Thyrotoxic periodic paralysis

INTRODUCTION — Periodic paralysis (PP) is a muscle disease in the family of diseases called channelopathies, manifested by episodes of painless muscle weakness. These episodes 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).

In contrast to other forms of thyroid disease, which are more common in females, thyrotoxic PP is much more frequently seen in males; the prevalence of thyrotoxic PP is also highest in East Asian populations [1,2]. This diagnosis should be considered when this demographic of patients presents with marked painless weakness after provocation with exercise or changes in diet [3].

Thyrotoxic PP will be reviewed here. Other causes of PP and other neurologic manifestations of thyrotoxicosis are discussed separately:

●(See "Hypokalemic periodic paralysis".)

●(See "Hyperkalemic periodic paralysis".)

●(See "Neurologic manifestations of hyperthyroidism and Graves' disease".)

EPIDEMIOLOGY — Thyrotoxic PP is a sporadic form of hypokalemic PP that may occur in association with hyperthyroidism. This contrasts with familial hypokalemic PP, which has an autosomal dominant inheritance [1].

Any etiology of hyperthyroidism, including thyroxine abuse, can be associated with thyrotoxic PP [4-8]. Graves' disease is the underlying disorder in most cases of thyrotoxic PP, as it is in most cases of hyperthyroidism [8-11]. (See "Disorders that cause hyperthyroidism".)

Thyrotoxic PP has been most widely reported and studied in East Asian populations, in which the incidence among patients with hyperthyroidism is approximately 2 percent [12,13]. This contrasts with other populations, in which the incidence of thyrotoxic PP among individuals with hyperthyroidism is estimated to be 0.1 to 0.2 percent. A New Zealand study found that Polynesians were also at higher risk for thyrotoxic PP compared with those of European descent [14].

Despite a higher incidence of hyperthyroidism in females, over 95 percent of thyrotoxic PP cases occur in males [11,15,16]. Thus, the incidence of thyrotoxic PP is particularly high among East Asian males with thyrotoxicosis (8.7 to 13 percent) [17,18].

The age of onset of symptoms in thyrotoxic PP is between 20 and 39 years in approximately 80 percent of patients [11,12,16,17,19-22]. Although this later age of onset is helpful to distinguish thyrotoxic PP from the familial PPs, which present at a younger age, adolescents with thyrotoxic PP have been reported [23,24].

PATHOGENESIS — The mechanism by which hyperthyroidism can produce hypokalemic PP is not well understood. Thyroid hormone increases tissue responsiveness to beta-adrenergic stimulation, which, along with thyroid hormone, increases sodium-potassium ATPase activity on the skeletal muscle membrane [19]. This tends to drive potassium into cells, perhaps leading to hyperpolarization of the muscle membrane and relative inexcitability of the muscle fibers. Thyrotoxic patients with PP have been found to have higher sodium pump activity than those without paralytic episodes [5,25]. In this way, excess thyroid hormone may predispose to paralytic episodes by increasing the susceptibility to the hypokalemic action of epinephrine or insulin [12,26].

Insulin resistance with compensatory hyperinsulinemia is suspected to have a role in the pathogenesis of thyrotoxic PP [27,28]. In one study, patients with a history of thyrotoxic PP were heavier and exhibited reduced insulin sensitivity compared with patients with thyrotoxicosis without thyrotoxic PP. Insulin also activates the sodium-potassium ATPase pump and may act synergistically with thyroid hormone to drive potassium into cells. This is consistent with the observation that a heavy meal can be a precipitant for attacks of thyrotoxic PP.

While patients with thyrotoxic PP do not have the genetic mutations associated with familial hypokalemic PP, it has been suggested that individuals who are susceptible to thyrotoxic PP may have an ion channel defect, which, in the euthyroid state, is not sufficient to produce symptoms [9,23,29-33]. A number of studies have identified specific susceptibility loci that confer risk for thyrotoxic PP. Many but not all of these affect KCNJ2 expression; this gene encodes Kir2.6, an inwardly rectifying potassium channel, expressed in skeletal muscle that is transcriptionally regulated by thyroid hormone [34-39]. Some but not all of these loci have been implicated in Graves' disease [36]. The frequency of these genes varies in different ethnic populations, which is thought to explain the higher prevalence of thyrotoxic PP in these populations.

