Repeated intravenous cardiosphere-derived cell therapy in late-stage Duchenne muscular dystrophy (HOPE-2): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Cardiosphere-derived cells (CDCs) ameliorate skeletal and cardiac muscle deterioration in experimental models of Duchenne muscular dystrophy. The HOPE-2 trial examined the safety and efficacy of sequential intravenous infusions of human allogeneic CDCs in late-stage Duchenne muscular dystrophy. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 2 trial, patients with Duchenne muscular dystrophy, aged 10 years or older with moderate upper limb impairment, were enrolled at seven centres in the USA. Patients were randomly assigned (1:1) using stratified permuted blocks to receive CAP-1002 (1·5 × 108 CDCs) or placebo intravenously every 3 months for a total of four infusions. Clinicians, caregivers, patients, and clinical operations personnel were fully masked to treatment groups. The primary outcome was the change in mid-level elbow Performance of Upper Limb version 1.2 (PUL 1.2) score at 12 months, assessed in the intention-to-treat population. Safety was assessed in all individuals who received an investigational product. This trial is registered with ClinicalTrials.gov, NCT03406780. FINDINGS: Between March 1, 2018, and March 31, 2020, 26 male patients with Duchenne muscular dystrophy were enrolled, of whom eight were randomly assigned to the CAP-1002 group and 12 to the placebo group (six were not randomised due to screening failure). In patients who had a post-treatment PUL 1.2 assessment (eight in the CAP-1002 group and 11 in the placebo group), the mean 12-month change from baseline in mid-level elbow PUL1.2 favoured CAP-1002 over placebo (percentile difference 36·2, 95% CI 12·7-59·7; difference of 2·6 points; p=0·014). Infusion-related hypersensitivity reactions without long-term sequelae were observed in three patients, with one patient discontinuing therapy due to a severe allergic reaction. No other major adverse reactions were noted, and no deaths occurred. INTERPRETATION: CAP-1002 cell therapy appears to be safe and effective in reducing deterioration of upper limb function in patients with late-stage Duchenne muscular dystrophy. Various measures of cardiac function and structure were also improved in the CAP-1002 group compared with the placebo group. Longer-term extension studies are needed to confirm the therapeutic durability and safety of CAP-1002 beyond 12 months for the treatment of skeletal myopathy and cardiomyopathy in Duchenne muscular dystrophy. FUNDING: Capricor Therapeutics.

Impact of growth friendly interventions on spine and pulmonary outcomes of patients with spinal muscular atrophy.

PURPOSE: Patients with spinal muscular atrophy (SMA) are often treated with growth friendly devices such as vertical expandable prosthetic titanium rib(VEPTR) and magnetically controlled growing rods(MCGR) to correct spinal deformity and improve pulmonary function. There is limited data on this topic, and the purpose of this study was to assess the effect of these constructs and the addition of chest wall support (CWS) on spinal deformity, thorax morphology and pulmonary outcomes. METHODS: This is a retrospective analysis of prospectively collected data. We included patients with chest wall deformity and scoliosis secondary to SMA who were treated with growth friendly interventions and had two-year follow-up. Descriptive statistics and univariate analyses were performed. RESULTS: This study included 66 patients (25% MCGR, 73% VEPTR, 2% unknown). Approximately 23% of constructs included CWS. The average Cobb angle improved from 67° (SD: 27°) to 50° (SD: 26°) at 2 years in patients with CWS (p = 0.02), and from 59° (SD: 20°) to 46° (SD: 15°) at 2 years in patients without CWS (p < 0.01). Hemithorax height improved in patients treated with and without CWS (p = 0.01), but hemithorax width only improved in patients with CWS (p = 0.01). One patient with CWS and two patients without CWS required additional respiratory support at 2 years. The rates of postoperative complications were not significantly different in patients treated with and without CWS (p = 0.31). CONCLUSIONS: Growth friendly constructs improve spinal deformity and may be effective in altering the progression toward respiratory failure in patients with SMA. Patients treated with CWS have significant improvements in thorax morphology compared to patients without CWS.

Outcomes and Complications in Management of Congenital Myopathy Early-Onset Scoliosis.

