Abstracts that will be presented in World Muscle Society Meeting 2014
Bone, Kidney and Intestine
Constipation in Duchenne muscular dystrophy: Common, nderdiagnosed and undertreated
D. Kraus, B.L. Wong,S.Y. Hu, P. Horn, I. Rybalsky, K.C. Shellenbarger, A. Kaul
Duchenne muscular dystrophy (DMD) is an X-linked progressive degenerative muscle disorder. Constipation as a co-morbidity in DMD has not been subject to a systematic study. To determine the prevalence of constipation, identify its predictive factors and evaluate different screening methods in a cohort of DMD patients. Design/Methods: This was a prospective cross-sectional study that evaluated a cohort of DMD patients for constipation using the pediatric Rome-III questionnaires (QPGS-RIII) and the Bristol stool chart. Additional clinical data collected included functional assessments and medications. Fecal load was assessed on routine spine X-rays. Logistic regression with backward elimination as a variable selection procedure was used to determine possible predictors of constipation. Among 98 male DMD patients (average age 11.3 ± 3.8 years), the overall prevalence of constipation fulfilling Rome-III criteria was 44.9%, of which 45% received symptomatic treatment and 11% were asymptomatic. The age distribution of patients with constipation (n = 44) was similar to that without (10.8 ± 2.6 vs 11.1 ± 3 years, p = 0.62). Prevalence of constipation did not correlate with functional status (Northstar ambulatory assessment scale, p = 0.39), treatment with calcium supplements (p = 0.92) or with stool load on abdominal X-ray (p = 0.82). The regression model failed to identify any predictive variables for constipation. The Bristol stool chart, abnormal abdominal exam (fullness, distension, tenderness, palpable masses or abnormal bowel sounds) and fecal load on X-ray were inferior to the Rome-III criteria in diagnosing constipation. (1) Constipation is a common co-morbidity in DMD, irrespective of age or the stage of disease. (2) Of the tests evaluated, the Rome III criteria may be the most appropriate screening tool for constipation in DMD patients. (3) Constipation in this cohort was underdiagnosed and either not treated or treated inadequately.
Prophylactic oral bisphosphonate therapy in Duchenne muscular dystrophy: The Newcastle upon Tyne experience
A. Sarkozy, R. Srinivasan, D. Rawlings, M. Guglieri, C. Owen, V. Straub, T. Cheetham, K. Bushby
Duchenne muscular dystrophy (DMD) is an X-linked condition characterized by progressive muscle weakness. Glucocorticoids (GC) are a key pharmacological intervention that is associated with prolonged ambulation, reduction of scoliosis and better-preserved respiratory function. However long-term GC therapy, in particular daily regimens, is a significant risk factor for osteoporosis and vertebral fractures. While bisphosphonates (BP) are recommended in case of fractures, prophylactic use of BP remains controversial. Here we summarize our experience of prophylactic BP therapy on a group of DMD patients on daily GC on follow up at the paediatric neuromuscular clinic in Newcastle upon Tyne. Patients were offered prophylactic BP (oral Risedronate) under the guidance of the local paediatric endocrinology team from January 2008. Patients were reviewed 6 monthly for tolerability, side effects, bone pain, frequency of fractures and impact on bone mineral density (BMD) determined by yearly DXA analysis. Vitamin D supplementation (800–1000 IU/L daily) was provided and insufficiencies/deficiencies were treated. Out of a total of 52 patients included in this study, 9 stopped treatment because of side effects (in particular abdominal or joint pain and flu like symptoms). 43 boys continued BP therapy for an average of 24 months (range 12–54 months). Median lumbar spine adjusted BMD (BMAD) Z-scores remained stable during treatment, being 0.11 at baseline and 0.21 at the 3rd year follow up. Z-scores for total body mineral content (minus head) were stable during the period of treatment. 7 patients suffered long bone fracture during therapy and 3 had vertebral fractures (VF), the majority having been on GC for >36 months at the time of fracture. Patients who suffered VF all had lumbar spine BMAD Z-scores <−1 at baseline. In summary, our results indicate that prophylactic BPs therapy is well tolerated by most patients and may have a role in preventing steroid-induced osteoporosis in DMD.