A role for testosterone in the pathogenesis for thyrotoxic PP is suggested by the predominance of this condition in men and the demonstration that testosterone increases sodium-potassium ATPase activity in animals [40-42].

CLINICAL FEATURES — As with all the PPs, attacks of weakness occur suddenly with generalized weakness and preserved consciousness.

In many patients, clinical features of hyperthyroidism precede the onset of PP by months or even years, but they have been noted to occur at the same time (in 43 to 60 percent of patients) or following the development of PP (in 11 to 17 percent) [12,15,18,19,21,22,43,44]. (See "Overview of the clinical manifestations of hyperthyroidism in adults".)

Neurologic examination during an attack demonstrates weakness, usually affecting proximal more than distal muscles, and the legs more than the arms [5,16,20,21,45]. Mild myalgia is a complaint in less than half of patients [16]. Decreased muscle tone with hyporeflexia or areflexia is typical, although normal or hyperactive reflexes may be observed. In one series, tachycardia (mean heart rate = 105 bpm) was noted at presentation and distinguished these patients from those with familial hypokalemic PP [43]. Exceptional cases of bulbar weakness and respiratory weakness requiring ventilatory support have been reported in thyrotoxic PP, as well as cases of severe, even fatal, arrhythmias (sinus arrest, second degree atrioventricular [AV] block, ventricular fibrillation, and ventricular tachycardia) [8,46-49].

Attacks vary in frequency and duration, as well as their association with inciting events:

●Intervals of weeks to months are common, but some patients experience several attacks per week [16,45].

●A duration of symptoms of several hours is typical, but can range from minutes to days.

●As with hypokalemic PP, attacks in thyrotoxic PP can be precipitated by events that are associated with an increased release of epinephrine or insulin, both of which cause movement of potassium into cells and low potassium blood levels [16,29]. Most commonly, the inciting event is either rest after strenuous physical activity, stress, or a high-carbohydrate load [11]. Other events reported to induce attacks in thyrotoxic PP include cold exposure, infection, alcohol intake, pulse corticosteroid therapy, beta-2 adrenergic bronchodilator use, and menses [12,22,50-54]. Administration of epinephrine, insulin, or thyroid supplements may also precipitate attacks. In many instances, no obvious precipitant is identified [11].

●Although attacks of weakness may occur at any time of the day, a high frequency of attacks at night or early in the morning has been reported in thyrotoxic PP [8]. A seasonal variation has also been suggested, with more frequent attacks in summer months [11,18].

LABORATORY FEATURES — The degree of hypokalemia during an attack is variable; in one series of 78 patients the mean serum potassium level was 2.1 mmol/L [20]. Cases with extremely low potassium levels <1.5 mEq/L are frequently reported [5,8,16,21,46-48,55]. However, in at least two cases of PP attributed to thyrotoxic PP, the ictal potassium level was normal [16,56,57]. Usually, the severity of weakness corresponds to the degree of hypokalemia [21].

Patients with thyrotoxic PP, by definition, have attacks in the hyperthyroid state. Supporting laboratory findings include elevation of serum thyroxine (T4) and low thyrotropin levels (TSH). Patients with elevated T3 and normal T4 levels have been reported [11,58].

Other common laboratory findings include mild hypophosphatemia and hypomagnesemia [8,21,22]. These findings may help distinguish thyrotoxic PP from familial hypokalemic PP [43,45,59]. In one study, a urine calcium to phosphate ratio of higher than 1.7 was a sensitive and specific test to distinguish thyrotoxic PP from familial hypokalemic PP [60]. Creatine kinase may be normal but has been reported to be mildly elevated in two-thirds of patients, and rhabdomyolysis has been reported [8,61]. In one case series, hypocreatininemia (0.6 ± 0.15 mg/dL) and a high estimated glomerular filtration rate (eGFR; 168.1 ± 37.8 mL/minute per 1.73 m²) were noted [11].

