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Myoglobinuria in boys with Duchenne muscular dystrophy on corticosteroid therapy
Neuromuscular Disorders 18 (2008) 71–73 www.elsevier.com/locate/nmd
Case report
Myoglobinuria in boys with Duchenne muscular dystrophy on corticosteroid therapy P. Garrood a
a,*
, M. Eagle a, P.E. Jardine b, K. Bushby a, V. Straub
a
Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK b Bristol Children’s Hospital, Bristol BS2 8BJ, UK Received 28 June 2007; received in revised form 28 June 2007; accepted 16 July 2007
Abstract Myoglobinuria is a recognised complication of Duchenne muscular dystrophy (DMD), but has only once been reported in ambulant boys on corticosteroid therapy [Dubowitz V, Kinali M, Main M, Mercuri E, Muntoni F. Remission of clinical signs in early Duchenne muscular dystrophy on intermittent low-dosage prednisolone therapy. Eur J Paediatr Neurol 2002;6(3):153–9.]. We present three prednisolone-treated boys with myoglobinuria and in two cases this was recurrent. All three showed improved motor performance in response to the introduction of corticosteroids. The greater activity of steroid-treated individuals may place their dystrophin-deficient muscles under greater mechanical stress, predisposing to further muscle fibre damage and consequent myoglobinuria. Families and physicians need to have an increased awareness of this possibility and of the appropriate management of myoglobinuria. 2007 Elsevier B.V. All rights reserved. Keywords: Duchenne muscular dystrophy; Myoglobinuria; Corticosteroids; Prednisolone
1. Introduction The advent of corticosteroid therapy for Duchenne muscular dystrophy has enabled many boys to maintain strength and functional ability for longer and to a greater degree than was previously possible [2,3]. In DMD, the lack of dystrophin is thought to render the sarcolemma of the muscle fibre uniquely vulnerable to contractioninduced injury, with eccentric contractions being particularly damaging [4]. One potential side-effect of steroid therapy is that the improved functional ability of DMD boys may lead them to place further stresses on their muscle fibres, resulting in increased levels of muscle fibre damage. Myoglobinuria, as a consequence of rhabdomyolysis, may be a presenting feature of dystrophinopathies [5,6]. Recent literature, however, chiefly describes myoglobinuria in DMD in the context of muscle fibre necrosis induced by volatile anaesthetics [7,8]. There is one previous report of *
Corresponding author. Tel.: +44 191 2418636; fax: +44 191 2418770. E-mail address: [email protected] (P. Garrood).
0960-8966/$ - see front matter 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2007.07.006
myoglobinuria in two ambulant boys on low-dose intermittent corticosteroids [1]. In this paper, we describe myoglobinuria in three boys with DMD, all of whom had a positive functional response to the introduction of prednisolone, in order to raise awareness of this potential complication of corticosteroid treatment. 2. Case series 2.1. Patient 1 This child was diagnosed with a deletion of exon 55 of the dystrophin gene and commenced prednisolone therapy aged five years and two months. His Hammersmith Motor Ability Scale (HAMA) score on treatment reached a plateau of 36/40. At his clinic review at eight years and nine months, his mother reported that he had had at least monthly episodes of dark-coloured urine over the preceding six months. These episodes usually occurred after physical activity and always settled within a day. At this stage his motor
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P. Garrood et al. / Neuromuscular Disorders 18 (2008) 71–73
performance was still excellent: he could run 200 m before tiring and was able to play football. He had been seen in primary care two weeks previously with dark urine, rightsided abdominal pain, renal angle tenderness and blood and protein on urine dipstick. He was treated for a urinary tract infection but urine culture was subsequently negative. His prednisolone was reduced, but he had a further episode of pigmenturia two months later, which was precipitated by playing on a bouncy castle. This episode was fully investigated but did not require active treatment. His urine dipstick showed ++++ protein and +++ blood but with normal microscopy. His urinary myoglobin was later reported at 359,000 lg/l (normal 0–10). The myoglobinuria resolved within 24 h. The repeated bouts of myoglobinuria combined with the intolerable behavioural effects of the prednisolone led to a joint decision with his mother that treatment should be tapered and discontinued. He had one further episode of pigmenturia shortly after discontinuation of prednisolone and, although his HAMA scores remain stable, he is less active since stopping steroid therapy. 