Pathophysiology Although the mechanism of thyrotoxic periodic paralysis remains uncertain, the two main ingredients that produce

a paralytic attack are thyrotoxicosis and hypokalemia. It has been shown [32] that a!,"!#A$%ase acti&ity in patients with thyrotoxic periodic paralysis was significantly higher than in healthy sub'ects or in thyrotoxic patients without a history of paralysis despite similar degree of hyperthyroidism. (ompared with thyrotoxic patients without paralysis, patients with thyrotoxic periodic paralysis respond to thyrotoxicosis with a smaller decrement in erythrocyte a!,"!#A$%ase acti&ity, howe&er, the difference is too small to represent a useful genetic marker for this disease entity.[33] $here are high le&els of immunoreacti&e insulin during spontaneous attacks in thyrotoxic periodic paralysis.[3)] An increase in plasma glucose concentration together with abnormally high le&els of serum immunoreacti&e insulin was obser&ed preceding a spontaneous attack of paralysis, and the affinity of erythrocyte insulin receptors was decreased during the attack.[3*] In thyrotoxic periodic paralysis, patients ha&e been found to ha&e hyperinsulinemia, and this is accompanied by increased a!,"!#A$%ase acti&ity.[3+] %recipitation of an attack by a carbohydrate diet was associated with only a modest fall in le&el of plasma potassium but with a marked rise in total blood cell potassium.[3,] It has been obser&ed that b#blockade with propranolol pre&ents paralysis, and this suggests that the de&elopment of paralysis is partly influenced by the hyperadrenergic state characteristic of thyrotoxicosis. [3-] .tudies in skeletal muscle ha&e shown that (A!!#A$%ase acti&ity and the calcium uptake by sarcoplasmic reticulum decrease during the attack of paralysis but re&ert to normal after the attack. [3/] $he decrease in the acti&ity of the calcium pump was proportional to the se&erity of paralysis and the degree of hypokalemia.[3/] .tudies suggest that chronically ele&ated plasma aldosterone le&els 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 se&ere stress, or e&en a normal or diurnal rise. [)0] In 1, hyperthyroid patients without paralysis, neurophysiologic e&aluation 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.[)1] In a study of , patients with thyrotoxic periodic paralysis by using glucose and insulin infusion, a paralytic attack de&eloped within /0 minutes in + of , patients. [)2] $hese results suggest that hyperaldosteronism may not be a trigger for the induced paralytic attack but may be a phenomenon due to &olume depletion and a change in potassium homeostasis induced by glucose and insulin infusion.[)2] 2lectromyographic studies in eight (hinese patients with thyrotoxic periodic paralysis showed that most had a myopathic pattern during an attack of paralysis that disappeared during remission. [)3] $he 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 e&oked muscle action potential on ner&e stimulation. [)3] %eripheral ner&e function was normal in these cases, and it was concluded that the weakness in thyrotoxic periodic paralysis is myopathic and that the peripheral ner&e function during paralysis is normal.[)3] 3ight microscopy of the biopsied 4uadriceps muscles during paralysis in 1, patients with thyrotoxic periodic paralysis showed no abnormalities in 23.*5, sarcolemmal nuclear proliferation in 3*.*5, atrophy of muscle fibers in 2/.)5, central nuclei in 23.*5, fatty infiltration in 1,.+5, &acuolation in 11.-5, and sarcoplasmic masses in 11.-5.[))] $hese muscles were also examined by electron microscopy in 10 patients6 the main changes obser&ed were &acuolation in /05, mitochondrial abnormalities in 1005, glycogen granules accumulation in 1005, disruption of the myofibers in *05, and changes in the $ system in )05.)) $he light and electron microscopic changes in the skeletal muscles during paralysis were not well#correlated with the se&erity of the muscle weakness of hypokalemia.[))] In another study,[)*] 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 $ system, which leads to disturbances of conductance of action potential into the fiber. $hese changes affect the function of the end cisterns and lead to distortion of the processes of con'ugation of excitation#contraction with resulting de&elopment of paresis and paralysis of muscles.[)*] In animal studies,[)+] thyroid hormone appears to regulate a channels in cultured rat skeletal myotubes by two opposing mechanisms, 718 direct stimulation of a channel synthesis and 728 indirect decrease in synthesis mediated by an increase in cytosolic (a [2]!. $he results indicate that thyroid hormone may play an important role in de&elopmental expression of a channels in excitable tissue. [)+] In rats, triiodothyronine induced upregulation of the concentration on a ! channels and a!,"! pumps, which was associated with a progressi&e loss of contractile endurance. [),] $hese obser&ations 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 a !.[),] In rat soleus muscle, thyroid hormone at physiologic doses seems to be the ma'or endocrine factor determining the concentration of a!,"! pumps in skeletal muscle,[)-] and endurance is a function of the ratio between the concentration of a! channels and a!,"! pumps.[)/] In rat skeletal muscle, the stimulation of the a9: antiport by physiologic concentrations of thyroid hormones results in a dose#dependent increase in intracellular p:. [*0] $hese findings suggest that thyroid hormones may ha&e an acti&e role in the reco&ery from muscular acidosis through direct stimulation of the a9: antiport.[*0] .tudies of the interaction of the thyroid state and skeletal myosin hea&y chain expression in rats suggest that for patients with ner&e damage and9or paralysis, both muscle mass and biochemical properties can also be affected by the thyroid state.[*1] In rat heart, the status of sarcolemmal (a[2]! transport processes is regulated by thyroid hormones, and the modification of (a[2]! fluxes across the sarcolemmal membrane may play a crucial role in the de&elopment of thyroid state#dependent contractile changes in the heart. [*2] In hyperthyroid cats with hypokalemia and skeletal muscle weakness manifested as &entroflexion of the neck, correction of the hypokalemia led to reco&ery in muscle strength.[*3] In the rat brain, a!,"!#A$%ase acti&ity has been noted to be significantly greater in males than in females,[*)] and testosterone induces an increase in the a !,"!#A$%ase acti&ity.[**] ;ther studies in rats showed that hepatic a!,"!# A$%ase acti&ity is inhibited by estrogen. [*+] %rogesterone or progesterone deri&ati&es also inhibited a!,"!#A$%ase acti&ity in the canine kidney[*,] and in the guinea pig heart and brain.[*-] $hese effects of sex hormones on the a!,"! pump may contribute to the predisposition for thyrotoxic periodic paralysis in men. Genetics <nlike familial hypokalemic periodic paralysis, thyrotoxic periodic paralysis is not usually associated with family history. $here is, howe&er, an association with the presence of :3A#=>w-, and data suggest that this gene may play a significant role in the susceptibility to thyrotoxic periodic paralysis among ?apanese men.[*/] In a pair of mono@ygous adolescent male twins with hyperthyroidism, one had thyroiditis while the other had muscle weakness and paralysis. [+0] $he finding of :3A antigens A2AB22 and AB1/A1, in (hinese patients with thyrotoxic periodic paralysis but not in patients without the disorder raises the possibility that these haplotypes may ser&e as genetic markers. [+1] In a black patient, phenotyping re&ealed neither of the two genetic markers pre&iously obser&ed among (hinese patients with thyrotoxic periodic paralysis, indicating that the haplotypes do not ser&e as markers for the disorder in black patients.[2,] Although the :3A system has been suggested to pro&ide a link to a presumed immunogenetic etiology of the thyrotoxic periodic paralysis, this seems to be an unlikely explanation in &iew of the numerous patients with the disorder whose thyrotoxicosis is not related to autoimmune mechanism. $he high incidence of the disorder in Asians suggests that the basic defect may be genetically determined, but the defect manifests itself only when challenged by thyrotoxicosis.[2] Treatment

