Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
ABSTRACT 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.
To review available evidence on corticosteroid treatment of boys with Duchenne dystrophy.
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.
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.
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.
- SourceAvailable from: distrofiamuscular.net[Show abstract] [Hide abstract]
ABSTRACT: We compare the clinical course of 74 boys 10-18 years of age with Duchenne muscular dystrophy (DMD) treated (40) and not treated (34) with deflazacort. Treated boys were able to rise from supine to standing, climb stairs and walk 10 m without aids, 3-5 years longer than boys not treated. After 10 years of age, treated boys had significantly better pulmonary function than boys not treated and after 15 years of age, 8 of 17 boys not treated required nocturnal ventilation compared with none of the 40 treated boys. For boys over 15 years of age, 11 of 17 boys not treated required assistance with feeding compared to none of the treated boys. By 18 years, 30 of 34 boys not treated had a spinal curve greater than 20 degrees compared to 4 of 40 treated boys. By 18 years, 7 of 34 boys not treated had lost 25% or more of their body weight (treated 0 of 40) and 4 of those 7 boys required a gastric feeding tube. By 18 years, 20 of 34 boys not treated had cardiac left ventricular ejection fractions less than 45% compared to 4 of 40 treated boys and 12 of 34 died in their second decade (mean 17.6 +/- 1.7 years) primarily of cardiorespiratory complications. Two of 40 boys treated with deflazacort died at 13 and 18 years of age from cardiac failure. The treated boys were significantly shorter, did not have excessive weight gain and 22 of 40 had asymptomatic cataracts. Long bone fractures occurred in 25% of boys in both the treated and not treated groups. This longer-term study demonstrates that deflazacort has a very significant impact on health, quality of life and health care costs for boys with DMD and their families, and is associated with few side effects.Neuromuscular Disorders 05/2006; 16(4):249-55. · 3.46 Impact Factor
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ABSTRACT: Antagonists of myostatin, a blood-borne negative regulator of muscle growth produced in muscle cells, have shown considerable promise for enhancing muscle mass and strength in rodent studies and could serve as potential therapeutic agents for human muscle diseases. One of the most potent of these agents, follistatin, is both safe and effective in mice, but similar tests have not been performed in nonhuman primates. To assess this important criterion for clinical translation, we tested an alternatively spliced form of human follistatin that affects skeletal muscle but that has only minimal effects on nonmuscle cells. When injected into the quadriceps of cynomolgus macaque monkeys, a follistatin isoform expressed from an adeno-associated virus serotype 1 vector, AAV1-FS344, induced pronounced and durable increases in muscle size and strength. Long-term expression of the transgene did not produce any abnormal changes in the morphology or function of key organs, indicating the safety of gene delivery by intramuscular injection of an AAV1 vector. Our results, together with the findings in mice, suggest that therapy with AAV1-FS344 may improve muscle mass and function in patients with certain degenerative muscle disorders.Science translational medicine 11/2009; 1(6):6ra15. · 10.76 Impact Factor
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ABSTRACT: Golden retriever muscular dystrophy (GRMD) is a genetic myopathy corresponding to Duchenne muscular dystrophy (DMD) in humans. Muscle atrophy is known to be associated with degradation of the dystrophin-glycoprotein complex (DGC) via the ubiquitin-proteasome pathway. In the present study, we investigated the effect of bortezomib treatment on the muscle fibers of GRMD dogs. Five GRMD dogs were examined; two were treated (TD- Treated dogs) with the proteasome inhibitor bortezomib, and three were control dogs (CD). Dogs were treated with bortezomib using the same treatment regimen used for multiple myeloma. Pharmacodynamics were evaluated by measuring the inhibition of 20S proteasome activity in whole blood after treatment and comparing it to that in CD. We performed immunohistochemical studies on muscle biopsy specimens to evaluate the rescue of dystrophin and dystrophin-associated proteins in the muscles of GRMD dogs treated with bortezomib. Skeletal tissue from TD had lower levels of connective tissue deposition and inflammatory cell infiltration than CD as determined by histology, collagen morphometry and ultrastructural analysis. The CD showed higher expression of phospho-NFκB and TGF-β1, suggesting a more pronounced activation of anti-apoptotic factors and inflammatory molecules and greater connective tissue deposition, respectively. Immunohistochemical analysis demonstrated that dystrophin was not present in the sarcoplasmic membrane of either group. However, bortezomib-TD showed higher expression of α- and β-dystroglycan, indicating an improved disease histopathology phenotype. Significant inhibition of 20S proteasome activity was observed 1 hour after bortezomib administration in the last cycle when the dose was higher. Proteasome inhibitors may thus improve the appearance of GRMD muscle fibers, lessen connective tissue deposition and reduce the infiltration of inflammatory cells. In addition, proteasome inhibitors may rescue some dystrophin-associated proteins in the muscle fiber membrane.PLoS ONE 04/2013; 8(4):e61367. · 3.53 Impact Factor
Practice Parameter: Corticosteroid Treatment of Duchenne Dystrophy
Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of
the Child Neurology Society
R.T. Moxley III, MD; S. Ashwal, MD; S. Pandya, MS, PT; A. Connolly, MD; J. Florence, MHS, PT; K. Mathews,
MD; L. Baumbach, MD; C. McDonald, MD; M. Sussman, MD; and C. Wade, PhD, PT, RN
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.
