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Cardiac transplantation in Becker muscular dystrophy
Neuromusc.Disord.,Vol. 2, No. 3, pp. 165-167, 1992 Printed in Great Britain
0960-8966/92 $5.00 + 0.00 PergamonPress Ltd
REVIEW ARTICLE CARDIAC
TRANSPLANTATION
IN BECKER
MUSCULAR
DYSTROPHY
R. M. QUINLIVAN* and V. D U B O W I T Z t *The Marjorie Crowe Neuromuscular Clinic, Newcomen Centre, Guy's Hospital, St. Thomas' Street, London SE1; and i" The Neuromuscular Clinic, Department of Paediatdcs and Neonatal Medicine, Royal Postgraduate Medical School, London W12 0NN, U.K. (Received 28 April 1992; accepted 25 June 1992)
Abstract--Becker muscular dystrophy is associated with abnormal cardiac features in about 75% of cases; up to one-third will develop ventricular dilatation leading to congestive cardiac failure. As this form of muscular dystrophy is relatively benign, failure to respond to medical treatment warrants assessment for cardiac transplantation. Key words: Muscular dystrophy, Becker muscular dystrophy, cardiomyopathy, cardiac failure, cardiac transplant.
Following the pioneering work of Lower and Shumway, the first successful human cardiac transplant was performed by Barnard at the Groote Schuur Hospital in Cape Town in 1967 [1]. The patient lived for 18 days before succumbing to respiratory complications. Initial optimism in the procedure led to the evolution of a number of transplant centres world-wide. The results were, however, uniformly poor with a very high mortality and the procedure was, for the most part, abandoned. The advent of cyclosporin A in the 1980s led to a new wave of optimism with a resurgence in the number of patients transplanted. The 1 yr survival rate is now about 90°/0, although there is a high level of coronary vascular disease at 5 yr (40%). Most patients will need retransplantation after 10-15 yr because of gradual deterioration of the graft. Cardiac transplantation is the mainstay of treatment for patients with end-stage cardiac disease (defined as an expected survival of less than 1 yr and/or an ejection fraction of less than 10°/0). Almost one-half of the patients transplanted have idiopathic dilated cardiomyopathy, the rest have mainly ischaemic heart disease and a small number (about 5%) have miscellaneous conditions such as end-stage valvular disease. Chronic obstructive airways disease and malignancy are considered to be the only contraindications for surgery [2]. Patients are no longer excluded from surgery because of
age (previously excluded over 55 yr) or associated life limiting diseases. For this reason we seek to dispel any prejudice as far as patients with Becker muscular dystrophy are concerned. Becker and Keiner [3] first described this benign form of muscular dystrophy. As with Duchenne muscular dystrophy (DMD), the condition is sex linked, presents with pseudohypertrophy of the calf muscles and proximal muscle weakness. The serum creatine kinase is markedly elevated. Becker realized that these patients differed from D M D , the age at onset of symptoms occurred later (often the second decade) and the rate of progression was generally slower. Only 10% of Becker's patients were chairbound before the age of 40 and none before 16 yr. In 1976 Emery and Skinner [4] reviewed the progress of 67 patients with BMD. All of them had pelvic girdle weakness, upper limb weakness did not become apparent until some 14 yr after the diagnosis was made. Pes cavus was common, but only a few patients developed contractures. Scoliosis and thoracic deformities occurred less frequently and were less severe than DMD. Only 38% of this cohort became chairbound, mobility being lost between 20 and 30 yr after the onset of symptoms. The life expectancy o f BMD patients was slightly reduced; however, some patients survived into the seventh decade. Twenty per cent of Emery's patients showed some evidence of cardiac 165
166
ReviewArticle
