Respiratory function in LAMA2-related muscular dystrophy and SELENON-related congenital myopathy, a 1.5-year natural history study

INTRODUCTION: LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON(SEPN1)-related congenital myopathy (SELENON-RM) are rare neuromuscular diseases with respiratory impairment from a young age. Prospective natural history studies are needed for prevalence estimations, respiratory characterization, optimizing clinical care and selecting outcome measures for trial readiness.METHODS: Our prospective 1.5-year natural history study included spirometry (forced vital capacity (FVC); difference between upright and supine vital capacity (dVC)), respiratory muscle strength tests (sniff nasal inspiratory pressure (SNIP)) (age≥5 years), and diaphragm ultrasound (thickness; thickening; echogenicity; all ages).RESULTS: Twenty-six LAMA2-MD patients (M = 8, median 21 [9; 31] years) and 11 SELENON-RM patients (M = 8, 20 [10; 33] years) were included. At baseline, 17 (85 %) LAMA2-MD (FVC%: 59 % [33; 68]) and all SELENON-RM patients (FVC%: 34 % [31; 46]) had an impaired respiratory function (FVC%&lt;80 %). Nine (35 %) LAMA2-MD and eight (73 %) SELENON-RM patients received mechanical ventilation at baseline, and two additional SELENON-RM patients started during follow-up. Contrarily to LAMA2-MD, SELENON-RM patients had severe diaphragm atrophy (diaphragm thickness z-score: 2.5 [-3.1; -2.1]) and dysfunction (diaphragm thickness ratio: 1.2 [1.0; 1.7]; dVC: 30 % [7.7; 41]). SNIP was low in both neuromuscular diseases and correlated with motor function. In SELENON-RM, respiratory function decreased during follow-up.CONCLUSION: The majority of LAMA2-MD and all SELENON-RM patients had respiratory impairment. SELENON-RM patients showed lower respiratory function which was progressive, more prevalent mechanical ventilation, and more severe diaphragm atrophy and dysfunction than LAMA2-MD patients. Spirometry (FVC%, dVC) and respiratory muscle strength tests (SNIP) are useful in clinical care and as outcome measure in clinical trials.CLINICAL TRIAL NUMBER: NCT04478981.</p

Long-term follow-up of respiratory function in facioscapulohumeral muscular dystrophy

OBJECTIVE: To evaluate the 5-year change in respiratory function in patients with facioscapulohumeral muscular dystrophy (FSHD). METHODS: Genetically confirmed patients with FSHD aged ≥ 18 years were examined twice over five years. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were measured using hand-held spirometry with a face mask. Several clinical outcome measures were correlated to respiratory function. RESULTS: Ninety-two patients were included (57% male, age 18–75 years). At baseline, the spirometry outcomes of 41 patients showed a restrictive ventilatory pattern (FVC  10% predicted. The subgroup of 15 patients was more severely affected at baseline (p = 0.002 for FSHD clinical score and 0.007 for Ricci score). They developed more frequently spinal and thorax deformities (p < 0.001 for kyphoscoliosis and 0.012 for pectus excavatum) and had a larger decline in axial muscle function (p = 0.020). Only weak correlations were found between the change in FVC% predicted and the change in clinical scores between baseline and follow-up. INTERPRETATION: Respiratory function remained stable in most patients with FSHD, but a subgroup of patients showed a pronounced deterioration. They showed more severe muscle weakness including the leg muscles at baseline (Ricci score ≥ 6), had spinal and thorax deformities and a relatively fast decline in axial muscle function at follow-up

Speckle tracking echography allows sonographic assessment of diaphragmatic loading

Introduction: Assessment of diaphragm function should ideally be assessed using magnetic twitch pressure or esophageal and gastric balloons. Conventional sonographic techniques as thickness and fractional thickening (FT), only provide limited insight in diaphragm function. Speckle tracking echocardiography allows reliable quantification of muscle function by tracking of grey patterns and their motion; strain as parameter of muscle deformation and strain rate as deformation velocity. Aim: To investigate whether speckle tracking can quantify loading of the diaphragm, superior to FT. Methods: 13 healthy volunteers underwent an inspiratory loading protocol with recording of transdiaphragmatic pressure (Pdi) and diaphragm electromyography (EMGdi). Inspiratory loading of 0 to 30% of maximal inspiratory pressure was applied in random order for 5 minutes per applied load. Diaphragmatic sonography was performed using a 2-4 MHz linear phased array transducer positioned at the right-lateral thoracic wall in the anterior axillary line longitudinal to the body axis. Ultrasound recordings of the diaphragm were made at the marked location during 10 seconds. Results: Increased inspiratory loading increased Pdi and EMGdi. Sonographic markers of contractility increased with incremental loading. Pdi correlated with strain (r=0.75; p=0.000) and strain rate (r=0.77; p=0.000). Contrarily, FT was not correlated with Pdi. Conclusion: Speckle tracking of the diaphragm can detect changes in diaphragmatic loading up to 30% of maximal inspiratory pressure. It might be a valuable tool to detect changes in loading in specific patient categories, including patients with acute respiratory failure and ventilated ICU patients

