Corticosteroid Treatment and Functional Improvement in Duchenne Muscular Dystrophy Long-Term Effect

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1 Authors: Birol Balaban, MD Dennis J. Matthews, MD Gerald H. Clayton, PhD Terri Carry, MS, PT Affiliations: From the Department of Physical Medicine and Rehabilitation, Gulhane Military Medical Academy, Etlik- Ankara, Turkey (BB); and the Department of Physical Medicine and Rehabilitation, University of Colorado HSC, Children s Hospital, Denver, Colorado (DJM, GHC, TC). Correspondence: All correspondence and requests for reprints should be addressed to Birol Balaban, MD, Department of Physical Medicine and Rehabilitation, Gulhane Military Medical Academy, Etlik- Ankara, Turkey Disclosures: This study was conducted at the Department of Rehabilitation Medicine, Children s Hospital, Denver, Colorado /05/ /0 American Journal of Physical Medicine & Rehabilitation Copyright 2005 by Lippincott Williams & Wilkins DOI: /01.phm d0 RESEARCH ARTICLE Corticosteroid Treatment and Functional Improvement in Duchenne Muscular Dystrophy Long-Term Effect ABSTRACT Neuromuscular Balaban B, Matthews DJ, Clayton GH, Carry T: Corticosteroid treatment and functional improvement in Duchenne muscular dystrophy: Long-term effect. Am J Phys Med Rehabil 2005;84: Objective: To determine and compare the long-term effects of prednisone and deflazacort on the functional status of children with Duchenne muscular dystrophy. Design: A total of 49 boys with Duchenne muscular dystrophy, between the age of 12 and 15 yrs, who were observed over a 7-yr period were reviewed retrospectively. Eighteen had been treated with prednisone, 12 with deflazacort, and 19 had no drug treatment. All boys treated with steroids received medication for 2 yrs before losing their ambulation. Lower and upper limb motor functions, pulmonary function, prevalence of surgery for scoliosis, and side effects were compared. Results: Boys in the steroid groups were significantly more functional and performed better on all tests than boys not treated (P 0.05). There was no significant difference between the deflazacort- and prednisonetreated groups (P 0.05). The number of boys having scoliosis surgery in treated groups was significantly less than nontreated boys (P 0.05). The control group s pulmonary capacity was decreasing and significantly less than both prednisone- and deflazacort-treated boys. Both deflazacort and prednisone had beneficial effect on pulmonary function and scoliosis. Cataracts, hypertension, behavioral changes, excessive weight gain, and vertebral fracture were noted as serious side effects. Conclusions: and deflazacort have a significant beneficial effect on slowing the disease progress. Their usage in Duchenne muscular dystrophy may prolong ambulation and upper limb function with similar potency. Both steroids also improve pulmonary function, in addition to delaying the need for spinal interventions, with similar therapeutic profiles. Key Words: Duchenne Muscular Dystrophy,, Deflazacort, Rehabilitation November 2005 Corticosteroids in DMD 843

2 Duchenne muscular dystrophy (DMD) is an X- linked recessive disorder and characterized by a progressive weakness of skeletal muscle. 1 The lack of dystrophin, a muscle structural protein, and other associated transmembrane glycoproteins apparently results in an unstable muscle fiber membrane and impaired intracellular homeostasis. 2,3 The prevalence of Duchenne dystrophy has been estimated to be around 1 in 3500 live male births. 1,4 Boys with DMD exhibit a progressive deterioration of muscle function. 3,5 Diagnosis is usually made between the ages of 2 and 5 yrs and is followed by early loss of ambulation between 7 and 12 yrs of age, with a mean age of 10 yrs of age, resulting in wheelchair dependency. Life expectancy is between the late teens and early twenties. Although prolongation of ambulation has been achieved by releasing contractures and the use of light-weight ankle foot orthoses, 6 no increase in muscle strength can be expected by these procedures. 7 Many medications have been tried over the years to increase muscle strength. Of all the therapeutic drugs studied in DMD, only catabolic steroids such as prednisone and deflazacort seem to have potential for improving or preserving functional status Nevertheless, there is still variation in perception and practice regarding corticosteroid treatment for DMD. Besides their positive effects on preserving muscle function, prednisone and deflazacort are also associated with significant side effects. 