Publications by authors named "Bart Bartels"

25 Publications

  • Page 1 of 1

Motor Unit and Capillary Recruitment During Fatiguing Arm-Cycling Exercise in Spinal Muscular Atrophy Types 3 and 4.

J Neuromuscul Dis 2022 ;9(3):397-409

Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.

Background: Exercise intolerance is an important impairment in patients with SMA, but little is known about the mechanisms underlying this symptom.

Objective: To investigate if reduced motor unit and capillary recruitment capacity in patients with SMA contribute to exercise intolerance.

Methods: Adolescent and adult patients with SMA types 3 and 4 (n = 15) and age- and gender matched controls (n = 15) performed a maximal upper body exercise test. We applied respiratory gas analyses, non-invasive surface electromyography (sEMG) and continuous wave near-infrared spectroscopy (CW-NIRS) to study oxygen consumption, arm muscle motor unit- and capillary recruitment, respectively.

Results: Maximal exercise duration was twofold lower (p < 0.001) and work of breathing and ventilation was 1.6- and 1.8-fold higher (p < 0.05) in patients compared to controls, respectively. Regarding motor unit recruitment, we found higher normalized RMS amplitude onset values of sEMG signals from all muscles and the increase in normalized RMS amplitudes was similar in the m. triceps brachii, m. brachioradialis and m. flexor digitorum in SMA compared to controls. Median frequency, onset values were similar in patients and controls. We found a similar decrease in median frequencies of sEMG recordings from the m. biceps brachii, a diminished decrease from the m. brachioradialis and m. flexor digitorum, but a larger decrease from the m. triceps brachii. With respect to capillary recruitment, CW-NIRS recordings in m. biceps brachii revealed dynamics that were both qualitatively and quantitatively similar in patients and controls.

Conclusion: We found no evidence for the contribution of motor unit and capillary recruitment capacity of the upper arm muscles in adolescent and adult patients with SMA types 3 and 4 as primary limiting factors to premature fatigue during execution of a maximal arm-cycling task.
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http://dx.doi.org/10.3233/JND-210765DOI Listing
May 2022

Short-term effect of air stacking and mechanical insufflation-exsufflation on lung function in patients with neuromuscular diseases.

Chron Respir Dis 2022 Jan-Dec;19:14799731221094619

Department of Neurology, Brain Centre Rudolf Magnus, 89098University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Air stacking (AS) and mechanical insufflation-exsufflation (MI-E) aim to increase cough efficacy by augmenting inspiratory lung volumes in patients with neuromuscular diseases (NMDs). We studied the short-term effect of AS and MI-E on lung function. We prospectively included NMD patients familiar with daily AS or MI-E use. Studied outcomes were forced vital capacity (FVC), forced expiratory volume in one second (FEV), and peak expiratory flow (PEF) prior to, immediately after, and up to 2 h after treatment. Paired sample T-test and Wilcoxon signed-rank test was used. Sixty-seven patients participated. We observed increased FVC and FEV immediately after AS with a mean difference of respectively 0.090 L (95% CI 0.045; 0.135, < .001) and 0.073 L (95% CI 0.017; 0.128, = .012). Increased FVC immediately after MI-E (mean difference 0.059 L (95% CI 0.010; 0.109, = .021) persisted 1 hour (mean difference 0.079 L (95% CI 0.034; 0.125, = .003). The effect of treatment was more pronounced in patients diagnosed with Spinal Muscular Atrophy, compared to patients with Duchenne muscular dystrophy. AS and MI-E improved FVC immediately after treatment, which persisted 1 h after MI-E. There is insufficient evidence that short-lasting increases in FVC would explain the possible beneficial effect of AS and MI-E.
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http://dx.doi.org/10.1177/14799731221094619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9024083PMC
April 2022

Natural history of respiratory muscle strength in spinal muscular atrophy: a prospective national cohort study.

Orphanet J Rare Dis 2022 02 21;17(1):70. Epub 2022 Feb 21.

Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Background: Respiratory complications are the most important cause of morbidity and mortality in spinal muscular atrophy (SMA). Respiratory muscle weakness results in impaired cough, recurrent respiratory tract infections and eventually can cause respiratory failure. We assessed longitudinal patterns of respiratory muscle strength in a national cohort of treatment-naïve children and adults with SMA, hypothesizing a continued decline throughout life.

Methods: We measured maximal expiratory and inspiratory pressure (PE and PI), Sniff Nasal inspiratory pressure (SNIP), peak expiratory flow (PEF), and peak cough flow (PCF) in treatment-naïve patients with SMA. We used mixed-models to analyze natural history patterns.

Results: We included 2172 measurements of respiratory muscle function from 80 treatment-naïve patients with SMA types 1c-3b. All outcomes were lower in the more severe phenotypes. Significant differences in PEF were present between SMA types from early ages onwards. PEF decline was linear (1-2%/year). PEF reached values below 80% during early childhood in types 1c-2, and during adolescence in type 3a. PE and PI were severely lowered in most patients throughout life, with PE values abnormally low (i.e. < 80 cmHO) in virtually all patients. The PE/PI ratio was < 1 throughout life in all SMA types, indicating that expiratory muscles were most affected. All but SMA type 3b patients had a lowered PCF. Patients with types 2b and 3a had PCF levels between 160 and 270 L/min, those with type 2a around 160 L/min and patients with type 1c well below 160 L/min. Finally, SNIP was low in nearly all patients, most pronounced in more severely affected patients.

Conclusions: There are clear differences in respiratory muscle strength and its progressive decline between SMA types. We observed lower outcomes in more severe SMA types. Particularly PEF may be a suitable outcome measure for the follow-up of respiratory strength in patients with SMA. PEF declines in a rather linear pattern in all SMA types, with clear differences at baseline. These natural history data may serve as a reference for longer-term treatment efficacy assessments.
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http://dx.doi.org/10.1186/s13023-022-02227-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8862532PMC
February 2022

Multi-parametric quantitative magnetic resonance imaging of the upper arm muscles of patients with spinal muscular atrophy.

