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Background: Nonalcoholic steatohepatitis (NASH) is an important etiology of hepatocellular carcinoma (HCC), and there is no established therapy for this syndrome. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumor (ROHHAD(NET)) is an extremely rare syndrome considered to be life-threatening, with death occurring around 10 years of age. We present the oldest known autopsy case of this syndrome that developed HCC. This case provided important information on not only improving the course of this syndrome, but also understanding the natural history and therapeutic modalities of NASH and HCC., Methods: The patient was diagnosed with ROHHAD(NET) syndrome in childhood, and liver cirrhosis due to NASH was diagnosed at age 17. HCC was detected at age 20, and embolization and irradiation were performed. At age 21, she died from accidental acute pancreatitis and subsequent liver failure and pulmonary hemorrhage., Results: Rapid onset of obesity, hypoventilation, and hypothalamic disturbance appeared in childhood and was diagnosed as this syndrome. At age 17, liver cirrhosis due to NASH was diagnosed by liver biopsy, and at age 20, HCC was diagnosed by imaging. Transarterial chemoembolization and irradiation were performed, and the HCC was well controlled for a year., Conclusion: At age 21, she died from accidental acute pancreatitis, subsequent liver failure and pulmonary hemorrhage. Autopsy revealed that the HCC was mostly necrotized. This case was valuable not only for other ROHHAD(NET) syndrome cases, but also in improving our understanding of the natural history of NASH and HCC., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Chiari type 1 malformation (CM1) may occasionally lead to central sleep apnea (CSA). We studied, in a large clinical cohort of pediatric CM1 patients, the effect of CM1 on breathing during sleep., Methods: This is a retrospective single pediatric pulmonology center study with a systematic evaluation of pediatric CM1 patients under age 18 with polysomnography (PSG) during 2008-2020. Children with syndromes were excluded. All patients had undergone head and spine magnetic resonance imaging., Results: We included 104 children with CM1 with a median age of 7 (interquartile range (IQR) 5-13) years. The median extent of tonsillar descent (TD) was 13 (IQR 10-18) mm. Syringomyelia was present in 19 children (18%). Of all children, 53 (51%) had normal PSG, 35 (34%) showed periodic breathing or central apnea and hypopnea index ≥5 h -1 , and 16 (15%) displayed features of compensated central hypoventilation and end-tidal or transcutaneous carbon dioxide 99 th percentile level above 50 mmHg. TD had the best predictive value for central breathing disorders. In a linear model, both age (61%) and TD (39%) predicted median breathing frequency (R = 0.33, p < 0.001)., Conclusions: Although severe CSA is a rare complication of brainstem compression in pediatric patients with CM1, short arousal-triggered episodes of periodic breathing and mild compensated central hypoventilation are common. TD shows the best but still poor prediction of the presence of a central breathing disorder. This highlights the use of PSG in patient evaluation. Posterior fossa decompression surgery effectively treats central breathing disorders., Competing Interests: Declaration of competing interest The authors have no conflicting of interest relevant to this article to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Few data on alveolar hypoventilation in Prader-Willi syndrome (PWS) are available and the respiratory follow-up of these patients is not standardized. The objectives of this study were to evaluate the prevalence of alveolar hypoventilation in children with PWS and identify potential risk factors., Study Design: This retrospective study included children with PWS recorded by polysomnography (PSG) with transcutaneous carbon dioxide pressure (PtcCO2) or end-tidal CO2 (ETCO2) measurements, between 2007 and 2021, in a tertiary hospital center. The primary outcome was the presence of alveolar hypoventilation defined as partial pressure of carbon dioxide (pCO2) ≥ 50 mmHg during ≥2% of total sleep time (TST) or more than five consecutive minutes., Results: Among the 57 included children (38 boys, median age 4.8 years, range 0.1-15.6, 60% treated with growth hormone [GH], 37% obese), 19 (33%) had moderate-to-severe obstructive sleep apnea syndrome (defined as obstructive apnea-hypopnea index ≥5/h) and 20 (35%) had hypoventilation. The median (range) pCO2 max was 49 mmHg (38-69). Among the children with hypoventilation, 25% were asymptomatic. Median age and GH treatment were significantly higher in children with hypoventilation compared to those without. There was no significant difference in terms of sex, BMI, obstructive or central apnea-hypopnea index between both groups., Conclusion: The frequency of alveolar hypoventilation in children and adolescents with PWS is of concern and may increase with age and GH treatment. A regular screening by oximetry-capnography appears to be indicated whatever the sex, BMI, and rate of obstructive or central apneas., (© 2024 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Autism spectrum disorder is a neurodevelopmental condition that involves limitations in social communication and various stereotypical repetitive behaviors. Genetic and environmental factors both play a role in the etiology. Numerous genetic syndromes accompanying autism spectrum disorders have been reported. Hypoventilation, hypotonia, intellectual disability, epilepsy, eye abnormality (HIDEA) syndrome is a rare genetic condition consisting of a combination of features such as hypoventilation, hypotonia, intellectual disability, eye abnormalities, and epilepsy. Very few cases of HIDEA syndrome have been reported in the literature to date. To the best of our knowledge, no cases of comorbid autism spectrum disorder and HIDEA syndrome have previously been reported. This report describes two brothers with a pathogenic P4HTM gene variant and autism spectrum disorder. One was diagnosed with HIDEA syndrome, while the other was a healthy carrier., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cerebral hypoxia is a frequent cause of secondary brain damage in patients with acute brain injury. Although hypercapnia can increase intracranial pressure, it may have beneficial effects on tissue oxygenation. We aimed to assess the effects of hypercapnia on brain tissue oxygenation (PbtO 2 )., Methods: This single-center retrospective study (November 2014 to June 2022) included all patients admitted to the intensive care unit after acute brain injury who required multimodal monitoring, including PbtO 2 monitoring, and who underwent induced moderate hypoventilation and hypercapnia according to the decision of the treating physician. Patients with imminent brain death were excluded. Responders to hypercapnia were defined as those with an increase of at least 20% in PbtO 2 values when compared to their baseline levels., Results: On a total of 163 eligible patients, we identified 23 (14%) patients who underwent moderate hypoventilation (arterial partial pressure of carbon dioxide [PaCO 2 ] from 44 [42-45] to 50 [49-53] mm Hg; p < 0.001) during the study period at a median of 6 (4-10) days following intensive care unit admission; six patients had traumatic brain injury, and 17 had subarachnoid hemorrhage. A significant overall increase in median PbtO 2 values from baseline (21 [19-26] to 24 [22-26] mm Hg; p = 0.02) was observed. Eight (35%) patients were considered as responders, with a median increase of 7 (from 4 to 11) mm Hg of PbtO 2 , whereas nonresponders showed no changes (from - 1 to 2 mm Hg of PbtO 2 ). Because of the small sample size, no variable independently associated with PbtO 2 response was identified. No correlation between changes in PaCO 2 and in PbtO 2 was observed., Conclusions: In this study, a heterogeneous response of PbtO 2 to induced hypercapnia was observed but without any deleterious elevations of intracranial pressure., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Congenital central hypoventilation syndrome (CCHS), a rare disease caused by paired-like homeobox 2B variants, affects control of breathing. We report on a 21-month-old boy with CCHS caused by a novel nonpolyalanine repeat mutation, neuroblastoma, severe obstructive and central sleep apnea, and sleep-related hypoxemia without hypoventilation. At 10 months, due to persistent central sleep apnea during serial polysomnography, bilevel positive airway pressure therapy was initiated despite the absence of hypoventilation. Nonpolyalanine repeat mutations are associated with severe phenotypes requiring continuous assisted ventilation, Hirschsprung's disease, and neural crest tumors; however, our patient had a relatively milder respiratory phenotype requiring sleep-only assisted ventilation without tracheostomy. Although alveolar hypoventilation is the hallmark of CCHS, our patient lacked hypoventilation. Bilevel positive airway pressure could be considered in some infants with CCHS requiring sleep-only assisted ventilation for tracheostomy avoidance. Our case demonstrates the expanding phenotypic spectrum in CCHS and the importance of formulating an individualized care plan., Citation: Fain ME, Raghunandan S, Pencheva B, Leu RM, Kasi AS. Images: atypical presentation of congenital central hypoventilation syndrome in an infant with central and obstructive sleep apnea. J Clin Sleep Med . 2024;20(3):478-481., (© 2024 American Academy of Sleep Medicine.)

