eMedicine Specialties > Neurology > Neuromuscular Diseases

Periodic Paralyses

Naganand Sripathi, MD, Director, Neuromuscular Clinic, Department of Neurology, Henry Ford Hospital

Updated: Aug 26, 2009

Introduction

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.

Pathophysiology

*The deficit was described in 2 small families and has not been substantiated by others.^{[1,2 ]}

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 periodic paralyses (PP). Chloride channelopathies are not associated with episodic weakness and are discussed in more detail in the articles on myotonic disorders.

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.

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.^{[3 ]} 

Glucocorticosteroids cause HypoPP by stimulating Na⁺ K⁺ ATPase mediated by insulin and amylin.^{[4 ]}

Potassium channel gene

Potassium channel mutations are seen in Andersen-Tawil syndrome. The triad of dysmorphic features, periodic paralysis, and cardiac arrhythmias characterizes Andersen-Tawil syndrome. This syndrome is associated with mutations in the KCNJ2 gene.^{[5 ]}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.

Frequency

United States

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.

International

Not known

Race

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

Clinical

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.

• 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
  • 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.
  • 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.
• Potassium-aggravated myotonia
  • These autosomal dominant inherited disorders have been divided into 3 categories, myotonia fluctuans, myotonia permanens, and acetazolamide-responsive MC.
  • Weakness is rare in these disorders, but episodic muscle pain and stiffness due to myotonia is present in myotonia fluctuans and acetazolamide-responsive MC, while it is continuous in myotonia permanens.
  • Attacks begin at rest soon after exercise in myotonia fluctuans but are more common with exercise in acetazolamide-responsive MC. Potassium and cold aggravate the myotonia in all 3 disorders.
• Paramyotonia congenita
  • In this autosomal dominant inherited disorder, myotonia worsens with activity (paradoxical myotonia) or cold temperatures.
  • Symptoms are most pronounced in the face.
  • 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.
  • 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.^{[6 ]}
• 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.   

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

Causes

Refer to Pathophysiology and Table 2 and Table 3.

Differential Diagnoses

Other Problems to Be Considered

Table 4. Differential Diagnosis of Other Entities Causing Acute Generalized Weakness

Workup

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^{[7 ]}). 

Table 5. Medical Conditions Associated With Hypokalemia

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

Other Tests

• Electrodiagnosis
  • Nerve conduction studies
    • The compound muscle action potential (CMAP) amplitude declines during the paralytic attack, more so in hypokalemic periodic paralysis (PP). Sensory nerve conduction study findings are normal in most patients with PP. Nerve conduction findings may be abnormal when the patient has peripheral neuropathy associated with thyrotoxicosis.
    • Repetitive nerve stimulation in hyperkalemic periodic paralysis (PP) 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.^{[8 ]}
  • Muscle cooling
    • Cooling of muscle to 20°C leads to force reduction and prolonged twitch-relaxation in PC and hyperkalemic PP. 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.^{[8 ]}
  • Exercise test in periodic paralyses
    • This is one of the most informative diagnostic tests for PP. The test is based on 2 previously described observations: that CMAP amplitude is low in the muscle weakened by PP 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 PP 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 PP (98% specificity) but does not distinguish between hyperkalemic, hypokalemic, and thyrotoxic PP. 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

      	Paramyotonia Congenita	Hyperkalemic Periodic Paralysis	Hypokalemic Periodic Paralysis
      Electrophysiological pattern	I	IV	V
      Channel mutations	Sodium T1313M, R1448C	Sodium T704M	Calcium R528H
      Short Exercise Test:
      Post exercise myotonic potentials	Yes	No	No
      CMAP amplitude change after First trial	Increase or decrease	Increase	No
      CMAP amplitude change after second and third trial	Gradual increase	Gradual increase	No
      Long Exercise Test:
      Immediate change of CMAP amplitude	Decrease	Increase	No
      Late change of CMAP amplitude	Decrease	Decrease	Decrease

      Modified from Fournier et al, 2004.^{[9 ]}
  • Needle electrode examination
    • Insertional activity: The presence of myotonia usually excludes the diagnosis of hypokalemic PP. In hyperkalemic PP, 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.
• 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 PP: 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.

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.

