Alkalosis-induced hypoventilation in cystic fibrosis: The importance of efficient renal adaptation.

The lungs and kidneys are pivotal organs in the regulation of body acid-base homeostasis. In cystic fibrosis (CF), the impaired renal ability to excrete an excess amount of HCO3- into the urine leads to metabolic alkalosis [P. Berg et al., J. Am. Soc. Nephrol. 31, 1711-1727 (2020); F. Al-Ghimlas, M. E. Faughnan, E. Tullis, Open Respir. Med. J. 6, 59-62 (2012)]. This is caused by defective HCO3- secretion in the ß-intercalated cells of the collecting duct that requires both the cystic fibrosis transmembrane conductance regulator (CFTR) and pendrin for normal function [P. Berg et al., J. Am. Soc. Nephrol. 31, 1711-1727 (2020)]. We studied the ventilatory consequences of acute oral base loading in normal, pendrin knockout (KO), and CFTR KO mice. In wild-type mice, oral base loading induced a dose-dependent metabolic alkalosis, fast urinary removal of base, and a moderate base load did not perturb ventilation. In contrast, CFTR and pendrin KO mice, which are unable to rapidly excrete excess base into the urine, developed a marked and transient depression of ventilation when subjected to the same base load. Therefore, swift renal base elimination in response to an acute oral base load is a necessary physiological function to avoid ventilatory depression. The transient urinary alkalization in the postprandial state is suggested to have evolved for proactive avoidance of hypoventilation. In CF, metabolic alkalosis may contribute to the commonly reduced lung function via a suppression of ventilatory drive.

Cerebral Autoregulation during Orthostatic Challenge in Congenital Central Hypoventilation Syndrome.

Rationale: Congenital central hypoventilation syndrome (CCHS) is a rare autonomic disorder with altered regulation of breathing, heart rate (HR), and blood pressure (BP). Aberrant cerebral oxygenation in response to hypercapnia/hypoxia in CCHS raises the concern that altered cerebral autoregulation may contribute to CCHS-related, variably impaired neurodevelopment. Objectives: To evaluate cerebral autoregulation in response to orthostatic challenge in CCHS cases versus controls. Methods: CCHS and age- and sex-matched control subjects were studied with head-up tilt (HUT) testing to induce orthostatic stress. Fifty CCHS and 100 control HUT recordings were included. HR, BP, and cerebral oxygen saturation (regional oxygen saturation) were continuously monitored. The cerebral oximetry index (COx), a real-time measure of cerebral autoregulation based on these measures, was calculated. Measurements and Main Results: HUT resulted in a greater mean BP decrease from baseline in CCHS versus controls (11% vs. 6%; P < 0.05) and a diminished increase in HR in CCHS versus controls (11% vs. 18%; P < 0.01) in the 5 minutes after tilt-up. Despite a similar COx at baseline, orthostatic provocation within 5 minutes of tilt-up caused a 50% greater increase in COx (P < 0.01) and a 29% increase in minutes of impaired autoregulation (P < 0.02) in CCHS versus controls (4.0 vs. 3.1 min). Conclusions: Cerebral autoregulatory mechanisms appear to be intact in CCHS, but the greater hypotension observed in CCHS consequent to orthostatic provocation is associated with greater values of COx/impaired autoregulation when BP is below the lower limits of autoregulation. Effects of repeated orthostatic challenges in everyday living in CCHS necessitate further study to determine their influence on neurodevelopmental disease burden.

Respiratory depressant effects of fentanyl analogs are opioid receptor-mediated.

