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1.  Pentoxifylline as a rescue treatment for DMD 
Neurology  2012;78(12):904-913.
To determine whether pentoxifylline (PTX) slows the decline of muscle strength and function in ambulatory boys with Duchenne muscular dystrophy (DMD).
This was a multicenter, randomized, double-blinded, controlled trial comparing 12 months of daily treatment with PTX or placebo in corticosteroid-treated boys with DMD using a slow-release PTX formulation (∼20 mg/kg/day). The primary outcome was the change in mean total quantitative muscle testing (QMT) score. Secondary outcomes included changes in QMT subscales, manual muscle strength, pulmonary function, and timed function tests. Outcomes were compared using Student t tests and a linear mixed-effects model. Adverse events (AEs) were compared using the Fisher exact test.
A total of 64 boys with DMD with a mean age of 9.9 ± 2.9 years were randomly assigned to PTX or placebo in 11 participating Cooperative International Neuromuscular Research Group centers. There was no significant difference between PTX and the placebo group in total QMT scores (p = 0.14) or in most of the secondary outcomes after a 12-month treatment. The use of PTX was associated with mild to moderate gastrointestinal or hematologic AEs.
The addition of PTX to corticosteroid-treated boys with DMD at a moderate to late ambulatory stage of disease did not improve or halt the deterioration of muscle strength and function over a 12-month study period.
Classification of evidence:
This study provides Class I evidence that treatment with PTX does not prevent deterioration in muscle function or strength in corticosteroid-treated boys with DMD.
PMCID: PMC3306159  PMID: 22402864
2.  Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy 
Neurology  2011;77(5):444-452.
To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD).
A total of 64 boys with DMD who were between 4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months.
Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone.
Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens.
Classification of evidence:
This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period.
PMCID: PMC3146308  PMID: 21753160
3.  CINRG Pilot trial of Coenzyme Q10 in steroid treated Duchenne Muscular Dystrophy 
Muscle & nerve  2011;44(2):174-178.
Corticosteroid treatment slows disease progression and is the standard of care for Duchenne muscular dystrophy (DMD). Coenzyme Q10 (CoQ10) is a potent antioxidant that may improve function in dystrophin deficient muscle.
We performed an open label, “add-on” pilot study of CoQ10 in thirteen 5–10 year old DMD patients on steroids. The primary outcome measure was the total Quantitative Muscle Testing (QMT) score.
Twelve of 16 children (mean age 8.03±1.64 years) completed the trial. Target serum levels of CoQ10 (≥2.5 μg/ml) were shown to be subject- and administration-dependent. Nine of 12 subjects showed an increase in total QMT score. Overall, CoQ10 treatment resulted in 8.5 % increase in muscle strength (p=0.03).
This pilot study found the addition of CoQ10 to prednisone therapy in DMD patients resulted in an increase in muscle strength. These results warrant a larger, controlled trial of CoQ10 in DMD.
PMCID: PMC3136634  PMID: 21698649
Duchenne muscular dystrophy; CoQ10; steroids; muscle strength testing; clinical trial
4.  Quantitative magnetization transfer imaging of human brain at 7 T☆ 
NeuroImage  2012;64:640-649.
Quantitative magnetization transfer (qMT) imaging yields indices describing the interactions between free water protons and immobile macromolecular protons. These indices include the macromolecular to free pool size ratio (PSR), which has been shown to be correlated with myelin content in white matter. Because of the long scan times required for whole-brain imaging (≈20–30 min), qMT studies of the human brain have not found widespread application. Herein, we investigated whether the increased signal-to-noise ratio available at 7.0 T could be used to reduce qMT scan times. More specifically, we developed a selective inversion recovery (SIR) qMT imaging protocol with a i) novel transmit radiofrequency (B1+) and static field (B0) insensitive inversion pulse, ii) turbo field-echo readout, and iii) reduced TR. In vivo qMT data were obtained in the brains of healthy volunteers at 7.0 T using the resulting protocol (scan time≈40 s/slice, resolution=2×2×3 mm3). Reliability was also assessed in repeated acquisitions. The results of this study demonstrate that SIR qMT imaging can be reliably performed within the radiofrequency power restrictions present at 7.0 T, even in the presence of large B1+ and B0 inhomogeneities. Consistent with qMT studies at lower field strengths, the observed PSR values were higher in white matter (mean±SD=17.6±1.3%) relative to gray matter (10.3±1.6%) at 7.0 T. In addition, regional variations in PSR were observed in white matter. Together, these results suggest that qMT measurements are feasible at 7.0 T and may eventually allow for the high-resolution assessment of changes in composition throughout the normal and diseased human brain in vivo.
PMCID: PMC3625658  PMID: 22940589
Magnetization transfer; 7 T; White matter; Myelin; Brain; Multiple sclerosis
5.  Importance of SPP1 genotype as a covariate in clinical trials in Duchenne muscular dystrophy 
Neurology  2012;79(2):159-162.