Background: The high prevalence of obstructive sleep apnea syndrome (OSAS) in children with Down syndrome (DS) has been attributed to a reduced upper airway size, while the role of ventilatory control is unclear. The objectives of our case-control study were to evaluate the upper airway reduction in children with DS and moderate to severe OSAS as compared to typically developing (TD) children with similar OSAS severity and to evaluate the degree of chemical loop gain modifications including its components: controller and plant gains (CG, PG)., Methods: Thirteen children with DS were matched for age, sex, OSAS severity and ethnicity with 26 TD children. They had undergone acoustic rhinometry and pharyngometry, chemical LG obtained during awake tidal breathing measurement and hypercapnic-hyperoxic ventilatory response testing., Results: As compared to TD, children with DS depicted reduced oropharyngeal dimensions, significantly lower CG and LG and no different PG. Their hypercapnic ventilatory response slopes were not different., Conclusions: We concluded that the decreased CG in DS was related to decreased peripheral chemoreceptor sensitivity, and while central chemosensitivity was normal, the former explained the increased end-tidal PCO 2 observed in children with DS as compared to TD. Pharyngeal dimensions are reduced in children with DS and OSAS., Impact: Reduced upper airway size and nocturnal alveolar hypoventilation in children with Down syndrome (DS) have been previously reported. We confirmed that children with DS and moderate-to-severe OSA have reduced oropharyngeal size as compared to typically developing children with similar OSAS severity and demonstrated decreased peripheral chemosensitivity explaining the alveolar hypoventilation observed in children with DS. Central chemosensitivity appears to be intact in children with DS and moderate to severe OSAS Our results support growing evidence that Down syndrome is associated with autonomic nervous system dysfunction., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Sleep disordered breathing (SDB) is prevalent among children with neuromuscular disorders (NMD). The combination of respiratory muscle weakness, altered drive, and chest wall distortion due to scoliosis make sleep a stressful state in this population. Symptomatology can range from absent to snoring, nocturnal awakenings, morning headaches, and excessive daytime sleepiness. Sequelae of untreated SDB includes cardiovascular effects, metabolic derangements, and neurocognitive concerns which can be compounded by those innate to the NMD. The clinician should have a low threshold for obtaining polysomnography and recognize the nuances of individual disorders due to disproportionately impacted muscle groups such as hypoventilation in ambulating patients from diaphragm weakness. Non-invasive or invasive ventilation are the mainstay of treatment. In this review we explore the diagnosis and treatment of SDB in children with various NMD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Congenital central hypoventilation syndrome is a rare disorder due to a mutation in the PHOX2B gene, characterized by a failure in autonomic control of breathing with diminished or absent response to hypoxia and hypercapnia, which is most pronounced during sleep. Most patients present from birth with central apneas and hypoventilation, or later in the setting of a physiologic stress. Recent literature in mice with a Phox2b27Ala/+ mutation suggests a predisposition to obstructive apneas likely due to hypoglossal dysgenesis. We report on three patients with obstructive sleep apneas with absent or mild hypoventilation. Our cases propose that obstructive apneas can be the primary presentation in patients who subsequently develop the classic phenotype of congenital central hypoventilation syndrome and emphasize their close monitoring and surveillance., Citation: Kagan O, Zhang C, McElyea C, Keens TG, Davidson Ward SL, Perez IA. Obstructive sleep apnea as a presentation of congenital central hypoventilation syndrome. J Clin Sleep Med . 2023;19(9):1697-1700., (© 2023 American Academy of Sleep Medicine.)

Background: Only 15 patients of autoimmune encephalitis with metabotropic glutamate receptor 5 (mGluR5) antibodies have been reported worldwide since 2011, mostly from western countries. Patients with different genetic backgrounds are necessary to further clarify the clinical phenotype and prognosis of this rare disease., Objective: We initially describe a case series from China to confirm the previous findings, expand the clinical phenotype, and identify the prognostic factors of autoimmune encephalitis with mGluR5 antibodies., Methods: Observational data with follow-up were prospectively collected from autoimmune encephalitis patients with mGluR5 antibodies. Clinical information and outcomes on current and previously reported cases were combined and analyzed., Results: We identified five patients (median age 35 years); two were female. The main clinical manifestations were behavioral/personality changes (five of five, 100%) and cognitive disorders (four of five, 80%), accompanied with other neurologic symptoms. Hypoventilation occurred in two (40%) patients, which was life-threatening. One patient had meningoencephalitis, suggesting a new phenotype in anti-mGluR5 encephalitis. All patients received immunotherapy. At the last follow-up (median 18 months), two (40%) patients showed complete recovery, two (40%) patients showed partial recovery, and one (20%) patient died. One (20%) patient had multiple relapses. Together with the 15 previously reported cases, associated tumors occurred in seven of 12 (58%) Western patients vs. one of eight (13%) Chinese patients. Modified Rankin Scale (mRS) scores at the last follow-up (median 31 months) were available in 16 patients. Patients with bad outcomes (mRS > 2, n = 4) were more likely to have hypoventilation at onset and higher mRS scores at peak of the disease., Conclusions: In patients with different genetic background, as Chinese, the clinical phenotype of anti-mGluR5 encephalitis is similar. Fewer paraneoplastic cases were observed in Chinese patients. Most patients showed good responses to immunotherapy and cancer treatment. The clinical outcomes were favorable in most patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Guo, Liu, Gong, Li, Liu, Li, Zhou and Hong.)