$he definiti&e therapy for thyrotoxic periodic paralysis is the management of the thyrotoxic state by medical therapy, surgery, or radioacti&e iodine therapy. $he resolution of periodic paralysis with restoration of euthyroidism has been acknowledged as a uni&ersal finding.[2] $he a!,"!#A$%ase acti&ity in >A(s was found to be impaired in Cra&esD disease, and thioamide treatment restored the normal acti&ity.[+2] ;ne case was an exception, howe&er, because the periodic paralysis persisted e&en when the patientDs clinical and laboratory features suggested a euthyroid state. $his patient continued to ha&e symptoms of periodic paralysis when he progressed to hypothyroidism after radioacti&e iodine ablation.[+3] ;nce the paralytic attack has started, administration of potassium is standard therapy, and reco&ery of the periodic paralysis may be hastened.[+)] Although the serum potassium le&el will e&entually normali@e spontaneously as potassium mo&es from the intracellular space to the extracellular space, the administration of potassium is not done to correct the hypokalemia. It is gi&en mainly to pre&ent cardiac arrhythmias that potentially can be life#threatening. %otassium is usually administered intra&enously, e&en though there is no pro&en benefit or ad&antage in using this method of administration. As potassium is released from the cells into the circulation during the reco&ery phase of the paralytic attack, aggressi&e potassium administration can lead to hyperkalemia, as happened in our case 2 patient with a potassium le&el of +.1 mmol93 after recei&ing a dose of only +0 m24 "(l. A patient who had a potassium le&el of 1./ m2493 progressed to a le&el of +.) m2493 after recei&ing 100 m24 "(l intra&enously o&er 10 hours.20 In cases with associated hypophosphatemia, as in our patientsD cases and those of orris et al[13] and Cuthrie et al,[1*] it has been obser&ed that serum phosphate le&els returned to normal after gi&ing only potassium. After initiating the definiti&e therapy for the thyrotoxicosis, patients should be ad&ised to a&oid precipitating factors while awaiting normali@ation of the thyrotoxic state. ;thers ha&e ad&ocated supplementation with oral potassium to pre&ent attacks of paralysis in some patients, though this approach is not consistently effecti&e. Aceta@olamide has been used in the familial hypokalemic periodic paralysis6 howe&er, in one case a :ispanic man was gi&en aceta@olamide 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.[1-] In some cases, the efficacy of using spironolactone [2] or aldosterone antagonist .(/)20+* in pre&enting paralytic attacks is well#documented. b#Adrenergic blockade induced with propranolol therapy has resulted in marked relief of the episodes of paralysis [3-] and is probably the most useful pre&enti&e therapy until a euthyroid state is achie&ed. Summary $hyrotoxic periodic paralysis is a thyroid#related disorder manifested as recurrent episodes of hypokalemia and muscle weakness lasting from hours to days. $he onset of paralytic attacks coincides with the onset of thyrotoxicosis, which could be due to &arious causes. $his condition predominantly affects men and usually occurs in the third to fifth decades of life. $he usual precipitating factors are ingestion of a high#carbohydrate meal and strenuous physical acti&ity followed by rest. Although the mechanism of thyrotoxic periodic paralysis remains uncertain, the two main ingredients to produce a paralytic attack are thyrotoxicosis and hypokalemia. $he high incidence of thyrotoxic periodic paralysis among Asian people suggests that the basic defect may be genetically determined, but the defect manifests itself only when challenged by thyrotoxicosis. %ropranolol and spironolactone ha&e been used to pre&ent paralytic attacks, but the definiti&e therapy is management of the thyrotoxicosis. %otassium administration is mainly done to pre&ent cardiac arrhythmias and to hasten the reco&ery of the paraly@ed muscles. ;ur cases are the ninth and tenth reports of thyrotoxic periodic paralysis in blacks. :ypokalemic periodic paralyses 7%>;C ;.I.8
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<ntreated patients may experience fixed proximal weakness, which may interfere with acti&ities. .e&eral deaths ha&e been reported, mostly related to aspiration pneumonia or inability to clear secretions.