Opioid-related fatalities involving synthetic opioids have reached unprecedented levels. This study evaluated the respiratory depressant effects of seven fentanyl analogs that have either emerged in the illicit drug supply or been identified in toxicological analyses following fatal or non-fatal intoxications. Adult male Swiss Webster mice were administered fentanyl analogs (isobutyrylfentanyl, crotonylfentanyl, para-methoxyfentanyl, para-methoxybutyrylfentanyl, 3-furanylfentanyl, thiophenefentanyl, and benzodioxolefentanyl) and their effects on minute volume as compared to mu-opioid receptor (MOR) agonist standards (fentanyl, morphine, and buprenorphine) were measured using whole body plethysmography (WBP). All drugs elicited significant (p ≤ 0.05) hypoventilation relative to vehicle for at least one dose tested: morphine (1, 3.2, 10, 32 mg/kg), buprenorphine, (0.032, 0.1, 0.32, 1, 3.2 mg/kg), fentanyl (0.0032, 0.01, 0.032, 0.1, 1, 32 mg/kg), isobutyrylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), crotonylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para-methoxyfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para-methoxybutyrylfentanyl (0.32, 1, 3.2, 10 mg/kg), 3-furanylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), thiophenefentanyl (1, 3.2, 10, 32, 100 mg/kg), and benzodioxolefentanyl (3.2, 10, 32, 100 mg/kg). The ED50 values for hypoventilation showed a rank order of potency as follows: fentanyl (ED50 = 0.96 mg/kg) > 3-furanylfentanyl (ED50 = 2.60 mg/kg) > crotonylfentanyl (ED50 = 2.72 mg/kg) > para-methoxyfentanyl (ED50 = 3.31 mg/kg) > buprenorphine (ED50 = 10.8 mg/kg) > isobutyrylfentanyl (ED50 = 13.5 mg/kg) > para-methoxybutyrylfentanyl (ED50 = 16.1 mg/kg) > thiophenefentanyl (ED50 = 18.0 mg/kg) > morphine (ED50 = 55.3 mg/kg) > benzodioxolefentanyl (ED50 = 10,168 mg/kg). A naloxone pretreatment (10 mg/kg) attenuated the hypoventilatory effects of all drugs. These results establish that the respiratory depressant effects of these fentanyl analogs are at least in part mediated by the MOR.

Gavage approach to oxygen supplementation with oxygen therapeutic Ox66™ in a hypoventilation rodent model of respiratory distress.

Acute respiratory distress syndrome (ARDS) features pulmonary dysfunction capable of causing life-threatening hypoxaemia. Ventilation and hyperoxic therapies force oxygen through dysfunctional alveoli but risk exacerbating damage. Ox66™ is an ingestible, solid-state oxygen product designed for oxygen supplementation. Eighteen anaesthetized, ventilated rats were subjected to a 40% reduction in tidal volume to produce a hypoventilatory simulation of the hypoxia in ARDS (HV-ARDS). After 60 min, animals were randomized to receive either normal saline (Saline; volume control) or Ox66™ gavage. Cardiovascular function and blood oximetry/chemistry were measured alongside interstitial oxygenation (PISFO2) of the peripheral spinotrapezius muscle. HV-ARDS reduced mean arterial pressure by ∼20% and PISFO2 by ∼35% for both groups. Ox66™ gavage treatment at 60 min improved PISFO2 over Saline (p < .0001), restoring baseline values, however, the effect was temporary. A second bolus at 120 min repeated the OX66™ PISFO2 response, which remained elevated over Saline (p < .01) until study end and was supported by systemic parameters of lactate, PaO2, SO2, and base deficit. Saline remained hypotensive, whereas Ox66™ became normotensive. Vasoconstriction was observed in the Saline, but not Ox66™ group. Supplemental oxygenation through Ox66™ gavage increased peripheral tissue oxygenation, warranting further study for disorders featuring dysfunction of pulmonary perfusion like ARDS.

Obstructive Apneas in a Mouse Model of Congenital Central Hypoventilation Syndrome.

