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Arch Dis Child: first published as 10.1136/adc.46.249.594 on 1 October 1971. Downloaded from

Archives of Disease in Childhood, 1971, 46, 594.

Idiopathic D. C. L. SAVAGE, MEHROO FORBES*, and G. W. PEARCE From the Department of Child Health, Dundee University; and the Department of Pathology, Newcastle General Hospital, Newcastle upon Tyne

Savage, D. C. L., Forbes, M., and Pearce, G. W. (1971). Archives of Disease in Childhood, 46, 594. Idiopathic rhabdomyolysis. The clinical, biochemical, and pathological findings in 2 children with idiopathic rhabdomyolysis are reported. Hypocalcaemic tetany, a previously unrecognized complication of severe muscle damage, was seen in one child and was associated with hyperphosphataemia and hyperphosphaturia consequent on the rhabdomyolysis. Respiratory distress and an acute tubular necrosis contributed to her eventual death. The second child recovered; an intracellular granular material of unknown nature was seen in his muscle biopsy on electron microscopy. The literature of idiopathic recurrent rhabdomyolysis occurring in childhood is reviewed. Idiopathic rhabdomyolysis, which may be re- with 72 mg/100 ml. contained a trace current, is a rare and potentially lethal disorder of of sugar and ketones. , not previously recorded in the The child died shortly after admission to hospital, and copyright. British paediatric literature. Two forms of the death was recorded as being due to diabetic . At necropsy no abnormality was found; muscle tissue disease have been described: Type I usually pre- was not examined. In retrospect the CSF glucose ceded by physical exertion, and Type II often level makes this diagnosis untenable and it is probable associated with mild infections. Both are charac- that this child died from a similar disease to that of terized by rhabdomyolysis and , her sister (Case 2). and death may result from the immediate hyper- kalaemia or later from respiratory muscle paralysis Case 2. This 14-month-old child was admitted or renal tubular necrosis. The aetiology is in December 1967. Previously in excellent health, http://adc.bmj.com/ unknown and the term probably embraces a number she had for a few days a mnild upper respiratory tract of distinct entities. This paper reports two chil- infection. On the morning of admission she had on dren with Type II rhabdomyolysis and includes a waking appeared unwell, and her condition rapidly third child, the sister of one of them, who died- deteriorated. On examination there was respiratory distress and she was in circulatory failure, with cyanosis probably from the same disease. of the lips and extremities. No other abnormality was noted.

Case Reports Chest x-ray clear; CSF-no abnormality; Hb 11 g/ on September 29, 2021 by guest. Protected Case 1. This 3j-year-old girl was admitted in 100 ml, WBC 20,000/mm', neutrophil leucocytosis; November 1964. Previously in excellent health she ESR 7 mm/hr; plasma 45 mg/100 ml; plasma had had for two days, a mild upper respiratory tract sodium, potassium, chloride, and CO2 were 131, 6-3, infection. On the morning of admission to hospital 104, and 17 mEq/l., respectively. pH 7-26; base she complained on waking of in her limbs and there deficit minus 9; Pco2 37 mmHg; blood glucose 115 mg/ was difficulty in walking. Within an hour she could 100 ml; ketones positive; plasma cortisol 83-5 pg/100 not move her legs and her general condition deteriorated ml. Urine: dark red-brown in colour, chemically so rapidly that she appeared moribund. positive for blood, glucose, ketones, and protein; WBC 25,000/mm3, neutrophil leucocytosis; plasma SG 1020; pH 5. On microscopy, numerous fine potassium 6- 2 mEq/l., CO. content 18 mEq/l. Plasma needle-shaped crystals were present; no cells or bacilli urea and other were normal; CSF normal were seen. It was suspected that the child had a septicaemia with Received 8 March 1971. haemolysis and haemoglobinuria. Therapy included *Present address: Congenital Anomalies Research Unit, Depart- intravenous fluids, with immediate correction of the inent of Child Health, University of Sheffield. metabolic acidosis, antibiotics, and steroids. By 594 Arch Dis Child: first published as 10.1136/adc.46.249.594 on 1 October 1971. Downloaded from

