Case Reports

His history included two similar episodes of acute weakness that required hospitalization. The first was in 1993, when he complained of weakness and cramping of muscles, especially the legs, on the night before admission. He awakened at 5:00 AM and fell to the floor when he tried to get out of bed. He was taken to a nearby hospital ER, where his pulse was 40/min. Electrocardiographic (ECG) monitoring showed sinus bradycardia, for which he was given atropine. Laboratory values were serum potassium, 1.7 mmol/L (normal, 3.5 to 5 mmol/L); phosphorus, 1.1 mg/dL (normal, 2.5 to 4.5 mg/dL); other electrolytes, normal; and total creatine kinase (CK), 638 U/L (normal, 20 to 320 U/L), predominantly CK-MM.

Physical examination revealed proximal muscle weakness, good distal muscle strength, diminished deep tendon reflexes, and no sensory deficit. He recovered his strength after receiving a total of 80 mEq intravenous (IV) potassium chloride 1 g/mL (KCl), and serum potassium improved to a level of 4.3 mmol/L 13 hours after IV KCl was started. The serum phosphorus level normalized without replacement therapy. The patient was discharged with a diagnosis of hypokalemic periodic paralysis and home medication was oral KCl 20 mEq/day, which he took for only 1 month.

After approximately 1 year, he awoke with difficulty moving his arms and legs. He had diarrhea for 3 days before his weakness. At the ER, laboratory values were serum potassium, 1.9 mmol/L; phosphorus, 1.4 mg/dL; magnesium, 1.2 mEq/L (normal, 1.3 to 1.9 mEq/L); and total CK, 696 U/L. Electrocardiography showed second-degree atrioventricular (AV) block. Proximal muscle weakness was present, with relative strength preservation in the distal muscles. Muscle fasciculations were also observed in the extremities. Intravenous KCl (60 mEq over 6 hours) was initiated, and serum potassium increased to 5.2 mmol/L 8 hours after therapy began. Serum phosphorus normalized without replacement therapy, while serum magnesium normalized after magnesium replacement. The patient regained strength, and the second-degree AV block disappeared on ECG. He was thought to have weakness resulting from hypokalemia, hypophosphatemia, and hypomagnesemia due to diarrhea and was prescribed oral KCl 20 mEq twice daily as home medication.

At the ER on this admission (1997), he again had pronounced proximal muscle weakness and almost normal distal muscle strength, decreased deep tendon reflexes, and no sensory deficit. The thyroid gland was diffusely enlarged with a bruit. Laboratory values were serum potassium, 1.7 mmol/L; phosphorus, 1.3 mg/dL; and magnesium, 1.28 mEq/L. Electrocardiography showed second-degree AV block, and arterial blood gas measurements on room air were pH, 7.33; PCO₂, 48 mm Hg; PO₂, 102 mm Hg; HCO₃, 25 mmol/L; and SaO₂, 97%. Serum potassium level was 5.3 mmol/L 6 hours later, after starting IV potassium phosphate (40 mEq over 4 hours) and a dose of oral KCl (40 mEq). The patient recovered his strength and the second-degree AV block on ECG resolved. Results of thyroid function tests were thyroid-stimulating hormone (TSH), <0.03 mIU/mL (normal, 0.5 to 6 mIU/L); and free thyroxine (T₄), 7.58 ng/dL (normal, 0.8 to 1.8 ng/dL). Thyroid scan revealed a diffusely enlarged gland with an uptake of 46%. He was discharged on oral propranolol (40 mg twice daily), oral KCl (20 mEq twice daily), and oral propylthiouracil (150 mg every 8 hours). Thyroid hormone levels decreased, though they had remained above normal despite a propylthiouracil dose of up to 600 mg daily. Because of the persistence of thyrotoxicosis despite propylthiouracil therapy for 10 months, radioactive iodine therapy was given. There has been no recurrence of periodic paralysis in 2 years of follow-up after the control of thyrotoxicosis.

