IJCA-21911; No of Pages 2 International Journal of Cardiology xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Myocarditis in myasthenia gravis Josef Finsterer a,⁎, Claudia Stöllberger b a b
Krankenanstalt Rudolfstiftung, Vienna, Austria 2nd Medical Department with Cardiology and Intensive Care Medicine, Krankenanstalt Rudolfstiftung, Vienna, Austria
a r t i c l e
i n f o
Article history: Received 5 January 2016 Accepted 6 January 2016 Available online xxxx Keywords: Neuromuscular disorder Myocarditis Cardiac MRI Cardiac involvement Myocardium Cardiomyopathy
With interest we read the article by Mavrogeni et al. about a study of 33 patients with myasthenia gravis of which three were diagnosed with myocarditis, as assessed by cardiac MRI [1]. We have the following comments and concerns. Myocardial biopsy is still the golden standard for diagnosing myocarditis [2]. Did the three patients with myocarditis on cardiac MRI (cMRI) also undergo endo-myocardial biopsy to confirm the imaging diagnosis? Myocarditis was diagnosed if 2 of 3 cMRI abnormalities were present (STIR-T2 ratio N 2, early gadolinium enhancement (EGE) N4, or late gadolinium enhancement (LGE) N 0) [1]. These criteria were met in only one patient [1]. In the two other patients only LGE was present [1]. The presence of LGE alone, however, does not necessarily imply myocarditis. It could represent scarring due to other causes as well. The authors found myocarditis on cMRI in 9.1% of their myasthenia patients [1]. This figure is unexpectedly high and has not been previously reported. How do they explain the high prevalence of myocarditis compared to the previous findings? Are their cMRI findings false positive? Possibly, LGE does not represent myocarditis but rather fibrosis or other pathologies. The authors do not mention which are the clinical implications of their findings [1]. Did the three patients with current or previous myocarditis receive an additional immuno-suppression or was the therapeutic regimen for myasthenia changed because of the cMRI findings?
⁎ Corresponding author at: Postfach 20, 1180, Vienna, Austria. E-mail address: fifi[email protected] (J. Finsterer).
Did any of the three patients experience cardiac symptoms indicative of myocarditis at the time of the cMRI or previously? Myasthenia gravis not only affects the neuromuscular junction with consecutive exercise-induced muscle weakness and the heart in form of myocarditis, but may also affect the liver (primary sclerosing cholangitis), the pancreas (pancreatitis) [3], the thyroid gland (thyroiditis) [4], the joints (rheumatoid arthritis) [3], the arteries (systemic lupus erythematosus) [4], the muscle (myositis) [1], and the thymus (thymoma) [4]. Did the included patients also present with any of these other associated disorders? How many of the included patients had developed thymoma or hyperplasia of the thymus? How many of them had undergone thymectomy? We do not agree with the statement that takotsubo syndrome (TTS) is a manifestation of myasthenia gravis [1]. TTS usually results from excessive psychogenic or physical stress frequently occurring during a myasthenic crisis [5] but myasthenia without complications usually does not go along with TTS [6]. Myasthenia may be also associated with obstructive cardiomyopathy [7], heart failure [8], or troponin-T elevation [7,9,10]. Were there any indications for these cardiac abnormalities in the presented patients in addition to myocarditis? Ten to twenty percent of the patients with myasthenia do not present with any of the known antibodies associated with myasthenia [4]. Interestingly, all included patients were seropositive (AchR (n = 23), MUSK (n = 7), LPR4 (n = 4)) [1]. Did the authors deliberately only include patients who were seropositive? All patients were under a treatment with steroids and azathioprine 1–5 y after diagnosis [1]. This is surprising for two reasons. First, longterm treatment with steroids over five years is contraindicated because of the known side effects. Second, it is reported that anti-MUSK positive myasthenia often does not respond favorably to azathioprine [11]. Usually these patients require a more intense immunosuppressive management with, for example, cyclophosphamide or rituximab [11]. Another inconsistency is that all patients were under a medication with steroids and azathioprine since at least 1 y [1]. Why should patients under long-term immune-suppression develop myocarditis? Do the authors assume that long-term immune-suppression is the cause of myocarditis or are steroids and azathioprin ineffective for myocarditis? Though it is under debate if the antibody titer is correlated with disease severity it would be interesting to know if the degree or extension of myocarditis was correlated with the antibody titers in the presented patients? Was any other of the cMRI parameters correlated with the antibody titer?
