M mutations, increase in CMAP amplitude (approximately 23%) occurs. In HypoPP1 and HypoPP2 patients, the increase is not significantly different from the control subjects (about 5%).

In the long exercise test, the muscle is contracted for 5 minutes, with brief (3- to 4-second) rests every 15 seconds to prevent muscle ischemia. The CMAP is recorded every minute during exercise and every 1-2 minutes after exercise for a period of 30 minutes or until no further decrement is observed in the amplitude of CMAP. Percentage of decrement is calculated by subtracting the smallest amplitude after exercise from the greatest amplitude after exercise and dividing it by the greatest amplitude after exercise. After a brief increase in CMAP amplitude, a decrease of more than 40% in the CMAP amplitude after 20 minutes is considered abnormal. An abnormal result is highly suggestive of periodic paralyses (98% specificity) but does not distinguish between hyperkalemic, hypokalemic, and thyrotoxic periodic paralyses. Different electrophysiologic patterns are identified in different group of patients with distinct mutations by using both these tests.

Table 7. Electrophysiological Patterns to Exercise Testing

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Needle electrode examination

See the list below:

• Insertional activity: The presence of myotonia usually excludes the diagnosis of hypokalemic periodic paralyses. In hyperkalemic periodic paralyses, no abnormality is detectable between attacks. In those patients with both clinical and electrical myotonia, mild to moderate spontaneous activity is seen, consisting of fibrillation potentials, positive sharp waves, and myotonic discharges.
• Myotonia: Electrical myotonia consists of repetitive discharges at rates of 20-80 Hz. The shape of the potentials can be either positive sharp waves or small biphasic waves; the former is seen while moving the needle electrode and the latter following muscle contraction. Another criterion distinct for myotonia is waxing and waning of the amplitude and frequency of the discharges (ie, dive-bomber discharges). These discharges should last a minimum of 500 milliseconds. They should be elicited in at least 3 areas outside the endplate region in order to distinguish minimal electromyographic myotonia from insertional activity. Demonstration of myotonia may be facilitated by potassium administration and cold temperature.
• Motor unit action potential (MUAP): During the paralytic attack, recruitment is reduced, with few voluntary MUAPs. The amplitude and duration of MUAPs may be reduced. In patients who develop myopathy, the MUAPs tend to show decreased amplitude, reduced duration, and increased proportion of polyphasic potentials.

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Provocative Testing

General precautions for such testing include (1) physician presence during testing, (2) performance of testing in an intensive care setting, (3) avoidance of testing patients with serum potassium disturbances, diabetes mellitus, or renal or cardiac dysfunction, (4) close monitoring of ECG, and (5) capability for rapid electrolyte and glucose testing and correction.

Hypokalemic periodic paralyses

Provocative testing is dangerous and is not the first line of diagnostic testing.

• Oral glucose loading test: Glucose is given orally at a dose of 1.5 g/kg to a maximum of 100 g over a period of 3 minutes with or without 10-20 units of subcutaneous insulin. Muscle strength is tested every 30 minutes. Full electrolyte profile is tested every 30 minutes for 3 hours and hourly for the next 2 hours. Weakness usually is detected within 2-3 hours, and if not patients should be considered for intravenous (IV) glucose challenge.
• Intravenous glucose challenge: Good IV access is essential and availability of more than one IV line is preferred. Glucose is infused IV over a period of 1 hour at a dose of 3 g/kg to a maximum of 200 g (in water at 2 g/5 mL). If no weakness is detectable at 30 minutes, 0.1 U/kg of IV insulin is given. Insulin can be repeated in 60 minutes if weakness is not detected. Strength is evaluated every 15 minutes for 2 hours. Electrolytes, glucose, and carbon dioxide are measured every 30 minutes and once more after the patient becomes weak. ECG is repeated every 30 minutes. The most dangerous period of the testing is between 75-150 minutes when severe hypoglycemia occurs. This should be reversed immediately.
• Intra-arterial epinephrine test: Two mcg/min of epinephrine is infused into the brachial artery for 5 minutes and the amplitude of the CMAP is recorded from a hand muscle. CMAPs are recorded before, during, and 30 minutes after infusion. The result is considered positive if a decrement of more than 30% occurs within 10 minutes of infusion.

Hyperkalemic periodic paralyses

Potassium chloride 0.05 g/kg in a sugar-free liquid is given orally over 3 minutes in a fasting state, just after exercise. If no weakness occurs, an additional amount of potassium chloride (0.10-0.15 g/kg) is given. Electrolyte profile, ECG, and strength are tested every 15 minutes for 2 hours and then every 30 minutes for the next 2 hours. Weakness usually is detected between 90-180 minutes after initiation of testing.