To review available evidence on corticosteroid treatment of boys with Duchenne dystrophy.
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.
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.
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.
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.
Duchenne Muscular Dystrophy
NEUROLOGY 64 January (1 of 2) 2005 Page 2
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,
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.
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)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 genes(9); 2) reducing cytotoxic T lymphocytes(10,11); 3)
powering calcium influx and concentration(12,13); 4) increasing laminin expression and myogenic repair(14); 5)
retarding muscle apoptosis and cellular infiltration(15); 6) enhancing dystrophin expression(16); 7) affecting
neuromuscular transmission(17); 8) protecting against mechanically induced fiber damage(18); 9) attenuating
muscle fiber necrosis(19); 10) slowing the rate of skeletal muscle breakdown(20-22); 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
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 Contents using the search terms Duchenne
dystrophy, corticosteroids, steroids, prednisone, deflazacort, and treatment. All search titles and abstracts were
analyzed for content. The search included all languages. Articles on therapy, prognosis, and side effects were
selected, including original and review articles. There were 25 peer-reviewed articles chosen for detailed
review. Individual committee members reviewed, abstracted, and classified these articles to assess the quality
of data related to study design and treatment effect. Abstracted data included the number of patients, age range,
design of study, duration, dosage, outcome measures, response to treatment, and side effects.
A four-tiered classification scheme for therapeutic evidence recently approved by the Quality Standards
Subcommittee was utilized as part of this assessment (see appendix 1). Depending on the strength of this
evidence, it was decided whether specific recommendations could be made and, if so, the strength of these
Duchenne Muscular Dystrophy
NEUROLOGY 64 January (1 of 2) 2005 Page 3
recommendations (see appendix 2). Evidence pertinent to each treatment together with the committee’s
evidence-based recommendations is presented.
Prednisone/prednisolone: What are the benefits and side effects of prednisone/prednisolone in boys
Class I studies: therapeutic effects. Seven class I studies (n = 276) have demonstrated that prednisone is
beneficial in DD and that 0.75 mg/kg/day is optimal as an initial dosage for boys between 5 and 15 years old
(see table E-1 on the Neurology Web site at www.neurology.org). Six of the seven studies involved the vast
majority of patients (n = 221) and ranged in duration from 6 to 18 months.(24-29) The relatively short duration of
treatment in these six studies made the use of endpoints, such as cessation of ambulation or decline in forced
vital capacity (FVC), impractical as measures of efficacy. These potential endpoints to evaluate treatment
require a few years or longer to reach. The seven class I studies have relied on standardized measurements of
muscle strength and function as described below to assess efficacy.
Four of the class I trials evaluated the dose–response relation, onset of action, and duration of response to daily
treatment with prednisone and were performed by the Collaborative Investigations in Duchenne Dystrophy
Study Group.(24-27) Prednisone (1.5, 0.75, or 0.3 mg/kg/day) was given daily for 6 months, and at each dose, it
led to improvements in muscle strength, in the 24-hour urinary excretion of creatinine (a surrogate measure of
muscle mass), and in muscle and pulmonary function.