Purpose of Review: This paper reviews how sleep is impacted in patients with Prader-Willi syndrome (PWS), focusing on sleep-related breathing disturbances and excessive daytime sleepiness (EDS)., Recent Findings: Hypothalamic dysfunction may underlie several aspects of the PWS phenotype. Central sleep apnea (CSA) can persist beyond infancy. Nocturnal hypoventilation is common and may occur without central or obstructive sleep apnea (OSA). Adenotonsillectomy, a mainstay of OSA treatment, may cause velopharyngeal insufficiency. Growth hormone (GH) is considered safe, but close surveillance for OSA remains important. Cardiac autonomic dysfunction occurs during slow wave sleep and may increase the risk of cardiovascular events. EDS and narcolepsy are also common. Modafinil and pitolisant are treatment options currently being studied. Sleep disorders are prevalent in individuals with PWS. Sleep-related breathing disorders present as CSA in infancy and later in life as OSA and hypoventilation. GH therapy has improved the clinical outcomes of patients with PWS, but close surveillance and treatment for OSA is recommended. EDS can persist even after sleep-related breathing disorders are treated, and some individuals may even develop narcolepsy. Early recognition and treatment of sleep-related disorders may prevent morbidity and result in improved survival of patients with PWS., (© 2023. The Author(s).)

Chronic respiratory failure is a common, important complication of many types of neuromuscular and chest wall disorders. While the pathophysiology of each disease may be different, these disorders can variably affect all muscles involved in breathing, including inspiratory, expiratory, and bulbar muscles, ultimately leading to chronic respiratory failure and hypoventilation. The use of home assisted ventilation through noninvasive interfaces aims to improve the symptoms of hypoventilation, improve sleep quality, and, when possible, improve mortality. An increasing variety of interfaces has allowed for improved comfort and compliance. In a minority of scenarios, noninvasive ventilation is either not appropriate or no longer effective due to disease progression, and a transition to tracheal ventilation should be considered.

Study Objectives: Although obesity hypoventilation syndrome (OHS) is associated with increased morbidity and mortality, post-bariatric surgery OHS risk remains unclear due to often nonsystematic OHS assessments., Methods: We leverage a clinical cohort with nocturnal CO 2 monitoring during polysomnography to address the hypothesis that patients with obesity-associated sleep hypoventilation (OaSH; ie, stage II OHS) have increased adverse postoperative bariatric surgery outcomes. We retrospectively analyzed data from patients undergoing pre-bariatric surgery polysomnography at the Cleveland Clinic from 2011-2018. OaSH was defined by body mass index ≥ 30 kg/m 2 and either polysomnography-based end-tidal CO 2 ≥ 45 mmHg or serum bicarbonate ≥ 27 mEq/L. Outcomes considered were as follows: intensive care unit stay, intubation, tracheostomy, discharge disposition other than home or 30-day readmission individually and as a composite, and all-cause mortality. Two-sample t test or Wilcoxon rank-sum test for continuous variables and chi-square or Fisher's exact test for categorical variables were used for OaSH vs non-OaSH comparisons. All-cause mortality was compared using Kaplan-Meier estimation and Cox proportional hazards models., Results: The analytic sample (n = 1,665) was aged 45.2 ± 12 years, 20.4% were male, had a body mass index of 48.7 ± 9 kg/m 2 , and 63.6% were White. OaSH prevalence was 68.5%. OaSH patients were older and more likely to be male with a higher BMI, apnea-hypopnea index, and glycated hemoglobin. The composite outcome was higher in OaSH vs non-OaSH patients (18.9% vs 14.3%, P = .021). Although some individual outcomes were respectively higher in OaSH vs non-OaSH patients, differences were not statistically significant: intubation (1.5% vs 1.3%, P = .81) and 30-day readmission (13.8% vs 11.3%, P = .16). Long-term mortality (median follow-up: 22.9 months) was not significantly different between groups, likely due to overall low event rate (hazard ratio = 1.39, 95% confidence interval: 0.56, 3.42)., Conclusions: In this largest sample to date of systematically phenotyped OaSH in a bariatric surgery cohort, we identify increased postoperative morbidity in those with sleep-related hypoventilation in stage II OHS when a composite outcome was considered, but individual contributors of intubation, intensive care unit admission, and hospital length of stay were not increased. Further study is needed to identify whether perioperative treatment of OaSH improves post-bariatric surgery outcomes., Citation: Chindamporn P, Wang L, Bena J, et al. Obesity-associated sleep hypoventilation and increased adverse postoperative bariatric surgery outcomes in a large clinical retrospective cohort. J Clin Sleep Med . 2022;18(12):2793-2801., (© 2022 American Academy of Sleep Medicine.)

Objective: We investigated the effect of growth and development level on polysomnography results in preschool children with obstructive sleep apnea (OSA)., Methods: Preschool children (ages 3-6) with symptoms of snoring and were diagnosed with OSA by polysomnography in the sleep center were selected as the research object. They were split into three groups based on their growth rates: restricted, normal, and excessive. Sleep structure, respiratory events, and oxygenation index were compared between the three groups., Results: A total of 183 (111 boys and 72 girls) preschool children were enrolled. There were 26 cases in the growth restricted group, 112 cases in the normal growth group, and 45 cases in the overgrowth group. The weight and Body Mass Index (BMI) of children in the growth restricted and overgrowth groups were significantly different from those in the normal group. In terms of sleep structure, the sleep efficiency of the growth restricted group was poorer than that of the normal group. For sleep breathing events, the growth restricted group showed a greater apnea-hypopnea index (AHI), obstructive apnea hypopnea index (OAHI), hypoventilation index, and more hypoventilation than the normal group. In terms of oxygenation, the difference in degree of hypoxia between the three groups was statistically significant, and the overgrowth group had lower minimum oxygen saturation during the rapid eye movement phase than the normal group, as well as a quicker mean heart rate., Conclusions: OSA is more likely in preschool-aged children with stunted or overgrown growth than in children with OSA alone, and the more severe the disorder, especially when accompanied with stunted growth., Competing Interests: Declaration of competing interest There is no conflict of interest declared by the authors., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Central hypoventilation is a rare cause of respiratory failure that has been associated with multiple underlying disorders, including congenital central hypoventilation syndrome, obesity hypoventilation syndrome, and several neuromuscular conditions. We report the case of an adolescent who presented with respiratory failure in the setting of acute demyelinating encephalomyelitis whose clinical history was consistent with a congenital myopathy and whom we found to have a Tropomyosin 3 ( TPM3 ) genetic variant on further genetic testing. This case expands the clinical spectrum of causes for late-onset central hypoventilation in the setting of a neuromuscular disorder., Citation: Stringel V, Bizargity P, Laureta E, Kothare S. A late presentation of TPM3 myopathy presenting as sleep hypoventilation in the setting of acute demyelinating encephalomyelitis. J Clin Sleep Med . 2022;18(11):2695-2698., (© 2022 American Academy of Sleep Medicine.)

