Scoliosis Development in Spinal Muscular Atrophy: The Influences of Genetic Severity, Functional Level, and Disease-Modifying Treatments.

BACKGROUND: Spinal muscular atrophy (SMA) is caused by abnormalities of the survival motor neuron (SMN) 1 gene, leading to deficiency in SMN protein and loss of spinal cord alpha motor neurons. Newer disease-modifying agents (DMA) targeting the involved genes, including nusinersen and gene replacement therapies, have improved gross motor and respiratory function, but their impact on scoliosis development has not been established. This study aimed to determine risk factors for scoliosis development in SMA, specifically genetic severity and DMA use. METHODS: In this retrospective cohort study, children with SMA and minimum 2-year follow-up were included. The primary outcome was the prevalence of clinically relevant scoliosis. Secondary outcomes included SMA type, SMN2 copy number, Hammersmith Functional Motor Scale (HFMS), ambulatory status [functional mobility scale at 50m (FMS50)], DMA use, and hip displacement as risk factors. Univariate/multivariate logistic regression analyses were performed to identify dependent/independent risk factors. RESULTS: One hundred sixty-five patients (51% female) with SMA types I-III met the inclusion criteria, with total follow-up of 9.8 years. The prevalence of scoliosis was 79%; age of onset 7.9 years. The major curve angle for the entire cohort at first assessment and final follow-up was 37 degrees (SD: 27 degrees) and 62 degrees (SD: 31 degrees) (P<0.0001), respectively. Significant risk factors for scoliosis by univariate analysis were SMA type (I/II, P=0.02), HFMS (>23, P<0.001), nonambulatory status (FMS50=1, P<0.0001), DMA treatment (P=0.02), and hip displacement (P<0.0001). Multivariate analysis revealed that HFMS >23 (P=0.02) and DMA (P=0.05) treatment were independent (protective) risk factors. CONCLUSIONS: The development of scoliosis in SMA is high, with risk factors associated with proxy measures of disease severity, including SMA type, nonambulatory status, hip displacement, and most notably, gross motor function (by HFMS). DMA use and HFMS >23 were associated with a decreased risk of scoliosis development. Identified risk factors can be used in the development of surveillance programs for early detection of scoliosis in SMA. LEVEL OF EVIDENCE: Level III.

No difference in postoperative complication rates or cardiopulmonary function for early versus late scoliosis correction in Duchenne muscular dystrophy.

BACKGROUND: Given reduced rates of both pulmonary function decline and scoliosis progression with steroid treatment in Duchenne muscular dystrophy (DMD), the role of early scoliosis surgery has been questioned. The purpose of this study was to compare the postoperative complication rates of early versus late scoliosis correction in DMD. METHODS: This study was a retrospective cohort, conducted at an academic tertiary level children's hospital. Patients with DMD who underwent posterior scoliosis correction, with preoperative pulmonary function testing [forced vital capacity (FVC)] were included and divided into two groups by preoperative curve angles: ≤ 45° and > 45°. The primary outcome variable was postoperative complications by Clavien-Dindo classification grading. Secondary outcome variables included postoperative complications occurring after the first 90 days, age at surgery, duration of wheelchair dependency preoperatively, pulmonary function, steroid utilization, shortening fraction by echocardiogram, surgery duration, intensive care unit/hospital length of stay, days intubated, infection, and percent curve correction. Two-tailed t-test and Chi-square testing were used for analysis of patient factors and Clavien-Dindo complication grade, respectively. RESULTS: Thirty-one patients were included with a total follow-up of 8.3 ± 3.2 years, 4.8 ± 2.2 years post-spinal fusion. Steroid treatment (prednisone, deflazacort) was utilized for 21 (67.7%) patients. Primary curve correction was not different between groups (65.0% vs 71.4% [p = 0.37]). There were no significant differences in Clavien-Dindo classification grades between groups (p > 0.05). For the entire cohort, the overall complication rate was higher for patients with steroid treatment (61.9% vs 10.0% [p = 0.008]). Neither forced vital capacity nor fractional shortening on echocardiogram was different between groups at final follow-up (p = 0.6 and p = 0.4, respectively). CONCLUSION: The comparable risk of perioperative complications for early and late scoliosis correction supports a "watchful waiting" approach, whereby curves less than 45° can be carefully followed while cardiopulmonary function is maintained. Patients undergoing steroid treatment should be counseled regarding the higher risk of postoperative blood transfusion and deep wound infection. LEVEL OF EVIDENCE: III Retrospective cohort.

