Comment
accuracy, track disease progression, and ideally change in response to treatment. The MRI substudy suggests that such measures might be on the horizon and highlights the value of exploring potential biomarkers within clinical trials. With advances in our understanding of the pathogenesis of multiple system atrophy, new therapies might soon be available for testing, and the present study will aid in the approach to future clinical trials aimed at slowing this devastating neurological disease.
2 3
4
5 6
Wendy R Galpern
7
National Institute of Neurological Disorders and Stroke, National Institutes of Health, 6001 Executive Boulevard, #2225, Bethesda, MD 20892, USA [email protected]
8
I declare no competing interests. 1
Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008; 71: 670–76.
9
10
Stefanova N, Bucke P, Duerr S, Wenning GK. Multiple system atrophy: an update. Lancet Neurol 2009; 8: 1172–78. Poewe W, Seppi K, Fitzer-Attas CJ, et al. Efficacy of rasagiline in patients with the parkinsonian variant of multiple system atrophy: a randomised, placebo-controlled trial. Lancet Neurol 2014; published online Dec 8. http://dx.doi.org/10.1016/S1474-4422(14)70288-1. Wenning GK, Tison F, Seppi K, et al. Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS). Mov Disord 2004; 19: 1391–402. Wenning GK, Geser F, Krismer F, et al. The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol 2013; 12: 264–74. Stankovic I, Krismer F, Jesic A, et al. Cognitive impairment in multiple system atrophy: a position statement by the Neuropsychology Task Force of the MDS Multiple System Atrophy (MODIMSA) study group. Mov Disord 2014; 29: 857–67. Brooks DJ, Seppi K. Proposed neuroimaging criteria for the diagnosis of multiple system atrophy. Mov Disord 2009; 24: 949–64. Stefanova N, Poewe W, Wenning GK. Rasagiline is neuroprotective in a transgenic model of multiple system atrophy. Exp Neurol 2008; 210: 421–27. Low PA, Robertson D, Gilman S, et al. Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014; 13: 268–75. Achey M, Aldred JL, Aljehani N, et al. The past, present, and future of telemedicine for Parkinson’s disease. Mov Disord 2014; 29: 871–83.
Prevention of cardiomyopathy in Duchenne muscular dystrophy Duchenne muscular dystrophy is a severe X-linked disease due to loss of dystrophin in skeletal and cardiac muscle. Boys develop progressive weakness and lose the ability to walk by 10 years of age, then develop dilated cardiomyopathy, a leading cause of death. In this context, Subha V Raman and colleagues1 present a placebo-controlled randomised trial in 42 boys from three US centres with Duchenne muscular dystrophy treated with either eplerenone or placebo in association with background angiotensin-converting-enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Two patterns of cardiac involvement are recognised in Duchenne muscular dystrophy: a left ventricular wall motion abnormality, which is frequent in the early stage of the disease, and dilated cardiomyopathy,2,3 which is more frequent in the second decade of life, the age of the patients recruited in the study by Raman and colleagues.1 To prolong survival in boys presenting with a restrictive ventilatory defect and sleep-related hypoxyaemia, ventilatory support and aggressive respiratory management are required.2 Prolonged survival owing to improvement in clinical care, such as non-invasive positive pressure ventilation, has led to an increased incidence of cardiomyopathy.3 www.thelancet.com/neurology Vol 14 February 2015
In some patients, the progression of Duchenne muscular dystrophy is responsive to corticosteroids, which can prolong walking ability by about a year and improve quality of life, although the benefits and severity of sideeffects are variable. In 2004, a European Neuromuscular Centre workshop recommended daily steroids as the gold standard, on the basis of their benefit on skeletal and respiratory muscle function,4,5 but other regimens are under investigation. Results from a retrospective analysis showed that steroid-naive patients aged 10 years or younger were four times more likely to have decreased cardiac function than patients in the same age group who had received steroids, whereas patients older than 10 years who had not received steroids were 15-times more likely to have decreased cardiac function than patients in this age group who had taken steroids.6 In a small randomised trial, early ACEI (ie, perindopril) monotherapy in 9·5–13·0 year-old boys with Duchenne muscular dystrophy delayed the onset and the progression of left ventricular dysfunction, monitored by decline in ejection fraction.7 The beneficial effect of combined β-blockers and ACEI was established in 56 wheelchair-bound patients (mean age 19·5 years [SD 5·8] at study entry) with a 5-year survival of 93% and 7-year survival of 84%8. In the study by Raman