NMR Biomed 2022 Jul 14;35(7):e4696. Epub 2022 Feb 14.

UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Quantitative magnetic resonance imaging (qMRI) is frequently used to map the disease state and disease progression in the lower extremity muscles of patients with spinal muscular atrophy (SMA). This is in stark contrast to the almost complete lack of data on the upper extremity muscles, which are essential for carrying out daily activities. The aim of this study was therefore to assess the disease state in the upper arm muscles of patients with SMA in comparison with healthy controls by quantitative assessment of fat fraction, diffusion indices, and water T2 relaxation times, and to relate these measures to muscle force. We evaluated 13 patients with SMA and 15 healthy controls with a 3-T MRI protocol consisting of DIXON, diffusion tensor imaging, and T2 sequences. qMRI measures were compared between groups and related to muscle force measured with quantitative myometry. Fat fraction was significantly increased in all upper arm muscles of the patients with SMA compared with healthy controls and correlated negatively with muscle force. Additionally, fat fraction was heterogeneously distributed within the triceps brachii (TB) and brachialis muscle, but not in the biceps brachii muscle. Diffusion indices and water T2 relaxation times were similar between patients with SMA and healthy controls, but we did find a slightly reduced mean diffusivity (MD), λ1, and λ3 in the TB of patients with SMA. Furthermore, MD was positively correlated with muscle force in the TB of patients with SMA. The variation in fat fraction further substantiates the selective vulnerability of muscles. The reduced diffusion tensor imaging indices, along with the positive correlation of MD with muscle force, point to myofiber atrophy. Our results show the feasibility of qMRI to map the disease state in the upper arm muscles of patients with SMA. Longitudinal data in a larger cohort are needed to further explore qMRI to map disease progression and to capture the possible effects of therapeutic interventions.
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http://dx.doi.org/10.1002/nbm.4696DOI Listing
July 2022

Cardiopulmonary exercise testing in neuromuscular disease: a systematic review.

Expert Rev Cardiovasc Ther 2021 Nov;19(11):975-991

Child Development & Exercise Center, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.

Introduction: Cardiopulmonary exercise testing (CPET) is increasingly used to determine aerobic fitness in health and disability conditions. Patients with neuromuscular diseases (NMDs) often present with symptoms of cardiac and/or skeletal muscle dysfunction and fatigue that might impede the ability to deliver maximal cardiopulmonary effort. Although an increasing number of studies report on NMDs' physical fitness, the applicability of CPET remains largely unknown.

Areas Covered: This systematic review synthesized evidence about the quality and feasibility of CPET in NMDs and patient's aerobic fitness. The review followed the PRISMA guidelines (PROSPERO number CRD42020211068). Between September and October 2020 one independent reviewer searched the PubMed/MEDLINE, EMBASE, SCOPUS, and Web of Science databases. Excluding reviews and protocol description articles without baseline data, all study designs using CPET to assess adult or pediatric patients with NMDs were included. The methodological quality was assessed according to the American Thoracic Society/American College of Chest Physicians (ATS/ACCP) recommendations.

Expert Opinion: CPET is feasible for ambulatory patients with NMDs when their functional level and the exercise modality are taken into account. However, there is still a vast potential for standardizing and designing disease-specific CPET protocols for patients with NMDs. Moreover, future studies are urged to follow the ATS/ACCP recommendations.
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http://dx.doi.org/10.1080/14779072.2021.2009802DOI Listing
November 2021

Magnetic resonance reveals mitochondrial dysfunction and muscle remodelling in spinal muscular atrophy.

Brain 2022 05;145(4):1422-1435

Centre for Child Development, Exercise and Physical Literacy, Wilhelmina Children's Hospital, University Medical Centre Utrecht, P.O. Box 85090, 3508 AB Utrecht, the Netherlands.

Genetic therapy has changed the prognosis of hereditary proximal spinal muscular atrophy, although treatment efficacy has been variable. There is a clear need for deeper understanding of underlying causes of muscle weakness and exercise intolerance in patients with this disease to further optimize treatment strategies. Animal models suggest that in addition to motor neuron and associated musculature degeneration, intrinsic abnormalities of muscle itself including mitochondrial dysfunction contribute to the disease aetiology. To test this hypothesis in patients, we conducted the first in vivo clinical investigation of muscle bioenergetics. We recruited 15 patients and 15 healthy age and gender-matched control subjects in this cross-sectional clinico-radiological study. MRI and 31P magnetic resonance spectroscopy, the modality of choice to interrogate muscle energetics and phenotypic fibre-type makeup, was performed of the proximal arm musculature in combination with fatiguing arm-cycling exercise and blood lactate testing. We derived bioenergetic parameter estimates including: blood lactate, intramuscular pH and inorganic phosphate accumulation during exercise, and muscle dynamic recovery constants. A linear correlation was used to test for associations between muscle morphological and bioenergetic parameters and clinico-functional measures of muscle weakness. MRI showed significant atrophy of triceps but not biceps muscles in patients. Maximal voluntary contraction force normalized to muscle cross-sectional area for both arm muscles was 1.4-fold lower in patients than in controls, indicating altered intrinsic muscle properties other than atrophy contributed to muscle weakness in this cohort. In vivo31P magnetic resonance spectroscopy identified white-to-red remodelling of residual proximal arm musculature in patients on the basis of altered intramuscular inorganic phosphate accumulation during arm-cycling in red versus white and intermediate myofibres. Blood lactate rise during arm-cycling was blunted in patients and correlated with muscle weakness and phenotypic muscle makeup. Post-exercise metabolic recovery was slower in residual intramuscular white myofibres in patients demonstrating mitochondrial ATP synthetic dysfunction in this particular fibre type. This study provides the first in vivo evidence in patients that degeneration of motor neurons and associated musculature causing atrophy and muscle weakness in 5q spinal muscular atrophy type 3 and 4 is aggravated by disproportionate depletion of myofibres that contract fastest and strongest. Our finding of decreased mitochondrial ATP synthetic function selectively in residual white myofibres provides both a possible clue to understanding the apparent vulnerability of this particular fibre type in 5q spinal muscular atrophy types 3 and 4 as well as a new biomarker and target for therapy.
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http://dx.doi.org/10.1093/brain/awab411DOI Listing
May 2022

Motor unit reserve capacity in spinal muscular atrophy during fatiguing endurance performance.