Strength was assessed using a standardized scoring system that evaluated 34 muscle groups (using a scale of 0
to 10 for each muscle, in which 10 equaled normal strength). Scores were combined to calculate an average
muscle strength score for the 34 muscle groups. In these studies, strength reached a maximum by 3 months and
was maintained at 6 months(25,27) and at 18 months.(24) Comparison of the average muscle strength scores before
and after 6 months of treatment showed a 4.8% decrease in the placebo group compared with a 6.7% increase
in the 0.75 mg/kg/day prednisone group (p < 0.0001) and a 5.0% increase in the 1.5 mg/kg/day prednisone
group (p < 0.0001). This response to treatment gives a net percentage increase in average strength score of 11%
for boys receiving 0.75 mg/kg/day of prednisone and 9.8% for boys receiving 1.5 mg/kg/day compared with
placebo.(25) These improvements were accompanied by an increase in muscle mass and by an improvement in
Twenty-four-hour urinary excretion of creatinine
After 6 months, boys receiving placebo showed a decline in 24-hour excretion of creatinine (baseline = 203
mg/24 hours; after 6 months =190 mg/24 hours), consistent with a mild loss of muscle bulk.(25) In contrast,
urinary creatinine excretion increased after 6 months by 30.5% in boys taking 0.75 mg/kg/day of prednisone
and by 28.6% in those taking 1.5 mg/kg/day (p < 0.0001), consistent with an increase in muscle mass for both
doses of prednisone. These findings demonstrate an anabolic action of prednisone in DD in contrast to its stated
catabolic effects on skeletal muscle in normal unaffected individuals.
Each patient had standardized timed function testing (e.g., time to climb four stairs, travel 9 m, or arise from
supine to standing), and comparisons were carried out between the mean times for each group. Results after 6
months of treatment showed that the average time to climb four stairs was 7.05 seconds in the placebo group
and approximately 4.0 seconds in the 0.75 and 1.5 mg/kg/day prednisone groups (p < 0.0001), an average of
3.0 seconds faster (i.e., 43% faster) with prednisone treatment.(25) The average time to travel 9 m was 9.68
seconds in the placebo group and approximately 2 seconds faster (i.e., 28% faster) in the two treatment groups
(p < 0.005). The average time to arise from supine to standing was 6.17 seconds in the placebo group and was
2.0 (32%) and 2.7 (44%) seconds faster in the 0.75 and 1.5 mg/kg/day prednisone groups (p < 0.0002).(25)
Duchenne Muscular Dystrophy
NEUROLOGY 64 January (1 of 2) 2005 Page 4
Standardized measurements of FVC were higher after 6 months of daily prednisone. In the placebo group, FVC
averaged 1.52 L, whereas FVC was 10.5% (p < 0.0004) and 8.3% (p < 0.002) higher in the 0.75 and 1.5
mg/kg/day prednisone groups.(25)
Every-other-day treatment with prednisone
At the completion of one of the 6-month trials of daily prednisone (placebo vs 0.75 and 1.5 mg/kg/day dosages
of prednisone),(25) patients were kept blind to their treatment; each group underwent a switch to alternate-day
therapy (every other day) with prednisone (placebo group to 2.5 mg/kg every other day, 0.75 mg/kg/day group
to 1.25 mg/kg every other day, and 1.5 mg/kg/day group to 2.5 mg/kg every other day).(26) During the initial 3
months of alternate-day therapy, there was no significant difference in average muscle strength score
comparing alternate-day with daily prednisone between the groups (see table E-1 on the Neurology Web site).
However, during months 4 to 6 of alternate-day therapy, patients taking prednisone 1.25 or 2.5 mg/kg every
other day lost the major benefits on strength and muscle function(26) that had occurred previously with daily
prednisone and showed a decline in average muscle strength that paralleled the previously established rates
typical for the natural history of DD.(4,5) These findings indicate that alternate-day prednisone at dosages of
1.25 and 2.5 mg/kg every other day is not sufficient to achieve the sustained beneficial effects that occur with
daily prednisone in dosages ranging from 0.3 to 1.5 mg/kg/day.
An earlier class I study(30) evaluated the efficacy of 5.0 mg/kg every other day of prednisolone. Investigators
gave prednisolone 5.0 mg/kg every other day or placebo every other day for 3 years. All seven boys in the
placebo group became nonambulatory, whereas six of the seven boys receiving prednisolone remained
ambulatory after 36 months of treatment. At the time of publication, the authors felt that prednisolone had no
ultimate value in the treatment of DD. In recent years, they have changed their interpretation (personal
communication at MDA Clinic Directors Meeting, 2002). Their observations suggest that a dosage of
prednisolone higher than 2.5 mg/kg every other day is necessary to produce sustained improvement comparable
with the improvement that occurs with daily prednisone (see tables E-1 and E-2 on the Neurology Web site).