Published Online December 30, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70326-6 See Articles page 153
127
Comment
and colleagues,1 boys with Duchenne muscular dystrophy (aged 11–19 years) were given eplerenone (25 mg) or placebo in addition to other cardioprotective drugs; children were followed-up for 12 months, and a significant decrease in left ventricle circumferential strain on cardiac MRI (primary outcome) was reported in the eplerenone group compared with the placebo group.1 Longer follow-up would be necessary to determine whether the combination of eplerenone and other cardioprotective treatments results in prolonged survival. Another potential limitation of this trial is the small cohort of patients, but in a rare disorder such as Duchenne muscular dystrophy, it is difficult to enrol an adequate number of patients and undertake blinded cardiac MRI. A third possible limitation is the fact that participants were taking several different drugs in addition to eplerenone or placebo. In fact, duration of use of ACE inhibitors, ARBs, and β-blockers was 1–2 years. Most patients (35 [83%] of 42) were on steroids in addition to eplerenone or placebo, for a mean of 5·5 years (either around 30 mg of prednisone or around 25 mg of deflazacort per day). In patients already treated with steroids, an aldosterone inhibitor could conceivably be more beneficial because of the secondary mineral-corticoid effect of steroids. Alternatively, corticosteroid treatment might itself affect the development of cardiomyopathy.3,5,6 Raman and colleauges1 neither discuss the role of the different steroids used nor specify whether they had differential benefit. In fact, increase in bodyweight might negatively affect cardiac function, and a differential weight increase has been noted with deflazacort versus prednisone.9 A future trial could assess the effects of eplerenone on left ventricular function in younger patients and on motor outcomes. When investigating potential new drugs for Duchenne muscular dystrophy it will also be important to realise that drugs used for adult heart failure do not necessarily benefit children, and that the dystrophic processes differ between heart and muscle: in the heart, necrosis starts from the posterobasal region of the left ventricle, then remodelling occurs with ventricular dilatation and reduction of ejection fraction,3 whereas muscle is uniformly affected by degeneration. Despite the difficulty in testing new therapies for Duchenne muscular dystrophy, several drugs are now clinically available at various stages of the disease: corticosteroids, cardioprotective drugs, and, following this study, possibly also eplerenone. Much attention 128
has been given to molecular therapies—ie, antisense oligonucleotides to skip specific deletion mutations and ataluren to bypass stop-codon mutations.10 The benefit of molecular therapies remains an open issue, because both drugs bring a modest increase in 6-min walk test, but whether they lead to increased survival is unclear. These drugs await validation in larger cohorts of patients. Furthermore, both types of therapy can only benefit the subsets of patients with Duchenne muscular dystrophy who have the relevant mutations.10 The absence of important contraindications for eplerenone offers a new drug to clinical practice that could potentially improve and prolong the life of boys with Duchenne muscular dystrophy: the progress of this disease, once judged fatal by 20 years of age, has now shifted and many patients are surviving up to the fourth decade with various combinations of clinical care. Future trials should investigate whether treatment of cardiomyopathy with eplerenone could benefit not only patients with Duchenne muscular dystrophy, but also those with severe cardiomyopathy associated with other muscular dystrophies, such as Becker muscular dystrophy, sarcoglycanopathies, or laminopathies. Corrado Angelini IRCCS Fondazione San Camillo Hospital, Venice, Italy [email protected] I declare no competing interests. 1