Clin Neurophysiol 2021 03 28;132(3):800-807. Epub 2021 Jan 28.

Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam, Van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands.

Objective: To investigate the availability of any motor unit reserve capacity during fatiguing endurance testing in patients with spinal muscular atrophy (SMA).

Methods: We recorded surface electromyography (sEMG) of various muscles of upper- and lower extremities of 70 patients with SMA types 2-4 and 19 healthy controls performing endurance shuttle tests (ESTs) of arm and legs. We quantitatively evaluated the development of fatigability and motor unit recruitment using time courses of median frequencies and amplitudes of sEMG signals. Linear mixed effect statistical models were used to evaluate group differences in median frequency and normalized amplitude at onset and its time course.

Results: Normalized sEMG amplitudes at onset of upper body ESTs were significantly higher in patients compared to controls, yet submaximal when related to maximal voluntary contractions, and showed an inverse correlation to SMA phenotype. sEMG median frequencies decreased and amplitudes increased in various muscles during execution of ESTs in patients and controls.

Conclusions: Decreasing median frequencies and increasing amplitudes reveal motor unit reserve capacity in individual SMA patients during ESTs at submaximal performance intensities.

Significance: Preserving, if not expanding motor unit reserve capacity may present a potential therapeutic target in clinical care to reduce fatigability in individual patients with SMA.
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http://dx.doi.org/10.1016/j.clinph.2020.11.044DOI Listing
March 2021

Correlates of Fatigability in Patients With Spinal Muscular Atrophy.

Neurology 2021 02 20;96(6):e845-e852. Epub 2020 Nov 20.

From the Child Development and Exercise Center (B.B., L.E.H.) and Department of Pediatric Gastroenterology (E.E.S.N.), Wilhelmina Children's Hospital, and UMC Utrecht Brain Center (R.I.W., F.-L.A., R.P.A.v.E., H.S.G., W.L.v.d.P.), University Medical Center Utrecht; Knowledge Institute for Medical Specialists (J.F.d.G.), University of Applied Sciences; and Biostatistics & Research Support (R.P.A.v.E.), Julius Center for Health Sciences and Primary Care, Utrecht, the Netherlands.

Objective: To determine the associations between fatigability and muscle strength, motor function, neuromuscular junction (NMJ) function, and perceived fatigue in spinal muscular atrophy (SMA), we assessed 61 patients with SMA.

Methods: Fatigability was defined as the inability to continue a 20-minute submaximal repetitive task of either walking or proximal or distal arm function and expressed as drop-out on the Endurance Shuttle Test Combined Score (ESTCS). We assessed muscle strength with the Medical Research Council (MRC) sum score, motor function with the Hammersmith Functional Motor Scale Expanded (HFMSE) and Motor Function Measure (MFM), NMJ function with repetitive nerve stimulation of the accessory and ulnar nerve, and perceived fatigue with the PROMIS Fatigue Short Form questionnaire in 61 children and adults with SMA types 2-4. We applied Cox regression analysis to explore the associations between fatigability and these factors.

Results: The hazard of drop-out on the ESTCS decreased 0.8%, 2%, and 1.3% for each point increase in the MRC sum score, the HFMSE score, and the MFM percentual score, respectively. However, we observed prominent fatigability with preserved muscle function and vice versa in 13%-16% of patients. We did not find an association between NMJ dysfunction of the accessory ( = 0.37) and ulnar nerve ( = 0.063) and fatigability, which could be due to a large number of missing values. Perceived fatigue in SMA was comparable to reference values and was not associated with fatigability ( = 0.52).

Conclusion: Fatigability in SMA is associated with, yet not equivalent to, muscle strength and motor function.
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http://dx.doi.org/10.1212/WNL.0000000000011230DOI Listing
February 2021

Muscle strength and motor function in adolescents and adults with spinal muscular atrophy.

Neurology 2020 10 30;95(14):e1988-e1998. Epub 2020 Jul 30.

From the Department of Neurology (C.A.W., M.S., L.A.M.O., F.-L.A., R.P.A.v.E., L.H.v.d.B., H.S.G., R.I.W., W.L.v.d.P.), UMC Utrecht Brain Center, Child Development and Exercise Center (B.B.), and Department of Biostatistics & Research Support (R.P.A.v.E.), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, the Netherlands.

Objective: To assess longitudinal patterns of muscle strength, motor function, and maximal compound muscle action potential amplitudes (CMAP) in older patients with spinal muscular atrophy (SMA), hypothesizing a continued decline of motor function parameters throughout life.

Methods: We measured muscle strength (Medical Research Council), motor function (Hammersmith Functional Motor Scale Expanded [HFMSE] and Motor Function Measure), and CMAP in treatment-naive patients. We used both longitudinal and cross-sectional data in mixed models to analyze natural history patterns.

Results: We included 250 patients with SMA types 1c through 4. Median patient age at assessment was 26.8 years, the number of assessments per patient ranged from 1 to 6. Baseline muscle strength and motor function scores differed significantly between SMA types, but annual rates of decline were largely similar and mostly linear. HFMSE floor effects were present for all patients with SMA type 1c, and adolescents and adults with types 2 and 3a. CMAP differed significantly between SMA types but did not decline significantly with increasing age. Muscle strength correlated very strongly with motor function (τ ≥ 0.8) but only moderately with CMAP (τ ≈ 0.5-0.6).