BACKGROUND: Congenital myopathies (CMs) are complex conditions often associated with early-onset scoliosis (EOS). The purpose of this study was to investigate radiographic outcomes in CM patients undergoing EOS instrumentation as well as complications. Secondarily, we sought to compare these patients to a population with higher prevalence, cerebral palsy (CP) EOS patients. METHODS: This is a retrospective study of a prospectively collected multicenter registry. The registry was queried for EOS patients with growth-sparing instrumentation (vertical expandable prosthetic titanium ribs, magnetically controlled growing rods, traditional growing rod, or Shilla) and a CM or CP diagnosis with minimum 2 years follow-up. Outcomes included major curve magnitude, T1-S1 height, kyphosis, and complications. RESULTS: Sixteen patients with CM were included. Six (37.5%) children with CM experienced 11 complications by 2 years. Mean major curve magnitude for CM patients was improved postoperatively and maintained at 2 years (P<0.01), with no significant increase in T1-S1 height or maximum kyphosis(P>0.05). Ninety-seven patients with CP EOS were included as a comparative cohort. Fewer CP patients required baseline respiratory support compared with CM patients (20.0% vs. 92.9%, P<0.01). Fifty-four (55.7%) CP patients experienced a total of 105 complications at 2 years. There was no evidence that the risk of complication or radiographic outcomes differs between cohorts at 2 years, though CP EOS patients experienced significant improvement in all measurements at 2 years. CONCLUSIONS: EOS CM children face a high risk of complication after growing instrumentation, with similar curve correction and risk of complication to CP patients. LEVEL OF EVIDENCE: Level III.

Comparison of T1-S1 Spine Height of Postoperative Rib-based Implant Patients With Age-matched Peers.

BACKGROUND: Severe early-onset scoliosis leads to deficient spine height, thoracic growth inhibition, and ultimately pulmonary compromise. Rib-based growing instrumentation seeks to correct thoracic deformities, in part by correcting the spinal deformity, adding height, increasing thoracic volume, and allowing for continual spinal growth until maturity. However, the amount of growth in these patients relative to their peers is unknown. METHODS: Sixty patients who had undergone surgical intervention for the treatment of early-onset scoliosis were assessed via radiographic measurements of coronal T1-S1 height and major curve angle before implantation and again at most recent follow-up (minimum 2 years). T1-S1 measurements were then compared with age-matched peers to assess growth differences. Clinical information was examined for relevant parameters. RESULTS: The average age of our cohort at initial surgery and most recent follow-up was 4.4±3.8 and 10.0±4.4 years old, respectively. In this patient set, there was an average increase in T1-S1 height of 13.1±11.1 mm per year, with the majority of growth occurring in the first 2 years following implantation, and improvement in a major curve from 68±8 to 53±7 degrees. Overall, 77% of patients saw improvement in the major curve at most recent follow-up. Furthermore, a statistically significant greater percent of expected growth was seen in congenital compared with neuromuscular scoliosis (P<0.001). In addition, a weak negative correlation was observed between a number of surgical lengthenings and T1-S1 growth. CONCLUSIONS: Rib-based implant intervention has been shown to improve the major curve, but only improves growth potential to around 80% of expected growth. Scoliosis diagnosis type also influences growth rate potential, with congenital scoliosis patients being surgically treated earlier in life and having a growth rate approaching that of a healthy individual. LEVEL OF EVIDENCE: Level III-Case control.

Understanding Respiratory Restrictions as a Function of the Scoliotic Spinal Curve in Thoracic Insufficiency Syndrome: A 4D Dynamic MR Imaging Study.

BACKGROUND: Over the past 100 years, many procedures have been developed for correcting restrictive thoracic deformities which cause thoracic insufficiency syndrome. However, none of them have been assessed by a robust metric incorporating thoracic dynamics. In this paper, we investigate the relationship between radiographic spinal curve and lung volumes derived from thoracic dynamic magnetic resonance imaging (dMRI). Our central hypothesis is that different anteroposterior major spinal curve types induce different restrictions on the left and right lungs and their dynamics. METHODS: Retrospectively, we included 25 consecutive patients with thoracic insufficiency syndrome (14 neuromuscular, 7 congenital, 4 other) who underwent vertical expandable prosthetic titanium rib surgery and received preimplantation and postimplantation thoracic dMRI for clinical care. We measured thoracic and lumbar major curves by the Cobb measurement method from anteroposterior radiographs and classified the curves as per Scoliosis Research Society (SRS)-defined curve types. From 4D dMRI images, we derived static volumes and tidal volumes of left and right lung, along with left and right chest wall and left and right diaphragm tidal volumes (excursions), and analyzed their association with curve type and major curve angles. RESULTS: Thoracic and lumbar major curve angles ranged from 0 to 136 and 0 to 116 degrees, respectively. A dramatic postoperative increase in chest wall and diaphragmatic excursion was seen qualitatively. All components of volume increased postoperatively by up to 533%, with a mean of 70%. As the major curve, main thoracic curve (MTC) was associated with higher tidal volumes (effect size range: 0.7 to 1.0) than thoracolumbar curve (TLC) in preoperative and postoperative situation. Neither MTC nor TLC showed any meaningful correlation between volumes and major curve angles preoperatively or postoperatively. Moderate correlations (0.65) were observed for specific conditions like volumes at end-inspiration or end-expiration. CONCLUSIONS: The relationships between component tidal volumes and the spinal curve type are complex and are beyond intuitive reasoning and guessing. TLC has a much greater influence on restricting chest wall and diaphragm tidal volumes than MTC. Major curve angles are not indicative of passive resting volumes or tidal volumes. LEVEL OF EVIDENCE: Level II-diagnostic.