The observations that 5.0 mg/kg of prednisolone every other day is effective but 2.5 mg/kg of prednisone does
not produce a sustained benefit provides a rationale for future research to investigate the efficacy of high-
dosage alternate-day or intermittent corticosteroid treatments.
Lower portion of dose response for prednisone in DD
Three class I studies in which prednisone was given daily have examined the lower end of the dose–response
curve (see table E-1 on the Neurology Web site).(24,27,29) In two of these studies, there was a comparison of the
efficacy of 0.3 and 0.75 mg/kg/day of prednisone.(24,27) Average muscle strength increased significantly by 10
days with 0.3 and 0.75 mg/kg/day dosages of prednisone, indicating that there is an early beneficial effect prior
to the time that one would expect an increase in muscle mass. The increase is significantly greater for 0.75
compared with 0.3 mg/kg/day. There is continued improvement in strength up to 3 months, at which point
improvement in strength and function reached a maximum. This maximum benefit was sustained for at least 18
The beneficial effects most apparent to patients and their care providers were improvements in their timed
function tests. Each timed function test showed a parallel and highly significant improvement after 6 months of
treatment with 0.3 and 0.75 mg/kg/day doses of prednisone.(27) The time to climb four stairs averaged 8.44
seconds in the placebo group and was 2.7 (32%) seconds faster in the 0.3 mg/kg/day prednisone group and 4.2
(50%) seconds faster in the 0.75 mg/kg/day group (p <0.0001). The time to travel 9 m averaged 8.51 seconds in
the placebo group and was 1.2 (14%) and 2.1 (25%) seconds faster in the 0.3 and 0.75 mg/kg/day prednisone
groups (p < 0.003). The time to arise from supine to standing averaged 8.23 seconds in the placebo group and
was 1.6 (19%) and 3.7 (45%) seconds faster in the 0.3 and 0.75 mg/kg/day prednisone groups (p < 0.0003). The
FVC also increased after 6 months of prednisone. It averaged 1.48 L in the placebo group and increased by
10% in the 0.3 mg/kg/day prednisone group and 11.6% in the 0.75 mg/kg/day group (p < 0.001). (27)
Optional time to begin treatment with prednisone
There have been no class I studies that examined the optimal age to begin treatment or the optimal duration of
treatment with corticosteroids.
Duchenne Muscular Dystrophy
NEUROLOGY 64 January (1 of 2) 2005 Page 5
Class I studies: side effects
The class I studies that evaluated daily prednisone treatment (0.3, 0.75, or 1.5 mg/kg/day) found that the most
common side effects were weight gain and development of a cushingoid facial appearance 6 to 18 months after
treatment. (24,25,27) There was no significant increase in the number of patients with hypertension, diabetes
mellitus, gastrointestinal bleeding, psychosis, compression fractures, or cataracts (see table E-1 on the
Neurology Web site). Frequency and severity of side effects were similar in patients receiving high-dose daily
prednisone (0.75 or 1.5 mg/kg/day) and comparable alternate-day treatment (1.25 or 2.5 mg/kg every other
day).(26) Behavioral changes, gastrointestinal symptoms, and acne occurred equally in boys receiving placebo or
prednisone for 6 to 18 months. (24,25,27)
Weight gain was the most common side effect and occurred over a range of prednisone dosages (0.3 to 1.5
mg/kg/day). Table E-2 (see the Neurology Web site) presents data on the weight gained over baseline weight
for two of the class I studies of 6 months’ duration(25,27) and for one class I study of 18 months’ duration. In
patients treated for 6 months, 20 to 24% of those receiving placebo developed an increase in weight of ≥10% in
contrast to 48% of patients receiving 0.3 mg of prednisone and to 75 to 80% of patients receiving 0.75
mg/kg/day. (24,27) Likewise, 43% of patients receiving placebo gained >20% of their baseline weight after 18
months in contrast to 66% of patients receiving 0.3 mg/kg/day and 75% of patients receiving 0.75 mg/kg/day.
(24) Despite gain in weight, patients showed clinical improvement as described above.
The distribution of the weight gained (fat vs muscle) differed between patients receiving prednisone compared
with placebo. Analysis of the 24-hour urinary creatinine excretion at the completion of the 18-month
prednisone trial demonstrated a 36% increase in muscle mass in the 0.75 mg/kg/day prednisone group
compared with placebo-treated patients. (24) This observation points out that the weight gained with prednisone
is not solely an undesirable side effect, and it also poses a challenge to us as care providers to determine an
appropriate definition of “excessive weight gain” in DD patients receiving corticosteroids.
