Journal ofNeurology, , and 1982;45:1144-1146 Short report The forearm ischaemic work test - hazardous to McArdle patients?

HM MEINCK,* HH GOEBEL,t KW RUMPF,4 H KAISER,4 P NEUMANN§ From the Departments of , * Neuropathology, t Medicinet and Nuclear ,§ University of Gottingen, Gottingen, Federal Republic of Germany

SUMMARY A 57-year-old patient suffering from late-onset McArdle's disease developed myoglobinaemia, massive myoglobinuria and marked serum creatine kinase elevation subsequent to a routinely performed forearm ischaemic work test. Twenty hours after the test, enhancement of99mTc methylene-diphosphonate activity was demonstrated exclusively in the tested forearm. It is concluded that the forearm ischaemic work test is potentially hazardous to McArdle patients, as it might induce myoglobinuria sufficient to result in acute myoglobinuric renal failure.

The forearm ischaemic work test is established as a increased, and serum creatine kinase and levels useful tool for differentiating between remained high. Serum (normally with and without defects of anaerobic glycogenolysis below 195 gi/l) was observed between values of 163 and 263 and glycolysis. So far no dangerous effects of this test I/l. Repeated ECGs and tests of left ventricular function have We report a case of late-onset (measured scintigraphically by means of gated blood pool been described. imaging) were normal. McArdle's disease' (glycogenosis V2), in which Neurological examination revealed atrophy and paresis massive myoglobinaemia and myoglobinuria (degrees III to IV on the MRC scale) of the shoulder girdle developed subsequent to this test. By means of and proximal arm muscles including bilateral scapula conventional whole body bone scanning, local winging, and paresis of the ankle dorsiflexors. Deep tendon was demonstrated in the tested reflexes were brisk in the arms, but weak or lacking in the legs. forearm. Abdominal and plantar reflexes were normal, but the palmomental, glabellar, and snout reflexes were positive. Case report There was a stocking-like sensory loss for touch, pin-prick, and vibration in his legs, and ataxia was evidentwhen hestood A 57-year-old male patient complained of weakness and with his eyes closed. Orthodromic measurement of sensory rapid fatigue of his shoulder and arm muscles as well as conduction velocities (right sural and left median and ulnar intermittent claudication-like cramps in his legs in the four nerves) revealed no nerve compound action potentials. The years prior to admission (1980). Since 1979, elevated serum motor nerve conduction velocity of the right peroneal nerve creatine kinase (120-560 >/l, normal range: 2-70 1l) and was 40 m/s and distal motor latency 5 - 2 ms (both values creatinine (101-160 ,imol/l, normal range: 44-97 ,umol/l) abnormal), whereas in the left median nerve they were within levels were noted. Initially these complaints and symptoms the normal range. Electromyography of the shoulder and were ascribed to chronic arterial occlusive disease and proximal arm muscles revealed disseminated low-intensity alcoholic polyneuropathy, since the patient had been an fibrillation and positive sharp waves. Motor unit potentials alcoholic and a heavy smoker. There was no history of were on the whole normal, but there were a few shortened excretion of dark , of myoglobinuria, or of acute renal (2-5 ms) as well as polyphasic and prolonged (15-30 ms) failure, nor was there any evidence of exercise-induced potentials as well. In the ankle dorsiflexors, typical and contractures. In retrospect, however, a typical "second wind" distinct signs of a neurogenic alteration were observed. These phenomenon was described. There was no relevant family findings were interpreted as indicating an alcohol history. In March 1980, the patient underwent abdominal polyneuropathy plus either a toxic shoulder girdle for duodenal ulcer, and did not drink alcohol amyotrophy, or a spinal muscular atrophy. In order to exclude thereafter. However, his complaints of muscular weakness chronic regional alcohol rhabdomyolysis as a possible cause of serum creatine kinase elevation, a whole body 99mTc scan was which Address for reprint requests: Dr HM Meinck, Abt f klinische methylene-diphosphonate performed yielded Neurophysiologie, Neues Klinikum, 3400 Gottingen, FRG. no abnormal findings. Biopsies from the biceps and quadriceps muscles revealed increased fibre diameter, rare Received 2 April 1982 and in revised form 20 June 1982. phagocytosis within muscle fibres, rimmed vacuoles, and Accepted 6 July 1982. vacuoles located in the periphery of several muscle fibres. 1144 The forearm ischaemic work test - hazardous to McArdle patients? 1145 Scanty fibre type grouping and angulated type II b fibres suggested a neurogenic component probably due to a mild alcohol polyneuropathy. Histochemical examination (PAS stain) revealed that glycogen had only lightly accumulated. However, amylophosphorylase activity was absent from fibres of both biopsies, though not from smooth muscle fibres of intramuscular arterial walls, which indicated the validity of the phosphorylase preparations. With electron microscopy, abundant free cytoplasmic glycogen was present beneath the sarcolemma and among myofibrils. There was considerable attenuation ofsarcomeres in several muscle fibres as well as empty loops ofbasal laminae indicating muscle fibre atrophy. Biochemically, phosphorylase activity in fresh frozen muscle tissue was 0-08 ,Lmol GIP/min/g as compared to 21P9 ± 5-5 (SD) in 44 controls (assay by courtesy of S. DiMauro, MD, Columbia University, New York City), indicating virtual absence of phosphorylase activity in the muscle. Because of these biochemical, enzyme-histochemical and electron microscopic findings, phosphorylase deficiency was diagnosed. The ischaemic work test was performed on the right forearm. A sphygmomanometer cuff attached to the right arm was inflated to above systolic blood pressure, and a rubber ball was rhythmically pressed to about 1 bar with the right hand at a rate of 1 per second. Blood samples were taken from the right antecubital vein before ischaemia and at 0, 1, 2, 3, 5, 10, and 20 minutes after deflating the cuff. Normal subjects are easily capable of performing this manoeuvre for one minute. However, after 40 seconds of ischaemic exercise, the patient developed a contracture ofhis right forearm which