2.2. Patient 2 This boy with DMD has a deletion of exons 51–54 and commenced daily prednisolone 15 mg (0.75 mg/kg) when he was five years and nine months old. Seven months after starting corticosteroids, his HAMA score had jumped from 30/40 to 37/40 and his time to run 11 m had halved to 4 s. He presented to the local hospital ten months after starting treatment with a febrile illness and complaining of back and leg pain. His physical examination and blood pressure were normal. His urine was ‘‘cola-coloured’’ with ++++ blood, +++ protein on dipstick but with normal microscopy. He was commenced on benzylpenicillin for suspected glomerulonephritis and required treatment for oliguria and hyperkalaemia (serum potassium 6 mmol/l). An ultrasound showed normally-sized kidneys with echogenic cortex and a bladder containing multiple echoes, suggestive of debris. His C-reactive protein rose to 154 mg/l with white blood cells at presentation of 20.8 · 109/l. His creatinine remained stable and his urinary myoglobin came back as 82 lg/l. His HAMA score shortly after discharge was 39/ 40 and a repeat renal ultrasound was normal. At two years since his episode of myoglobinuria he remains well on prednisolone with no further episodes. 2.3. Patient 3 This boy was diagnosed at four and a half years of age with a deletion of intron 49 and exon 50. He transferred from alternate-day to daily prednisolone 15 mg (0.74 mg/kg) at the age of six years and two months, with an improvement in his HAMA score from 36 to 40/40. He had six episodes of myoglobinuria over a 15-month period. The first was at the age of six and a half following a strenuous football match. At lunch he became pale and
sweaty and slumped forward at the table. Soon afterward he had red urine. This was tested at the local Accident and Emergency department and was positive for blood. He was treated for a presumed urinary tract infection and the pigmenturia resolved with a second micturition. A renal ultrasound was normal. Further episodes lasted less than 24 h and were precipitated by physical exercise. 3. Discussion The majority of episodes of myoglobinuria described above were related to physical exercise, although it is not clear what triggered rhabdomyolysis in child 2. All three boys had shown a substantial improvement in motor ability on prednisolone therapy. The cases also illustrate the variable presentation, even by the same child, with some episodes accompanied by systemic upset and others not. Although myoglobinuria may lead to acute tubular necrosis [9,10], the episodes experienced by children 1 and 3 were short-lived and did not require treatment. The mild, self-limiting nature of most of these episodes does not detract from the importance of prompt recognition of myoglobinuria and the institution of appropriate management. There are published guidelines on the management of severe rhabdomyolysis [9,10]. For milder episodes, an increase in fluid intake and appropriate monitoring of renal function may be all that is required. Initial recognition may be problematic, however. It is essential that the parents of all corticosteroid-treated boys are aware of the possibility of myoglobinuria and the need to increase oral fluid intake and seek medical attention should it occur. A lack of awareness among junior medical staff may delay diagnosis and lead to a battery of investigations which may not be helpful, or to inappropriate treatment for urinary tract infection. The results of a urinary myoglobin assay may take several days to arrive, rendering it of little value in the clinical management of the initial presentation. A clue in the acute situation may be obtained from a positive urine dipstick for blood in the absence of red cells on urine microscopy, since the benzidine dipstick does not differentiate between haemoglobin and myoglobin. Therefore, in DMD boys, a history of dark, tea- or cola-coloured urine, with a urine dipstick positive for blood but with no red blood cells, bacilli or leucocytes on microscopy, should be considered to be myoglobinuria, pending laboratory confirmation, and treatment instituted accordingly. Acknowledgement We wish to thank Dr. A. Fall, Consultant Paediatrician, James Cook University Hospital, Middlesbrough for provision of clinical information for this case report. Dr. Garrood and the work of the Muscle Centre, Institute of Human Genetics, are supported by funding from the Muscular Dystrophy Campaign.