10,13 Although a few studies comparing benefits and side effects of both steroids were reported, a long-term, prospective, randomized or retrospective reviewed study comparing prednisone and deflazacort has not yet been reported. Thus, this retrospective study was designed to clarify and compare the beneficial and adverse effects of two steroids in the long-term treatment of DMD. MATERIALS AND METHODS The medical records of DMD patients who had received steroid therapy for 2 yrs before losing ambulation and observed for more than a 7-yr period were reviewed. All patients were ambulatory at the time of entry into the clinic and participated in their follow-up visits regularly. The subjects fulfilled the following diagnostic criteria of DMD: (1) male, (2) onset of weakness before the age of 5 yrs, (3) initial proximal muscle weakness with pseudohypertrophy, (4) increased serum creatine kinase, and (5) diagnosis confirmed by muscle biopsy, dystrophin genotyping studies, and electromyography. Patients who changed between different types of steroid, started steroid after loss of walking, or had additional disease comorbidities, such as glycerol kinase deficiency and significant mental delay, that affected the natural history of DMD were excluded. Parents had been informed about treatment alternatives and offered the option of having their child initiate steroid medication or not. The steroid treatment consisted of two medications: deflazacort or prednisone. Parents were presented with both options. Mechanism of action, complications, and drug interactions were explained. Cost of deflazacort was much more than prednisone ($3/day vs. $0.50/day). Unfortunately, some families chose on the basis of cost. Potential side effects of medication was the primary concern for not choosing steroid treatment. The patients received steroid therapy for 2 yrs and started medication before losing ambulation. The children treated with steroids were also placed on oral supplements of vitamin D plus calcium to diminish the risk for osteoporosis. The children who had declined the use of steroids were otherwise treated identically. There were no differences in the physical therapy program between the study groups. The respiratory management was similar for the different groups of older boys, including incentive/expiratory spirometry, cough assist techniques, cough exsufflation, and noninvasive and invasive ventilation. The frequency and use of cough assist varied with symptoms and was similar in both steroid groups. Evaluation Each patient had a follow-up visit every 6 mos with a standard clinical protocol. Two additional monitoring sessions were carried out at months 2 and 4 during the start of steroid therapy. Patient and family satisfaction, muscle function, pulmonary function, and social and neuromuscular evaluations were done at every follow-up with a standard clinical protocol. A single physical therapist performed functional tests independent of the physiatrist. All functional tests were done by the same physical therapist for better patient cooperation to minimize interrater reliability. Lower limb functional testing was evaluated, including measurement of time needed to walk or run 30 feet, time to get up from the floor (Gowers sign), time to climb four standard-size steps, and time to stand from sitting position. Grip and pinch strength, the maximum hand-held weight that could be lifted overhead, were documented as a means of evaluating upper limb function. Pulmonary function (vital capacity) was determined with a hand-held spirometer. Weight, height, pulse, and blood pressure were recorded at each visit. Side effects were monitored by a patient questionnaire and by routine urine and blood examination, including complete blood count, glucose, serum creatine kinase, electrolytes, and hepatorenal functions. Radiographic 844 Balaban et al. Am. J. Phys. Med. 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3 TABLE 1 Motor function results of boys with Duchenne muscular dystrophy Deflazacort vs. P Deflazacort Log Rank (n 18) Deflazacort (n 12) Loss of Ability Control (n 19) P Log Rank P P Log Rank Log Rank Mean Survival Time, yrs Mean Survival Mean Survival Time, yrs a Time, yrs Walking b b b Getting up b b b Climbing b b b Standing up b b b Lifting weight b b b Lifting hand b b b a 95% confidence interval. b Statistically significant at P evaluation of the spine was evaluated yearly, including dual-energy x-ray absorptiometry scan after loss of ambulation. Study Protocol Data from each follow-up visit, occurring between the ages of 7 and 15 yrs, was recorded. Motor functional evaluation of the lower limb was assessed and end dates established by following the timed-muscle function