http://dx.doi.org/10.1016/j.ijcard.2016.01.156 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: J. Finsterer, C. Stöllberger, Myocarditis in myasthenia gravis, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2016.01.156
2
Correspondence
The authors also mention that some patients had myositis [1]. How did they diagnose myositis in their myasthenia patients? Did they undergo muscle biopsy, which is the golden standard for diagnosing myositis? Which were the clinical manifestations of myositis? Overall, this interesting study requires some clarifications concerning the high frequency of myocarditis on cMRI and confirmation of the diagnosis by myocardial biopsy. It should be also investigated if myocarditis parameters correlate with the titer of antibodies responsible for myasthenia. Long-term treatment of myasthenia with steroids over 5 y should be avoided. Further studies are required to find out if steroids and azathioprine are ineffective for myasthenia-associated myocarditis or even induce it. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References
[2] M. Testolina, A. Schiavo, R. Marcolongo, S. Iliceto, Endomyocardial biopsy should be performed in every patient with suspected myocarditis, G. Ital. Cardiol. (Rome) 16 (2015) 533–538. [3] T. Ichikawa, K. Nakao, K. Hamasaki, K. Ohkubo, K. Toriyama, K. Eguchi, An autopsy case of acute pancreatitis with a high serum IgG4 complicated by amyloidosis and rheumatoid arthritis, World J. Gastroenterol. 11 (2005) 2032–2034. [4] N.E. Gilhus, J.J. Verschuuren, Myasthenia gravis: subgroup classification and therapeutic strategies, Lancet Neurol. 14 (2015) 1023–1036. [5] J. Finsterer, C. Stöllberger, Stress from myasthenic crisis triggers takotsubo (broken heart) syndrome, Int. J. Cardiol. 203 (2016) 616–617. [6] S. Mayor-Gomez, F. Lacruz, D. Ezpeleta, Myasthenic crisis and takotsubo syndrome: a non-chance relationship, Rev. Neurol. 55 (2012) 725–728. [7] S. Leone, A. Mancuso, B. La Fata, P. Camarda, G. Di Giovanni, F. Pasta, et al., Obstructive cardiomyopathy with persistent marked elevation of troponin T in myasthenia gravis, Int. J. Cardiol. 203 (2016) 128–130. [8] E. Venturini, A. Pellegrinetti, C. Marabotti, L. Magni, R. Testa, Myasthenia gravis and heart failure: is ivabradine a useful drug? Int. J. Cardiol. 174 (2014) e4–e6. [9] S. Kumagai, T. Kato, A. Ozaki, S. Hirose, E. Minamino, Y. Kimura, et al., Serial measurements of cardiac troponin I in patients with myasthenia gravis-related cardiomyopathy, Int. J. Cardiol. 168 (2013) e79–e80. [10] G. Stavroulakis, M. Papadopoulou, G. Koutroulis, V. Zouvelou, J. Katsavochristos, E. Georgiadis, et al., Myasthenia gravis. A potential cause of false positively elevated troponin T? Case report and brief review, Int. J. Cardiol. 199 (2015) 40–41. [11] K. El-Salem, A. Yassin, K. Al-Hayk, S. Yahya, D. Al-Shorafat, S.S. Dahbour, Treatment of MuSK-associated myasthenia gravis, Curr. Treat. Options Neurol. 16 (4) (2014 Apr) 283, http://dx.doi.org/10.1007/s11940-014-0283-8.
[1] S. Mavrogeni, T. Ntoskas, E. Gialafos, G. Karabela, M. Krommida, S. Gatzonis, et al., Silent myocarditis in myasthenia gravis. Role of cardiovascular magnetic resonance imaging, Int. J. Cardiol. 202 (2015) 629–630.