2 3
4
5
6 7
8
9 10
Raman SV, Hor KN, Mazur W, et al. Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, placebo-controlled trial. Lancet Neurol 2014; published online Dec 30. http://dx.doi.org/10.1016/ S1474-4422(14)70318-7. Melacini P. Cardiac problems in DMD. In: Angelini C, ed. Muscular dystrophy: causes and management. New York: Nova Science Publisher, 2013: 367–80. Melacini P, Vianello A, Villanova C, et al. Cardiac and respiratory involvement in advanced stage Duchenne muscular dystrophy. Neuromusc Disord 1996; 6: 367–76. Bushby K, Muntoni F, Urtizberea A, et al. Report on the 124th ENMC International Workshop. Treatment of Duchenne muscular dystrophy; defining the gold standards of management in the use of corticosteroids. Neuromusc Disord 2004; 14: 526–34. Biggar WD, Harris VA, Eliasoph L, Alman B. Long-term benefits of Deflazacort treatment for boys with Duchenne muscular dystrophy in their second decade. Neuromusc Disord 2006; 16: 249–55. Markham LW, Spicer RL, Khoury PR, et al. Steroid therapy and cardiac function in Duchenne muscular dystrophy. Pediatr Cardiol 2005; 26: 768–71. Duboc D, Meune C, Lerebours G, Devaux JY, Vaksmann G, Becane HM. Effect of perindopril on the onset and progression of left ventricular dysfunction in Duchenne muscular dystrophy. J Am Coll Cardiol 2005; 45: 855–57. Ogata H, Ishikawa Y, Ishikawa Y, Minami R. Beneficial effects of beta-blockers and angiotensin-converting enzyme inhibitors in Duchenne muscular dystrophy. J Cardiol 2009; 53: 72–78. Angelini C. The role of corticosteroids in muscular dystrophy: a critical appraisal. Muscle Nerve 2007; 36: 424–35. Finkel RS, Flanigan KM, Wong B, et al. Phase 2a study of Ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dystrophy. PLos One 2013; 8: e81302.
www.thelancet.com/neurology Vol 14 February 2015
accuracy, track disease progression, and ideally change in response to treatment. The MRI substudy suggests that such measures might be on the horizon and highlights the value of exploring potential biomarkers within clinical trials. With advances in our understanding of the pathogenesis of multiple system atrophy, new therapies might soon be available for testing, and the present study will aid in the approach to future clinical trials aimed at slowing this devastating neurological disease.
2 3
4
5 6
Wendy R Galpern
7
National Institute of Neurological Disorders and Stroke, National Institutes of Health, 6001 Executive Boulevard, #2225, Bethesda, MD 20892, USA [email protected]
8
I declare no competing interests. 1
Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008; 71: 670–76.
9
10
Stefanova N, Bucke P, Duerr S, Wenning GK. Multiple system atrophy: an update. Lancet Neurol 2009; 8: 1172–78. Poewe W, Seppi K, Fitzer-Attas CJ, et al. Efficacy of rasagiline in patients with the parkinsonian variant of multiple system atrophy: a randomised, placebo-controlled trial. Lancet Neurol 2014; published online Dec 8. http://dx.doi.org/10.1016/S1474-4422(14)70288-1. Wenning GK, Tison F, Seppi K, et al. Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS). Mov Disord 2004; 19: 1391–402. Wenning GK, Geser F, Krismer F, et al. The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol 2013; 12: 264–74. Stankovic I, Krismer F, Jesic A, et al. Cognitive impairment in multiple system atrophy: a position statement by the Neuropsychology Task Force of the MDS Multiple System Atrophy (MODIMSA) study group. Mov Disord 2014; 29: 857–67. Brooks DJ, Seppi K. Proposed neuroimaging criteria for the diagnosis of multiple system atrophy. Mov Disord 2009; 24: 949–64. Stefanova N, Poewe W, Wenning GK. Rasagiline is neuroprotective in a transgenic model of multiple system atrophy. Exp Neurol 2008; 210: 421–27. Low PA, Robertson D, Gilman S, et al. Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014; 13: 268–75. Achey M, Aldred JL, Aljehani N, et al. The past, present, and future of telemedicine for Parkinson’s disease. Mov Disord 2014; 29: 871–83.