To test the effect of the single nucleotide polymorphism −66 T>G (rs28357094) in the osteopontin gene (SPP1) on functional measures over 12 months in Duchenne muscular dystrophy (DMD).
This study was conducted on a cohort of ambulatory patients with DMD from a network of Italian neuromuscular centers, evaluated longitudinally with the North Star Ambulatory Assessment (NSAA) and the 6-Minute Walk Test (6MWT) at study entry and after 12 months. Genotype at rs28357094 was determined after completion of the clinical evaluations. Patients were stratified in 2 groups according to a dominant model (TT homozygotes vs TG heterozygotes and GG homozygotes) and clinical data were retrospectively compared between groups.
Eighty patients were selected (age 4.1–19.3 years; mean 8.3 ± 2.7 SD). There were no differences in age or steroid treatment between the 2 subgroups. Paired t test showed a significant difference in both NSAA (p = 0.013) and 6MWT (p = 0.03) between baseline and follow-up after 12 months in patients with DMD carrying the G allele. The difference was not significant in the T subgroup. The analysis of covariance using age and baseline values as covariate and SPP1 genotype as fixed effect showed that these parameters are significantly correlated with the 12-month values.
These data provide evidence of the role of SPP1 genotype as a disease modifier in DMD and support its relevance in the selection of homogeneous groups of patients for future clinical trials.
PMCID: PMC3390537  PMID: 22744661
6.  Participation in daily life activities and its relationship to strength and functional measures in boys with Duchenne muscular dystrophy 
Disability and rehabilitation  2014;36(22):1918-1923.
While most studies of Duchenne muscular dystrophy (DMD) have focused on physical impairment, there is a need to explore how impairment impacts real life experiences in order to provide intervention strategies focused on participation. Objectives were: 1) to investigate the domains of participation in a sample of boys with Duchenne muscular dystrophy; 2) to compare a younger (<10 years) and older (≥10 years) group of boys with DMD with regard to participation; 3) to investigate strength and timed functional tests in a sample of boys with Duchenne muscular dystrophy; 4) to compare a younger (<10 years) and older (≥10 years) group of boys with DMD with regard to strength and timed functional tests; and 5) to explore associations between participation and strength and timed functional tests for our DMD cohorts.
This cross-sectional study included sixty boys with DMD (mean 9.3 years ±0.3). Boys completed strength testing, timed functional tests, the Children’s Assessment of Participation and Enjoyment and the ACTIVLIM. Independent samples t-tests were used to test for differences in all measures between our younger and older cohorts; Spearman’s (rank) correlation was used to assess relationships between participation and strength and time functional tests.
Significant differences were found between our younger and older boys with DMD in the areas of recreational (p≤0.01), social (p≤0.001), and skill-based activities (p≤0.05), as well as with whom and where the activities were performed (p≤0.05 and 0.001, respectively). Older boys with DMD report lower levels of participation in these areas, as well as less engagement in activities with individuals other than family members and less participation outside of the home. Lower levels of strength and slower rates of functional performance correlate with participation in fewer physical activities for our younger cohort and fewer physical and social activities for our older cohort.
Strength and function relate to the variability and type of activities in which boys with DMD participate. A key finding is the significant decline in social activities and community-based engagement as the boys with DMD age. The ultimate goal of an intervention is for our children to be as actively engaged in life as they desire. This requires addressing participation when measuring outcomes in order to more fully understand limitations and provide appropriate strategies for continued participation for boys and their families.
PMCID: PMC4125555  PMID: 24499260
Duchenne muscular dystrophy; participation; strength outcomes; functional outcomes; social engagement
NeuroImage  2012;62(3):1390-1398.
Magnetization transfer (MT) imaging quantitatively assesses cerebral white matter disease through its sensitivity to macromolecule-bound protons including those associated with myelin proteins and lipid bilayers. However, traditional MT contrast measured by the MT ratio (MTR) lacks pathologic specificity as demyelination, axon loss, inflammation and edema all impact MTR, directly and/or indirectly through multiple covariances among imaging parameters (particularly MTR with T1) and tissue features (e.g. axon loss with demyelination). In this study, more complex modeling of MT phenomena (“quantitative” MT or qMT) was applied to a less complex disease model (the myelin mutant shaking [sh] pup, featuring hypomyelination but neither inflammation nor axon loss) in order to eliminate the covariances on both sides of the MR-pathology “equation” and characterize these important relationships free from the usual confounds. qMT measurements were acquired longitudinally in 6 sh pups and 5 age-matched controls ranging from 3 to 16 months of age and compared with histology. The qMT parameter, bound pool fraction (f), was the most distinctive between diseased and control animals; both f and longitudinal relaxation rate R1 tracked myelination with normal aging, whereas MTR did not—presumably owing to counterbalancing MT and R1 effects. qMT imaging provides a more accurate and potentially more specific non-invasive tissue characterization.
