Search

Abstract Background Behavior change is not simple, and the introduction of guidelines or protocols does not mean that they will be followed. As such, implementation strategies are vital for the uptake and sustainability of changes in medical protocols. Medical or mental emergencies may be life-threatening, especially in children due to their unique physiological needs. In emergency departments (EDs), where timely decisions are often made, practice change requires thoughtful considerations regarding the best approaches to implementation. As there are many studies reporting on a wide variety of implementation strategies in the emergency management of children in EDs, we aim to identify and map the characteristics of these studies. Methods We will conduct a scoping review to identify various implementation strategies in the emergency management of children using the Arksey and O’Malley framework. We will search MEDLINE (Ovid), Embase (Ovid), Cochrane Central (Wiley), and CINAHL (Ebsco), from inception to May 29, 2019, for implementation studies among the pediatric population (≤ 21 years) in a pediatric emergency setting. Two pairs of reviewers will independently select studies for inclusion and extract the data. We will perform a descriptive, narrative analysis of the characteristics of the identified implementation strategies. Discussion We will present specific characteristics and outcome measures of all included studies in a tabular form. The results of this review are expected to help identify and characterize successful implementation strategies in the emergency management of children in EDs. Systematic review registration Open Science Framework https://osf.io/h6jv2

BackgroundImplementation strategies are vital for the uptake of evidence to improve health, healthcare delivery, and decision-making. Medical or mental emergencies may be life-threatening, especially in children, due to their unique physiological needs when presenting in the emergency departments (EDs). Thus, practice change in EDs attending to children requires evidence-informed considerations regarding the best approaches to implementing research evidence. We aimed to identify and map the characteristics of implementation strategies used in the emergency management of children.MethodsWe conducted a scoping review using Arksey and O'Malley's framework. We searched four databases [Medline (Ovid), Embase (Ovid), Cochrane Central (Wiley) and CINAHL (Ebsco)] from inception to May 2019, for implementation studies in children (≤21 years) in emergency settings. Two pairs of reviewers independently selected studies for inclusion and extracted the data. We performed a descriptive analysis of the included studies.ResultsWe included 87 studies from a total of 9,607 retrieved citations. Most of the studies were before and after study design (n = 68, 61%) conducted in North America (n = 63, 70%); less than one-tenth of the included studies (n = 7, 8%) were randomized controlled trials (RCTs). About one-third of the included studies used a single strategy to improve the uptake of research evidence. Dissemination strategies were more commonly utilized (n = 77, 89%) compared to other implementation strategies; process (n = 47, 54%), integration (n = 49, 56%), and capacity building and scale-up strategies (n = 13, 15%). Studies that adopted capacity building and scale-up as part of the strategies were most effective (100%) compared to dissemination (90%), process (88%) and integration (85%).ConclusionsStudies on implementation strategies in emergency management of children have mostly been non-randomized studies. This review suggests that 'dissemination' is the most common strategy used, and 'capacity building and scale-up' are the most effective strategies. Higher-quality evidence from randomized-controlled trials is needed to accurately assess the effectiveness of implementation strategies in emergency management of children.

We analyzed the vertical distribution of atmospheric methane (CH 4 ) retrieved from measurements by ground-based Fourier Transform Spectrometer (FTS) instrument in Sodankylä, Northern Finland. The retrieved dataset covers 2009−2018. We used a dimension reduction retrieval method to extract the profile information, since each measurement contains around three pieces of information about the profile shape between 0 and 40 km. We compared the retrieved profiles against Atmospheric Chemistry Experiment Fourier Transform Spectrometer (ACE-FTS) satellite measurements and AirCore balloon-borne profile measurements. Additional comparison at the lowest tropospheric layer was done against in-situ measurements from a 50-m-high mast. In general, the ground-based FTS and ACE-FTS profiles agreed within 10% below 20 km and within 30% in the stratosphere between 20 and 40 km. Our method was able to accurately capture reduced methane concentrations inside the polar vortex in the Arctic stratosphere. The method produced similar trend characteristics as the reference instruments even when a static prior profile was used. Finally, we analyzed the time series of the CH 4 profile datasets and estimated the trend using the dynamic linear model (DLM).