P. Garrood et al. / Neuromuscular Disorders 18 (2008) 71–73
References [1] Dubowitz V, Kinali M, Main M, Mercuri E, Muntoni F. Remission of clinical signs in early Duchenne muscular dystrophy on intermittent low-dosage prednisolone therapy. Eur J Paediatr Neurol 2002;6(3):153–9. [2] Bushby K, Muntoni F, Urtizberea A, Hughes R, Griggs R. Report on the 124th ENMC International Workshop. Treatment of Duchenne muscular dystrophy; defining the gold standards of management in the use of corticosteroids. 2–4 April 2004, Naarden, The Netherlands. Neuromuscular Disorders 2004;14(8–9):526–34. [3] Manzur AY, Kuntzer T, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev 2006:4, [Systematic Review]. [4] Petrof BJ, Shrager JB, Stedman HH, Kelly AM, Sweeney HL. Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc Natl Acad Sci USA 1993;90(8): 3710–4.
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[5] Figarella-Branger D, Baeta Machado AM, Putzu GA, Malzac P, Voelckel MA, Pellissier JF. Exertional rhabdomyolysis and exercise intolerance revealing dystrophinopathies. Acta Neuropathol 1997;94(1):48–53. [6] Yokota R, Shirotani M, Kouchi I, et al. Subclinical Becker’s muscular dystrophy presenting with severe heart failure. Int Med 2004;43(3):204–8. [7] Girshin M, Mukherjee J, Clowney R, Singer LP, Wasnick J. The postoperative cardiovascular arrest of a 5-year-old male: an initial presentation of Duchenne’s muscular dystrophy. Paediatr Anaesth 2006;16(2):170–3. [8] Obata R, Yasumi Y, Suzuki A, Nakajima Y, Sato S. Rhabdomyolysis in association with Duchenne’s muscular dystrophy. Can J Anaesth 1999;46(6):564–6. [9] Sauret JM, Marinides G, Wang GK. Rhabdomyolysis. Am Fam Physician 2002;65(5):907–12. [10] Evenepoel P. Acute toxic renal failure. Best Pract Res Clin Anaesthesiol 2004;18(1):37–52.
Case report
Myoglobinuria in boys with Duchenne muscular dystrophy on corticosteroid therapy P. Garrood a
a,*
, M. Eagle a, P.E. Jardine b, K. Bushby a, V. Straub
a
Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK b Bristol Children’s Hospital, Bristol BS2 8BJ, UK Received 28 June 2007; received in revised form 28 June 2007; accepted 16 July 2007
Abstract Myoglobinuria is a recognised complication of Duchenne muscular dystrophy (DMD), but has only once been reported in ambulant boys on corticosteroid therapy [Dubowitz V, Kinali M, Main M, Mercuri E, Muntoni F. Remission of clinical signs in early Duchenne muscular dystrophy on intermittent low-dosage prednisolone therapy. Eur J Paediatr Neurol 2002;6(3):153–9.]. We present three prednisolone-treated boys with myoglobinuria and in two cases this was recurrent. All three showed improved motor performance in response to the introduction of corticosteroids. The greater activity of steroid-treated individuals may place their dystrophin-deficient muscles under greater mechanical stress, predisposing to further muscle fibre damage and consequent myoglobinuria. Families and physicians need to have an increased awareness of this possibility and of the appropriate management of myoglobinuria. 2007 Elsevier B.V. All rights reserved. Keywords: Duchenne muscular dystrophy; Myoglobinuria; Corticosteroids; Prednisolone
1. Introduction The advent of corticosteroid therapy for Duchenne muscular dystrophy has enabled many boys to maintain strength and functional ability for longer and to a greater degree than was previously possible [2,3]. In DMD, the lack of dystrophin is thought to render the sarcolemma of the muscle fibre uniquely vulnerable to contractioninduced injury, with eccentric contractions being particularly damaging [4]. One potential side-effect of steroid therapy is that the improved functional ability of DMD boys may lead them to place further stresses on their muscle fibres, resulting in increased levels of muscle fibre damage. Myoglobinuria, as a consequence of rhabdomyolysis, may be a presenting feature of dystrophinopathies [5,6]. Recent literature, however, chiefly describes myoglobinuria in DMD in the context of muscle fibre necrosis induced by volatile anaesthetics [7,8]. There is one previous report of *
Corresponding author. Tel.: +44 191 2418636; fax: +44 191 2418770. E-mail address: [email protected] (P. Garrood).