Myoglobin in urine -2500 3 6 Betore schemia 150 ng/ml 3 6 1315- 2200 29660 ng/mi 31/456 22 9°O 642 ngAnl 2000- 5.6 <4 ng/ml

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>1 E 10001 9 El 1000~ (B) a) Fig (A) Course ofserum (top) and serum --O creatine kinase (bottom) levels after theforearm ischaemic 100 L work test. Myoglobin levels in urine are given in the top Normal range right inset. Note the log scalefor serum creatine kinase. Testperiod is indicated by the shaded vertical bar. Border 100000 n ofnormal range is indicated by a horizontal broken line. (B) 99m Tc methylene-diphosphonate whole body scan 912 D 20 hours after theforearm ischaemic work test showing 1000 v enhanced radiotracer activity in the rightforearm. A detailed investigation ofthe rightforearm showed E CD radiotracer labelling particularly ofthe longfingerflexors. V)ina) 1U I lasted for 20 minutes. The characteristic normal increase of NormalIr'ange the serum lactate level in the venous blood of the right forearm was lacking. In normal subjects, serum myoglobin levels remain constant during and after the test. However, in (U10n - 0' 5' 1020' the patient serum myoglobin (determined by means of a

(A) 3681 46 81 6681 96fE81 radioimmuno-assay3) began to increase about 10 minutes 1146 Meinck, Goebel, Rumpf, Kaiser, Neumann after deflating the cuff, and excessive myoglobinuria was concentrations in urine would have most probably observed during the subsequent night (fig A). In order to increased to substantially higher levels. prevent renal failure due to myoglobinuria, the patient was instructed to drink at least 3 1 per day in the following days, The forearm ischaemic work test must therefore be and serum creatinine levels remained in the pre-test range considered potentially hazardous to McArdle patients. during the next week. The serum creatine kinase initially Therefore renal function as well as creatine kinase and remained at the pre-test level, too, but the following morning myoglobin levels should be carefully checked after this was found to be about 10 000 ,u/l. Both myoglobinuria and test. A sufficient diuresis should be induced, simply by increased serum creatine kinase fell to the base line levels in prescribing large quantities of water. In addition, a the following days, the creatine kinase showing a delayed ketogenic diet possibly prevents rhabdomyolysis and decline. creatine kinase elevation after the test in McArdle Because of suspected iatrogenic rhabdomyolysis due to the patients8. forearm ischaemic work test, a whole body scan was performed about 20 hours after the test. A distinct enhancement of 99Tc methylene-diphosphonate was found to The authors are indebted to Ms U Spaar and to Ms K be restricted to the musculature of the right forearm (fig B). Thater for skillful technical assistance, and to Mr R Six weeks later, a scan showed normal distribution of the Krebs for revision of the English text. This work was tracer. supported in part by the Deutsche Forschungs- gemeinschaft (SFB 33 and SFB 89). Discussion From these results it seems that local rhabdomyolysis in the right forearm and subsequent myoglobinuria were induced by the ischaemic work test. As our References patient exhibited the typical features of