Treatment

Medical Care

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

• 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).^{[10 ]} 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, acetazolamide is administered at a dose of 125-1500 mg/d in divided doses. Dichlorphenamide 50-150 mg/d has been shown recently to be equally effective. This can be used as a first line of therapy or in patients who became refractory after initial improvement with acetazolamide. 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.
• Thyrotoxic PP: Treatment consists of controlling thyrotoxicosis and beta-blocking agents. Potassium supplementation, propranolol, and spironolactone may be helpful during the attacks as well as for prophylaxis. 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. 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 patient. Potassium supplementation, potassium-sparing diuretics, beta-adrenergic blockers, and carbonic anhydrase inhibitors have all been found effective. Implantation of a cardiac defibrillator has rarely been performed.

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.     

Diet

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

Medication

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

Carbonic anhydrase inhibitors

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.

Acetazolamide (Diamox)

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).

Dosing

Adult

125-1000 mg/d PO

Pediatric

Not established

Interactions

Can decrease therapeutic levels of lithium and alter excretion of drugs (eg, amphetamines, quinidine, phenobarbital, salicylates) by alkalinizing urine

Contraindications

Documented hypersensitivity; hypersensitivity to sulfonamides or thiazide diuretics; hyponatremia; hypokalemia; hepatic or renal insufficiency; hyperchloremic failure; adrenal gland failure; chronic noncongestive glaucoma

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Patients with impaired hepatic function may go into coma; may cause substantial increase in blood glucose in some diabetic patients; caution in pulmonary obstruction and emphysema; may cause drowsiness, paresthesias with increasing doses, aplastic anemia, thrombocytopenia

Dichlorphenamide (Daranide)

May improve clinical condition of patients with hypokalemic PP or hyperkalemic PP. Kaliopenic effect of CA inhibitors may be beneficial.

Dosing

Adult

50-150 mg PO qd

Pediatric

Not established

Interactions

High-dose aspirin may produce anorexia, tachypnea, and coma; can decrease therapeutic levels of lithium and alter excretion of drugs (eg, amphetamines, quinidine, phenobarbital, salicylates) by alkalinizing urine

Contraindications

Documented hypersensitivity; hepatic insufficiency; renal failure; adrenocortical insufficiency; severe pulmonary obstruction; hyponatremia; hypokalemia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hypokalemia may occur; caution in patients with respiratory failure

Follow-up

Prognosis

• 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.

Patient Education

• 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.

Miscellaneous

Medicolegal Pitfalls

• The major medicolegal risks are misdiagnosis or delayed diagnosis. However, PP can be notoriously difficult to diagnose, and typically patients have been evaluated by multiple physicians (including specialists) before the diagnosis is confirmed.
• Adequate instruction/education should be provided to patients and their families or caregivers to ensure their safety when acute attacks occur.

References

1. Miller TM, Dias da Silva MR, Miller HA, et al. Correlating phenotype and genotype in the periodic paralyses. Neurology. Nov 9 2004;63(9):1647-55. [Medline].

2. Venance SL, Cannon SC, Fialho D, et al. The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain. Jan 2006;129(Pt 1):8-17. [Medline].

3. Matthews E, Labrum R, Sweeney MG, Sud R, Haworth A, Chinnery PF, et al. Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology. May 5 2009;72(18):1544-7. [Medline].

4. Arzel-Hezode M, McGoey S, Sternberg D, Vicart S, Eymard B, Fontaine B. Glucocorticoids may trigger attacks in several types of periodic paralysis. Neuromuscul Disord. Mar 2009;19(3):217-9. [Medline].

5. Donaldson MR, Yoon G, Fu YH, Ptacek LJ. Andersen-Tawil syndrome: a model of clinical variability, pleiotropy, and genetic heterogeneity. Ann Med. 2004;36 Suppl 1:92-7. [Medline].

6. Dias Da Silva MR, Cerutti JM, Arnaldi LA, Maciel RM. A mutation in the KCNE3 potassium channel gene is associated with susceptibility to thyrotoxic hypokalemic periodic paralysis. J Clin Endocrinol Metab. Nov 2002;87(11):4881-4. [Medline].

7. Assadi F. Diagnosis of hypokalemia: a problem-solving approach to clinical cases. Iran J Kidney Dis. Jul 2008;2(3):115-22. [Medline].

