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Thyrotoxic periodic paralysis
Thyrotoxic .JE~
Periodic
M.D., i JOE 11. DORMAN, Hethesda,
Paralysis* M.D. $ and \I’. KING
ENGEI..
ht.~.
Maryland
In an Uriental patient with thyrotoxic periodic paralysis, six weeks of therapy with reserpine alone returned the pulse rate to normal and reduced nervousness but did not prevent the attacks of periodic paralysis. These observations imply that hyperactivity of the sympathetic nervous system is not an essential feature of the mechanism I,) which hyperthyroidism predisposes certain patients to hypokalemic periodic paralysis. Prior to antithyroid treatment. aldosterone secretion and metabolic clearance rates were prominently elevated; after propylthiouracil therapy. both returned to normal. An intravenous glucose and insulin provocation test prior to antithyroid therapy produced striking hypokalemia and paralysis, but after antithyroid treatment an identical challenge failed to do so. The periodic paralysis disappeared on therapy \rith propvlthiouracil and baseline muscle strength rose remarkablv.
T
lowers the threshold for attacks of h)-pokalcrriic periodic paralysis in people who arc susceptible by virtue of a latent Inetabolic defect. On the other hand. patic-nts with idiopathic hypokalenlic periodic paralysis do not suffer IIWI‘~ frc,quent attacks \vhcn rendered thyrotoxic b\ administration of tri-iodothyroninc or thyroidstilnulatinq hornionc [J]. The Illechanisrn by which hypcrthyroidisln triggers periodic paralysis is not know-n. Son~e sy11ip:oms of hypcrth) roidislii ar? IIOW rccognized to be a rnanifcstation of excessive activit) of the synlpathctic nervous s)‘steln and CYIJI h alleviated by usr of adrenergic blocking agents. Reductioll or disappearance of palpitation, tachycardia, nervousness, trenlor and lid-lag has been observed in hyperthyroid subjects after treatnlent with guanethidinc [5] or reserpine [S], without reduction of the elevated proteinbound iodine or radioactive iodine uptake values. It has not been determined prcGously, however, whether adrenergic blockade will prevent episodic weakness in patients will1 thyrotoxic periodic paralysis. This report describes our observations in a patient with thyrotoxic periodic paralysis who was treated initially with reserpine alone and was noted to have no reduction in the occurrcncc of paralytic attacks. Treatment with spec,ific antithyroid drugs eliminated his attacks and was
periodic paralysis occurs as a complication of hyperthyroidisrn in a slllall proportion of Oriental patients [ 1,2], and orcasionally in C:aucasians. The paralytic attacks are rlinicallv identical with those observed in the idiopa&r type of hypokaleInic periodic paral!.sis, sharing the following features : lowcring of scrutn potassiulll often to subnornial \.alues> precipitation bl. excessive carboh>.drate loading or by rrst after exercise, flaccid and areHexic paral>-sis of skeletal rnusclc accompanied by electrical inexcitability of ~nusclc, responsivencss to trcatnlent with potassiunl salts, of \racuolization of 1nusc1c and dilatation sarcoplasnlic rcticulunl or T system. 111 thyrotoxir periodic paralysis, attacks nearly always cease when the hyperthyroidism leas been treated successfully but Inay recur if IIyperthyroidisnl escapes control. This phvnonlt~Ion is apparently not related to thyroidstirilulatinq horrtlone, as one patient who had been attack-free for SCVCII years after his hyperthyroitlisrr~ was treated successfully by surgery rxp?ricnced a rccurrenc‘e of hypokalemic paralysis when hr \.oluntaril>, took an excessi\Tc dose of tri-iodothyrollinc I,?]. 1 t is assumed that there cbxisrs a latent defect in such patients which beconies evident only in the presence of excessive rhyroid hornlone. Apparently, some as yet trndcfined asprct of the hyperthyroid state HYROTOXIC
* From the Medical Neurology Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health. Public Health Service. U. S. Department of Health. Education, and Welfare, Bethesda, Maryland 20014. Keyuests &r reprints should be addressed to Dr. 1%‘.King Engel at the Medical New&~); Branch. Manuscript rvceiwd December 17, 1968. t Prrst nt address: 125 Strawberry Hill Avcnuc, Stamford, Connecticut 06902. 1 Prrscnt address: Division of Neurology, Harbor General IIospital, Torrance, California 90505. vo,.
47.
NOVEMBER
1969
831
832 followed muscular challenge
Thyrotoxic
Periodic
by striking changes in his baseline strength, response to a glucose-insulin and aldosterone secretion rate. CASE REPORT
The patient (NIH No. 06-42-39) was a thirty-six year old Cambodian male physician admitted for the first time in October 1965 to the Medical Neurology Branch, NINDB, of the National Institutes of Health, with the chief complaint of episodic weakness of three and a half weeks’ duration. He awoke one morning with mild weakness of the legs. The mild weakness persisted for days and became worse each evening after supper. He also noticed a discomfort in the medial aspect of both thighs, aggravated by certain movements. On a cool evening two weeks before admission he rode in an open convertible car just before retiring to bed at midnight and at 3 A.M. he awoke with severe weakness of the proximal leg muscles. This attack cleared partially over several hours, and the following morning he was admitted to a local hospital. Evaluation there disclosed weakness in the limbs and trunk with no abnormality of cranial nerves, sensory function, reflexes or sphincters. His serum potassium was 2.0 mEq. per L. His strength improved within hours after admission to the hospital on no therapy, and he was discharged five days later with advice to drink orange juice. His strength continued to improve gradually and two days before his admission to NIH he felt well enough to return to work. However, on the day of his admission to NIH he again awoke with weakness in the lower extremities which became more severe after a heavy lunch. Several times after the initial weakness had occurred the patient counted his pulse and found it to be between 100 and 140 beats per minute. One evening his pulse was rapid and irregular, and an electrocardiogram demonstrated multiple atria1 extrasystoles which disappeared after treatment with sodium pentobarbital. He had lost 3 kg. in weight in the three weeks before his admission to NIH although previous to that his weight had been stable. There had been no recent change in his heat tolerance. He used only one blanket at night and never wore sweaters. He denied increased prominence of the eyes, change in bowel habits or change in texture of skin or hair. He had been somewhat nervous all his life without definite recent increase. Past illnesses included, in addition to the usual childhood diseases, variola, malaria and amebic dysentery. He had been hospitalized previously for an appendectomy at age twenty-seven and a right pyelolithotomy at age thirty-five. His mother was half Siamese and half English and his father was Indoeuropean. There was no family history of thyroid or paralytic diseases with the exception of a distant cousin who died in her twenties with leg paralysis. Physical examination at the time of his first admission to NIH revealed an alert, moderately anxious
Paralysis-Resnick
et al.
