The clinical use of mechanical insufflation-exsufflation in children with neuromuscular disorders in Europe

Mechanical insufflation-exsufflation (MI-E) is a strategy to treat pulmonary exacerbations in neuromuscular disorders (NMDs). Pediatric guidelines for optimal setting titration of MI-E are lacking and the settings used in studies vary. Our objective was to assess the actual MI-E settings being used in current clinical treatment of children with NMDs and a survey was sent in July 2016 to European expertise centers. Ten centers from seven countries gave information on MI-E settings for 240 children aged 4 months to 17.8 years (mean 10.5). Settings varied greatly between the centers. Auto mode was used in 71%, triggering of insufflation in 21% and manual mode in 8% of the cases. Mean (SD) time for insufflation (Ti) and exsufflation (Te) were 1.9 (0.5) and 1.8 (0.6) s respectively, both ranging from 1 to 4 s. Asymmetric time settings were common (65%). Mean (SD) insufflation (Pi) and exsufflation (Pe) pressures were 32.4 (7.8) and −36.9 (7.4), ranging 10 to 50 and −10 to −60 cmH2O, respectively. Asymmetric pressures were as common as symmetric. Both Ti, Te, Pi and Pe increased with age (p < 0.001). In conclusion, pediatric MI-E settings in clinical use varied greatly and altered with age, highlighting the need of more studies to improve our knowledge of optimal settings in MI-E in children with NMDs.publishedVersio

Exercise Training in Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

Objective: To evaluate the effects and safety of exercise training, and to determine the most effective exercise intervention for people with Duchenne muscular dystrophy. Exercise training was compared with no training, placebo or alternative exercise training. Primary outcomes were functioning and health-related quality of life. Secondary outcomes were muscular strength, endurance and lung function. Data sources: A systematic literature search was conducted in Medline, EMBASE, CINAHL, Cochrane Central, PEDro and Scopus. Study selection and data extraction: Screening, data extraction, risk of bias and quality assessment were carried out. Risk of bias was assessed using the Cochrane Collaborations risk of bias tools. The certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. Data synthesis: Twelve studies with 282 participants were included. A narrative synthesis showed limited or no improvements in functioning compared with controls. Health-related quality of life was assessed in only 1 study. A meta-analysis showed a significant difference in muscular strength and endurance in favour of exercise training compared with no training and placebo. However, the certainty of evidence was very low. Conclusion: Exercise training may be beneficial in Duchenne muscular dystrophy, but the evidence remains uncertain. Further research is needed on exercise training to promote functioning and health-related quality of life in Duchenne muscular dystrophy.publishedVersio

Clinical responses following inspiratory muscle training in exercise-induced laryngeal obstruction

Purpose Exercise-induced laryngeal obstruction (EILO) is relatively common in young people. Treatment rests on poor evidence; however, inspiratory muscle training (IMT) has been proposed a promising strategy. We aimed to assess laryngeal outcomes shortly after IMT, and to compare self-reported symptoms with a control group 4–6 years later. Methods Two groups were retrospectively identified from the EILO-register at Haukeland University Hospital, Norway; one group had received only information and breathing advice (IBA), and another additionally IMT (IBA + IMT). At diagnosis, all participants performed continuous laryngoscopy during exercise (CLE), with findings split by glottic and supraglottic scores, and completed a questionnaire mapping exercise-related symptoms. After 2–4 weeks, the IBA + IMT-group was re-evaluated with CLE-test. After 4–6 years, both groups were re-assessed with a questionnaire. Results We identified 116 eligible patients from the EILO-register. Response rates after 4–6 years were 23/58 (40%) and 32/58 (55%) in the IBA and IBA + IMT-group, respectively. At diagnosis, both groups rated symptoms similarly, but laryngeal scores were higher in the IBA + IMT-group (P = 0.003). After 2–4 weeks, 23/32 in the IBA + IMT-group reported symptom improvements, associated with a decrease of mainly glottic scores (1.7–0.3; P < 0.001), contrasting unchanged scores in the 9/32 without symptom improvements. After 4–6 years, exercise-related symptoms and activity levels had decreased to similar levels in both groups, with no added benefit from IMT; however, full symptom resolution was reported by only 8/55 participants. Conclusion Self-reported EILO symptoms had improved after 4–6 years, irrespective of initial treatment. Full symptom resolution was rare, suggesting individual follow-up should be offered.publishedVersio

