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.

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.

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.

Therapeutic Role of Nusinersen on Respiratory Progression in Pediatric Patients With Spinal Muscular Atrophy Type 2 and Nonambulant Type 3.

Background and Objectives: Nusinersen has shown significant functional motor benefit in the milder types of spinal muscular atrophy (SMA). Less is known on the respiratory outcomes in patients with nusinersen-treated SMA. The aim of this study was to describe changes in respiratory function in pediatric patients with SMA type 2 and 3 on regular treatment with nusinersen within the iSMAc international cohort and to compare their trajectory with the natural history (NH) data published by the consortium in 2020. Methods: This is a 5-year retrospective observational study of pediatric SMA type 2 and nonambulant type 3 (age ≤18 years) treated with nusinersen. The primary objective was to compare the slopes of decline in forced vital capacity % predicted (FVC% pred.), FVC, and age when FVC dropped below 60% between the treated patients and a control group from the natural history cohort. Data on peak cough flow and the use of noninvasive ventilation (NIV) and cough assist were collected. Results: Data were available for 69 treated patients, 53 were SMA type 2 and 16 type 3. The mean (SD) age at first injection was 8.5 (3.2) and 9.7 (3.7) years, respectively. The median (interquartile range) treatment duration was 1 (0.7; 1.9) and 1.2 (0.9; 1.9) years, respectively. At the time of the first nusinersen injection, 24 of 52 (46%) patients with SMA type 2 and 2 of 16 (13%) patients with SMA type 3 were on NIV. Forty-three of 53 (81%) and 4 of 16 (25%) patients used cough device. FVC% pred. in treated patients with SMA type 2 declined annually by 2.3% vs 3.9% in NH (p = 0.08) and in treated patients with type 3 by 2.6% vs 3.4% NH (p = 0.59). Patients treated reached FVC <60% later than untreated (12.1 vs 10 years, p = 0.05). A higher percentage of treated vs untreated patients maintained FVC% pred. equal/above their baseline after 12 (65% vs 36%) and 24 (50% vs 24%) months, respectively. NIV use among treated did not significantly change throughout 1-year follow-up. Discussion: This study included the largest real-world cohort of pediatric patients with milder SMA types. The results suggest a positive role of nusinersen in delaying the respiratory decline in patients treated longer than 1 year when compared with natural history. Larger cohorts and longer observation are planned. Classification of Evidence: This study provided Class III evidence that nusinersen slows progression for patients with SMA types 2 and 3 compared with a natural history cohort.