Idiopathic Rh&zbdomyolysis 595 evening obvious carpopedal was present. quadriceps under local anaesthesia 48 hours after Chvostek's sign was positive and serum calcium 2 7 admission. The muscle was noted to be extremely mEq/1. Calcium gluconate intravenously lessened pale (Mr. W. A. F. McAdam). Local anaesthesia was but did not eradicate the tetany (Fig. 1). used as there are reports of rhabdomyolysis after general anaesthesia (Herzberg, Michener, and Kiser, 1967; Bowden et al., 1956; Haase and Engel, 1960). Over the next few days there was severe respiratory difficulty. The child's diaphragm appeared paralysed, and respirations were rapid and laboured. In addition there was a generalized and extreme muscle . Throughout this period, though no further myoglobi- nuria was detected, serum muscle enzymes remained high. On the sixth day of the illness, the serum aldolase was 14 units and the creatine phosphokinase 5800 units. Her did not settle and a persistent paralytic ileus necessitated continuous intravenous therapy; apart from a transitory hypokalaemia no further or acid-base disturbance occurred...... During the second week of her illness her condition S~~~~~~~~~~~~~~~~~~~~~. slowly deteriorated. The kidneys became firmly enlarged and macroscopical haematuria developed. On urinary microscopy numerous casts and red blood cells were seen and macroscopical flecks of a brown material, thought to be a mixture of , protein, and cellular debris, appeared in her urine. The urinary output remained satisfactory, though the specific gravity became fixed at 1010; slight and obvious persisted. On the eleventh day of her illness blood and urine cultures grew Escherichia copyright. FIG. 1.-Carpopedal spasm and myoglobinuria. coli. Despite intensive therapy she died suddenly on the fourteenth day of her illness. The following morning the urine, now alkaline, was No cytopathic agent was found on virus studies of still a dark brown colour; the previously noted needle- faeces, blood, and CSF. shaped crystals were no longer present. Investigations: The parents of these two sisters were not consan- plasma urea 54 mg/100 ml; plasma sodium, potassium, guineous and their serum muscle enzymes were normal. and CO2 were 138, 4-6, and 27 mEq/l., respectively; There was no known muscle disease on either side of 7- base excess+3; blood glucose 120 100 ml; the family and there were no other children in the family. pH 46; mg/ http://adc.bmj.com/ serum calcium 3 4 mEq/l.; serum phosphate 4- 3 mEq/l.; blood culture: sterile. Blood spectroscopy: Case 3. This 7-year-old boy was admitted in no abnormality noted. Urine spectroscopy: metmyo- March 1968 with a seven-day history of 'influenza'. globin and oxymyoglobin detected; haemoglobin not Two days before admission he complained of present (Miss J. Bowden). Porphyrins and urobilino- behind his knees and in his thighs. His mother noticed gen were absent from the urine. that his urine became dark brown during this time. Now that the urinary pigment was recognized the He was admitted to hospital because of increasing pain probable diagnosis appeared to be idiopathic rhabdo- in his legs and inability to walk. He had not been myolysis. The following investigations supported this. seriously ill in the past, and there was no family history on September 29, 2021 by guest. Protected Serum aspartate aminotransferase 100 units (normal of muscle disease. His parents were not consangui- <40 units); serum alanine aminotransferase 800 units neous and both they and a sib were alive and well. (normal <40 units; aldolase 217 units (normal <4 units); On admission he was pale and unwell. Both thighs lactic dehydrogenase 1730 units (normal <300 units); were considerably swollen and exquisitely tender on hydroxybutryric dehydrogenase 3600 units (normal palpation. There was pain on handling his calves and < 150 units); creatine phosphokinase 3500 units also the muscles of the upper arms. Movements in all (normal <60 units). During the first three days limbs were poor and he was unable to raise his legs; urinary amino acids showed an obvious increase in both feet were extended in plantar flexion (Fig. 2). taurine and ,-amino-isobutyric acid (Dr. J. Mellon). Examination was otherwise normal. Electrophoresis of the urine confirmed the presence of Routine investigations were essentially normal but myoglobin (Dr. J. Rae). The muscles, particularly there was a neutrophil leucocytosis and the sedimenta- those of the legs and upper arms, were tender and tion rate was raised. The serum calcium was low at swollen and it was now appreciated that it was because 4 - 0 mEq/l. Unfortunately phosphate was not of this that the child lay so still and disliked being measured and there were no further estimations of touched. Muscle biopsy was taken from the right serum calcium. The urine was smoky and was chemi- Arch Dis Child: first published as 10.1136/adc.46.249.594 on 1 October 1971. Downloaded from

596 Savage, Forbes, and Pearce striking feature was a haphazard focal necrosis of muscle fibres (Fig. 3). A few fibres appeared swollen, with loss of cross striation and poor staining reaction (Fig. 4). Others were fragmented or in the process of phago- cytosis. There was extensive necrosis in the diaphragm, intercostals, and quadriceps, but only focal lesions in the sternomastoid muscles. There was no replace- ment of muscle by or fibrous tissue and no sarco- plasmic basophilia or vesicular nuclei with prominent nucleoli to indicate regeneration. Staining with Azur B for RNA was negative. Inflammatory infiltrate was limited to an occasional polymorph or lymphocyte.

}. ~~~~~~~~~~~~~~~~~~~~~~...... Muscle spindles, peripheral nerves, and blood vessels all appeared normal. Enzyme histochemistry showed no abnormality of acid phosphatase, phosphorylase, adenosintriphosphatase or lactic, malic, and succinic dehydrogenase. Kidneys. Macroscopically both kidneys were en- larged and swollen. They weighed 80 g each, more than twice the normal weight for a child of 14 months. The subcapsular surface showed numerous petechial haemorrhages and the cortex was pale and increased in width while the medulla was intensely congested. Calyces and pelvis were filled with a reddish-brown granular material. Microscopically there were the features of acute distal tubular necrosis. The glomeruli showed no FIG. 2.-Case 3. Feet in plantar flexion, thighs swollen abnormality. A few proximal convoluted tubules