Machine learning for automatic identification of thoracoabdominal asynchrony in children.

BACKGROUND: The current methods for assessment of thoracoabdominal asynchrony (TAA) require offline analysis on the part of physicians (respiratory inductance plethysmography (RIP)) or require experts for interpretation of the data (sleep apnea detection). METHODS: To assess synchrony between the thorax and abdomen, the movements of the two compartments during quiet breathing were measured using pneuRIP. Fifty-one recordings were obtained: 20 were used to train a machine-learning (ML) model with elastic-net regularization, and 31 were used to test the model's performance. Two feature sets were explored: (1) phase difference (ɸ) between the thoracic and abdominal signals and (2) inverse cumulative percentage (ICP), which is an alternate measure of data distribution. To compute accuracy of training, the model outcomes were compared with five experts' assessments. RESULTS: Accuracies of 61.3% and 90.3% were obtained using ɸ and ICP features, respectively. The inter-rater reliability (i.r.r.) of the assessments of experts was 0.402 and 0.684 when they used ɸ and ICP to identify TAA, respectively. CONCLUSIONS: With this pilot study, we show the efficacy of the ICP feature and ML in developing an accurate automated approach to identifying TAA that reduces time and effort for diagnosis. ICP also helped improve consensus among experts. IMPACT: Our article presents an automated approach to identifying thoracic abdominal asynchrony using machine learning and the pneuRIP device. It also shows how a modified statistical measure of cumulative frequency can be used to visualize the progression of the pulmonary functionality along time. The pulmonary testing method we developed gives patients and doctors a noninvasive and easy to administer and diagnose approach. It can be administered remotely, and alerts can be transmitted to the physician. Further, the test can also be used to monitor and assess pulmonary function continuously for prolonged periods, if needed.

Diagnostic differences in respiratory breathing patterns and work of breathing indices in children with Duchenne muscular dystrophy.

RATIONALE: Pulmonary function testing (PFT) provides diagnostic information regarding respiratory physiology. However, many forms of PFT are time-intensive and require patient cooperation. Respiratory inductance plethysmography (RIP) provides thoracoabdominal asynchrony (TAA) and work of breathing (WOB) data. pneuRIPTM is a noninvasive, wireless analyzer that provides real-time assessment of RIP via an iPad. In this study, we show that pneuRIPTM can be used in a hospital clinic setting to differentiate WOB indices and breathing patterns in children with DMD as compared to age-matched healthy subjects. METHODS: RIP using the pneuRIPTM was conducted on 9 healthy volunteers and 7 DMD participants (ages 5-18) recruited from the neuromuscular clinic, under normal resting conditions over 3-5 min during routine outpatient visits. The tests were completed in less than 10 minutes and did not add excessive time to the clinic visit. Variables recorded included labored-breathing index (LBI), phase angle (Φ) between abdomen and rib cage, respiratory rate (RR), percentage of rib cage input (RC%), and heart rate (HR). The data were displayed in histogram plots to identify distribution patterns within the normal ranges. The percentages of data within the ranges (0≤ Φ ≤30 deg.; median RC %±10%; median RR±5%; 1≤LBI≤1.1) were compared. Unpaired t-tests determined significance of the data between groups. RESULTS: 100% patient compliance demonstrates the feasibility of such testing in clinical settings. DMD patients showed a significant elevation in Φ, LBI, and HR averages (P<0.006, P<0.002, P<0.046, respectively). Healthy subjects and DMD patients had similar BPM and RC% averages. All DMD data distributions were statistically different from healthy subjects based on analysis of histograms. The DMD patients showed significantly less data within the normal ranges, with only 49.7% Φ, 48.0% RC%, 69.2% RR, and 50.7% LBI. CONCLUSION: In this study, noninvasive pneuRIPTM testing provided instantaneous PFT diagnostic results. As compared to healthy subjects, patients with DMD showed abnormal results with increased markers of TAA, WOB indices, and different breathing patterns. These results are similar to previous studies evaluating RIP in preterm infants. Further studies are needed to compare these results to other pulmonary testing methods. The pneuRIPTM testing approach provides immediate diagnostic information in outpatient settings.

Measures of respiratory inductance plethysmography (RIP) in children with neuromuscular disease.