Quantitative Dynamic Thoracic MRI: Application to Thoracic Insufficiency Syndrome in Pediatric Patients.

Background Available methods to quantify regional dynamic thoracic function in thoracic insufficiency syndrome (TIS) are limited. Purpose To evaluate the use of quantitative dynamic MRI to depict changes in regional dynamic thoracic function before and after surgical correction of TIS. Materials and Methods Images from free-breathing dynamic MRI in pediatric patients with TIS (July 2009-August 2015) were retrospectively evaluated before and after surgical correction by using vertical expandable prosthetic titanium rib (VEPTR). Eleven volumetric parameters were derived from lung, chest wall, and diaphragm segmentations, and parameter changes before versus after operation were correlated with changes in clinical parameters. Paired analysis from Student t test on MRI parameters and clinical parameters was performed to detect if changes (from preoperative to postoperative condition) were statistically significant. Results Left and right lung volumes at end inspiration and end expiration increased substantially after operation in pediatric patients with thoracic insufficiency syndrome, especially right lung volume with 22.9% and 26.3% volume increase at end expiration (P = .001) and end inspiration (P = .002), respectively. The average lung tidal volumes increased after operation for TIS; there was a 43.8% and 55.3% increase for left lung tidal volume and right lung tidal volume (P < .001 for both), respectively. However, clinical parameters did not show significant changes from pre- to posttreatment states. Thoracic and lumbar Cobb angle were poor predictors of MRI tidal volumes (chest wall, diaphragm, and left and right separately), but assisted ventilation rating and forced vital capacity showed moderate correlations with tidal volumes (chest wall, diaphragm, and left and right separately). Conclusion Vertical expandable prosthetic titanium rib operation was associated with postoperative increases in all components of tidal volume (left and right chest wall and diaphragm, and left and right lung tidal volumes) measured at MRI. Clinical parameters did not demonstrate improvements in postoperative tidal volumes. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Paltiel in this issue.

Pulmonary function and clinical correlation in DMD.

Duchenne muscular dystrophy [DMD] is the most common inherited myopathy and is caused by a defect in the dystrophin gene on the X chromosome causing production of a dysfunctional dystrophin protein. Over the last decade there have been advances in disease modifying pharmacotherapy beyond the widely used strategy of corticosteroids into products to impact both dystrophin production itself and also some of the downstream effects of absent of dysfunctional dystrophin. This manuscript will explore the respiratory progression of DMD including some proposed functional and clinical correlations and the overlap between loss of function in different muscle groups. Options for symptomatic treatment and support are presented and direction as to when the different options should be considered is provided. The manuscript will also review the currently available and late phase developmental pharmacotherapies for DMD.

VEPTR: Are We Reducing Respiratory Assistance Requirements?