Rationale: Congenital central hypoventilation syndrome (CCHS) is characterized by life-threatening sleep hypoventilation and is caused by PHOX2B gene mutations, most frequently the PHOX2B27Ala/+ mutation, with patients requiring lifelong ventilatory support. It is unclear whether obstructive apneas are part of the syndrome. Objectives: To determine if Phox2b27Ala/+ mice, which present the main symptoms of CCHS and die within hours after birth, also express obstructive apneas, and to investigate potential underlying mechanisms. Methods: Apneas were classified as central, obstructive, or mixed by using a novel system combining pneumotachography and laser detection of abdominal movement immediately after birth. Several respiratory nuclei involved in airway patency were examined by immunohistochemistry and electrophysiology in brainstem-spinal cord preparations. Measurements and Main Results: The median (interquartile range) of obstructive apnea frequency was 2.3 (1.5-3.3)/min in Phox2b27Ala/+ pups versus 0.6 (0.4-1.0)/min in wild types (P < 0.0001). Obstructive apnea duration was 2.7 seconds (2.3-3.9) in Phox2b27Ala/+ pups versus 1.7 seconds (1.1-1.9) in wild types (P < 0.0001). Central and mixed apneas presented similar significant differences. In Phox2b27Ala/+ preparations, the hypoglossal nucleus had fewer (P < 0.05) and smaller (P < 0.01) neurons, compared with wild-type preparations. Importantly, coordination of phrenic and hypoglossal motor activities was disrupted, as evidenced by the longer and variable delay of hypoglossal activity with respect to phrenic activity onset (P < 0.001). Conclusions: The Phox2b27Ala/+ mutation predisposed pups not only to hypoventilation and central apneas, but also to obstructive and mixed apneas, likely because of hypoglossal dysgenesis. These results thus demand attention toward obstructive events in infants with CCHS.

Hypoxia inducible factor 1-α is minimally involved in determining the time domains of the hypoxic ventilatory response in adult zebrafish (Danio rerio).

In the current study, adult zebrafish (Danio rerio) were exposed to 72 h hypoxia (90 mmHg) to assess the time domains of the hypoxia ventilatory response (HVR) and the consequence on a subsequent more severe (40 mmHg) bout of acute hypoxia. Experiments were performed on wild-type fish and mutants in which one or both paralogs of hypoxia inducible factor-1α (hif-1α) were knocked out. Although there were subtle differences among the wild-type and knockout fish, resting fV was reestablished after 2-8 h of continuous hypoxia in both groups, a striking example of hypoxic ventilatory decline (HVD). When fish were subsequently exposed to more severe hypoxia, a rapid increase in fV was observed, the magnitude of which was independent of genotype or prior exposure history. During recovery, fish that had been exposed to 72 h of 90 mmHg hypoxia exhibited a pronounced undershoot in fV, which was absent in the hif-1α double knockouts. Overall, the results revealed distinct time domains of the HVR in zebrafish that were largely Hif-1α-independent.

Neonatal apneic phenotype in a murine congenital central hypoventilation syndrome model is induced through non-cell autonomous developmental mechanisms.

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 CO2 and/or O2 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.

The severity of sleep hypoventilation in stable chronic obstructive pulmonary disease.

PURPOSE: An increase in PaCO2 is the element that defines sleep hypoventilation (SH). We queried if patients with SH, and those with PaCO2 increases during sleep for shorter time periods than SH (shamSH) differed from the patients without SH (noSH) in other ways. METHODS: This was a retrospective re-analysis of data from 100 stable inpatients with COPD with and without chronic hypercapnic respiratory failure. COPD was defined by criteria of the Global initiative for Chronic Obstructive Lung Disease (GOLD). For this study, SH was defined by an increase in PaCO2 ≥ 1.33 kPa to a value exceeding 6.7 kPa for ≥ 10 min (≥ 20 epochs of 30 s). Patients fulfilling the increase in PaCO2 for less than 10 min (1-19 epochs) were designated shamSH. All patients had daytime arterial blood gases, lung function tests, and polysomnography (PSG) with transcutaneous CO2 (PtcCO2). RESULTS: Of 100 patients, 25 had PtcCO2 increase ≥ 1.33 kPa. One never exceeded 6.7 kPa, 15 had SH, and 9 shamSH. SH and shamSH patients had extra CO2 load (= PtcCO2*time) both during and between the SH periods compared to the noSH group, the SH group more than the shamSH group. CONCLUSION: Using CO2 load as a measure of severity of sleep hypoventilation, SH patients have worse hypoventilation than the shamSH. Both shamSH and SH groups have extra CO2 load during and between SH periods, indicating that the SH/shamSH patients may represent a separate group of true hypoventilators during sleep.