0960-8966/$ - see front matter 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2007.07.006
myoglobinuria in two ambulant boys on low-dose intermittent corticosteroids [1]. In this paper, we describe myoglobinuria in three boys with DMD, all of whom had a positive functional response to the introduction of prednisolone, in order to raise awareness of this potential complication of corticosteroid treatment. 2. Case series 2.1. Patient 1 This child was diagnosed with a deletion of exon 55 of the dystrophin gene and commenced prednisolone therapy aged five years and two months. His Hammersmith Motor Ability Scale (HAMA) score on treatment reached a plateau of 36/40. At his clinic review at eight years and nine months, his mother reported that he had had at least monthly episodes of dark-coloured urine over the preceding six months. These episodes usually occurred after physical activity and always settled within a day. At this stage his motor
72
P. Garrood et al. / Neuromuscular Disorders 18 (2008) 71–73
performance was still excellent: he could run 200 m before tiring and was able to play football. He had been seen in primary care two weeks previously with dark urine, rightsided abdominal pain, renal angle tenderness and blood and protein on urine dipstick. He was treated for a urinary tract infection but urine culture was subsequently negative. His prednisolone was reduced, but he had a further episode of pigmenturia two months later, which was precipitated by playing on a bouncy castle. This episode was fully investigated but did not require active treatment. His urine dipstick showed ++++ protein and +++ blood but with normal microscopy. His urinary myoglobin was later reported at 359,000 lg/l (normal 0–10). The myoglobinuria resolved within 24 h. The repeated bouts of myoglobinuria combined with the intolerable behavioural effects of the prednisolone led to a joint decision with his mother that treatment should be tapered and discontinued. He had one further episode of pigmenturia shortly after discontinuation of prednisolone and, although his HAMA scores remain stable, he is less active since stopping steroid therapy. 2.2. Patient 2 This boy with DMD has a deletion of exons 51–54 and commenced daily prednisolone 15 mg (0.75 mg/kg) when he was five years and nine months old. Seven months after starting corticosteroids, his HAMA score had jumped from 30/40 to 37/40 and his time to run 11 m had halved to 4 s. He presented to the local hospital ten months after starting treatment with a febrile illness and complaining of back and leg pain. His physical examination and blood pressure were normal. His urine was ‘‘cola-coloured’’ with ++++ blood, +++ protein on dipstick but with normal microscopy. He was commenced on benzylpenicillin for suspected glomerulonephritis and required treatment for oliguria and hyperkalaemia (serum potassium 6 mmol/l). An ultrasound showed normally-sized kidneys with echogenic cortex and a bladder containing multiple echoes, suggestive of debris. His C-reactive protein rose to 154 mg/l with white blood cells at presentation of 20.8 · 109/l. His creatinine remained stable and his urinary myoglobin came back as 82 lg/l. His HAMA score shortly after discharge was 39/ 40 and a repeat renal ultrasound was normal. At two years since his episode of myoglobinuria he remains well on prednisolone with no further episodes. 2.3. Patient 3 This boy was diagnosed at four and a half years of age with a deletion of intron 49 and exon 50. He transferred from alternate-day to daily prednisolone 15 mg (0.74 mg/kg) at the age of six years and two months, with an improvement in his HAMA score from 36 to 40/40. He had six episodes of myoglobinuria over a 15-month period. The first was at the age of six and a half following a strenuous football match. At lunch he became pale and