Changes in height and age adjusted DXA bone indices with oral bisphosphonate treatment in Duchenne muscular dystrophy
C. Tian, M. Rutter, L. Hornung, J. Khoury, L. Miller, J. Bange, I. Rybalsky,
B. Wong
Osteoporosis is a major problem in Duchenne Muscular Dystrophy (DMD) due to long term glucocorticoid(GC) therapy and impaired mobility. There are currently no standard of care guidelines for detection or treatment of osteoporosis in DMD. There is limited data on bisphosphonate (BP) treatment of osteoporosis in pediatric DMD patients. This is the first study using height and age adjusted Z scores to assess changes in bone mineral density (BMD) and bone mineral content (BMC) in DMD boys treated with oral BP. To assess changes in bone mineral density (BMD) and bone mineral content (BMC) in DMD boys treated with oral BP. Retrospective study of total body (TB) and lumbar spine (LS) BMD and BMC by DXA in DMD boys treated with oral alendronate, studied between January 2005 and July 2012. Height- and age-adjusted Z-scores (HAZ) were derived. Paired t-tests were used to compare changes in BMD and BMC one year prior and one year post BP treatment. We studied 26 BP-treated DMD boys (mean age ± SD 10.9 ± 3.8 yrs and daily GC duration 3.3 ± 1.5 yrs at BP start). BP treatment duration at the end of the study period was 2.8 ± 1.1 yrs. Prior to starting BP, TB BMD and BMC-HAZ decreased progressively, while LS BMD and BMC-HAZ remained stable. Mean TB BMD and BMC-HAZ were −1.89 and −2.90 and mean LS BMD and BMC-HAZ were −0.89 and −1.07 at BP initiation. DXA bone indices stabilized or improved with BP treatment. There was significant improvement in LS BMD-HAZ (p < 0.0001) and BMC-HAZ (p < 0.0001), and TB BMC-HAZ (p = 0.0092) after one year of BP treatment. Oral BP treatment stabilized further decline of TB bone indices, and improved LS BMD and BMC HAZ and TB BMC HAZ. Our study suggests that oral BP may be beneficial for bone health in DMD boys. Further study to assess clinical correlation of changes in DXA bone indices is needed to evaluate efficacy of oral BP treatment for osteoporosis in DMD patients.
Non-fatal fat embolism syndrome in Duchene muscular dystrophy
L.C. McAdam, K. MacLeod, N. Serrao, W.D. Biggar
Fat Embolism Syndrome (FES) is associated with multisystem dysfunction. It has a wide spectrum of presentation and severity. Our first report of FES in Duchenne Muscular Dystrophy (DMD), onset soon after injury was associated with an early and rapid death. Since then, we have reviewed 6 boys with DMD who developed FES and survived. The boys were between 13 and 19 years (mean 16.3), taking Deflazacort and were obese. All 6 boys had osteoporosis, straight spines, and good cardiac and pulmonary function. All 6 boys had a history of trauma: 4 falls (1 walking, 1 ceiling tract transfer and 2 from wheelchair seatbelt unfastened), 1 forward flexion injury at the beach and 1 arm trauma during transfer. Long-bone fractures occurred in 3 boys: 2 femoral and 1 radial. Using Gurd’s clinical criteria for FES, all 6 boys had 2 major FES criteria. All had CNS signs/symptoms, 5 of 6 had respiratory symptoms and the 6th had petechiae. All 6 boys had at least 2 minor criteria. All had tachycardia and 1 or more of retinal changes, thrombocytopenia, anemia and fever. The time between the trauma and onset of symptoms ranged from 30 min to 24 h (mean 11.5 h). On discharge, 5 of 6 boys had normal CNS function. Cardio-pulmonary function returned to baseline by 6 mos. The sixth boy had severe neurologic sequelae. He requires g-tube feeds, is fully dependent for care and does not speak. FES may be more common than previously recognized. In 5 of 6 cases reported here, the onset of symptoms was delayed compared to our previously reported cases with a fatal outcome. It is important for physicians and families to consider a diagnosis of FES when a boy with DMD presents with acute symptoms following trauma. All boys required early and intensive respiratory and cardiac support. Since all the injuries were accidental, education for accident prevention is critical.
