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Hypokalemic periodic paralysis

Hypokalemic periodic paralysis
Literature review current through: Jan 2024.
This topic last updated: Aug 09, 2023.

INTRODUCTION — Periodic paralysis (PP) is a rare neuromuscular disorder related to a defect in muscle ion channels, characterized by episodes of painless muscle weakness, which may be precipitated by heavy exercise, fasting, or high-carbohydrate meals.

PP 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. Acquired cases of hypokalemic PP have been described in association with hyperthyroidism. The clinical features of these disorders are summarized in the table (table 1).

Hypokalemic PP and the PP associated with the Andersen syndrome will be reviewed here. Other causes of PP are discussed separately. (See "Hyperkalemic periodic paralysis" and "Thyrotoxic periodic paralysis".)

EPIDEMIOLOGY — Hypokalemic PP is the most common of the periodic paralyses, but is still quite rare, with an estimated prevalence of 1 in 100,000 [1]. Hypokalemic PP may be familial with autosomal dominant inheritance or may be acquired in patients with thyrotoxicosis [2-7]. (See "Thyrotoxic periodic paralysis".)

Clinical penetrance is often incomplete, especially in females [8,9]. The disorder is three to four times more commonly clinically expressed in males. Approximately one-third of cases represent new mutations [10,11].

PATHOGENESIS — Different genetic mutations have been found to underlie hypokalemic PP:

Calcium channel disorders – A mutation in the gene that codes for the alpha-1 subunit of the dihydropyridine-sensitive calcium channel in skeletal muscle is the most common genetic abnormality in hypokalemic PP and is found in approximately 70 percent of patients [12-15].

It is not known how the calcium channel defect leads to episodic potassium movement into the cells and causes weakness. Electrophysiologic studies have found a decreased calcium current density as well as slower rate of activation [11,16,17]. However, calcium movement is not clearly responsible for either altered potassium fluxes or clinical symptoms. In addition to calcium conductance, the dihydropyridine-sensitive calcium channel has been shown to also act as a voltage sensor for excitation-contraction coupling in skeletal muscle [18]. Investigators have found that hypokalemic PP is associated with a reduced sarcolemmal adenosine triphosphate (ATP)-sensitive potassium current [19]. This finding can be tied to the clinical manifestations of hypokalemic PP, but the relationship with the primary calcium channel defect is unclear. The investigators suggest the possibility of a secondary, calcium-sensitive channelopathy. In vitro studies showed that blocking the dihydropyridine-sensitive calcium channel in muscle fibers from patients with hypokalemic PP does not prevent insulin-induced membrane depolarization [20]. This is also consistent with a secondary channelopathy [20].

Sodium channel disorders – A mutation in the skeletal muscle sodium channel, SCN4A, is responsible for this syndrome in other families [21,22]. Families with this mutation demonstrate more complete clinical penetrance, affecting males and females equally [21].

The mechanism of paralysis in patients with sodium channel defect is better understood. Mutant sodium channels produce an anomalous gating pore current that may cause aberrant depolarization during attacks of weakness [23-25].

Others – Kindreds with hypokalemic PP who have neither of these defects [10,11] and some with other potentially associated mutations [26] have been reported.

CLINICAL FEATURES

Attacks — As with all the periodic paralyses, attacks occur suddenly with generalized weakness. Consciousness is preserved and bulbar and respiratory muscles are only mildly affected, if at all.

In hypokalemic PP, attacks begin in late childhood or teenage years. These attacks vary in frequency and duration. Intervals of weeks to months are common, but some patients experience several attacks per week. Attacks typically last several hours, but the duration can range from minutes to days. Attacks may be triggered by rest after vigorous exercise, stress, or a high-carbohydrate meal, often after a delay of several hours. These events are often associated with an increased release of epinephrine or insulin, both of which cause movement of potassium into cells and low potassium blood levels [2]. One patient with known hypokalemic PP developed acute weakness after using an albuterol inhaler [27].

Neurologic examination during an attack demonstrates weakness, usually affecting proximal more than distal muscles, and the legs more than the arms; hyporeflexia or areflexia is typical. Between attacks, the neurologic examination is usually normal; the myotonia typical of hyperkalemic PP is not a feature of hypokalemic PP. Some patients experience a milder degree of weakness between attacks that fluctuates and improves with mild exercise. Electromyography (EMG) findings during attacks are described below. (See 'Electromyography' below.)