BACKGROUND: The assisted ventilation rating (AVR) indicates the degree of external respiratory support required in children with thoracic insufficiency syndrome (TIS) and early onset scoliosis. For skeletally immature patients with TIS, the vertical expandable prosthetic titanium rib (VEPTR) device can be used to improve lung volume and growth. We hypothesized that patients who underwent early thoracic reconstruction by VEPTR treatment had an improved respiratory status. METHODS: Preoperative and postoperative AVR ratings were prospectively collected in a multicenter study group and compared to determine change after VEPTR treatment. Patients under 10 years of age at initial implant with minimum of 2-year follow-up data were included. Patients were excluded if there were incomplete data or if initial AVR was normal (breathing on room air). Statistical analysis was performed on groups which had stable, declined, and improved AVR at final follow-up. RESULTS: Database search yielded 77 patients with initial abnormal AVR. Average follow-up was 5.6 years. The most frequent primary diagnoses were congenital scoliosis (n=14) and spinal muscular atrophy (n=14). In total, 19 (24%) demonstrated improvement, 9 (12%) patients deteriorated, and 49 (64%) remained at the same level. The average preoperative major curve in those with improvement (58.4 degrees) and those with no change (63.5 degrees) was less than in those with deterioration (85.5 degrees) (P=0.014). The average age in years at implant of those with improvement (4) was less than those declined (6.7) and those with no change (5.5). In total, 16 (84.2%) of those that improved had a normal AVR and did not require respiratory support at last follow-up. CONCLUSIONS: There is evidence that a subset of patients with early onset scoliosis and TIS who received early thoracic reconstruction with VEPTR treatment show complete resolution of pulmonary support at final follow-up. In total, 89% of 79 patients did not experience respiratory deterioration. A total of 24% (n=19) had a positive change with over 84% (n=16) of this group no longer requiring support. LEVEL OF EVIDENCE: Level III-prognostic.

A comprehensive review of thoracic deformity parameters in scoliosis.

PURPOSE: The combined spine and rib cage deformity in scoliosis is best described as a thoracic deformity, and recent advances in imaging have enabled better definition of three-dimensional (3D) deformity of the thorax in scoliosis. However, a comprehensive report that summarizes the published thorax deformity quantification parameter studies is lacking in the orthopaedic literature. METHODS: An extensive literature review on the quantification of thorax deformity was performed, and a total of 25 thorax deformity parameters were compiled into eight independent categories based on their similarities of deformity assessment. RESULTS: This review serves as the first comprehensive summary of radiographic and CT-based thorax deformity quantification measures. CONCLUSIONS: Future work on the complex relationships between spine and ribcage deformity and the relationship with pulmonary function could help improve clinical interventions for scoliosis treatment.

Auto-segmentation of hemi-diaphragms in free-breathing dynamic MRI of pediatric subjects with thoracic insufficiency syndrome.

Purpose: In respiratory disorders such as thoracic insufficiency syndrome (TIS), the quantitative study of the regional motion of the left hemi-diaphragm (LHD) and right hemi-diaphragm (RHD) can give detailed insights into the distribution and severity of the abnormalities in individual patients. Dynamic magnetic resonance imaging (dMRI) is a preferred imaging modality for capturing dynamic images of respiration since dMRI does not involve ionizing radiation and can be obtained under free-breathing conditions. Using 4D images constructed from dMRI of sagittal locations, diaphragm segmentation is an evident step for the said quantitative analysis of LHD and RHD in these 4D images. Methods: In this paper, we segment the LHD and RHD in three steps: recognition of diaphragm, delineation of diaphragm, and separation of diaphragm along the mid-sagittal plane into LHD and RHD. The challenges involved in dMRI images are low resolution, motion blur, suboptimal contrast resolution, inconsistent meaning of gray-level intensities for the same object across multiple scans, and low signal-to-noise ratio. We have utilized deep learning (DL) concepts such as Path Aggregation Network and Dual Attention Network for the recognition step, Dense-Net and Residual-Net in an enhanced encoder-decoder architecture for the delineation step, and a combination of GoogleNet and Recurrent Neural Network for the identification of the mid-sagittal plane in the separation step. Due to the challenging images of TIS patients attributed to their highly distorted and variable anatomy of the thorax, in such images we localize the diaphragm using the auto-segmentations of the lungs and the thoraco-abdominal skin. Results: We achieved an average±SD mean-Hausdorff distance of ∼3±3 mm for the delineation step and a positional error of ∼3±3 mm in recognizing the mid-sagittal plane in 100 3D test images of TIS patients with a different set of ∼430 3D images of TIS patients utilized for building the models for delineation, and separation. We showed that auto-segmentations of the diaphragm are indistinguishable from segmentations by experts, in images of near-normal subjects. In addition, the algorithmic identification of the mid-sagittal plane is indistinguishable from its identification by experts in images of near-normal subjects. Conclusions: Motivated by applications in surgical planning for disorders such as TIS, we have shown an auto-segmentation set-up for the diaphragm in dMRI images of TIS pediatric subjects. The results are promising, showing that our system can handle the aforesaid challenges. We intend to use the auto-segmentations of the diaphragm to create the initial ground truth (GT) for newly acquired data and then refining them, to expedite the process of creating GT for diaphragm motion analysis, and to test the efficacy of our proposed method to optimize pre-treatment planning and post-operative assessment of patients with TIS and other disorders.