The Effect of Tonsillectomy and Adenoidectomy on Isolated Sleep Associated Hypoventilation in Children.

OBJECTIVE: Sleep associated hypoventilation (SAH) is diagnosed when more than 25% of total sleep time (%TST) is spent with end tidal carbon dioxide (EtCO2 ) > 50 mmHg. SAH in children occurs as a single entity or combined with obstructive sleep apnea. Outcomes of surgical treatment for isolated SAH in children have not been reported. METHODS: The medical charts of children who were diagnosed with isolated SAH and did not have OSA at a tertiary children's hospital between January 2013 and December 2019 were reviewed. Data collection included information on history and physical examination, past medical history, polysomnography (PSG) findings, and surgical management. RESULTS: Seventeen children (10 male, 7 female, age range: 3-14 years) were diagnosed with isolated SAH. Comorbid conditions included asthma in four children, Down syndrome in one, and seizure in two. Eight children were normal weight, four were overweight, and five were obese. Children did not have obstructive or central sleep apnea. Three children (18%) had persistent SAH as documented by PSG. All normal weight children had resolution of SAH whereas two obese children and one overweight child had residual SAH. %TST with CO2 > 50 mmHg after upper airway surgery (3.4% ± 1.6%) was significantly less than that of before TA (59.1% ± 5.5%) (P < .001). CONCLUSIONS: The majority of children with isolated SAH had normalization of hypercapnia after TA. Further studies in larger groups of children are needed to identify the risk factors for residual isolated SAH after TA. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1380-E1382, 2021.

Sleep-disordered breathing, respiratory patterns during wakefulness and functional capacity in pediatric patients with rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation syndrome.

OBJECTIVE: To characterize the clinical presentation of sleep-disordered breathing and respiratory patterns at rest and during a 6-min walk test (6MWT) in children with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome. METHODS: Retrospective study of children with ROHHAD who had a diagnostic baseline polysomnography, daytime cardiorespiratory monitoring at rest and a 6MWT. Polysomnography data were also compared with body mass index-, age-, and sex-matched controls. RESULTS: Of the eight children with ROHHAD, all eight (100%) had obstructive sleep apnea (OSA) and 2/8 (25%) had nocturnal hypoventilation (NH) on their baseline polysomnography. Comparing the ROHHAD group to the control group, there were no significant differences in the median (interquartile range [IQR]) obstructive apnea-hypopnea index (11.1 [4.3-58.4] vs. 14.4 [10.3-23.3] events/h, respectively; p = .78). However, children with ROHHAD showed a significantly higher desaturation index compared to the control group (37.9 [13.7-59.8] vs. 14.7 [4.3-27.6] events/h; p = .05). While awake at rest, some children with ROHHAD experienced significant desaturations associated with central pauses. During the 6MWT, no significant desaturations were observed, but two children showed moderate functional limitation. CONCLUSIONS: Among children with ROHHAD, respiratory instability may be demonstrated by a significant number and severity of oxygen desaturations during sleep in the presence of OSA, with or without NH, and oxygen desaturations with central pauses at rest during wakefulness. Interestingly, during daily activities that require submaximal effort, children may not experience oxygen desaturations. Early recognition of respiratory abnormalities and targeted therapeutic interventions are important to limit associated morbidity and mortality in ROHHAD.

Trastorno de hipoventilación central del sueño en pediatría: causas poco frecuentes / Central hypoventilation disorders sleep-related in pediatrics: unusual causes

Congenital central hypoventilation syndrome (CCHS) and rapid-onset obesity syndrome with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) are rare causes of hypoventilation during sleep in the pediatric population. This group of disorders are characterized by the absence or decrease in the automatic control of ventilation, decreased sensitivity of chemoreceptors to CO2, causing hypoventilation during sleep and even in wakefulness, in the most severe cases. For these reasons it is important to diagnose and treat them promptly. The objective of this review is to provide current and complete literature, to be able to identify, treat and refer this group of children early, and thus reduce the complications and/or associated comorbidities in the short and long term, improving their quality of life.