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Histologic Findings

Muscle biopsy is abnormal, more typically in patients with hypokalemic periodic paralysis (PP) than in patients with hyperkalemic periodic paralysis (PP). Histologic findings in hypokalemic PP include the following:

• The most characteristic abnormality is the presence of vacuoles in the muscle fibers. Sometimes, they fill the muscle fibers, and in some patients, groups of vacuoles may be noted. These changes are more marked in hypokalemic PP than in hyperkalemic PP. In the latter, the vacuoles are small and peripherally located. Reports of muscle biopsy findings in PC are few and the vacuolar changes are less frequent.
• Signs of myopathy include muscle fiber size variability, split fibers, and internal nuclei. Muscle fiber atrophy may be present in clinically affected muscles.
• Tubular aggregates may be seen in some patients. Tubular aggregates are seen in type II fibers. They are subsarcolemmal in location. This abnormality is seen only in hypokalemic PP.
• Muscle fiber necrosis is rare.

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Medical Care

Treatment is often necessary for acute attacks of hypokalemic periodic paralysis but seldom for hyperkalemic periodic paralysis. Prophylactic treatment is necessary when the attacks are frequent.

Dichlorphenamide, a carbonic anhydrase inhibitor, was approved by the FDA in August 2015 for the management of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants. Approval was based on 2 randomized, double-blinded placebo-controlled studies that included 138 patients. Treatment with dichlorphenamide resulted in significantly fewer muscle weakness attacks/week compared with placebo (2.3 to 3.9 fewer attacks/week with hyperkalemic periodic paralysis; 2.2 fewer attacks/week with hypokalemic periodic paralysis).^[16]

Hypokalemic periodic paralyses

During attacks, oral potassium supplementation is preferable to IV supplementation. The latter is reserved for patients who are nauseated or unable to swallow. Potassium chloride is the preferred agent for an acute attack (assuming a normal renal function).^[17] A reasonable initial dose for a 60-120 kg man (ie, 0.5-1 mEq/kg) is 60 mEq. Typically, 40-60 mEq of K⁺ raises the potassium concentration by 1.0-1.5 mEq/L, and 135-160 mEq of K⁺ raises plasma potassium by 2.5-3.5 mEq/L. Aqueous potassium is favored for quicker results. If there is no response in 30 minutes, an additional 0.3 mEq/kg may be given. This should be repeated up to 100 mEq of potassium. Beyond this, monitoring of serum potassium is warranted prior to further supplementation. Typically, one should not exceed a total dose of 200 mEq in a day.

Intravenous potassium is reserved for cardiac arrhythmia or airway compromise due to ictal dysphagia or accessory respiratory muscle paralysis. IV potassium chloride 0.05-0.1 mEq/kg body weight in 5% mannitol as a bolus is preferable to continuous infusion. Mannitol should be used as solvent, as both sodium and dextrose worsen the attack. Only 10 mEq at a time should be infused with intervals of 20-60 minutes, unless in situations of cardiac arrhythmia or respiratory compromise. This is to avoid hyperkalemia at the end of an attack with shift of potassium from intracellular compartment into the blood. Continuous ECG monitoring and sequential serum potassium measurements are mandatory.

For prophylaxis, dichlorphenamide 50-100 mg BID may be considered for the management of primary hypokalemic periodic paralysis. Acetazolamide is an off-label alternative that is administered at a dose of 125-1500 mg/d in divided doses. Potassium-sparing diuretics like triamterene (25-100 mg/d) and spironolactone (25-100 mg/d) are second-line drugs to be used in patients in whom the weakness worsens, or in those who do not respond to carbonic anhydrase inhibitors. Spironolactone may cause gynecomastia, but this is less with eplerenone. Blood pressure monitoring is advised. Because these diuretics are potassium sparing, potassium supplements may not be necessary.

Approximately 50% of genotyped patients with HypoPP respond to acetazolamide. Poor response is predicted with substitution of arginine with smaller glycine in the residues of voltage sensors near the extracellular side of the sarcolemma. Almost 60% of patients with common CACNA1S mutations show favorable response to acetazolamide, whereas only 16% of patients with SCN4A mutations benefited from acetazolamide. In both cohorts, this poor response is predicted with substitution of arginine with smaller glycine in the residues of the voltage sensor near the extracellular side of the sarcolemma.^[18]

Thyrotoxic periodic paralysis

Treatment consists of controlling thyrotoxicosis and beta-blocking agents. Potassium supplementation, dichlorphenamide, propranolol, and spironolactone may be helpful during the attacks as well as for prophylaxis. Dichlorphenamide 50-100 mg BID or propranolol in doses of 20-40 mg twice a day may be sufficient to control recurrent attacks of periodic paralysis.