The mean plasma potassium concentration during the attack in one series was 2.4 mEq/L [10]. Levels can be as low as 1.5; however, concentrations less than 2 mEq/L should suggest a secondary cause of hypokalemic paralysis, such as that seen in some cases of severe hypokalemia due to distal renal tubular acidosis (RTA). Between attacks, potassium levels normalize in hypokalemic PP, but remain low in secondary hypokalemia. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance".)

Cardiac arrhythmias, such as tachycardia, atrial fibrillation, paroxysmal supraventricular tachycardia, or ventricular fibrillation, are not common but have been reported during attacks [3]. During attacks, the electrocardiogram (ECG) may otherwise show findings consistent with hypokalemia, including depression of the ST segment, decrease in the amplitude of the T wave, and an increase in the amplitude of U waves. (waveform 1). (See "ECG tutorial: Miscellaneous diagnoses", section on 'Hypokalemia'.)

Myopathy — A progressive proximal myopathy ultimately develops in most patients with hypokalemic PP [28]. This becomes clinically manifest in most individuals after the age of 50 years, as attacks of paralysis wane. Evidence of muscle disease may be evident on muscle biopsy, computed tomography scans, or magnetic resonance imaging several years before it manifests clinically [28-30]. In one study of 25 subjects, vacuoles containing glycogen were a consistent finding on muscle biopsy [31]. Clinically and pathologically, the myopathy is most profound in muscles of the pelvic girdle as well as the proximal upper and lower extremities. The severity of the myopathy is variable; patients may be only mildly affected or severely disabled. While a correlation between the severity of the myopathy and the number of paralytic attacks is suggested by some, there is little evidence to support this, and in at least one family, this association was not found [28,32-34].

Genetic-phenotypic associations — Some suggest that hypokalemic PP associated with sodium channel abnormalities is phenotypically as well as genetically distinct from the calcium channel disorder, with more prominent myalgias, a younger age of onset, shorter duration of attacks, and less severe myopathy [10,21]. Worsening, rather than improvement of symptoms with acetazolamide, occurs in some, but not all, patients with the sodium channel variant of hypokalemic PP. (See 'Preventive treatment' below.)

DIFFERENTIAL DIAGNOSIS — Hypokalemic PP must be distinguished from other causes of PP, which are discussed separately. In particular, paralytic attacks in thyrotoxicosis and in the Andersen syndrome can be associated with hypokalemia and must be explicitly excluded because treatment and preventive strategies are different in these disorders. The distinguishing clinical features of these disorders are summarized in the table (table 1). (See 'Andersen syndrome' below and "Hyperkalemic periodic paralysis" and "Neurologic manifestations of hyperthyroidism and Graves' disease", section on 'Thyrotoxic periodic paralysis'.)

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 hypokalemic PP. In contrast to PP, when profound weakness occurs in a myasthenic crisis, respiratory muscle involvement is common. (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".)

Secondary hypokalemia. Episodic weakness may be seen in association with severe hypokalemia due to renal, gastrointestinal, or other causes including Sjögren's disease [35-42]. There is typically clinical or laboratory evidence of the underlying systemic disease, and hypokalemia persists between attacks. (See "Clinical manifestations and treatment of hypokalemia in adults" and "Causes of hypokalemia in adults".)

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. However, the finding of hypokalemia generally alerts the clinician to the diagnosis of hypokalemic PP.

DIAGNOSTIC EVALUATION — When there is an established family history of hypokalemic PP, episodes of PP often require no further diagnostic evaluation. Otherwise, the diagnosis of hypokalemic PP is suggested by documentation of hypokalemia during a typical attack of weakness. Even when this is demonstrated, other testing is required to rule out alternative diagnoses.

When patients are evaluated after or between attacks, the diagnosis may be difficult. Further diagnostic options include genetic tests, provocative testing, and electromyography (EMG). No diagnostic criteria are published for this disorder; a diagnosis is based upon the preponderance of findings consistent with the disorder along with response to treatment.

Initial laboratory evaluation — During an acute attack, measurement of serum potassium is required, both for diagnosis and to guide treatment. (See 'Acute treatment' below.)