involvement (resting tachycardia, systolic murmurs, abnormal ECG), although myocardial failure was uncommon, occurring only in 3% of patients as a late phenomenon. More recently, the isolation of the D M D gene [5] and its product dystrophin, has led to improved diagnostic accuracy and the diagnosis of increasing numbers of BMD cases [6]. In addition, it has become apparent that the clinical spectrum of the disease is much more varied than originally thought. Bushby et al. [7] reviewed the incidence and prevalence of BMD in their local community. Deletion studies identified a number of patients who had previously been misdiagnosed as spinal muscular atrophy or limb girdle dystrophy. These authors established an incidence of at least 1 : 18,400 male births, a figure substantially higher than the previously quoted incidence of 1 : 30,000 live male births. Sunohara et al. [8] identified four new cases from a cohort of patients with a diagnosis of quadriceps myopathy: two had serious myocardial involvement. Gospe et al. [9] reported a kindred in whom the only features of a positive Xp21 deletion were myalgia and muscle cramps on exercise. Cardiac involvement occurs in over 80% of D M D patients, but overt cardiac failure is a terminal event in only about 10%. Consequently, the assumption has been that the milder BMD patients will be less likely to succumb due to myocardial involvement. Unfortunately, there is a growing body of evidence to the contrary [10-14]. It now appears that up to 50% of BMD cases will develop abnormal cardiac features, and cardiac failure is not necessarily a late feature of the disease. These reports suggest that the rate of progression of cardiac disease may be independent of the skeletal myopathy. There is some evidence that in certain cases the onset of cardiac disease pre-dates the skeletal myopathy. We know of one patient attending our clinic who developed cardiac manifestations 7 yr before the onset of muscle weakness; the diagnosis of BMD was made when he was 62 yr old, and at 67 yr he is still mobile. Sakata et al. reported a young patient who presented in cardiac failure [15]. Gold et al. [12] described a BMD kindred in whom cardiomyopathy was the presenting feature, and Hootsmans and Meerschwan [16] detected two patients with probable BMD following a study of E M G findings in patients with idiopathic hypertrophic cardiomyopathy.
Steare et al. [17] investigated 19 BMD patients. Two were dyspnoeic on exertion, the rest were asymptomatic. The ECG was abnormal in 74%, intraventricular conduction delay or right bundle branch block was present in 42%. Echocardiography demonstrated left ventricular dilatation in 37%, while 6 3 o had subnormal systolic function due to global hypokinesia. Six of these patients were less than 22 yr of age. We believe the evidence for significant myocardial involvement to be sufficient to warrant screening of all BMD patients at regular intervals using ECG and echocardiography. Close follow-up will be needed for those affected. Once detected, cardiac failure should be assumed to be progressive. Rapid deterioration may occur in some cases and should be anticipated. Initially, the patient can be managed conservatively with diuretics, vasodilators and/ or cardiac glycosides. Once end-stage cardiac failure occurs the only hope for survival is cardiac transplantation. Cardiologists are likely to have reservations about accepting such patients for surgery. When they ask "what is the prognosis for the patient?", the clinician might justifiably respond that the prognosis depends entirely on the transplant and not on the muscle disease, given that the latter may be relatively mild and the patient is relatively free of any respiratory deficit. Anaesthetising any patient with end-stage cardiac failure is hazardous and there is a high risk of cardiac arrest during induction. Becker patients will have the small additional risk of rhabdomyolysis and/or the malignant hyperthermia reaction [18]. In general, antiarrhythmic agents are safe, but it would be advisable to avoid slow calcium channel blockers such as verapamil, phenytoin and procainamide which have been shown to increase skeletal weakness in D M D [19, 20]. To date, there have been five successful BMD transplants (and one female Emery-Dreifuss) [13, 14, 21, 22]. At least two have been reported to be doing well and have returned to full time employment. It will be interesting to see whether long-term immunosuppression with prednisolone has a beneficial effect in delaying the progression of skeletal muscle weakness [23, 24]. In conclusion, BMD is more common than previously thought. The mode of presentation and rate of progression is variable. Serious cardiac manifestations can present early, sometimes before the skeletal symptoms are
Review Article
apparent. The benign nature of the skeletal myopathy, which is compatible with many years of mobility and longevity, makes these patients suitable candidates for cardiac transplantation. REFERENCES
I.
2.
3.
4. 5.
6.
7. 8. 9.
10.