were dilated and some of them contained a little hyaline copyright. cally positive for blood and albumin. On microscopy material. Distal tubules showed various stages of no cells were seen. Spectroscopy showed the pigment degeneration. There was dilatation of the lumen and to be myoglobin. The serum aspartate aminotrans- flattening ofthe epithelium with cytosplasmic basophilia, ferase was 1270 units; alanine aminotransferase 370 prominent nuclei, and an occasional mitotic figure. units; creatine phosphokinase over 6000 units; aldolase The lumina of these tubules were filled with desqua- 95 units; EMG and conduction studies: 'nerve conduc- mated cells, polymorphs, and an occasional cast. tions are normal: needle EMG showed high frequency Collecting tubules were full of granular and pigment low voltage polyphasic units suggestive of a polymyositis' casts. (Dr. J. A. R. Lenman). Muscle biopsy was taken from tissue an inflammatory http://adc.bmj.com/ the left two weeks after the onset of the child's The interstitial showed thigh infiltrate which was particularly prominent at the cortico- illness. medullary junction and consisted of neutrophil poly- The level of enzymes in the blood slowly returned to leucocytes, lymphocytes, and plasma and the child made an uninterrupted recovery. morphonuclear normal cells. The arteries in all the sections examined appeared was from three weeks after the He discharged hospital normal but many small veins were partially occluded by onset of the illness with no evidence of any residual thrombus. An occasional tubulo-venous or He has remained well. organizing paralysis. anastomotic lesion was present (Fig. 5). Intravascular was seen in the vasa recta of the medulla. Pathological Data haemopoiesis on September 29, 2021 by guest. Protected Case 2. The most striking feature of the renal histology was Muscle biopsy. This was taken from the right the number and variety of the pigment casts occluding quadriceps two days after admission. Histological distal and collecting tubules and lying free in the pelvis. findings were identical with those found in the muscle The casts were in a variety of shapes-balls, chains, at necrospy and described below. crystals, and many were clearly laminated in appearance Necropsy. This was performed 7 hours after death. (Fig. 6). An attempt was made to define the exact Significant pathological findings were confined to the composition of the casts by a variety of histological skeletal muscles and the kidneys. methods. These included the special methods for the Muscles. All the muscles were pale. Portions of demonstration of fibrin at all ages and also special the quadriceps, intercostals, diaphragm, and sterno- combination stains suitable for the (Lendrum mastoid were fixed in 10% buffered formalin for light et al., 1962; Lendrum, Fraser, and Slidders, 1964) microscopy and fresh frozen for enzyme histochemistry. together with the Amido black method for haemoglobin Microscopically the fibres showed little variation in size (Puchtler and Sweat, 1962). These confirmed that the throughout each section of muscle examined (i.e. casts contained old and recent deposits of fibrin, 12-20 I,u average 16 u, normal for age). The most haemoglobin, myoglobin, and derivatives. Arch Dis Child: first published as 10.1136/adc.46.249.594 on 1 October 1971. Downloaded from

Idiopathic Rhabdomyolysis 597

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FIG. 3.-Case 2. Quadriceps showing stippled areas offocal necrosis. (Phosphotungstic acid haematoxylin. x 670.)

Case 3. with fibrils fused together and only fragments of dis- Muscle biopsy. A biopsy was taken from the right organized Z-bands remaining; interfibrillar structures quadriceps 12 days after admission when the myo- including mitochondria were then absent. Below the globinuric episode had subsided and muscle pain was sarcolemma and between the myofibrils of many less severe. The biopsy was divided into four fragments regions there was an accumulation of amorphous which were fixed in formol corrosive for light micro- material of irregular shape without a limiting membrane http://adc.bmj.com/ scopy, frozen by liquid hexane for enzyme histo- which was particularly concentrated in areas of myo- chemistry, fixed in glutaraldehyde for electronmicro- fibrillar loss. Occasional large subsarcolemmal collec- scopy studies, and frozen at -20 °C for biochemistry. tions of this material were present where there was local Microscopically sections stained with H. and E. elevation of the sarcolemma (Fig. 7). Identification of PAS, PTAH and picro-Mallory showed no significant this material has not been achieved and apparently it abnormality. There was no evidence of muscle fibre is morphologically similar to that reported by Scarpelli, regeneration and Azur B staining failed to demonstrate Greider, and Frajola (1963) who described it as 'necrotic

RNA. Enzyme histochemistry also showed no abnor- sarcoplasm' and commented upon the absence of myo- on September 29, 2021 by guest. Protected mality of acid phosphatase, phosphorylase, adenosintri- fibrils in such areas. This substance does not appear phosphatase oxylactic, malic, and succinic dehydro- to be artefact but could be coagulated proteinaceous genase. material. Hampers and Prager (1964) found round Electron microscopy. Small selected blocks of tissue bodies which contained particles resembling . were removed from the biopsy and fixed in ice-cold Mitochondria varied considerably in appearance with 5% glutaraldehyde in cacodylate buffer 0-1 M for 4 many showing little definite change but others were hours with subsequent fixation in 10% osmium tetroxide enlarged and excessively round with a considerable for 1 hour. After alcohol araldite embed- loss of internal cristae. The sarcolemma was remarkably ding was carried out. Sections were cut on an LKB well preserved and sarcoreticulum and T-tubules showed Ultrotome, and stained with lead citrate. The muscle no change other than local loss of their normal relation fibre myofibrils showed a variety of changes varying to myofibrils where these structures were severely from Z-band irregularity or slight myofibrillar loss to changed or lost. Nuclei were also normal morphologi- almost complete loss of the constituent myofilaments. cally. Small groups of RNA-like particles were Adjacent myofibrils were often morphologically normal. occasionally found related to myofibril damage and may In a few regions all muscle fibre architecture was lost, represent a regeneration response to injury. Arch Dis Child: first published as 10.1136/adc.46.249.594 on 1 October 1971. Downloaded from

598 Savage, Forbes, and Pearce copyright. FIG. 4.-Case 2. Quadriceps showing swollen fibres in various stages of degeneration with loss of cross striations. (Phosphotungstic acid haematoxylin. x 1500.)