Markov Chain Monte Carlo (MCMC) is a powerful and promising tool for assessing the uncertainties in the Orbiting Carbon Observatory 2 (OCO-2) satellite’s carbon dioxide measurements. Previous research in comparing MCMC and Optimal Estimation (OE) for the OCO-2 retrieval has highlighted the issues of slow convergence of MCMC, and furthermore OE and MCMC not necessarily agreeing with the simulated ground truth. In this work, we exploit the inherent low information content of the OCO-2 measurement and use the Likelihood-Informed Subspace (LIS) dimension reduction to significantly speed up the convergence of MCMC. We demonstrate the strength of this analysis method by assessing the non-Gaussian shape of the retrieval’s posterior distribution, and the effect of operational OCO-2 prior covariance’s aerosol parameters on the retrieval. We further show that in our test cases we can use this analysis to improve the retrieval to retrieve the simulated true state significantly more accurately and to characterize the non-Gaussian form of the posterior distribution of the retrieval problem.

Background: Spinal muscular atrophy (SMA) is caused by deficiency of survival motor neuron (SMN) protein. Intrathecal nusinersen treatment increases SMN protein in motor neurons and has been shown to improve motor function in symptomatic children with SMA., Objective: We used quantitative MRI to gain insight in microstructure and fat content of muscle during treatment and to explore its use as biomarker for treatment effect., Methods: We used a quantitative MRI protocol before start of treatment and following the 4th and 6th injection of nusinersen in 8 children with SMA type 2 and 3 during the first year of treatment. The MR protocol allowed DIXON, T2 mapping and diffusion tensor imaging acquisitions. We also assessed muscle strength and motor function scores., Results: Fat fraction of all thigh muscles with the exception of the m. adductor longus increased in all patients during treatment (+3.2%, p = 0.02). WaterT2 showed no significant changes over time (-0.7 ms, p = 0.3). DTI parameters MD and AD demonstrate a significant decrease in the hamstrings towards values observed in healthy muscle., Conclusions: Thigh muscles of children with SMA treated with nusinersen showed ongoing fatty infiltration and possible normalization of thigh muscle microstructure during the first year of nusinersen treatment. Quantitative muscle MRI shows potential as biomarker for the effects of SMA treatment strategies.

Background: Progressive lung function decline, resulting in respiratory failure, is an important complication of spinal muscular atrophy (SMA). The ability to predict the need for mechanical ventilation is important. We assessed longitudinal patterns of lung function prior to chronic respiratory failure in a national cohort of treatment-naïve children and adults with SMA, hypothesizing an accelerated decline prior to chronic respiratory failure., Methods: We included treatment-naïve SMA patients participating in a prospective national cohort study if they required mechanical ventilation because of chronic respiratory failure and if lung function test results were available from the years prior to initiation of ventilation. We analyzed Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 s (FEV 1 ), Peak Expiratory Flow (PEF) and Maximum Expiratory Pressure (PE max ). We studied the longitudinal course using linear mixed-effects models. We compared patients who electively started mechanical ventilation compared to patients who could not be weaned after acute respiratory failure., Results: We analyzed 385 lung function tests from 38 patients with SMA types 1c-3a. At initiation of ventilation median age was 18.8 years (IQR: 13.2-30.1) and median standardized FVC, FEV 1 and PEF were 28.8% (95% CI: 23.5; 34.2), 28.8% (95% CI: 24.0; 33.7) and 30.0% (95% CI: 23.4; 36.7), with an average annual decline of 1.75% (95% CI: 0.86; 2.66), 1.72% (95% CI: 1.04; 2.40) and 1.65% (95% CI: 0.71; 2.59), respectively. Our data did not support the hypothesis of an accelerated decline prior to initiation of mechanical ventilation. Median PE max was 35.3 cmH 2 O (95% CI: 29.4; 41.2) at initiation of mechanical ventilation and relatively stable in the years preceding ventilation. Median FVC, FEV 1, PEF and PE max were lower in patients who electively started mechanical ventilation (p < 0.001)., Conclusions: Patterns of lung function decline cannot predict impending respiratory failure: SMA is characterized by a gradual decline of lung function. We found no evidence for an accelerated deterioration. In addition, PE max remains low and stable in the years preceding initiation of ventilation. Patients who electively started mechanical ventilation had more restrictive lung function at initiation of ventilation, compared to patients who could not be weaned after surgery or a respiratory tract infection., (© 2023. The Author(s).)