Oriental with a regular pulse of 100 and blood pressure of 125/65 mm. Hg. There was a suggestion of prominence to the eyes, an inconstant slight lid-lag but no limitation of ocular motility. The thyroid gland was diffusely and slightly enlarged without bruits. Skin, hair texture and sweating were normal. The mental, cranial nerve and sensory examinations were normal. Mild to moderate weakness was symmetrically present in the proximal extremities with maximum involvement in the iliopsoas muscles, which did not have a full range of movement against gravity alone. There was a fine, rapid, irregular tremor of the outstretched fingers, and a slight action tremor. The muscles of the lower extremities were slightly tender to palpation. Deep tendon reflexes had a normal amplitude and a short latency. Bilateral Chvostek signs were present. Serum potassium was 3.8 mEq. per L. on admission. During the few hours after admission his strength improved gradually without treatment. The following laboratory values were normal during his first hospital admission : hemoglobin, hematocrit, white blood cell count and differential, reticulocyte count, platelet count, total eosinophil count, silicone clotting time, prothrombin time, serum iron and iron-binding capacity, three lupus erythematosus preparations, Venereal Disease Research Laboratory flocculation, serum sodium, serum chloride, serum bicarbonate, serum calcium, and serum magnesium, fasting blood glucose, blood urea nitrogen, serum creatinine, direct and total bilirubin, uric acid, cephalin flocculation, serum protein electrophoresis, alkaline phosphatase, serum glutamic pyruvate transaminase (32 units), serum glutamic oxaloacetic transaminase (21 units), lactic dehydrogenase (452 units), aldolase (10 to 14 units) and creatine phosphokinase (0.6 to 0.8 units), routine urinalysis and urine culture, and twenty-four hour urinary porphyrins, 17-ketosteroids and 17-hydroxycorticoids. The thymol turbidity of serum was 5 Shank-Hoagland units (normal 0 to 4 Shank-Hoagland units), and Westergren sedimentation rates varied from 17 to 27 mm. per hour (normal 0 to 15 mm. per hour for males). Studies of thyroid function: The initial serum protein-bound iodine was elevated to 13.5 gg. per cent and subsequent values before antithyroid therapy varied from 9.6 to 12.0 pg. per cent (normal range 4 to 8 pg. per cent). Serum thyroxine by column values was 7.9 and 8.4 pg. per cent before any treatment and 9.0 pg. per cent while he was receiving reserpine alone (normal range 3.2 to 6.4 pg. per cent). Radioactive iodine uptake in twenty-four hours was 54 per cent before treatment, and 45 and 41 per cent while he was receiving reserpine only (normal 15 to 45 per cent). The basal metabolic rate was f15 per cent before treatment and i-35 and +15 per cent while he was receiving reserpine. Roentgenographic examinations revealed no abnormality apart from a small, punctate calcification in the right upper quadrant of the abdomen, probably AMERICAN
JOURNAL
OF
MEDICINE
Thyrotoxic
Periodic
r~prcscnting renal lithiasie. and a linear calcification ui uncertain origin in the right gluteal region. An electrocardiogram with thr patient in a baseline state and the serum potassium normal revealed U waves and somewhat prominent ‘r waves. Elcctromyography of the right quadriceps muscle demonstrated an interference pattern of normal amplitude on maximal effort. The mean duration of 21 motor unit potentials waq 22 per cent reduced by Brichtlial Standards (more than 20 per cent reduction is ccmsiclercd abnormal). The left anterior tibia1 rnusclc produced a mixed to interference pattern of normal voltaye on maximal effort, with a reduction of .X per cent in thr mean duration of 29 motor unit potentials. ‘The left triceps muscle had a mixed pattern of slightly low voltage with maximal effort and a 27 1rcr cent reduction in the mean duration of 27 potrnCal<. Recruitment was not pathologically facile in anyrnuscl(.. The rlectromyographic examinations were iierformed \vith the patient in a baseline. nonattack state and the findings ~vere interpreted as showing mild non&agnostic abnormality. Motor conduction velocity in the right peroneal nerve was normal (56 metrrt per second). as was distal latency. Serum potassium determinations were obtained daily ;rt 8 A.M. and frequently also at 5 P.M. during his four weeks of hospitalization. Although slight weakness of scattered muscles was often present on examination. no spontaneous attack was observed during hospitalization. His serum potassium concentration ranged from 3.8 to 5.1 mEq. per L., \vith a mean of 1.5 mEq. per I,. On the two occasions when his potassium was 3.8 mEq. per L. there was no unusual weakness. ‘Total body potassium was 54.1 mE;q. per kg. as determined by a whole body counter unit ::normal range 41.3 to 57.4 mEq. per kg). On the sixth hospital day an attack was induced by glucohc-insulin infusion. Initially 100 gm. of glucose mixed wit11 10 units of regular insulin were given intravenously in 500 cc. of water over one hour. There \vas little response to the first infusion, so following a forty-five minute rest period a second infusion of 100 gm. glucose with 10 units insulin was given in 200 cc. water over a thirty minute period. The second infusion promptly initiated a profound and progressive decrease in both strength and serum potassium. At the point of maximal weakness the serum potassium level had fallen to 2.1 mEq. per L., and the electrocardiogram revealed flattening of the T waves and frequent premature ventricular contractions. Profound weakness developed in the iliopsoas ancl quadriccps muscles, which showed just a flicker of contraction, and in the right triceps muscle, which could contract through a full range of motion only with gravity eliminated. Neck and trunk flexors, right biceps, wrist extensors, ankle extensors and hand grips became moderately weak. A slow, intravenous drip of potassium chloride (28 mEq. potassium in four hours, in 5 per cent glucose) was begun, with gradual improvement in strength and elimination of premature “Or.
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NOVEMBER
1969
Paralysis-Resnick
et al.