Case 2. A 25-year-old black male prison inmate fell to the floor at 6:00 AM, while attempting to rise from bed. A fellow inmate found him on the floor, weak and unable to move lower extremities. He was conscious and denied any pain but vaguely mentioned a history of dizziness and excessive sweating. He did not notice anything unusual the previous night except that he had a big, carbohydrate-rich meal. His only significant medical history was chronic back pain, and he denied alcohol or drug abuse. He was taken to the nearest hospital, where his blood pressure was 84/50 mm Hg. At the ER, ventricular tachycardia developed, then ventricular fibrillation. Cardiopulmonary resuscitation was done, and the cardiac rhythm was immediately converted to sinus tachycardia after administration of epinephrine, defibrillation, lidocaine, and procainamide. Abnormal laboratory values were serum potassium, 1.3 mmol/L; phosphorus, 1.3 mg/dL; total CK, 357 U/L; and alanine aminotransferase, 75 U/L (normal, 5 to 50 U/L). Complete blood count values were white blood cells (WBCs), 17.3 x 103/mL; neutrophils, 83.3%; hemoglobin, 13.5 g/dL (normal, 14 to 18 g/dL); hematocrit, 39.9% (normal, 42% to 52%); and platelets, 356 x 103/mL (normal, 130 to 400 x 103/mL).

Potassium therapy was started with 40 mEq KCl intravenously over 2 hours and a dose of oral KCl 20 mEq; the patient was then transferred to our facility. In the ER, he was alert and oriented, with a temperature of 101.2°F. He had good muscle strength, mild tremors in the fingers, and enlarged tonsils. Blood tests showed a potassium level of 6.1 mmol/L (after a total dose of 60 mEq KCl over a period of <6 hours) and a phosphorus level of 5.9 mg/dL (despite no replacement therapy); ECG showed sinus tachycardia. Urinalysis revealed 21 to 50 WBCs and 6 to 10 WBC casts per high power field. Trimethoprim/sulfamethoxazole therapy was started for a urinary tract infection.

The next day, the patient's serum potassium level was 5.4 mmol/L. His fever resolved and he remained hemodynamically stable, but the sinus tachycardia persisted. Results of ECG and electrophysiologic studies were normal. Our endocrinology division was consulted because of the abnormal and fluctuating potassium levels. A modest, diffuse enlargement of a low-lying thyroid gland was noted. Results of thyroid function tests were TSH, <0.03 mIU/mL; total T₄, 18.5 mg/dL (normal, 4.8 to 11 mg/dL); T₃ resin uptake, 54.2% (normal, 22% to 38%). The diagnosis of Graves' disease was made, and treatment was begun with oral metoprolol (50 mg every 6 hours). Thyroid scan showed a diffusely enlarged thyroid gland with 69% radioactive iodine uptake at 24 hours. The patient was treated with radioactive iodine and was discharged with metoprolol and KCl as prescribed medicines. Serum potassium levels remained normal on subsequent visits to the endocrine clinic. Hypothyroidism developed 3 months after the radioactive iodine therapy, and thyroid hormone replacement therapy was initiated. There has been no recurrence of paralysis since the radioactive iodine therapy 21/₂ years ago.

Discussion

Clinical Presentation

A notable early symptom during the initial stage of an attack is a sensation arising in the affected muscles variously described as aching, stiffness, pain, or cramp.^[2] Paralysis occurs only when the patient is at rest, and usually in bed at night. The rest commonly follows a period of unusually great physical activity and consumption of a high-carbohydrate meal.^[2] Observant patients, realizing that paralysis did not occur while they were active, rapidly learn to "work off" an impending attack on the appearance of premonitory symptoms.^[2] The attacks of paralysis vary widely in severity and range from weakness of the muscles of the pelvic girdle, lasting several hours, to a total paralysis of all the muscles from the neck downward, lasting up to 48 hours.^[2] Proximal muscles are affected more severely than distal muscles. The paralysis can be asymmetrical in distribution, severely affecting the proximal muscles and the muscle groups that underwent the most strenuous physical exertion before the attack.^[2,3] Rare presentations include findings of upper motor neuron disorder, suggesting a possible spinal cord lesion4 or impairment of ventilatory function.^[5] In our patient in case 1, respiratory acidosis was found in arterial blood gas, which could signify a weakness of the respiratory muscles. Other reported cases have had respiratory and bulbar paralysis6 and paralysis of the pharyngolaryngeal junction.^[7] Mental function and sensation are not affected, and deep tendon reflexes are either absent or reduced. Recession of the paralysis is usually in the reverse order of its appearance.^[2] The muscles are commonly tender during and for a short time after recovery.^[2]