Discussion tained oxygen and allowing a continuance of the The main intracellular constituents of muscle are much more efficient oxidative breakdown of lactate, protein, glycogen, potassium, and phosphorus. pyruvate, and similar metabolites (Adams, Denny-

The immediate result of rhabdomyolysis is libera- Brown, and Pearson, 1962). http://adc.bmj.com/ tion of these substances into the plasma, causing Both myoglobin and haemoglobin impart a red- constitutional and biochemical abnormalities. brown colour to the urine, and give positive results on standard testing for the presence of blood in Myoglobin. Among the muscle proteins is urine. To distinguish these two pigments the the pigmented myoglobin which is present in the simplest, but not the most reliable, method is the sarcoplasm of striated muscle fibres and gives the ammonium sulphate precipitation test, in which at dark red brown colour to the urine in acute muscle 80% concentration of ammonium sulphate, haemo- necrosis. Myoglobin is an iron protein compound globin precipitates while myoglobin does not on September 29, 2021 by guest. Protected and in structure it is very similar to haemoglobin, (Blondheim, Margoliash, and Shafrir, 1958). Spec- being a combination of proto-porphyrin, iron, and a trophotometry is more specific, but since the absorp- specific globulin. Haemoglobin has four Fe atoms tion spectra of oxyhaemoglobin and oxymyoglobin per molecule and a molecular weight of 68,000, as are very similar, difficulties may arise. Electro- compared with myoglobin which has a molecular phoresis or ultracentrifugation are perhaps the most weight of 17,500 and contains only one Fe atom. specific methods available. The chief function of myoglobin is that of a very A normal coloured plasma in the presence of a temporary oxygen storehouse. It is not absolutely urine which is benzidine-positive is suggestive of essential to muscle function, since the cytochromes myoglobinuria. This is because the degree of can assume its role in the presence of an adequate binding, and therefore renal clearance of haemo- supply of oxygen. However, during brief periods globin and myoglobin, is very different. Free of relative muscle anoxia, myoglobin reduces the extracorpuscular haemoglobin arises at a plasma need for glycolytic processes by releasing its con- concentration above 125 mg/100 ml, but unbound Arch Dis Child: first published as 10.1136/adc.46.249.594 on 1 October 1971. Downloaded from

Idiopathic Rhabdomyolysis 599 copyright.

/- FIG. 5.-Case 2. Kidney: showing tubulo-venous anastomosiis. The tubule is surrounded by organized thrombus and has

herniated through the wall ofa small veini. (Haematoxylin and eosin. x 200.) http://adc.bmj.com/ E, Endothelium of vein. T, Tubule with flattened epithelium. F, Fibrin thrombus. G, . myoglobin at a concentration of only 25 mg/100 ml. intermediaries in the glycolytic series are only In consequence, as neither pigment will colour present in small amounts. During rhabdomyo- the plasma at a concentration below 40 mg/lOOml, lysis blood glycogen levels may be raised (Bowden myoglobin appears in the urine before it is visible et al., 1956) and glycosuria has often been noted in the plasma. (Buchanan and Steiner, 1951; Schaar, 1955; on September 29, 2021 by guest. Protected Myoglobin, like haemoglobin, may cause distal Favara et al., 1967). It was this, in association renal tubular necrosis. As it is soluble at a basic with the severe metabolic acidosis and ketosis, that pH it has been suggested that alkalinization of the led to the diagnosis of diabetic ketosis as the cause urine may protect the kidney, but despite this of death in Case 1; similarly in Case 2, glycosuria, precaution in some instances, as in Case 2, tubular , and a metabolic acidosis were found necrosis has occurred. The fine needle-shaped though the blood glucose was within normal limits. crystals of myoglobin which were initially seen in Case 2 did not reappear once the urine had become Potassium. Muscle contains a large amount of alkaline: they were similar to those described and potassium, and its release during cell damage may illustrated by Berenbaum, Birch, and Moreland give rise to cardiac arrhythmias: sudden or early (1955). deaths in acute muscle damage may have followed ventricular fibrillation. The rapidly fatal illness in Glycogen. The main constituent Case 1 was similar to that reported in proven cases of muscle is glycogen and other carbohydrate of idiopathic paroxysmal myoglobinuria (Bowden

3 Arch Dis Child: first published as 10.1136/adc.46.249.594 on 1 October 1971. Downloaded from

600 Savage, Forbes, and Pearce

FIG.V6.-Kdney:astsicolletingtuules bizarr staining effects.(Obadiah -m copyright.

FIG. 6.-Kidney casts in collecting tubules showing bizarre staining effects. (Obadiah method. x 280.) et al., 1956; Favara et al., 1967). In some instances deposition of calcium and phosphorous salts may a very high serum potassium has been recorded result and it is of interest that in Reiner's first case (Hed, 1955). In both Cases 1 and 2 the plasma (Reiner et al., 1956) and that recorded by Ford potassium was high, and in Case 2 the ECG findings (1966) calcium phosphate was found in the necrotic were consistent with hyperkalaemia. muscle tissue. Tetany is a previously unrecog- http://adc.bmj.com/ nized complication of this illness, though in the Phosphorus. The large amount of intra- patient described by Tavill et al. (1964) both cellular phosphorus in muscle is present mainly as hypocalcaemia and hyperphosphataemia were re- adenosine triphosphate and phosphocreatinine, and corded during the first few days and thought to be it is probable that during severe and acute rhabdo- the result of acute renal failure. Our observations myolysis hyperphosphataemia occurs. In Case 2 are of particular interest since in over half the cases the serum phosphate on the second and third day of idiopathic rhabdomyolysis the patients' feet was raised, and the urinary phosphate/ have been noted to be in the equinus position, on September 29, 2021 by guest. Protected ratios were higher than the normal values published indeed many writers refer to the 'ballet dancer' by Thalassinos et al. (1970). They reported a position as a typical finding (see Fig. 2). While ratio ranging from 0 75 to 1 9 in children under pedal spasm may partly be directly due to muscle 2 years of age whereas in our patient the ratios were injury, serum calcium and phosphorus estimations 5 0 and 2 3. No calcium was present in the urine in future cases should clarify this point. at this time. We believe that the initial hyper- It is interesting that hyperphosphataemia and phosphataemia caused the hypocalcaemic tetany, hypocalcaemia have recently been reported in a and that as the raised serum phosphate fell during patient with malignant hyperpyrexia during general the first three days (HPO4 4 3, 4 0, 2 7 mEq/l.; anaesthesia in whom the authors demonstrated normal range 2-1-3 5 mEq/l.) the child's serum considerable muscle damage (Denborough et al., calcium returned to normal levels (2.7, 3 4, 4-4 1970a). Though the aetiology of malignant hyper- mEq/l.; normal range 4 * 5-5 - 7 mEq/l.). If the pyrexia is unknown, it is now recognized that it product, ionized Ca X P04 (as mEq/l.) exceeds 15, may occur in patients with an underlying abnor- Arch Dis Child: first published as 10.1136/adc.46.249.594 on 1 October 1971. Downloaded from

Idiopathic Rhabdomyolysis 601 copyright.