Obesity hypoventilation syndrome (OHS) is defined as daytime hypercapnia in obese individuals in the absence of other underlying causes. In the United States, OHS is present in 10%-20% of obese patients with obstructive sleep apnea and is linked to hypoventilation during sleep. OHS leads to high cardiorespiratory morbidity and mortality, and there is no effective pharmacotherapy. The depressed hypercapnic ventilatory response plays a key role in OHS. The pathogenesis of OHS has been linked to resistance to an adipocyte-produced hormone, leptin, a major regulator of metabolism and control of breathing. Mechanisms by which leptin modulates the control of breathing are potential targets for novel therapeutic strategies in OHS. Recent advances shed light on the molecular pathways related to the central chemoreceptor function in health and disease. Leptin signaling in the nucleus of the solitary tract, retrotrapezoid nucleus, hypoglossal nucleus, and dorsomedial hypothalamus, and anatomical projections from these nuclei to the respiratory control centers, may contribute to OHS. In this review, we describe current views on leptin-mediated mechanisms that regulate breathing and CO2 homeostasis with a focus on potential therapeutics for the treatment of OHS., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: An episodic increase in transcutaneous carbon dioxide pressure (PtcCO 2 ) is often recognized in patients with advanced chronic obstructive pulmonary disease (COPD) by overnight PtcCO 2 monitoring. This phenomenon, called episodic nocturnal hypercapnia (eNH), mainly corresponds to rapid eye movement (REM) sleep-related hypoventilation. However, it is unclear whether eNH is associated with the frequency of COPD exacerbation. We aimed to investigate whether a relationship exists between COPD exacerbation and eNH., Patients and Methods: We enrolled consecutive patients with stable, severe, or very severe COPD with a daytime arterial carbon dioxide pressure (PaCO 2 ) <55.0 mmHg who underwent overnight PtcCO 2 monitoring from April 2013 to January 2017. We retrospectively analyzed the prevalence of eNH and sleep-associated hypoventilation (SH) as defined by the American Academy of Sleep Medicine. Moreover, we compared the relationship between the frequency of COPD exacerbations in the previous year and eNH or SH., Results: Twenty-four patients were included in this study. The study patients had a mean daytime PaCO 2 and nocturnal PtcCO 2 of 43.3 ± 6.8 mmHg and 42.9 ± 9.6 mmHg, respectively. Six (25.0%) and 11 (45.9%) of the 24 patients met the SH and eNH criteria, respectively. The odds ratios of SH and eNH for at least one annual exacerbation were 1.0 [95% confidence interval (CI): 0.16-6.00] and 11.1 [95% CI: 1.39-87.7], respectively. The odds ratios of SH and eNH for at least two annual exacerbations were 0.3 [95% CI: 0.04-2.64] and 6.6 [95% CI: 1.06-39.4], respectively., Conclusion: In patients with advanced COPD and a daytime PaCO 2 <55.0 mmHg, eNH may be associated with a history of more frequent exacerbations than SH. Further studies are required to validate these findings., Competing Interests: Dr Hisanori Amimoto reports personal fees from AstraZeneca, personal fees from CHUGAI PHARMACEUTICAL CO., LTD., personal fees from TAIHO PHARMACEUTICAL CO., LTD., during the conduct of the study. The authors report no other conflicts of interest in this work., (© 2022 Kitajima et al.)

Rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome is a rare complex disorder associated with alterations in the endocrine system, autonomic nervous system, and respiratory system. Previously published case reports and studies have noted sleep-disordered breathing in patients with ROHHAD syndrome. Nocturnal respiratory manifestations, which if untreated early by respiratory support, may cause cardiorespiratory arrest and a life-threatening condition. More recently, it has been recognized that children with ROHHAD syndrome have central pauses during wakefulness associated with intermittent oxygen desaturations. We report novel findings of a child with ROHHAD syndrome displaying an irregular breathing pattern and significant central pauses associated with oxygen desaturations during wakefulness, whose respiratory status improved while chewing gum. This was used as an alternative to supplemental oxygen therapy., Citation: Sunkonkit K, Selvadurai S, Yeh EA, Hamilton J, Narang I. Chewing gum: alternative therapy to oxygen intolerance. J Clin Sleep Med . 2022;18(6):1723-1726., (© 2022 American Academy of Sleep Medicine.)

Study Objectives: Pulmonary hypertension (PH) is a rare yet serious complication of obstructive sleep apnea (OSA). Echocardiographic screening for PH is recommended in children with severe OSA, but the health care burden of universal screening is high. We sought to determine the prevalence of PH on echocardiogram among children with severe OSA and identify variables associated with a positive PH screen., Methods: Retrospective study of 318 children with severe OSA (obstructive apnea-hypopnea index ≥ 10 events/h) and echocardiogram within 1 year of polysomnogram. PH-positive echocardiogram was defined by peak tricuspid regurgitation velocity ≥ 2.5 m/s and/or 2 or more right-heart abnormalities suggestive of elevated pulmonary artery pressure. Patient characteristics and polysomnogram data were compared to identify factors associated with PH., Results: Twenty-six children (8.2%; 95% confidence interval [CI] 5.4-11.8%) had echocardiographic evidence of PH. There was no difference in age, sex, body mass index, obstructive apnea-hypopnea index, or oxygenation indices between patients with and without PH. Sleep-related hypoventilation (end-tidal CO 2 > 50 mmHg for > 25% of total sleep time) was present in 25% of children with PH compared with 6.3% of children without PH (adjusted prevalence ratio = 2.73; 95% CI 1.18-6.35). Forty-six percent of children (12/26) with PH had Down syndrome vs 14% (41/292) without PH (adjusted prevalence ratio = 3.11; 95% CI 1.46-6.65)., Conclusions: There was a relatively high prevalence of PH on echocardiogram in our cohort of children with severe OSA. The findings of increased PH prevalence among children with sleep-related hypoventilation or Down syndrome may help inform the development of targeted screening recommendations for specific pediatric OSA populations., Citation: Maloney MA, Davidson Ward SL, Su JA, et al. Prevalence of pulmonary hypertension on echocardiogram in children with severe obstructive sleep apnea. J Clin Sleep Med . 2022;18(6):1629-1637., (© 2022 American Academy of Sleep Medicine.)

Introduction: The abnormalities in the vertebrobasilar arterial system such as enlarged, tortuous or dilated arteries and aneurysms can generate pressure and distortion of brain structures especially in the medulla and pons. This brainstem compression by abnormal arteries can lead to various sleep disorders such as sleep related hypoventilation, central sleep apnea, obstructive sleep apnea, and positional sleep apnea., Aim: To highlight brainstem compression due to vascular abnormalities as a cause of sleep disordered breathing., Methods: Manuscripts were identified using the National Institutes of Health PubMed literature search system. Search terms included sleep disorders, vertebrobasilar dolichoectasia, tortuous vertebral arteries, vertebrobasilar aneurysms, vascular compression and brainstem compression. Inclusion criteria required that the articles were written in English, highlighted both a sleep disorder and a vascular abnormality., Results: The literature search resulted in 10 case reports where vascular abnormalities were leading to sleep disorders. Out of these: four patients had central sleep apnea; three had sleep related hypoventilation; one had positional central sleep apnea; one had positional central apnea along with obstructive sleep apnea; and one had obstructive sleep apnea. The various vascular lesions identified were: megadolichobasilar artery; dolichoectatic vertebral artery; fusiform vertebrobasilar aneurysm; tortuous and elongated vertebral arteries; calcified vertebral artery and medullary telangiectasia., Conclusions: Arterial compression of the respiratory centers in the pons and medulla can lead to central sleep apnea. Obstructive sleep apnea can also result from vascular compression of the medulla. The proposed mechanism is compression of nucleus ambiguus which controls pharyngeal tone. Pressure on cranial nerves IX and X can lead to pharyngeal dysfunction leading to occlusive apnea., Competing Interests: Declaration of Competing Interest None, (Copyright © 2022 Elsevier Inc. All rights reserved.)