PMCID: PMC3408843  PMID: 22664569
quantitative magnetization transfer; cross-relaxation imaging; white matter; myelin; animal models; relaxometry
8.  The 6 Minute Walk Test and Performance of Upper Limb in Ambulant Duchenne Muscular Dystrophy Boys 
PLoS Currents  2014;
The Performance of Upper Limb (PUL) test was specifically developed for the assessment of upper limbs in Duchenne muscular dystrophy (DMD). The first published data have shown that early signs of involvement can also be found in ambulant DMD boys. The aim of this longitudinal Italian multicentric study was to evaluate the correlation between the 6 Minute Walk Test (6MWT) and the PUL in ambulant DMD boys. Both 6MWT and PUL were administered to 164 ambulant DMD boys of age between 5.0 and 16.17 years (mean 8.82). The 6 minute walk distance (6MWD) ranged between 118 and 557 (mean: 376.38, SD: 90.59). The PUL total scores ranged between 52 and 74 (mean: 70.74, SD: 4.66). The correlation between the two measures was 0.499. The scores on the PUL largely reflect the overall impairment observed on the 6MWT but the correlation was not linear. The use of the PUL appeared to be less relevant in the very strong patients with 6MWD above 400 meters, who, with few exceptions had near full scores. In patients with lower 6MWD the severity of upper limb involvement was more variable and could not always be predicted by the 6MWD value or by the use of steroids. Our results confirm that upper limb involvement can already be found in DMD boys even in the ambulant phase.
PMCID: PMC4208936  PMID: 25642376
9.  Physical training in boys with Duchenne Muscular Dystrophy: the protocol of the No Use is Disuse study 
BMC Pediatrics  2010;10:55.
"Use it or lose it" is a well known saying which is applicable to boys with Duchenne Muscular Dystrophy (DMD). Besides the direct effects of the muscular dystrophy, the increasing effort to perform activities, the fear of falling and the use of personal aids indirectly impair leg and arm functions as a result of disuse. Physical training could oppose this secondary physical deterioration. The No Use is Disuse (NUD) study is the first study in human subjects with DMD that will examine whether a low-intensity physical training is beneficial in terms of preservation of muscle endurance and functional abilities. The study consists of two training intervention studies: study 1 "Dynamic leg and arm training for ambulant and recently wheelchair-dependent boys with DMD and, study 2 "Functional training with arm support for boys with DMD who have been confined to a wheelchair for several years". This paper describes the hypotheses and methods of the NUD study.
Study 1 is an explorative randomized controlled trial with multiple baseline measurements. Thirty boys with a DNA-established diagnosis of DMD will be included. The intervention consists of a six-months physical training during which boys train their legs and arms with active and/or assisted cycling training equipment. The primary study outcomes are muscle endurance and functional abilities, assessed with a Six-Minute Bicycle Test and the Motor Function Measure. Study 2 has a within-group repeated measurements design and will include ten boys with DMD who have already been confined to a wheelchair for several years. The six-months physical training program consists of 1) a computer-assisted training and 2) a functional training with an arm support. The primary study outcome is functional abilities of the upper extremity, assessed with the Action Research Arm Test.
The NUD study will fill part of the gap in the current knowledge about the possible effects of training in boys with DMD and will increase insight into what type of exercise should be recommended to boys with DMD. The study will finish at the end of 2010 and results are expected in 2011.
Trial registration
The Netherlands National Trial Register1631
PMCID: PMC2929216  PMID: 20691042
10.  24 Month Longitudinal Data in Ambulant Boys with Duchenne Muscular Dystrophy 
PLoS ONE  2013;8(1):e52512.
The aim of the study was i) to assess the spectrum of changes over 24 months in ambulant boys affected by Duchenne muscular dystrophy, ii) to establish the difference between the first and the second year results and iii) to identify possible early markers of loss of ambulation.
One hundred and thirteen patients (age range 4.1–17, mean 8.2) fulfilled the inclusion criteria, 67 of the 113 were on daily and 40 on intermittent steroids, while 6 were not on steroids. All were assessed using the 6 Minute Walk Test (6MWT), the North Star Ambulatory Assessment (NSAA) and timed test.
On the 6MWT there was an average overall decline of −22.7 (SD 81.0) in the first year and of −64.7 (SD 123.1) in the second year. On the NSAA the average overall decline was of −1.86 (SD 4.21) in the first year and of −2.98 (SD 5.19) in the second year. Fourteen children lost ambulation, one in the first year and the other 13 in the second year of the study. A distance of at least 330 meters on the 6MWT, or a NSAA score of 18 at baseline reduced significantly the risk of losing ambulation within 2 years.
These results can be of help at the time of using inclusion criteria for a study in ambulant patients in order to minimize the risk of patients who may lose ambulation within the time of the trial.