Electrocardiogram (ECG) changes are common in an attack of thyrotoxic PP. These include those findings consistent with hypokalemia: ST depression, sinus tachycardia, U waves (waveform 1), as well as those not consistently associated with hypokalemia: an elevated higher heart rate, abnormal PR interval, higher QRS voltage, and first-degree atrioventricular (AV) block [55,62]. The latter category of ECG findings is more common in patients with thyrotoxic PP as compared with patients with familial hypokalemic PP [59]. Severe arrhythmias (eg, sinus arrest, second-degree AV block, ventricular fibrillation, and ventricular tachycardia) are not common but are described [63].

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS — In an acute attack, thyrotoxic PP must be distinguished from other causes of acute quadriparesis, such as myasthenic crisis, Guillain-Barré syndrome, acute myelopathy (eg, transverse myelitis), acute thyrotoxic myopathy, tick paralysis, and botulism [4,8,64]. Other forms of PP are also considered (table 1).

The finding of hypokalemia and recovery with treatment generally alerts the clinician to the diagnosis of hypokalemic PP, in which the possibility of thyrotoxicosis must always be evaluated, particularly in the absence of a family history of PP. (See "Hypokalemic periodic paralysis" and "Diagnosis of hyperthyroidism".)

After a thyrotoxic state is established, the patient is further evaluated to determine the underlying cause. (See "Disorders that cause hyperthyroidism".)

The results of electromyography, provocative testing, and muscle biopsy are similar to those seen in familial hypokalemic PP, but these tests are often unnecessary. (See "Hypokalemic periodic paralysis", section on 'Diagnostic evaluation'.)

If thyrotoxicosis is not established as the cause, an ECG should be performed to identify a prolonged QT or QU interval suggestive of Andersen syndrome (waveform 2). (See "Hypokalemic periodic paralysis", section on 'Andersen syndrome'.)

ACUTE TREATMENT — Patients with acute paralysis are typically hospitalized in a monitored setting for cardiac arrhythmias as well as dysphagia.

Potassium supplementation — A suggested protocol is 30 mEq of oral potassium every two hours until improvement begins, with a maximum dose of 90 mEq in 24 hours [65]. Some recommend slower rates of administration (<10 mEq per hour) [5,66]. Intravenous supplementation may be necessary for patients with severe hypokalemia or impaired swallowing. (See "Clinical manifestations and treatment of hypokalemia in adults", section on 'Intravenous potassium repletion'.)

As with familial hypokalemic PP, potassium supplementation may lead to improvement of weakness. One prospective study compared treatment with intravenous potassium chloride to normal saline infusion and found a shorter recovery time with use of potassium (6.3 versus 13.5 hours) [66]. In a retrospective case series, patients who received intravenous potassium recovered more quickly than those who received oral supplementation [57]. There may be a delayed response of a few hours following potassium administration [48]. Required doses of potassium supplementation are variable and range from 10 to 200 mEq [5,8,20].

Rebound hyperkalemia appears to be a prominent problem in thyrotoxic PP, occurring in approximately 40 to 59 percent of treated attacks [8,20,21]. In one study, 80 percent of patients who developed rebound hyperkalemia had received greater than 90 mEq of potassium within 24 hours. In one case series, a fall in serum potassium occurred during initial treatment in one-fourth of patients; these patients also had higher free thyroxine levels, ultimately required higher doses of potassium supplementation, and were more likely to have severe rebound hyperkalemia [20].

Monitoring — Close monitoring of serum potassium during the acute paralysis is essential.

Continuous cardiac monitoring is recommended for all patients during treatment and observation. A cardiology consultation should be obtained for severe arrhythmias/ECG changes. Correction of hypomagnesemia, if present, is also recommended.