Respiratory muscle function in patients with nemaline myopathy

Publisher Copyright: © 2022 The AuthorsIn this cross-sectional study, we comprehensively assessed respiratory muscle function in various clinical forms of nemaline myopathy (NM) including non-volitional tests for diaphragm function. Forty-two patients with NM were included (10 males (25-74 y/o); 32 females (11-76 y/o)). The NM forms were typical (n=11), mild (n=7), or childhood-onset with slowness of movements (n=24). Forced vital capacity (FVC) and maximal inspiratory pressure were decreased in typical NM in comparison with childhood-onset NM with slowness (32.0 [29.0-58.5] vs 81.0 [75.0-87.0]%, p<0.01, and 35.0 [24.0-55.0] vs 81.0 [65.0-102.5] cmH2O, p<0.01). Eight patients with childhood-onset NM with slowness had respiratory muscle weakness. There was a low correlation between FVC and Motor Function Measure scores (r=0.48, p<0.01). End-inspiratory diaphragm thickness and twitch mouth pressure were decreased in patients requiring home mechanical ventilation compared to non-ventilated patients with normal lung function (1.8 [1.5-2.4] vs 3.1 [2.0-4.6] mm, p=0.049, and -7.9 [-10.9- -4.0] vs -14.9 [-17.3- -12.6], p=0.04). Our results show that respiratory muscle weakness is present in all NM forms, including childhood-onset NM with slowness, and may be present irrespective of the degree of general motor function impairment. These findings highlight the importance for screening of respiratory function in patients with NM to guide respiratory management.Peer reviewe

Respiratory features of centronuclear myopathy in the Netherlands

Centronuclear myopathy (CNM) is a heterogeneous group of muscle disorders primarily characterized by muscle weakness and variable degrees of respiratory dysfunction caused by mutations in MTM1, DNM2, RYR1, TTN and BIN1. X-linked myotubular myopathy has been the focus of recent natural history studies and clinical trials. Data on respiratory function for other genotypes is limited. To better understand the respiratory properties of the CNM spectrum, we performed a retrospective study in a non-selective Dutch CNM cohort. Respiratory dysfunction was defined as an FVC below 70% of predicted and/or a daytime pCO2 higher than 6 kPa. We collected results of other pulmonary function values (FEV1/FVC ratio) and treatment data from the home mechanical ventilation centres. Sixty-one CNM patients were included. Symptoms of respiratory weakness were reported by 15/47 (32%) patients. Thirty-three individuals (54%) with different genotypes except autosomal dominant (AD)-BIN1-related CNM showed respiratory dysfunction. Spirometry showed decreased FVC, FEV1 &amp; PEF values in all but two patients. Sixteen patients were using HMV (26%), thirteen of them only during night-time. In conclusion, this study provides insight into the prevalence of respiratory symptoms in four genetic forms of CNM in the Netherlands and offers the basis for future natural history studies.</p

Monitoring and preventing diaphragm injury

Purpose of Review: The present review summarizes developments in the field of respiratory muscle monitoring, in particular in critically ill patients. Recent Findings: Patients admitted to the ICU may develop severe respiratory muscle dysfunction in a very short time span. Among other factors, disuse and sepsis have been associated with respiratory muscle dysfunction in these patients. Because weakness is associated with adverse outcome, including prolonged mechanical ventilation and mortality, it is surprising that respiratory muscle dysfunction largely develops without being noticed by the clinician. Respiratory muscle monitoring is not standard of care in most ICUs. Improvements in technology have opened windows for monitoring the respiratory muscles in critically ill patients. Diaphragm electromyography and esophageal pressure measurement are feasible techniques for respiratory muscle monitoring, although the effect on outcome remains to be investigated. Summary: Respiratory muscle dysfunction develops rapidly in selected critically ill patients and is associated with adverse outcome. Recent technological advances allow real-time monitoring of respiratory muscle activity in these patients. Although this field is in its infancy, from a physiological perspective, it is reasonable to assume that monitoring respiratory muscle activity improves outcome in these patients

Deep learning segmentation of transverse musculoskeletal ultrasound images for neuromuscular disease assessment