PMCID: PMC3543414  PMID: 23326337
11.  A suspended act: increased reflectivity and gender-dependent electrophysiological change following Quadrato Motor Training 
Quadrato Motor Training (QMT) is a specifically-structured walking meditation, aimed at improving reflectivity and lowering habitual thought and movement. Here we set out to examine the possible effect of QMT on reflectivity, employing the Hidden Figures Test (HFT), which assesses both spatial performance (measured by correct answers) as well as reflectivity (interpolated from correct answers and reaction time). In the first study (n = 24, only females), we showed that QMT significantly improves HFT performance, compared to two groups, controlling for cognitive or motor aspects of the QMT: Verbal Training (identical cognitive training with verbal response) and Simple Motor Training (similar motor training with reduced choice requirements). These results show that QMT improves HFT performance above the pre-post expected learning. In the second study, building on previous literature showing gender-dependent effects on cognitive performance, we conducted a preliminary pilot examining gender-dependent effect of training on reflectivity and its electrophysiological counterparts. EEG analyses focused on theta, alpha and gamma coherence. HFT performance and resting-state EEG were measured in 37 participants (20 males), using a within-subject pre-post design. Following training, HFT performance improved in both genders. However, we found a gender-dependent difference in functional connectivity: while theta and alpha intra-hemispheric coherence was enhanced in females, the opposite pattern was found in males. These results are discussed in relation to neuronal efficiency theory. Together, the results demonstrate that QMT improves spatial performance, and may involve a gender-dependent electrophysiological effect. This study emphasizes both the importance of studying gender-related training effects within the contemplative neuroscience endeavor, as well as the need to widen its scope toward including “contemplation in action.”
PMCID: PMC3909823  PMID: 24550872
motor training; reflectivity; spatial cognition; EEG coherence; gender
12.  Changes in cerebellar activity and inter-hemispheric coherence accompany improved reading performance following Quadrato Motor Training 
Dyslexia is a multifactorial reading deficit that involves multiple brain systems. Among other theories, it has been suggested that cerebellar dysfunction may be involved in dyslexia. This theory has been supported by findings from anatomical and functional imaging. A possible rationale for cerebellar involvement in dyslexia could lie in the cerebellum’s role as an oscillator, producing synchronized activity within neuronal networks including sensorimotor networks critical for reading. If these findings are causally related to dyslexia, a training regimen that enhances cerebellar oscillatory activity should improve reading performance. We examined the cognitive and neural effects of Quadrato Motor Training (QMT), a structured sensorimotor training program that involves sequencing of motor responses based on verbal commands. Twenty-two adult Hebrew readers (12 dyslexics and 10 controls) were recruited for the study. Using Magnetoencephalography (MEG), we measured changes in alpha power and coherence following QMT in a within-subject design. Reading performance was assessed pre- and post-training using a comprehensive battery of behavioral tests. Our results demonstrate improved performance on a speeded reading task following one month of intensive QMT in both the dyslexic and control groups. Dyslexic participants, but not controls, showed significant increase in cerebellar oscillatory alpha power following training. In addition, across both time points, inter-hemispheric alpha coherence was higher in the dyslexic group compared to the control group. In conclusion, the current findings suggest that the combination of motor and language training embedded in QMT increases cerebellar oscillatory activity in dyslexics and improves reading performance. These results support the hypothesis that the cerebellum plays a role in skilled reading, and begin to unravel the underlying mechanisms that mediate cerebellar contribution in cognitive and neuronal augmentation.
PMCID: PMC4023028  PMID: 24847224
dyslexia; MEG; motor training; cerebellum; alpha power; coherence; reading
Muscle & nerve  2013;48(1):32-54.
Contemporary natural history data in Duchenne muscular dystrophy (DMD) is needed to assess care recommendations and aid in planning future trials.
The Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 individuals, aged 2–28 years, with DMD in a longitudinal, observational study at 20 centers. Assessments obtained every 3 months for 1 year, at 18 months, and annually thereafter included: clinical history; anthropometrics; goniometry; manual muscle testing; quantitative muscle strength; timed function tests; pulmonary function; and patient-reported outcomes/ health-related quality-of-life instruments.
Glucocorticoid (GC) use at baseline was 62% present, 14% past, and 24% GC-naive. In those ≥6 years of age, 16% lost ambulation over the first 12 months (mean age 10.8 years).
Detailed information on the study methodology of the CINRG DMD-NHS lays the groundwork for future analyses of prospective longitudinal natural history data. These data will assist investigators in designing clinical trials of novel therapeutics.