Lansman S L, Ergin M, Grieppe R. A history of cardiac transplantation. In: Wallwork J. ed. Heart and Lung Transplantation. Philadelphia: W B Saunders, 1989: 3-20. Thompson M. Recipient selection and assessment: indications for transplantation. In: Wallwork J, ed. Heart and Lung Transplantation. Philadelphia: W B Saunders, 1989: 87-100. Walton J, Gardner-Medwin D. Progressive muscular dystrophy and the myotonic disorders. In: Walton J, ed. Disorders of Voluntary Muscle. Edinburgh: Churchill Livingstone, 198 l : 4 t h Edn. 481-524. Emery A E H, Skinner R. Clinical studies in benign (Becker type) X linked muscular dystrophy. Clin Genet 1976; 10: 189-201. Baumbach L, Chambelain J S, Ward P A, Ferwall N J, Caskey C T. Molecular and clinical correlations of deletions leading to Duchenne and Becker muscular dystrophies. Neurology 1989; 39: 465--474. McDonald T D, Medori R, Younger D S, et al. Becker muscular dystrophy or spinal muscular atrophy?--dystrophin studies resolve conflicting results of electromyography and muscle biopsy. Neuromusc Disord 1991; 1: 195-200. Bushby K M D, Thambyanan M, Gardner-Medwin D. The prevalence and incidence of Becker muscular dystrophy. Lancet 1991; 337: 1022-1024. Sunohara N, Arahata K, Hoffman E P, et al. Quadriceps myopathy: forme fruste of Becker muscular dystrophy. Ann Neurol 1990; 28: 634-639. Gospe S M, Lazaro R P, Laura N S, Grootschollter P M, Scott M O, Fischbeck K H. Familial X linked myalgia and cramps. A non-progressive myopathy associated with a deletion in the dystrophin gene. Neurology 1989; 39: 1277-1280. Ringel S P, Carvoll J E, Schold C. The spectrum of X linked recessive muscular dystrophy. Arch Neurol 1977; 34: 408-416.
167
11. Katlyer B C, Misra S, Somani P N, Chaterji A M. Congestive cardiomyopathy in a family of Becker's X linked muscular dystrophy. Postgrad Med J 1977; 53: 12-15. 12. Gold R, Kress W, Meurers B, Meng G, Muller C. Brief communication: Becker muscular dystrophy: detection of unusual disease courses by combined approach to dystrophin analysis. Muscle Nerve 1992; 15: 214-218. 13. Casazzo F, Bambilla S G, Salvato A, Moraidi L, Gonda E, Bonacina E. Cardiac transplantation in Becker muscular dystrophy. J. Neurol 1988; 235: 496498. 14. Donofrio D, Challa V, Hackshaw B, Mills S, Cordwell R. Cardiac transplantation in a patient with Becker muscular dystrophy and cardiomyopathy. Arch Neurol 1989; 46: 705-707. 15. Sakata C, Sunohara N, Nonaka I, Arahata K, Sugita H. A case of Becket muscular dystrophy presenting cardiac failure as an initial symptom. Rinsho Shinkeigaku 1990; 30:210-213 (in Japanese). 16. Hootsmans W J M, Meerschwan I S. Electromyography in patients with hypertrophic obstructive cardiomyopathy. Neurology 1971; 21: 801816. 17. Steare S E, Benatar A, Dubowitz V. Subclinical cardiomyopathy in Becker muscular dystrophy. Br Heart J 1992; (in press). 18. Bush A, Dubowitz V. Fatal rhabdomyolysis complicating general anaesthesia in a child with Becker muscular dystrophy. Neuromusc D isord 1991; 1: 201-204. 19. Zalman F, PerloffJ K, Durrant N, Campion D. Acute respiratory failure following intravenous verapamil in Duchenne muscular dystrophy. Am Heart J 1983; 3: 195-200. 20. Ilan Y. Intravenous verapamil for tachyarrhythmias in Duchenne muscular dystrophy. Pediatr Cardiol 1990; I1: 177-178. 21. Sakata C, Yamaada H, Sunohara N, Arahata K, Nonaka I. Cardiomyopathy in Becker muscular dystrophy. Rinsho Shinkeigaku 1990; 30:952-955 (in Japanese). 22. Merchut M P, Zdonczyk D, Gujrati M. Cardiac transplantation in a female with Emery Dreifuss muscular dystrophy. J. Neurol 1990; 237:31 6-319. 23. Dubowitz V. Prednisone in Duchenne dystrophy. Neuromusc Disord 1991; 1: 161-163. 24. Griggs R C, Moxley R T, Mendell J R, et al. Prednisone in Duchenne dystrophy: a randomised controlled trial defining the time course and dose response. Arch Neurol 1991; 48: 383-388.