Characterizing Lung Parenchymal Aeration via Standardized Signal Intensity from Free-breathing 4D Dynamic MRI in Phantoms, Healthy Children, and Pediatric Patients with Thoracic Insufficiency Syndrome.

Purpose To investigate free-breathing thoracic bright-blood four-dimensional (4D) dynamic MRI (dMRI) to characterize aeration of parenchymal lung tissue in healthy children and patients with thoracic insufficiency syndrome (TIS). Materials and Methods All dMR images in patients with TIS were collected from July 2009 to June 2017. Standardized signal intensity (sSI) was investigated, first using a lung aeration phantom to establish feasibility and sensitivity and then in a retrospective research study of 40 healthy children (16 male, 24 female; mean age, 9.6 years ± 2.1 [SD]), 20 patients with TIS before and after surgery (11 male, nine female; mean age, 6.2 years ± 4.2), and another 10 healthy children who underwent repeated dMRI examinations (seven male, three female; mean age, 9 years ± 3.6). Individual lungs in 4D dMR images were segmented, and sSI was assessed for each lung at end expiration (EE), at end inspiration (EI), preoperatively, postoperatively, in comparison to normal lungs, and in repeated scans. Results Air content changes of approximately 6% were detectable in phantoms via sSI. sSI within phantoms significantly correlated with air occupation (Pearson correlation coefficient = -0.96 [P < .001]). For healthy children, right lung sSI was significantly lower than that of left lung sSI (at EE: 41 ± 6 vs 47 ± 6 and at EI: 39 ± 6 vs 43 ± 7, respectively; P < .001), lung sSI at EI was significantly lower than that at EE (P < .001), and left lung sSI at EE linearly decreased with age (r = -0.82). Lung sSI at EE and EI decreased after surgery for patients (although not statistically significantly, with P values of sSI before surgery vs sSI after surgery, left and right lung separately, in the range of 0.13-0.51). sSI varied within 1.6%-4.7% between repeated scans. Conclusion This study demonstrates the feasibility of detecting change in sSI in phantoms via bright-blood dMRI when air occupancy changes. The observed reduction in average lung sSI after surgery in pediatric patients with TIS may indicate postoperative improvement in parenchymal aeration. Keywords: MR Imaging, Thorax, Lung, Pediatrics, Thoracic Surgery, Lung Parenchymal Aeration, Free-breathing Dynamic MRI, MRI Intensity Standardization, Thoracic Insufficiency Syndrome Supplemental material is available for this article. © RSNA, 2024.

Quantifying Normal Diaphragmatic Motion and Shape and their Developmental Changes via Dynamic MRI.

Background: The diaphragm is a critical structure in respiratory function, yet in-vivo quantitative description of its motion available in the literature is limited. Research Question: How to quantitatively describe regional hemi-diaphragmatic motion and curvature via free-breathing dynamic magnetic resonance imaging (dMRI)? Study Design and Methods: In this prospective cohort study we gathered dMRI images of 177 normal children and segmented hemi-diaphragm domes in end-inspiration and end-expiration phases of the constructed 4D image. We selected 25 points uniformly located on each 3D hemi-diaphragm surface. Based on the motion and local shape of hemi-diaphragm at these points, we computed the velocities and sagittal and coronal curvatures in 13 regions on each hemi-diaphragm surface and analyzed the change in these properties with age and gender. Results: Our cohort consisted of 94 Females, 6-20 years (12.09 + 3.73), and 83 Males, 6-20 years (11.88 + 3.57). We observed velocity range: ∼2mm/s to ∼13mm/s; Curvature range -Sagittal: ∼3m -1 to ∼27m -1 ; Coronal: ∼6m -1 to ∼20m -1 . There was no significant difference in velocity between genders, although the pattern of change in velocity with age was different for the two groups. Strong correlations in velocity were observed between homologous regions of right and left hemi-diaphragms. There was no significant difference in curvatures between genders or change in curvatures with age. Interpretation: Regional motion/curvature of the 3D diaphragmatic surface can be estimated using free-breathing dynamic MRI. Our analysis sheds light on here-to-fore unknown matters such as how the pediatric 3D hemi-diaphragm motion/shape varies regionally, between right and left hemi-diaphragms, between genders, and with age.

Do Rib-Based Anchors Impair Chest Wall Motion in Early Onset Scoliosis (EOS)?