FIG. 7.-Case 3. An area ofmyofibril andmyofilament loss ispresent, which contains three round lipid bodies. Within the intermyofibrillar spaces and particularly in the region of myofibril destruction there is irregularly shaped amor- phous material the nature ofwhich is not known but which might be coagulatedproteinaceous material. Mitochondria http://adc.bmj.com/ show no gross internal defects but they have lost their normal topographic relations. The sarcolemma and T-systems also show no defect. (x 14,450.) A = amorphous material; M = mitochondria; S = sarcolemma; Z = Z lines; L = lipid; MF = myofibril; and T = T- system. mality of skeletal muscle (Steers, Tallack, and isobutyric acid was found in the urine of Case 2 Thompson, 1970; Denborough et al., 1970b) and over the first three days but not thereafter. Though it has been suggested that it is a severe this compound is normally found in 5-10% of the

rhabdomyo- on September 29, 2021 by guest. Protected lysis which leads to the hyperpyrexia (Denborough population, its disappearance from later urine et al., 1970a). These facts are relevant because, specimens suggests that it arose during the extensive though rhabdomyolysis has only recently been rhabdomyolysis. Increased amounts of fl-amino- incriminated in malignant hyperpyrexia, myoglo- isobutyric acid has been noted in the urine of binuria is recognized and muscular hypertonicity subjects with disorders associated with tissue with carpopedal spasm reported (Purkis et al., destruction, and it is thought to arise from the 1967). breakdown of thymine, a constituent of DNA An added risk with hypocalcaemia is that its (Levey, Woods, and Abbott, 1963). association with hyperkalaemia will aggravate Apart from these biochemical abnormalities, the cardiac arrhythmias which may prove fatal. plasma level of muscle enzymes, particularly Abnormal urinary patterns have been creatine phosphokinase, is raised. There is often found in patients with muscle necrosis (Bowden an associated fever and leucocytosis. Rhabdo- et al., 1956), the major abnormality being, as in myolosis causes pain, oedema, and partial or Case 2, an increased excretion of taurine. fl-amino- complete paralysis of the muscles involved. In Arch Dis Child: first published as 10.1136/adc.46.249.594 on 1 October 1971. Downloaded from

602 Savage, Forbes, and Pearce some recorded cases this latter finding has occa- recurrent episodes of black or bloody urine asso- sioned a diagnosis of poliomyelitis, and severe ciated with severe . For this respiratory difficulties have caused death (Buchanan reason Meyer-Betz's name is often linked with and Steiner, 1951). idiopathic paroxysmal myoglobinuria, though it is probable that his patient in fact suffered from a Causes of rhabdomyolysis. Acute rhabdo- form of . In 1959 Korein, myolysis has been reported in a number of different Coddon, and Mowrey reviewed all those cases disorders. It may follow a crush injury, or the recorded as idiopathic paroxysmal myoglobinuria. occlusion of a major limb artery with secondary They suggested that two main types could be ischaemic necrosis of skeletal muscle. During differentiated. In the first, Type I, the disease prolonged convulsions there may be relative tissue appeared to be precipitated by exertion, and the anoxia and high voltage accidents will cause direct second, Type II, was usually associated with or tissue damage. Persons with polymyositis or a preceded by an infection. Korein suggested that muscular dystrophy occasionally develop myo- Type I should be called exertional myoglobinuria globinuria and an alcoholic with myo- and Type II toxic myoglobinuria. Later reviews globinuria is recognized. In normal subjects have included those by Bowden et al. (1956), rhabdomyolysis can follow severe exercise, and in Wheby and Miller (1960), and Verger and Battin military groups which emphasize physical fitness, (1962). We have reviewed the literature, but the incidence of rhabdomyolysis is especially high included only those cases starting in childhood (Smith, 1968). There have been three epidemics (15 years or younger). We have used the same of Haff disease in which myoglobinuria seems to be clinical differentiation as Korein, but our findings of infective or toxic aetiology, the epidemics occur- differ slightly, presumably because of the age ring in Eastern Europe lakeside communities, who restriction we have used. Tables I and II detail have ingested fish and eels caught in inlets ('haff') these individual cases and Table III summarizes thought to be contaminated by factory waste the main features. products (Berlin, 1948). Finally, there is a group In this paediatric series the average age on onset copyright. of patients in whom the cause of the myoglobinuria of toxic myoglobinuria (Type II) is earlier and the is unknown, and it is to these that the term idio- disease more common than exertional myoglobi- pathic recurrent rhabdomyolysis or paroxysmal nuria (Type I), though in adults the latter is the myoglobinuria has been given. more common illness. There is little difference between the sexes in the incidence of toxic myoglo- Idiopathic rhabdomyolysis. The first recorded binuria, but there is a predominance of males with case of myoglobinuria is credited to Meyer-Betz exertional myoglobinuria. In the occasional patient