0960-8966/92 $5.00 + 0.00 PergamonPress Ltd
REVIEW ARTICLE CARDIAC
TRANSPLANTATION
IN BECKER
MUSCULAR
DYSTROPHY
R. M. QUINLIVAN* and V. D U B O W I T Z t *The Marjorie Crowe Neuromuscular Clinic, Newcomen Centre, Guy's Hospital, St. Thomas' Street, London SE1; and i" The Neuromuscular Clinic, Department of Paediatdcs and Neonatal Medicine, Royal Postgraduate Medical School, London W12 0NN, U.K. (Received 28 April 1992; accepted 25 June 1992)
Abstract--Becker muscular dystrophy is associated with abnormal cardiac features in about 75% of cases; up to one-third will develop ventricular dilatation leading to congestive cardiac failure. As this form of muscular dystrophy is relatively benign, failure to respond to medical treatment warrants assessment for cardiac transplantation. Key words: Muscular dystrophy, Becker muscular dystrophy, cardiomyopathy, cardiac failure, cardiac transplant.
Following the pioneering work of Lower and Shumway, the first successful human cardiac transplant was performed by Barnard at the Groote Schuur Hospital in Cape Town in 1967 [1]. The patient lived for 18 days before succumbing to respiratory complications. Initial optimism in the procedure led to the evolution of a number of transplant centres world-wide. The results were, however, uniformly poor with a very high mortality and the procedure was, for the most part, abandoned. The advent of cyclosporin A in the 1980s led to a new wave of optimism with a resurgence in the number of patients transplanted. The 1 yr survival rate is now about 90°/0, although there is a high level of coronary vascular disease at 5 yr (40%). Most patients will need retransplantation after 10-15 yr because of gradual deterioration of the graft. Cardiac transplantation is the mainstay of treatment for patients with end-stage cardiac disease (defined as an expected survival of less than 1 yr and/or an ejection fraction of less than 10°/0). Almost one-half of the patients transplanted have idiopathic dilated cardiomyopathy, the rest have mainly ischaemic heart disease and a small number (about 5%) have miscellaneous conditions such as end-stage valvular disease. Chronic obstructive airways disease and malignancy are considered to be the only contraindications for surgery [2]. Patients are no longer excluded from surgery because of
age (previously excluded over 55 yr) or associated life limiting diseases. For this reason we seek to dispel any prejudice as far as patients with Becker muscular dystrophy are concerned. Becker and Keiner [3] first described this benign form of muscular dystrophy. As with Duchenne muscular dystrophy (DMD), the condition is sex linked, presents with pseudohypertrophy of the calf muscles and proximal muscle weakness. The serum creatine kinase is markedly elevated. Becker realized that these patients differed from D M D , the age at onset of symptoms occurred later (often the second decade) and the rate of progression was generally slower. Only 10% of Becker's patients were chairbound before the age of 40 and none before 16 yr. In 1976 Emery and Skinner [4] reviewed the progress of 67 patients with BMD. All of them had pelvic girdle weakness, upper limb weakness did not become apparent until some 14 yr after the diagnosis was made. Pes cavus was common, but only a few patients developed contractures. Scoliosis and thoracic deformities occurred less frequently and were less severe than DMD. Only 38% of this cohort became chairbound, mobility being lost between 20 and 30 yr after the onset of symptoms. The life expectancy o f BMD patients was slightly reduced; however, some patients survived into the seventh decade. Twenty per cent of Emery's patients showed some evidence of cardiac 165
166
ReviewArticle