Hereditary proximal spinal muscular atrophy causes weakness and increased fatigability of repetitive motor functions. The neuromuscular junction is anatomically and functionally abnormal in patients with spinal muscular atrophy. Pharmacological improvement of neuromuscular transmission may therefore represent a promising additional treatment strategy. We conducted a Phase II, monocentre, placebo-controlled, double-blind, cross-over trial with the acetylcholinesterase inhibitor pyridostigmine in treatment-naïve patients with spinal muscular atrophy types 2-4. We investigated the safety and efficacy of pyridostigmine on fatigability and motor function. Each participant received pyridostigmine and a placebo for 8 weeks, in random order. Primary outcomes were the repeated nine-hole peg test for fatigability and motor function measure. Secondary outcomes were patient-reported effects, endurance shuttle test combined scores and adverse events. We included 35 patients. For the repeated nine-hole peg test, the mean difference was 0.17 s/trial (95% confidence interval: -1.17-1.49; P = 0.8), favouring placebo, and for the motor function measure, 0.74% (95% confidence interval: 0.00-1.49; P = 0.05), favouring pyridostigmine. Around 74% of patients reported medium-to-large beneficial effects of pyridostigmine on fatigability, compared with 29.7% in the placebo arm. This was paralleled by a reduced dropout risk of 70% on the endurance shuttle test combined scores (hazard ratio: 0.30; 95% confidence interval: 0.15-0.58) under pyridostigmine. Adverse events, mostly mild and self-limiting, occurred more frequently under pyridostigmine. No serious adverse events related to the study medication were observed. Patients with spinal muscular atrophy tolerated pyridostigmine well. There were no significant differences in primary outcomes, but the self-reported reduction of fatigability and improved endurance shuttle test combined score performance suggest that pyridostigmine may be useful as an additional therapy to survival motor neuron-augmenting drugs. Trial registration number: EudraCT: 2011-004369-34, NCT02941328., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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 max and PI max ), 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 max and PI max were severely lowered in most patients throughout life, with PE max values abnormally low (i.e. < 80 cmH 2 O) in virtually all patients. The PE max /PI max 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., (© 2022. The Author(s).)

Objectives: Quantitative MRI (qMRI) of muscles is a promising tool to measure disease progression or to assess therapeutic effects in neuromuscular diseases. Longitudinal imaging studies are needed to show sensitivity of qMRI in detecting disease progression in spinal muscular atrophy (SMA). In this pilot study we therefore studied one-year changes in quantitative MR parameters in relation to clinical scores., Methods: We repeated quantitative 3 T MR analysis of thigh muscles and clinical testing one year after baseline in 10 treatment-naïve patients with SMA, 5 with Type 2 (21.6 ± 7.0 years) and 5 with Type 3 (33.4 ± 11.9 years). MR protocol consisted of Dixon, T 2 mapping and diffusion tensor imaging (DTI). The temporal relation of parameters was examined with a mixed model., Results: We detected a significant increase in fat fraction (baseline, 38.2% SE 0.6; follow-up, 39.5% SE 0.6; +1.3%, p = 0.001) in all muscles. Muscles with moderate to high fat infiltration at baseline show a larger increase over time (+1.6%, p < 0.001). We did not find any changes in DTI parameters except for low fat-infiltration muscles (m. adductor longus and m. biceps femoris (short head)). The T 2 of muscles decreased from 28.2 ms to 28.0 ms (p = 0.07). Muscle strength and motor function scores were not significantly different between follow-up and baseline., Conclusion: Longitudinal imaging data show slow disease progression in skeletal muscle of the thigh of (young-) adult patients with SMA despite stable strength and motor function scores. Quantitative muscle imaging demonstrates potential as a biomarker for disease activity and monitoring of therapy response., (© 2021 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Purpose: Multi-echo spin-echo (MSE) transverse relaxometry mapping using multi-component models is used to study disease activity in neuromuscular disease by assessing the T 2 of the myocytic component (T 2water ). Current extended phase graph algorithms are not optimized for fat fractions above 50% and the effects of inaccuracies in the T 2fat calibration remain unexplored. Hence, we aimed to improve the performance of extended phase graph fitting methods over a large range of fat fractions, by including the slice-selection flip angle profile, a through-plane chemical-shift displacement correction, and optimized calibration of T 2fat ., Methods: Simulation experiments were used to study the influence of the slice flip-angle profile with chemical-shift and T 2fat estimations. Next, in vivo data from four neuromuscular disease cohorts were studied for different T 2fat calibration methods and T 2water estimations., Results: Excluding slice flip-angle profiles or chemical-shift displacement resulted in a bias in T 2water up to 10 ms. Furthermore, a wrongly calibrated T 2fat caused a bias of up to 4 ms in T 2water . For the in vivo data, one-component calibration led to a lower T 2fat compared with a two-component method, and T 2water decreased with increasing fat fractions., Conclusion: In vivo data showed a decline in T 2water for increasing fat fractions, which has important implications for clinical studies, especially in multicenter settings. We recommend using an extended phase graph-based model for fitting T 2water from MSE sequences with two-component T 2fat calibration. Moreover, we recommend including the slice flip-angle profile in the model with correction for through-plane chemical-shift displacements., (© 2020 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Objective: To assess longitudinal patterns of muscle strength, motor function, and maximal compound muscle action potential amplitudes (CMAP MAX ) 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 MAX 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 MAX 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 MAX (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., (© 2020 American Academy of Neurology.)