El síndrome de hipoventilación central congénita (CCHS) y síndrome de obesidad de inicio rápido con disfunción hipotalámica, hipoventilación y desregulación autonómica (ROHHAD), son causas poco comunes de hipoventilación durante el sueño en la población pediátrica. Este grupo de trastornos se caracterizan por ausencia o disminución en el control automático de la ventilación, sensibilidad disminuida de los quimioreceptores al CO2, provocando hipoventilación durante el sueño e incluso en vigilia, en los casos más severos. Por estas razones es importante diagnosticarlos y tratarlos oportunamente. El objetivo de esta revisión es proporcionar literatura actual y completa, para poder identificar, tratar y referir a éste grupo de niños tempranamente, y así disminuir las complicaciones y/o comorbilidades asociadas a corto y largo plazo, mejorando su calidad de vida.

Breath holding as an example of extreme hypoventilation: experimental testing of a new model describing alveolar gas pathways.

NEW FINDINGS: What is the central question of this study? We modelled the alveolar pathway during breath holding on the hypothesis that it follows a hypoventilation loop on the O2 -CO2 diagram. What is the main finding and its importance? Validation of the model was possible within the range of alveolar gas compositions compatible with consciousness. Within this range, the experimental data were compatible with the proposed model. The model and its characteristics might allow predictions of alveolar gas composition whenever the alveolar ventilation goes to zero; for example, static and dynamic breath holding at the surface or during ventilation/intubation failure in anaesthesia. ABSTRACT: According to the hypothesis that alveolar partial pressures of O2 and CO2 during breath holding (BH) should vary following a hypoventilation loop, we modelled the alveolar gas pathways during BH on the O2 -CO2 diagram and tested it experimentally during ambient air and pure oxygen breathing. In air, the model was constructed using the inspired and alveolar partial pressures of O2 ( PIO2 and PAO2 , respectively) and CO2 ( PICO2 and PACO2 , respectively) and the steady-state values of the pre-BH respiratory exchange ratio (RER). In pure oxygen, the model respected the constraint of PACO2=-PAO2+PIO2 . To test this, 12 subjects performed several BHs of increasing duration and one maximal BH at rest and during exercise (30 W cycling supine), while breathing air or pure oxygen. We measured gas flows, PAO2 and PACO2 before and at the end of all BHs. Measured data were fitted through the model. In air, PIO2  = 150 ± 1 mmHg and PICO2  = 0.3 ± 0.0 mmHg, both at rest and at 30 W. Before BH, steady-state RER was 0.83 ± 0.16 at rest and 0.77 ± 0.14 at 30 W; PAO2  = 107 ± 7 mmHg at rest and 102 ± 8 mmHg at 30 W; and PACO2  = 36 ± 4 mmHg at rest and 38 ± 3 mmHg at 30 W. By model fitting, we computed the RER during the early phase of BH: 0.10 [95% confidence interval (95% CI) = 0.08-0.12] at rest and 0.13 (95% CI = 0.11-0.15) at 30 W. In oxygen, model fitting provided PIO2 : 692 (95% CI = 688-696) mmHg at rest and 693 (95% CI = 689-698) mmHg at 30 W. The experimental data are compatible with the proposed model, within its physiological range.

Long-term survival following initiation of home non-invasive ventilation: a European study.