(1910) who noted that a 13-year-old boy had myoglobinuria has followed either infection or http://adc.bmj.com/ TAB] Idiopathic Rhabdomyolysis Type

at Author Age(yr) Sex AgeOnset HistoryFamily Exertion Episodes

Bywaters and Dible, 1943a 24 M Early childhood - + Multiple on September 29, 2021 by guest. Protected Spaet et al., 1954 23 M Early childhood - + Multiple Hed, 1955 30 M 14 + + Multiple Reiner et al., 1956 (Case 1) 46 M Early childhood - + Multiple Segar, 1959 15 M Early childhood _ + Multiple Javid et al., 1959 18 M 14 - + 3 Lyons, 1963 23 M Early childhood + + Multiple Tavill et al., 1964 28 M 5 _ + Multiph Rowland et al., 1964 (Case 2) 12 F 12 _ + 1 Rowland et al., 1964 (Case 5) 16 F 14 _ + 3 Boroian and Attwood, 1965 6 M 6 + + 1 Hinz et al., 1965 17 M 15 - + Multiple Ford, 1966 29 M Early childhood + + Multiplh Ozsoylo and Aklgun, 1966 21 M 9 _ + Multiple Goldberg and Chakrabarti, 1966 28 M 7 - + Multiple Engel et al., 1970 18 F 5 + + Multiple Engel et al., 1970 18 F 5 + + Multiple Arch Dis Child: first published as 10.1136/adc.46.249.594 on 1 October 1971. Downloaded from

Idiopathic Rhabdomyolysis 603 exertion and has even been apparently spontaneous. light microscopical appearance of the muscle Recurrent attacks of myoglobinuria are more fre- biopsy of our Case 3 was essentially normal. quent in Type I, most cases of Type II having Cardiac and smooth muscle are unaffected. only one and usually less then three reported Acute tubular necrosis with renal failure is a well- episodes. Fever and leucocytosis, which occur recognized complication of paroxysmal myoglobi- more regularly in Type II, probably reflect that nuria and in a few of the described cases it has this is the more acute illness. Korein noted proved fatal. It appears to be an uncommon uraemia less commonly in exertional myoglobinuria, cause of death in the paediatric age group, and in though we have found it in this paediatric review fact our Case 2 appears to be the only reported with equal frequency in both types, suggesting that child in which myoglobinuric nephropathy led to when exertional myoglobinuria starts in childhood death. The histological picture in the kidneys was it carries a more serious prognosis. Fatalities are very similar to that described by Bywaters and Dible more common in Type II. It is perhaps significant (1943b) in their review of traumatic anuria. There that no deaths have occurred in exertional myoglo- were severe lesions affecting the distal tubule with binuria during childhood, but that the two fatalities striking formation of pigment casts in the collecting which arose later resulted when the illness was tubules and occasional tubulo-venous anastomoses. apparently provoked or aggravated by an associated This latter feature is rarely described in contempor- infection (Bywaters and Dible, 1943a; Ford, 1966). ary literature (Heptinstall, 1966), though empha- Residual muscle atrophy is rarely reported. sized as an important finding in acute tubular necrosis in the older reports (Dunn, Gillespie, and Histopathology. The two constant histological Niven, 1941). findings in the skeletal muscle in this condition are focal necrosis of fibres, and an absence of significant Aetiology. The aetiology of paroxysmal myo- inflammatory infiltrate. Some authors (Haase globinuria is unknown, but it may be that a meta- and Engel, 1960; Reiner et al., 1956; Larsson et al., bolic defect exists, which under the stress of fever,

1964; and Kossmann, Camp, and Engle, 1963) infection, or exercise produces cell damage. copyright. describe evidence of regeneration such as sarco- Abnormalities of muscle protein have been plasmic basophilia, proliferation of sarcolemmal suggested and fetal myoglobin has been reported in nuclei, and the presence of multinucleate giant cells, some cases. Benoit et al. (1964) recorded such a but there was no suggestion of this in our Case 2 case and Perkoff (1964) found increased concentra- and there was no RNA activity on Azur B staining. tion of fetal protein in the muscle of a patient with Benoit, Theil, and Watten (1964), Hinz, Drucker, myoglobinuria. However, more recently on re- and Lamer (1965), and Tavill et al. (1964) describe examination of his preparations, Perkoff has con- little in their reports, the firmed the observation of others et al., change in the muscle and (Wolfson http://adc.bmj.com/

Reported Cases Starting in Childhood) Muscle Febrile Associated Uraemia Respiratory M Dege Onset Illness Difficulty Atrophy Fatality Myoglobinuria Degeneration |______l Histologically

Not usually Respiratory infection + _ _ + Hb + on September 29, 2021 by guest. Protected in fatal illness

_-_ + - - - Hb + Not usually __ + + + _ + + + + + Diarrhoea - _ - - +H - + - - - ~+Hb-

+ Coryza/diarrhoea in + + _ + + + fatal illness Diarrhoea + -_ - + _~~ ~ ~ + Arch Dis Child: first published as 10.1136/adc.46.249.594 on 1 October 1971. Downloaded from

