Myocarditis in Duchenne Muscular Dystrophy After Changing Steroids

Key Points

Question  What are the cardiac complications of underdosing steroids in Duchenne muscular dystrophy, and how can they be avoided?

Findings  In this case report, an 18-year-old patient switched his oral steroids from deflazacort to underdosed prednisone and developed acute myocarditis with systolic dysfunction. The inflammation and systolic dysfunction resolved when he was resumed receiving the appropriate dose of deflazacort.

Meaning  In Duchenne muscular dystrophy, switching between steroid classes should be done with caution, and dosing should be weight based and not equivalence based.

Importance  Cardiac dysfunction is a leading cause of morbidity and mortality in Duchenne muscular dystrophy (DMD). This case highlights the importance of steroids in treating cardiac complications of DMD and the dangers of discontinuing or switching between steroid classes.

Objective  To recognize the presentation of acute myocardial inflammation, or dystrophinitis, in DMD, which presents as myocarditis and to treat the myocardial inflammation and dilated cardiomyopathy associated with DMD through guideline-directed medical therapy, steroids, and serial surveillance for cardiac dysfunction.

Design, Setting, and Participant  A case report of an 18-year-old patient with DMD and with steroid withdrawal–induced myocarditis followed up for 3 years to observe for cardiac function recovery and the natural history of cardiomyopathy in DMD, who was hospitalized in the cardiac care unit and followed up between November 3, 2016, and March 27, 2017.

Exposures  Switching from deflazacort to underdosed prednisone for 7 days.

Main Outcomes and Measures  Increased myocardial inflammation, edema, and fibrosis after stopping deflazacort abruptly.

Results  An 18-year-old male patient with DMD presented to the emergency department with acute-onset chest pain. Ischemic changes were present on electrocardiogram, and elevated cardiac enzymes were detected. Depressed cardiac function and potential evidence of inflammation were seen on cardiac magnetic resonance (CMR) imaging, characterized by elevated T2 values and late gadolinium enhancement. These findings were all consistent with acute myocarditis but without a viral prodrome. Several days prior to presentation, the patient’s deflazacort was abruptly discontinued and converted to an equivalent dose of prednisone. After restarting deflazacort, his symptoms improved, and subsequent CMR showed resolution of myocardial edema and improved left ventricular function.

Conclusions and Relevance  This case highlights adverse effects associated with changing between corticosteroid classes in DMD cardiomyopathy and also demonstrates the utility of CMR in detecting myocardial inflammation and monitoring response to treatment.

Duchenne muscular dystrophy (DMD) is an X-linked muscular dystrophy that affects approximately 20 000 men worldwide each year. Glucocorticoid steroids are used to treat DMD, typically as prednisone or deflazacort, an oxazolone derivative of prednisone.¹ In DMD, steroids are given in the mid first decade of life and sometimes continue beyond loss of ambulation, depending on adverse effect profiles. Steroids have been shown to prolong ambulation in DMD and lessen complications including progressive cardiomyopathy and respiratory failure.² In 2017, the US Food and Drug Administration approved deflazacort for use in DMD; prior to this, US patients obtained the drug from non-US sources. This case highlights the potential cardiac complications of altering between steroid classes and steroid dosing in DMD and offers insight into the mechanism of dysfunction in DMD cardiomyopathy, specifically ongoing myocardial inflammation.

An 18-year-old man with DMD presented to the emergency department with acute substernal chest pain that was not positional or pleuritic in nature. He denied any viral prodrome, palpitations, shortness of breath, orthopnea, or lower extremity edema. His history was significant for receiving a diagnosis of DMD at age 8 years owing to deletion of exons 45-50 of the DMD gene. At the time of diagnosis, he started taking deflazacort; he lost ambulation at age 12 years. He started using noninvasive ventilation nocturnally at age 13 years. He had a history of DMD-associated cardiomyopathy seen as left ventricular (LV) dysfunction detected through screening echocardiography. He responded favorably to β-blockade and angiotensin-converting enzyme (ACE) inhibition, with recovery to a normal LV ejection fraction (LVEF) of 60% shortly before presentation.