Conclusion: Muscle strength and motor function decline in older patients with SMA are constant without periods of slower progression or a plateau phase. The floor effects of the HFMSE preclude its use for long-term follow-up of adult patients with SMA types 1c through 3a. Muscle strength sum scores represent an alternative, feasible outcome measure for adolescent and adult patients with SMA.
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http://dx.doi.org/10.1212/WNL.0000000000010540DOI Listing
October 2020

Quantitative MRI of skeletal muscle in a cross-sectional cohort of patients with spinal muscular atrophy types 2 and 3.

NMR Biomed 2020 10 18;33(10):e4357. Epub 2020 Jul 18.

Department of Radiology, University Medical Center Utrecht, Utrecht University, the Netherlands.

The aim of this study was to document upper leg involvement in spinal muscular atrophy (SMA) with quantitative MRI (qMRI) in a cross-sectional cohort of patients of varying type, disease severity and age. Thirty-one patients with SMA types 2 and 3 (aged 29.6 [7.6-73.9] years) and 20 healthy controls (aged 37.9 [17.7-71.6] years) were evaluated in a 3 T MRI with a protocol consisting of DIXON, T2 mapping and diffusion tensor imaging (DTI). qMRI measures were compared with clinical scores of motor function (Hammersmith Functional Motor Scale Expanded [HFMSE]) and muscle strength. Patients exhibited an increased fat fraction and fractional anisotropy (FA), and decreased mean diffusivity (MD) and T2 compared with controls (all P < .001). DTI parameters FA and MD manifest stronger effects than can be accounted for the effect of fatty replacement. Fat fraction, FA and MD show moderate correlation with muscle strength and motor function: FA is negatively associated with HFMSE and Medical Research Council sum score (τ = -0.56 and -0.59; both P < .001) whereas for fat fraction values are τ = -0.50 and -0.58, respectively (both P < .001). This study shows that DTI parameters correlate with muscle strength and motor function. DTI findings indirectly indicate cell atrophy and act as a measure independently of fat fraction. Combined these data suggest the potential of muscle DTI in monitoring disease progression and to study SMA pathogenesis in muscle.
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http://dx.doi.org/10.1002/nbm.4357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507182PMC
October 2020

Fatigability in spinal muscular atrophy: validity and reliability of endurance shuttle tests.

Orphanet J Rare Dis 2020 03 23;15(1):75. Epub 2020 Mar 23.

University Medical Center Utrecht, UMC Utrecht Brain Center, Utrecht, The Netherlands.

Background: To determine construct validity and test-retest reliability of Endurance Shuttle Tests as outcome measures for fatigability of remaining motor functions in children and adults with Spinal Muscular Atrophy (SMA) across the severity spectrum.

Results: We assessed the Endurance Shuttle - Nine Hole Peg Test (ESNHPT), - Box and Block Test (ESBBT) and - Walk Test (ESWT) in 61 patients with SMA types 2-4, 25 healthy controls (HC) and 15 disease controls (DC). Convergent validity, discriminative validity and test-retest reliability were investigated. Additionally, we compiled the Endurance Shuttle Combined Score (ESTCS) by selecting the most relevant endurance test of each individual. 54, 70 and 73% of patients with SMA demonstrated increased fatigability on the ESNHPT, ESBBT and the ESWT. Endurance response in SMA was characterized by a decrease in muscle strength, an increase in muscle fatigue and an increase in motor adaptions, thereby confirming convergent validity. Patients with SMA showed increased drop-out rates and a shorter endurance time compared to HC and DC demonstrating good discriminative validity. Test-retest reliability was moderate to excellent (ICC's ranging from .78 to .91) with a trend towards better performance on retest. The ESTCS increased sample size and drop-out rate up to 100 and 85%.

Conclusions: Fatigability is an important additional dimension of physical impairments across the severity spectrum in children and adults with SMA. The EST's are reliable and valid to document fatigability of walking, proximal- and distal arm function in SMA and thus are promising outcome measures for use in clinical trials.
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http://dx.doi.org/10.1186/s13023-020-1348-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092552PMC
March 2020

Natural history of lung function in spinal muscular atrophy.

Orphanet J Rare Dis 2020 04 10;15(1):88. Epub 2020 Apr 10.

Department of Neurology, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht University, Heidelberglaan 100, 3508, GA, Utrecht, The Netherlands.

Background: Respiratory muscle weakness is an important feature of spinal muscular atrophy (SMA). Progressive lung function decline is the most important cause of mortality and morbidity in patients. The natural history of lung function in SMA has, however, not been studied in much detail.

Results: We analysed 2098 measurements of lung function from 170 treatment-naïve patients with SMA types 1c-4, aged 4-74 years. All patients are participating in an ongoing population-based prevalence cohort study. We measured Forced Expiratory Volume in 1 s (FEV), Forced Vital Capacity (FVC), and Vital Capacity (VC). Longitudinal patterns of lung function were analysed using linear mixed-effects and non-linear models. Additionally, we also assessed postural effects on results of FEV and FVC tests. In early-onset SMA types (1c-3a), we observed a progressive decline of lung function at younger ages with relative stabilisation during adulthood. Estimated baseline values were significantly lower in more severely affected patients: %FEV ranged from 42% in SMA type 1c to 100% in type 3b, %FVC 50 to 109%, and %VC 44 to 96%. Average annual decline rates also differed significantly between SMA types, ranging from - 0.1% to - 1.4% for FEV, - 0.2% to - 1.4% for FVC, and + 0.2% to - 1.7% for VC. In contrast to SMA types 1c-3a, we found normal values for all outcomes in later-onset SMA types 3b and 4 throughout life, although with some exceptions and based on limited available data. Finally, we found no important differences in FVC or FEV values measured in either sitting or supine position.

