Hypokalemia-associated weakness does not usually become problematic until potassium levels fall toward and then below 1.5 mEq/L, with mild weakness, fatigue, and muscle cramping giving way to severe and generalized weakness, myoglobinuria, and cardiac arrhythmias. Common hypokalemia etiologies include excessive renal loss (e.g., diuretic use, primary aldosteronism) and gastrointestinal sources (e.g., vomiting and diarrhea). Mild-to-moderate hypokalemia is treated safely with oral potassium supplementation, while more severe hypokalemia requires intravenous potassium replacement.
Hyperkalemia of moderate-to–severe degree (>6.5 mEq/L) may be associated with muscle pain and paresthesias and, rarely, muscle weakness per se. However, cardiac rhythm disturbances with an abnormal electrocardiogram (ECG) (peaked T waves and QRS complex widening) are common, requiring immediate treatment. Common causes include reduced renal excretion secondary to renal failure, drugs inhibiting potassium excretion, metabolic acidosis, and primary adrenocortical insufficiency (Addison disease). Cardiac arrhythmias require treatment with insulin, bicarbonate, and beta-agonists to lower serum potassium rapidly by shifting potassium intracellularly.
PERIODIC PARALYSIS
Hypokalemia and hyperkalemia-associated weakness may be caused by membrane excitability disorders, particularly autosomal dominant (AD) channelopathies. Hypokalemic periodic paralysis (HYPOKPP) is caused by a skeletal muscle voltage-sensitive calcium channel gene mutation. Hyperkalemic periodic paralysis (HYPERKPP) is secondary to voltage-gated sodium channel SCN4A gene mutations. Andersen-Tawil syndrome is secondary to potassium channel gene mutations.
HYPOKPP is an autosomal dominant disorder more frequent and severe in men than women. Episodes of paralysis begin in the second or third decade, often preceded by sensations of muscle tightness and soreness. These vary from quadriplegia to mild weakness in a single limb; muscle stretch reflexes are almost always diminished or absent. Respiratory and cranial nerve–supplied muscles are spared. Attacks average 12 to 24 hours in duration, resolving over 3 to 6 hours, with recovery noted initially in muscles initially paralyzed. Provoking factors include rest after exertion, large carbohydrate-rich meals, cold exposure, stress, and alcohol. Attacks often begin during sleep. Between attacks, the examination is usually normal, but in some patients with multiple attacks, prominent limb-girdle weakness develops.
During an attack of total paralysis, serum potassium is usually depressed to 2 to 3 mEq/L, but it may be normal. The paralyzed muscles are electrically inexcitable. Hypokalemia induces cardiographic changes, including bradycardia, U waves, flattened T waves, and lengthened P-R and Q-T intervals. CK is elevated during and, less commonly, between attacks.
The acute attack is treated with oral potassium. As prophylaxis, the patient is instructed to avoid high-carbohydrate meals, reduce salt intake, and avoid unaccustomed physical activity. Acetazolamide (125-150 mg/day) prevents most attacks by producing a metabolic acidosis impeding potassium movement into cells.
Thyrotoxic periodic paralysis (THYPP) is a sporadic disorder typically occurring in 2% to 8% of hyperthyroid Asian populations, particularly men (80%). Clinical and biochemical features are identical to familial HYPOKPP. Patients with the familial disorder have normal thyroid function, with attacks only when a hyperthyroid state exists. Correction of the hyperthyroid state is the definitive treatment. Once the patient becomes euthyroidic, spontaneous episodes of periodic paralysis cease.
HYPERKPP is autosomal dominant, occurring equally in men and women. Attacks begin earlier than with HYPOKPP, generally before age 10 years. Attacks are usually brief and mild, lasting 0.5 to 4 hours; serum potassium may be slightly elevated but may be normal. Myotonia is prominent on both clinical and, particularly, electromyographic (EMG) evaluation. Attacks occur during the day or early in the night. Exercise at the first hint of weakness may delay an attack. Rest after exercise, stress, cold, administration of potassium, and fasting provokes attacks. As in HYPOKPP, permanent proximal limb-girdle muscle weakness may develop with age.
During attacks with elevated serum potassium, there may be electrocardiographic changes, including tall, slender T waves and tachyarrhythmias. CK may be elevated during and between attacks. Between attacks, EMG of weak muscles discloses myotonic discharges. In fully paralyzed muscles, the EMG is silent. Acetazolamide is effective in reducing attack frequency. Mexiletine is the treatment for clinical myotonia.
Andersen-Tawil is a rare syndrome characterized by episodic weakness, dysmorphic features (short stature, hypertelorism, low-set ears, mandibular hypoplasia, clinodactyly), and life-threatening arrhythmias, frequently bigeminy or bidirectional ventricular tachyarrhythmia. Episodic weakness may be associated with hypokalemia, hyperkalemia, or normokalemia. Acetazolamide may reduce attack frequency.
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