involvement (resting tachycardia, systolic murmurs, abnormal ECG), although myocardial failure was uncommon, occurring only in 3% of patients as a late phenomenon. More recently, the isolation of the D M D gene [5] and its product dystrophin, has led to improved diagnostic accuracy and the diagnosis of increasing numbers of BMD cases [6]. In addition, it has become apparent that the clinical spectrum of the disease is much more varied than originally thought. Bushby et al. [7] reviewed the incidence and prevalence of BMD in their local community. Deletion studies identified a number of patients who had previously been misdiagnosed as spinal muscular atrophy or limb girdle dystrophy. These authors established an incidence of at least 1 : 18,400 male births, a figure substantially higher than the previously quoted incidence of 1 : 30,000 live male births. Sunohara et al. [8] identified four new cases from a cohort of patients with a diagnosis of quadriceps myopathy: two had serious myocardial involvement. Gospe et al. [9] reported a kindred in whom the only features of a positive Xp21 deletion were myalgia and muscle cramps on exercise. Cardiac involvement occurs in over 80% of D M D patients, but overt cardiac failure is a terminal event in only about 10%. Consequently, the assumption has been that the milder BMD patients will be less likely to succumb due to myocardial involvement. Unfortunately, there is a growing body of evidence to the contrary [10-14]. It now appears that up to 50% of BMD cases will develop abnormal cardiac features, and cardiac failure is not necessarily a late feature of the disease. These reports suggest that the rate of progression of cardiac disease may be independent of the skeletal myopathy. There is some evidence that in certain cases the onset of cardiac disease pre-dates the skeletal myopathy. We know of one patient attending our clinic who developed cardiac manifestations 7 yr before the onset of muscle weakness; the diagnosis of BMD was made when he was 62 yr old, and at 67 yr he is still mobile. Sakata et al. reported a young patient who presented in cardiac failure [15]. Gold et al. [12] described a BMD kindred in whom cardiomyopathy was the presenting feature, and Hootsmans and Meerschwan [16] detected two patients with probable BMD following a study of E M G findings in patients with idiopathic hypertrophic cardiomyopathy.
Steare et al. [17] investigated 19 BMD patients. Two were dyspnoeic on exertion, the rest were asymptomatic. The ECG was abnormal in 74%, intraventricular conduction delay or right bundle branch block was present in 42%. Echocardiography demonstrated left ventricular dilatation in 37%, while 6 3 o had subnormal systolic function due to global hypokinesia. Six of these patients were less than 22 yr of age. We believe the evidence for significant myocardial involvement to be sufficient to warrant screening of all BMD patients at regular intervals using ECG and echocardiography. Close follow-up will be needed for those affected. Once detected, cardiac failure should be assumed to be progressive. Rapid deterioration may occur in some cases and should be anticipated. Initially, the patient can be managed conservatively with diuretics, vasodilators and/ or cardiac glycosides. Once end-stage cardiac failure occurs the only hope for survival is cardiac transplantation. Cardiologists are likely to have reservations about accepting such patients for surgery. When they ask "what is the prognosis for the patient?", the clinician might justifiably respond that the prognosis depends entirely on the transplant and not on the muscle disease, given that the latter may be relatively mild and the patient is relatively free of any respiratory deficit. Anaesthetising any patient with end-stage cardiac failure is hazardous and there is a high risk of cardiac arrest during induction. Becker patients will have the small additional risk of rhabdomyolysis and/or the malignant hyperthermia reaction [18]. In general, antiarrhythmic agents are safe, but it would be advisable to avoid slow calcium channel blockers such as verapamil, phenytoin and procainamide which have been shown to increase skeletal weakness in D M D [19, 20]. To date, there have been five successful BMD transplants (and one female Emery-Dreifuss) [13, 14, 21, 22]. At least two have been reported to be doing well and have returned to full time employment. It will be interesting to see whether long-term immunosuppression with prednisolone has a beneficial effect in delaying the progression of skeletal muscle weakness [23, 24]. In conclusion, BMD is more common than previously thought. The mode of presentation and rate of progression is variable. Serious cardiac manifestations can present early, sometimes before the skeletal symptoms are
Review Article
apparent. The benign nature of the skeletal myopathy, which is compatible with many years of mobility and longevity, makes these patients suitable candidates for cardiac transplantation. REFERENCES
I.
2.
3.
4. 5.
6.
7. 8. 9.
10.