Conclusions: Our data illustrate the longitudinal course of lung function in patients with SMA, which is characterised by a progressive decline in childhood and stabilisation in early adulthood. The data do not support an additional benefit of measuring FEV or FVC in both sitting and supine position. These data may serve as a reference to assess longer-term outcomes in clinical trials.
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http://dx.doi.org/10.1186/s13023-020-01367-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7149916PMC
April 2020

Natural course of scoliosis and lifetime risk of scoliosis surgery in spinal muscular atrophy.

Neurology 2019 07 4;93(2):e149-e158. Epub 2019 Jun 4.

From the Department of Neurology and Neurosurgery (C.A.W., F.A.S.d.K., M.S., L.A.M.O., F.-L.A., R.P.A.v.E., J.S., I.C., L.H.v.d.B., R.I.W., W-L.v.d.P), Department of Rehabilitation (M.V.), Department of Orthopedic Surgery (R.C.B., R.M.C.), Department of Pediatrics, Child Development and Exercise Centre (B.B), and Biostatistics & Research Support Julius Centre for Health Sciences and Primary Care (R.P.A.v.E.), University Medical Centre Utrecht, Utrecht University, the Netherlands.

Objective: To investigate the natural course of scoliosis and to estimate lifetime probability of scoliosis surgery in spinal muscular atrophy (SMA).

Methods: We analyzed cross-sectional data from 283 patients from our population-based cohort study. Additional longitudinal data on scoliosis progression and spinal surgery were collected from 36 consecutive patients who received scoliosis surgery at our center.

Results: The lifetime probability of receiving scoliosis surgery was ≈80% in SMA types 1c and 2. Patients with type 2 who only learned to sit (type 2a) were significantly younger at time of surgery than those who learned to sit and stand (type 2b). The lifetime risk of surgery was lower in type 3a (40%) and strongly associated with age at loss of ambulation: 71% in patients losing ambulation before 10 years of age vs 22% losing ambulation after the age of 10 years ( = 0.005). In type 3a, preserving the ability to walk 1 year longer corresponded to a 15% decrease in lifetime risk of scoliosis surgery (hazard ratio 0.852, = 0.017). Scoliosis development was characterized by initial slow progression, followed by acceleration in the 1.5- to 2-year period before surgery.

Conclusion: The lifetime probability of scoliosis surgery is high in SMA types 1c and 2 and depends on age at loss of ambulation in type 3. Motor milestones such as standing that are not part of the standard classification system are of additional predictive value. Our data may act as a reference to assess long-term effects of new SMA-specific therapies.
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http://dx.doi.org/10.1212/WNL.0000000000007742DOI Listing
July 2019

Physical exercise training for type 3 spinal muscular atrophy.

Cochrane Database Syst Rev 2019 Mar 1;3:CD012120. Epub 2019 Mar 1.

Child Development and Exercise Center, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6, Utrecht, Utrecht, Netherlands, 3508 AB.

Background: Physical exercise training might improve muscle and cardiorespiratory function in spinal muscular atrophy (SMA). Optimization of aerobic capacity or other resources in residual muscle tissue through exercise may counteract the muscle deterioration that occurs secondary to motor neuron loss and inactivity in SMA. There is currently no evidence synthesis available on physical exercise training in people with SMA type 3.

Objectives: To assess the effects of physical exercise training on functional performance in people with SMA type 3, and to identify any adverse effects.

Search Methods: On 8 May 2018, we searched the Cochrane Neuromuscular Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, AMED, and LILACS. On 25 April 2018 we searched NHSEED, DARE, and ClinicalTrials.gov and WHO ICTRP for ongoing trials.

Selection Criteria: We included randomized controlled trials (RCTs) or quasi-RCTs lasting at least 12 weeks that compared physical exercise training (strength training, aerobic exercise training, or both) to placebo, standard or usual care, or another type of non-physical intervention for SMA type 3. Participants were adults and children from the age of five years with a diagnosis of SMA type 3 (Kugelberg-Welander syndrome), confirmed by genetic analysis.

Data Collection And Analysis: We used standard Cochrane methodological procedures.

Main Results: We included one RCT that studied the effects of a six-month, home-based, combined muscle strength and recumbent cycle ergometry training program versus usual care in 14 ambulatory people with SMA. The age range of the participants was between 10 years and 48 years. The study was evaluator-blinded, but personnel and participants could not be blinded to the intervention, which placed the results at a high risk of bias. Participants performed strength training as prescribed, but 50% of the participants did not achieve the intended aerobic exercise training regimen. The trial used change in walking distance on the six-minute walk test as a measure of function; a minimal detectable change is 24.0 m. The change from baseline to six months' follow-up in the training group (9.4 m) was not detectably different from the change in the usual care group (-0.14 m) (mean difference (MD) 9.54 m, 95% confidence interval (CI) -83.04 to 102.12; N = 12). Cardiopulmonary exercise capacity, assessed by the change from baseline to six months' follow-up in peak oxygen uptake (VO) was similar in the training group (-0.12 mL/kg/min) and the usual care group (-1.34 mL/kg/min) (MD 1.22 mL/kg/min, 95% CI -2.16 to 4.6; N = 12). A clinically meaningful increase in VO is 3.5 mL/kg/min.The trial assessed function on the Hammersmith Functional Motor Scale - Expanded (HFMSE), which has a range of possible scores from 0 to 66, with an increase of 3 or more points indicating clinically meaningful improvement. The HFMSE score in the training group increased by 2 points from baseline to six months' follow-up, with no change in the usual care group (MD 2.00, 95% CI -2.06 to 6.06; N = 12). The training group showed a slight improvement in muscle strength, expressed as the manual muscle testing (MMT) total score, which ranges from 28 (weakest) to 280 (strongest). The change from baseline in MMT total score was 6.8 in the training group compared to -5.14 in the usual care group (MD 11.94, 95% CI -3.44 to 27.32; N = 12).The trial stated that training had no statistically significant effects on fatigue and quality of life. The certainty of evidence for all outcomes was very low because of study limitations and imprecision. The study did not assess the effects of physical exercise training on physical activity levels. No study-related serious adverse events or adverse events leading to withdrawal occurred, but we cannot draw wider conclusions from this very low-certainty evidence.