INTRODUCTION: Although home non-invasive ventilation (NIV) is increasingly used to manage patients with chronic ventilatory failure, there are limited data on the long-term outcome of these patients. Our aim was to report on home NIV populations and the long-term outcome from two European centres. METHODS: Cohort analysis including all patients established on home NIV from two European centres between 2008 and 2014. RESULTS: Home NIV was initiated in 1746 patients to treat chronic ventilatory failure caused by (1) obesity hypoventilation syndrome±obstructive sleep apnoea (OHS±OSA) (29.5%); (2) neuromuscular disease (NMD) (22.7%); and (3) obstructive airway diseases (OAD) (19.1%). Overall cohort median survival following NIV initiation was 6.6 years. Median survival varied by underlying aetiology of respiratory failure: rapidly progressive NMD 1.1 years, OAD 2.7 years, OHS±OSA >7 years and slowly progressive NMD >7 years. Multivariate analysis demonstrated higher mortality in patients with rapidly progressive NMD (HR 4.78, 95% CI 3.38 to 6.75), COPD (HR 2.25, 95% CI 1.64 to 3.10), age >60 years at initiation of home NIV (HR 2.41, 95% CI 1.92 to 3.02) and NIV initiation following an acute admission (HR 1.38, 95% CI 1.13 to 1.68). Factors associated with lower mortality were NIV adherence >4 hours per day (HR 0.64, 95% CI 0.51 to 0.79), OSA (HR 0.51, 95% CI 0.31 to 0.84) and female gender (HR 0.79, 95% CI 0.65 to 0.96). CONCLUSION: The mortality rate following initiation of home NIV is high but varies significantly according to underlying aetiology of respiratory failure. In patients with chronic respiratory failure, initiation of home NIV following an acute admission and low levels of NIV adherence are poor prognostic features and may be amenable to intervention.

Perinatal exposure to ethanol in rats induces permanent disturbances of breathing and chemosensitivity during adulthood.

Perinatal exposure to drugs of abuse, including alcohol (ethanol), is known to impinge the development of respiratory function. However, most studies described the short-term effects of these exposures, focusing mostly on the early postnatal life. After exposure to ethanol during gestation and lactation we have previously shown that 3-4 week-old rat exhibit chronic hypoventilation and an altered response to hypoxia at the end of ethanol exposure. However, whether these deficits are reversible following ethanol withdrawal remained unknown. Here, we investigated through whole-body plethysmography the respiratory activity of 2 months-old rats exposed to ethanol from gestation to weaning followed by one month of ethanol withdrawal. After ethanol withdrawal, rats persistently exhibited a significant reduction in respiratory frequency without change in tidal volume associated to a lower arterial blood oxygen content. In addition, the response to hypoxia in these rats was reduced whereas the response to hypercapnia remained unaltered. In conclusion perinatal exposure to ethanol in rats, unlike exposure to cocaine, morphine or nicotine, is characterized by selective alterations of basal respiratory activity and chemosensitivity that persist long after withdrawal.

Consensus-Based Care Recommendations for Pulmonologists Treating Adults with Myotonic Dystrophy Type 1.

PURPOSE OF REVIEW: Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects approximately 1 in 2,500 individuals globally [Ashizawa et al.: Neurol Clin Pract 2018;8(6):507-20]. In patients with DM1, respiratory muscle weakness frequently evolves, leading to respiratory failure as the main cause of death in this patient population, followed by cardiac complications [de Die-Smulders et al.: Brain 1998;121(Pt 8):1557-63], [Mathieu et al.: Neurology 1999;52(8):1658-62], [Groh et al.: Muscle Nerve 2011;43(5):648-51]. This paper provides a more detailed outline on the diagnostic and management protocols, which can guide pulmonologists who may not have experience with DM1 or who are not part of a neuromuscular multidisciplinary clinic. A group of neuromuscular experts in DM1 including pulmonologists, respiratory physiotherapists and sleep specialists discussed respiratory testing and management at baseline and during follow-up visits, based on their clinical experience with patients with DM1. The details are presented in this report. RECENT FINDINGS: Myotonic recruited 66 international clinicians experienced in the treatment of people living with DM1 to develop and publish consensus-based care recommendations targeting all body systems affected by this disease [Ashizawa et al.: Neurol Clin Pract. 2018;8(6):507-20]. Myotonic then worked with 12 international respiratory therapists, pulmonologists and neurologists with long-standing experience in DM respiratory care to develop consensus-based care recommendations for pulmonologists using a methodology called the Single Text Procedure. This process generated a 7-page document that provides detailed respiratory care recommendations for the management of patients living with DM1. This consensus is completely based on expert opinion and not backed up by empirical evidence due to limited clinical care data available for respiratory care management in DM patients. Nevertheless, we believe it is of relevance for professionals treating adults with myotonic dystrophy because it addresses practical issues related to respiratory management and care, which have been adapted to meet the specific issues in patients with DM1. SUMMARY: The resulting recommendations are intended to improve respiratory care for the most vulnerable of DM1 patients and lower the risk of untoward respiratory complications and mortality by providing pulmonologist who are less experienced with DM1 with practical indications on which tests and when to perform them, adapting the general respiratory knowledge to specific issues related to this multiorgan disease.