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., (© 2020 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Objective: To assess motor unit (MU) changes in patients with spinal muscular atrophy (SMA) using compound muscle action potential (CMAP) scans., Methods: We performed CMAP scan recordings in median nerves of 24 treatment-naïve patients (median age 39; range 12-75 years) with SMA types 2-4. From each scan, we determined maximum CMAP amplitude (CMAP max ), a motor unit number estimate (MUNE), and D50 which quantifies the largest discontinuities within CMAP scans., Results: Median CMAP max was 8.1 mV (range 0.9-14.6 mV), MUNE was 29 (range 6-131), and D50 was 25 (range 2-57). We found a reduced D50 (<25) in patients with normal CMAP max (n = 12), indicating MU loss and enlarged MUs due to reinnervation. Lower D50 values were associated with decreased MUNE (P < 0.001, r = 0.68, n = 43). CMAP max , MUNE and D50 values differed between SMA types (P < 0.001). Lower motor function scores were related to patients with lower CMAP max , MUNE and D50 values (P < 0.001)., Conclusions: The CMAP scan is an easily applicable technique that is superior to routine assessment of CMAP max in SMA., Significance: The detection of pathological MU changes across the spectrum of SMA may provide important biomarkers for evaluating disease course and monitoring treatment efficacy., Competing Interests: Declaration of Competing Interest B. Sleutjes, C. Wijngaarde, R. Wadman, L. Otto, F. Asselman, I. Cuppen, W.L. van der Pol, and H.S. Goedee have no potential conflicts of interest to be disclosed. L. van den Berg reports grants from ALS Foundation Netherlands, grants from The. Netherlands Organization for Health Research and Development (Vici scheme), grants. from The Netherlands Organization for Health Research and Development (SOPHIA, STRENGTH, ALS-CarE project), funded through the EU Joint Programme – Neurodegenerative Disease Research, JPND), and personal fees from Shire, Biogen, Cytokinetics, and Treeway., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate probabilities of survival and its surrogate, that is, mechanical ventilation, in patients with spinal muscular atrophy (SMA)., Methods: We studied survival in a population-based cohort on clinical prevalence of genetically confirmed, treatment-naive patients with SMA, stratified for best acquired motor milestone (i.e., none: type 1a/b; head control in supine position or rolling: type 1c; sitting independently: type 2a; standing: type 2b; walking: type 3a/b; adult onset: type 4). We also assessed the need for mechanical ventilation as a surrogate endpoint for survival., Results: We included 307 patients with a total follow-up of 7,141 person-years. Median survival was 9 days in SMA type 1a, 7.7 months in type 1b, and 17.0 years in type 1c. Patients with type 2a had endpoint-free survival probabilities of 74.2% and 61.5% at ages 40 and 60 years, respectively. Endpoint-free survival of SMA types 2b, 3, and 4 was relatively normal, at least within the first 60 years of life. Patients with SMA types 1c and 2a required mechanical ventilation more frequently and from younger ages compared to patients with milder SMA types. In our cohort, patients ventilated up to 12 h/d progressed not gradually, but abruptly, to ≥16 h/d., Conclusions: Shortened endpoint-free survival is an important characteristic of SMA types 1 and 2a, but not types 2b, 3, and 4. For SMA types 1c and 2a, the age at which initiation of mechanical ventilation is necessary may be a more suitable endpoint than the arbitrarily set 16 h/d., (© 2020 American Academy of Neurology.)

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 1 ), 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 1 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 1 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 1 , - 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 1 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 1 or FVC in both sitting and supine position. These data may serve as a reference to assess longer-term outcomes in clinical trials.

