Airway obstruction in two children with congenital central hypoventilation syndrome and review of the literature.

Congenital central hypoventilation syndrome (CCHS) is an autosomal dominant disease that is caused by heterozygous mutations in the paired-like homeobox 2B gene (PHOX2B). Madani et al. described an abnormally high degree of not only central apnea but also obstructive and mixed apnea in Phox2b27Ala/+newborn mice. Newborns with CCHS must undergo polysomnography for obstructive respiratory events in order to guide the optimal ventilation strategy if oxygen desaturation, bradycardia, and malaise persist under noninvasive ventilation. Newborns and infants with CCHS must be systematically tested for obstructive apnea, especially in cases of inefficient noninvasive ventilation.

Central sleep apnoea: not just one phenotype.

Recent scientific findings in the field of sleep disordered breathing have characterised a variety of phenotypes in obstructive sleep apnoea. These findings have prompted investigations aiming to achieve a more precise differentiation and description of the entities of central sleep apnoea (CSA). There is increasing evidence for the heterogeneity of CSA in terms of underlying aetiology, pathophysiological concepts, treatment response and outcome. Assigning patients to these phenotypes allows for the selection of individualised therapies. Major pathophysiological characteristics include loop gain, apnoeic threshold, breathing regulation and neuromuscular mechanics. Chronic heart failure is the most important underlying disease, leading to nonhypercapnic CSA based on increased loop and controller gain. Although many questions remain, this review tries to describe the current knowledge on the pathophysiology of the clinical entities. The description of prognostic aspects may guide treatment indication and the selection of pharmacotherapy and invasive options. In addition, the paper provides an update on the current understanding of adaptive servo-ventilation and its role in the treatment of CSA.

The epidemiological characteristics of sleep disordered breathing in congestive heart failure: A prospective, single centre study in Southeast Asia.

BACKGROUND: The presence of sleep-disordered breathing (SDB) in congestive heart failure (CHF) is associated with poor prognosis and is underdiagnosed despite advances in CHF management. The prevalence of SDB in CHF remains understudied in South East Asia. METHODS: A prospective, observational single-centre study was conducted where 116 consecutive patients in a specialised heart failure clinic underwent level 1, attended polysomnography (PSG). RESULTS: The prevalence of SDB was 78% using the apnoea-hypopnea index (AHI), AHI ⩾ 5/h threshold, and 59% with the AHI ⩾ 15/h threshold. Obstructive sleep apnoea (OSA) was the predominant type of SDB and was associated with increased body mass index and neck circumference. STOP-BANG was predictive of SDB, especially in men. Central sleep apnoea (CSA) patients had worse sleep indexes and lower awake arterial carbon dioxide. SDB was also homogenously present in preserved ejection fraction (EF) CHF. CONCLUSION: Most of the CHF patients were found to have SDB with the utility of PSG. Local CHF guidelines should include sleep testing for all patients with CHF.The study is registered on ClinicalTrials.gov (NCT05332223) as 'The Epidemiological Characteristics of SDB in Patients with Reduced or Preserved EF CHF'.

Association of Sex With Cardiovascular Outcomes in Heart Failure Patients With Obstructive or Central Sleep Apnea.