604 Savage, Forbes, and Pearce TABLI Idiopathic Rhabdomyolysis Type 1

Author Author | ~~(yr)Age Sex AgeOnsetat HistoryFamily Exertion Episodes

Debr6 et al., 1934 6 F 29/12 _ _ Multiple Huber et al., 1938 4 M 4 - _ 1 Buchanan and Steiner, 1951 4 M 2 _* 2 Stokes, 1953 15 F 15 1 Schaar,1955 0 M 9 _* 1 Berenbaum et al., 1955 I 10 F 4 -2 Bowden et al., 1956 4 M 14/12 + - Multiple Bowden et al., 1956 8 F Multiple Bowden et al., 1956 6* M 6* -_ 1 Bowden et al., 1956 4 F 4 + I1 Watson and Ainbender, 1959 6 M 5 -+ 2 Wheby and Miller, 1960 16 F 4 + + Multiple Wheby and Miller, 1960 15 F 12 + + Multiple Haase and Engel, 1960 7 M 2} - - Multiple Bailie, 1964 3 M 1 2 Bacon, 1967 14 M 14 - -* 3 Miller and Gross, 1967 I 11 M 11 -? 1 Favara et al., 1967 21 M 2* + - 1 Favara et al., 1967 9 M 3* + - 1 Favara et al., 1967 9/12 M 9/12 + - 2 Current report Case 1 3 F 3 + 1 Case 2 18/12 F I18/12 + I Case 3 7 M 7 - - 1

Hb, myohaemoglobinuria. *Possible association. ?Unknown.

TABLE III and that fasting greatly facilitated the ease with copyright. Idiopathic Rhabdomyolysis (Starting in Childhood) which attacks could be induced. He was able to produce myoglobinuria in one brother while at Type I Type II rest by administration of a diet low in carbohydrate. (Exertional) (Non-exertional) Similarly, in the adult reported by Kontos et al. Cases 17 23 (1963) attacks of exertional myoglobinuria were (M 13, F 4) (M 14, F 9) and exercise was better Average age onset (yr) 10 5 aggravated by fasting, Positive family history 3 4 tolerated if preceded by a high caloric diet. 17 2 Associated exertion The patient described by Ford (1966) noted that a http://adc.bmj.com/ Associated illness 4 20 Multiple episodes 13 6 large lunch on a hunting trip would avert the Fever 5 20 attack that would otherwise occur. Similar find- Uraemia and/or dyspnoea 8 10 Fatal 2 8 ings have been noted by other authors: Hinz et al. Muscular atrophy 1 3 (1965) found raised blood lactic acid after exercise, and suggested the possibility that in some cases 1-967) that the major haemoprotein was fetal abnormalities may exist in the Krebs cycle. The haemoglobin and he believes that reports of fetal family described by Favara et al. (1967) was con- myoglobin in patients with myoglobinuria must be sidered to have an inborn error of glycogen metabo- on September 29, 2021 by guest. Protected considered to have alternative explanations (Perkoff, lism with excessive phosphorylase activity. A 1968). There have been no other reports of curious disease with myoglobinuria is well recog- abnormal myoglobins in idiopathic rhabdomyolysis, nized in veterinary medicine. Draught horses, but since inherited structural variation of human after a weekend in stable on high caloric feeds and myoglobin does occur it may be that in some within an hour of starting heavy work, may fall to instances such an abnormality is responsible for the ground with profound weakness and apparent paroxysmal myoglobinuria (Boyer, Fainer, and pain in the limbs. The urine is dark and contains Naughton, 1963). myoglobin. The condition is frequently fatal and it It has often been suggested that rhabdomyolysis has been suggested that it results from excessive might be precipitated by an intracellular disorder intracellular lactic acid production during glycolysis of carbohydrate metabolism. Hed (1955) found (Kreutzer, Strait, and Kerr, 1948). that in three brothers with myoglobinuria, In a comprehensive report, Larsson et al. (1964) paroxysms were always precipitated by exercise, have described 14 patients belonging to five families, Arch Dis Child: first published as 10.1136/adc.46.249.594 on 1 October 1971. Downloaded from Idiopathic Rhabdomyolysis 605

