Periodic Paralysis (PP)

Genetic disorder involving ion channels of the cellular membrane and affecting electrolyte conductance leading to episodic muscle weakness. It is characterized by episodes of flaccid muscle weakness occuring at irregular intervals. Most of the conditions are hereditary.

Familial Periodic Paralysis, Hypokalemia, Hyperkalemia, Myotonia, Paramyotonia Congenita, Potassium-aggravated Myotonia; Becker Myotonia Congenita; Thomsen Myotonia Congenita; Adynamia Episodica Hereditaria with or without Myotonia; Gamstorp Disease; Thyrotoxic Periodic Paralysis.

Primary periodic paralysis can be classified according to the membrane electrolyte defect:

Sodium Channel: Hyperkalemic PP; Paramyotonia Congenita; Potassium-aggravated myotonia

Calcium Channel: Hypokalemic PP; Thyrotoxic PP (secondary form)

Chloride Channel: Normokalemic PP; Becker Myotonia Congenita; Thomsen Myotonia Congenita

In the United States, the frequency for all forms of PP remains unknown. Hypokalemic periodic paralysis form is the most common. It has a prevalence of 1 per 100,000 population. Becker myotonia congenita has a reported prevalence of 1 per 50,000, whereas Thomsen myotonia congenita seems significantly rarer. Internationally, the incidence for this medical condition has not been established. Thyrotoxic periodic paralysis is more common in males (85%) of Asian descent, leading to a frequency of approximately 2%.

All are autosomal dominant but penetrance seems to be variable in female carriers. Hypokalemic periodic paralysis is caused by a mutation in the alpha-1 unit of the dihydropyridine-sensitive calcium channel CACNL1A3; the gene is located on chromosome 1q31-32. Hyperkalemic periodic paralysis is caused by a mutation in the alpha subunit of the Na channel SCN4A; the gene is located on chromosome 17q13.1-q13.3. It is the same gene as paramyotonia congenita. The gene of normokalemic periodic paralysis is still unknown—whether it is a separate entity or a subgroup of the hyperkalemic form is a subject of debate.

The physiopathologic basis of flaccid muscle weakness is inexcitability of the muscle membrane, i.e., the sarcolemma. In the hypokalemic form, potassium (K) outflow is diminished by altered calcium homeostasis in the muscle fibers; in the hyperkalemic form, the muscle fibers remain depolarized and their membranes are inexcitable.

Based on history, clinical examination, and measurement of serum electrolytes during the attacks.

Hypokalemic form: Onset rarely occurs before the second decade of life. Attacks of muscle weakness typically occur at night or in the early morning. They are triggered by increased physical exercise, stress, cold, or a large carbohydrate intake. Paralysis is flaccid, affects mainly the girdle of the lower limbs, and spares the respiratory muscles as well as the muscles supplied by the cranial nerves. The attack usually lasts 6 to 24 hours. ECG signs of hypokalemia can be observed. Treatment: Oral KCl in case of attack but electrolytes should be monitored as rebound hyperkalemia is frequent; prophylaxis with acetazolamide or spironolactone. Thyrotoxic periodic paralysis is the most common hypokalemic PP. It is most common in adults 20-40 years of age. Hyperinsulinemia, carbohydrate load, and exercise may all cause PP attacks. When severe, it may involve respiratory and bulbar muscles. Attacks last hours to days. The prevalence of thyrotoxicosis PP in patients affected with thyrotoxicosis is 0.2% in caucasians and 13-14% in Chinese. Ninety-five percent are sporadic.

Hyperkalemic form: Onset usually occurs in the first decade of life but cases starting in infancy have been observed. Attacks are triggered by rest after exercise, cold, hunger, stress, and ingestion of K. Paralysis affects mainly the spinal muscles and rarely the neck and facial muscles; in severe forms, intercostal muscles are affected too. The attack is often heralded by peribuccal or limb paresthesia. An attack lasts typically 30 to 120 minutes. A myotonic response to muscle percussion (mainly the tongue and the eyelids) is often observed during and between attacks. ECG signs of hyperkalemia can be observed. Treatment: acetazolamide, thiazide-like diuretics; a carbohydrate-rich and potassium-poor diet is recommended.

Normokalemic form: Onset usually occurs in early childhood. The attacks are severe with loss of the cough reflex; they last a few days and can be accompanied by multifocal ectopic beats. K administration decreases the arrhythmia but worsens the weakness. Treatment: Large doses of Na to correct or prevent paralysis and cardiac arrhythmia are recommended; fluorohydrocortisone and acetazolamide can be used for prophylaxis.

Monitor serum electrolytes; appropriate premedication to avoid preoperative stress. Hypokalemic form: usual acetazolamide or spironolactone dose. Hyperkalemic form: prolonged preoperative fasting and K-containing IV fluids should be avoided; start a glucose-containing solution at the beginning of fasting time. Normokalemic form: Na loading and avoidance of prolonged preoperative fasting.

Avoidance of hypothermia (heating blanket, forced warm air) maintaining K level and acid-base status in the normal range, continuous ECG monitoring and as follows. Hypokalemic form: A case of malignant hyperthermia has been described but the response to in vitro muscle testing was equivocal; there seems to be no association between hypokalemic periodic paralysis and malignant hyperthermia but because of the dysregulation of muscular calcium metabolism, a hypermetabolic state mimicking malignant hyperthermia without hyperkalemia and muscular rigidity is possible. Avoid infusion of glucose-containing solutions except in case of documented hypoglycemia, when you should provide K in the IV infusion. Monitor muscle relaxation at the facial nerve because it is usually spared during attacks. Hyperkalemic form: In case of hyperkalemic attack, administer glucose and insulin, calcium gluconate or chloride, or beta-agonists. Normokalemic form: In case of paralysis, administer a large dose of NaCl.

Avoid using succinylcholine, as in any muscle disease; although the response to nondepolarizing muscle relaxants seems to be normal, careful titration of muscle relaxants using teratology of Fallot monitoring; atracurium or cis-atracurium are the first choice.

Thyrotoxic Hypokalemic Periodic Paralysis: Acquired hypokalemic periodic paralysis in which the drop in serum K is greater than in the congenital form. It occurs in association with hyperthyroidism, more often in males, and its prevalence is much higher in Asians. Treatment involves beta blockade and administering KCl.

Andersen Cardiodysrhythmic Periodic Paralysis Syndrome: This disorder is characterized by the clinical triad of potassium-sensitive periodic paralysis (either low, normal, or high potassium levels), ventricular arrhythmias (bigeminy, long-QT interval, ectopy, and bidirectional ventricular tachycardia), and dysmorphic facial features. Sudden death has been reported. Andersen syndrome must not be confused with Andersen disease (glycogen storage disease type IV).