tests: unable to walk 30 feet on a level floor, unable to get up from the floor, unable to climb four standard-size steps, unable to stand from sitting position. End dates of losing capability in the following tests of upper limb function were established: unable to lift 2.5 pounds of weight overhead and unable to lift hands overhead. The date of first visit that the patient was not able to do the evaluation test was chosen as the end date of test. Grip and pinch strength values of both hands at the age of 10 and 15 yrs were also recorded as a hand function evaluation result. Forced vital capacity (FVC) measurements of all patients at the ages of 7, 10, and 15 yrs old were recorded in the determination of pulmonary function evaluation. Each patient record was reviewed for DMDdependent scoliosis. Those who had a spine fusion surgery due to scoliosis and the patient s age at the time of surgery were recorded. The common side effects of steroid treatment, such as weight gain, behavioral changes, gastrointestinal complications, blood pressure changes, glucosuria, acne, and hirsutism were documented in the steroid-treated group. The study protocol was approved by the institutional review board committee. Statistical Analysis All of the statistical analyses were performed by SPSS 10.0 (SPSS, Chicago, IL) software. Descriptive statistics are shown as mean SD. For the median survival times, 95% confidence intervals are given. Comparisons of groups were done by Kruskal Wallis and Mann Whitney U tests with Bonferroni correction. Post hoc power analysis of the study to detect the observed difference between medication groups with 0.05 was The Friedman test and Wilcoxon signed-rank test with Bonferroni correction were used for repeated measurements. Kaplan Meier survival analysis and logrank test were also applied to calculate and compare the median survival times. P values of 0.05 were considered statistically significant. RESULTS A total of 49 boys met the selection criteria and were divided into three groups: 18 were treated with prednisone, 12 were treated with deflazacort, and 19 were in the control group. Five patients who November 2005 Corticosteroids in DMD 845

4 TABLE 2 Course of hand strength measurements Deflazacort vs. Deflazacort Control Deflazacort Mean SD P Mean SD P Mean SD P P P P Measurement Grip strength 10 yrs old a NS NS NS 15 yrs old a Pinch strength 10 yrs old a a a 15 yrs old a a a Statistically significant at P had changes between different types of steroids and one patient who started steroid therapy after loss of walking were excluded. The mean age of the groups are as follows: yrs for the nonsteroid (control) group, yrs for the prednisone group, yrs for the deflazacort group. The age of every patient was recorded according to the date of their last follow-up visit. The mean age of starting deflazacort was yrs, the mean duration of treatment was , and the dose of deflazacort was 0.9 mg/kg/day. The mean age of starting prednisone was , the mean duration of treatment was yrs, and the dose of prednisone was 0.75 mg/ kg/day. Motor Function Mean survival age of loss of ability is shown in Table 1. All 19 boys in the control group lost the ability to do lower limb function tests, whereas two boys in each steroid group were still able to perform all tests at age 12. Two boys in the control group still had the capability to lift 2.5 pounds of weight over their heads. Mean age of these boys was 11.0 yrs. The mean age of eight boys with the capability to lift 2.5 pounds of weight over their heads in the deflazacort group was yrs, and the mean age of nine boys who were able to lift both hands were yrs. In the prednisone group, six boys were still lifting weight at yrs of age, and seven boys were lifting their hands at yrs of age. The number of boys having the ability to do all tests in the steroid groups were significantly higher than nontreated boys (P 0.05). There was no significant difference between the two steroid groups (P 0.05). Change in grip strength with age of yrs was only statistically significant in the deflazacort-treated group (P 0.05). On the other hand, pinch strength change was statistically significant in the control group (P 0.05). There was no improvement in the prednisone group for either hand strength measurement (P 0.05). Although no significant difference was detected between the two steroid groups, boys treated with deflazacort were significantly stronger than controls at age 15 (P 0.05) (Table 2). Back Surgery Patients were observed with spinal radiography. If the curve was 35 degrees or progressing very rapidly, they were referred for scoliosis surgery. Most of the boys had a posterior spinal fusion if the curve was 45 degrees and relatively flexible. If the curve is 45 degrees and the spine is rigid, the option is to do an anteroposterior spinal fusion. Back surgery occurred in 52.6% of the patients in the control group (n 10) and 11.1% of the 846 Balaban et al. Am. J. Phys. Med. Rehabil. Vol. 84, No. 11