PMCID: PMC4147958  PMID: 23677550
adolescent; adult; child/preschool; follow-up study; health status; human; locomotion; male; muscle strength/physiology; muscular dystrophies/classification; muscular dystrophies/Duchenne/physiopathology; muscular dystrophies/therapy; phenotype; quality of life/psychology; respiratory function test
14.  Participation and quality of life in children with Duchenne muscular dystrophy using the International Classification of Functioning, Disability, and Health 
Duchenne muscular dystrophy (DMD) is characterized by muscle damage and progressive loss of muscle function in male children. DMD is one of the most devastating genetically linked neuromuscular diseases for which there is currently no cure. Most clinical studies for DMD utilize a standard protocol for measurement exploring pathophysiology, muscle strength and timed tasks. However, we propose that examining broader components of health as emphasized by the International Classification of Functioning, Disability and Health-Children and Youth Version (ICF-CY) may be of great value to children and their families, and important outcomes for future clinical trials.
Fifty boys with DMD and 25 unaffected age-matched boys completed two self-report measures: the Children’s Assessment of Participation and Enjoyment and the Pediatric Quality of Life InventoryTM 4.0. We investigated differences between the two groups with regard to participation in life activities and perceived quality of life (QoL). Additionally, we compared participation in activities and QoL in both cohorts of younger and older boys.
Participation in physical activities was significantly lower in boys with DMD than unaffected boys. Perceived QoL was markedly diminished in children with DMD relative to unaffected controls, except in the emotional domain. The amount of time boys engage in an activity, as well as participation in social activities, declined for our older boys with DMD but no changes were observed for our older unaffected boys. For both groups, QoL remained constant over time.
The ICF-CY provides a conceptual framework and specific terminology that facilitates investigation of the consequences of impairment in children and youth. Our study is one of the first to explore participation in a cohort of boys with DMD. It was not surprising that activities of choice for boys with DMD were less physical in nature than unaffected boys their age, but the consequences of less social engagement as the boys with DMD age is of great concern. Results from our study underscore the need to further evaluate activities that children elect to participate in, with special emphasis on facilitators and barriers to participation and how participation changes throughout the course of a disease.
PMCID: PMC3358238  PMID: 22545870
Duchenne muscular dystrophy; ICF; Participation; Quality of life
15.  The radial diffusivity and magnetization transfer pool size ratio are sensitive markers for demyelination in a rat model of type III multiple sclerosis (MS) lesions 
NeuroImage  2013;74:298-305.
Determining biophysical sensitivity and specificity of quantitative magnetic resonance imaging is essential to develop effective imaging metrics of neurodegeneration. Among these metrics apparent pool size ratio (PSR) from quantitative magnetization transfer (qMT) imaging and radial diffusivity (RD) from diffusion tensor imaging (DTI) are both known to relate to histological measure of myelin density and integrity. However their relative sensitivities towards quantitative myelin detection are unknown. In this study, we correlated high-resolution quantitative magnetic resonance imaging measures of subvoxel tissue structures with corresponding quantitative myelin histology in a lipopolysacharide (LPS) mediated animal model of MS. Specifically, we acquired quantitative magnetization transfer (qMT) and diffusion tensor imaging (DTI) metrics (on the same tissue sample) in an animal model system of type III oligodendrogliopathy which lacked prominent lymphocytic infiltration, a system that had not been previously examined with quantitative MRI. We find that the qMT measured apparent pool size ratio (PSR) showed the strongest correlation with a histological measure of myelin content. DTI measured RD showed the next strongest correlation, and other DTI and relaxation parameters (such as the longitudinal relaxation rate (R1f) or fractional anisotropy (FA)) showed considerably weaker correlations with myelin content.
PMCID: PMC3995162  PMID: 23481461
Quantitative magnetization transfer (qMT); Diffusion Tensor Imaging (DTI); 9.4T; White matter; Myelin; demyelination; lippopolysaccharide (LPS); Rat brain; Multiple Sclerosis (MS)
16.  6 Minute Walk Test in Duchenne MD Patients with Different Mutations: 12 Month Changes 
PLoS ONE  2014;9(1):e83400.
In the last few years some of the therapeutical approaches for Duchenne muscular dystrophy (DMD) are specifically targeting distinct groups of mutations, such as deletions eligible for skipping of individual exons. The aim of this observational study was to establish whether patients with distinct groups of mutations have different profiles of changes on the 6 minute walk test (6MWT) over a 12 month period.
The 6MWT was performed in 191 ambulant DMD boys at baseline and 12 months later. The results were analysed using a test for heterogeneity in order to establish possible differences among different types of mutations (deletions, duplications, point mutations) and among subgroups of deletions eligible to skip individual exons.
At baseline the 6MWD ranged between 180 and 560,80 metres (mean 378,06, SD 74,13). The 12 month changes ranged between −325 and 175 (mean −10.8 meters, SD 69.2). Although boys with duplications had better results than those with the other types of mutations, the difference was not significant.