FIG. 1. Depicted are results of the attempts to induce hypokalemic paralysis before and after treatment of hyperthyroidism with antithyroid agents. During each of the hvo periods indicated by shaded blocks on the diagram, 100 gm. glucose and 10 units insulin were given intravenously. Figures for hand strength are in arbitrary units taken from a dynamometer. Induction was succcssful during the hyperthyroid state and unsuccessful six months later when the patient was euthyroid. ventricular contractions. The time course of changes in serum potassium and hand strength are plotted in Figure 1; it can be seen that strength began to improve before the serum potassium level had fallen to its lowest value of 1.8 mEq. per L. The muscle biopsy specimen was obtained from the left quadriceps muscle two hours after it had been nearly totally paralyzed by the induced attack. Strength had only partially returned at the time of biopsy. Part of the specimen was paraffin-embedded for routine stains and part was fresh frozen and stained for twelve histochemical reactions as detailed elsewhere [7]. The biopsy specimen was virtually normal. The only minor abnormalities noted were occasional tiny muscle fibers. very dark with the oxidative enzyme reactions, rare medium-sized angulated fibers slightly darker with oxidative enzymes, one fiber being phagocytosed, and a mild atrophy of type II fibers as revealed by the fiber-diameter histogram. On the eleventh hospital day, after three days of preparation on a metabolic diet containing 109 mEq. sodium and not over 200 gm. of carbohydrate daily, the aldosterone secretion and metabolic clearance rates were determined by the methods of Peterson [8] and Tait [Q], respectively. No attacks of weakness occurred during the preparation or study days. Urinary aldosterone was measured by the method of Kliman and Peterson [TO]. Both the aldosterone secretion rate, which was 620 pg. per twentyfour hours (normal under 200 pg. per twenty-four
831
Thyrotoxic
Periodic
Fro 2. Spontaneous paralytic attacks occurred during treatment with reserpine but were eliminated by treatment with antithyroid agents. The values given for baseline muscle strength are in arbitrary units and each plotted point represents the summed totals of sixteen separate limb movements measured quantitatively on an isometric strain gauge. hours), and the metabolic clearance rate, which was 3,489 L. per twenty-four hours (normal 1,631 f 106 (S.E.) L. per twenty-four hours) were markedly elevated. Thus the calculated mean plasma aldosterone concentration was 18.2 mpg. per 100 ml. (normal 4 to 12 mpg. per 100 ml.). With the patient’s consent it was decided to treat the hyperthyroidism first with reserpine alone in sufficient dosage to lower the pulse rate to normal, and to note whether this had any effect on the periodic paralysis. Treatment was begun during the third week of hospitalization with total intramuscular doses of 0.6 and 2.0 mg. reserpine on the first and second day, respectively; none was given on the third day because of side effects (nausea, retching and postural hypotension). The oral administration of reserpine was begun on the fourth day of treatment and was continued for six weeks, initially at a level of 0.1 to 0.2 mg. per day. In the final three weeks it was found necessary to increase the amount to 0.3 mg. per day in order to keep the resting pulse stable at about 80. While the patient was taking reserpine his average pulse rate fell from 90 to 80 per minute, he felt calmer and gained 3 kg. in weight, but the fine tremor persisted and there was no lowering of the
et al.
Paralysis-Resnick
basal metabolic rate. Nasal congestion persisted throughout treatment. Spontaneous attacks of weakness continued during reserpine treatment (Fig. 2), usually mild and coming on two hours after his evening meal. In the sixth week of treatment a meal containing 200 gm. of carbohydrate was eaten in the hospital. One and a half hours later his serum potassium level had fallen from 4.1 to 3.3 mEq. per L., and three and a half hours after the meal he became moderately and asymmetrically weak. (Two previous attempts in the hospital to precipitate attacks with meals containing 135 and 150 gm. of carbohydrate had been unsuccessful while the patient was taking reserpine.) On December 31,1966, the patient began taking 15 mg. methimazole (Tapazole@) every eight hours, and reserpine therapy was discontinued on January 4, 1966. Propylthiouracil (PTU), 150 mg. every eight hours, was substituted for methimazole on January 20 because of an urticarial reaction, and by February 14 the dose of PTU had been reduced to 50 mg. every eight hours and has been maintained at that level since. Within two weeks of starting antithyroid medication the patient felt the cold weather more intensely, and in six weeks his fine tremor had disappeared. Attacks of spontaneous weakness ceased four weeks after methimazole therapy was started and have not recurred. After the patient became clinically euthyroid, protein-bound iodine levels ranged between 3.4 and 4.6 pg. per cent and two thyroxine by column values were 2.5 and 3.7 pg. per cent. When the patient had been on antithyroid treatment for over five months and had been free of episodic weakness for four months he was again challenged with an interrupted intravenous infusion of 200 gm. glucose and 20 units of regular insulin. This time no weakness developed and no change occurred in reflexes or in the electrocardiogram, although the serum potassium level fell from an initial value of 3.9 mEq. per L. to a low of 3.3 mEq. per L. (Fig. I). The aldosterone secretion rate and metabolic clearance were again determined by the same methods and had falIen to normal values of 172 pg. per day and 844 L. per day, respectively. Thus the calculated mean plasma aldosterone concentration was 20.4 mpg. per 100 ml. During the course of his illness and recovery the patient’s muscle power was recorded by means of an isometric strain gauge apparatus for quantitative muscle testing [II]. The scores plotted in Figure 2 represent the summed scores of sixteen separate upper and lower limb movements, such as hip flexion and shoulder abduction. Three weeks after thyroid suppression was begun there was a significant and sustained increase in baseline strength. COMMENTS
Reserpine stored
amines
induces in
AMERICAN
a release adrenergic JOURNAL
and nerve OF
depletion terminals, MEDICINE
of
Thyrotoxic therc.t))
Periodic
rcduc,iilg the manifestations of sympaous s\stc~n activity. When subjects wit11 I1) pcrth!,rc&1n arc treated with rcscrpine, palpitatio11. tach)-cardia. sweating, tremor and 11d rclrac1ion ark reduced or eliminated despite conti111lcd V~V\ atic of serum protein-bound iodine (.O11(.(‘1ltI-itlioi1 [inI. Until this report, no obscr\ ations 1~ t‘ bcru made to determine \vh(stl1cr lr(‘at1l1cl1t Lvith reserpine can eliminate attac,ks of hypokalemic~ periodic paralysis in One could patiakncss continued to occur and it was still possible to induce an attack of hypokalc111ic pc.rioclic paral>,sis with a carbohydrate load. The in~plicarion of these observations is tha1 Ii)-peracti\ i1y of the sympathetic nervous systnrl is 1101 an cbssential feature of the mecha1&n I)) which II!-pcrthyroidism predisposes ccrlain l)alicilTs TO hypokaleinic periodic paralysis. .\ uscsful confirlnalor)study would be to treat another patient \virh thyrotoxic periodic paral\.sis \vith yuanclhidinc. Iti our patient the aldosterone secretion and 1l1ctabolic. c~lcar;mctr rates were strikingly ele\,atc,d. according to a single observation, before ant lrcat11tc’tiT of his thyrotoxicosis; because bo;h were’ cle~a1cti /~ri passu the calculated 1nean plasma aldostcrone concentration was onlv 111odrratcl\- c*lc\.ated. The secretion raLe was 1tor1nnl a11cl lh(, 111etabolic clearance rate actu;Jly low aftc>r thyroid function had returned IO normal on PTL- therapy. As the result of thcasc chan~(,s the calculated mean plasma aldostc~ronc~ roncentration was not signific-antly diff-rc,nt after tr‘~aTillellt than it had been before treat1ncnt. .4 patient with thyrotoxic periodic paralysis described b)- Crane [13] also had an (slevatccl urinar!. aldostc,rone level before treat11tent. and 11or1nal excretion after treatlnent b) subtotal th\-roiclecro1nv. Campanacci ct al. i 141, ho\vc,\.er, found a normal value for aldosteronca cscretion before treatment in one case. Leutschcr ct al. 1751 studied four patients with hypcrtt1)~roidis1~l. Lvithout periodic paralysis. and fo1md thar the aldosterone sccrction rates thetic
INW
Paralysis
- -l&.rnickrt ai.