Study Objectives: Pulmonary hypertension (PH) is prevalent in obesity hypoventilation syndrome (OHS). However, there is a paucity of data assessing pathogenic factors associated with PH. Our objective is to assess risk factors that may be involved in the pathogenesis of PH in untreated OHS., Methods: In a post hoc analysis of the Pickwick trial, we performed a bivariate analysis of baseline characteristics between patients with and without PH. Variables with a P value ≤ .10 were defined as potential risk factors and were grouped by theoretical pathogenic mechanisms in several adjusted models. Similar analysis was carried out for the 2 OHS phenotypes, with and without severe concomitant obstructive sleep apnea., Results: Of 246 patients with OHS, 122 (50%) had echocardiographic evidence of PH defined as systolic pulmonary artery pressure ≥ 40 mm Hg. Lower levels of awake PaO 2 and higher body mass index were independent risk factors in the multivariate model, with a negative and positive adjusted linear association, respectively (adjusted odds ratio 0.96; 95% confidence interval 0.93 to 0.98; P = .003 for PaO 2 , and 1.07; 95% confidence interval 1.03 to 1.12; P = .001 for body mass index). In separate analyses, body mass index and PaO 2 were independent risk factors in the severe obstructive sleep apnea phenotype, whereas body mass index and peak in-flow velocity in early/late diastole ratio were independent risk factors in the nonsevere obstructive sleep apnea phenotype., Conclusions: This study identifies obesity per se as a major independent risk factor for PH, regardless of OHS phenotype. Therapeutic interventions targeting weight loss may play a critical role in improving PH in this patient population., Clinical Trial Registration: Registry: Clinicaltrial.gov; Name: Alternative of Treatment in Obesity Hypoventilation Syndrome; URL: https://clinicaltrials.gov/ct2/show/NCT01405976; Identifier: NCT01405976., Citation: Masa JF, Benítez ID, Javaheri S, et al. Risk factors associated with pulmonary hypertension in obesity hypoventilation syndrome. J Clin Sleep Med . 2022;18(4):983-992., (© 2022 American Academy of Sleep Medicine.)

Objective: To describe the clinical and neurologic signs, diagnostic investigations, definitive or presumptive diagnosis, treatment, and outcome of dogs presented with acute onset central cord syndrome (CCS)., Animals: 74 client-owned dogs evaluated for CCS at 5 referral hospitals between January 2016 and March 2021., Procedures: Data were collected from the medical records of each dog, including patient signalment, physical and neurologic examination results, presence of signs of respiratory failure, diagnostic imaging findings, definitive or presumptive diagnosis, treatment and follow-up information. Descriptive statistics were calculated and bivariable analysis was performed to identify associations between selected variables., Results: 2 neuroanatomic locations for the CCS were identified: C1-C5 spinal cord segments in 65 of 74 (88%) dogs and C6-T2 in 9 (12%) dogs. Neurolocalization did not correlate with the imaging findings in 43 (58%) dogs. Different diseases were associated with CCS. The most common condition was Hansen type I disk herniation in 27 (36%) dogs and hydrated nucleus pulposus extrusion in 16 (22%) dogs. Main lesion locations within the vertebral column associated with CCS were C3-C4 and C4-C5 intervertebral disk spaces in 21 (28%) and 18 (24%) dogs, respectively. Outcome was favorable in 69 (93%) dogs. Patients presenting with hypoventilation were 14.7 times more likely to have a poor outcome., Clinical Relevance: CCS in dogs may be seen with lesions in the C1-C5 and C6-T2 spinal cord segments. Etiologies are variable. Total or partial improvement was achieved in most dogs with the appropriate treatment. Hypoventilation was associated with death.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare and potentially lethal disorder of respiratory control, autonomic, and hypothalamic dysfunction of unknown etiology. We report a 15-year-old girl with ROHHAD who developed hyperphagia and rapid weight gain of 16 kg between 2.5 and 4 years of age and cardiorespiratory arrest at 4 years. Initial polysomnography showed central sleep apnea and severe oxygen desaturations without hypoventilation. Mild obstructive sleep apnea and intermittent hypoxemia were identified at 4.5 years, following which nocturnal bilevel positive airway pressure therapy was initiated. At 6 years, she developed sleep-related hypoventilation, and subsequent polysomnograms continued to show obstructive sleep apnea and hypoventilation requiring bilevel positive airway pressure. Clinicians interpreting polysomnograms should become familiar with the evolution of sleep-disordered breathing in ROHHAD and that hypoventilation may develop over time. Our case highlights the importance of serial polysomnography in patients with ROHHAD and optimal ventilatory management., Citation: Ghosh R, Malik M, Daley TC, Kasi AS. Images: Sleep-disordered breathing and hypoventilation in a child with obesity and hypothalamic dysfunction. J Clin Sleep Med . 2022;18(1):339-342., (© 2022 American Academy of Sleep Medicine.)

Background and Purpose: Perry disease (or Perry syndrome) is an autosomal dominant neurodegenerative disorder characterized by parkinsonism, neuropsychiatric symptoms, central hypoventilation, weight loss and distinct TDP-43 pathology. It is caused by mutations of the DCTN1 gene encoding an essential component of axonal transport. The objectives were to provide the current state of knowledge on clinical, pathological and genetic aspects of Perry disease, as well as practical suggestions for the management of the disease., Methods: Data on new patients from New Zealand, Poland and Colombia were collected, including autopsy report. Also all of the published papers since the original work by Perry in 1975 were gathered and analyzed., Results: Parkinsonism was symmetrical, progressed rapidly and was poorly responsive to L-Dopa; nonetheless, a trial with high doses of L-Dopa is warranted. Depression was severe, associated with suicidal ideations, and benefited from antidepressants and L-Dopa. Respiratory symptoms were the leading cause of death, and artificial ventilation or a diaphragm pacemaker prolonged survival. Weight loss occurred in most patients and was of multifactorial etiology. Autonomic dysfunction was frequent but underdiagnosed. There was a clinical overlap with other neurodegenerative disorders. An autopsy showed distinctive pallidonigral degeneration with TDP-43 pathology. Genetic testing provided evidence of a common founder for two families. There was striking phenotypic variability in DCTN1-related disorders. It is hypothesized that oligogenic or polygenic inheritance is at play., Conclusions: Perry disease and other DCTN1-related diseases are increasingly diagnosed worldwide. Relatively effective symptomatic treatments are available. Further studies are needed to pave the way toward curative/gene therapy., (© 2021 European Academy of Neurology.)