all of whom had a myopathy comparable in some intestinal infection in children susceptible to respects to Type I myoglobinuria. Larsson muscle damage. Fever has been incriminated, showed that during exercise oxygen utilization in Berg and Frenkel (1958) inducing myoglobinuria in copyright. the patients' muscles was low, whereas lactic and their patient by raising his temperature with typhoid pyruvic concentrations in the blood increased to a vaccine. greater extent than in normal subjects, and he Acheson and McAlpine (1953) suggested that concluded that glycolysis was abnormal. As abnormal adrenal metabolism might be involved, nearly all these patients had hypertrophy of the and in their patient reported increased 17-oxosteroid calf muscles, we have however not included them excretion in the urine. In our Case 2, 24-hour as examples of idiopathic myoglobinuria. urinary 17-oxosteroids on admission and during Recently, Engel et al. (1970) have described an the subsequent day were 0x65 and 1 1 mg/24 hr, http://adc.bmj.com/ apparent defect in the breakdown of long-chain normal results in a child of this age. The 17- fatty acids in identical twins with myoglobinuria. hydroxycorticosteroids were raised to 10*4 mg/ Since Fritz (1961) has shown that the energy 24 hr during the first few days, falling to 5*5 mg/ supply of skeletal muscle, especially under sus- 24 hr subsequently. The initial high figures are tained work performance, probably comes from the result of stress. In Case 3 the 17-oxosteroids plasma free fatty acids, it is surprising that abnor- were 0 9 and 1x6 mg/24 hr on two occasions and malities in metabolism have not been the 17-hydroxycorticosteroids 3 *4 and 3 * 6 mg/ more frequently reported. It is of interest that 24 hr. All these results are within the normal on September 29, 2021 by guest. Protected heart muscle in patients with myoglobinuria is range for a child of this age. normally unaffected, for cardiac muscle appears to In some instances general anaesthesia has precipi- depend largely on fatty acid for its energy supply tated myoglobinuria though what part it plays in (Lancet, 1970). the exacerbation of rhabdomyolysis is unknown. A number of patients with rhabdomyolysis have It may be that the period of fasting, the relative had diarrhoea and on stool culture a dysentery anoxia, variations in temperature, or indeed the organism has been found (Bowden et al., 1956; action of anaesthetic drugs including muscle Rowland et al., 1964); while this may be a chance relaxants themselves are of consequence. Recently finding, it is known that muscle degeneration it has been suggested that the frequently fatal can occur in typhoid fever. It is possible that the malignant hyperpyrexia which has occurred during muscle changes in these cases were the result of an general anaesthesia follows rhabdomyolysis in Arch Dis Child: first published as 10.1136/adc.46.249.594 on 1 October 1971. Downloaded from 606 Savage, Forbes, and Pearce susceptible individuals (Denborough et al., 1970a). Therapy. Treatment is unsatisfactory. Patients It will have become apparent how little is known with exertional myoglobinuria should be advised to about the aetiology of idiopathic recurrent rhabdo- avoid excessive exercise and to take extra calories myolysis. It is probable that the reported cases before undertaking any activity. During an epi- represent a variety of different entities. In future sode of myoglobinuria the urine should be made cases, histochemistry and electron microscopy of alkaline and the urinary output maintained. muscle tissue with myoglobin finger printing, Renal dialysis and respirator care may be necessary. and investigation of carbohydrate and lipid meta- In the presence of extensive muscle necrosis bolism, will be essential if abnormalities of these prophylactic antibiotics should be given. There systems are to be determined. is no evidence that steroids are of value in prophy- laxis or therapy. Genetic transmission. There have been a few cases of paroxysmal myoglobinuria occurring in We thank Professor J. L. Henderson for his interest, families. In those recorded by Bowden et al. Drs. Mary Kerr, Constance C. Forsyth, and S. G. F. Wilson for permission to report cases, Professor J. N. (1956), Wheby and Miller (1960), Favara et al. Walton, Newcastle General Hospital, for the use of his (1967), and our own first 2 cases, sibs have been electron microscope laboratory, Mr. John Fulthorpe, affected. In all these the disease has been of the Mr. Michael Taylor. and Miss Margaret Jenkinson for so-called toxic type, and the illness has been technical assistance, and Mr. Ron Fawkes for severe, 6 of the 9 children having died, and in 2 photography. who survived, sisters reported by Wheby and Miller (1960), recurrent severe episodes were REFERENCES Acheson, D., and McAlpine, D. (1953). Muscular dystrophy recorded. Similarly in the family described by associated with paroxysmal myoglobinuria and excessive Fitz (1957) of 3 adult sibs with Type II myoglo- excretion of ketosteroids. Lancet, 2, 372. binuria, 2 died during episodes of rhabdomyolysis. Adams, R. D., Denny-Brown, D., and Pearson, C. M. (1962). Diseases of Muscle. Kimpton, London. 3 brothers were reported by Hed (1955) with Type Bacon, A. E., Jr. (1967). Acute idiopathic rhabdomyolysis with I myoglobinuria, but in only 1 did the illness start myoglobinuria. Delaware Medical Journal, 39, 302. Bailie, M. D. (1964). Primary paroxysmal myoglobinuria. New in childhood and in none was it fatal. The twins England Journal of Medicine, 271, 186. of Engel et al. (1970) survived recurrent episodes of Benoit, F. L., Theil, G. B., and Watten, R. H. (1964). Myoglo- copyright. binuria and persistence of fetal myoglobin. Annals of Internal exertional myoglobinuria. Medicine, 61, 1133. It does seem that the prognosis, especially with Berenbaum, M. C., Birch, C. A., and Moreland, J. D. (1955). II Paroxysmal myoglobinuria. Lancet, 1, 892. Type myoglobinuria, is more serious when Berg, P., and Frenkel, E. P. (1958). Myoglobinuria after spon- there is a positive family history, though any taneous and induced fever. Annals of Internal Medicine, 48, patient with rhabdomyolysis must be regarded as 380. Berlin, R. (1948). Haff disease in Sweden. 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paralysis (Meyer-Betz disease). Archives of Neurology and on September 29, 2021 by guest. Protected though the proportion of children affected in many Psychiatry, 66, 107. Bywaters, E. G. L., and Dible, J. H. (1943a). Acute paralytic families suggests a dominant of incomplete pene- myohaemoglobinuria in man. J'ournal of Pathology and trance. Ford's (1966) family, in which 2 brothers Bacteriology, 55, 7. and their father were similarly affected, presumes Bywaters, E. G. L., and Dible, J. H. (1943b). The renal lesion in traumatic anuria. Journal of Pathology and Bacteriology, a dominant inheritance. Many reports, however, 54,111. have an inadequate family history or none at all, Debre, R., Gernez, C., and See, G. (1934). Crises myopathiques paroxystiques avec h6moglobinurie. Bulletins et Memoires de la and the presence or absence of consanguinity of Societe Midicale des HOpitaux de Paris, 50, 1640). parents is seldom mentioned, though this was Denborough, M. A., Ebeling, P., King, J. O., and Zapf, P. (1970a). Myopathy and malignant hyperpyrexia. Lancet, 1, 1138. noted in the case of Tavill's patient. For this Denborough, M. A., Forster, J. F. A., Hudson, M. C., Carter, reason and because there are so few recorded N. G., and Zapf, P. (1970b). Biochemical changes in malig- cases it is impossible to do more than surmise at nant hyperpyrexia. Lancet, 1, 1137. Dunn, J. S., Gillespie, M., and Niven, J. S. F. (1941). Renal the genetic transmission involved. lesions in two cases of crush syndrome. Lancet, 2, 549. Arch Dis Child: first published as 10.1136/adc.46.249.594 on 1 October 1971. Downloaded from

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