Other testing is also required to rule out alternative diagnoses:

Hyperthyroidism should be excluded with laboratory testing: T3, T4, and thyroid-stimulating hormone (TSH) levels. In the acute setting, findings of tachycardia and hypophosphatemia can raise suspicion of this disorder [43]. (See "Neurologic manifestations of hyperthyroidism and Graves' disease", section on 'Thyrotoxic periodic paralysis'.)

An ECG should be performed to identify a prolonged QT or QU interval suggestive of Andersen syndrome (waveform 2) (see 'Andersen syndrome' below). During an attack of hypokalemic PP, the ECG may otherwise show findings consistent with hypokalemia, including depression of the ST segment, decrease in the amplitude of the T wave, and an increase in the amplitude of U waves. (waveform 1). (See "ECG tutorial: Miscellaneous diagnoses", section on 'Hypokalemia'.)

An arterial blood gas, blood urea nitrogen, creatinine, and other electrolytes (phosphate, calcium, and magnesium) should be measured during an acute attack.

In one case series, a metabolic acidosis or alkalosis was found in all cases with secondary hypokalemia and in none of the patients with PP [43].

Hypophosphatemia can cause acute paralysis in patients with diabetic ketoacidosis who may also have hypokalemia [44].

In one study, the following findings during an acute attack were reliable tests to distinguish hypokalemic PP from secondary hypokalemic paralysis: a low urine potassium-creatinine concentration ratio (<22 mEq/g or <2.5 mEq/mmol) and a low transtubular potassium concentration gradient (<3.0) as calculated from (urine K/plasma K) ÷ (urine osmolality/plasma osmolality) [40]. (See "Evaluation of the adult patient with hypokalemia".)

Normal plasma potassium levels between attacks help distinguish primary hypokalemic PP from other secondary causes of hypokalemic paralysis, such as distal renal tubular acidosis (RTA) [45]. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance".)

The value of these tests is illustrated in case series. Diagnostic evaluation in 34 patients with episodic weakness from Thailand determined that 11 had thyrotoxic PP, 8 had distal RTA, and 15 had hypokalemic PP [46]. Hypokalemic PP occurred without a known family history in two-thirds of cases. Among those with RTA, a metabolic acidosis was noted in only two patients. Only subtle clinical signs of hyperthyroidism were observed in 4 of 11 patients with hyperthyroidism. In a larger case series of 97 patients with an initial diagnosis of hypokalemic PP in the emergency department, 31 had hypokalemic PP, 39 had thyrotoxic PP, and 24 had secondary hypokalemia (RTA, aldosteronism, Bartter syndrome, others) [43]. Only two patients with hypokalemic PP had a family history in this series.

Genetic testing — It is possible to test for many but not all of the mutations that underlie hypokalemic PP. (See 'Pathogenesis' above.)

When an associated mutation is found, this is sufficient to make a positive diagnosis in a patient with typical clinical symptoms.

When genetic testing is negative, further testing with provocative testing and/or EMG may help establish the diagnosis of hypokalemic PP.

Provocative testing — 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:

Precipitating an attack of hypokalemic PP with an oral glucose load, 2 g/kg, and/or insulin administration, 10 units subcutaneously, is an option, but this can be risky [47]. This should be done in an inpatient setting with continuous cardiac monitoring and with availability of emergency resuscitative measures in case cardiac arrhythmias occur. Preexisting cardiac or renal disease precludes such testing and should be excluded prior to this test.

Exercise, such as 30 minutes of running on the treadmill, may provide a safer alternative to glucose or insulin administration. A positive response, weakness with accompanying hypokalemia, is more helpful than a negative response, because some patients do not have reliably induced attacks.

Both hypokalemic PP and hyperkalemic PP can be induced with corticotropin (ACTH). In one study, in five patients with suspected hypokalemic PP, ACTH 80 to 100 international units intramuscular was administered in the evening [48]. 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 fall in serum potassium to <2.5 mmol/L 13 to 27 hours after ACTH administration in four patients. Significant side effects did not occur, but hospitalization and careful monitoring is recommended for provocative testing.

Electromyography — During an attack, EMG may show decreased amplitude of the compound muscle action potential (CMAP), with reduced motor unit recruitment or electrical silence, depending on the severity of weakness [11,47,49]. Other findings more variably described include increased insertional activity, increased polyphasic motor unit potentials, and reduced muscle fiber conduction velocity.