8. Streib EW. AAEE minimonograph #27: Differential diagnosis of myotonic syndromes. Muscle Nerve. Sep 1987;10(7):603-15. [Medline].

9. Fournier E, Arzel M, Sternberg D, et al. Electromyography guides toward subgroups of mutations in muscle channelopathies. Ann Neurol. Nov 2004;56(5):650-61. [Medline].

10. Levitt JO. Practical aspects in the management of hypokalemic periodic paralysis. J Transl Med. Apr 21 2008;6:18. [Medline].

11. Elbaz A, Vale-Santos J, Jurkat-Rott K. Hypokalemic periodic paralysis and the dihydropyridine receptor (CACNL1A3): genotype/phenotype correlations for two predominant mutations and evidence for the absence of a founder effect in 16 caucasian families. Am J Hum Genet. Feb 1995;56(2):374-80. [Medline].

12. Engel AG, Lambert EH, Rosevear JW, Tauxe WN. Clinical and electromyographic studies in a patient with primary hypokalemic periodic paralysis. Am J Med. Apr 1965;38:626-40. [Medline].

13. Griggs RC. Evaluation and Treatment of Myopathies. 1995. Philadelphia: FA Davis; 318-354.

14. Hoffman EP, Lehmann-Horn F, Rudel R. Overexcited or inactive: ion channels in muscle disease. Cell. Mar 10 1995;80(5):681-6. [Medline].

15. Junker J, Haverkamp W, Schulze-Bahr E, et al. Amiodarone and acetazolamide for the treatment of genetically confirmed severe Andersen syndrome. Neurology. Aug 13 2002;59(3):466. [Medline].

16. Koch MC, Steinmeyer K, Lorenz C. The skeletal muscle chloride channel in dominant and recessive human myotonia. Science. Aug 7 1992;257(5071):797-800. [Medline].

17. Lin SH, Lin YF, Chen DT, et al. Laboratory tests to determine the cause of hypokalemia and paralysis. Arch Intern Med. Jul 26 2004;164(14):1561-6. [Medline].

18. McManis PG, Lambert EH, Daube JR. The exercise test in periodic paralysis. Muscle Nerve. Oct 1986;9(8):704-10. [Medline].

19. Meola G, Sansone V. Treatment in myotonia and periodic paralysis. Rev Neurol (Paris). May 2004;160(5 Pt 2):S55-69. [Medline].

20. Ptacek L. The familial periodic paralyses and nondystrophic myotonias. Am J Med. Jul 1998;105(1):58-70. [Medline].

21. Ptacek LJ, Johnson KJ, Griggs RC. Genetics and physiology of the myotonic muscle disorders. N Engl J Med. Feb 18 1993;328(7):482-9. [Medline].

22. Ruff RL. Slow inactivation: slow but not dull. Neurology. Mar 4 2008;70(10):746-7. [Medline].

23. Tricarico D, Barbieri M, Mele A, et al. Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channelof K+-deficient rats. FASEB J. Apr 2004;18(6):760-1. [Medline].

24. Zhang J, George AL, Griggs RC. Mutations in the human skeletal muscle chloride channel gene (CLCN1) associated with dominant and recessive myotonia congenita. Neurology. Oct 1996;47(4):993-8. [Medline].

Keywords

periodic paralysis, hypokalemia, hyperkalemia, myotonia, paramyotonia congenita, potassium-aggravated myotonia, voltage-sensitive ion channels, voltage-gated ion channels, channelopathy, calcium channels, sodium channels, chloride channels, thyrotoxicosis, periodic paralyses, PP

Contributor Information and Disclosures

Author

Naganand Sripathi, MD, Director, Neuromuscular Clinic, Department of Neurology, Henry Ford Hospital
Naganand Sripathi, MD is a member of the following medical societies: American Academy of Neurology, American Medical Association, Michigan State Medical Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

Paul E Barkhaus, MD, Professor, Department of Neurology, Medical College of Wisconsin; Director of Neuromuscular Diseases, Milwaukee Veterans Administration Medical Center
Paul E Barkhaus, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Neurological Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCare, Consulting Staff, Barnes Jewish Hospital
Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)