Hyperkalemic periodic paralysis

INTRODUCTION — Periodic paralysis (PP) is a muscle disease that causes episodic muscle weakness, in the family of diseases called channelopathies [1]. It is classified as hypokalemic when episodes occur in association with low potassium blood levels or as hyperkalemic when episodes can be induced by elevated potassium. Most cases of PP are hereditary, usually with an autosomal dominant inheritance pattern [2,3].

Hyperkalemic PP is a muscle disease that has onset in infancy or early childhood and is manifested by transient episodes of paralysis, usually precipitated by cold exposure, rest after exercise, fasting, or the ingestion of small amounts of potassium [2,3]. The first description in 1951 was of a family with frequent attacks of paralysis that were of short duration and precipitated by rest after exercise, stress, and certain foods [4]. Later, an important observation made was that potassium levels were high in some patients and potassium administration frequently precipitated these attacks [5].

This topic discusses hyperkalemic PP. Other causes of PP are discussed separately. (See "Hypokalemic periodic paralysis" and "Thyrotoxic periodic paralysis".)

EPIDEMIOLOGY — Hyperkalemic PP is a rare disorder, with an estimated prevalence of 1:200,000 [6]. Women and men appear to be equally affected.

PATHOGENESIS — Hyperkalemic PP is an autosomal dominant condition with nearly complete penetrance. The cause of hyperkalemic PP is a change in a gene that regulates the production of a protein (SCN4A) in the sodium channel of skeletal muscle. The gene is located in chromosome 17q23, and is known as SCN4A [2,3,7,8]. At least nine different mutations in this gene have been identified that can cause hyperkalemic PP [6,8,9].

The sodium channel is a large molecule in the cell membrane of the muscle fiber. It consists of four subunits arranged pairwise around a central opening. When muscle receptors bind transmitters released from a nerve, the sodium channel opens to allow sodium to pass into the muscle cell. This process activates a chain of electrical impulses, triggering muscle contraction. In the resting phase that follows the contraction, the sodium channel is closed.

In hyperkalemic PP, the sodium channel closes too slowly, and sodium ions continue to leak into the muscle cell [6,7,10-12]. This leads to oversensitivity and stiffness in the muscle (myotonia). If the channel remains open the muscle will become desensitized and, as a result, paralyzed. During the episode of muscle weakness or paralysis, potassium ions are released from the muscle and the concentration of potassium in the bloodstream (serum potassium) rises.

Studies have further shown that, in an environment that is high in potassium ion concentration, lowering calcium depresses contractile force in both normal muscles and in hyperkalemic PP muscles [13]. In hyperkalemic PP muscles, lowering calcium will also produce depressed contractile forces when potassium ion concentration is normal. This higher susceptibility to low calcium-induced depression of force in hyperkalemic PP muscle may be due to the ease of depolarization of muscle fibers caused by the gain-of-function effect from the sodium channel abnormality, even during normal calcium concentrations.

CLINICAL FEATURES

Attacks — Symptoms usually begin early in life, usually in the first decade but as early as the first year, with attacks of generalized weakness. The weakness in an attack of hyperkalemic PP can be focal, affecting only one limb, but generalized weakness with hypotonia is more common. Some patients have myalgia with attacks [14]. Consciousness is preserved, and cranial and respiratory muscles are usually spared. Hyperkalemic-induced arrhythmias have been reported [15-17].

Reported precipitants of attacks in hyperkalemic PP include anesthesia, cold exposure, rest after exercise, fasting, or the ingestion of small amounts of potassium [2,3,18].

The overlapping range of both the duration and frequency of episodes among patients with hyperkalemic PP and hypokalemic PP make these features unreliable to distinguish them (table 1) [3,14]. It is generally reported that episodes in hyperkalemic PP tend to be more frequent (occurring as often as several times in one day), less severe, and shorter in duration (minutes to hours) compared with hypokalemic PP. However, in one case series, the average duration of 24 hours seen in patients with hyperkalemic PP was similar to that in patients with hypokalemic PP [3]. Episodes lasting for more than one month have been reported [19].

