Practice Parameter: Corticosteroid treatment of Duchenne dystrophy

Background: The Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society develop practice parameters as strategies for patient management based on analysis of evidence. Objective: To review available evidence on corticosteroid treatment of boys with Duchenne dystrophy. Methods: Relevant literature was reviewed, abstracted, and classified. Recommendations were based on a four-tiered scheme of evidence classification, and areas for future research are defined. Results: Seven class I studies and numerous less rigorous trials all demonstrated that corticosteroid treatment for 6 months with prednisone (0.75 or 1.5 mg/kg/day) increased muscle strength, performance, and pulmonary function and significantly slowed the progression of weakness. Two class I trials examined the effect of lower dosage of prednisone (0.30 and 0.35 mg/kg/day), demonstrated lesser but similar benefits, and showed a lower frequency of side effects (e.g., weight gain). The only significant side effects in all class I trials were weight gain and development of a cushingoid facial appearance. One longer-term trial of daily prednisone (0.3 to 0.7 mg/kg/day), a class III study, showed prolongation of functional ability and slower progression of weakness in patients during 3 years of treatment. One class IV, open trial of alternate-day prednisone (2 mg/kg for 2 months, then two-thirds dose every other day) extended ambulation by approximately 2 years in treated compared with untreated patients. Deflazacort, a corticosteroid similar in structure to prednisone, produced similar improvement in muscle strength and function with a similar side effect profile. Conclusions: Prednisone has been demonstrated to have a beneficial effect on muscle strength and function in boys with Duchenne dystrophy and should be offered (at a dose of 0.75 mg/kg/day) as treatment. If side effects require a decrease in prednisone, tapering to dosages as low as 0.3 mg/kg/day gives less robust but significant improvement. Deflazacort (0.9 mg/kg/day) can also be used for the treatment of Duchenne dystrophy in countries in which it is available. Benefits and side effects of corticosteroid therapy need to be monitored. The offer of treatment with corticosteroids should include a balanced discussion of potential risks. NEUROLOGY 2005;64:13–20 Duchenne dystrophy (DD), an X-linked, recessive disorder, with onset before age 5 years, is the most common and severe form of childhood muscular dystrophy.1-3 The specific molecular defect is an absence or marked deficiency of dystrophin, a large membrane-associated protein that is part of the dystrophin–glycoprotein complex.1 Affected boys develop neck flexor, anterior abdominal, hip, and shoulder girdle muscle weakness in early childhood, with loss of ambulation between ages 7 and 12.4,5 Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the January 11 issue to find the title link for this article. Address correspondence and reprint requests to American Academy of Neurology, 1080 Montreal Avenue, St. Paul, MN 55116. Approved by the QSS on February 13, 2004; by the Practice Committee on August 7, 2004; and by the AAN Board of Directors on October 16, 2004. From the Department of Neurology (Dr. Moxley, S. Pandya), University of Rochester School of Medicine and Dentistry, NY; Division of Child Neurology (Dr. Ashwal), Department of Pediatrics, Loma Linda University School of Medicine; Department of Physical Medicine and Rehabilitation (Dr. McDonald), University of California–Davis School of Medicine, Sacramento; Department of Neurology (Dr. Connolly), Washington University School of Medicine (J. Florence), St. Louis, MO; Departments of Pediatrics and Neurology (Dr. Mathews), University of Iowa Hospitals, Iowa City; Institute for Molecular Genetics (Dr. Baumbach), Baylor College of Medicine, Houston, TX; Department of Orthopedic Surgery (Dr. Sussman), Shriners Hospitals for Children, Portland, OR; and Department of Zoology and Physiology (Dr. Wade), University of Wyoming, Laramie. Received March 3, 2004. Accepted in final form September 10, 2004. Copyright © 2005 by AAN Enterprises, Inc. 13 Death usually occurs in the 20s, with the chance of surviving to age 25 being determined mainly by the use of ventilatory support.6 Until treatment of the basic genetic defect becomes available, management depends on medical, surgical, and rehabilitative approaches that optimize and maintain patient function and comfort.7 Of the different medications that have been tried as potential treatments for DD, only the corticosteroids prednisone and deflazacort have shown potential for providing temporary improvement. This improvement results mainly from slowing the rate of progression or stabilizing muscle strength and function. Corticosteroid therapy also leads to side effects; as yet, there is no consensus regarding its use as standard treatment for DD.3 The specific cellular events responsible for the beneficial effects of corticosteroid therapy in DD are not known. Investigators have proposed various possibilities based mainly on observations in mouse models of muscular dystrophy and on a limited number of studies in patients.8 These possibilities include 1) altering the mRNA levels of structural, signaling, and immune response genes9; 2) reducing cytotoxic T lymphocytes10,11; 3) lowering calcium influx and concentration12,13; 4) increasing laminin expression and myogenic repair14; 5) retarding muscle apoptosis and cellular infiltration15; 6) enhancing dystrophin expression16; 7) affecting neuromuscular transmission17; 8) protecting against mechanically induced fiber damage18; 9) attenuating muscle fiber necrosis19; 10) slowing the rate of skeletal muscle breakdown20-22; and 11) increasing muscle levels of taurine and creatine.23 More studies are necessary to establish the precise cellular mechanism(s) by which corticosteroids produce their beneficial effects in DD. Studies using azathioprine as an alternative immunosuppressive treatment to prednisone showed no beneficial effect and suggested that the effects of prednisone observed in clinical studies are unlikely to result from its immunosuppressive actions.24 This practice parameter examines previously published data on the use of different corticosteroids in the treatment of DD to determine whether there are sufficient benefits with limited risks to recommend their use in this condition. Description of process. Computer-assisted literature searches were conducted with the assistance of the University of Minnesota Biomedical Information Services Research Librarian for relevant articles published from 1966 to 2004. Databases searched included Medline (1966 to 2004) and Current