Purpose: There is a concern in pediatric surgery practice that rib-based fixation may limit chest wall motion in early onset scoliosis (EOS). The purpose of this study is to address the above concern by assessing the contribution of chest wall excursion to respiration before and after surgery. Methods: Quantitative dynamic magnetic resonance imaging (QdMRI) is performed on EOS patients (before and after surgery) and normal children in this retrospective study. QdMRI is purely an image-based approach and allows free breathing image acquisition. Tidal volume parameters for chest walls (CWtv) and hemi-diaphragms (Dtv) were analyzed on concave and convex sides of the spinal curve. EOS patients (1-14 years) and normal children (5-18 years) were enrolled, with an average interval of two years for dMRI acquisition before and after surgery. Results: CWtv significantly increased after surgery in the global comparison including all EOS patients (p < 0.05). For main thoracic curve (MTC) EOS patients, CWtv significantly improved by 50.24% (concave side) and 35.17% (convex side) after age correction (p < 0.05) after surgery. The average ratio of Dtv to CWtv on the convex side in MTC EOS patients was not significantly different from that in normal children (p=0.78), although the concave side showed the difference to be significant. Conclusion: Chest wall component tidal volumes in EOS patients measured via QdMRI did not decrease after rib-based surgery, suggesting that rib-based fixation does not impair chest wall motion in pediatric patients with EOS.

Virtual Growing Child (VGC): A general normative comparative system via quantitative dynamic MRI for quantifying pediatric regional respiratory anomalies with application in thoracic insufficiency syndrome (TIS).

Background: A normative database of regional respiratory structure and function in healthy children does not exist. Methods: VGC provides a database with four categories of regional respiratory measurement parameters including morphological, architectural, dynamic, and developmental. The database has 3,820 3D segmentations (around 100,000 2D slices with segmentations). Age and gender group analysis and comparisons for healthy children were performed using those parameters via two-sided t-testing to compare mean measurements, for left and right sides at end-inspiration (EI) and end-expiration (EE), for different age and gender specific groups. We also apply VGC measurements for comparison with TIS patients via an extrapolation approach to estimate the association between measurement and age via a linear model and to predict measurements for TIS patients. Furthermore, we check the Mahalanobis distance between TIS patients and healthy children of corresponding age. Findings: The difference between male and female groups (10-12 years) behave differently from that in other age groups which is consistent with physiology/natural growth behavior related to adolescence with higher right lung and right diaphragm tidal volumes for females(p<0.05). The comparison of TIS patients before and after surgery show that the right and left components are not symmetrical, and the left side diaphragm height and tidal volume has been significantly improved after surgery (p <0.05). The left lung volume at EE, and left diaphragm height at EI of TIS patients after surgery are closer to the normal children with a significant smaller Mahalanobis distance (MD) after surgery (p<0.05). Interpretation: The VGC system can serve as a reference standard to quantify regional respiratory abnormalities on dMRI in young patients with various respiratory conditions and facilitate treatment planning and response assessment. Funding: The grant R01HL150147 from the National Institutes of Health (PI Udupa).

Assessment of 3D hemi-diaphragmatic motion via free-breathing dynamic MRI in pediatric thoracic insufficiency syndrome.

Purpose: Thoracic insufficiency syndrome (TIS) affects ventilatory function due to spinal and thoracic deformities limiting lung space and diaphragmatic motion. Corrective orthopedic surgery can be used to help normalize skeletal anatomy, restoring lung space and diaphragmatic motion. This study employs free-breathing dynamic MRI (dMRI) and quantifies the 3D motion of each hemi-diaphragm surface in normal and TIS patients, and evaluates effects of surgical intervention. Materials and Methods: In a retrospective study of 149 pediatric patients with TIS and 190 healthy children, we constructed 4D images from free-breathing dMRI and manually delineated the diaphragm at end-expiration (EE) and end-inspiration (EI) time points. We automatically selected 25 points uniformly on each hemi-diaphragm surface, calculated their relative velocities between EE and EI, and derived mean velocities in 13 homologous regions for each hemi-diaphragm to provide measures of regional 3D hemi-diaphragm motion. T-testing was used to compare velocity changes before and after surgery, and to velocities in healthy controls. Results: The posterior-central region of the right hemi-diaphragm exhibited the highest average velocity post-operatively. Posterior regions showed greater velocity changes after surgery in both right and left hemi-diaphragms. Surgical reduction of thoracic Cobb angle displayed a stronger correlation with changes in diaphragm velocity than reduction in lumbar Cobb angle. Following surgery, the anterior regions of the left hemi-diaphragm tended to approach a more normal state. Conclusion: Quantification of regional motion of the 3D diaphragm surface in normal subjects and TIS patients via free-breathing dMRI is feasible. Derived measurements can be assessed in comparison to normal subjects to study TIS and the effects of surgery.