The main biochemical abnormalities during an attack are high levels of thyroid hormones and hypokalemia. Rarely, only the total triiodothyronine level is elevated.^[8] The hypokalemia probably does not reflect a depletion of the body's potassium stores. A study9 of total exchangeable potassium showed that patients with thyrotoxic periodic paralysis were not significantly different from controls when the value was related to lean body mass. A study10 of arteriovenous serum potassium and sodium changes during an induced attack of thyrotoxic periodic paralysis suggested that the mechanism of serum potassium reduction is the result of influx of extracellular potassium to the intracellular space. In some cases, the serum potassium remains at a normal level.^[2,11] The neuromuscular symptoms usually improve as the potassium moves back from the intracellular space into the extracellular space.^[12] In some instances, hypophosphatemia has been reported^[13-15] in association with thyrotoxic periodic paralysis and hypokalemia, as occurred in our two patients. The correction of hypophosphatemia without phosphate administration supports the possibility of intracellular shift of phosphate in our two patients and the cases reported by Norris et al^[13] and Guthrie et al.^[15]

Possible precipitating factors for the occurrence of paralysis include ingestion of a high carbohydrate load and strenuous physical activity followed by a period of rest.^[2] Other reported risk factors for the precipitation of paralysis include alcohol ingestion; trauma; cold exposure; infection; menses; emotional stresses; and medications such as diuretics (potassium wasting), adrenaline, physostigmine, pilocarpine, deoxycorticosterone acetate, corticotropin, insulin, and ammonium glycyrrhizinate.^[13] The paralytic attacks usually occur during weekends, since food intake, alcohol ingestion, and physical activity are relatively increased during this time of the week. Studies^[2] in Chinese men with thyrotoxic periodic paralysis revealed that they usually have jobs or recreations that involve strenuous muscular activity and eat a high carbohydrate diet, which is common in Asia.

The incidence of thyrotoxic periodic paralysis in Japan in 1991, when compared with the year 1957, indicated a >40% decrease.^[16] The possible reason for the decrease is related to changes in food consumption, wherein less carbohydrate and more potassium was consumed in 1991 than in 1957.^[16] The attacks of paralysis have a well-marked seasonal incidence, occurring usually during the warmer months of May to October but less often during the colder months of December to March.^[2] Sweating is greatly increased during summer, and the consequent loss of potassium may have a part to play.^[2] In summer, the resulting thirst is commonly quenched by cold drinks with high sugar content, which may precipitate attacks.^[2] A diurnal pattern of attacks also exists. Paralysis occurs only when the patient is at rest and, usually, in bed at night and never during physical exertion.^[2] Electrocardiographic manifestations may include typical features of hypokalemia and various arrythmias.^[2,17-21] Our first patient had sinus bradycardia and second-degree AV block, and our second patient had ventricular tachycardia and ventricular fibrillation.

Etiology

Epidemiology

Thyrotoxic periodic paralysis primarily afflicts men. In the review of 1,366 cases of hyperthyroidism in southern Chinese patients, 13% of the men and 0.17% of the women had thyrotoxic periodic paralysis.^[2] Of the known factors that provoke the onset of paralysis, it might be suggested that physical exertion would be greater in men. However, a large number of Chinese women are engaged in heavy manual labor, making the degree of physical exertion a less important precipitating factor. In the cases among black patients, including our 2 cases, eight patients were men and only two were women.