The purpose of this study was to evaluate temporal stability, multi-center reproducibility and the influence of covariates on a multimodal MR protocol for quantitative muscle imaging and to facilitate its use as a standardized protocol for evaluation of pathology in skeletal muscle. Quantitative T2, quantitative diffusion and four-point Dixon acquisitions of the calf muscles of both legs were repeated within one hour. Sixty-five healthy volunteers (31 females) were included in one of eight 3-T MR systems. Five traveling subjects were examined in six MR scanners. Average values over all slices of water-T2 relaxation time, proton density fat fraction (PDFF) and diffusion metrics were determined for seven muscles. Temporal stability was tested with repeated measured ANOVA and two-way random intraclass correlation coefficient (ICC). Multi-center reproducibility of traveling volunteers was assessed by a two-way mixed ICC. The factors age, body mass index, gender and muscle were tested for covariance. ICCs of temporal stability were between 0.963 and 0.999 for all parameters. Water-T2 relaxation decreased significantly (P < 10 -3 ) within one hour by ~ 1 ms. Multi-center reproducibility showed ICCs within 0.879-0.917 with the lowest ICC for mean diffusivity. Different muscles showed the highest covariance, explaining 20-40% of variance for observed parameters. Standardized acquisition and processing of quantitative muscle MRI data resulted in high comparability among centers. The imaging protocol exhibited high temporal stability over one hour except for water T2 relaxation times. These results show that data pooling is feasible and enables assembling data from patients with neuromuscular diseases, paving the way towards larger studies of rare muscle disorders., (© 2019 John Wiley & Sons, Ltd.)

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 ( p = 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, p = 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., (© 2019 American Academy of Neurology.)

Objective: In this study we investigated the potential value of magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) in characterizing changes in the cervical spinal cord and peripheral nerve roots in vivo in patients with spinal muscular atrophy (SMA)., Methods: We developed an MRI protocol with 4 sequences to investigate the cervical spinal cord and nerve roots on a 3 Tesla MRI system. We used 2 anatomical MRI sequences to investigate cross-sectional area (CSA) at each spinal segment and the diameter of ventral and dorsal nerve roots, and two diffusion tensor imaging (DTI) techniques to estimate the fractional anisotropy (FA), mean (MD), axial (AD) and radial diffusivity (RD) in 10 SMA patients and 20 healthy controls., Results: There were no significant differences in CSA (p > .1), although an 8.5% reduction of CSA in patients compared to healthy controls was apparent at segment C7. DTI data showed a higher AD in grey matter of patients compared to healthy controls (p = .033). Significantly lower MD, AD and RD values were found in rostral nerve roots (C3-C5) in patients (p < .045)., Conclusions: We showed feasibility of an advanced 3 T MRI protocol that allowed differences to be determined between patients and healthy controls, confirming the potential of this technique to assess pathological mechanisms in SMA. After further development and confirmation of findings in a larger sample, these techniques may be used to study disease course of SMA in vivo and evaluate response to survival motor neuron (SMN) augmenting therapy., (Copyright © 2019. Published by Elsevier Inc.)

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., Competing Interests: Competing interests: BB serves on scientific advisory board for Roche Hoffman-La Roche, Zurich. LHvdB serves on the scientific advisory boards for the Prinses Beatrix Spierfonds, Thierry Latran Foundation, Biogen Idec and Cytokinetics; received an educational grant from Baxter International; serves on the editorial board of Amyotrophic Lateral Sclerosis and the Journal of Neurology, Neurosurgery and Psychiatry and receives research support from the Prinses Beatrix Fonds, Netherlands ALS Foundation, The European Community’s Health Seventh Framework Programme (grant agreement no 259867), The Netherlands Organisation for Health Research and Development (Vici Scheme, JPND (SOPHIA, STRENGTH)). WLvdP serves on the scientific advisory boards of Biogen and Avexis and the LMI070 data monitoring committee of Novartis and receives research support from the Prinses Beatrix Spierfonds, Netherlands ALS Foundation and Stichting Spieren voor Spieren., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: Natural history studies in spinal muscular atrophy (SMA) have primarily focused on infants and children. Natural history studies encompassing all age groups and SMA types are important for the interpretation of treatment effects of recently introduced survival motor neuron gene-augmenting therapies., Methods: We conducted a cross-sectional study to investigate muscle strength, Hammersmith Functional Motor Scale (Expanded) score and the patterns of muscle weakness in relation to age and SMA type., Results: We included 180 patients with SMA types 1-4 in the age range 1-77.5 years with median disease duration of 18 (range 0-65.8) years. With the exception of the early phases of disease in which children with SMA types 2 and 3 may achieve new motor skills and show a temporary increase in muscle strength, cross-sectional data suggested that declining muscle strength and loss of motor skills over time are characteristic of all SMA types. Mean loss of strength was at least 1 point on the Medical Research Council score and 0.5 point on the Hammersmith Functional Motor Scale (Expanded) score per year. Trend lines compatible with deterioration of motor function and muscle strength started in childhood and continued into adulthood. The age at loss of specific motor skills was associated with disease severity. Triceps, deltoid, iliopsoas and quadriceps were the weakest muscles in all patients. Hierarchical cluster analysis did not show a segmental distribution of muscle weakness as suggested previously., Conclusions: Progressive muscle weakness and loss of motor function are characteristic of all SMA types and all ages., (© 2017 EAN.)