Table E-2 (see the Neurology Web site) provides additional data describing the weight gain observed in
patients receiving 0.3 and 0.75 mg/kg/day of prednisone. Patients receiving these dosages of prednisone had
similar increases in appetite and irritability, whereas patients receiving 0.75 mg/kg/day had a greater frequency
of hirsutism and cushingoid appearance. (24)
It is interesting to note that in one study, the investigators found no difference in weight gain in ambulatory
prednisone-treated patients compared with those receiving placebo, (29) but in the nonambulatory patients
receiving prednisone, those patients had a greater weight gain than the placebo group. A similar observation,
that weight gain is not a significant side effect in ambulatory patients receiving the corticosteroid deflazacort,
has been made in other studies. (32) The beneficial effects of ambulation and physical activity in preventing
weight gain during treatment with prednisone and deflazacort suggest that weight bearing and exercise
ameliorate weight gain during corticosteroid therapy in patients with DD. Further studies are necessary to
clarify the role of exercise in DD in patients receiving or not receiving prednisone or other corticosteroids. For
the present, it seems prudent for patients to follow an individualized preventive nutrition and exercise program
to avoid weight gain associated with corticosteroid therapy.
Class IV studies and treatment regimens
Results of 11 class IV studies (n = 237) of prednisone (see table E-3 on the Neurology Web site) are all
consistent with the results of the class I studies summarized in table E-1. Five studies involved participation of
≥14 patients whose ages ranged from 3 to 15 years. (33-36,40) The duration of treatment varied from 6 months to
Long-term daily prednisone
One long-term study of daily prednisone showed significant sustained improvements in arm and leg function,
timed function tests, and FVC after 3 years of treatment. (31) In this study, the most common side effect was
weight gain. The annual percentage weight gain was 24% for boys receiving prednisone in a dosage of >0.65
mg/kg/day and 28% in the group receiving a dose of <0.65 mg/kg/day. Of the total population of 92 boys
receiving daily prednisone, 10 developed asymptomatic cataracts and 10 had transient glucosuria. Glucosuria
resolved after dosage reduction.
Duchenne Muscular Dystrophy
NEUROLOGY 64 January (1 of 2) 2005 Page 6
Combinations of dosage regimens for prednisone
Four studies have examined various combinations of daily, alternate-day, or cyclical prednisone treatment (see
table E-3 on the Neurology Web site). (33,34,36,40) Two class IV studies (n =30; 2 mg/kg/day for 2 months
followed by alternate-day prednisone at two thirds the original daily dose) have demonstrated that alternate-day
prednisone prolongs ambulation.(33,34) In the 12 patients who received long-term treatment, ambulation was
prolonged for >2 years.(34) A study of 32 patients, age 6 to 14 years, found that intermittent cyclical daily
prednisone (0.75 mg/kg/ day for 10 days each month) had no long-term benefit. (36) In contrast, another class IV
study of 20 patients, age 5 to 11, found that high-dose, intermittent, weekly oral prednisone (5 mg/kg given
each Friday and Saturday) significantly improved strength over a 6-month period but did not improve timed
function tests. (40)
Studies of prednisone in patients under age 5
Limited publications are available to guide clinicians as to the desirability of initiating corticosteroids in
patients before age 5 years.(37-39,41) Two previous reports describe initiating treatment in two very young
patients: one age 3 years and the other age 3 years 6 months.(33,34) Only a few more recent studies are available
to guide clinicians in determining if starting prednisone in preschool-age patients is safe and appropriate.
Four reports, encompassing a total of 12 patients, have described encouraging results when corticosteroid
therapy was begun before 5 years of age. In these studies, the treatment regimens have employed either pulsed
therapy, giving corticosteroid four to six times per year, (37) intermittent corticosteroid treatment, given in cycles
of 10 days on and 10 days off, (38,39) or alternate-day prednisone. (41) It is important to note that these class IV
studies are not randomized controlled investigations. They are observational studies and need confirmation
with appropriately designed double-blind, randomized, controlled studies.
Deflazacort: What are the benefits and side effects of treatment with deflazacort in boys with DD?