5 TABLE 3 Pulmonary function changes of study groups in the progression of Duchenne muscular dystrophy Deflazacort vs. Deflazacort Control Deflazacort Mean SD P Mean SD P Mean SD P P P P a a a NS NS NS FVC change between the ages of 7 and 10 yrs a a a a FVC change between the ages of 7 and 15 yrs FVC, forced vital capacity. a Statistically significant at P prednisone group (n 2); none of the boys treated with deflazacort have yet met the criteria for scoliosis surgery. Four boys (one treated with prednisone, three in the control group) who had a scoliosis curve of 50 degrees were spinal surgery candidates whose families declined the procedure, for reasons that were not related to severity of the curve. To avoid controversy, these boys were excluded from the analysis. The number of boys having surgery in steroid-treated groups was significantly less than for nontreated boys (P 0.05). However, there was no statistically significant difference between the two steroid groups (P 0.05). Although mean surgery age in the control group was yrs, five of six patients who did not have surgery were younger than those having surgery, with a mean age of yrs. In the prednisone group, mean age at surgery was yrs, and the mean age of subjects who did not have spine surgery was yrs. Of boys 14 yrs of age at the last evaluation, 10 of 11 (90.9%) in the control group had undergone surgery, whereas only 2 of 15 (13.3%) in the prednisone group had undergone surgery. Pulmonary Function Baseline pulmonary function values for the control, deflazacort, and prednisone groups at the age of 7 yrs were liters, liters, and liters, respectively. When the boys were 10 yrs of age, FVC of all boys had a tendency to increase, and mean change of FVC between the ages of 7 and 10 yrs was statistically significant for each group (Table 3). The mean change values were still not statistically significant for intergroup comparison (P 0.05). Between the age of 10 and 15 yrs, the deflazacort group was still having a mild tendency to increase, whereas the prednisone group was almost unchanged. The value between these two groups was not statistically significant (P 0.05). On the other hand, the control group capacity was decreasing and significantly less than both prednisone- and deflazacorttreated boys (Table 3, Figure 1). Side Effects At 7 yrs of age, the mean weights for control, prednisone-treated, and deflazacort-treated boys were kg, kg, and kg, respectively, and similar to each other. -treated boys had excessive weight gain during the first years of treatment. Their weight increased to the 75th and 90th percentiles at 10 yrs of age, whereas the boys in the control and deflazacort groups had similar weight gain between the 25th and 50th percentiles. The mean weight for the deflazacort group started to exceed the mean weight of the control group at the age of 12 yrs. November 2005 Corticosteroids in DMD 847

6 FIGURE 1 Pulmonary function change during development (ages 7 15 yrs). FVC, forced vital capacity. The tendency for weight gain in the deflazacort group remained almost constant between the 50th and 75th percentiles after 12 yrs of age, whereas the prednisone-treated group stayed within the 75th and 90th percentiles during that time period. Although, the control group boys did keep gaining weight between the ages of 11 and 13 yrs in 50th and 75th percentiles, their weight percentile decreased between the 25th to 50th percentiles at 14 yrs of age and between the 10th to 25th percentiles at the age of 15. In boys with unacceptable weight gain during the maintenance phase, the prednisone dose was reduced to 0.5 mg/kg/day, then to 0.25 mg/kg/day or discontinued, if necessary. In the deflazacort group, dosing was maintained at 0.9 mg/kg/day and never changed during the treatment because of early weight gain. Acne, excessive hair growth, and gastric complications were tolerable, and none of the boys stopped treatment due to these side effects. Urine and blood measurements were all within normal limits. In addition, throughout the treatment period, no glucosuria or gastrointestinal bleeding was detected. Hemoglobin and hematocrits were stable, and no one complained of melena or blood in stool. In the deflazacort group, two boys had bilateral cataracts, but