Familial Periodic paralysis is characterized by recurrent attacks of flaccid weakness usually associated with abnormally high or low serum potassium concentrations. Many cases are familial. In sporadic cases the abnormality may be secondary to identifiable aberrations of potassium metabolism.
Etiology and Parthenogenesis.
dominant inheritance, Hypokalemia during attacks was the first metabolic abnormality to be recognized, with no membrane potential has not been substantiated by direct measurement with intracellularloss of potassium in urine. It was therefore presumed that potassium shifted from extracellular to intracellular compartments, especially muscle. This has been difficult to prove, and the anticipated hyperpolarization of the muscle.
Familial cases are distributed in a pattern consistent with autosomal electrodes. Abnormalities of glucose metabolism have been suspected, because attacks can be precipitated by infusions of glucose and insulin, by eating a large meal, or by administration of epinephrine. However, biochemical studies have failed to pinpoint the abnormality.
During {he past decade it has been recognized that the serum potassium tends to rise in some patients, and attacks in these individuals are induced by the ingestion of potassium. This variety is therefore called “hyperkalemic periodic paralysis,” and is generally considered to be the mirror image of the hypokalemic type, with potassium presumably shifting out of muscle and into blood during attacks. Why this should happen is not clear, but at least in the hyperkalemic type there are alterations of the intracellular potential in the direction required by theory. There are clinical differences between the two forms of periodic paralysis, but there are so many areas of overlap and so many common features that it is difficult to decide just how many genetically distinct forms there really are.
Pathology of Familial Periodic Paralysis .
In both forms of periodic paralysis there may be vacuoles within muscle fibers. These may be numerous or scanty, and it is not clear that they are more frequent in paralyzed muscle. Most electron microscopists believe that the vacuoles are derived from the sarcoplasmic reticulum, but others think they originate in the T-system in areas of necrotic muscle. Glycogen seems to be increased in amount in ultrastructural studies, but the results of biochemical analysis have been inconsistent. There is no evidence that other organs are affected in either form of the disease. The heart is usually spared pathologically.
Clinical Manifestations of Familial Periodic Paralysis.
There are clinical differences between the two forms. In the hypokalemic variety, attacks tend to start in late childhood or adolescence, frequently occur at night, are apt to be severe, and last for a day or more. In the hyperkalemic variety, attacks start at an early age, occur much more frequently, tend to be milder, and may last minutes or hours. Moreover, patients with hyperkalemic periodic paralysis usually have some evidence of myotonia, which is rarely symptomatic and often limited to percussion myotonia of the tongue. Lid-lag and Chvostek’s sign are identified with the hyperkalemic type.
These clinical distinctions may break down in application to individual cases and are therefore only crude guides. Moreover, many features are common to both types: a dominant pattern of inheritance, a susceptibility to attacks during periods of rest after vigorous exercise, the ability to ward off attacks by mild exercise after a mild attack has begun, persistent weakness between attacks, vacuoles in muscle, a lack of clear relation between the serum potassium concentration and the sever- ity of paresis, the induction of local weakness by cooling, and protection against attacks by acetazo- lamide. Some patients are affected by attacks in which the serum potassium may be either high or low.
Typical attacks start with weakness of the legs that ascends to the arms. Cranial muscles are affected in severe attacks only, and respiratory insufficiency is exceptional. The attacks may be mild and brief, or severe and prolonged, with all gradations in between. During severe attacks, the myotatic reflexes are lost, and the muscles are electrically inexcitable. Attacks are rarely apoplectic in onset and usually take an hour or more to develop, except that attacks beginning in sleep may be fully developed when the patient awakes. Paresthesias and myalgia may be prominent at the onset, or may be completely lacking. Some patients are aware of oliguria during the attack and of diuresis afterward.
The serum potassium is in the range of 2.5 to 3.5 mEq. per liter in hypokalemic attacks, and 5.0 to 7.0 mEq. per liter in the hyperkalemic type. Between attacks serum potassium values may be normal. The electrocardiogram is altered as would be predicted from the serum values, with low T- waves in hypokalemia and peaked T-waves in hyperkalemia.
Patients with hyperkalemic periodic paralysis may have mild symptoms attributable to myotonia, especially of the hands. When individuals in a family are studied, some may be found to have myotonia without any history of periodic paralysis.