Potassium levels are normal or modestly elevated during attacks; the disorder is so-named because hyperkalemia can precipitate attacks. In one series, the average potassium level recorded during an attack was 5.3 mEq/L [3].

Interictal symptoms and natural history — Between attacks, myotonia (delayed muscle relaxation after contraction) can be elicited on examination in approximately 20 to 70 percent of patients [3,20]. This is often subclinical and generally not disabling, although some patients do report muscle stiffness. In addition to the classic maneuvers to elicit myotonia, having the patient repeatedly open and close his or her eyes to elicit eyelid myotonia is reported to be a sensitive test for this clinical feature [21]. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Myotonia'.)

Attacks are most frequent during adolescence and early adulthood. Later in life, in the fourth to sixth decades, paralytic attacks subside. As these attacks decrease in frequency, most patients develop myopathic weakness, which may be mild or disabling and affects mainly the muscles of the pelvic girdle and lower extremities [6,18,19]. In one case series, muscle weakness was accompanied by progressive muscle atrophy, edema, and fatty change on lower extremity magnetic resonance imaging (MRI) [22]. This progressive degenerative myopathy occurs with equal frequency in hyperkalemic PP as in hypokalemic PP, although it is not as widely recognized in the former.

DIFFERENTIAL DIAGNOSIS — Hyperkalemic PP must be distinguished from other causes of PP, which are discussed separately. The PP in the Andersen syndrome can be associated with normal or high (as well as low) serum potassium, and should be explicitly excluded because preventive strategies can differ. The distinguishing clinical features of these disorders are summarized in the table (table 1). (See "Hypokalemic periodic paralysis".)

In a first attack of quadriparesis, other diagnoses such as Guillain-Barré syndrome, acute myelopathy (eg, transverse myelitis), myasthenic crisis, tick paralysis, and botulism may be considered initially. In contrast with hyperkalemic PP, when profound weakness occurs in these disorders, respiratory muscle involvement is common. Also, bulbar and extraocular muscle weakness are common in Guillain-Barré syndrome, myasthenic crisis, tick paralysis, and botulism, and are rare in hyperkalemic PP. The differential diagnosis of acute quadriparesis is discussed in detail separately. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis", section on 'Differential diagnosis'.)

Other disorders that can cause intermittent muscle weakness include:

●Myasthenia gravis. Weakness in myasthenia gravis typically occurs predictably in the setting of milder degrees of exertion, does not occur in "attacks" as does PP, and often involves bulbar and extraocular muscles, which are rarely if ever affected in hyperkalemic PP. (See "Clinical manifestations of myasthenia gravis".)

●Metabolic myopathies. Patients with a metabolic myopathy typically complain of exercise intolerance, with myalgias and muscle fatigability, rather than attacks of weakness. Myoglobinuria may accompany or follow more severe symptoms. (See "Approach to the metabolic myopathies".)

DIAGNOSIS — When there is an established family history of hyperkalemic PP, further diagnostic evaluation is often not required.

During an acute attack — An elevated serum potassium concentration during an attack may alert the clinician to the diagnosis of hyperkalemic PP. However, the level may be normal or insufficiently abnormal to raise suspicion for this disorder, and other testing for causes of acute muscle weakness may be initiated, such as cervical magnetic resonance imaging (MRI), electromyography (EMG), and lumbar puncture. (See 'Differential diagnosis' above.)

The presence of peaked T waves on electrocardiogram (ECG) can be helpful to alert the clinician to the diagnosis of hyperkalemic PP (waveform 1). An ECG should be performed in all patients with PP to exclude a long QT or QU interval suggesting Andersen syndrome (waveform 2). (See "Hypokalemic periodic paralysis", section on 'Andersen syndrome'.)

Between attacks — Hyperkalemic PP may be difficult to diagnose when patients are evaluated after or between attacks when muscle strength and serum potassium are normal [6]. Creatine kinase is often elevated between attacks of paralysis, but this is neither sensitive nor specific for hyperkalemic PP.