Ultrasound imaging is a patient-friendly and robust technique for studying physiological and pathological muscles. An automatic deep learning (DL) system for the analysis of ultrasound images could be useful to support an expert operator, allowing the study of large datasets requiring less human interaction. The purpose of this study is to present a deep learning algorithm for the cross-sectional area (CSA) segmentation in transverse musculoskeletal ultrasound images, providing a quantitative grayscale analysis which is useful for studying muscles, and to validate the results in a large dataset. The dataset included 3917 images of biceps brachii, tibialis anterior and gastrocnemius medialis acquired on 1283 subjects (mean age 50 ± 21 years, 729 male). The algorithm was based on multiple deep-learning architectures, and its performance was compared to a manual expert segmentation. We compared the mean grayscale value inside the automatic and manual CSA using Bland-Altman plots and a correlation analysis. Classification in healthy and abnormal muscles between automatic and manual segmentation were compared using the grayscale value z-scores. In the test set, a Precision of 0.88 ± 0.12 and a Recall of 0.92 ± 0.09 was achieved. The network segmentation performance was slightly less in abnormal muscles, without a loss of discrimination between healthy and abnormal muscle images. Bland-Altman plots showed no clear trend in the error distribution and the two readings have a 0.99 Pearson's correlation coefficient (p < 0.001, test set). The ICC(A, 1) calculated between the z-score readings was 0.99. The algorithm achieves robust CSA segmentation performance and gives mean grayscale level information comparable to a manual operator. This could provide a helpful tool for clinicians in neuromuscular disease diagnosis and follow-up. The entire dataset and code are made available for the research community

The differential diagnosis for failure to wean from mechanical ventilation

PURPOSE OF REVIEW: In this review, we discuss the causes for a failed weaning trial and specific diagnostic tests that could be conducted to identify the cause for weaning failure. We briefly highlight treatment strategies that may enhance the chance of weaning success. RECENT FINDINGS: Impaired respiratory mechanics, respiratory muscle dysfunction, cardiac dysfunction, cognitive dysfunction, and metabolic disorders are recognized causes for weaning failure. In addition, iatrogenic factors may be at play. Most studies have focused on respiratory muscle dysfunction and cardiac dysfunction. Recent studies demonstrate that both ultrasound and electromyography are valuable tools to evaluate respiratory muscle function in ventilated patients. Sophisticated ultrasound techniques and biomarkers such as B-type natriuretic peptide, are valuable tools to identify cardiac dysfunction as a cause for weaning failure. Once a cause for weaning failure has been identified specific treatment should be instituted. Concerning treatment, both strength training and endurance training should be considered for patients with respiratory muscle weakness. Inotropes and vasodilators should be considered in case of heart failure. SUMMARY: Understanding the complex pathophysiology of weaning failure in combination with a systematic diagnostic approach allows identification of the primary cause of weaning failure. This will help the clinician to choose a specific treatment strategy and therefore may fasten liberation from mechanical ventilation

Reproducibility and robustness of motor cortical stimulation to assess muscle relaxation kinetics

Abstract Transcranial magnetic stimulation (TMS) of the motor cortex can be used during a voluntary contraction to inhibit corticospinal drive to the muscle and consequently induce involuntary muscle relaxation. Our aim was to evaluate the reproducibility and the effect of varying experimental conditions (robustness) of TMS‐induced muscle relaxation. Relaxation of deep finger flexors was assessed in 10 healthy subjects (5 M, 5 F) using handgrip dynamometry with normalized peak relaxation rate as main outcome measure, that is, peak relaxation rate divided by (voluntary plus TMS‐evoked)force prior to relaxation. Both interday and interrater reliability of relaxation rate were high with intraclass correlation coefficient of 0.88 and 0.92 and coefficient of variation of 3.8 and 3.7%, respectively. Target forces of 37.5% of maximal voluntary force or higher resulted in similar relaxation rate. From 50% of maximal stimulator output and higher relaxation rate remained the same. Only the most lateral position (>2 cm from the vertex) rendered lower relaxation rate (mean ± SD: 11.1 ± 3.0 s−1, 95% CI: 9.0–13.3 s−1) compared to stimulation at the vertex (12.8 ± 1.89 s−1, 95% CI: 11.6–14.1 s−1). Within the range of baseline skin temperatures, an average change of 0.5 ± 0.2 s−1 in normalized peak relaxation rate was measured per 1°C change in skin temperature. In conclusion, interday and interrater reproducibility and reliability of TMS‐induced muscle relaxation of the finger flexors were high. Furthermore, this technique is robust with limited effect of target force, stimulation intensity, and coil position. Muscle relaxation is strongly affected by skin temperature; however, this effect is marginal within the normal skin temperature range. We deem this technique well suited for clinical and scientific assessment of muscle relaxation