Deflazacort is an oxazoline analogue of prednisone and has an estimated dosage equivalency of 1:1.3 compared
with prednisone. That is, 1.3 mg of deflazacort is approximately equivalent to 1.0 mg of prednisone, and in the
trials of daily treatment, 0.9 mg/kg/day of deflazacort is almost equivalent to 0.75 mg/kg/day of prednisone. (42)
It is important to emphasize that biologic equivalence between deflazacort and prednisone also depends on the
specific actions under examination. Deflazacort was evaluated in the hope that it would have fewer side effects
than prednisone. It is not available in the United States.
Class I studies: therapeutic effects
Evidence from two class I studies of deflazacort (see table E-4 on the Neurology Web site) demonstrated that
daily treatment for 9 months with 1.0 mg/kg/day(43) and alternate-day treatment for 2 years with 2.0 mg/kg
every other day(44) increase muscle strength and function. In contrast to the results of alternate day therapy with
prednisone (1.25 and 2.5 mg/kg every other day), (30) one study used a dosage of deflazacort of 2.0 mg/kg every
other day and showed sustained improvement over 2 years, including improvement in average muscle strength
and in timed function testing (gait, stair climb, arising from the floor). (44) Eleven patients lost their ability to
ambulate during the trial of deflazacort: seven in the placebo group and four in the deflazacort groups. The
mean prolongation of ambulation was 13 months.
Class I studies: side effects
Side effects are summarized in table E-4 (see the Neurology Web site). The findings in both class I trials of
deflazacort indicate that deflazacort, like prednisone, produces beneficial effects on muscle strength and
function and that side effects were similar to prednisone.
Class II to IV studies, Therapeutic effects
Table E-4 (see the Neurology Web site) includes and summarizes two relatively long-term class IV (3.2 and 5.4
years) open trials of daily treatment with deflazacort. (32,48) In one study, all 24 untreated patients stopped
walking at an average age of 9.8 ± 1.8 years. (32) Of the 30 boys receiving deflazacort, only 7 stopped walking
(at 12.3 ± 2.7 years). Of the 23 boys who continued to walk, 21 are older than 10. Treatment with deflazacort
maintained their FVC, and spine stabilization surgery was not needed in any of the deflazacort-treated patients.
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(32) The second trial of treatment with deflazacort also showed a significant and sustained increase in muscle
strength and FVC compared with untreated patients. (48)
Mean weight in deflazacort-treated patients in one of the above-mentioned studies remained between the 25th
and 50th percentiles, whereas the untreated group mean weight rose to the 75th to 90th percentiles at age 13. (32)
As noted previously, the beneficial effects of greater increased muscular activity may have lessened the
potential side effect of weight gain. Ten of the 30 deflazacort-treated patients in this study had asymptomatic
cataracts. There were no cataracts in the untreated group.
Side effects were more frequent in a longer-term study that lasted for >5 years. (48) Two of 13 children were
obese, 6 had asymptomatic cataracts, and 11 had decreased linear growth. There was no difference in the
occurrence of fractures or degree of osteoporosis in the group receiving deflazacort compared with untreated
patients. Three of the studies with deflazacort provide specific data comparing weight gain in deflazacort-
treated patients and control subjects. (44,48,32) One class I study found that 8 of 13 patients (only 13 of 17 treated
boys completed 2 years of therapy) receiving alternate-day deflazacort (2 mg/kg) gained weight (>20% over
baseline) compared with 3 of 6 placebo-treated patients (only 6 of 11 boys receiving placebo completed 2 years
of treatment). (44) Data from two class IV studies in which lower-dose daily deflazacort (0.9 mg/kg/day) was
used showed few side effects. (48,32) For example, in one of the studies, there was a range in body mass index
(i.e., weight in kg/m2 surface area) of 13.3 to 27.0 kg/m2 for the 13 boys receiving deflazacort and 10.3 to 26.4
kg/m2 for the 13 untreated boys after 65 months. (48) In the other study, the mean height for the 12 boys who
received deflazacort for >3 years was at the 3rd percentile, while their weights ranged between the 25th and
50th percentiles. (32) Of the 24 untreated boys, their mean heights and weights both ranged between the 25th
and 50th percentiles, indicating a greater mean weight for age for height after 3 years of treatment. (32) Despite
this relative weight gain, the treated boys had greater function (ability to walk, climb stairs, arise from the
floor) than untreated boys with normal weight for height.