Reliability of translaryngeal airway resistance measurements during maximal exercise

Objective Exercise-induced laryngeal obstruction is an important cause of exertional dyspnoea. The diagnosis rests on visual judgement of relative changes of the laryngeal inlet during continuous laryngoscopy exercise (CLE) tests, but we lack objective measures that reflect functional consequences. We aimed to investigate repeatability and normal values of translaryngeal airway resistance measured at maximal intensity exercise. Methods 31 healthy nonsmokers without exercise-related breathing problems were recruited. Participants performed two CLE tests with verified positioning of two pressure sensors, one at the tip of the epiglottis (supraglottic) and one by the fifth tracheal ring (subglottic). Airway pressure and flow data were continuously collected breath-by-breath and used to calculate translaryngeal resistance at peak exercise. Laryngeal obstruction was assessed according to a standardised CLE score system. Results Data from 26 participants (16 females) with two successful tests and equal CLE scores on both test sessions were included in the translaryngeal resistance repeatability analyses. The coefficient of repeatability (CR) was 0.62 cmH2O·L−1·s−1, corresponding to a CR% of 21%. Mean±sd translaryngeal airway resistance (cmH2O·L−1·s−1) in participants with no laryngeal obstruction (n=15) was 2.88±0.50 in females and 2.18±0.50 in males. Higher CLE scores correlated with higher translaryngeal resistance in females (r=0.81, p<0.001). Conclusions This study establishes translaryngeal airway resistance obtained during exercise as a reliable parameter in respiratory medicine, opening the door for more informed treatment decisions and future research on the role of the larynx in health and disease.publishedVersio

Exercise-induced Laryngeal Obstruction: Protocol for a Randomized Controlled Treatment Trial

Background: Exercise-induced laryngeal obstruction (EILO) is a common cause of exertional breathing problems in young individuals, caused by paradoxical inspiratory adduction of laryngeal structures, and diagnosed by continuous visualization of the larynx during high-intensity exercise. Empirical data suggest that EILO consists of different subtypes, possibly requiring different therapeutic approaches. Currently applied treatments do not rest on randomized controlled trials, and international guidelines based on good evidence can therefore not be established. This study aims to provide evidence-based information on treatment schemes commonly applied in patients with EILO. Methods and Analysis: Consenting patients consecutively diagnosed with EILO at Haukeland University Hospital will be randomized into four non-invasive treatment arms, based on promising reports from non-randomized studies: (A) standardized information and breathing advice only (IBA), (B) IBA plus inspiratory muscle training, (C) IBA plus speech therapy, and (D) IBA plus inspiratory muscle training and speech therapy. Differential effects in predefined EILO subtypes will be addressed. Patients failing the non-invasive approach and otherwise qualifying for surgical treatment by current department policy will be considered for randomization into (E) standard or (F) minimally invasive laser supraglottoplasty or (G) no surgery. Power calculations are based on the main outcomes, laryngeal adduction during peak exercise, rated by a validated scoring system before and after the interventions. Ethics and Dissemination: The study will assess approaches to EILO treatments that despite widespread use, are insufficiently tested in structured, verifiable, randomized, controlled studies, and is therefore considered ethically sound. The study will provide knowledge listed as a priority in a recent statement issued by the European Respiratory Society, requested by clinicians and researchers engaged in this area, and relevant to 5–7% of young people. Dissemination will occur in peer-reviewed journals, at relevant media platforms and conferences, and by engaging with patient organizations and the healthcare bureaucracy.publishedVersio