Prevention of cardiomyopathy in Duchenne muscular dystrophy Duchenne muscular dystrophy is a severe X-linked disease due to loss of dystrophin in skeletal and cardiac muscle. Boys develop progressive weakness and lose the ability to walk by 10 years of age, then develop dilated cardiomyopathy, a leading cause of death. In this context, Subha V Raman and colleagues1 present a placebo-controlled randomised trial in 42 boys from three US centres with Duchenne muscular dystrophy treated with either eplerenone or placebo in association with background angiotensin-converting-enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Two patterns of cardiac involvement are recognised in Duchenne muscular dystrophy: a left ventricular wall motion abnormality, which is frequent in the early stage of the disease, and dilated cardiomyopathy,2,3 which is more frequent in the second decade of life, the age of the patients recruited in the study by Raman and colleagues.1 To prolong survival in boys presenting with a restrictive ventilatory defect and sleep-related hypoxyaemia, ventilatory support and aggressive respiratory management are required.2 Prolonged survival owing to improvement in clinical care, such as non-invasive positive pressure ventilation, has led to an increased incidence of cardiomyopathy.3 www.thelancet.com/neurology Vol 14 February 2015
In some patients, the progression of Duchenne muscular dystrophy is responsive to corticosteroids, which can prolong walking ability by about a year and improve quality of life, although the benefits and severity of sideeffects are variable. In 2004, a European Neuromuscular Centre workshop recommended daily steroids as the gold standard, on the basis of their benefit on skeletal and respiratory muscle function,4,5 but other regimens are under investigation. Results from a retrospective analysis showed that steroid-naive patients aged 10 years or younger were four times more likely to have decreased cardiac function than patients in the same age group who had received steroids, whereas patients older than 10 years who had not received steroids were 15-times more likely to have decreased cardiac function than patients in this age group who had taken steroids.6 In a small randomised trial, early ACEI (ie, perindopril) monotherapy in 9·5–13·0 year-old boys with Duchenne muscular dystrophy delayed the onset and the progression of left ventricular dysfunction, monitored by decline in ejection fraction.7 The beneficial effect of combined β-blockers and ACEI was established in 56 wheelchair-bound patients (mean age 19·5 years [SD 5·8] at study entry) with a 5-year survival of 93% and 7-year survival of 84%8. In the study by Raman
Published Online December 30, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70326-6 See Articles page 153
127
Comment
and colleagues,1 boys with Duchenne muscular dystrophy (aged 11–19 years) were given eplerenone (25 mg) or placebo in addition to other cardioprotective drugs; children were followed-up for 12 months, and a significant decrease in left ventricle circumferential strain on cardiac MRI (primary outcome) was reported in the eplerenone group compared with the placebo group.1 Longer follow-up would be necessary to determine whether the combination of eplerenone and other cardioprotective treatments results in prolonged survival. Another potential limitation of this trial is the small cohort of patients, but in a rare disorder such as Duchenne muscular dystrophy, it is difficult to enrol an adequate number of patients and undertake blinded cardiac MRI. A third possible limitation is the fact that participants were taking several different drugs in addition to eplerenone or placebo. In fact, duration of use of ACE inhibitors, ARBs, and β-blockers was 1–2 years. Most patients (35 [83%] of 42) were on steroids in addition to eplerenone or placebo, for a mean of 5·5 years (either around 30 mg of prednisone or around 25 mg of deflazacort per day). In patients already treated with steroids, an aldosterone inhibitor could conceivably be more beneficial because of the secondary mineral-corticoid effect of steroids. Alternatively, corticosteroid treatment might itself affect the development of cardiomyopathy.3,5,6 Raman and colleauges1 neither discuss