Studies comparing deflazacort with prednisone
There are three additional open trials in which deflazacort (0.9 mg/kg/day) was compared with prednisone
(0.75 mg/kg/day) (45-47) (see table E-4 on the Neurology Web site). These trials ranged in duration from 12 to 24
months and found that daily prednisone and daily deflazacort produced similar sustained improvement in
muscle strength and function. One study provided the most comparative details about side effects, although the
number of patients enrolled was small (n = 9 for deflazacort, n = 9 for prednisone, n = 7 for ambulant control
subjects, total n = 25). (47) The mean increase in body weight in patients receiving deflazacort was 2.17 kg (9%)
compared with 5.08 kg (21.3%) in patients receiving prednisone after the first 12 months of treatment. No
specific data were given about differences in lean body mass between groups. Both deflazacort and prednisone-
treated boys showed comparable improvement in function as well as strength testing.
Seven class I studies and a larger number of class IV trials have all demonstrated that prednisone is beneficial
in the treatment of DD. There is a significant increase in strength, timed muscle function, and pulmonary
function. Daily treatment with prednisone at a starting dosage of 0.75 mg/kg/day or deflazacort at a starting
dosage of 0.9 mg/kg/day offers an optimal and effective initial treatment. The most frequent side effects are
weight gain and development of a cushingoid facial appearance. Very recently, there was a Cochrane review of
glucocorticoid corticosteroid therapy in DD, and the conclusions were in full agreement with those cited above.
(49) Two class I studies and several class II to IV studies have also demonstrated similar efficacy and side effect
profiles with deflazacort. There are insufficient data that directly compare prednisone and deflazacort to
determine if deflazacort has fewer side effects.
1. Prednisone has been demonstrated to have a beneficial effect on muscle strength and function in boys with
DD and should be offered (at a dose of 0.75 mg/kg/day) as treatment (Level A). Maintaining a dosage of
0.75 mg/kg/day is optimal, but if side effects require a decrease in prednisone, a gradual tapering of
prednisone (as indicated below) to dosages as low as 0.3 mg/kg/day will give less robust but significant
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NEUROLOGY 64 January (1 of 2) 2005 Page 8
2. Benefits and side effects of corticosteroid therapy need to be monitored. Timed function tests, pulmonary
function tests, and age at loss of independent ambulation are useful to assess benefits. An offer of
treatment with corticosteroids should include a balanced discussion of potential risks. Potential side effects
of corticosteroid therapy (weight gain, cushingoid appearance, cataracts, short stature [i.e., a decrease in
linear growth], acne, excessive hair growth, gastrointestinal symptoms, and behavioral changes) also need
to be assessed. If excessive weight gain occurs (>20% over estimated normal weight for height over a 12-
month period), based on available data, it is recommended that the dosage of prednisone be decreased (to
0.5 mg/kg/day with a further decrease after 3 to 4 months to 0.3 mg/kg/day if excessive weight gain
continues) (Level A).
3. Deflazacort (0.9 mg/kg/day) can also be used for the treatment of DD in countries in which it is available
(Level A). Patients should be monitored for asymptomatic cataracts as well as weight gain during
treatment with deflazacort.
1. Double-blind, randomized, controlled studies are needed to compare daily treatment with prednisone (0.75
mg/kg/day) with other treatment regimens such as 1) higher-dose alternate-day treatment (5 mg/kg every
other day), 2) intermittent treatment (0.75 mg/kg/day for 10 days—stop for 10 days— repeat cycle), 3)
high-dose pulses on weekends (5 mg/kg on Friday and Saturday), and 4) deflazacort (0.9 mg/kg/day). The
goal of these studies is to establish more clearly the optimal dose, optimal age to initiate treatment, and
optimal dose schedule to improve function with the least possible side effects.
2. Studies are needed to determine if daily prednisone has a beneficial effect on cardiac, respiratory,
gastrointestinal, and cognitive function in patients with DD.
3. Natural history studies of DD from birth to age 6 years and dose–response studies of corticosteroid
treatment with prednisone and deflazacort beginning at an early age (2 to 4 years) are needed to determine
if corticosteroid therapy is beneficial if it is started in very young patients.
4. In vitro and animal model studies are needed to identify the mechanism(s) responsible for the beneficial
effects of corticosteroids in DD.
5. Better methods need to be developed and studies performed to assess the quality of life in patients with DD
from infancy to adulthood. Those methods need to be used to examine the influence of long-term
corticosteroid therapy on the quality of life in DD.