Similarly, boys eligible for skipping of the exon 44 had better baseline results and less drastic changes than those eligible for skipping exon 45 or 53, but the difference was not significant.
even if there are some differences among subgroups, the mean 12 month changes in each subgroup were all within a narrow Range: from the mean of the whole DMD cohort. This information will be of help at the time of designing clinical trials with small numbers of eligible patients.
PMCID: PMC3885414  PMID: 24421885
17.  Motor and Cognitive Assessment of Infants and Young Boys with Duchenne Muscular Dystrophy; Results from the Muscular Dystrophy Association DMD Clinical Research Network 
Neuromuscular disorders : NMD  2013;23(7):529-539.
Therapeutic trials in Duchenne Muscular dystrophy (DMD) exclude young boys because traditional outcome measures rely on cooperation. The Bayley-III Scales of Infant and Toddler Development (Bayley-III) have been validated in developing children and those with developmental disorders but have not been studied in DMD. Expanded Hammersmith Functional Motor Scale (HFMSE) and North Star Ambulatory Assessment (NSAA) may also be useful in this young DMD population. Clinical evaluators from the MDA-DMD Clinical Research Network were trained in these assessment tools. Infants and boys with DMD (n=24; 1.9±0.7 years) were assessed. The mean Bayley-III motor composite score was low (82.8 ± 8; p=<.0001)(normal=100 ± 15). Mean gross motor and fine motor function scaled scores were low (both p=<.0001). The mean cognitive comprehensive (p=.0002), receptive language (p=<.0001), and expressive language (p=.0001) were also low compared to normal children. Age was negatively associated with Bayley-III gross motor (r=−0.44 p=.02) but not with fine motor, cognitive, or language scores. HFMSE (n=23) showed a mean score of 31 ± 13. NSAA (n =18 boys; 2.2 ± 0.4years) showed a mean score of 12 ± 5. Outcome assessments of young boys with DMD are feasible and in this multicenter study were best demonstrated using the Bayley-III.
PMCID: PMC3743677  PMID: 23726376
18.  Six-Minute Walk Test: Reference Values and Prediction Equation in Healthy Boys Aged 5 to12 Years 
PLoS ONE  2013;8(12):e84120.
This study aimed to (1) generate normative data in healthy boys aged 5–12 years for the six-minute walk test (6MWT), an outcome measure currently used in clinical trials in Duchenne muscular dystrophy (DMD), (2) to describe the relation with anthropometric variables and myometry, and (3) to compare our data with published equations.
The 6MWT was conducted in 442 boys according to a standardized protocol, as currently used in clinical trials in DMD. Maximal voluntary isometric contractions for knee flexion and extension were recorded with a hand-held myometer.
The 6MWD increased significantly with age, from 478.0±44.1 m at age 5, to 650.0±76.8 m at age 12, with the steepest increase between 5 and 8 years. Age- and height related percentile curves of the 6MWD were developed. Correlations with anthropometric variables were fair to good (age r = 0.60, height r = 0.57, weight r = 0.44). Myometric variables (knee flexors and extensors) showed correlations of 0.46 and 0.50 respectively. When dividing into two age categories (5–8 years, 9–12 years), these magnitudes of correlations only applied to the younger age group. Additionally, predicted values were calculated according to available reference equations (Geiger and Ben Saad), indicating an overestimation by those equations. Finally, the Geiger equation was refitted to our population.
The percentile curves according to age and height provide a useful tool in the assessment of ambulatory capacity in boys aged 5 to 12 years. Significant correlations with anthropometric variables and myometry were only found in the 5–8 years age group. The Geiger prediction equation, currently used to assess ambulatory capacity in DMD was refitted to obtain a more accurate prediction model based on a large sample with a homogenous distribution across the age categories 5 to 12 years and applying the methodology as currently used in clinical trials in DMD.
PMCID: PMC3877199  PMID: 24391899
19.  Percent-Predicted 6-Minute Walk Distance in Duchenne Muscular Dystrophy to Account for Maturational Influences 
PLoS Currents  2012;4:RRN1297.
We recently described a modified version of the 6-minute walk test (6MWT) for Duchenne muscular dystrophy (DMD) based partly on the American Thoracic Society (ATS) guidelines. This measure has shown reliability, validity and utility as a primary outcome measure in DMD clinical trials. Because loss of muscle function in DMD occurs against the background of normal childhood growth and development, younger children with DMD can show increase in distance walked during 6MWT over ~1 year despite progressive muscular impairment. In this study, we compare 6-minute walk distance (6MWD) data from DMD boys (n=17) and typically developing control subjects (n=22) to existing normative data from age- and sex-matched children and adolescents. An age- and height-based equation fitted to normative data by Geiger and colleagues was used to convert 6MWD to a percent-predicted (%-predicted) value in boys with DMD. Analysis of %-predicted 6MWD data represents a method to account for normal growth and development, and shows that gains in function at early ages represents stable rather than improving abilities in boys with DMD. Boys with DMD from 4-7 years of age maintain a stable 6MWD approximately 80% of that of typically developing peers, with the deficit progressing at a variable rate thereafter.