Phase 1 Open-Label Study of Omigapil in Patients With LAMA2- or COL6-Related Dystrophy.

Background and Objectives: Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy subtypes LAMA2-related dystrophy (LAMA2-RD) and COL6-related dystrophy (COL6-RD). Studies of omigapil in the (dyw/dyw) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy2J/dy2J) LAMA2-RD mouse model and the (Col6a1-/-) COL6-RD mouse model demonstrated decreased apoptosis. Methods: A phase 1 open-label, sequential group, ascending oral dose, cohort study of omigapil in patients with LAMA2-RD or COL6-RD ages 5-16 years was performed (1) to establish the pharmacokinetic (PK) profile of omigapil at a range of doses, (2) to evaluate the safety and tolerability of omigapil at a range of doses, and (3) to establish the feasibility of conducting disease-relevant clinical assessments. Patients were enrolled in cohorts of size 4, with each patient receiving 4 weeks of vehicle run-in and 12 weeks of study drug (at daily doses ranging from 0.02 to 0.08 mg/kg). PK data from each cohort were analyzed before each subsequent dosing cohort was enrolled. A novel, adaptive dose-finding method (stochastic approximation with virtual observation recursion) was used to allow for dose escalation/reduction between cohorts based on PK data. Results: Twenty patients were enrolled at the NIH (LAMA2-RD: N = 10; COL6-RD: N = 10). Slightly greater than dose-proportional increases in systemic exposure to omigapil were seen at doses 0.02-0.08 mg/kg/d. The dose which achieved patient exposure within the pre-established target area under the plasma concentration-vs-time curve (AUC0-24h) range was 0.06 mg/kg/d. In general, omigapil was safe and well tolerated. No consistent changes were seen in the disease-relevant clinical assessments during the duration of the study. Discussion: This study represents the thus far only clinical trial of a therapeutic small molecule for LAMA2-RD and COL6-RD, completed with an adaptive trial design to arrive at dose adjustments. The trial met its primary end point and established that the PK profile of omigapil is suitable for further development in pediatric patients with LAMA2-RD or COL6-RD, the most common forms of congenital muscular dystrophy. While within the short duration of the study disease-relevant clinical assessments did not demonstrate significant changes, this study establishes the feasibility of performing interventional clinical trials in these rare disease patient populations. Classification of Evidence: This study provides Class IV evidence of omigapil in a dose-finding phase 1 study. Trial Registration Information: Clinical Trials NCT01805024.

Year in review 2021: Neuromuscular diseases.

In this years' review of neuromuscular respiratory medicine, there were a series of articles on home mechanical ventilation, real-world studies assessing the impact of nusinersen, and studies describing upper airway dysfunction. Beyond this, we highlight two excellent reviews regarding cardiac dysfunction in neuromuscular diseases.

Assessment of Regional Functional Effects of Surgical Treatment in Thoracic Insufficiency Syndrome via Dynamic Magnetic Resonance Imaging.

BACKGROUND: Quantitative regional assessment of thoracic function would enable clinicians to better understand the regional effects of therapy and the degree of deviation from normality in patients with thoracic insufficiency syndrome (TIS). The purpose of this study was to determine the regional functional effects of surgical treatment in TIS via quantitative dynamic magnetic resonance imaging (MRI) in comparison with healthy children. METHODS: Volumetric parameters were derived via 129 dynamic MRI scans from 51 normal children (November 2017 to March 2019) and 39 patients with TIS (preoperatively and postoperatively, July 2009 to May 2018) for the left and right lungs, the left and right hemi-diaphragms, and the left and right hemi-chest walls during tidal breathing. Paired t testing was performed to compare the parameters from patients with TIS preoperatively and postoperatively. Mahalanobis distances between parameters of patients with TIS and age-matched normal children were assessed to evaluate the closeness of patient lung function to normality. Linear regression functions were utilized to estimate volume deviations of patients with TIS from normality, taking into account the growth of the subjects. RESULTS: The mean Mahalanobis distances for the right hemi-diaphragm tidal volume (RDtv) were -1.32 ± 1.04 preoperatively and -0.05 ± 1.11 postoperatively (p = 0.001). Similarly, the mean Mahalanobis distances for the right lung tidal volume (RLtv) were -1.12 ± 1.04 preoperatively and -0.10 ± 1.26 postoperatively (p = 0.01). The mean Mahalanobis distances for the ratio of bilateral hemi-diaphragm tidal volume to bilateral lung tidal volume (BDtv/BLtv) were -1.68 ± 1.21 preoperatively and -0.04 ± 1.10 postoperatively (p = 0.003). Mahalanobis distances decreased after treatment, suggesting reduced deviations from normality. Regression results showed that all volumes and tidal volumes significantly increased after treatment (p < 0.001), and the tidal volume increases were significantly greater than those expected from normal growth for RDtv, RLtv, BDtv, and BLtv (p < 0.05). CONCLUSIONS: Postoperative tidal volumes of bilateral lungs and bilateral hemi-diaphragms of patients with TIS came closer to those of normal children, indicating positive treatment effects from the surgical procedure. Quantitative dynamic MRI facilitates the assessment of regional effects of a surgical procedure to treat TIS. LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Functional and Clinical Outcomes Associated with Steroid Treatment among Non-ambulatory Patients with Duchenne Muscular Dystrophy1.