In both types of the disease, there may be persistent weakness between attacks, most often proximal, sometimes distal. In the past this has been attributed to a permanent “myopathy,” but experience with acetazolamide therapy indicates that even long-lasting weakness may be reversible, regardless of pathologic changes in muscle. A few patients with intermittent normo- kalemic or hyperkalemic paralysis have had persistent cardiac arrhythmia, especially bigem- iny, and bouts of ventricular tachycardia. The cardiac disorder is neither temporally related to attacks of limb weakness nor related to serum potassium content.
Diagnosis.
Periodic paralysis can be recognized by the history of typical attacks; no other disease causes this pattern of recurrent weakness. In myasthenia gravis, weakness may come and go, but less abruptly and with a duration of weeks rather than hours or days; remissions are Jess frequent so that it is less “periodic.” Polymyositis may be transient, but episodes are rarely shorter than several weeks or months. Attacks of myoglobinuric weakness could conceivably be confusing if the pigmenturia were not recognized, but myalgia and malaise are so prominent that it is rarely confused with periodic paralysis. Hysterical attacks might, be confusing.
If the patient is seen during the attack and the serum potassium is abnormal, other causes of hypo- or hyperkalemia must be considered. Low serum potassium concentrations with paralysis are also encountered in hyperaldosteronism, potassium-losing nephritis, potassium depletion caused by laxative abuse or diarrhea, and thyrotoxicosis. Hyperkalemia is most often due to renal insufficiency, but may also occur in adrenal insufficiency, after administration of spironolactone, or as a manifestation of aldosterone deficiency
The signs of these other disorders usually provide appropriate diagnostic clues. A family history of periodic paralysis is useful in diagnosis, of course, but apparently sporadic cases may be indistinguishable, from the familial disorder. If the patient is not having a spontaneous attack when studied, the only way to distinguish the two forms is to provoke an attack. The techniques to be described have been used in numerous centers with many patients, without serious complications. But induced attacks may be frightening to patient and physician, and should be left to experienced investigators.
Facilities for supported respiration should be immediately available. Appropriately informed consent is mandatory. Because of the uncertainty of clinical distinction, it is advisable to start with glucose (100 grams) given intravenously in one hour, with 20 units of regular insulin either in the infusion or given subcutaneously. Hypoglycemic symptoms should be anticipated, and the electrocardiogram should be monitored.
Hypokalemia is induced as the blood sugar falls, usually within one hour after the infusion is completed. If an attack is induced, it can be terminated with administration of 7 to 10 grams of potassium chloride (KC1) by mouth. Whether or not an attack is induced by glucose and insulin, but especially if it is not, the patient should then be challenged with potassium.
This poses delicate problems because it is not clear how much potassium constitutes an adequate challenge. We start with 3 grams of KC1 by mouth. If this fails we gradually increase the dose on successive days to a maximum of 8 or 10 grams. Patients with hyperkalemic paralysis have attacks with serum potassium levels between 5 and 8 mEq. per liter.Other members of the family should be investigated clinically and electromyographically for evidence of myotonia.
Treatment of Familial Periodic Paralysis.
Acute attacks of hypokalemic paralysis are best treated with oral KC1, 5 to 10 grams. Relief of weakness usually commences within 30 minutes but may take several hours, and some attacks are peculiarly refractory. Hyperkalemia may be relieved by infusions of glucose and insulin. Chlorothiazide and calcium gluconate have also been reported to be effective. In severe attacks, weakness may persist even after the serum potassium has returned to normal concentrations.
The traditional method used to protect patients against hypokalemic paralysis was, until recently, a low-sodium diet supplemented by oral KC1, or perhaps by spironolactone or dexamethasone. Then, acetazolamide in small doses, sometimes only 250 per mg. daily, sometimes more, was found to be effective prophylaxis in the hyperkalemic type. Subsequently, it was found that similar doses of acetazolamide were equally effective in the hypokalemic variety, so a single drug is beneficial in both forms. How it exerts this effect is not known. The best-known effects of this compound relate to its ability to inhibit carbonic anhydrase, but muscle lacks this enzyme, and no systemic effects of the drilg have been recognized in the doses used.