Pathophysiology

It has been observed that b-blockade with propranolol prevents paralysis, and this suggests that the development of paralysis is partly influenced by the hyperadrenergic state characteristic of thyrotoxicosis.^[38] Studies in skeletal muscle have shown that CA⁺⁺-ATPase activity and the calcium uptake by sarcoplasmic reticulum decrease during the attack of paralysis but revert to normal after the attack.^[39] The decrease in the activity of the calcium pump was proportional to the severity of paralysis and the degree of hypokalemia.^[39]

Studies suggest that chronically elevated plasma aldosterone levels may contribute to the occurrence of periodic paralysis of thyrotoxicosis in some patients, especially when further stimulated by a prompt increase in endogenous corticotropin as the result of severe stress, or even a normal or diurnal rise.^[40] In 17 hyperthyroid patients without paralysis, neurophysiologic evaluation of untreated hyperthyroid patients showed abnormalities mainly in the proximal muscles, and these findings suggest the presence of an initial axonal type of mild polyneuropathy.^[41] In a study of 7 patients with thyrotoxic periodic paralysis by using glucose and insulin infusion, a paralytic attack developed within 90 minutes in 6 of 7 patients.^[42] These results suggest that hyperaldosteronism may not be a trigger for the induced paralytic attack but may be a phenomenon due to volume depletion and a change in potassium homeostasis induced by glucose and insulin infusion.^[42]

Electromyographic studies in eight Chinese patients with thyrotoxic periodic paralysis showed that most had a myopathic pattern during an attack of paralysis that disappeared during remission.^[43] The myopathic changes were a decrease in duration of muscle action potentials, an increase in polyphasic potentials, a satisfactory interface pattern with reduced amplitude, and a reduced amplitude of the evoked muscle action potential on nerve stimulation.^[43] Peripheral nerve function was normal in these cases, and it was concluded that the weakness in thyrotoxic periodic paralysis is myopathic and that the peripheral nerve function during paralysis is normal.^[43]

Light microscopy of the biopsied quadriceps muscles during paralysis in 17 patients with thyrotoxic periodic paralysis showed no abnormalities in 23.5%, sarcolemmal nuclear proliferation in 35.5%, atrophy of muscle fibers in 29.4%, central nuclei in 23.5%, fatty infiltration in 17.6%, vacuolation in 11.8%, and sarcoplasmic masses in 11.8%.^[44] These muscles were also examined by electron microscopy in 10 patients; the main changes observed were vacuolation in 90%, mitochondrial abnormalities in 100%, glycogen granules accumulation in 100%, disruption of the myofibers in 50%, and changes in the T system in 40%.44 The light and electron microscopic changes in the skeletal muscles during paralysis were not well-correlated with the severity of the muscle weakness of hypokalemia.^[44]

In another study,^[45] electron microscopic examination of muscle biopsy specimens made it possible to assume that in thyrotoxic periodic paralysis, the action of the thyroid hormone not only causes impairment of the mineral metabolism, but also brings about changes in the structure of the membranes of the sarcolemma and T system, which leads to disturbances of conductance of action potential into the fiber. These changes affect the function of the end cisterns and lead to distortion of the processes of conjugation of excitation-contraction with resulting development of paresis and paralysis of muscles.^[45]