nornral in these patients; in two llir rric’labolic clearance rate was normal and in tcvo it was elevated. Accordingly, the n1can plasuta aldosterone concentrations ranged froll1 11or1nal to low values in those patients. As yet thcrr are too few observations in the literature tri allow clarification of the role of in thyrotoxic periodic paral>,&. aldosterone If the hepatic blood flow in our patic,nt was increased during the thyrotoxic period. ir could have accour1ted for the elevated clearance rate for which an increased secretory rate could have been compensatory. Whatever the explanation. the plasma concentration was the sa1nc as aStcr treatment when the metabolic clearance race had decreased to approxiinately a quarter of tl1r value durinq thyrotoxicosis. In idiopathic pcriodic paralysis studies of aldosteronc sccrction have likewise given inconsistent results 11’61. The question of whether aldosteronc play:5 a pathophysiologic role in idiopathic periodic paralysis 1771 remains unresolved [ Iti 1. Thrre was a dramatic change in our patient’s response to a glucose and insulin infusion after he became euthyroid (Fig. l), a result whirh confirms previous reports 121. It is held that the attacks arc accompaniccl by and paralytic probably caused by a shift of cxtraccllular potassium into muscle cells [ 781, althol1gh the: occurrence of such a shift is yet to 1~ dircrtl)proved. The success of glucose loadin? in l)rovoking attacks is thought to depend on its [VIIdency to initiate or magnify a shift of potassium into cells. It is interesting that sontc Orictnral thyrotoxic subjects with no history of pcr1odic paralysis inay ne\pcrtheless have an arrack of hypokalclnic periodic paralysis induced t)) glucose and insulin [2]. Despite thcsc gcilcaralitics about potassium shifts, our cxpcricncc~ with a number of patients having idiopathic, pcG)dic paralysis (nonthyrotoxir) has shown that t11crc. is not a qood correlation bctwccn 111~.scru1l1 potassium concrntration and the tic~rcc of weakness in all attacks of those patients. In o11r patient, during the first glucose-insulin pro~~bcation, strength began to itttprove after Ihc potassiu1n infusion was begun when the scr11tll potassium concentration was still falling (Fig. 1,J. .4 striking improvement in the gvnc.ral interattack muscle strength, 11leasurcd quantitativcl) with an isometric strain gauge apparatus, accompanied treatment of h>-pertIt!-roidism with antithvroid drugs (Fig. 2). It nlay t)e asked whether the inter-attack weakness was a c.hronic were
836
Thyrotoxic
Periodic
manifestation of the metabolic derangement that causes periodic paralysis, or whether it was due to the unrecognized superimposition of a thyrotoxic myopathy. Since thyrotoxic myopathy does not have specific histologic or histochemical stigmata [79], the patient’s muscle biopsy does not answer that question. Acknowledgment: Dr. Marvin C. Korengold referred the patient to us. Electromyography was performed by Drs. Wayne E. Tobin, Tillye Cornman and Frederic Q. Vroom. The aldosterone assays were carried out in the Endocrinology Branch, National Heart Institute, through the collaboration of Drs. Frederic C. Bartter and Warren W. Davis. Dr. Bartter also helpfully reviewed the manuscript. REFERENCES 1. OKINAKA, S.,SHIZUME, K., WATANABE, A., IRIE, M., NOGUCHI, A., KUMA, S., KUMA, K. and ITO, T. The association of periodic paralysis and hyperthyroidism in Japan. J. Clin. Endocrinol., 17: 1454, 1957. 2. MCFADZEAN, A. .I. S. and YEUNG, R. Periodic
paralysis complicating thyrotoxicosis in Chinese.
Brit. M. J., I: 451, 1967. 3. OKIHIRO, M. M. and NORDYKE, R. A. Hypokalemic periodic paralysis. Experimental precipitation with sodium liothyronine. J.A.M.A., 198: 949, 1966. 4. ENGEL, A. G. Thyroid function and periodic paralysis. Am. J. Med., 30: 327, 1961. 5. GAFFNEY, T-E., BRAUNWALD,E. and KAHLER, R. L. Effects of guanethidine on tri-iodothyronineinduced hyperthyroidism in man. New England J. Med., 265: 16, 1961. 6. CANARY, J. J., SCHAAF, M., DUFFY, B. J., JR. and KYLE, L. H. Effects of oral and intramuscular administration of reserpine in thyrotoxicosis. New England J. Med., 257: 435, 1957. 7. ENGEL, W. K. and BROOKE, M. H. Muscle biopsy as a clinical diagnostic aid. In: Neurological Diagnostic Techniques, pp. 90-146. Edited by Fields, W. S. Springfield, Ill., 1966. Charles C Thomas.
Paralysis-Resnick
et al.
8. PETERSON,R. E. The miscible pool and turnover rate of adrenocortical steroids in man. Recent Progr. Hormone Res., 15: 231, 1959. 9. TAIT, J. F., LITTLE, B., TAIT, S. A. S. and FLOOD, C. The metabolic clearance rate of aldosterone in pregnant and nonpregnant subjects estimated by both single-injection and constant-infusion methods. J. Clin. Invest., 41: 2093, 1962. 10. KLIMAN, B. and PETERSON,R. E. Double isotope derivative assay of aldosterone in biological extracts. J. Biol. Chem., 235 : 1639, 1960. 11. COLLIS, W. J., FRIED, D. M. and ENGEL, W. K. A new system for quantitating muscle strength. In preparation. 12. PUDENZ, R. H., MCINTOSH, J. F. and MCEACHERN, D. The role of potassium in familial periodic paralysis. J.A.M.A., 111: 2253, 1938. 13. CRANE, M. Periodic paralysis associated with hyperthyroidism. California Med., 92: 285, 1960. 14. CAMPANACCI, L., POLI, D., MASCHIO, G., ROMAGNOLI, G. F., MENDOLA, R. and MIONI, G. La paralisi muscolare periodica ipokaliemica. Studio clinice e metabolico di un case di paralisi periodica in torso di morbo di Basedow. Gior. clin. med., 47: 101, 1966. 15. LEUTSCHER,J. A., COHN, A. P., CAMARGO, C. A., DOWDY, A. J. and CALLAGHAN,A. M. Aldosterone secretion and metabolism in hyperthyroidism and myxedema. J. Clin. Endocrinol., 23: 873, 1963. 16. STREETEN, D. H. P. Periodic paralysis. In: The Metabolic Basis of Inherited Disease. Edited by Stanbury, J. B., Wyngaarden, J. B. and Fredrickson, D.S. New York, 1966. McGraw-Hill Publishing Co. 17. CONN, J. TN.,FAJANS,S. S., LOUIS, L. H., STREETEN, D. H. P. and JOHNSON, R. D. Intermittent aldosteronism in periodic paralysis: dependence of attacks on retention of sodium, and failure to induce attacks by restriction of dietary sodium. Lancet, 1: 802, 1957. 18. GROB, D. and JOHNS, R. J. Potassium movement in patients with familial periodic paralysis. Am. J. Med., 23: 356, 1957. 19. ENGEL, W. K. Diseases of the neuromuscular junction and muscle. In: Neurohistochemistry, pp. 622-672. Edited by Adams, C. Amsterdam, 1965. Elsevier Publishing Co.