the role of the different steroids used nor specify whether they had differential benefit. In fact, increase in bodyweight might negatively affect cardiac function, and a differential weight increase has been noted with deflazacort versus prednisone.9 A future trial could assess the effects of eplerenone on left ventricular function in younger patients and on motor outcomes. When investigating potential new drugs for Duchenne muscular dystrophy it will also be important to realise that drugs used for adult heart failure do not necessarily benefit children, and that the dystrophic processes differ between heart and muscle: in the heart, necrosis starts from the posterobasal region of the left ventricle, then remodelling occurs with ventricular dilatation and reduction of ejection fraction,3 whereas muscle is uniformly affected by degeneration. Despite the difficulty in testing new therapies for Duchenne muscular dystrophy, several drugs are now clinically available at various stages of the disease: corticosteroids, cardioprotective drugs, and, following this study, possibly also eplerenone. Much attention 128
has been given to molecular therapies—ie, antisense oligonucleotides to skip specific deletion mutations and ataluren to bypass stop-codon mutations.10 The benefit of molecular therapies remains an open issue, because both drugs bring a modest increase in 6-min walk test, but whether they lead to increased survival is unclear. These drugs await validation in larger cohorts of patients. Furthermore, both types of therapy can only benefit the subsets of patients with Duchenne muscular dystrophy who have the relevant mutations.10 The absence of important contraindications for eplerenone offers a new drug to clinical practice that could potentially improve and prolong the life of boys with Duchenne muscular dystrophy: the progress of this disease, once judged fatal by 20 years of age, has now shifted and many patients are surviving up to the fourth decade with various combinations of clinical care. Future trials should investigate whether treatment of cardiomyopathy with eplerenone could benefit not only patients with Duchenne muscular dystrophy, but also those with severe cardiomyopathy associated with other muscular dystrophies, such as Becker muscular dystrophy, sarcoglycanopathies, or laminopathies. Corrado Angelini IRCCS Fondazione San Camillo Hospital, Venice, Italy [email protected] I declare no competing interests. 1
2 3
4
5
6 7
8
9 10
Raman SV, Hor KN, Mazur W, et al. Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, placebo-controlled trial. Lancet Neurol 2014; published online Dec 30. http://dx.doi.org/10.1016/ S1474-4422(14)70318-7. Melacini P. Cardiac problems in DMD. In: Angelini C, ed. Muscular dystrophy: causes and management. New York: Nova Science Publisher, 2013: 367–80. Melacini P, Vianello A, Villanova C, et al. Cardiac and respiratory involvement in advanced stage Duchenne muscular dystrophy. Neuromusc Disord 1996; 6: 367–76. Bushby K, Muntoni F, Urtizberea A, et al. Report on the 124th ENMC International Workshop. Treatment of Duchenne muscular dystrophy; defining the gold standards of management in the use of corticosteroids. Neuromusc Disord 2004; 14: 526–34. Biggar WD, Harris VA, Eliasoph L, Alman B. Long-term benefits of Deflazacort treatment for boys with Duchenne muscular dystrophy in their second decade. Neuromusc Disord 2006; 16: 249–55. Markham LW, Spicer RL, Khoury PR, et al. Steroid therapy and cardiac function in Duchenne muscular dystrophy. Pediatr Cardiol 2005; 26: 768–71. Duboc D, Meune C, Lerebours G, Devaux JY, Vaksmann G, Becane HM. Effect of perindopril on the onset and progression of left ventricular dysfunction in Duchenne muscular dystrophy. J Am Coll Cardiol 2005; 45: 855–57. Ogata H, Ishikawa Y, Ishikawa Y, Minami R. Beneficial effects of beta-blockers and angiotensin-converting enzyme inhibitors in Duchenne muscular dystrophy. J Cardiol 2009; 53: 72–78. Angelini C. The role of corticosteroids in muscular dystrophy: a critical appraisal. Muscle Nerve 2007; 36: 424–35. Finkel RS, Flanigan KM, Wong B, et al. Phase 2a study of Ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dystrophy. PLos One 2013; 8: e81302.
www.thelancet.com/neurology Vol 14 February 2015