We report a 13-year-old female with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome, panhypopituitarism, dyslipidemia, type 2 diabetes mellitus, and nonalcoholic fatty liver disease, who developed rhabdomyolysis and acute kidney injury, two weeks after switching from lovastatin to rosuvastatin. She had been on lovastatin for eight years without any adverse effects., Competing Interests: Declaration of Competing Interest All the authors have no con-flicts of interest to disclose., (Copyright © 2021 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Perry disease (Perry syndrome), a hereditary TAR DNA-binding protein 43 (TDP-43) proteinopathy, is caused by dynactin subunit 1 (DCNT1) mutations and is characterized by rapidly progressive parkinsonism accompanied by depression, apathy, unexpected weight loss, and respiratory symptoms including central hypoventilation and central sleep apnea. Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is considered a diagnostic biomarker for Lewy body disease (LBD), as denervation of cardiac sympathetic nerves is a pathological feature in LBD. However, our previous studies have reported a decreased cardiac uptake of MIBG in patients with Perry disease. In this study, we aimed to correlate the MIBG myocardial scintigraphy findings with clinical features in Perry disease., Methods: We evaluated data obtained from a multicenter survey of patients of Japanese origin with suspected Perry disease, who visited neurology departments in Japan from January 2010 to December 2018. We screened each patient's DNA for the DCTN1 mutation using Sanger sequencing and obtained the clinical details of all patients including findings from their MIBG myocardial scintigraphy., Results: We identified two novel mutations, p.G71V and p.K68E, in DCTN1 in patients from two different families. The majority of patients (7/8, 87.5%) showed a decrease in cardiac uptake (heart to mediastinum ratio) in MIBG myocardial scintigraphy. These patients commonly presented with symptoms related to autonomic dysfunction: constipation, fecal incontinence, urinary disturbance, and orthostatic hypotension., Conclusions: MIBG myocardial scintigraphy may be a useful biomarker of autonomic dysfunction in Perry disease., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Congenital central hypoventilation syndrome (CCHS) represents a rare genetic disorder usually caused by mutations in the homeodomain transcription factor PHOX2B. Some CCHS patients suffer mainly from deficiencies in CO 2 and/or O 2 respiratory chemoreflex, whereas other patients present with full apnea shortly after birth. Our goal was to identify the neuropathological mechanisms of apneic presentations in CCHS. In the developing murine neuroepithelium, Phox2b is expressed in three discrete progenitor domains across the dorsal-ventral axis, with different domains responsible for producing unique autonomic or visceral motor neurons. Restricting the expression of mutant Phox2b to the ventral visceral motor neuron domain induces marked newborn apnea together with a significant loss of visceral motor neurons, RTN ablation, and preBötzinger complex dysfunction. This finding suggests that the observed apnea develops through non-cell autonomous developmental mechanisms. Mutant Phox2b expression in dorsal rhombencephalic neurons did not generate significant respiratory dysfunction, but did result in subtle metabolic thermoregulatory deficiencies. We confirm the expression of a novel murine Phox2b splice variant which shares exons 1 and 2 with the more widely studied Phox2b splice variant, but which differs in exon 3 where most CCHS mutations occur. We also show that mutant Phox2b expression in the visceral motor neuron progenitor domain increases cell proliferation at the expense of visceral motor neuron development. We propose that visceral motor neurons may function as organizers of brainstem respiratory neuron development, and that disruptions in their development result in secondary/non-cell autonomous maldevelopment of key brainstem respiratory neurons., (© 2020 International Society of Neuropathology.)

None: Diaphragm pacing (DP), a modality of ventilatory support in children with congenital central hypoventilation syndrome, generates respiration using the patient's own diaphragm as the respiratory pump. We report a 14-year-old boy with congenital central hypoventilation syndrome who uses DP with an uncapped tracheostomy during sleep. Polysomnography to titrate DP settings identified artifacts occurring in regular intervals coinciding with the onset of inspiration during all sleep stages in several channels including legs, snore, and electrocardiogram. Clinicians interpreting polysomnograms performed during DP should become familiar with the multichannel artifacts due to DP impulses. We also identified that our patient was hyperventilated on home DP settings that led to adjustment of DP settings during the polysomnogram to achieve optimal oxygenation and ventilation. Our case also highlights the utility of polysomnography to ensure optimal gas exchange during sleep in children with congenital central hypoventilation syndrome using DP., (© 2020 American Academy of Sleep Medicine.)

Study Objectives: Rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare condition. Little is known about sleep/wake and slow-wave activity in this condition, although the central hypothalamic dysfunction associated with autonomic dysregulation would make the occurrence of SWA deregulation most likely., Methods: Two children with clinical presentation of ROHHAD syndrome were evaluated, diagnosed, and treated. Their polysomnographic studies were compared with 4 matched children with obstructive sleep apnea and 6 controls., Results: Children that were clinically diagnosed with ROHHAD exhibited significantly weaker slow-wave activity power and shallower slow-wave activity slopes during the first 2 sleep cycles compared with children with obstructive sleep apnea or controls., Conclusions: This study shows that children with ROHHAD have suppressed slow-wave activity, possibly because of hypothalamic dysregulation that may contribute to their rapid-onset obesity and excessive daytime sleepiness., (© 2020 American Academy of Sleep Medicine.)

Introduction: Perry syndrome, also recognized as Perry disease, is a rare autosomal dominant disorder characterized by midlife-onset atypical parkinsonism, apathy or depression, respiratory failure and weight loss caused by a mutation in the Dynactin (DCTN1) gene., Case Description: A fifty-six years-old adopted male presented with atypical parkinsonism with bradykinesia and postural instability, apathy, weight loss, and recurrent respiratory failure due to central hypoventilation requiring tracheostomy., Methods and Results: Clinical workup revealed a novel DCTN1 p.Tyr78His variant. Using bioinformatic protein structure modeling, we compare our patient's variant to known DCTN1 mutations and predict protein stability of each variant at the CAP-Gly domain of p150 Glued . All eight variants causing Perry syndrome, as well as Tyr78His, are located at site expected to interact with MAPRE1 tail and are predicted to be destabilizing. Variants causing atypical parkinsonism with incomplete Perry syndrome phenotype (K56R and K68E) are not significantly destabilizing in silico., Conclusion: We propose p.Tyr78His as the ninth pathogenic DCTN1 variant causing Perry syndrome. Bioinformatic protein modeling may provide additional window to understand and interpret DCTN1 variants, as we observed non-destabilizing variants to have different phenotype than destabilizing variants., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Dynactin-1 (DCTN1)-related Parkinson-plus disorder (Perry syndrome) is an autosomal dominant neurodegenerative disorder characterised by levodopa-resistant parkinsonism, weight loss, mood change and central hypoventilation. Ventilatory insufficiency is the predominant cause of death. It has been previously described in 87 people from 20 families with a worldwide distribution. It is now recognised as a distinct TDP-43 proteinopathy caused by a pathological mutation in DCTN1. Its rarity and clinical overlap with other neurodegenerative diseases increase the risk of delayed or incorrect diagnosis. Ventilatory support can improve life expectancy but this depends upon its recognition; overall its prognosis remains poor. We report a patient with DCTN1-related Parkinson-plus disorder, in whom genetic confirmation came only after death., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Transitioning children with Congenital Central Hypoventilation Syndrome (CCHS) from nocturnal invasive ventilation via tracheostomy to noninvasive positive pressure ventilation (NIPPV) is challenging due to the leak caused by the tracheocutaneous fistula (TCF), resulting in insufficient ventilation. Decannulation and primary closure of the TCF with immediate transition to nocturnal NIPPV was performed in two children with CCHS at a tertiary care children's hospital. Neither child developed significant adverse effects such as pneumomediastinum or pneumothorax. This technique is a novel approach that may improve decannulation outcomes and aid transition to NIPPV in this patient population., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier B.V.)