PMCID: PMC3269886  PMID: 22306689
20.  Percent-Predicted 6-Minute Walk Distance in Duchenne Muscular Dystrophy to Account for Maturational Influences 
PLoS Currents  2012;4:RRN1297.
We recently described a modified version of the 6-minute walk test (6MWT) for Duchenne muscular dystrophy (DMD) based partly on the American Thoracic Society (ATS) guidelines. This measure has shown reliability, validity and utility as a primary outcome measure in DMD clinical trials. Because loss of muscle function in DMD occurs against the background of normal childhood growth and development, younger children with DMD can show increase in distance walked during 6MWT over ~1 year despite progressive muscular impairment. In this study, we compare 6-minute walk distance (6MWD) data from DMD boys (n=17) and typically developing control subjects (n=22) to existing normative data from age- and sex-matched children and adolescents. An age- and height-based equation fitted to normative data by Geiger and colleagues was used to convert 6MWD to a percent-predicted (%-predicted) value in boys with DMD. Analysis of %-predicted 6MWD data represents a method to account for normal growth and development, and shows that gains in function at early ages represents stable rather than improving abilities in boys with DMD. Boys with DMD from 4-7 years of age maintain a stable 6MWD approximately 80% of that of typically developing peers, with the deficit progressing at a variable rate thereafter.
PMCID: PMC3269886  PMID: 22306689
21.  Longitudinal assessment of grip strength using bulb dynamometer in Duchenne Muscular Dystrophy 
Grip strength is used to infer functional status in several pathological conditions, and the hand dynamometer has been used to estimate performance in other areas. However, this relationship is controversial in neuromuscular diseases and studies with the bulb dynamometer comparing healthy children and children with Duchenne Muscular Dystrophy (DMD) are limited.
The evolution of grip strength and the magnitude of weakness were examined in boys with DMD compared to healthy boys. The functional data of the DMD boys were correlated with grip strength.
Grip strength was recorded in 18 ambulant boys with DMD (Duchenne Group, DG) aged 4 to 13 years (mean 7.4±2.1) and 150 healthy volunteers (Control Group, CG) age-matched using a bulb dynamometer (North Coast- NC70154). The follow-up of the DG was 6 to 33 months (3-12 sessions), and functional performance was verified using the Vignos scale.
There was no difference between grip strength obtained by the dominant and non-dominant side for both groups. Grip strength increased in the CG with chronological age while the DG remained stable or decreased. The comparison between groups showed significant difference in grip strength, with CG values higher than DG values (confidence interval of 95%). In summary, there was an increment in the differences between the groups with increasing age. Participants with 24 months or more of follow-up showed a progression of weakness as well as maintained Vignos scores.
The amplitude of weakness increased with age in the DG. The bulb dynamometer detected the progression of muscular weakness. Functional performance remained virtually unchanged in spite of the increase in weakness.
PMCID: PMC4183492  PMID: 25003277
muscular dystrophy; skeletal muscle; muscle strength; dynamometer; physical therapy
22.  Electrical impedance myography for the assessment of children with muscular dystrophy: a preliminary study 
Electrical impedance myography (EIM) provides a non-invasive approach for quantifying the severity of neuromuscular disease. Here we determine how well EIM data correlates to functional and ultrasound (US) measures of disease in children with Duchenne muscular dystrophy (DMD) and healthy subjects. Thirteen healthy boys, aged 2-12 years and 14 boys with DMD aged 4-12 years underwent both EIM and US measurements of deltoid, biceps, wrist flexors, quadriceps, tibialis anterior, and medial gastrocnemius. EIM measurements were performed with a custom-designed probe using a commercial multifrequency bioimpedance device. US luminosity data were quantified using a gray-scale analysis approach. Children also underwent the 6-minute walk test, timed tests and strength measurements. EIM and US data were combined across muscles. EIM 50 kHz phase was able to discriminate DMD children from healthy subjects with 98% accuracy. In the DMD patients, average EIM phase measurements also correlated well with standard functional measures. For example the 50 kHz phase correlated with the Northstar Ambulatory Assessment test (R = 0.83, p = 0.02). EIM 50 kHz phase and US correlated as well, with R = −0.79 (p < 0.001). These results show that EIM provides valuable objective measures Duchenne muscular dystrophy severity.
PMCID: PMC3721184  PMID: 23894248
23.  Magnetic Resonance Imaging and Spectroscopy Assessment of Lower Extremity Skeletal Muscles in Boys with Duchenne Muscular Dystrophy: A Multicenter Cross Sectional Study 
PLoS ONE  2014;9(9):e106435.
Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder that results in functional deficits. However, these functional declines are often not able to be quantified in clinical trials for DMD until after age 7. In this study, we hypothesized that 1H2O T2 derived using 1H-MRS and MRI-T2 will be sensitive to muscle involvement at a young age (5–7 years) consistent with increased inflammation and muscle damage in a large cohort of DMD subjects compared to controls.
MR data were acquired from 123 boys with DMD (ages 5–14 years; mean 8.6 SD 2.2 years) and 31 healthy controls (age 9.7 SD 2.3 years) using 3-Tesla MRI instruments at three institutions (University of Florida, Oregon Health & Science University, and Children’s Hospital of Philadelphia). T2-weighted multi-slice spin echo (SE) axial images and single voxel 1H-MRS were acquired from the lower leg and thigh to measure lipid fraction and 1H2O T2.
MRI-T2, 1H2O T2, and lipid fraction were greater (p<0.05) in DMD compared to controls. In the youngest age group, DMD values were different (p<0.05) than controls for the soleus MRI-T2, 1H2O T2 and lipid fraction and vastus lateralis MRI-T2 and 1H2O T2. In the boys with DMD, MRI-T2 and lipid fraction were greater (p<0.05) in the oldest age group (11–14 years) than the youngest age group (5–6.9 years), while 1H2O T2 was lower in the oldest age group compared to the young age group.
Overall, MR measures of T2 and lipid fraction revealed differences between DMD and Controls. Furthermore, MRI-T2 was greater in the older age group compared to the young age group, which was associated with higher lipid fractions. Overall, MR measures of T2 and lipid fraction show excellent sensitivity to DMD disease pathologies and potential therapeutic interventions in DMD, even in the younger boys.
PMCID: PMC4159278  PMID: 25203313
24.  Improving recognition of Duchenne muscular dystrophy: a retrospective case note review 
Archives of Disease in Childhood  2014;99(12):1074-1077.
Over the last 30 years, there has been little improvement in the age of diagnosis of Duchenne muscular dystrophy (DMD) (mean age of 4.5–4.11 years).
To review the diagnostic process for DMD in boys without a family history in order to identify where delays occur and suggest areas for improvement.
A retrospective case note review.
A tertiary centre for neuromuscular diseases in England.
All boys without family history diagnosed with DMD in the last 10 years (n=20).
Outcome measures
Mean age at four key steps in the diagnostic pathway of DMD.
(1) Age at first reported symptoms of DMD was 32.5 (8–72) months (2.7 years). (2) First engagement of a healthcare professional was at 42.9 (10–90) months. (3) Creatine kinase (CK) levels were checked at 50.1 (14–91) months. (4) Diagnosis of DMD was confirmed at 51.7 (16–91) months (4.3 years). The total delay from parental concern to diagnosis was 19.2 (4–50) months (1.6 years).
Our study shows an improvement in the age of diagnosis of DMD although there continues to be a delay in presentation to a health professional and a delay in obtaining a CK test. To reduce these delays, we propose screening for DMD as part of the Child Health Surveillance Programme, in addition to lowering the threshold for CK testing in primary care by promoting a new DMD mnemonic MUSCLE. An earlier diagnosis of DMD will allow timely access to genetic counselling, standards of care and clinical trials.
PMCID: PMC4251173  PMID: 25187493
Paediatrics; Duchenne muscular dystrophy; developmental delay; creatine kinase; diagnosis
25.  Autologous bone marrow mononuclear cell transplantation in Duchenne muscular dystrophy – a case report 
Patient: Male, 9
Final Diagnosis: Duchenne muscular dystrophy
Symptoms: Hyporeflexia • hypotonia • weaknes of lower limbs
Medication: —
Clinical Procedure: —
Specialty: Neurology
Congenital defects/diseases
Duchenne muscular dystrophy (DMD) is a fatal, genetic, progressive, degenerating muscle disorder. Current treatment options are palliative. Newer options of cellular therapy promise to alter the disease process. Preclinical studies have successfully tested myogenic, neurogenic potential and dystrophin expression of bone marrow mononuclear cells.
Case Report:
We treated a 9-year-old boy suffering from DMD with serial autologous bone marrow mononuclear cell transplantations followed by multidisciplinary rehabilitation. Brooke-Vignos score was 10 and he was wheelchair-bound. Over 36 months, gradual progressive improvement was noticed in muscle strength, ambulation with assistive devices, fine motor movements, Brooke-Vignos score, and functional independence measure score. Nine months after the transplantation, electromyography findings showed development of new normal motor unit potentials of the vastus medialis muscle.
Magnetic resonance imaging scan of musculoskeletal systems showed no increase in fatty infiltration. This case report provides early investigative findings or the restorative effects of cellular therapy in DMD.
PMCID: PMC3976215  PMID: 24711886
Stem Cell Transplantation; Autologous Bone Marrow Mono Nuclear Cells; Electromyography; Muscular Dystrophy; Duchenne – congenital

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