BACKGROUND: This study investigated the association of sex with cardiovascular outcomes in a prospective cohort of patients with heart failure (HF) with obstructive sleep apnea or central sleep apnea. METHODS AND RESULTS: Patients were screened for sleep apnea on admission using multichannel cardiopulmonary monitoring from May 2015 to July 2018. The primary outcome was a composite of cardiovascular death or unplanned hospitalization for worsening HF. Ultimately, 453 patients with HF with obstructive sleep apnea or central sleep apnea were included; 71 (15.7%) and 382 (84.3%) were women and men, respectively. During a median follow-up of 2.33 years, 248 (54.7%) patients experienced the primary outcome. In the overall population, after adjusting for potential confounders, women had an increased risk of the primary outcome (66.2% versus 52.6%; hazard ratio [HR], 1.47 [95% CI, 1.05-2.04]; P=0.024) and HF rehospitalization (62.0% versus 46.6%; HR, 1.55 [95% CI, 1.10-2.19]; P=0.013) compared with men but a comparable risk of cardiovascular death (21.1% versus 23.3%; HR, 0.78 [95% CI, 0.44-1.37]; P=0.383). Likewise, in patients with HF with obstructive sleep apnea, women had a higher risk of the primary outcome (81.8% versus 46.3%, HR, 2.37 [95% CI, 1.28-4.38]; P=0.006) and HF rehospitalization (81.8% versus 44.7%, HR, 2.46 [95% CI, 1.32-4.56], P=0.004). However, in patients with HF with central sleep apnea, there was no statistically significant difference between women and men. CONCLUSIONS: In hospitalized patients with HF, female sex was associated with an increased risk of the primary outcome and HF rehospitalization, especially in those with obstructive sleep apnea. Screening for sleep apnea should be emphasized to improve the prognosis. REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02664818.

Ictal Central Apnea Is Predictive of Mesial Temporal Seizure Onset: An Intracranial Investigation.

OBJECTIVE: Ictal central apnea (ICA) is a semiological sign of focal epilepsy, associated with temporal and frontal lobe seizures. In this study, using qualitative and quantitative approaches, we aimed to assess the localizational value of ICA. We also aimed to compare ICA clinical utility in relation to other seizure semiological features of focal epilepsy. METHODS: We analyzed seizures in patients with medically refractory focal epilepsy undergoing intracranial stereotactic electroencephalographic (SEEG) evaluations with simultaneous multimodal cardiorespiratory monitoring. A total of 179 seizures in 72 patients with reliable artifact-free respiratory signal were analyzed. RESULTS: ICA was seen in 55 of 179 (30.7%) seizures. Presence of ICA predicted a mesial temporal seizure onset compared to those without ICA (odds ratio = 3.8, 95% confidence interval = 1.3-11.6, p = 0.01). ICA specificity was 0.82. ICA onset was correlated with increased high-frequency broadband gamma (60-150Hz) activity in specific mesial or basal temporal regions, including amygdala, hippocampus, and fusiform and lingual gyri. Based on our results, ICA has an almost 4-fold greater association with mesial temporal seizure onset zones compared to those without ICA and is highly specific for mesial temporal seizure onset zones. As evidence of symptomatogenic areas, onset-synchronous increase in high gamma activity in mesial or basal temporal structures was seen in early onset ICA, likely representing anatomical substrates for ICA generation. INTERPRETATION: ICA recognition may help anatomoelectroclinical localization of clinical seizure onset to specific mesial and basal temporal brain regions, and the inclusion of these regions in SEEG evaluations may help accurately pinpoint seizure onset zones for resection. ANN NEUROL 2024;95:998-1008.

An unusual ophthalmologic finding in a patient with congenital central hypoventilation syndrome.

INTRODUCTION: Congenital Central Hypoventilation Syndrome (CCHS) is a rare disease due to a severely impaired central control of breathing and dysfunction of the autonomic nervous system. Ophthalmologic abnormalities are common in patients with CCHS and include horizontal strabismus, pupil and iris abnormalities and ptosis. We report a unique case of CCHS in association with monocular elevation deficit (MED) in a boy diagnosed with CCHS at birth. CASE DESCRIPTION: We report a case of a boy with a confirmed diagnosis of CCHS (complete sequencing of the paired-like homeobox 2b (PHOX2B) gene) after presenting little respiratory effort and cyanosis at birth. The ophthalmological examination shows an impaired elevation of the left eye, both in adduction and abduction, associated with mild and variable left ptosis. His mother has observed that the left eyelid elevates when the child feeds. A deviation in the primary gaze position or a chin-up position are not present. The funduscopic examination is normal. Given that deviation is limited to upgaze, the ptosis is mild and the patient's age, observation is decided. CONCLUSIONS: Ophthalmologic abnormalities are common in patients with CCHS and include horizontal strabismus, pupil and iris abnormalities and ptosis. To the best of our knowledge, this is the first report of MED in association with CCHS. Further studies are needed to determine if an association between MED and CCHS exists or is just a casual finding in this case.