Authors' Conclusions: It is uncertain whether combined strength and aerobic exercise training is beneficial or harmful in people with SMA type 3, as the quality of evidence is very low. We need well-designed and adequately powered studies using protocols that meet international standards for the development of training interventions, in order to improve our understanding of the exercise response in people with SMA type 3 and eventually develop exercise guidelines for this condition.
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http://dx.doi.org/10.1002/14651858.CD012120.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396106PMC
March 2019

Assessment of fatigability in patients with spinal muscular atrophy: development and content validity of a set of endurance tests.

BMC Neurol 2019 Feb 9;19(1):21. Epub 2019 Feb 9.

Child Development and Exercise Center, Wilhelmina Children's Hospital, University Medical Center Utrecht, PO Box 85090, KB 02.056.0, 3508, AB, Utrecht, The Netherlands.

Background: Fatigability has emerged as an important dimension of physical impairment in patients with Spinal Muscular Atrophy (SMA). At present reliable and valid outcome measures for both mildly and severely affected patients are lacking. Therefore the primary aim of this study is the development of clinical outcome measures for fatigability in patients with SMA across the range of severity.

Methods: We developed a set of endurance tests using five methodological steps as recommended by the 'COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). In this iterative process, data from multiple sources were triangulated including a scoping review of scientific literature, input from a scientific and clinical multidisciplinary expert panel and three pilot studies including healthy persons (N = 9), paediatric patients with chronic disorders (N = 10) and patients with SMA (N = 15).

Results: Fatigability in SMA was operationalised as the decline in physical performance. The following test criteria were established; one method of testing for patients with SMA type 2-4, a set of outcome measures that mimic daily life activities, a submaximal test protocol of repetitive activities over a longer period; external regulation of pace. The scoping review did not generate suitable outcome measures. We therefore adapted the Endurance Shuttle Walk Test for ambulatory patients and developed the Endurance Shuttle Box and Block Test and the - Nine Hole Peg Test for fatigability testing of proximal and distal arm function. Content validity was established through input from experts and patients. Pilot testing showed that the set of endurance tests are comprehensible, feasible and meet all predefined test criteria.

Conclusions: The development of this comprehensive set of endurance tests is a pivotal step to address fatigability in patients with SMA.
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http://dx.doi.org/10.1186/s12883-019-1244-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368708PMC
February 2019

A continuous repetitive task to detect fatigability in spinal muscular atrophy.

Orphanet J Rare Dis 2018 09 12;13(1):160. Epub 2018 Sep 12.

Department of Neurology, Brain Center Rudolf Magnus Institute of Neuroscience, Utrecht University, University Medical Center Utrecht, Heidelberglaan 100, F02.230, 3508 GA, Utrecht, The Netherlands.

Background: To determine the value of a continuous repetitive task to detect and quantify fatigability as additional dimension of impaired motor function in patients with hereditary proximal spinal muscular atrophy (SMA).

Results: In this repeated measure case-control study 52 patients with SMA types 2-4, 17 healthy and 29 disease controls performed five consecutive rounds of the Nine-Hole Peg test to determine the presence of fatigability. We analysed differences in test performance and associations with disease characteristics. Five patients with SMA type 2 (22%) and 1 disease control (3%) could not finish five rounds due to fatigue (p = 0.01). Patients with SMA type 2 performed the test significantly more slowly than all other groups (p < 0.005) and disease controls were slower than healthy controls (p < 0.05). Patients with SMA type 2 performed round five 27% slower than round one, while healthy controls performed round five 14% faster than round one (p = 0.005). There was no difference between SMA type 3a, type 3b/4 or disease controls and healthy controls (p > 0.4). Time needed to complete each round during the five-round task increased in 15 patients with SMA type 2 (65%), 4 with type 3a (36%), 4 with type 3b/4 (22%), 9 disease controls (31%) and 1 healthy control (6%). There was no effect of age at disease onset or disease duration in SMA type 2 (p = 0.39). Test-retest reliability was high.

Conclusion: Fatigability of remaining arm function is a feature of SMA type 2 and can be determined with continuous repetitive tasks.
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http://dx.doi.org/10.1186/s13023-018-0904-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134509PMC
September 2018

Consensus statement on physical rehabilitation in children and adolescents with osteogenesis imperfecta.

Orphanet J Rare Dis 2018 09 10;13(1):158. Epub 2018 Sep 10.

University of Cologne, Children's Hospital, Kerpenerstraße 62, 50931, Cologne, Germany.

On the occasion of the 13th International Conference on Osteogenesis imperfecta in August 2017 an expert panel was convened to develop an international consensus paper regarding physical rehabilitation in children and adolescents with Osteogenesis imperfecta. The experts were chosen based on their clinical experience with children with osteogenesis imperfecta and were identified by sending out questionnaires to specialized centers and patient organizations in 26 different countries. The final expert-group included 16 representatives (12 physiotherapists, two occupational therapists and two medical doctors) from 14 countries. Within the framework of a collation of personal experiences and the results of a literature search, the participating physiotherapists, occupational therapists and medical doctors formulated 17 expert-statements on physical rehabilitation in patients aged 0-18 years with osteogenesis imperfecta.
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http://dx.doi.org/10.1186/s13023-018-0905-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131938PMC
September 2018

Protocol for a phase II, monocentre, double-blind, placebo-controlled, cross-over trial to assess efficacy of pyridostigmine in patients with spinal muscular atrophy types 2-4 (SPACE trial).

BMJ Open 2018 07 30;8(7):e019932. Epub 2018 Jul 30.

Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Introduction: Hereditary proximal spinal muscular atrophy (SMA) is caused by homozygous loss of function of the survival motor neuron 1 gene. The main characteristic of SMA is degeneration of alpha motor neurons in the anterior horn of the spinal cord, but recent studies in animal models and patients have shown additional anatomical abnormalities and dysfunction of the neuromuscular junction (NMJ). NMJ dysfunction could contribute to symptoms of weakness and fatigability in patients with SMA. We hypothesise that pyridostigmine, an acetylcholinesterase inhibitor that improves neuromuscular transmission, could improve NMJ function and thereby muscle strength and fatigability in patients with SMA.