Refractory patients — Replacement of potassium may be insufficient to resolve an attack. Intravenous propranolol has been reported to reverse weakness and hypokalemia in patients with thyrotoxic PP that is unresponsive to potassium administration [48,50,67,68]. These patients received doses of 1 mg of intravenous propranolol every 10 minutes up to a maximum dose of 3 mg. In one report, oral propranolol, 3 mg/kg, administered without potassium supplementation reversed both weakness and hypokalemia in two patients with an acute attack of thyrotoxic PP without inducing rebound hyperkalemia [26].

Propranolol, a beta adrenergic blocker, presumably reverses the excessive stimulation of the sodium-potassium ATPase and excessive drive of potassium into cells. (See 'Pathogenesis' above.)

PREVENTIVE TREATMENT — Restoration of euthyroidism eliminates attacks of thyrotoxic PP [11,12,69]. When patients become euthyroid, the electromyography (EMG) exercise test normalizes, and attacks are no longer inducible [70]. Thyrotoxic PP can reemerge if thyrotoxicosis recurs. The management of hyperthyroidism differs according to the underlying etiology. In a series of 16 patients with thyrotoxic PP secondary to Graves' disease who were followed for 14 years, treatment with radioactive iodine or surgery appeared to be more effective in preventing relapses than treatment with antithyroid drugs alone [71].

The administration of beta-blocking medications such as propranolol, 40 to 120 mg daily, with or without potassium supplementation appears to decrease the frequency and severity of attacks, and may be used as a temporizing measure until a euthyroid state is achieved [19,26,58,67,72,73]. A nonselective beta blocker (eg, propranolol) should be given; beta-1 selective agents are less likely to inhibit the beta-2 receptor-mediated hypokalemic effect of epinephrine and may therefore be less likely to prevent paralytic episodes [12].

In contrast to familial hypokalemic PP, carbonic anhydrase inhibitors have not been shown to be of benefit in thyrotoxic PP and may even increase the frequency of attacks [74]. Potassium supplementation is not effective as prophylaxis in thyrotoxic PP [9]. As with hypokalemic PP, precipitating factors, such as heavy exercise, high-carbohydrate diets, and alcohol, should be avoided.

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

SUMMARY AND RECOMMENDATIONS

●Epidemiology and pathogenesis – Thyrotoxic periodic paralysis (PP) represents an acquired form of hypokalemic PP. Any cause of hyperthyroidism can be associated with thyrotoxic PP. (See 'Pathogenesis' above.)

Thyrotoxic PP is more prevalent in East Asian compared with other populations and also in males compared with females. (See 'Epidemiology' above.)

●Clinical and laboratory features – Attacks of generalized weakness are often precipitated by rest after strenuous exercise or a high carbohydrate load. Potassium levels are often very low but are sometimes normal. (See 'Clinical features' above and 'Laboratory features' above.)

●Diagnosis – The diagnosis of thyrotoxic PP is made when a patient presents with a paralytic attack that is associated with hypokalemia and hyperthyroidism. The distinguishing clinical features of hypokalemic, thyrotoxic, and hyperkalemic PP, and the Andersen syndrome, are summarized in the table (table 1). (See 'Diagnosis and differential diagnosis' above.)

●Acute treatment – For treatment of an acute attack of thyrotoxic PP with severe weakness, we recommend administration of potassium chloride (Grade 1B). Patients should be on cardiac monitoring, and potassium levels should be monitored for potential rebound hyperkalemia for 24 hours. A suggested protocol is potassium 30 mEq every two hours, with a maximum dose of 90 mEq in 24 hours. Oral administration, if possible, is preferred. (See 'Acute treatment' above.)

For acute weakness, which is not responding to potassium administration, we suggest using propranolol, 1 mg intravenously or 3 mg/kg orally (Grade 2C). (See 'Acute treatment' above.)

●Preventive and long-term management – Attacks of PP will cease with return to euthyroid state. Interim measures to ameliorate attacks include avoiding strenuous exercise and high-carbohydrate loads. If attacks continue to be problematic, we recommend prophylactic use of propranolol until euthyroidism is achieved (Grade 1C). (See 'Preventive treatment' above.)