Bone mineral density and body composition in 39 Duchenne muscular dystrophy patients: A two-years follow up
M.B. Pasanisi, S. Vai, G. Baranello, L. Maggi, I. Moroni, M.T. Arnoldi, C. Bussolino, G. Brenna, M.L. Bianchi, L. Morandi
Individuals affected with Duchenne muscular dystrophy (DMD) show significantly altered whole-body composition compared with normal control population. We assessed for at least two years 39 DMD-patients to evaluate how their bone mass and body composition change during time. All patients underwent clinical evaluation and dual-energy-X-ray-absorptiometry (DXA) assessment every six months. By DXA we obtained subtotal total body (without head) and spine bone mineral density (BMD), lean tissue mass (LTM) and body fat percentage (PFAT). We compared data using Wilcoxon tests. At baseline visit the average age was 7 ± 1.62 (range 4–11) years, 11 patients were already treated with steroids since a mean of 3 years, 17 started therapy after that visit and 4 about 1 year later. At baseline we found significant Spearman correlations between all four DXA parameters each other and with weight, height and BMI. We observed an increasing trend (with statistically significant differences) in all DXA parameters during the two-years follow-up, especially in PFAT. Comparing boys over 10 years old with others we found significant differences in all parameters. These results confirm usefulness of DXA as tool both for DMD follow up and for treatment adjustment. Correlation with clinical outcome measures will be presented.
Age-specific prevalence of osteoporosis and frequency of poor bone health indices in Duchenne Muscular Dystrophy
C. Tian, B. Wong, L. Hornung, J. Khoury, L. Miller, J. Bange, I. Rybalsky,
M. Rutter
Osteoporosis is a major problem in Duchenne Muscular Dystrophy (DMD) patients due to long termglucocorticoid (GC) therapy and immobility. There is neither age-specific prevalence data nor consensus on management of osteoporosis in DMD. To determine age-specific prevalence of osteoporosis and frequency of poor bone health indices in pediatric DMD patients. Methods: We retrospectively examined age-specific prevalence of osteoporosis and poor bone health indices in GC-treated DMD patients seen between January 2005 and July 2012 at Cincinnati Children’s Hospital. Outcomes of interest were fractures (total, vertebral, long bone), and low age- and height-adjusted z-scores (<−2) of total body (TB) and lumbar spine (LS) bone mineral density (BMD) and content (BMC) by DXA. We studied 408 patients with 1415 clinical visits (median 3 visits per patient). Ages ranged from 3.0 to 19.3 (mean 10.6 ± 3.7) years at last follow up. By the last visit: 85 (20.8%) were on bisphosphonates, 293 (71.8%) were ambulatory, 339 (83.1%) were prepubertal, and mean daily GC duration was 4.4 ± 2.8 years. DMD patients acquired vertebral and long bone fractures at a young age. Fracture prevalence increased with age. Prevalence of total fractures was 16.5%, 37.4% and 83.3% at ages 5, 10 and 18 years respectively. Prevalence of vertebral fractures was 4.4%, 19.1% and 58.3% at the same ages. Prevalence of osteoporosis as defined by the ISCD 2013 was similar (4.4%, 20.9% and 58.3%). Frequency of low BMD and BMC z-scores also increased with age, and varied with site of measurement. Osteoporosis is frequent in DMD patients from a young age. Our study is the first to examine age-specific prevalence of osteoporosis and frequency of poor bone health indices throughout the pediatric age span in a large DMD cohort. These data also highlight the complexity of bone health measures, and the urgent need to improve detection, prevention and treatment of osteoporosis in DMD.