His family history was remarkable for DMD on his maternal side. He denied any alcohol, tobacco, or illicit drug use. His medications included deflazacort, 30 mg daily, metoprolol succinate, 25 mg daily, lisinopril, 5 mg daily, alendronate, 10 mg weekly, and testosterone, 100 mg intramuscular, every other week. Seven days prior to presentation, he was unable to obtain deflazacort from his UK source and began using prednisone, 25 mg daily, as a substitute.

On examination, he was afebrile, blood pressure was 121/59 mm Hg, heart rate was 97 bpm, and 96% oxygen saturation on room air. His cardiac examination revealed neither gallop nor rub, his lungs were clear to auscultation, jugular venous pressure was normal, and there was no lower extremity edema. The initial 12-lead electrocardiogram showed normal sinus rhythm, with significant inferior ST elevations (Figure 1). Initial serum troponin I level was 39 ng/mL and peaked at greater than the laboratory upper limit of 73 ng/mL (normal range, 0.0-0.4 ng/mL; to convert to micrograms per liter, multiply by 1). Serum CK-MB and brain natriuretic peptide peaked at 359.5 ng/mL and 291 pg/mL, respectively (to convert brain natriuretic peptide to nanograms per liter, multiply by 1). The chest radiography showed a normal cardiac silhouette without cardiomegaly or pulmonary edema.

He was taken emergently for coronary angiography, which revealed normal coronary anatomy without disease (Figure 2). A subsequent echocardiogram measured an LVEF of 46%, with global hypokinesis that was most severe in the basal to mid inferolateral and anterolateral walls. Cardiac magnetic resonance (CMR) imaging revealed septal and lateral wall myocardial edema with elevated T2 values (57 milliseconds; normal reference 40-55 milliseconds) and the presence of late gadolinium enhancement (LGE) in the basal to midlateral walls consistent with acute myocarditis (Figure 3A).

Antibody testing results for viruses associated with myocarditis were negative. His complete blood cell count, basic chemistry, thyrotropin, and HIV test results were unremarkable. He received 2 days of colchicine and continued receiving prednisone with resolution of his chest pain. Within a week, he restarted his deflazacort, with 4-month follow-up CMR showing improvement in LVEF to 52% and resolution of myocardial edema, with T2 values of 42 milliseconds to 49 milliseconds (Figure 3B). The patient was diagnosed as having DMD myocarditis associated with steroid withdrawal when deflazacort was substituted with prednisone.

Duchenne muscular dystrophy is caused by a mutation in the dystrophin protein that links to a transmembrane complex of glycoproteins to provide stability to the sarcolemma in skeletal myofibers and cardiomyocytes.² Pulmonary function in DMD is impaired owing to a combination of scoliosis and respiratory muscle weakness. With advances in respiratory care, cardiac complications have become a leading cause of morbidity and mortality in DMD.² Current screening recommendations for cardiomyopathy in DMD suggest echocardiographic evaluation every 2 years starting at age 6 years and yearly starting at age 10 years.^1,2 If abnormalities are seen at any age, follow-up echocardiograms should occur every 6 months, with initiation of medical therapy for heart failure.²

Duchenne muscular dystrophy cardiomyopathy typically onsets in the second decade, with treatment following similar guideline-directed medical therapies applied to adult patients with heart failure.¹ Angiotensin-converting enzyme–inhibitors (ACEi) are a first-line treatment for DMD cardiomyopathy because they delay onset of LV dysfunction and dramatically reduce 10-year mortality.^3,4 Interestingly, animal models examining ACEi in conjunction with mineralocorticoid receptor antagonism support a reduction in myocardial damage that precedes a reduction in LVEF.⁵ Moreover, eplerenone addition to standard ACEi treatment reduces the decline in myocardial performance compared with ACEi alone.⁶ Studies evaluating the combined association of β-blockers and ACEi with DMD cardiomyopathy also showed a mortality reduction.⁵