Please cite this article as: J. Finsterer, C. Stöllberger, Myocarditis in myasthenia gravis, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2016.01.156
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Myocarditis in myasthenia gravis Josef Finsterer a,⁎, Claudia Stöllberger b a b
Krankenanstalt Rudolfstiftung, Vienna, Austria 2nd Medical Department with Cardiology and Intensive Care Medicine, Krankenanstalt Rudolfstiftung, Vienna, Austria
a r t i c l e
i n f o
Article history: Received 5 January 2016 Accepted 6 January 2016 Available online xxxx Keywords: Neuromuscular disorder Myocarditis Cardiac MRI Cardiac involvement Myocardium Cardiomyopathy
With interest we read the article by Mavrogeni et al. about a study of 33 patients with myasthenia gravis of which three were diagnosed with myocarditis, as assessed by cardiac MRI [1]. We have the following comments and concerns. Myocardial biopsy is still the golden standard for diagnosing myocarditis [2]. Did the three patients with myocarditis on cardiac MRI (cMRI) also undergo endo-myocardial biopsy to confirm the imaging diagnosis? Myocarditis was diagnosed if 2 of 3 cMRI abnormalities were present (STIR-T2 ratio N 2, early gadolinium enhancement (EGE) N4, or late gadolinium enhancement (LGE) N 0) [1]. These criteria were met in only one patient [1]. In the two other patients only LGE was present [1]. The presence of LGE alone, however, does not necessarily imply myocarditis. It could represent scarring due to other causes as well. The authors found myocarditis on cMRI in 9.1% of their myasthenia patients [1]. This figure is unexpectedly high and has not been previously reported. How do they explain the high prevalence of myocarditis compared to the previous findings? Are their cMRI findings false positive? Possibly, LGE does not represent myocarditis but rather fibrosis or other pathologies. The authors do not mention which are the clinical implications of their findings [1]. Did the three patients with current or previous myocarditis receive an additional immuno-suppression or was the therapeutic regimen for myasthenia changed because of the cMRI findings?
⁎ Corresponding author at: Postfach 20, 1180, Vienna, Austria. E-mail address: fifi[email protected] (J. Finsterer).
Did any of the three patients experience cardiac symptoms indicative of myocarditis at the time of the cMRI or previously? Myasthenia gravis not only affects the neuromuscular junction with consecutive exercise-induced muscle weakness and the heart in form of myocarditis, but may also affect the liver (primary sclerosing cholangitis), the pancreas (pancreatitis) [3], the thyroid gland (thyroiditis) [4], the joints (rheumatoid arthritis) [3], the arteries (systemic lupus erythematosus) [4], the muscle (myositis) [1], and the thymus (thymoma) [4]. Did the included patients also present with any of these other associated disorders? How many of the included patients had developed thymoma or hyperplasia of the thymus? How many of them had undergone thymectomy? We do not agree with the statement that takotsubo syndrome (TTS) is a manifestation of myasthenia gravis [1]. TTS usually results from excessive psychogenic or physical stress frequently occurring during a myasthenic crisis [5] but myasthenia without complications usually does not go along with TTS [6]. Myasthenia may be also associated with obstructive cardiomyopathy [7], heart failure [8], or troponin-T elevation [7,9,10]. Were there any indications for these cardiac abnormalities in the presented patients in addition to myocarditis? Ten to twenty percent of the patients with myasthenia do not present with any of the known antibodies associated with myasthenia [4]. Interestingly, all included patients were seropositive (AchR (n = 23), MUSK (n = 7), LPR4 (n = 4)) [1]. Did the authors deliberately only include patients who were seropositive? All patients were under a treatment with steroids and azathioprine 1–5 y after diagnosis [1]. This is surprising for two reasons. First, longterm treatment with steroids over five years is contraindicated because of the known side effects. Second, it is reported that anti-MUSK positive myasthenia often does not respond favorably to azathioprine [11]. Usually these patients require a more intense immunosuppressive management with, for example, cyclophosphamide or rituximab [11]. Another inconsistency is that all patients were under a medication with steroids and azathioprine since at least 1 y [1]. Why should patients under long-term immune-suppression develop myocarditis? Do the authors assume that long-term immune-suppression is the cause of myocarditis or are steroids and azathioprin ineffective for myocarditis? Though it is under debate if the antibody titer is correlated with disease severity it would be interesting to know if the degree or extension of myocarditis was correlated with the antibody titers in the presented patients? Was any other of the cMRI parameters correlated with the antibody titer?