Traces of trauma – a multivariate pattern analysis of childhood trauma, brain structure and clinical phenotypes

Background: Childhood trauma (CT) is a major yet elusive psychiatric risk factor, whose multidimensional conceptualization and heterogeneous effects on brain morphology might demand advanced mathematical modeling. Therefore, we present an unsupervised machine learning approach to characterize the clinical and neuroanatomical complexity of CT in a larger, transdiagnostic context. Methods: We used a multicenter European cohort of 1076 female and male individuals (discovery: n = 649; replication: n = 427) comprising young, minimally medicated patients with clinical high-risk states for psychosis; patients with recent-onset depression or psychosis; and healthy volunteers. We employed multivariate sparse partial least squares analysis to detect parsimonious associations between combinations of items from the Childhood Trauma Questionnaire and gray matter volume and tested their generalizability via nested cross-validation as well as via external validation. We investigated the associations of these CT signatures with state (functioning, depressivity, quality of life), trait (personality), and sociodemographic levels. Results: We discovered signatures of age-dependent sexual abuse and sex-dependent physical and sexual abuse, as well as emotional trauma, which projected onto gray matter volume patterns in prefronto-cerebellar, limbic, and sensory networks. These signatures were associated with predominantly impaired clinical state- and trait-level phenotypes, while pointing toward an interaction between sexual abuse, age, urbanicity, and education. We validated the clinical profiles for all three CT signatures in the replication sample. Conclusions: Our results suggest distinct multilayered associations between partially age- and sex-dependent patterns of CT, distributed neuroanatomical networks, and clinical profiles. Hence, our study highlights how machine learning approaches can shape future, more fine-grained CT research

Laryngeal response patterns during mechanically assisted cough in Amyotrophic Lateral Sclerosis

Background: Patients with amyotrophic lateral sclerosis (ALS) are treated with mechanical cough assist devices using the technique of mechanical insufflationexsufflation (MI-E) in order to improve cough and enhance clearance of airway secretions. The aim of treatment is to prevent lung infections and to provide a better quality of life. The technique often fails in ALS patients with bulbar involvement, allegedly due to upper airway malfunction. Laryngeal collapse during exsufflation has been proposed to explain the ineffectiveness of MI-E in bulbar ALS. However, there are a lack of studies utilizing comprehensive and verifiable methods to investigate the role played by the larynx of patients in whom MI-E appears to be nonsuccessful. Objectives: Study #I: To examine the feasibility of transnasal fiberoptic laryngoscopy (TFL) during ongoing MI-E in healthy volunteers, and to describe normal laryngeal response pattern(s) to MI-E. Study #II: To investigate laryngeal response patterns to MI-E in a cross-sectional study of ALS of different phenotypes. Study #III: To examine and describe changes in laryngeal response patterns to MI-E as ALS progresses, and to explore if treatment protocols can possibly be modified and improved in these patients. Design: Population-based, explorative, descriptive, observational studies, with crosssectional design in Study #I and #II, and prospective cohort design in the Study #III. Subjects: Study #I: Twenty healthy medical students. Study #II: Twenty patients with ALS together with 20 healthy volunteers, matched for age and gender. Study #III: Thirteen eligible patients with ALS, recruited from Study II, prospectively followed during disease progression for up to 5 years. Methods: ALS was phenotyped according to established international standards. Upper and lower motor neuron symptoms were characterized, and the respiratory function determined. Video recorded flexible TFL was applied during ongoing cough assisted by MI-E that was applied using various pressures according to a preset protocol. The video files were used to carefully assess and tabulate the laryngeal movements. The examinations were performed at outpatient visits that were scheduled at set time-intervals. Results: Study #I: The larynx could be studied with TFL during ongoing MI-E. The laryngeal responses to MI-E in healthy volunteers were compatible to that described in normal cough. Study #II: The laryngeal structures of patients with ALS and bulbar symptoms tended to adduct, especially during insufflation, which in some patients severely compromised the size of the laryngeal inlet, especially if high pressures were applied. Study #III: During ALS disease progression, the first signs of laryngeal adduction occurred with the highest insufflation pressures and prior to any clinically evident signs of bulbar involvement. Hypopharyngeal constriction during exsufflation was observed in all subjects regardless of bulbar symptoms, and later in the disease progression than the above described adverse events during insufflation. Cough gradually became less expulsive and also less synchronized at the laryngeal level. Triggering of swallowing reflexes by the positive air flow from the MI-E further complicated these matters. Attempts of careful individual tailoring of the MI-E therapy as the patients’ condition deteriorated seemed to prolong its successful use. Conclusions and interpretations: Laryngoscopy can safely be performed during ongoing MI-E, and appears a feasible tool to visualize the laryngeal responses to this therapy. In bulbar ALS, laryngeal structures are prone to adduct throughout the various pressure cycles of MI-E, especially if applying high insufflation pressures, thereby severely obstructing the airflow and thus hampering the effect of the treatment. Cough patterns alter as ALS progresses, and rapidly alternating MI-E pressure cycles may become challenging or even impossible to handle for patients. Individually tailored MI-E treatment can improve and may possible extend the use of non-invasive ventilatory support in ALS, and TFL can become a feasible and valuable tool in this respect