Context: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation and neural crest tumor (ROHHHAD[NET]) is a rare and potentially fatal disease. No specific diagnostic biomarker is currently available, making prompt diagnosis challenging. Since its first definition in 2007, a complete clinical analysis leading to specific diagnosis and follow-up recommendations is still missing., Objective: The purpose of this work is to describe the clinical timeline of symptoms of ROHHAD(NET) and propose recommendations for diagnosis and follow-up., Design: We conducted a systematic review of all ROHHAD(NET) case studies and report a new ROHHAD patient with early diagnosis and multidisciplinary care., Methods: All the articles that meet the definition of ROHHAD(NET) and provide chronological clinical data were reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis individual patient data guidelines. The data were grouped into 7 categories: hypothalamic dysfunction, autonomic dysregulation, hypoventilation, NET, psychiatric symptoms, other clinical manifestations, and outcome., Results: Forty-three individual patient data descriptions were analyzed. The timeline of the disease shows rapid-onset obesity followed shortly by hypothalamic dysfunction. Dysautonomia was reported at a median age of 4.95 years and hypoventilation at 5.33 years, or 2.2 years after the initial obesity. A NET was reported in 56% of the patients, and 70% of these tumors were diagnosed within 2 years after initial weight gain., Conclusion: Because early diagnosis improves the clinical management and the prognosis in ROHHAD(NET), this diagnosis should be considered for any child with rapid and early obesity. We propose guidance for systematic follow-up and advise multidisciplinary management with the aim of improving prognosis and life expectancy., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: There is a high prevalence of obstructive sleep apnea (OSA) in children with Down syndrome (DS), sometimes associated with alveolar hypoventilation., Objective: To compare transcutaneous partial pressure of carbon dioxide (PtcCO 2 ) and pulse oximetry (SpO 2 ) in children with DS and in control children with OSA., Patients and Methods: This retrospective case-control study involved children followed in Trousseau Hospital (Paris) Sleep Center. Polysomnography (PSG) recordings and clinical files of children with DS were reviewed to identify clinical signs of OSA and comorbidities associated with DS. Controls were children who presented with OSA of ENT origin without other comorbidities (exceptions: two overweight, one obese, and three with well-controlled asthma). DS subjects and controls were matched for age and apnea hypopnea index., Results: There were 28 children in each group. Mean PtcCO 2 during sleep was significantly higher in patients with DS compared to controls (44 mm Hg vs 42 mm Hg, P = .001). Five (21%) patients with DS met the American Academy of Sleep medicine criteria for hypoventilation, compared to one (4%) in the control group. The mean PtcO 2 during sleep was significantly lower in patients with DS (77 mm Hg vs 82 mm Hg, P = .003)., Conclusions: This is the first study to compare nocturnal gas exchange in children with DS to a control group of children with similar OSA. Our data demonstrate that children with DS have increased PtcCO 2 regardless of the presence of OSA and its severity. This may be due to respiratory muscle hypotonia and/or ventilatory control alteration in patients with DS., (© 2020 Wiley Periodicals, Inc.)

Congenital central hypoventilation syndrome (CCHS) patients are at risk for life-threatening cardiac arrhythmias, and presentation is dependent on their PHOX2B gene mutation. We describe the presentation of life-threatening arrhythmias in our cohort of CCHS patients. We reviewed the records of 72 CCHS patients seen at CHLA from 2004 to 2018. Data collected included demographics, PHOX2B genotype, ventilatory support, clinical symptoms, ambulatory cardiac monitoring results, and presence of cardiac pacemaker. Sixteen of 72 patients had evidence of potential life-threatening cardiac arrhythmias. PHOX2B genotypes were 20/25 polyalanine repeat expansion mutation (PARM), 20/26 PARM, 20/27 PARM, 20/32 PARM, and c.245C > T non-polyalanine repeat mutation. 11/16 patients were ventilated during sleep only. Symptoms included syncope, dizziness, chest pain, tingling in the left arm, and palpitations. 15/16 patients had recorded ambulatory cardiac monitoring. 5/16 patients were symptomatic without significant sinus pauses. 12/16 patients had implantation of cardiac pacemakers. 9/12 had significant sinus pauses on ambulatory monitoring, and 7/12 patients were symptomatic.Conclusion: CCHS patients have potential life-threatening arrhythmias requiring cardiac pacemaker implantation. Many of these patients are symptomatic with significant sinus pauses on ambulatory monitoring. However, some symptomatic patients with no significant pauses on ambulatory monitoring may still require cardiac pacemaker implantation.What is Known:• CCHS patients are at risk for life-threatening sinus pauses and require cardiac pacemaker implantation.What is New:• CCHS patients regardless of PHOX2B genotype are at risk for significant sinus pauses. Many CCHS patients with significant sinus pause on ambulatory cardiac monitoring are symptomatic and most present with syncope. Some symptomatic patients do not have significant sinus pauses but may still require cardiac pacemaker implantation.

Objectives: Classically, Pierre Robin Sequence (PRS) is a triad of micrognathia, glossoptosis, and airway obstruction, although frequently associated with cleft palate. Current literature reports that Stickler syndrome is the most common syndrome associated with PRS, and 22q11 deletion syndrome (22q11 DS) as the second most common. This study identifies associations between PRS and genetic syndromes., Methods: A retrospective chart review was performed to identify patients diagnosed with PRS over a 10-year period from 4/1/2007 to 4/1/2017 at a tertiary children's hospital., Results: 4,052 consecutive charts were reviewed and 234 patients had a diagnosis of PRS confirmed with the triad of micrognathia, glossoptosis, and airway obstruction. Of note, all of these patients had cleft palate. Of the 234 patients with PRS, 65 patients had syndromic diagnoses (28%). One patient had 22q11 DS (0.43%), and 31 patients had Stickler syndrome (13.2%). Additionally, 3 patients had central hypoventilation syndrome, 3 patients had Duane syndrome, 2 patients had Cornelia de Lange syndrome, 2 patients had Emanuel syndrome, 2 patients had Gordon syndrome, 2 patients had Mobius syndrome, 2 patients had Nager syndrome. Multiple other syndromes were identified, but occurred in isolated cases., Conclusion: This study supports literature that PRS is most commonly associated with Stickler Syndrome but rarely associated with 22q11 DS given that only 1 patient had both PRS and 22q11 DS., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Alzheimer's disease is the most common neurodegenerative disease, and many patients also present with vascular dysfunction. In this study, we aimed to assess cerebral blood flow (CBF) and cerebrovascular response (CVR) as early, pre-symptomatic (3 months of age), imaging markers in a bigenic model of Alzheimer's disease (APP.V717IxTau.P301L, biAT) and in the monogenic parental strains. We further developed our previously published combination of pulsed arterial spin labeling perfusion MRI and hypo-ventilation paradigm, which allows weaning of the mice from the ventilator. Furthermore, the commonly used isoflurane anesthesia induces vasodilation and is thereby inherently a vascular challenge. We therefore assessed perfusion differences in the mouse models under free-breathing isoflurane conditions. We report (i) that we can determine CBF and hypoventilation-based CVR under ketamine/midazolam anesthesia and wean mice from the ventilator, making it a valuable tool for assessment of CBF and CVR in mice, (ii) that biAT mice exhibit lower cortical CBF than wild-type mice at age 3 months, (iii) that CVR was increased in both biAT and APP.V717I mice but not in Tau.P301L mice, identifying the APP genotype as a strong influencer of brain CVR and (iv) that perfusion differences at baseline are masked by the widely used isoflurane anesthesia., (© 2018 John Wiley & Sons, Ltd.)