AMERICAN
JOURNAL
OF
MEDICINE
Periodic
M.D., i JOE 11. DORMAN, Hethesda,
Paralysis* M.D. $ and \I’. KING
ENGEI..
ht.~.
Maryland
In an Uriental patient with thyrotoxic periodic paralysis, six weeks of therapy with reserpine alone returned the pulse rate to normal and reduced nervousness but did not prevent the attacks of periodic paralysis. These observations imply that hyperactivity of the sympathetic nervous system is not an essential feature of the mechanism I,) which hyperthyroidism predisposes certain patients to hypokalemic periodic paralysis. Prior to antithyroid treatment. aldosterone secretion and metabolic clearance rates were prominently elevated; after propylthiouracil therapy. both returned to normal. An intravenous glucose and insulin provocation test prior to antithyroid therapy produced striking hypokalemia and paralysis, but after antithyroid treatment an identical challenge failed to do so. The periodic paralysis disappeared on therapy \rith propvlthiouracil and baseline muscle strength rose remarkablv.
T
lowers the threshold for attacks of h)-pokalcrriic periodic paralysis in people who arc susceptible by virtue of a latent Inetabolic defect. On the other hand. patic-nts with idiopathic hypokalenlic periodic paralysis do not suffer IIWI‘~ frc,quent attacks \vhcn rendered thyrotoxic b\ administration of tri-iodothyroninc or thyroidstilnulatinq hornionc [J]. The Illechanisrn by which hypcrthyroidisln triggers periodic paralysis is not know-n. Son~e sy11ip:oms of hypcrth) roidislii ar? IIOW rccognized to be a rnanifcstation of excessive activit) of the synlpathctic nervous s)‘steln and CYIJI h alleviated by usr of adrenergic blocking agents. Reductioll or disappearance of palpitation, tachycardia, nervousness, trenlor and lid-lag has been observed in hyperthyroid subjects after treatnlent with guanethidinc [5] or reserpine [S], without reduction of the elevated proteinbound iodine or radioactive iodine uptake values. It has not been determined prcGously, however, whether adrenergic blockade will prevent episodic weakness in patients will1 thyrotoxic periodic paralysis. This report describes our observations in a patient with thyrotoxic periodic paralysis who was treated initially with reserpine alone and was noted to have no reduction in the occurrcncc of paralytic attacks. Treatment with spec,ific antithyroid drugs eliminated his attacks and was
periodic paralysis occurs as a complication of hyperthyroidisrn in a slllall proportion of Oriental patients [ 1,2], and orcasionally in C:aucasians. The paralytic attacks are rlinicallv identical with those observed in the idiopa&r type of hypokaleInic periodic paral!.sis, sharing the following features : lowcring of scrutn potassiulll often to subnornial \.alues> precipitation bl. excessive carboh>.drate loading or by rrst after exercise, flaccid and areHexic paral>-sis of skeletal rnusclc accompanied by electrical inexcitability of ~nusclc, responsivencss to trcatnlent with potassiunl salts, of \racuolization of 1nusc1c and dilatation sarcoplasnlic rcticulunl or T system. 111 thyrotoxir periodic paralysis, attacks nearly always cease when the hyperthyroidism leas been treated successfully but Inay recur if IIyperthyroidisnl escapes control. This phvnonlt~Ion is apparently not related to thyroidstirilulatinq horrtlone, as one patient who had been attack-free for SCVCII years after his hyperthyroitlisrr~ was treated successfully by surgery rxp?ricnced a rccurrenc‘e of hypokalemic paralysis when hr \.oluntaril>, took an excessi\Tc dose of tri-iodothyrollinc I,?]. 1 t is assumed that there cbxisrs a latent defect in such patients which beconies evident only in the presence of excessive rhyroid hornlone. Apparently, some as yet trndcfined asprct of the hyperthyroid state HYROTOXIC
* From the Medical Neurology Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health. Public Health Service. U. S. Department of Health. Education, and Welfare, Bethesda, Maryland 20014. Keyuests &r reprints should be addressed to Dr. 1%‘.King Engel at the Medical New&~); Branch. Manuscript rvceiwd December 17, 1968. t Prrst nt address: 125 Strawberry Hill Avcnuc, Stamford, Connecticut 06902. 1 Prrscnt address: Division of Neurology, Harbor General IIospital, Torrance, California 90505. vo,.