The presence of myotonia on EMG strongly suggests the alternative diagnosis of hyperkalemic PP. This finding is seen in up to 80 percent of patients with hyperkalemic PP, in no patients with hypokalemic PP associated with the calcium channel defect, and rarely in patients with the sodium channel variant of hypokalemic PP or without an identified mutation [10,50]. (See "Hyperkalemic periodic paralysis".)

When myasthenia gravis is considered, other techniques such as repetitive nerve stimulation and single-fiber EMG are useful tests. (See "Diagnosis of myasthenia gravis".)

Exercise test — An EMG technique that may be used to help confirm the diagnosis between attacks is the "long exercise test" (LET), which is more likely to be abnormal than the short exercise test in this disorder [51,52]. CMAPs following a single supramaximal electrical stimulus are recorded at rest and every one to two minutes following two to five minutes of exercise [53]. Exercise consists of maximal contraction of a muscle (biceps or anterior tibialis) for two to five minutes with three- to four-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 to hypokalemic PP [51,53].

This test had a sensitivity of 71 percent in a case series of patients with PP (either hypokalemic PP, hyperkalemic PP, or thyrotoxic PP) [53]. The sensitivity declines when attacks have not been recent [54]. In one case series, 67 patients with episodic paralysis and suspected PP had both LET and genetic testing [52]. The overall sensitivity of LET for genetically confirmed PP was 71 percent; those with more frequent attacks of paralysis were more likely to have positive LET. Thus, a negative LET in the setting of frequent attacks makes a diagnosis very unlikely; however, a negative LET does not rule out PP in less severely affected patients. Electrophysiologic short exercise testing before LET resulted in a false-negative test for some patients who had both tests at the same session. Other investigators have found that the test is also highly specific (97 to 98 percent) for muscle ion channel disorders [54,55].

One report suggests that the LET 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 in only 1 of 13 patients with hypokalemic PP associated with a calcium channel defect [56]. Of the two patients with the sodium channel variant of hypokalemic PP, one had this finding.

Muscle biopsy — A muscle biopsy is not usually performed in the diagnosis of PP. Vacuolar changes, representing reduplication of the sarcoplasmic reticulum and transverse tubules, are invariably found but are nonspecific findings common to all periodic paralyses [11,31]. Tubular aggregates are less often seen, but may be more common in the sodium channel mutation variant of hypokalemic PP and in the Andersen syndrome [11].

More significant myopathic changes on muscle biopsy are described in patients who develop the progressive myopathy, usually several years after their initial presentation [28,29]. However, in one cross-sectional study of patients with hypokalemic PP and calcium voltage-gated channel subunit alpha1 S (CACNA1S) mutations, vacuolar change appeared independently of the frequency or severity of attacks or the patient's age [31].

ACUTE TREATMENT — The oral administration of 60 to 120 mEq of potassium chloride, given incrementally, usually aborts acute attacks of hypokalemic PP. Recovery may take minutes to hours. Important caveats of acute treatment include the following:

The presence of hypokalemia must be confirmed prior to therapy, since potassium administration can worsen episodes due to hyperkalemic PP [2,57].

Potassium administration during an acute episode may lead to posttreatment hyperkalemia as potassium moves back out of the cells [3,5,40,58-60]. Treatment should therefore be administered incrementally, and posttreatment potassium levels should be monitored for 24 hours.

Potassium should not be administered in solutions containing dextrose, as patients have an exaggerated insulin response to carbohydrate loads [61,62].

Cardiac monitoring is recommended during treatment and posttreatment monitoring.

A suggested protocol is potassium chloride 30 mEq orally every 30 minutes until serum potassium normalizes [11]. However, some recommend slower rates of administration, 10 mEq per hour, to minimize rebound hyperkalemia [40].

Milder attacks can be aborted by low-level exercise [1].