Methods And Analysis: We designed a monocentre, placebo-controlled, double-blind cross-over trial with pyridostigmine and placebo to investigate the effect and efficacy of pyridostigmine on muscle strength and fatigability in patients with genetically confirmed SMA. We aim to include 45 patients with SMA types 2-4, aged 12 years and older in the Netherlands. Participants receive 8 weeks of treatment with pyridostigmine and 8 weeks of treatment with placebo in a random order separated by a washout period of 1 week. Treatment allocation is double blinded. Treatment dose will gradually be increased from 2 mg/kg/day to the maximum dose of 6 mg/kg/day in four daily doses, in the first week of each treatment period. The primary outcome measures are a change in the Motor Function Measure and repeated nine-hole peg test before and after treatment. Secondary outcome measures are changes in recently developed endurance tests, that is, the endurance shuttle nine-hole peg test, the endurance shuttle box and block test and the endurance shuttle walk test, muscle strength, level of daily functioning, quality of and activity in life, perceived fatigue and fatigability, presence of decrement on repetitive nerve stimulation and adverse events.

Ethics And Dissemination: The protocol is approved by the local medical ethical review committee at the University Medical Center Utrecht and by the national Central Committee on Research Involving Human Subjects. Findings will be shared with the academic and medical community, funding and patient organisations in order to contribute to optimisation of medical care and quality of life for patients with SMA.

Trial Registration Number: NCT02941328.
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http://dx.doi.org/10.1136/bmjopen-2017-019932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067401PMC
July 2018

Cardiopulmonary Exercise Testing in Children and Adolescents With Dystrophinopathies: A Pilot Study.

Pediatr Phys Ther 2015 ;27(3):227-34

Child Development and Exercise Center (Mr Bartels, Drs Takken and de Groot), Wilhelmina Children's Hospital, University Medical Center, Utrecht, the Netherlands; Department of Pediatric Cardiology (Dr Blank), Wilhelmina Children's Hospital, University Medical Center Utrecht, the Netherlands; Research Group Lifestyle and Health (Mr van Moorsel and Dr de Groot), University of Applied Sciences, Utrecht, the Netherlands; Department of Neurology (Dr van der Pol), University Medical Center Utrecht, the Netherlands.

Purpose: To determine exercise response during cardiopulmonary exercise testing in children and adolescents with dystrophinopathies.

Methods: Exercise response on the cardiopulmonary exercise test (CPET) was compared with a standard care test protocol.

Results: Nine boys (aged 10.8 ± 4.7 years) with Becker muscular dystrophy (n = 6) and Duchenne muscular dystrophy (n = 3) were included. The feasibility of the CPET was similar to a standard care test protocol, and no serious adverse events occurred. In 67% of the subjects with normal or only mildly impaired functional capacity, the CPET could be used to detect moderate to severe cardiopulmonary exercise limitations.

Conclusions: The CPET seems to be a promising outcome measure for cardiopulmonary exercise limitations in youth with mild functional limitations. Further research with larger samples is warranted to confirm current findings and investigate the additional value of the CPET to longitudinal follow-up of cardiomyopathy and the development of safe exercise programs for youth with dystrophinopathies.
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http://dx.doi.org/10.1097/PEP.0000000000000159DOI Listing
April 2016

Prevalence of fatigue, pain, and affective disorders in adults with duchenne muscular dystrophy and their associations with quality of life.

Arch Phys Med Rehabil 2015 Jul 27;96(7):1242-7. Epub 2015 Feb 27.

Department of Rehabilitation Medicine and Physical Therapy, Erasmus University Medical Center, Rotterdam, The Netherlands; Rijndam Rehabilitation, Rotterdam, The Netherlands.

Objectives: To assess the prevalence of fatigue, pain, anxiety, and depression in adults with Duchenne muscular dystrophy (DMD), and to analyze their relationship with health-related quality of life.

Design: Cross-sectional study.

Setting: Home of participants.

Participants: Adults (N=80) with DMD.

Interventions: Not applicable.

Main Outcome Measures: Fatigue was assessed with the Fatigue Severity Scale; pain with 1 item of the Medical Outcomes Study 36-Item Short-Form Health Survey and by interview; and anxiety and depression by using the Hospital Anxiety and Depression Scale. Health-related quality of life was assessed using the World Health Organization Quality of Life Scale-Brief Version. Associations between these conditions and quality of life were assessed by means of univariate and multivariate logistic regression analyses.

Results: Symptoms of fatigue (40.5%), pain (73.4%), anxiety (24%), and depression (19%) were frequently found. Individuals often had multiple conditions. Fatigue was related to overall quality of life and to the quality-of-life domains of physical health and environment; anxiety was related to the psychological domain.

Conclusions: Fatigue, pain, anxiety, and depression, potentially treatable symptoms, occur frequently in adults with DMD and significantly influence health-related quality of life.
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http://dx.doi.org/10.1016/j.apmr.2015.02.012DOI Listing
July 2015

Quality of life of adult men with Duchenne muscular dystrophy in the Netherlands: implications for care.

J Rehabil Med 2015 Feb;47(2):161-6

Department of Rehabilitation Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

Objective: To assess quality of life of adults with Duchenne muscular dystrophy in the Netherlands and to identify domains and major problems influencing quality of life.

Design: Cross-sectional.

Subjects: Seventy-nine men aged ≥ 20 years with Duchenne muscular dystrophy.

Methods: The Medical Outcome Study Short Form-36 (SF-36), World Health Organization Quality of Life - BREF (WHOQOL-BREF) and an interview were used to assess quality of life and problems.