Renal function in children and adolescents with Duchenne muscular dystrophy: a prospective study
L. De Waele , E. Braat, P. Vermeersch, O. Gheysens, E. Levtchenko, H. Pottel, L. Hoste, N. Goemans
Objectives: Improved life expectancy and the need for robust tools to monitor renal safety of emerging new therapies have fueled the interest in renal function in patients with Duchenne muscular dystrophy (DMD). We aimed to establish methodology for studying renal function in patients with DMD and using this methodology, to describe their renal function in detail. Methods: Twenty participants (5–22 years old) were selected for a prospective cross-sectional study. Medical history was obtained and all patients underwent a physical examination, 24-h ambulatory blood pressure monitoring, ultrasound of the kidneys, 51Cr-EDTA for GFR measurement (mGFR), blood and urine analysis. Results: Between February 2013 and July 2013, twenty patients were included. The median age was 15.5 years. Twelve patients were treated with corticosteroids. Total protein/creatinine was increased in 17/18 patients, whereas 24-h urine protein was normal in 18/18 subjects. We detected nine patients with 51Cr-EDTA GFR >P90 (135 ml/min/m2) and one patient with 51Cr-EDTA GFR <90 ml/min/m2. Median mGFR was 128 ml/min/1.73 m2. Nephromegaly (1 or 2 kidneys with a length >2SD) was found in 6/20 subjects. Hypertension (systolic and/or diastolic blood pressure >P95) was found in 9/20 subjects and a non-dipping profile was found in 13/20 subjects. Conclusions: This small prospective study demonstrates that urinary protein excretion expressed in mg creatinine is not reliable in DMD patients because of low urinary creatinine. We report a high prevalence of hyperfiltration, nephromegaly and hypertension corrected for body size. Our current findings on renal function and outcome in DMD patients require further studies to investigate the pathogenesis, the confounding issue of chronic steroid treatment and long-term prognosis.
Are current formulas for estimated glomerular filtration rate reliable in children and adolescents with Duchenne muscular dystrophy?
L. De Waele, E. Braat, P. Vermeersch, O. Gheysens, E. Levtchenko, H. Pottel, L. Hoste, N. Goemans
Improved life expectancy and the need to monitor renal safety of new therapies have fueled interest in renal function in patients with Duchenne muscular dystrophy (DMD). We assessed the usefulness of estimated glomerular filtration rate (eGFR) formulas based on serum creatinine (sCr) and/or cystatin C (CysC) in children and adolescents with DMD. DMD patients have low sCr values since they have less muscle mass. SCr-based formulas may therefore have limitations. CysC, being independent of muscle mass, may serve as a valuable alternative for eGFR in DMD. In a prospective cross-sectional study, 18 patients (5–22 years) underwent 51Cr-EDTA for GFR measurement (mGFR), blood and urine analysis. Values for renal clearance obtained with sCr-based, CysC-based and sCr/CysC-based eGFR formulas were compared to mGFR. Median mGFR was 128 ml/min/1.73 m2. Nine patients had a mGFR >P90 (135 ml/min/m2). Because of very low sCr values (mean ± SD: 0.16 ± 0.07 mg/dL), sCr-based and sCr/CysC-based formulas overestimate GFR. Mean eGFR ± SD was 464.0 ± 264.1 ml/min/1.73 m2 for Schwartz, 464.2 ± 269.4 ml/min/1.73 m2 for Flanders Metadata, 178.7 ± 61.1 ml/min/1.73 m2 for height-independent and 479.9 ± 327.0 ml/min/1.73 m2for the Q (height) equation. CysC values (0.78 ± 0.13 mg/L) are within normal adult reference ranges. However, sCr/CysC-based formulas result in mean eGFR ± SD of 154.2 ± 34.7 ml/min/1.73 m2 for Zappitelli and 169.2 ± 43.7 ml/min/1.73 m2 for Bouvet. Concerning CysC-based equations the mean eGFR ± SD was 153.8 ± 60.3 ml/min/1.73 m2 for Larsson, 125.4 ± 21.9 ml/min/1.73 m2 for Filler and 105.4 ± 19.1 ml/min/1.73 m2 for Zappitelli. This study demonstrates that sCr-based and sCr/CysC-based formulas should not be used for eGFR in DMD. However, even though mGFR and CysC-based equations showed a better agreement, more research is needed to confirm the preliminary findings that CysC-based equations are suitable for eGFR in DMD patients.