PREVENTIVE TREATMENT — Nonpharmacologic interventions that may be effective for preventing attacks include a low-carbohydrate diet and refraining from vigorous exercise. When attacks continue to be disabling, prophylactic treatment is indicated to avoid morbidity, even mortality, which can be associated with hospitalization and acute treatment [63]. Medications, symptomatic potassium supplementation, potassium-sparing diuretics, and carbonic anhydrase inhibitors are used when lifestyle changes are not sufficiently effective [3,64,65]:

Carbonic anhydrase inhibitors appear to be effective in reducing attacks of PP. Acetazolamide 250 mg twice daily is commonly reported to be effective in reducing attacks [1,11,66]. The subset of patients who experience mild, fluctuating weakness between attacks reportedly find acetazolamide treatment helpful [1]. However, one retrospective study found that only half of patients respond to acetazolamide therapy [67].

Dichlorphenamide 50 mg twice daily was demonstrated to be more effective than placebo in reducing attack frequency in the only clinical trial demonstrating a benefit for treatment in PP [68,69]. Previously unavailable in the United States, dichlorphenamide was approved for treatment of hypokalemic PP by the US Food and Drug Administration (FDA) in August 2015 [70].

In one case report, two twin boys with attacks refractory to a combined acetazolamide and spironolactone regimen were treated with topiramate 75 to 100 mg twice daily [71]. While attack frequency increased, the severity of individual attacks was decreased, resulting in fewer emergency department visits and an overall improved quality of life.

The mechanism whereby carbonic anhydrase inhibitors are effective in hypokalemic PP is not clear, but appears to be independent of carbonic anhydrase inhibition [72,73]. Studies in animal models suggest that these agents trigger calcium-activated potassium channels on skeletal muscle. Side effects such as malaise and fatigue limit tolerability in some patients [68]. Kidney stones are a potential complication of treatment with these agents.

A potassium-sparing diuretic, either spironolactone 100 mg daily or triamterene 150 mg daily, can be effective as monotherapy or as a supplement to carbonic anhydrase inhibitor [11]. Potassium supplementation should be avoided in these patients.

The efficacy of verapamil 240 mg daily was studied for three weeks in nine patients using a randomized, crossover design [66]. While verapamil treatment was not associated with a reduced frequency of events in the group as a whole, two patients experienced significant reduction of events on verapamil.

Pinacidil, a potassium channel opener, (not available in the United States) appeared to improve strength during episodes of induced hyperglycemia compared with placebo in four patients with hypokalemic PP [69,74]. However, no clinical paralytic attacks were provoked in either the placebo- or pinacidil-treated patients in this study.

The efficacy of these interventions may vary with the specific mutation, but this requires further analysis. In one retrospective review of 74 patients, those with mutations in CACNA1S were more likely to respond to treatment with acetazolamide compared with those with SCN4A mutation (56 versus 16 percent) [67]. In other reports, some family members with a specific mutation in the calcium channel had marked improvement with treatment with potassium-sparing diuretics after failing to respond to acetazolamide [75,76]. Acetazolamide has been reported to exacerbate symptoms in some families with mutations in the sodium channel, but not in others [21,77].

There is no known treatment for the late-onset myopathy in hypokalemic PP. While some believe that limiting attacks of PP ameliorates the subsequent myopathy, this is unproven [28,32,33].

The association between malignant hyperthermia and hypokalemia is uncertain, but has been described [63], suggesting caution be used when certain inhalational anesthetic agents or succinylcholine are used. (See "Susceptibility to malignant hyperthermia: Evaluation and management".)

ANDERSEN SYNDROME — A rare disorder, estimated at one-tenth the prevalence of hypokalemic PP, the Andersen-Tawil or Andersen syndrome is clinically and genetically distinct from other periodic paralyses. It is manifested by a triad of PP, ventricular dysrhythmias, and dysmorphic features (short stature, hypertelorism, clinodactyly, micrognathia) [78-81]. A prolonged QT interval on ECG is also a feature of this disorder (waveform 2). (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Andersen-Tawil syndrome'.)

Potassium may be low, normal, or high during paralytic attacks, which first manifest during the first or second decade of life [11,78-80,82]. Low potassium levels are noted somewhat more frequently. Similar to other syndromes, paralytic attacks are commonly precipitated by rest after exercise. However, a dietary trigger is rarely identified. Provocative challenges to induce hypokalemia or hyperkalemia should not be performed in these patients because of the risk of cardiac arrhythmias.