Hyperkalemic periodic paralyses

Fortunately, attacks are usually mild and rarely require treatment. Weakness promptly responds to high-carbohydrate foods. Beta-adrenergic stimulants, such as inhaled salbutamol, also improve the weakness (but are contraindicated in patients with cardiac arrhythmias).

In severe attacks, therapeutic measures that reduce hyperkalemia are utilized. Continuous ECG monitoring is always needed during the treatment. Dichlorphenamide 50-100 mg BID is indicated for hyperkalemic periodic paralysis. Thiazide diuretics and carbonic anhydrase inhibitors are used as prophylaxis. Thiazide diuretics have few short-term side effects; they are tried as first-line treatment. Occasionally, thiazide diuretics may result in paradoxical hypokalemic weakness, which responds to potassium supplementation.

Paramyotonia congenita

Because weakness is uncommon, treatment is aimed at reducing myotonia. While the above-mentioned diuretics can be tried, they are often not effective. Mexiletine has been shown to be helpful but is contraindicated in patients with heart block.

Potassium-associated myotonia

Treatment with mexiletine or a thiazide diuretic may reduce the severity of the myotonia.

Andersen-Tawil syndrome

A combination of amiodarone and acetazolamide resulted in a long-lasting improvement in one study.^[19]

Implantation of a cardiac defibrillator has rarely been performed.

Carbonic anhydrase inhibitors are used for preventing periodic paralysis.

Potassium supplementation prevents periodic paralysis and also reduces cardiac arrhythmia, shortening the QT interval.

For the control of cardiac symptoms, β-blockers or calcium channel blockers may be used.

Flecainide has been shown to be successful in treating bidirectional ventricular tachycardia, ventricular ectopy, and tachycardia-induced cardiomyopathy.^[20]

• References

Surgical Care

Malignant hyperthermia susceptibility has been noted in HypoPP with calcium channel mutations. It is prudent to monitor all patients with periodic paralysis for this complication.

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Diet

See the list below:

• Hypokalemic periodic paralyses: Low-carbohydrate and low-sodium diet may decrease the frequency of attacks.
• Hyperkalemic periodic paralyses: Glucose-containing candy or carbohydrate diet with low potassium may improve the weakness.

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Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

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Dichlorphenamide (Keveyis)

• Dosing, Interactions, etc.

Clinical Context:  Carbonic anhydrase inhibitor, but the exact mechanism by which dichlorphenamide is able to treat periodic paralysis is unknown. Inhibits H+ ion excretion in renal tubule, resulting in increased sodium, potassium, bicarbonate, and water excretion and producing alkaline diuresis. It is indicated for primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants.

• References

Acetazolamide (Diamox)

• Dosing, Interactions, etc.

Clinical Context:  Exact mechanism of action unknown. In hypokalemic PP, may decrease potassium inflow to muscle because of metabolic acidosis. In hyperkalemic PP, kaliopenic effect of CA inhibitors may be beneficial. Recent data suggest carbonic anhydrase inhibitors activate skeletal muscle BK channel (Ca²⁺ -activated potassium channel).

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Class Summary

Carbonic anhydrase (CA) is an enzyme found in many tissues of the body, including the eye. It catalyzes a reversible reaction whereby carbon dioxide becomes hydrated and carbonic acid dehydrated.

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Prognosis

See the list below:

• Hyperkalemic periodic paralyses and paramyotonia congenita

  • When not associated with weakness, these usually do not interfere with ability to work.
  • Myotonia may require treatment.
  • Life expectancy is not known to be affected.

   

  

   
• Hypokalemic periodic paralyses

  • Untreated patients may experience fixed proximal weakness, which may interfere with activities.
  • Several deaths have been reported, mostly related to aspiration pneumonia or inability to clear secretions.

   

  

   

• References

Patient Education

See the list below:

• Periodic Paralysis Resource Center (PPRC): This is the official Web site of the Periodic Paralysis Association.
• Periodic Paralysis (PP): A Web site of the Muscular Dystrophy association. Articles from Quest magazine provide information regarding PP. The Research Digest link provides references on the causes and treatments.

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