$reatment is often necessary for acute attacks of hypokalemic %% but seldom for hyperkalemic %%. %rophylactic treatment is necessary when the attacks are fre4uent.

:ypokalemic periodic paralyses

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=uring attacks, oral potassium supplementation is preferable to IE supplementation. $he latter is reser&ed for patients who are nauseated or unable to swallow. ;ral potassium salts at a dose of 0.2* m249kg should be gi&en e&ery 30 minutes until the weakness impro&es. A&oiding IE fluids is prudent. IE potassium chloride 0.0*#0.1 m249kg body weight in *5 mannitol as a bolus is preferable to continuous infusion. (ontinuous 2(C monitoring and se4uential serum potassium measurements are mandatory. For prophylaxis, aceta@olamide is administered at a dose of 12*#1*00 mg9day in di&ided doses. =ichlorphenamide *0#1*0 mg9day has been shown recently to be e4ually effecti&e. %otassium#sparing diuretics like triamterene 72*#100 mg9d8 and spironolactone 72*#100 mg9d8 are second#line drugs to be used in patients in whom the weakness worsens or in those who do not respond to carbonic anhydrase inhibitors. As these diuretics are potassium sparing, potassium supplements may not be necessary.

$hyrotoxic %%G $reatment consists of controlling thyrotoxicosis and beta#blocking agents. %otassium supplementation, propranolol, and spironolactone may be helpful during the attacks, as well as prophylaxis. %ropranolol in doses of 20#)0 mg twice a day may be sufficient to control recurrent attacks of periodic paralysis.

7=I2$8#:ypokalemic %%G 3ow#carbohydrate and low#sodium diet may decrease the fre4uency of attacks. Lab Studies

:ypokalemic periodic paralyses

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.erum potassium le&el decreases during attacks, but not necessarily below normal. (reatine phosphokinase 7(%"8 le&el rises during attacks. In a recent study, transtubular potassium concentration gradient 7$$"C8 and potassium#creatinine ratio 7%(>8 distinguished primary hypokalemic %% from secondary %% resulting from a large deficit of potassium. Ealues of more than 3.0 mmol9mmol 7$$"C8 and 2.* mmol9mmol 7%(>8 indicated secondary hypokalemic %%. 2(C may show sinus bradycardia and e&idence of hypokalemia 7flattening of $ wa&es, < wa&es in leads II, E2, E3, and E), and .$ segment depression8.
Hypokalemic PP .erum potassium .erum (%" 2(C Hildly depressed6 may reach 1#* m2493 Hoderately ele&ated during attacks Aradycardia Flat $ wa&es, < wa&es, .$ segment depression Hyperkalemic PP Increases from baseline but may not increase beyond normal range Hildly ele&ated during attacks $all $ wa&es

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