Detecting central apneas using multichannel signals in premature infants.

Objective. Monitoring of apnea of prematurity, performed in neonatal intensive care units by detecting central apneas (CAs) in the respiratory traces, is characterized by a high number of false alarms. A two-step approach consisting of a threshold-based apneic event detection algorithm followed by a machine learning model was recently presented in literature aiming to improve CA detection. However, since this is characterized by high complexity and low precision, we developed a new direct approach that only consists of a detection model based on machine learning directly working with multichannel signals.Approach. The dataset used in this study consisted of 48 h of ECG, chest impedance and peripheral oxygen saturation extracted from 10 premature infants. CAs were labeled by two clinical experts. 47 features were extracted from time series using 30 s moving windows with an overlap of 5 s and evaluated in sets of 4 consecutive moving windows, in a similar way to what was indicated for the two-step approach. An undersampling method was used to reduce imbalance in the training set while aiming at increasing precision. A detection model using logistic regression with elastic net penalty and leave-one-patient-out cross-validation was then tested on the full dataset.Main results. This detection model returned a mean area under the receiver operating characteristic curve value equal to 0.86 and, after the selection of a FPR equal to 0.1 and the use of smoothing, an increased precision (0.50 versus 0.42) at the expense of a decrease in recall (0.70 versus 0.78) compared to the two-step approach around suspected apneic events.Significance. The new direct approach guaranteed correct detections for more than 81% of CAs with lengthL≥ 20 s, which are considered among the most threatening apneic events for premature infants. These results require additional verifications using more extensive datasets but could lead to promising applications in clinical practice.

[Study of GCN repeats of PHOX2B gene among individuals from southwest China and diagnosis of two patients with Congenital central hypoventilation syndrome].

OBJECTIVE: To study the trinucleotide repeats of GCN (GCA, GCT, GCC, GCG) encoding Alanine in exon 3 of the PHOX2B gene among healthy individuals from southwest China and two patients with Congenital central hypoventilation syndrome (CCHS). METHODS: The number and sequence of the GCN repeats of the PHOX2B gene were analyzed by capillary electrophoresis, Sanger sequencing and cloning sequencing of 518 healthy individuals and two newborns with CCHS, respectively. RESULTS: Among the 1036 alleles of the 518 healthy individuals, five alleles were identified, including (GCN)7, (GCN)13, (GCN)14, (GCN)15 and (GCN)20. The frequency of the (GCN)20 allele was the highest (94.79%). And five genotypes were identified, which included (GCN)7/(GCN)20, (GCN)13/(GCN)20, (GCN)14/(GCN)20, (GCN)15/(GCN)20, (GCN)20/(GCN)20. The homozygous genotypes were all (GCN)20/(GCN)20, and the carrier rate was 89.58%. Four GCN sequences of the (GCN)20 homozygous genotypes were identified among the 464 healthy individuals. The GCN repeat numbers in the exon 3 of the PHOX2B gene showed no significant difference between the expected and observed values, and had fulfilled the,Hardy-Weinberg equilibrium. The genotypes of the two CCHS patients were (GCN)20/(GCN)25 and (GCN)20/(GCN)30, respectively. CONCLUSION: It is important to determine the GCN repeats and genotypic data of the exon 3 of the PHOX2B gene among the healthy individuals. The number of GCN repeats in 518 healthy individuals was all below 20. The selection of appropriate methods can accurately detect the polyalanine repeat mutations (PARMs) of the PHOX2B gene, which is conducive to the early diagnosis, intervention and treatment of CCHS.

Central Sleep Apnea in Patients With Coronary Heart Disease Taking P2Y12 Inhibitors.