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832 followed muscular challenge
Thyrotoxic
Periodic
by striking changes in his baseline strength, response to a glucose-insulin and aldosterone secretion rate. CASE REPORT
The patient (NIH No. 06-42-39) was a thirty-six year old Cambodian male physician admitted for the first time in October 1965 to the Medical Neurology Branch, NINDB, of the National Institutes of Health, with the chief complaint of episodic weakness of three and a half weeks’ duration. He awoke one morning with mild weakness of the legs. The mild weakness persisted for days and became worse each evening after supper. He also noticed a discomfort in the medial aspect of both thighs, aggravated by certain movements. On a cool evening two weeks before admission he rode in an open convertible car just before retiring to bed at midnight and at 3 A.M. he awoke with severe weakness of the proximal leg muscles. This attack cleared partially over several hours, and the following morning he was admitted to a local hospital. Evaluation there disclosed weakness in the limbs and trunk with no abnormality of cranial nerves, sensory function, reflexes or sphincters. His serum potassium was 2.0 mEq. per L. His strength improved within hours after admission to the hospital on no therapy, and he was discharged five days later with advice to drink orange juice. His strength continued to improve gradually and two days before his admission to NIH he felt well enough to return to work. However, on the day of his admission to NIH he again awoke with weakness in the lower extremities which became more severe after a heavy lunch. Several times after the initial weakness had occurred the patient counted his pulse and found it to be between 100 and 140 beats per minute. One evening his pulse was rapid and irregular, and an electrocardiogram demonstrated multiple atria1 extrasystoles which disappeared after treatment with sodium pentobarbital. He had lost 3 kg. in weight in the three weeks before his admission to NIH although previous to that his weight had been stable. There had been no recent change in his heat tolerance. He used only one blanket at night and never wore sweaters. He denied increased prominence of the eyes, change in bowel habits or change in texture of skin or hair. He had been somewhat nervous all his life without definite recent increase. Past illnesses included, in addition to the usual childhood diseases, variola, malaria and amebic dysentery. He had been hospitalized previously for an appendectomy at age twenty-seven and a right pyelolithotomy at age thirty-five. His mother was half Siamese and half English and his father was Indoeuropean. There was no family history of thyroid or paralytic diseases with the exception of a distant cousin who died in her twenties with leg paralysis. Physical examination at the time of his first admission to NIH revealed an alert, moderately anxious
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Oriental with a regular pulse of 100 and blood pressure of 125/65 mm. Hg. There was a suggestion of prominence to the eyes, an inconstant slight lid-lag but no limitation of ocular motility. The thyroid gland was diffusely and slightly enlarged without bruits. Skin, hair texture and sweating were normal. The mental, cranial nerve and sensory examinations were normal. Mild to moderate weakness was symmetrically present in the proximal extremities with maximum involvement in the iliopsoas muscles, which did not have a full range of movement against gravity alone. There was a fine, rapid, irregular tremor of the outstretched fingers, and a slight action tremor. The muscles of the lower extremities were slightly tender to palpation. Deep tendon reflexes had a normal amplitude and a short latency. Bilateral Chvostek signs were present. Serum potassium was 3.8 mEq. per L. on admission. During the few hours after admission his strength improved gradually without treatment. The following laboratory values were normal during his first hospital admission : hemoglobin, hematocrit, white blood cell count and differential, reticulocyte count, platelet count, total eosinophil count, silicone clotting time, prothrombin time, serum iron and iron-binding capacity, three lupus erythematosus preparations, Venereal Disease Research Laboratory flocculation, serum sodium, serum chloride, serum bicarbonate, serum calcium, and serum magnesium, fasting blood glucose, blood urea nitrogen, serum creatinine, direct and total bilirubin, uric acid, cephalin flocculation, serum protein electrophoresis, alkaline phosphatase, serum glutamic pyruvate transaminase (32 units), serum glutamic oxaloacetic transaminase (21 units), lactic dehydrogenase (452 units), aldolase (10 to 14 units) and creatine phosphokinase (0.6 to 0.8 units), routine urinalysis and urine culture, and twenty-four hour urinary porphyrins, 17-ketosteroids and 17-hydroxycorticoids. The thymol turbidity of serum was 5 Shank-Hoagland units (normal 0 to 4 Shank-Hoagland units), and Westergren sedimentation rates varied from 17 to 27 mm. per hour (normal 0 to 15 mm. per hour for males). Studies of thyroid function: The initial serum protein-bound iodine was elevated to 13.5 gg. per cent and subsequent values before antithyroid therapy varied from 9.6 to 12.0 pg. per cent (normal range 4 to 8 pg. per cent). Serum thyroxine by column values was 7.9 and 8.4 pg. per cent before any treatment and 9.0 pg. per cent while he was receiving reserpine alone (normal range 3.2 to 6.4 pg. per cent). Radioactive iodine uptake in twenty-four hours was 54 per cent before treatment, and 45 and 41 per cent while he was receiving reserpine only (normal 15 to 45 per cent). The basal metabolic rate was f15 per cent before treatment and i-35 and +15 per cent while he was receiving reserpine. Roentgenographic examinations revealed no abnormality apart from a small, punctate calcification in the right upper quadrant of the abdomen, probably AMERICAN
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r~prcscnting renal lithiasie. and a linear calcification ui uncertain origin in the right gluteal region. An electrocardiogram with thr patient in a baseline state and the serum potassium normal revealed U waves and somewhat prominent ‘r waves. Elcctromyography of the right quadriceps muscle demonstrated an interference pattern of normal amplitude on maximal effort. The mean duration of 21 motor unit potentials waq 22 per cent reduced by Brichtlial Standards (more than 20 per cent reduction is ccmsiclercd abnormal). The left anterior tibia1 rnusclc produced a mixed to interference pattern of normal voltaye on maximal effort, with a reduction of .X per cent in thr mean duration of 29 motor unit potentials. ‘The left triceps muscle had a mixed pattern of slightly low voltage with maximal effort and a 27 1rcr cent reduction in the mean duration of 27 potrnCal<. Recruitment was not pathologically facile in anyrnuscl(.. The rlectromyographic examinations were iierformed \vith the patient in a baseline. nonattack state and the findings ~vere interpreted as showing mild non&agnostic abnormality. Motor conduction velocity in the right peroneal nerve was normal (56 metrrt per second). as was distal latency. Serum potassium determinations were obtained daily ;rt 8 A.M. and frequently also at 5 P.M. during his four weeks of hospitalization. Although slight weakness of scattered muscles was often present on examination. no spontaneous attack was observed during hospitalization. His serum potassium concentration ranged from 3.8 to 5.1 mEq. per L., \vith a mean of 1.5 mEq. per I,. On the two occasions when his potassium was 3.8 mEq. per L. there was no unusual weakness. ‘Total body potassium was 54.1 mE;q. per kg. as determined by a whole body counter unit ::normal range 41.3 to 57.4 mEq. per kg). On the sixth hospital day an attack was induced by glucohc-insulin infusion. Initially 100 gm. of glucose mixed wit11 10 units of regular insulin were given intravenously in 500 cc. of water over one hour. There \vas little response to the first infusion, so following a forty-five minute rest period a second infusion of 100 gm. glucose with 10 units insulin was given in 200 cc. water over a thirty minute period. The second infusion promptly initiated a profound and progressive decrease in both strength and serum potassium. At the point of maximal weakness the serum potassium level had fallen to 2.1 mEq. per L., and the electrocardiogram revealed flattening of the T waves and frequent premature ventricular contractions. Profound weakness developed in the iliopsoas ancl quadriccps muscles, which showed just a flicker of contraction, and in the right triceps muscle, which could contract through a full range of motion only with gravity eliminated. Neck and trunk flexors, right biceps, wrist extensors, ankle extensors and hand grips became moderately weak. A slow, intravenous drip of potassium chloride (28 mEq. potassium in four hours, in 5 per cent glucose) was begun, with gradual improvement in strength and elimination of premature “Or.
