Periodic Paralyses . Dan Imler Morning Report. Background.
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The heterogeneous group of muscle diseases known as periodic paralyses (PP) is characterized by episodes of flaccid muscle weakness occurring at irregular intervals. Most of the conditions are hereditary and are more episodic than periodic.
The frequencies of hyperkalemic PP, PC, and PAM are not known. Hypokalemic PP has a prevalence of 1 case per 100,000 population.
Thyrotoxic PP is most common in males (85%) of Asian descent with a frequency of approximately 2%.
Patients with HypoKPP typically begin showing symptoms in the first or second decade of life, often as they enter puberty. About 65% develop symptoms before the age of 16
Mild depolarization (5-10 mV) of the myofiber membrane, which may be caused by increased extracellular potassium concentrations, results in the mutant channels being maintained in the noninactivated mode.
The persistent inward sodium current causes repetitive firing of the wild-type sodium channels, which is perceived as stiffness (ie, myotonia).
If a severe depolarization (20-30 mV) is present, both normal and abnormal channels are fixed in a state of inactivation, causing weakness or paralysis.
Thus, subtle differences in severity of membrane depolarization may make the difference between myotonia and paralysis.
Temperature may differentially affect the conformational change in the mutant channel.
Lower temperatures may stabilize the mutant channels in an abnormal state.
Mutations may alter the sensitivity of the channel to other cellular processes, such as phosphorylation or second messengers.
How a defect in the calcium channel might lead to episodic potassium movement into the cells is not known. Intracellular calcium is increased in these patients so the defect in the receptor may promote increased calcium entry into the cells.
However, the mechanism may not involve calcium movement; the dihydropyridine-sensitive calcium channel also acts as a voltage sensor for excitation-contraction coupling and the defect in hypokalemic periodic paralysis is associated with a reduced sarcolemmal ATP-sensitive potassium current.
The mechanism by which hyperthyroidism can produce hypokalemic periodic paralysis is not well understood.
Thyroid hormone increases Na-K-ATPase activity (thereby tending to drive potassium into cells), and thyrotoxic patients with periodic paralysis have higher sodium pump activity than those without paralytic episodes.
Excess thyroid hormone may therefore predispose to paralytic episodes by increasing the susceptibility to the hypokalemic action of epinephrine or insulin.
It is also possible that Asians who are susceptible to thyrotoxic periodic paralysis have a mutated calcium channel which, in the euthyroid state, is not sufficient to produce symptoms.
Acute attacks, in which the sudden movement of potassium into the cells can lower the plasma potassium concentration to as low as 1.5 to 2.5 meq/L, are often precipitated by rest after exercise, stress, or a carbohydrate meal, events that are often associated with increased release of epinephrine or insulin.
The hypokalemia is often accompanied by hypophosphatemia and hypomagnesemia.
Hypokalemic periodic paralysis may be familial with autosomal dominant inheritance (in which the penetrance may be only partial) or may be acquired in patients with thyrotoxicosis.
Asian males are at particular risk for thyrotoxic periodic paralysis; it has been estimated, for example, that the risk of developing the disease is 15 to 20 percent in hyperthyroid Chinese subjects.
In another report, 44 of 45 affected Chinese patients were male. In this study, only 29 percent were known to be hyperthyroid, 60 percent had clinical symptoms compatible with thyrotoxicosis, and 11 percent had subclinical disease.
The recurrent attacks with normal plasma potassium levels between attacks distinguish periodic paralysis from other causes of hypokalemic paralysis, such as that seen in some cases of severe hypokalemia due to distal renal tubular acidosis (RTA).
However, the ability to distinguish among these disorders is sometimes clinically difficult, as characteristic signs and symptoms may be absent.
Serum potassium level decreases during attacks, but not necessarily below normal.
Creatine phosphokinase (CPK) level rises during attacks.
In a recent study, transtubular potassium concentration gradient (TTKG) and potassium-creatinine ratio (PCR) distinguished primary hypokalemic PP from secondary PP resulting from a large deficit of potassium. Values of more than 3.0 mmol/mmol (TTKG) and 2.5 mmol/mmol (PCR) indicated secondary hypokalemic PP.
ECG may show sinus bradycardia and evidence of hypokalemia (flattening of T waves, U waves in leads II, V2, V3, and V4, and ST segment depression).
Intra-arterial epinephrine test: Two mcg/min of epinephrine is infused into the brachial artery for 5 minutes and the amplitude of the CMAP is recorded from a hand muscle. CMAPs are recorded before, during, and 30 minutes after infusion.
The result is considered positive if a decrement of more than 30% occurs within 10 minutes of infusion.
The oral administration of 60 to 120 meq (dose dependent in pediatrics) of potassium chloride usually aborts acute attacks of hypokalemic periodic paralysis within 15 to 20 minutes. Another 60 meq can be given if no improvement is noted.
Prevention of hypokalemic episodes consists of the restoration of euthyroidism in thyrotoxic patients and the administration of a ß-adrenergic blocker in either familial or thyrotoxic periodic paralysis.
ß-blockers can minimize the number and severity of attacks and, in most cases, limit the fall in the plasma potassium concentration.
A nonselective ß-blocker (such as propranolol) should be given; ß1-selective agents are less likely to inhibit the ß2 receptor-mediated hypokalemic effect of epinephrine and may therefore be less likely to prevent paralytic episodes.
Other modalities that may be effective for prevention include K+ supplementation, K+-sparing diuretics, a low-carbohydrate diet, and the carbonic anhydrase inhibitor acetazolamide.