Lansman S L, Ergin M, Grieppe R. A history of cardiac transplantation. In: Wallwork J. ed. Heart and Lung Transplantation. Philadelphia: W B Saunders, 1989: 3-20. Thompson M. Recipient selection and assessment: indications for transplantation. In: Wallwork J, ed. Heart and Lung Transplantation. Philadelphia: W B Saunders, 1989: 87-100. Walton J, Gardner-Medwin D. Progressive muscular dystrophy and the myotonic disorders. In: Walton J, ed. Disorders of Voluntary Muscle. Edinburgh: Churchill Livingstone, 198 l : 4 t h Edn. 481-524. Emery A E H, Skinner R. Clinical studies in benign (Becker type) X linked muscular dystrophy. Clin Genet 1976; 10: 189-201. Baumbach L, Chambelain J S, Ward P A, Ferwall N J, Caskey C T. Molecular and clinical correlations of deletions leading to Duchenne and Becker muscular dystrophies. Neurology 1989; 39: 465--474. McDonald T D, Medori R, Younger D S, et al. Becker muscular dystrophy or spinal muscular atrophy?--dystrophin studies resolve conflicting results of electromyography and muscle biopsy. Neuromusc Disord 1991; 1: 195-200. Bushby K M D, Thambyanan M, Gardner-Medwin D. The prevalence and incidence of Becker muscular dystrophy. Lancet 1991; 337: 1022-1024. Sunohara N, Arahata K, Hoffman E P, et al. Quadriceps myopathy: forme fruste of Becker muscular dystrophy. Ann Neurol 1990; 28: 634-639. Gospe S M, Lazaro R P, Laura N S, Grootschollter P M, Scott M O, Fischbeck K H. Familial X linked myalgia and cramps. A non-progressive myopathy associated with a deletion in the dystrophin gene. Neurology 1989; 39: 1277-1280. Ringel S P, Carvoll J E, Schold C. The spectrum of X linked recessive muscular dystrophy. Arch Neurol 1977; 34: 408-416.
167
11. Katlyer B C, Misra S, Somani P N, Chaterji A M. Congestive cardiomyopathy in a family of Becker's X linked muscular dystrophy. Postgrad Med J 1977; 53: 12-15. 12. Gold R, Kress W, Meurers B, Meng G, Muller C. Brief communication: Becker muscular dystrophy: detection of unusual disease courses by combined approach to dystrophin analysis. Muscle Nerve 1992; 15: 214-218. 13. Casazzo F, Bambilla S G, Salvato A, Moraidi L, Gonda E, Bonacina E. Cardiac transplantation in Becker muscular dystrophy. J. Neurol 1988; 235: 496498. 14. Donofrio D, Challa V, Hackshaw B, Mills S, Cordwell R. Cardiac transplantation in a patient with Becker muscular dystrophy and cardiomyopathy. Arch Neurol 1989; 46: 705-707. 15. Sakata C, Sunohara N, Nonaka I, Arahata K, Sugita H. A case of Becket muscular dystrophy presenting cardiac failure as an initial symptom. Rinsho Shinkeigaku 1990; 30:210-213 (in Japanese). 16. Hootsmans W J M, Meerschwan I S. Electromyography in patients with hypertrophic obstructive cardiomyopathy. Neurology 1971; 21: 801816. 17. Steare S E, Benatar A, Dubowitz V. Subclinical cardiomyopathy in Becker muscular dystrophy. Br Heart J 1992; (in press). 18. Bush A, Dubowitz V. Fatal rhabdomyolysis complicating general anaesthesia in a child with Becker muscular dystrophy. Neuromusc D isord 1991; 1: 201-204. 19. Zalman F, PerloffJ K, Durrant N, Campion D. Acute respiratory failure following intravenous verapamil in Duchenne muscular dystrophy. Am Heart J 1983; 3: 195-200. 20. Ilan Y. Intravenous verapamil for tachyarrhythmias in Duchenne muscular dystrophy. Pediatr Cardiol 1990; I1: 177-178. 21. Sakata C, Yamaada H, Sunohara N, Arahata K, Nonaka I. Cardiomyopathy in Becker muscular dystrophy. Rinsho Shinkeigaku 1990; 30:952-955 (in Japanese). 22. Merchut M P, Zdonczyk D, Gujrati M. Cardiac transplantation in a female with Emery Dreifuss muscular dystrophy. J. Neurol 1990; 237:31 6-319. 23. Dubowitz V. Prednisone in Duchenne dystrophy. Neuromusc Disord 1991; 1: 161-163. 24. Griggs R C, Moxley R T, Mendell J R, et al. Prednisone in Duchenne dystrophy: a randomised controlled trial defining the time course and dose response. Arch Neurol 1991; 48: 383-388.