Weakness is a common, albeit non-specific, presentation in both the emergency and outpatient setting. Although the differential diagnosis for the complaint of weakness is extensive (Table 1), the focus is considerably narrowed when a patient presents with a demonstrable decrease in muscle strength on physical exam. Strokes and tumors causing nerve compression are potentially life-threatening and must be ruled out first. Other relatively common neurologic concerns include post-ictal paralysis or one of the various motor neuron diseases. Diagnosis of these disorders requires obtaining a complete history with special consideration of timing, duration, and distribution of symptoms. Periodic Paralysis is often overlooked in the initial work-up.
There are several types of Periodic Paralysis associated with metabolic and electrolyte abnormalities. Of these, Hypokalemic Periodic Paralysis (HPP) is the most common with a prevalence of 1 in 100,000 . The clinical features of the syndrome vary somewhat depending on the underlying etiology but the most striking feature is the sudden onset of weakness ranging in severity from mild, transient weakness to severe disability resulting in life-threatening respiratory failure. Attacks may be provoked by stress such as a viral illness or fatigue, or certain medications such as beta-agonists, insulin or steroids. A perturbation of sodium and calcium ion channels results in low potassium levels and muscle dysfunction . As this is primarily a problem with muscle contraction rather than nerve conduction, tendon reflexes may be decreased or absent but sensation is generally intact. Although the serum potassium level is often alarmingly low, other electrolytes are usually normal. Indeed, total body potassium is actually normal with the change in the serum level reflecting a shift of potassium into cells . Electrocardiographic changes are common, but unlike patients who are truly potassium depleted (Table 2), the changes do not correlate well with the measured serum level . Diagnosis between paralytic episodes is difficult as the patient may have normal strength and potassium levels. Electromyography reveals abnormalities in some patients but is often normal, especially between episodes when no clinically detectable weakness is present.
HPP occurs in several settings and the diagnosis may require an extensive search for the underlying etiology since the treatment varies according to the cause. HPP may occur sporadically in the form of Familial Hypokalmic Paralysis (FHP), a poorly understood disorder which may occur spontaneously or as the result of autosomal dominant inheritance . This form of Periodic Paralysis is felt to be the result of disordered cellular potassium regulation perhaps due to sodium or calcium channel abnormalities [2, 5]. Mutations of the CACNA1S and SCN4A genes have been identified that cause abnormalities in sodium channels resulting in abnormal potassium ion flux. Acute paralytic episodes are treated with potassium replacement and close monitoring of the cardiac rhythm and serum potassium levels. Spironolactone and acetazolamide have been used for prophylaxis with some success although long-term potassium supplementation may be necessary .
Thyrotoxic Periodic Paralysis (TPP) occurs in the setting of hyperthyroidism. It is the most common form of HPP and is seen primarily in Asian males occurring in 1.9% of Japanese hyperthyroid patients overall and up to 8% of hyperthyroid Japanese men [6, 7]. Hispanic males are also at risk and several cases have been reported . The clinical features are similar to those seen with other forms of HPP, but also include the symptoms of thyrotoxicosis such as weight loss, tachycardia, and anxiety. In patients who develop HPP, however, the symptoms of hyperthyroidism are often quite mild and may be overlooked [4, 9]. Paralytic episodes often occur at night, as was the case with this patient . Any cause of hyperthyroidism can be associated with TPP but Grave's disease is the most common. The major feature distinguishing TPP from other Periodic Paralyses is the association of paralytic episodes with the hyperthyroid state. Paralytic episodes can be induced in these patients by administering insulin and glucose, but only when they are hyperthyroid . Euthyroid patients are typically free from spontaneous and induced attacks. The underlying mechanism is not known but is thought to be different from that of FHP since, in that disorder, thyroid hormone levels are normal and the administration of exogenous thyroid hormone does not result in paralytic episodes. Furthermore, the genetic abnormalities felt to be responsible for FHP have not been identified in patients with TPP . Although acute paralytic episodes are treated with potassium replacement, prophylactic potassium or acetazolamide administration is not felt to benefit these patients since potassium levels are normal between episodes and may result in dangerous hyperkalemia . Beta-blocking agents may prevent attacks but the definitive treatment is correction of the underlying thyrotoxicosis .
Rarely, HPP can result from substantial gastrointestinal or renal potassium losses. In these cases, total body potassium is depleted and requires aggressive replacement. Endocrine abnormalities such as hyperinsulinemia and primary hyperaldosteronism have been associated with HPP . Surgical removal of the aldosterone producing tumor is the preferred treatment although symptoms can often be managed with spironolactone.
Hyperkalemic Periodic Paralysis and Paramyotonia Congenita are rare forms of Periodic Paralysis that are also associated SCN4A mutations that cause gain-of-function abnormalities in the sodium channel resulting in prolonged muscle cell excitation . As a result these conditions worsen with repetitive activity and, in some cases, exposure to cold. Patients often have paralysis of the facial muscles and lower extremities are less affected. Most patients do not require treatment but are instructed to avoid paralysis-inducing situations. There may be some benefit of mexiletine which makes muscle tissue less sensitive to nerve impulses.
Anderson Tawil syndrome is a rare, autosomal dominant disorder that is caused by mutation of the KCNJ2 gene in 60% of cases . Mutation of this gene alters the structure and function of potassium channels disrupting the flow of potassium ions in muscle cells leading to Periodic Paralysis and long QT syndrome. Acetazolamide may prevent the paralytic episodes and antiarrhythmics or beta-blockers may prevent ventricular ectopy, but there is little data available.