ABSTRACT: Central sleep apnea (CSA) is common in patients with heart failure. Recent studies link ticagrelor use with CSA. We aimed to evaluate CSA prevalence in patients with coronary heart disease (CHD) and whether ticagrelor use is associated with CSA. We reviewed consecutive patients with CHD who underwent a polysomnography (PSG) test over a 5-year period from 3 sleep centers. We sampled patients who were on ticagrelor or clopidogrel during a PSG test at a 1:4 ticagrelor:clopidogrel ratio. Patients with an active opioid prescription during PSG test were excluded. Age, left ventricle (LV) dysfunction, and P2Y12 inhibitor use were included in a multivariate logistic regression. A total of 135 patients were included with 26 on ticagrelor and 109 on clopidogrel (age 64.1 ± 11.4, 32% male). High CSA burden (12%) and strict CSA (4.4%) were more common in patients on ticagrelor than in those on clopidogrel (27% vs. 8.3% and 10.0% vs. 1.8%). Ticagrelor use (vs. clopidogrel) was associated with high CSA burden (OR 3.53, 95% CI 1.04-12.9, P = 0.039) and trended toward significance for strict CSA (OR 6.32, 95% CI 1.03-51.4, P = 0.052) when adjusting for age and LV dysfunction. In an additional analysis also adjusting for history of atrial fibrillation, ticagrelor use and strict CSA became significantly associated (OR 10.0, 95% CI 1.32-117, P = 0.035). CSA was uncommon in patients with CHD undergoing sleep studies. Ticagrelor use (vs. clopidogrel) was associated with high CSA burden and trended toward significance for strict CSA.

Sleep disordered breathing assessment in patient with slowly progressive neuromuscular disease.

BACKGROUND: Sleep-disordered breathing (SDB) is common in patients with neuromuscular diseases (NMD). Focusing on hypercapnia may lead to the neglect of other SDB such as obstructive and/or central sleep apnea syndrome (SAS). Our objectives were to assess the risk of inappropriate SDB management according to different screening strategies and to evaluate the prevalence and determinants of isolated and overlapping sleep apnea in patients with slowly progressive NMD. METHODS: This monocentric, cross-sectional, retrospective study analyzed medical records of adult NMD patients referred to a sleep department. Diagnostic strategies, including respiratory polygraphy (RP), nocturnal transcutaneous capnography (tcCO2), and blood gases (BG), were assessed for their performance in diagnosing SDB. Demographics and pulmonary function test results were compared between patients with or without SDB to identify predictors. RESULTS: Among the 149 patients who underwent a full diagnostic panel (RP + tcCO2 + BG), 109 were diagnosed with SDB. Of these, 33% had isolated SAS, and central apneas were predominant. Using single diagnostic strategies would lead to inappropriate SDB management in two thirds of patients. A combination of 2 diagnostic tools resulted respectively in 21.1, 22.9 and 42.2 % of inappropriate SDB management for RP + tcCO2, RP + BG and tcCO2 + BG. CONCLUSION: The significant prevalence of sleep apnea syndrome in patients with slowly progressive NMD highlights the need for increased awareness among clinicians. Improved diagnostics involve a systematic approach addressing both sleep apnea and diurnal and nocturnal alveolar hypoventilation to avoid inappropriate management and limit the consequences of SDB.

Predictors of Initial CPAP Prescription and Subsequent Course with CPAP in Patients with Central Sleep Apneas at a Single Center.

PURPOSE: Guidelines recommend considering an initial trial of continuous positive airway pressure (CPAP) to treat central sleep apnea (CSA). However, practice patterns vary widely. This study investigated predictors for an initial trial of CPAP in patients with central apneas and whether those factors predict adequate treatment response in patients receiving an initial CPAP trial. METHODS: Charts of patients receiving a diagnostic code for CSA following a sleep study during 2016-2018 at a single center were reviewed. Patient factors, initial treatment prescriptions, and subsequent changes to therapy were extracted from electronic health records. Regression models were used to estimate factors associated with an initial CPAP prescription and the likelihood of an adequate CPAP response (no subsequent therapy change and no discontinuation of therapy) among patients prescribed CPAP. RESULTS: 429/588 (73%) patients with central apneas received an initial trial of CPAP. Younger age, diagnosis by home sleep testing, non-opiate etiology of central apneas, and a lower proportion of central apneas at diagnosis were independently associated with a higher likelihood of an initial CPAP trial. A lower proportion of central apneas was associated with a higher probability of adequate response, while current smoking and opiate-related central apneas predicted an unsuccessful CPAP trial. A new finding was that older age predicted a lower likelihood of an initial CPAP prescription but did not predict an unsatisfactory response to CPAP. CONCLUSION: Clinicians may incorrectly weigh certain clinical and sleep study characteristics when deciding whether to trial CPAP for patients with central apneas.