●EMG is probably the most useful test in the interictal evaluation of patients. In the EMG exercise test, compound muscle action potentials (CMAPs) following a single supramaximal electrical stimulus are recorded at rest and every one to two minutes following two to five minutes of exercise [23]. Exercise consists of maximal contraction of a muscle (biceps or anterior tibialis) for two to five minutes with 3- to 4-second rest periods every 15 seconds. A gradual reduction of over 40 percent in the evoked motor amplitude after 30 to 40 minutes is compatible with a diagnosis of PP but is not specific as to type. This test has been reported to have a sensitivity of 71 percent and a specificity of 98 percent for PP [23,24].

One report suggests that the EMG exercise test can discriminate between types of PP. These investigators found that an initial increase in CMAP followed by a delayed decrease was seen in five of six patients with hyperkalemic PP after short-duration exercise (10 to 12 seconds) and only 1 of 13 patients with hypokalemic PP associated with a calcium channel defect [25]. Of the two patients with the sodium channel variant of hypokalemic PP, one had this finding.

EMG can also discern subclinical myotonia, seen in 50 to 75 percent of patients with hyperkalemic PP, a finding that distinguishes this disorder from hypokalemic PP.

●Genetic testing for the nine most common mutations underlying hyperkalemic PP is available [6].

●Provocative testing can be employed, when genetic testing fails to identify an underlying mutation. Careful monitoring, usually in an inpatient setting, is recommended for all forms of provocative testing:

•Provocative testing with oral potassium load (1 to 2 mEq/kg) can also be done, but is dangerous, requiring cardiac monitoring in an inpatient setting [18].

•Exercise (eg, running for 30 minutes on a treadmill) can be a less dangerous alternative or can be used to supplement a potassium load, increasing the sensitivity of the test. Weakness and decreasing amplitude of the CMAP on EMG, usually occurring within one hour, support the diagnosis of hyperkalemic PP, but negative results do not rule out this condition.

•Both hyperkalemic PP and hypokalemic PP can be induced with plasma corticotropin (ACTH). In one study, in three patients with suspected hyperkalemic PP, ACTH (80 to 100 international units intramuscular) was administered in the morning [26]. Muscle strength was assessed in the hand with a dynamometer at baseline and every one to two hours, along with measurement of serum potassium. Weakness was observed along with a rise in serum potassium 5 to 6.5 hours later, and both recovered within the next hour. Significant side effects did not occur.

●An ECG should be performed in all patients with PP to exclude a long QT or QU interval suggesting Andersen syndrome (waveform 2). (See "Hypokalemic periodic paralysis", section on 'Andersen syndrome'.)

TREATMENT AND PREVENTION

Acute attacks — Acute attacks often do not require treatment, as they are brief. Some patients can abort attacks with sugar or mild exercise [14,20,27]. Thiazide diuretics, inhaled beta adrenergic agonists (eg, one to two puffs of 0.1 mg albuterol), and intravenous calcium can be used in more severe attacks, especially if accompanied by more severe hyperkalemia [20,27-31].

Beta-adrenergic agents likely work by stimulating the sodium-potassium pump, increasing potassium transport into cells. (See "Treatment and prevention of hyperkalemia in adults".)

Preventive measures — Dietary modifications to prevent attacks include a low potassium, high carbohydrate diet. Strenuous activity should be avoided. Some have noted that sustained mild exercise after a period of more vigorous activity can mitigate an attack [31]. Other patients have noted that high salt intake reduces the frequency and severity of episodes [32].

Medications, specifically the carbonic anhydrase inhibitors dichlorphenamide and acetazolamide, and the thiazide diuretic hydrochlorothiazide, appear to be helpful according to some reports:

●Prophylaxis with oral dichlorphenamide, a carbonic anhydrase inhibitor, was shown to be effective in reducing both the number and severity of attacks in a double-blind randomized crossover trial in 31 patients with hyperkalemic PP [33,34]. In a subsequent randomized trial that included 21 patients with hyperkalemic PP treated for eight weeks, dichlorphenamide also produced a lower attack rate than placebo (0.9 versus 4.8 percent), although the difference was not statistically significant and did not include a benefit for muscle strength or mass [35]. Dichlorphenamide was approved for treatment of hyperkalemic PP by the US Food and Drug Administration (FDA) in August 2015 [36]. Side effects include paresthesia and confusion.