6. Long-term studies evaluating corticosteroid treatment given over many years are needed to assess its effect
on the natural history of all manifestations of DD, including the effect on ambulation, respiratory and
cardiac function, as well as quality of life.
7. Studies to define the natural history of changes in bone mass and density as well as scoliosis and the
incidence of fractures are needed in children with DD and other muscle-wasting diseases in childhood.
Trials of treatment with calcium supplements and bisphosphates in these patients deserve consideration.
8. Evaluation is needed of short- and long-term effects of corticosteroid treatment on the spine and the role of
calcium supplements and bisphosphonates as adjuvant therapies in DD.
9. Studies to document the natural history of the late stages of DD and investigations to determine the
efficacy of corticosteroid therapy when initiated late in the course of DD (e.g., after 15 years of age) are
10. Studies of dietary modification and exercise are needed to evaluate their efficacy in ameliorating the
weight gain associated with corticosteroid therapy in DD.
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NEUROLOGY 64 January (1 of 2) 2005 Page 9
This statement is provided as an educational service of the American Academy of Neurology. It is based on an
assessment of current scientific and clinical information. It is not intended to include all possible proper
methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific
procedure. Neither is it intended to exclude any reasonable alternative methodologies. The AAN recognizes
that specific patient care decisions are the prerogative of the patient and the physician caring for the patient,
based on all of the circumstances involved.
The authors thank Tracy Forrester and Karen Berk for preparation of the text and tables for this manuscript.
AAN evidence classification scheme for a therapeutic article
Evidence provided by a prospective, randomized, controlled clinical trial with masked outcome assessment, in a
representative population. The following are required:
1. primary outcome(s) is/are clearly defined
2. exclusion/inclusion criteria are clearly defined
3. adequate accounting for drop-outs and crossovers with numbers sufficiently low to have minimal potential for
4. relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is
appropriate statistical adjustment for differences
Evidence provided by a prospective matched group cohort study in a representative population with masked
outcome assessment that meets a–d above OR a randomized control trial in a representative population that
lacks one criteria a–d
All other controlled trials (including well-defined natural history controls or patients serving as own controls)
in a representative population, where outcome assessment is independent of patient treatment
Evidence from uncontrolled studies, case series, case reports, or Expert opinion
AAN system for translation of evidence to recommendations
Translation of evidence to recommendations Rating of recommendation
Level A rating requires at least one convincing class I
study or at least two consistent, convincing class II
Level B rating requires at least one convincing class II
study or at least three consistent class III studies
A = Established as effective, ineffective or harmful for
the given condition in the specified population
B = Probably effective, ineffective or harmful (or
probably useful/predictive or not useful/predictive) for
the given condition in the specified population
C = Possibly effective, ineffective or harmful (or
possibly useful/predictive or not useful/predictive) for
the given condition in the specified population
U = Data inadequate or conflicting; given current
knowledge, treatment is unproven
Level C rating requires at least two convincing and
consistent class III studies
Quality Standards Subcommittee Members:
Gary Franklin, MD, MPH (cochair); Gary Gronseth, MD (co-chair); Charles E. Argoff, MD; Stephen A. Ashwal,
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NEUROLOGY 64 January (1 of 2) 2005 Page 10
MD (ex-officio); Christopher Bever, Jr., MD; Jody Corey-Bloom, MD, PhD; John D. England, MD; Jacqueline
French, MD (ex-officio); Gary H. Friday, MD; Michael J. Glantz, MD; Deborah Hirtz, MD; Donald J. Iverson, MD;
David J. Thurman, MD; Samuel Wiebe, MD; William J. Weiner, MD, and Catherine Zahn, MD (ex-officio).
CNS Practice Committee Members:
Carmela Tardo, MD (chair); Bruce Cohen, MD (vice-chair); Elias Chalhub, MD; Roy Elterman, MD; Murray Engel,
MD; Bhuwan P. Garg, MD; Brian Grabert, MD; Annette Grefe, MD; Michael Goldstein, MD; David Griesemer,
MD; Betty Koo, MD; Edward Kovnar, MD; Leslie Anne Morrison, MD; Colette Parker, MD; Ben Renfroe, MD;
Anthony Riela, MD; Michael Shevell, MD; Shlomo Shinnar, MD; Herald Silverboard, MD; Russell Snyder, MD;
Dean Timmons, MD; Greg Yim, MD; and Mary Anne Whelan, MD.
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