http://dx.doi.org/10.1016/j.ijcard.2016.01.156 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: J. Finsterer, C. Stöllberger, Myocarditis in myasthenia gravis, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2016.01.156
2
Correspondence
The authors also mention that some patients had myositis [1]. How did they diagnose myositis in their myasthenia patients? Did they undergo muscle biopsy, which is the golden standard for diagnosing myositis? Which were the clinical manifestations of myositis? Overall, this interesting study requires some clarifications concerning the high frequency of myocarditis on cMRI and confirmation of the diagnosis by myocardial biopsy. It should be also investigated if myocarditis parameters correlate with the titer of antibodies responsible for myasthenia. Long-term treatment of myasthenia with steroids over 5 y should be avoided. Further studies are required to find out if steroids and azathioprine are ineffective for myasthenia-associated myocarditis or even induce it. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References
[2] M. Testolina, A. Schiavo, R. Marcolongo, S. Iliceto, Endomyocardial biopsy should be performed in every patient with suspected myocarditis, G. Ital. Cardiol. (Rome) 16 (2015) 533–538. [3] T. Ichikawa, K. Nakao, K. Hamasaki, K. Ohkubo, K. Toriyama, K. Eguchi, An autopsy case of acute pancreatitis with a high serum IgG4 complicated by amyloidosis and rheumatoid arthritis, World J. Gastroenterol. 11 (2005) 2032–2034. [4] N.E. Gilhus, J.J. Verschuuren, Myasthenia gravis: subgroup classification and therapeutic strategies, Lancet Neurol. 14 (2015) 1023–1036. [5] J. Finsterer, C. Stöllberger, Stress from myasthenic crisis triggers takotsubo (broken heart) syndrome, Int. J. Cardiol. 203 (2016) 616–617. [6] S. Mayor-Gomez, F. Lacruz, D. Ezpeleta, Myasthenic crisis and takotsubo syndrome: a non-chance relationship, Rev. Neurol. 55 (2012) 725–728. [7] S. Leone, A. Mancuso, B. La Fata, P. Camarda, G. Di Giovanni, F. Pasta, et al., Obstructive cardiomyopathy with persistent marked elevation of troponin T in myasthenia gravis, Int. J. Cardiol. 203 (2016) 128–130. [8] E. Venturini, A. Pellegrinetti, C. Marabotti, L. Magni, R. Testa, Myasthenia gravis and heart failure: is ivabradine a useful drug? Int. J. Cardiol. 174 (2014) e4–e6. [9] S. Kumagai, T. Kato, A. Ozaki, S. Hirose, E. Minamino, Y. Kimura, et al., Serial measurements of cardiac troponin I in patients with myasthenia gravis-related cardiomyopathy, Int. J. Cardiol. 168 (2013) e79–e80. [10] G. Stavroulakis, M. Papadopoulou, G. Koutroulis, V. Zouvelou, J. Katsavochristos, E. Georgiadis, et al., Myasthenia gravis. A potential cause of false positively elevated troponin T? Case report and brief review, Int. J. Cardiol. 199 (2015) 40–41. [11] K. El-Salem, A. Yassin, K. Al-Hayk, S. Yahya, D. Al-Shorafat, S.S. Dahbour, Treatment of MuSK-associated myasthenia gravis, Curr. Treat. Options Neurol. 16 (4) (2014 Apr) 283, http://dx.doi.org/10.1007/s11940-014-0283-8.
[1] S. Mavrogeni, T. Ntoskas, E. Gialafos, G. Karabela, M. Krommida, S. Gatzonis, et al., Silent myocarditis in myasthenia gravis. Role of cardiovascular magnetic resonance imaging, Int. J. Cardiol. 202 (2015) 629–630.
Please cite this article as: J. Finsterer, C. Stöllberger, Myocarditis in myasthenia gravis, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2016.01.156