Objective: Quantitative ventilation monitoring and respiratory event detection are needed for the diagnosis of sleep apnea and hypoventilation. We developed a portable device with a chest belt, nasal cannula and finger sensor to continuously acquire multi-channel signals including tidal volume, nasal pressure, respiratory effort, body position, snoring sound, ECG and SpO 2 . The unique feature of the device is the continuous tidal volume signal obtained from real-time lung ventilation images produced by the electrical impedance tomography (EIT) technique., Approach: The chest belt includes 16 electrodes for real-time time-difference EIT imaging and ECG data acquisitions. It also includes a microphone, accelerometer, gyroscope, magnetometer and pressure sensor to acquire, respectively, snoring sound, respiratory effort, body position and nasal pressure signals. A separate finger sensor is used to measure SpO 2 . The minute ventilation signal is derived from the tidal volume signal and respiration rate., Main Results: The experimental results from a conductivity phantom, four swine subjects and one human volunteer show that the developed multi-parameter EIT device could supplement existing polysomnography (PSG) and home sleep test (HST) devices to improve the accuracy of sleep apnea diagnosis. The portable device could be also used as a new tool for continuous hypoventilation monitoring of non-intubated patients with respiratory depression., Significance: Following the feasibility study in this paper, future validation studies in comparison with in-lab PSG, HST and end-tidal CO 2 devices are suggested to find its clinical efficacy as a sleep apnea diagnosis and hypoventilation monitoring tool.

Objectives: To evaluate the sensitivity and specificity of a screening test panel for nocturnal hypoventilation (NH) and other sleep related respiratory events during monitoring of patients with chronic hypercapnic respiratory failure (CRF) treated with NIV., Methods: We performed a prospective study at Oslo University Hospital. Eligible for inclusion were consecutive adults with CRF due to neuromuscular diseases or chest wall disorders treated with NIV scheduled for a follow-up visit. All patients underwent the screening test panel (clinical evaluation, daytime arterial blood gas (ABG), nocturnal pulse oximetry (SpO 2 ) and data from ventilator software) and the reference tests; sleep polygraphy and nocturnal transcutaneous CO 2 ., Results: Of 67 patients included, NH was confirmed in 23-50 according to the 3 definitions used for NH, apnea-hypopnea index (AHI polygraphy ) ≥ 10 was confirmed in 16 and patient-ventilator asynchrony (PVA) ≥ 10% of total recording time in 14. Sensitivity of the combined screening test panel for NH was 87% (95% confidence interval 66-97), 84% (66-95) and 80% (66-90), for abnormal AHI polygraphy 91% (59-100) and for PVA 71% (42-92). Sensitivity for NH of SpO 2 was 48% (27-69), 39% (22-58) and 38% (24-53) and of daytime ABG 74% (52-90), 74% (55-88) and 68% (53-80). Sensitivity and specificity of AHI software for AHI polygraphy ≥ 10 was 93% (68-100) and 92% (81-98) respectively., Discussion: In patients treated with long term NIV, screening test panel, nocturnal SpO 2 and daytime ABG all failed to accurately detect NH, underlining the importance of nocturnal monitoring of CO 2 . AHI software accurately identified obstructive events and can be used to modify NIV settings., Trial Registration: N° NCT01845233., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Abstract: We report an unusual case of an adult patient carrying a germline PHOX2B frameshift mutation and hence was diagnosed with congenital central hypoventilation syndrome. He came to medical attention after the mutation was identified in his daughter who presented with hypoventilation and a neuroblastoma. Although PHOX2B mutations are usually associated with a phenotype of congenital hypoventilation, severe autonomic dysfunction and neural crest tumors, our patient had no complaints at the time of presentation. At polysomnography we found severe positional hypercapnic central sleep apnea, partly responsive to positional therapy. Eventually, he was titrated to noninvasive ventilation with resolution of the central breathing events and, in hindsight, a more refreshing sleep than before. Clinicians working in sleep medicine need to be aware of the variable expression of this rare condition to prevent late cardiorespiratory and neurocognitive complications., (© 2018 American Academy of Sleep Medicine.)

Sleep-disordered breathing (SDB) is relatively common in general population as well as in patients with neuromuscular disease. SDB comprises a wide spectrum of disorders varying from simple snoring to complete closure of the upper airway as seen in obstructive sleep apnoea (OSA). It includes also other disorders like prolonged hypoxemia, hypoventilation, and central sleep apnoea (CSA). Neuromuscular diseases (NMD) form a group of disorders that can cause significant reduction in the quality and span of life. The involvement of respiratory system in the context of these disorders is the most serious complication, and it is considered as the leading cause of death in those patients. NMD can affect ventilation, cough, swallowing, and phonation. The involvement of respiratory muscles makes NMD patients vulnerable to sleep-disordered breathing with a significant prevalence of SDB among such patients.

Objective: To establish international diagnostic criteria for Perry syndrome, a disorder characterised by clinical signs of parkinsonism, depression/apathy, weight loss, respiratory symptoms, mutations in the DCTN1 gene and TAR DNA-binding protein 43 (TDP-43) pathology., Methods: Data from the published literature and newly identified patients were gathered and analysed during and after the International Symposium on Perry syndrome in Tokyo to identify diagnostic criteria for Perry syndrome., Results: Eighty-seven patients with Perry syndrome carrying DCTN1 mutations from 20 families were included in this study, and common signs of the disorder were identified, including parkinsonism (95.2% of patients), depression/apathy (71.4%), respiratory symptoms (66.7%) and weight loss (49.2%)., Conclusions: Based on our findings, we propose the following definitive diagnostic criteria for Perry syndrome: the presence of four cardinal signs of Perry syndrome, accompanied by a mutation in DCTN1; or a family history of the disease, parkinsonism and a mutation in DCTN1 ; or the presence of four cardinal signs and pathological findings that include nigral neuronal loss and TDP-43 pathology. As patients with Perry syndrome present with uniform clinical, genetic and pathological features, we further propose the disorder be termed 'Perry disease.', Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. Patients with DS have a high risk of sudden unexplained death in epilepsy (SUDEP), widely believed to be due to cardiac mechanisms. Here we show that patients with DS commonly have peri-ictal respiratory dysfunction. One patient had severe and prolonged postictal hypoventilation during video EEG monitoring and died later of SUDEP. Mice with an Scn1aR1407X/+ loss-of-function mutation were monitored and died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures were induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea, bradycardia, and death were prevented by the same drugs given at doses high enough to cross the blood-brain barrier. When given via intracerebroventricular infusion at a very low dose, a muscarinic receptor antagonist prevented apnea, bradycardia, and death. We conclude that SUDEP in patients with DS can result from primary central apnea, which can cause bradycardia, presumably via a direct effect of hypoxemia on cardiac muscle.