BACKGROUND: Evidence on the long-term efficacy of steroids in Duchenne muscular dystrophy (DMD) after loss of ambulation is limited. OBJECTIVE: Characterize and compare disease progression by steroid treatment (prednisone, deflazacort, or no steroids) among non-ambulatory boys with DMD. METHODS: Disease progression was measured by functional status (Performance of Upper Limb Module for DMD 1.2 [PUL] and Egen Klassifikation Scale Version 2 [EK] scale) and by cardiac and pulmonary function (left ventricular ejection fraction [LVEF], forced vital capacity [FVC] % -predicted, cough peak flow [CPF]). Longitudinal changes in outcomes, progression to key disease milestones, and dosing and body composition metrics were analyzed descriptively and in multivariate models. RESULTS: This longitudinal cohort study included 86 non-ambulatory patients with DMD (mean age 13.4 years; n = 40 [deflazacort], n = 29 [prednisone], n = 17 [no steroids]). Deflazacort use resulted in slower average declines in FVC % -predicted vs. no steroids (+3.73 percentage points/year, p < 0.05). Both steroids were associated with significantly slower average declines in LVEF, improvement in CPF, and slower declines in total PUL score and EK total score vs. no steroids; deflazacort was associated with slower declines in total PUL score vs. prednisone (all p < 0.05). Both steroids also preserved functional abilities considered especially important to quality of life, including the abilities to perform hand-to-mouth function and to turn in bed at night unaided (all p < 0.05 vs. no steroids). CONCLUSIONS: Steroid use after loss of ambulation in DMD was associated with delayed progression of important pulmonary, cardiac, and upper extremity functional deficits, suggesting some benefits of deflazacort over prednisone.

Does ventilator use status correlate with quality of life in patients with early-onset scoliosis treated with rib-based growing system implantation?

PURPOSE: Pulmonary function and quality of life (QOL) are important outcome measures for patients with early-onset scoliosis (EOS) undergoing rib-based growing system (RBGS) implantation. The Assisted Ventilation Rating (AVR) measures ventilator requirements in this population. A higher, more severe, score implies negative changes in QOL. The EOS Questionnaire (EOSQ) is a validated outcome measure. Paired measurements for both ratings were compared to clarify correlation between ventilator status and QOL. Secondary analysis aimed at defining QOL between more broad subgroups defined by ventilator use. METHODS: AVR and EOSQ scores were extracted from the Pediatric Spine Study Group database for patients 10 years of age and under. Instances were excluded if the time between AVR and EOSQ assessment was greater than 6 months. Scores were compared using Spearman correlation coefficient. Subgroup analysis included control for age, gender, and etiology. Secondary analysis was performed for broad functional grouping using ranked analysis of variance for repeated measures using median scores. RESULTS: Two thousand five hundred and forty-two instances of paired EOSQ and AVR in 329 patients were analyzed. A statistically significant weak correlation between AVR and EOSQ was identified in Child's Health Related QOL and Family Impact sections, in nine subsets. Subgroup analysis showed little variation, except increased correlation in female patients to near moderate level. Analysis of variance for demonstrated decreased medians for all subdomains when comparing those mechanically ventilated to patients who did not require ventilation. CONCLUSION: Ventilator status tracks with QOL were measured by EOSQ. A more severe AVR is negatively correlated with most domains of the EOSQ for patients with EOS who have undergone RBGS implantation. The strength of this correlation is weak, and so AVR alone may be insufficient to precisely determine QOL in this population. LEVEL OF EVIDENCE: Level-III, Retrospective.