Tailoring NIV by dynamic laryngoscopy in a child with spinal muscular atrophy type I

Dynamic laryngoscopy during noninvasive (NIV) respiratory therapy is feasible and may facilitate optimal and individualized treatment in patients with chronic respiratory failure, also in children

Prevalence of long-term mechanical insufflation-exsufflation in children with neurological conditions: a population-based study

Aim To determine the prevalence of long-term mechanical insufflation-exsufflation (MI-E) and concomitant mechanical ventilation in children with neurological conditions, with reported reasons behind the initiation of treatment. Method This was a population-based, cross-sectional study using Norwegian national registries and a questionnaire. Results In total, 114 of 19 264 children with a neurological condition had an MI-E device. Seventy-three of 103 eligible children (31 females, 42 males), median (min–max) age of 10 years 1 month (1y 5mo–17y 10mo), reported their MI-E treatment initiation. Overall, 76% reported airway clearance as the main reason to start long-term MI-E. A prophylactic use was mainly reported by children with neuromuscular disorders (NMDs). Prevalence and age at initiation differed by diagnosis. In spinal muscular atrophy and muscular dystrophies, MI-E use was reported in 34% and 7% of children, of whom 83% and 57% respectively received ventilator support. One-third of the MI-E users were children with central nervous system (CNS) conditions, such as cerebral palsy and degenerative disorders, and ventilator support was provided in 31%. The overall use of concomitant ventilatory support among the long-term MI-E users was 56%

Exercise Training in Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

Objective: To evaluate the effects and safety of exercise training, and to determine the most effective exercise intervention for people with Duchenne muscular dystrophy. Exercise training was compared with no training, placebo or alternative exercise training. Primary outcomes were functioning and health-related quality of life. Secondary outcomes were muscular strength, endurance and lung function. Data sources: A systematic literature search was conducted in Medline, EMBASE, CINAHL, Cochrane Central, PEDro and Scopus. Study selection and data extraction: Screening, data extraction, risk of bias and quality assessment were carried out. Risk of bias was assessed using the Cochrane Collaborations risk of bias tools. The certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. Data synthesis: Twelve studies with 282 participants were included. A narrative synthesis showed limited or no improvements in functioning compared with controls. Health-related quality of life was assessed in only 1 study. A meta-analysis showed a significant difference in muscular strength and endurance in favour of exercise training compared with no training and placebo. However, the certainty of evidence was very low. Conclusion: Exercise training may be beneficial in Duchenne muscular dystrophy, but the evidence remains uncertain. Further research is needed on exercise training to promote functioning and health-related quality of life in Duchenne muscular dystrophy