Perry syndrome: a case of atypical parkinsonism with confirmed DCTN1 mutation.

Perry syndrome is a rare neurological condition characterised clinically by depression, sleep disturbance, central hypoventilation and parkinsonism. Perry syndrome is a TAR DNA-binding protein 43 (TDP-43) proteinopathy associated with mutated dynactin-1 protein, inherited in an autosomal dominant manner. Several pathogenic mutations in exon 2 in the dynactin 1 gene have been identified; p. F521, p. G67d, p. G71R, p. G71E, p. G71A, p. T72p, p. Q74p and p. Y78C. We present the second known case Perry syndrome with confirmed DCTN1 mutation (p. Y78C) in New Zealand, who initially was thought to have a depressive illness. Perry syndrome should be considered in the differential diagnosis of young parkinsonism, especially if there is family history of sleep disorders, weight loss and/or marked depression.

Clinical features of children with Haddad syndrome: A single-center experience.

BACKGROUND/PURPOSE: Haddad syndrome (HS) is a very rare disease considered a form of neurocristopathy. It is characterized by a combination of congenital central hypoventilation syndrome (CCHS) and Hirschsprung's disease (HD). We report the clinical features and disease progression of HS to provide better care for HS patients by achieving an earlier diagnosis and optimal treatment. METHODS: Medical records of patients diagnosed with HS from 2005 to 2016 were retrospectively reviewed. Demographic data including gestational age, birth weight and height, and paired-like homeobox 2b (PHOX2B) gene mutation were collected. RESULTS: Seven males and three females were identified (mean gestational age 39.76 ±â€¯1.49 weeks, mean birth weight 3117.5 ±â€¯288.9 g). PHOX2B gene mutation was identified in all patients. Immediate ventilation care after birth was required in five patients due to poor respiration. The current median age of the children is 5.4 years (range, 1.8-10.1). Tracheostomy was performed in nine patients. Eight patients required sleep ventilation and two patients, 24-h continuous ventilation support. Six patients showed rectosigmoid aganglionosis and four patients exhibited total colonic aganglionosis, of these one had aganglionosis extended to the distal small bowel. Soiling was observed in seven patients (5 with laparoscopy-assisted transanal endorectal pull-through and 2 with Duhamel procedure) and one patient showed grade 2 constipation with Duhamel procedure. Six patients had developmental delay. All patients are alive. CONCLUSIONS: HS may require lifelong medical care. This study could be helpful to understand the clinical features of HS including associated abnormalities and disease progression. By assisting to understand the clinical features, we could provide better care for HS patients by achieving an earlier diagnosis and appropriate treatment. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: Level IV.

Sleep disordered breathing (SDB) in neonates and implications for its long-term impact.

Sleep-disordered breathing (SDB) is a significant cause of morbidity in neonates and young infants. SDB occurs more commonly in preterm infants and in neonates with underlying syndromes. Recent evidence shows that infants with obstructive sleep apnoea (OSA) or SDB have greater health care resource utilization, including longer hospital stay. Management of SDB includes non-invasive ventilation or surgical interventions tailored to the patient. Screening high risk newborns should allow for early diagnosis and timely therapeutic intervention for this population. However, the thresholds for diagnosing SDB and for guiding and implementing treatment in neonates remain unclear. A collective effort is required to standardize the practice worldwide. This article will discuss neonatal sleep physiology and characteristics of neonatal sleep, with an emphasis on the epidemiology and diagnosis of SDB in neonates and its implications for long term outcomes.