Results: Compared with Dutch general population reference values, the SF-36 domains scores were lower on all domains except mental health and role limitations due to emotional problems. On the WHOQOL-BREF the social relationships domain score was lower. Main problems were intimate relationships, work, leisure, transport and meaningfulness of life. Seventy-three percent stated overall quality of life as "(very) good". The SF-36 domains mental health (rs 0.53, p < 0.001) and vitality (rs 0.49, p < 0.001) had the strongest associations with overall quality of life.

Conclusion: Adult men with Duchenne muscular dystrophy assess their health status as low in the physical, but not in the mental, domains. Experienced problems are mainly in the area of participation. They are generally satisfied with their overall quality of life.
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http://dx.doi.org/10.2340/16501977-1898DOI Listing
February 2015

Validity of the Pediatric Running-Based Anaerobic Sprint Test to Determine Anaerobic Performance in Healthy Children.

Pediatr Exerc Sci 2015 May 10;27(2):268-76. Epub 2014 Nov 10.

Child Development & Exercise Center, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands.

Purpose: To determine criterion validity of the pediatric running-based anaerobic sprint test (RAST) as a nonsophisticated field test for evaluating anaerobic performance in healthy children and adolescents.

Methods: Data from 65 healthy children (28 boys and 37 girls between 6 and 18 years of age, mean ± SD age: 10.0 ± 2.8 years) who completed both the pediatric RAST and the 30-s Wingate anaerobic test (WAnT) on a cycle ergometer in a randomized order were analyzed. Peak power (PP) and mean power (MP) were the primary outcome measures for both tests.

Results: There were no significant sex-differences in PP and MP attained at the pediatric RAST and the WAnT. Age was strongly correlated to pediatric RAST and WAnT performance (Spearman's rho values ranging from 0.85 to 0.90, with p < .001 for all coefficients). We found high correlation coefficients between pediatric RAST performance and WAnT performance for both PP (Spearman's rho: 0.86; p < .001) and MP (Spearman's rho: 0.91; p < .001).

Conclusion: The pediatric RAST can be used as a valid and nonsophisticated field test for the assessment of anaerobic performance in healthy children and adolescents. For clinical evaluative purposes, we suggest to use MP of the pediatric RAST when assessing glycolytic power in the absence of the WAnT.
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http://dx.doi.org/10.1123/pes.2014-0078DOI Listing
May 2015

The six-minute walk test in chronic pediatric conditions: a systematic review of measurement properties.

Phys Ther 2013 Apr 15;93(4):529-41. Epub 2012 Nov 15.

Child Development and Exercise Center, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: The Six-Minute Walk Test (6MWT) is increasingly being used as a functional outcome measure for chronic pediatric conditions. Knowledge about its measurement properties is needed to determine whether it is an appropriate test to use.

Purpose: The purpose of this study was to systematically review all published clinimetric studies on the 6MWT in chronic pediatric conditions.

Data Sources: The databases MEDLINE, EMBASE, CINAHL, PEDro, and SPORTDiscus were searched up to February 2012.

Study Selection: Studies designed to evaluate measurement properties of the 6MWT in a chronic pediatric condition were included in the systematic review.

Data Extraction: The methodological quality of the included studies and the measurement properties of the 6MWT were examined.

Data Synthesis: A best evidence synthesis was performed on 15 studies, including 9 different chronic pediatric conditions. Limited evidence to strong evidence was found for reliability in various chronic conditions. Strong evidence was found for positive criterion validity of the 6MWT with peak oxygen uptake in some populations, but negative criterion validity was found in other populations. Construct validity remained unclear in most patient groups because of methodological flaws. Little evidence was available for responsiveness and measurement error. Studies showed large variability in test procedures despite existing guidelines for the performance of the 6MWT.

Limitations: Unavailability of a specific checklist to evaluate the methodological quality of clinimetric studies on performance measures was a limitation of the study.

Conclusions: Evidence for measurement properties of the 6MWT varies largely among chronic pediatric conditions. Further research is needed in all patient groups to explore the ability of the 6MWT to measure significant and clinically important changes. Until then, changes measured with the 6MWT should be interpreted with caution. Future studies or consensus regarding modified test procedures in the pediatric population is recommended.
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http://dx.doi.org/10.2522/ptj.20120210DOI Listing
April 2013

Upper limb function in adults with Duchenne muscular dystrophy.

J Rehabil Med 2011 Sep;43(9):770-5

Department of Rehabilitation Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

Objective: To determine upper limb function and associated factors in adults with Duchenne muscular dystrophy.

Design: Cross-sectional study.

Subjects: A sample of 70 men with Duchenne muscular dystrophy (age range 20-43 years).

Methods: General motor function and, in particular, upper limb distal motor function, were assessed with the Motor Function Measure. Muscle strength and range of motion of the upper limb were evaluated using hand-held dynamo-metry, manual muscle-testing and goniometry. Associations were studied using Spearman's correlation coefficients and multiple linear regression analysis.

Results: General motor function was severely impaired. Wide variability was found in distal motor function, muscle strength and range of motion of the upper limb, especially in early adulthood. Muscle strength and range of motion explained 76% of the variance in upper limb distal motor function.

Conclusion: This study illustrates a large variability in upper limb function in adult patients with Duchenne muscular dystrophy, and identifies muscle strength and range of motion as factors strongly associated with upper limb function. These results suggest that preserving muscle strength and range of motion in Duchenne patients might be relevant for a better outcome of distal motor function of the upper limb when adult.
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http://dx.doi.org/10.2340/16501977-0841DOI Listing
September 2011

Pain assessment and management in children with neurologic impairment: a survey of pediatric physical therapists.

Pediatr Phys Ther 2010 ;22(3):336

Faculty of Medicine, Division of Pediatrics, Utrecht University, Child Development and Exercise Center, University Children's Hospital and Medical Center, Utrecht, The Netherlands.

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http://dx.doi.org/10.1097/PEP.0b013e3181eb6fddDOI Listing
December 2010
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