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1969
Paralysis-Resnick
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FIG. 1. Depicted are results of the attempts to induce hypokalemic paralysis before and after treatment of hyperthyroidism with antithyroid agents. During each of the hvo periods indicated by shaded blocks on the diagram, 100 gm. glucose and 10 units insulin were given intravenously. Figures for hand strength are in arbitrary units taken from a dynamometer. Induction was succcssful during the hyperthyroid state and unsuccessful six months later when the patient was euthyroid. ventricular contractions. The time course of changes in serum potassium and hand strength are plotted in Figure 1; it can be seen that strength began to improve before the serum potassium level had fallen to its lowest value of 1.8 mEq. per L. The muscle biopsy specimen was obtained from the left quadriceps muscle two hours after it had been nearly totally paralyzed by the induced attack. Strength had only partially returned at the time of biopsy. Part of the specimen was paraffin-embedded for routine stains and part was fresh frozen and stained for twelve histochemical reactions as detailed elsewhere [7]. The biopsy specimen was virtually normal. The only minor abnormalities noted were occasional tiny muscle fibers. very dark with the oxidative enzyme reactions, rare medium-sized angulated fibers slightly darker with oxidative enzymes, one fiber being phagocytosed, and a mild atrophy of type II fibers as revealed by the fiber-diameter histogram. On the eleventh hospital day, after three days of preparation on a metabolic diet containing 109 mEq. sodium and not over 200 gm. of carbohydrate daily, the aldosterone secretion and metabolic clearance rates were determined by the methods of Peterson [8] and Tait [Q], respectively. No attacks of weakness occurred during the preparation or study days. Urinary aldosterone was measured by the method of Kliman and Peterson [TO]. Both the aldosterone secretion rate, which was 620 pg. per twentyfour hours (normal under 200 pg. per twenty-four
831
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Fro 2. Spontaneous paralytic attacks occurred during treatment with reserpine but were eliminated by treatment with antithyroid agents. The values given for baseline muscle strength are in arbitrary units and each plotted point represents the summed totals of sixteen separate limb movements measured quantitatively on an isometric strain gauge. hours), and the metabolic clearance rate, which was 3,489 L. per twenty-four hours (normal 1,631 f 106 (S.E.) L. per twenty-four hours) were markedly elevated. Thus the calculated mean plasma aldosterone concentration was 18.2 mpg. per 100 ml. (normal 4 to 12 mpg. per 100 ml.). With the patient’s consent it was decided to treat the hyperthyroidism first with reserpine alone in sufficient dosage to lower the pulse rate to normal, and to note whether this had any effect on the periodic paralysis. Treatment was begun during the third week of hospitalization with total intramuscular doses of 0.6 and 2.0 mg. reserpine on the first and second day, respectively; none was given on the third day because of side effects (nausea, retching and postural hypotension). The oral administration of reserpine was begun on the fourth day of treatment and was continued for six weeks, initially at a level of 0.1 to 0.2 mg. per day. In the final three weeks it was found necessary to increase the amount to 0.3 mg. per day in order to keep the resting pulse stable at about 80. While the patient was taking reserpine his average pulse rate fell from 90 to 80 per minute, he felt calmer and gained 3 kg. in weight, but the fine tremor persisted and there was no lowering of the
et al.
Paralysis-Resnick
basal metabolic rate. Nasal congestion persisted throughout treatment. Spontaneous attacks of weakness continued during reserpine treatment (Fig. 2), usually mild and coming on two hours after his evening meal. In the sixth week of treatment a meal containing 200 gm. of carbohydrate was eaten in the hospital. One and a half hours later his serum potassium level had fallen from 4.1 to 3.3 mEq. per L., and three and a half hours after the meal he became moderately and asymmetrically weak. (Two previous attempts in the hospital to precipitate attacks with meals containing 135 and 150 gm. of carbohydrate had been unsuccessful while the patient was taking reserpine.) On December 31,1966, the patient began taking 15 mg. methimazole (Tapazole@) every eight hours, and reserpine therapy was discontinued on January 4, 1966. Propylthiouracil (PTU), 150 mg. every eight hours, was substituted for methimazole on January 20 because of an urticarial reaction, and by February 14 the dose of PTU had been reduced to 50 mg. every eight hours and has been maintained at that level since. Within two weeks of starting antithyroid medication the patient felt the cold weather more intensely, and in six weeks his fine tremor had disappeared. Attacks of spontaneous weakness ceased four weeks after methimazole therapy was started and have not recurred. After the patient became clinically euthyroid, protein-bound iodine levels ranged between 3.4 and 4.6 pg. per cent and two thyroxine by column values were 2.5 and 3.7 pg. per cent. When the patient had been on antithyroid treatment for over five months and had been free of episodic weakness for four months he was again challenged with an interrupted intravenous infusion of 200 gm. glucose and 20 units of regular insulin. This time no weakness developed and no change occurred in reflexes or in the electrocardiogram, although the serum potassium level fell from an initial value of 3.9 mEq. per L. to a low of 3.3 mEq. per L. (Fig. I). The aldosterone secretion rate and metabolic clearance were again determined by the same methods and had falIen to normal values of 172 pg. per day and 844 L. per day, respectively. Thus the calculated mean plasma aldosterone concentration was 20.4 mpg. per 100 ml. During the course of his illness and recovery the patient’s muscle power was recorded by means of an isometric strain gauge apparatus for quantitative muscle testing [II]. The scores plotted in Figure 2 represent the summed scores of sixteen separate upper and lower limb movements, such as hip flexion and shoulder abduction. Three weeks after thyroid suppression was begun there was a significant and sustained increase in baseline strength. COMMENTS
Reserpine stored
amines
induces in
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depletion terminals, MEDICINE
of
Thyrotoxic therc.t))
Periodic
rcduc,iilg the manifestations of sympaous s\stc~n activity. When subjects wit11 I1) pcrth!,rc&1n arc treated with rcscrpine, palpitatio11. tach)-cardia. sweating, tremor and 11d rclrac1ion ark reduced or eliminated despite conti111lcd V~V\ atic of serum protein-bound iodine (.O11(.(‘1ltI-itlioi1 [inI. Until this report, no obscr\ ations 1~ t‘ bcru made to determine \vh(stl1cr lr(‘at1l1cl1t Lvith reserpine can eliminate attac,ks of hypokalemic~ periodic paralysis in One could pati
INW
Paralysis
- -l&.rnickrt ai.