there were no visual problems and no need to stop treatment. The deflazacort treatment of three boys was tapered because of hypertension, behavioral changes, and vertebral fracture with improvement in symptoms. In the prednisone group, three boys had excessive weight gain, and their treatments were tapered off and discontinued. An additional three boys had behavioral changes, but only one stopped treatment due to this side effect. A vertebral fracture was determined in one patient, and prednisone was tapered due to this side effect. DISCUSSION Corticosteroid therapy has been shown by a number of studies to have positive effects on DMD Steroid treatment had no effect on dystrophin expression after treatment. 15 The mechanism of action of steroids in DMD is still poorly understood, but several theories have been put forward. 16 and deflazacort have both been found to be of definite benefit in improving muscle strength and delaying the loss of independent ambulation between 2 and 3 yrs. 10,13,17,18 In addition, other investigators found that both deflazacort and prednisone have similar effects in improving muscle strength However, it has not been reported whether deflazacort and prednisone have similar benefits in delaying the loss of independent ambulation. Our study shows that both steroids similarly slow the progression of DMD by prolonging ambulation. The absolute values of scores seemed better in the deflazacort group, but the difference was not statistically significant. The boys receiving steroid treatment also showed better results than nontreated boys on the basis of upper limb functions. Griggs and et al. 8 reported that boys treated with prednisone were significantly improved in lifting weights at their 6-mo follow-up period. Most of the boys having DMD lost ability to lift weights and raise their hands above their head before the age of 13 yrs. 5 In our study, 14 of 19 boys 13 yrs of age in a historically treated group lost ability at the age of yrs. However, only 6 of 27 boys 13 yrs of age lost ability in the steroid-treated groups. These results showed that both prednisone and deflazacort were also effective on preserving upper limb strength, and no significant difference was found between two medications. Related to these findings, we had an expectation of similar results on manual muscle strength measurements, but our findings did not support this. Mathiowetz et al. 22 reported that hand dominance did not significantly effect hand strength scores. Strength evaluation of dominant vs. nondominant limbs in DMD revealed no differences in weakness between each side. 3 Hand dominance did 848 Balaban et al. Am. J. Phys. Med. Rehabil. Vol. 84, No. 11

7 not have a significant effect on our test results. However, elbow and wrist positions did affect grip and pinch strength measurement. 23 In early stages of Duchenne dystrophy, it was possible to provide position in standardized grip and pinch evaluations. In the later phase of their disease, boys with DMD had trouble obtaining ideal shoulder, elbow, and wrist position. The presence of upper limb contractures or reduced strength of the deltoid, biceps, and forearm muscles in DMD were the main reason for losing the capability for standardized limb position. Contractures were rare before age 9 and present in nearly all subjects of 13 yrs of age. 3 Wrist contracture is known to limit function and limb position, even if strength is preserved. 24 Improper position of shoulder, elbow, and wrist might have some effect on the accurate findings in this study. The lack of cooperation and the possibility of submaximal effort while performing tests can effect reliability of grip and pinch strength measurement tests. 25,26 In this trial, measurement tests were done by the same therapists to reduce interrater reliability and the influence of effort and cooperation. However, our findings lead us to think that grip and pinch strength tests might be insufficient to evaluate manual muscle strength in boys with DMD. Pulmonary function is expected to increase for those ten and younger. 3,27 After 10 yrs of age, a linear decline in percentage of predicted FVC is apparent, and the average percentage of decline is approximately 8.5% per year. 3,28 It has been shown that prednisone improved pulmonary function in boys compared with natural history controls. 