A mutation in the gene encoding Kir2.1, an inward rectifier potassium channel expressed in cardiac and skeletal muscle, is identified in approximately two-thirds of patients. Nonpenetrance occurs in approximately 20 percent of individuals who inherit the mutation. Incomplete penetrance and marked intrafamilial phenotypic variation is also common; isolated features, particularly a long QT interval, may be manifest in family members who exhibit no other features of the disease [79,83]. The function of Kir2.1 is better established in cardiac than skeletal muscle; however, a reduction in inward potassium movement is thought to lead to sodium channel inactivation and persistent membrane depolarization. A second gene encoding the G-protein-activated inwardly rectifying potassium channel Kir3.4 has also been shown to cause the Andersen syndrome [84].

There is little information on the treatment or prognosis of PP in this setting. Myopathic weakness is described in some cases of Andersen syndrome, and myopathic changes and tubular aggregates are described on muscle biopsy [82,83]. Treatment is complicated by the potential to precipitate cardiac arrhythmias; diuretics are contraindicated in patients with the long QT syndrome. Carbonic anhydrase inhibitors, acetazolamide and dichlorphenamide, are reportedly useful in controlling attacks of weakness in some patients [11,78,82,83].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

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

SUMMARY AND RECOMMENDATIONS

Clinical features – Hypokalemic periodic paralysis (PP) is a rare inherited neuromuscular disorder, manifested by episodes of painless muscle weakness that may be triggered by rest after vigorous exercise, stress, or a high-carbohydrate meal. (See 'Clinical features' above.)

The distinguishing clinical features of hypokalemic PP in contrast to other PP disorders (thyrotoxic PP, hyperkalemic PP, and the Andersen syndrome) are summarized in the table (table 1).

Diagnostic evaluation – In an acute attack, the diagnosis of familial hypokalemic PP is made by documentation of hypokalemia and excluding thyrotoxicosis and secondary causes of hypokalemia. (See 'Diagnostic evaluation' above.)

An ECG should also be performed in all patients with PP to exclude a long QT or QU interval suggesting Andersen syndrome. (See 'Diagnostic evaluation' above and 'Andersen syndrome' above.)

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

When genetic testing is negative, electromyography (EMG) can be useful in the interictal evaluation of patients with PP, distinguishing hypokalemic PP from other periodic paralyses and other causes of intermittent weakness. (See 'Electromyography' above.)

We recommend not performing provocative testing with glucose loading or insulin administration as a routine test for hypokalemic PP. Monitoring weakness and potassium levels before and after exercise or corticotropin (ACTH) administration is a safer alternative. (See 'Provocative testing' above.)

Management of acute attacks – In an acute disabling attack, we recommend administering oral potassium (Grade 1B). Patients should be on cardiac monitoring, hypokalemia should be verified prior to treatment, and potassium levels should be monitored for potential rebound hyperkalemia for 24 hours. A suggested treatment protocol is potassium 30 mEq every 30 minutes until hypokalemia and weakness resolve. (See 'Acute treatment' above.)

Preventive strategies and prophylactic treatment – Nonpharmacologic preventive strategies in hypokalemic PP include avoiding strenuous exercise and high carbohydrate loads. (See 'Preventive treatment' above.)

For patients who continue to have disabling attacks, we recommend prophylactic treatment with a carbonic anhydrase inhibitor, either acetazolamide 250 mg twice daily or dichlorphenamide 50 mg twice daily (Grade 1B). Because a minority of patients have more attacks with this treatment, close monitoring is recommended during initiation.

We suggest potassium-sparing diuretics (eg, spironolactone 100 mg daily) as a supplement to the carbonic anhydrase inhibitor or as an alternative if a patient worsens on or cannot tolerate the carbonic anhydrase inhibitor (Grade 2C). (See 'Preventive treatment' above.)

Prognosis – Most patients with hypokalemic PP develop a myopathy in later life. The severity is variable. There are no known strategies to prevent or ameliorate the development of weakness. (See 'Clinical features' above.)

Andersen syndrome – The Andersen syndrome is a rare inherited disorder, manifested by a triad of PP (which may be associated with low, normal, or high potassium levels), ventricular arrhythmias, and dysmorphic features. A long QT or long QU interval on ECG suggests this disorder in a patient with PP. Carbonic anhydrase inhibitors are reported to limit attacks of weakness in some patients. (See 'Andersen syndrome' above and "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Andersen-Tawil syndrome'.)

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