nornral in these patients; in two llir rric’labolic clearance rate was normal and in tcvo it was elevated. Accordingly, the n1can plasuta aldosterone concentrations ranged froll1 11or1nal to low values in those patients. As yet thcrr are too few observations in the literature tri allow clarification of the role of in thyrotoxic periodic paral>,&. aldosterone If the hepatic blood flow in our patic,nt was increased during the thyrotoxic period. ir could have accour1ted for the elevated clearance rate for which an increased secretory rate could have been compensatory. Whatever the explanation. the plasma concentration was the sa1nc as aStcr treatment when the metabolic clearance race had decreased to approxiinately a quarter of tl1r value durinq thyrotoxicosis. In idiopathic pcriodic paralysis studies of aldosteronc sccrction have likewise given inconsistent results 11’61. The question of whether aldosteronc play:5 a pathophysiologic role in idiopathic periodic paralysis 1771 remains unresolved [ Iti 1. Thrre was a dramatic change in our patient’s response to a glucose and insulin infusion after he became euthyroid (Fig. l), a result whirh confirms previous reports 121. It is held that the attacks arc accompaniccl by and paralytic probably caused by a shift of cxtraccllular potassium into muscle cells [ 781, althol1gh the: occurrence of such a shift is yet to 1~ dircrtl)proved. The success of glucose loadin? in l)rovoking attacks is thought to depend on its [VIIdency to initiate or magnify a shift of potassium into cells. It is interesting that sontc Orictnral thyrotoxic subjects with no history of pcr1odic paralysis inay ne\pcrtheless have an arrack of hypokalclnic periodic paralysis induced t)) glucose and insulin [2]. Despite thcsc gcilcaralitics about potassium shifts, our cxpcricncc~ with a number of patients having idiopathic, pcG)dic paralysis (nonthyrotoxir) has shown that t11crc. is not a qood correlation bctwccn 111~.scru1l1 potassium concrntration and the tic~rcc of weakness in all attacks of those patients. In o11r patient, during the first glucose-insulin pro~~bcation, strength began to itttprove after Ihc potassiu1n infusion was begun when the scr11tll potassium concentration was still falling (Fig. 1,J. .4 striking improvement in the gvnc.ral interattack muscle strength, 11leasurcd quantitativcl) with an isometric strain gauge apparatus, accompanied treatment of h>-pertIt!-roidism with antithvroid drugs (Fig. 2). It nlay t)e asked whether the inter-attack weakness was a c.hronic were
836
Thyrotoxic
Periodic
manifestation of the metabolic derangement that causes periodic paralysis, or whether it was due to the unrecognized superimposition of a thyrotoxic myopathy. Since thyrotoxic myopathy does not have specific histologic or histochemical stigmata [79], the patient’s muscle biopsy does not answer that question. Acknowledgment: Dr. Marvin C. Korengold referred the patient to us. Electromyography was performed by Drs. Wayne E. Tobin, Tillye Cornman and Frederic Q. Vroom. The aldosterone assays were carried out in the Endocrinology Branch, National Heart Institute, through the collaboration of Drs. Frederic C. Bartter and Warren W. Davis. Dr. Bartter also helpfully reviewed the manuscript. REFERENCES 1. OKINAKA, S.,SHIZUME, K., WATANABE, A., IRIE, M., NOGUCHI, A., KUMA, S., KUMA, K. and ITO, T. The association of periodic paralysis and hyperthyroidism in Japan. J. Clin. Endocrinol., 17: 1454, 1957. 2. MCFADZEAN, A. .I. S. and YEUNG, R. Periodic
paralysis complicating thyrotoxicosis in Chinese.
Brit. M. J., I: 451, 1967. 3. OKIHIRO, M. M. and NORDYKE, R. A. Hypokalemic periodic paralysis. Experimental precipitation with sodium liothyronine. J.A.M.A., 198: 949, 1966. 4. ENGEL, A. G. Thyroid function and periodic paralysis. Am. J. Med., 30: 327, 1961. 5. GAFFNEY, T-E., BRAUNWALD,E. and KAHLER, R. L. Effects of guanethidine on tri-iodothyronineinduced hyperthyroidism in man. New England J. Med., 265: 16, 1961. 6. CANARY, J. J., SCHAAF, M., DUFFY, B. J., JR. and KYLE, L. H. Effects of oral and intramuscular administration of reserpine in thyrotoxicosis. New England J. Med., 257: 435, 1957. 7. ENGEL, W. K. and BROOKE, M. H. Muscle biopsy as a clinical diagnostic aid. In: Neurological Diagnostic Techniques, pp. 90-146. Edited by Fields, W. S. Springfield, Ill., 1966. Charles C Thomas.
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8. PETERSON,R. E. The miscible pool and turnover rate of adrenocortical steroids in man. Recent Progr. Hormone Res., 15: 231, 1959. 9. TAIT, J. F., LITTLE, B., TAIT, S. A. S. and FLOOD, C. The metabolic clearance rate of aldosterone in pregnant and nonpregnant subjects estimated by both single-injection and constant-infusion methods. J. Clin. Invest., 41: 2093, 1962. 10. KLIMAN, B. and PETERSON,R. E. Double isotope derivative assay of aldosterone in biological extracts. J. Biol. Chem., 235 : 1639, 1960. 11. COLLIS, W. J., FRIED, D. M. and ENGEL, W. K. A new system for quantitating muscle strength. In preparation. 12. PUDENZ, R. H., MCINTOSH, J. F. and MCEACHERN, D. The role of potassium in familial periodic paralysis. J.A.M.A., 111: 2253, 1938. 13. CRANE, M. Periodic paralysis associated with hyperthyroidism. California Med., 92: 285, 1960. 14. CAMPANACCI, L., POLI, D., MASCHIO, G., ROMAGNOLI, G. F., MENDOLA, R. and MIONI, G. La paralisi muscolare periodica ipokaliemica. Studio clinice e metabolico di un case di paralisi periodica in torso di morbo di Basedow. Gior. clin. med., 47: 101, 1966. 15. LEUTSCHER,J. A., COHN, A. P., CAMARGO, C. A., DOWDY, A. J. and CALLAGHAN,A. M. Aldosterone secretion and metabolism in hyperthyroidism and myxedema. J. Clin. Endocrinol., 23: 873, 1963. 16. STREETEN, D. H. P. Periodic paralysis. In: The Metabolic Basis of Inherited Disease. Edited by Stanbury, J. B., Wyngaarden, J. B. and Fredrickson, D.S. New York, 1966. McGraw-Hill Publishing Co. 17. CONN, J. TN.,FAJANS,S. S., LOUIS, L. H., STREETEN, D. H. P. and JOHNSON, R. D. Intermittent aldosteronism in periodic paralysis: dependence of attacks on retention of sodium, and failure to induce attacks by restriction of dietary sodium. Lancet, 1: 802, 1957. 18. GROB, D. and JOHNS, R. J. Potassium movement in patients with familial periodic paralysis. Am. J. Med., 23: 356, 1957. 19. ENGEL, W. K. Diseases of the neuromuscular junction and muscle. In: Neurohistochemistry, pp. 622-672. Edited by Adams, C. Amsterdam, 1965. Elsevier Publishing Co.
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