BACKGROUND: Pulmonary function testing (PFT) is essential for the clinical assessment of respiratory problems. Respiratory inductance plethysmography (RIP) is a non-invasive method of PFT requiring minimal patient cooperation. RIP measures the volumetric change in the ribcage and abdomen, from which work of breathing (WOB) indices are derived. WOB indices include: phase angle (Ф), percent ribcage (RC%), respiratory rate (RR), and labored breathing index (LBI). Heart rate (HR) is collected separately. AIM: The goal of this study was to assess the utility of a newly developed RIP system, the pneuRIP, in an outpatient clinic setting in children with neuromuscular (NM) disease. METHOD: The pneuRIP system measures and displays the WOB indices in real-time on an iPad display. Forty-three subjects, 22 NM patients and 21 healthy children (ages: 5-18 years) were enrolled. RESULTS: Patients' means showed an increase of 119.8% for Ф, 15.7% for LBI, and 19.9% for HR compared with healthy subjects, when adjusted for age and gender. The study found significant differences between the mean values of the healthy subjects and patients in Ф (P = 0.000), LBI (P = 0.001), and HR (P = 0.001). No differences were noted for RC% and RR between groups. Data for Ф in NM patients were diffusely distributed as compared with healthy subjects based on analysis of histograms. CONCLUSION: Non-invasive pneuRIP testing provided instantaneous PFT results. As compared to healthy subjects, NM patients showed abnormal results with increased markers of thoracoabdominal asynchrony, WOB indices, and biphasic breathing patterns likely resulting from NM weakness.

Quantitative Analysis of Thoracoabdominal Asynchrony in Pediatric Polysomnography.

STUDY OBJECTIVES: Objective measurements of thoracoabdominal asynchrony (TAA), such as average phase angle (θavg), can quantify airway obstruction. This study demonstrates and evaluates use of θavg for predicting obstructive sleep apnea (OSA) in pediatric polysomnography (PSG). METHODS: This prospective observational study recruited otherwise healthy 3- to 8-year-old children presenting for PSG due to snoring, behavioral problems, difficulty sleeping, and/or enlarged tonsils. Respiratory inductance plethysmography (RIP) was directly monitored and data were collected during each PSG. θavg and average labored breathing index (LBIavg) were calculated for earliest acceptable 5-minute periods of stage N3 sleep and stage R sleep. Associations between θavg and obstructive apnea index (OAI) and obstructive apnea-hypopnea index (OAHI), as well as between LBIavg and OAI and OAHI, were examined. RESULTS: Forty patients undergoing PSG were analyzed. Thirty percent of patients had OSA, 57.5% had enlarged tonsils, and 17.5% were obese. θavg during stage N3 sleep and stage R sleep had significant positive correlations with OAI (Spearman r = .35 [P = .03] and .40 [P = .01], respectively) and θavg during stage N3 sleep with OAHI (r = .35 [P = .03]). LBIavg showed lower correlations. Median θavg during stage R sleep (33.1) was significantly greater than during stage N3 sleep (13.7, P = .0005). CONCLUSIONS: Association of θavg with OAI and OAHI shows that θavg reflects airway obstruction and has potential use as a quantitative indicator of OSA. RIP provides valuable information that is readily available in PSG. The significant difference between θavg in stage N3 sleep and stage R sleep confirms the clinical observation that there is more asynchrony during rapid eye movement sleep than non-rapid eye movement sleep.

Critical Airway Stenosis in an Adolescent Male With Pompe Disease and Thoracic Lordosis: A Case Report.

An adolescent male with late-onset Pompe disease (glycogen storage disease type II) presented with a history of restrictive airway disease and a near-cardiorespiratory arrest during anesthesia for a liver biopsy initially thought to be due to bronchospasm. During a subsequent posterior spinal fusion procedure, he suffered cardiorespiratory arrest resulting in the procedure being aborted. Bronchoscopy performed shortly after resuscitation revealed an undiagnosed narrowing of the distal trachea and bronchi. This is the first description of a patient with late-onset Pompe disease with undiagnosed critical tracheal stenosis due to the progression of thoracic lordosis, which was ultimately relieved by posterior spinal fusion.

Effectiveness of Powered Intracapsular Tonsillectomy in Children With Severe Obstructive Sleep Apnea.