sweaty and slumped forward at the table. Soon afterward he had red urine. This was tested at the local Accident and Emergency department and was positive for blood. He was treated for a presumed urinary tract infection and the pigmenturia resolved with a second micturition. A renal ultrasound was normal. Further episodes lasted less than 24 h and were precipitated by physical exercise. 3. Discussion The majority of episodes of myoglobinuria described above were related to physical exercise, although it is not clear what triggered rhabdomyolysis in child 2. All three boys had shown a substantial improvement in motor ability on prednisolone therapy. The cases also illustrate the variable presentation, even by the same child, with some episodes accompanied by systemic upset and others not. Although myoglobinuria may lead to acute tubular necrosis [9,10], the episodes experienced by children 1 and 3 were short-lived and did not require treatment. The mild, self-limiting nature of most of these episodes does not detract from the importance of prompt recognition of myoglobinuria and the institution of appropriate management. There are published guidelines on the management of severe rhabdomyolysis [9,10]. For milder episodes, an increase in fluid intake and appropriate monitoring of renal function may be all that is required. Initial recognition may be problematic, however. It is essential that the parents of all corticosteroid-treated boys are aware of the possibility of myoglobinuria and the need to increase oral fluid intake and seek medical attention should it occur. A lack of awareness among junior medical staff may delay diagnosis and lead to a battery of investigations which may not be helpful, or to inappropriate treatment for urinary tract infection. The results of a urinary myoglobin assay may take several days to arrive, rendering it of little value in the clinical management of the initial presentation. A clue in the acute situation may be obtained from a positive urine dipstick for blood in the absence of red cells on urine microscopy, since the benzidine dipstick does not differentiate between haemoglobin and myoglobin. Therefore, in DMD boys, a history of dark, tea- or cola-coloured urine, with a urine dipstick positive for blood but with no red blood cells, bacilli or leucocytes on microscopy, should be considered to be myoglobinuria, pending laboratory confirmation, and treatment instituted accordingly. Acknowledgement We wish to thank Dr. A. Fall, Consultant Paediatrician, James Cook University Hospital, Middlesbrough for provision of clinical information for this case report. Dr. Garrood and the work of the Muscle Centre, Institute of Human Genetics, are supported by funding from the Muscular Dystrophy Campaign.
P. Garrood et al. / Neuromuscular Disorders 18 (2008) 71–73
References [1] Dubowitz V, Kinali M, Main M, Mercuri E, Muntoni F. Remission of clinical signs in early Duchenne muscular dystrophy on intermittent low-dosage prednisolone therapy. Eur J Paediatr Neurol 2002;6(3):153–9. [2] Bushby K, Muntoni F, Urtizberea A, Hughes R, Griggs R. Report on the 124th ENMC International Workshop. Treatment of Duchenne muscular dystrophy; defining the gold standards of management in the use of corticosteroids. 2–4 April 2004, Naarden, The Netherlands. Neuromuscular Disorders 2004;14(8–9):526–34. [3] Manzur AY, Kuntzer T, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev 2006:4, [Systematic Review]. [4] Petrof BJ, Shrager JB, Stedman HH, Kelly AM, Sweeney HL. Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc Natl Acad Sci USA 1993;90(8): 3710–4.
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[5] Figarella-Branger D, Baeta Machado AM, Putzu GA, Malzac P, Voelckel MA, Pellissier JF. Exertional rhabdomyolysis and exercise intolerance revealing dystrophinopathies. Acta Neuropathol 1997;94(1):48–53. [6] Yokota R, Shirotani M, Kouchi I, et al. Subclinical Becker’s muscular dystrophy presenting with severe heart failure. Int Med 2004;43(3):204–8. [7] Girshin M, Mukherjee J, Clowney R, Singer LP, Wasnick J. The postoperative cardiovascular arrest of a 5-year-old male: an initial presentation of Duchenne’s muscular dystrophy. Paediatr Anaesth 2006;16(2):170–3. [8] Obata R, Yasumi Y, Suzuki A, Nakajima Y, Sato S. Rhabdomyolysis in association with Duchenne’s muscular dystrophy. Can J Anaesth 1999;46(6):564–6. [9] Sauret JM, Marinides G, Wang GK. Rhabdomyolysis. Am Fam Physician 2002;65(5):907–12. [10] Evenepoel P. Acute toxic renal failure. Best Pract Res Clin Anaesthesiol 2004;18(1):37–52.