In animal studies,^[46] thyroid hormone appears to regulate Na channels in cultured rat skeletal myotubes by two opposing mechanisms, (1) direct stimulation of Na channel synthesis and (2) indirect decrease in synthesis mediated by an increase in cytosolic Ca^[2]+. The results indicate that thyroid hormone may play an important role in developmental expression of Na channels in excitable tissue.^[46] In rats, triiodothyronine induced upregulation of the concentration on Na⁺ channels and Na⁺,K⁺ pumps, which was associated with a progressive loss of contractile endurance.^[47] These observations are important for an understanding of the fatigue associated with hyperthyroidism and add further support to the hypothesis that muscle endurance depends on the leak-to-pump ratio for Na⁺.^[47] In rat soleus muscle, thyroid hormone at physiologic doses seems to be the major endocrine factor determining the concentration of Na⁺,K⁺ pumps in skeletal muscle,^[48] and endurance is a function of the ratio between the concentration of Na⁺ channels and Na⁺,K⁺ pumps.^[49] In rat skeletal muscle, the stimulation of the Na/H antiport by physiologic concentrations of thyroid hormones results in a dose-dependent increase in intracellular pH.^[50] These findings suggest that thyroid hormones may have an active role in the recovery from muscular acidosis through direct stimulation of the Na/H antiport.^[50]

Studies of the interaction of the thyroid state and skeletal myosin heavy chain expression in rats suggest that for patients with nerve damage and/or paralysis, both muscle mass and biochemical properties can also be affected by the thyroid state.^[51] In rat heart, the status of sarcolemmal Ca^[2]+ transport processes is regulated by thyroid hormones, and the modification of Ca^[2]+ fluxes across the sarcolemmal membrane may play a crucial role in the development of thyroid state-dependent contractile changes in the heart.^[52] In hyperthyroid cats with hypokalemia and skeletal muscle weakness manifested as ventroflexion of the neck, correction of the hypokalemia led to recovery in muscle strength.^[53]

In the rat brain, Na⁺,K⁺-ATPase activity has been noted to be significantly greater in males than in females,^[54] and testosterone induces an increase in the Na⁺,K⁺-ATPase activity.^[55] Other studies in rats showed that hepatic Na⁺,K⁺- ATPase activity is inhibited by estrogen.^[56] Progesterone or progesterone derivatives also inhibited Na⁺,K⁺-ATPase activity in the canine kidney^[57] and in the guinea pig heart and brain.^[58] These effects of sex hormones on the Na⁺,K⁺ pump may contribute to the predisposition for thyrotoxic periodic paralysis in men.

Genetics

Treatment

Once the paralytic attack has started, administration of potassium is standard therapy, and recovery of the periodic paralysis may be hastened.^[64] Although the serum potassium level will eventually normalize spontaneously as potassium moves from the intracellular space to the extracellular space, the administration of potassium is not done to correct the hypokalemia. It is given mainly to prevent cardiac arrhythmias that potentially can be life-threatening. Potassium is usually administered intravenously, even though there is no proven benefit or advantage in using this method of administration.

As potassium is released from the cells into the circulation during the recovery phase of the paralytic attack, aggressive potassium administration can lead to hyperkalemia, as happened in our case 2 patient with a potassium level of 6.1 mmol/L after receiving a dose of only 60 mEq KCl. A patient who had a potassium level of 1.9 mEq/L progressed to a level of 6.4 mEq/L after receiving 100 mEq KCl intravenously over 10 hours.20 In cases with associated hypophosphatemia, as in our patients' cases and those of Norris et al^[13] and Guthrie et al,^[15] it has been observed that serum phosphate levels returned to normal after giving only potassium.

After initiating the definitive therapy for the thyrotoxicosis, patients should be advised to avoid precipitating factors while awaiting normalization of the thyrotoxic state. Others have advocated supplementation with oral potassium to prevent attacks of paralysis in some patients, though this approach is not consistently effective. Acetazolamide has been used in the familial hypokalemic periodic paralysis; however, in one case a Hispanic man was given acetazolamide for his thyrotoxic periodic paralysis, which had been mistakenly diagnosed as familial hypokalemic periodic paralysis, and this resulted in near-total body paralysis 2 weeks later.^[18] In some cases, the efficacy of using spironolactone^[2] or aldosterone antagonist SC942065 in preventing paralytic attacks is well-documented. b-Adrenergic blockade induced with propranolol therapy has resulted in marked relief of the episodes of paralysis^[38] and is probably the most useful preventive therapy until a euthyroid state is achieved.

Summary