late-onset McArdle's disease, 145 Engel WK, Eyerman EL, Williams HE. Late-onset type muscle phosphorylase of skeletal-muscle phosphorylase deficiency. New Engl deficiency is most likely the basis for iatrogenic J Med 1963;268: 135-7 rhabdomyolysis. However, one might speculate as to 2 McArdle B. due to a defect in muscle glycogen whether his previous alcoholism played an additional breakdown. Clin Sci 195 1;10: 13-35 role in the pathogenesis of myophosphorylase 3Rosano TG, Kenny MA. A radioimmunoassay for human deficiency and local rhabdomyolysis in our patient. serum myoglobin. Method development and normal Although alcoholism may impair muscle values. Clin Chem 1977;23:69-75 phosphorylase activity (see ref 6), virtual absence- 4 Kost GJ, Verity MA. A new variant of late-onset myophosphorylase deficiency. Muscle Nerve 1980; enzyme-histochemically as well as biochemically-of 3:195-201 phosphorylase activity from striated muscle, as well as Mastaglia GC, McCollum JPK, Larson PF, Hudgson P. the fact that the patient had not consumed alcohol Steroid myopathy complicating McArdle's disease. since his abdominal surgery one year prior to the J Neurol Neurosurg Psychiatry 1970;33:111-20 biopsies, militate against his phosphorylase deficiency 6 Penn A. Myoglobin and myoglobinuria. In: Vinken PJ, as being due to chronic alcoholism. However, an Bruyn GW, eds. Handbook of Clinical . additional sensitisation of the primarily diseased vol. 41, Amsterdam: Elsevier, 1979:259-85 muscle metabolism is possible. DiMauro S. Metabolic myopathies. In: Vinken PJ, Generally, the forearm ischaemic work test is well Bruyn GW, eds. Handbook of Clinical Neurology. tolerated, and the outcome vol. 41, Amsterdam: Elsevier, 1979:175-234 of this diagnostic Kula RW, Brumback RA, Engel WK, Line BR. Ischemic procedure in our patient contrasts with its apparently contracture in muscle phosphorylase deficiency: clinical good tolerance even by McArdle patients. However, it scanning and histochemical and autoradiographic must be remembered that more than 50% of McArdle studies. Neurology (Minneap) 1977;27:401-2 patients show myoglobinuria, and renal failure due to 9 Swift TR, Brown M. Tc-99m pyrophosphate muscle myoglobinuria was reported in 8%.7 Moreover, Kula labelling in McArdle syndrome. J Nucl Med 1978;19: et al8 and Swift and Brown 9 reported signs of focal 295-7 rhabdomyolysis and creatine kinase elevations after Rumpf KW, Kaiser H, Matthaei D et al. Akutes Nieren- the ischaemic work test, but did not follow myoglobin versagen bei Alkoholmyopathie. Dtsch Med Wschr in serum 1979;104:736-42 levels and urine. Our case report shows that "Llach F, Felsenfeld AJ, Haussler MR. The pathophysiology myoglobinuria and serum creatine kinase might of altered calcium metabolism in rhabdomyolysis- increase after the test to levels at which-particularly induced acute renal failure. New Engl J Med 1981; under unfavourable circumstances such as 305:117-23 dehydration or low urinary pH-acute myoglobinuric 12 Siegel BA, Engel WK, Derrer EC. 99mTc-diphosphonate renal failure might occur.61011 Moreover, ifour patient uptake in skeletal muscle: a quantitative index of acute did not drink large quantities of water, myoglobin damage. Neurology (Minneap) 1975; 25:1055-8