IMPORTANCE: Powered intracapsular tonsillectomy and adenoidectomy (PITA) is an increasingly common pediatric procedure. Few studies have examined its effectiveness in children with severe obstructive sleep apnea (OSA). OBJECTIVE: To assess the effectiveness of PITA in patients with severe OSA as evidenced by change in polysomnographic parameters. DESIGN, SETTING, AND PARTICIPANTS: We performed a case series study with medical record review of 70 children with severe OSA who underwent PITA at a tertiary care pediatric hospital from January 1, 2010, through December 31, 2014. MAIN OUTCOMES AND MEASURES: Preoperative and postoperative polysomnographic parameters. RESULTS: Of the 70 children with severe OSA who underwent PITA, 39 (56%) were boys, and the median age at surgery was 3.7 years. There were significant mean (SD) decreases in the postoperative apnea-hypopnea index (32.4 [28.4] vs 5.8 [9.7], P < .001), obstructive apnea index (20.4 [17.97] vs 2.55 [5.9]), obstructive apnea-hypopnea index (25.5 [22.4] vs 3.9 [7.3], P < .001), arousal index (53.7 [33.9] vs 27.4 [22.6], P < .001), percentage of total sleep time spent snoring (28.6 [30.5] vs 13.6 [20.8], P = .001), and oxygen desaturation index of 4% or more (22.9 [26.4] vs 4.5 [9.9], P < .001). Mean (SD) oxygen saturation (96.8 [2.0] vs 98.2 [1.3], P < .001) and oxygen saturation nadir (75.5 [13.1] vs 88.4 [8.1], P < .001) increased significantly. A significant decrease in time was observed with an end-tidal carbon dioxide greater than 55 mm Hg (49.67 [97.5] vs 19.1 [73.9] minutes, P = .01). CONCLUSIONS AND RELEVANCE: Powered intracapsular tonsillectomy and adenoidectomy improved OSA in this series of pediatric patients by reducing obstructive apneas and hypopneas, oxygen desaturation, arousal index, carbon dioxide level, and snoring, as well as increasing oxygen saturation nadir. Results are comparable to those described for traditional electrocautery tonsillectomy and support the use of PITA for the treatment of severe OSA in children with adenotonsillar hypertrophy.

Diagnostic criteria for sarcoidosis.

Sarcoidosis is a multiorgan system disease that often presents insidiously. The diagnosis is often made fortuitously upon routine chest radiography or that done for other reasons. Blacks are more commonly affected than whites and age of onset is typically adolescents to young adults. Lung involvement is common and symptoms may include cough, dyspnea and chest pain. Extrapulmonary symptoms may include the skin, joint and eye findings. Bilateral hilar adenopathy is the classic finding on chest radiograph. Anemia or other cell line deficiencies, elevated liver enzymes, hypercalciuria, and EKG abnormalities may also be present. Angiotensin converting enzyme levels may be elevated but are not diagnostic. Histopathological confirmation of noncaseating granulomas is essential for diagnosis. It is generally performed through a biopsy of the most peripheral site possible, although transbronchial biopsy is commonly required. Finally, other possible etiologies must be evaluated and differentiated with a particular emphasis on tuberculosis due to the multiple overlapping symptoms and findings. Newer techniques such as proteomics and transcriptional gene signatures may contribute to the understanding of the pathophysiology of sarcoidosis, and may even serve as diagnostic tools in the future.

Achondroplasia-hypochondroplasia complex and abnormal pulmonary anatomy.

Achondroplasia and hypochondroplasia are two of the most common forms of skeletal dysplasia. They are both caused by activating mutations in FGFR3 and are inherited in an autosomal dominant manner. Our patient was born to parents with presumed achondroplasia, and found on prenatal testing to have p.G380R and p.N540K FGFR3 mutations. In addition to having typical problems associated with both achondroplasia and hypochondroplasia, our patient had several atypical findings including: abnormal lobulation of the lungs with respiratory insufficiency, C1 stenosis, and hypoglycemia following a Nissen fundoplication. After his reflux and aspiration were treated, the persistence of the tachypnea and increased respiratory effort indicated this was not the primary source of the respiratory distress. Our subsequent hypothesis was that primary restrictive lung disease was the cause of his respiratory distress. A closer examination of his chest circumference did not support this conclusion either. Following his death, an autopsy found the right lung had 2 lobes while the left lung had 3 lobes. A literature review demonstrates that other children with achondroplasia-hypochondroplasia complex have been described with abnormal pulmonary function and infants with thanatophoric dysplasia have similar abnormal pulmonary anatomy. We hypothesize that there may be a primary pulmonary phenotype associated with FGFR3-opathies, unrelated to chest size which leads to the consistent finding of increased respiratory signs and symptoms in these children. Further observation of respiratory status, combined with the macroscopic and microscopic analysis of pulmonary branching anatomy and alveolar structure in this patient population will be important to explore this hypothesis.