There is growing evidence that inflammation may be an inciting event in the development of cardiomyopathy in DMD.^7,8 Prior work demonstrated that patients with DMD with myocardial inflammation on cardiac biopsy, seen as leukocyte infiltrate (mainly T cells and macrophages), progressed faster to symptomatic heart failure compared with patients with DMD without inflammation.⁷ A hallmark of cardiac disease in DMD is lateral wall fibrosis owing to ongoing inflammation, which can be delayed with the use of steroids.² This fibrosis is often best characterized using CMR, which shows LGE as the result of replacement fibrosis.^1,9 At age 18 years, this patient showed LGE/myocardial fibrosis of his lateral wall on CMR.

The most commonly used steroid for DMD in the United States is prednisone.² Prior to US Food and Drug Administration approval in February 2017, patients with DMD have experienced limited availability of deflazacort owing to high cost and difficulty receiving it from non-US sources. The standard-of-practice dosing for deflazacort is 0.9 mg/kg/d compared with prednisone, in which patients are started at 0.75 mg/kg and are uptitrated as tolerated.^2,10 Although this patient was not receiving this recommended dose of deflazacort, lower doses are commonly prescribed to older patients with DMD. He was converted to an equivalent dose of prednisone (25 mg)¹¹ after abrupt discontinuation of deflazacort prior to presentation. However, while receiving prednisone, laboratory testing and imaging were consistent with progressive myocardial inflammation. When he returned to deflazacort, imaging showed a reduction in myocardial edema and improvement in LVEF. These findings are similar to those described by Hor et al⁹ and reflect the general diagnosis of dystrophinitis in DMD.

Our report has several limitations. Notably, this is a case report of a single patient; however, the findings of myocardial inflammation are consistent with existing literature.⁹ Also, the patient did not undergo cardiac biopsy. However, this report describes how a noninvasive CMR can aid in diagnosis and treatment of DMD-associated cardiomyopathy.

Based on the case presented, we assert that abrupt discontinuation of or conversions between steroid medications should be avoided in DMD, especially among boys and young men with cardiomyopathy. If a change is unavoidable, we contend that steroid dosing should be weight based and not dosed based on “equivalence dosing” because patients may be more responsive to 1 steroid class compared with others. In this case, sudden inflammation may have been avoided using higher doses of prednisone (38 mg).

To our knowledge, this is the first case in literature to reveal the potential dangers of changing between corticosteroid classes (eg, prednisone for deflazacort) with equivalence dosing in DMD. Additionally, our findings support the utility of CMR to identify potential myocardial inflammation in DMD and monitoring response to treatment.

Corresponding Author: Jane E. Wilcox, MD, MSc, Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, 676 N St Clair, Ste 600, Chicago, IL 60611 (jane-wilcox@northwestern.edu).

Accepted for Publication: July 12, 2016.

Published Online: August 29, 2018. doi:10.1001/jamacardio.2018.2695

Author Contributions: Dr Wilcox had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Abutaleb, McNally, Khan, Wilcox.

Acquisition, analysis, or interpretation of data: McNally, Anderson, Carr, Wilcox.

Drafting of the manuscript: Abutaleb, McNally, Wilcox.

Critical revision of the manuscript for important intellectual content: McNally, Khan, Anderson, Carr, Wilcox.

Administrative, technical, or material support: Carr.

Supervision: McNally, Khan, Wilcox.

Other - First author: Abutaleb.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Disclaimer: Dr McNally is Associate Editor of JAMA Cardiology, but she was not involved in any of the decisions regarding review of the manuscript or its acceptance.

Additional Contributions: We thank the patient for granting permission to publish this information.