Dichlorphenamide is initiated at a dose of 50 mg twice daily, which can be increased at weekly intervals if needed to a maximum daily dose of 200 mg. The medication is generally well tolerated; side effects include taste changes and abdominal cramps.

●Acetazolamide (250 mg twice daily; maximum dose 1000 mg daily) is another carbonic anhydrase inhibitor that has anecdotal evidence of efficacy [18,37].

Due to cost considerations, acetazolamide should be considered first, as there are no direct comparative studies with dichlorphenamide. However, one case report describes efficacy of dichlorphenamide in a patient who had an unsatisfactory response to acetazolamide [38].

●Thiazide diuretics (hydrochlorothiazide 25 to 75 mg daily) are also reported to be helpful in controlling attacks in some patients [18,31,39-41].

Surgery and general anesthesia — When surgery is contemplated, it is important that the anesthesia staff is aware of the diagnosis of hyperkalemic PP [42]. After recovering from general anesthesia, patients with this disorder may be paralyzed for hours. Opioids or depolarizing agents can precipitate a myotonic reaction that may interfere with intubation and ventilation [6,43-45]. Modification of the induction sequence may be needed. Prevention of carbohydrate depletion and the avoidance of muscle relaxants are recommended in this setting.

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●Basics topics (see "Patient education: Periodic paralysis syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical features – Hyperkalemic periodic paralysis (PP) is a rare inherited neuromuscular disorder related to a defect in muscle sodium channels, and manifest by episodes of generalized, painless muscle weakness that are precipitated by cold exposure, rest after exercise, fasting, or the ingestion of small amounts of potassium. (See 'Clinical features' above.)

●Evaluation and diagnosis – The clinical features of hyperkalemic PP overlap with other PP disorders (thyrotoxic PP, hypokalemic PP, and the Andersen syndrome) such that they can be difficult to distinguish without additional diagnostic testing (table 1).

In an acute attack, hyperkalemic PP may be distinguished from other PPs, as well as other causes of acute quadriparesis, including Guillain-Barré syndrome, botulism, and cervical myelopathy, by the presence of an elevated potassium concentration, the absence of respiratory and bulbar involvement, and spontaneous recovery within several hours. (See 'Differential diagnosis' above.)

An electrocardiogram (ECG) should be performed in all patients with PP to exclude a long QT or QU interval suggesting Andersen syndrome. (See 'Diagnosis' above and "Hypokalemic periodic paralysis", section on 'Andersen syndrome'.)

Genetic testing is available for most, but not all, of the mutations underlying hyperkalemic PP. Genetic testing may be unnecessary if there is an established family history. (See 'Diagnosis' above.)

Electromyography (EMG) is useful in the interictal evaluation of patients with PP when genetic testing is negative. Electrical myotonia with a history of attacks of weakness strongly suggests the diagnosis of hyperkalemic PP. Provocative testing is another alternative but is potentially dangerous and requires inpatient monitoring. (See 'Diagnosis' above.)

●Treatment of acute attacks – Acute treatment may not be necessary if the attacks are mild and brief. For patients with moderate or severe weakness and hyperkalemia, we suggest inhaled beta adrenergic agonists (1 to 2 puffs of 0.1 mg albuterol) (Grade 2B). (See 'Acute attacks' above.)

In rare situations, some patients will require emergency medical attention and lowering of potassium when severe hyperkalemia accompanies persistent weakness. (See "Treatment and prevention of hyperkalemia in adults".)

●Prevention of attacks – In patients with hyperkalemic PP who have disabling attacks that are not responsive to nonpharmacologic measures (high-carbohydrate diet, avoiding strenuous exercise), we suggest prophylaxis with a carbonic anhydrase inhibitor (acetazolamide or dichlorphenamide) (Grade 2C). Thiazide diuretics can be used as a supplement or as an alternative if carbonic anhydrase inhibitors are ineffective or not tolerated. (See 'Treatment and prevention' above.)

Precautions are required in the setting of surgery and general anesthesia. (See 'Surgery and general anesthesia' above.)