8,13,29 Biggar et al. 18 also reported similar results for deflazacort in their retrospective study. Our trial showed both steroids had almost equal beneficial effect on pulmonary function. The maintenance of muscle strength in the respiratory muscles might be postulated as the reason for FVC improvement in treated boys. As reported by Hahn et al., 28 lung volume changes in DMD patients correlate with respiratory muscle weakness. Spinal deformity delay in treated boys may also be another factor for keeping pulmonary functions optimum. Kurz et al. 30 proposed that scoliosis would have a significant effect in the development of restrictive lung disease; other investigators found no correlation between the degree of spinal deformity and percentage of predicted FVC at various ages. 31,32 In their study, McDonald et al. 3 reported that age, ambulatory status, and spine deformity all affected predicted FVC but that age was the major factor. The prevalence of scoliosis increased between ages of 11 and 16, with approximately 50% of patients acquiring scoliosis between ages of 12 and 15, a time of rapid spinal growth. 3 Deflazacort treatment slows the progression of scoliosis in boys with DMD, and the timing for scoliosis surgery is delayed. 18,33 However, the effect of prednisone delaying or avoiding scoliosis surgery had not been evaluated to date. Our findings show that both prednisone and deflazacort delay or change the timing for scoliosis surgery. The slowed progression of scoliosis during adolescence may obviate the need for surgery. 33 On the other hand, the deformity may occur after 15 yrs of age with greater surgical risks. Because of variations in the severity of the clinical course of DMD patients, it is difficult to determine the need for such interventions. Not only the degree of curve, but also the condition of pulmonary function is important in the decision. Longer-term evaluations of these patients will clarify the ultimate outcome. A number of side effects are associated with steroid use: cataracts, hypertension, behavioral changes, excessive weight gain, and vertebral fracture. Early excessive weight gain is the most common adverse effect of prednisone treatment, 34 whereas this has not been observed with deflazacort therapy. 18 Previously, an approximately 10% difference in weight gain favoring deflazacort over prednisone was reported. 34 Our data showed that the boys having prednisone therapy had early excessive weight gain, but the boys treated with deflazacort were similar to controls in the first years of therapy. It is unlikely that the difference in weight results from different physical activity because the children in both steroid groups had similar functional abilities. Decreased motor activity after the age of 12 may be the primary reason of more weight increase in deflazacort-treated boys. Although weight gain at the age of yrs was similar in both steroid groups, the necessity for dose reduction due to early excessive weight gain seems the major disadvantage of prednisone treatment in our trial. Although, this study is a retrospective review, the patients in the treatment and control groups were similar. All boys were ambulatory at the time of entry into the clinic and when starting steroid treatment. The mean age at the start of steroid treatment, duration of treatment, initial body weights, and pulmonary function results were also similar to each other. Thus, our findings extend previous observations and describe the long-term functional performance of boys with DMD treated with prednisone and deflazacort. CONCLUSIONS This study showed that steroid treatment with prednisone or deflazacort has a significant beneficial effect on slowing the disease progress and functional loss in boys with DMD. These steroids are not a cure, but both significantly slow the progression of muscle weakness in DMD. Their November 2005 Corticosteroids in DMD 849

8 usage in DMD may prolong ambulation and upper limb function with similar potencies. Both steroids also improve pulmonary functions, in addition to delaying the need for spinal interventions, with similar therapeutic profiles. If the side effects are tolerable, we recommend the continuation of deflazacort or prednisone after the patient becomes nonambulatory. REFERENCES 1. Dubowitz V: Duchenne muscular dystrophy, in: Muscle Disorders in Childhood, ed 2. London, Saunders, Hutter OF: The membrane hypothesis of Duchenne muscular dystrophy: Quest for function evidence. J Inherit Metab Dis 1992;15: McDonald CM, Abresch RT, Carter GT, et al: Profiles of neuromuscular diseases. Am J Phys Med Rehabil 1995; 74(suppl 5): Emery AEH: Population frequencies of inherited neuromuscular diseases: A world survey. Neuromuscul Disord 1991;1: Brooke MH, Fenichel GM, Griggs RC, et al: Duchenne muscular dystrophy: Patterns of clinical progression and effects of supportive therapy. 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