Sleep disordered breathing in infants identified through newborn screening with spinal muscular atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) is a genetic disorder that may result in neuromuscular weakness and respiratory insufficiency. Gene replacement therapy has changed the trajectory of this condition, but long-term outcomes related to sleep disordered breathing are not known. METHODS: This was a retrospective review of infants with SMA identified via newborn screening who subsequently received onasemnogene abeparvovec at the Hospital for Sick Children (Ontario, Canada). Polysomnograms were conducted at the time of confirmed diagnosis as well as regularly thereafter. RESULTS: Eleven children (4 female) were identified via newborn screen (7 with 2 copies of the SMN2 gene and 4 with 3 copies of the SMN2 gene) and received onasemnogene abeparvovec at a median age of 3.6 weeks. All eleven infants met criteria for sleep disordered breathing based on their first completed polysomnograms but improved over time. Three infants required respiratory technology, including a premature infant who was prescribed nocturnal supplemental oxygen therapy for central sleep apnea and two symptomatic infants with neuromuscular weakness who required nocturnal noninvasive ventilation. We did not find a correlation between motor scores and polysomnogram parameters. CONCLUSION: Children treated with onasemnogene abeparvovec have reduced sleep disordered breathing over time. Polysomnograms revealed abnormal parameters in all children, but the clinical significance of these findings was unclear for children who were asymptomatic for sleep disordered breathing or neuromuscular weakness. These results highlight the need to evaluate both motor scores and respiratory symptoms to ensure a holistic evaluation of clinical status.

Occurrence of sleep-disordered breathing in children with pulmonary hypertension.

BACKGROUND: Obstructive sleep apnea (OSA) has been associated with pulmonary hypertension (PH) through a complex and bidirectional relationship. The prevalence of OSA and other forms of sleep-disordered breathing (SDB) among children with PH is not well understood. A better understanding could help elucidate contributing factors for PH, guide diagnostic testing, and inform therapies. We therefore determined the proportion of SDB codiagnosis and OSA risk factors among a cohort of children with PH. METHODS: Retrospective chart review was performed for children 0-21 years old with PH who underwent polysomnography (PSG) between 1 January 2010 and 31 August 2020. The primary outcome was OSA occurrence and risk based on demographics, diagnoses, and PH classification. The secondary outcome was occurrence and risk of other SDB diagnoses based on PH classification. RESULTS: Among 89 children identified, diagnoses included OSA (N = 79, 89%), central sleep apnea (N = 11, 12%), sleep-related hypoventilation (N = 6, 7%), and non-apneic hypoxemia (N = 28, 31%). Trisomy 21 diagnosis (N = 38, 43%) was associated with increased OSA risk (RR: 1.24, 95% CI: [1.09-1.42]) and age >12 months at PSG was associated with decreased OSA risk (N = 52, 58%, RR: 0.60, 95% CI: [0.45-0.81]). There was no difference in SDB risk based on Group 1 (N = 56, 63%) or Group 3 (N = 33, 37%) PH and no difference in OSA severity based on demographics and diagnoses. CONCLUSION: OSA was diagnosed among a majority of children with PH, and other SDB diagnoses were identified in a significant proportion of children. These findings support routine screening for SDB with PSG in children with PH.

Contribution of central sleep apnea to severe sleep apnea hypopnea syndrome.

PURPOSE: Central sleep apnea (CSA) is usually distinguished from obstructive sleep apnea (OSA). In fact, CSA is often a component of severe sleep apnea hypopnea syndrome (SAHS), rather than occurring alone. We investigated the clinical characteristics and polysomnography (PSG) parameters of CSA components in patients with severe SAHS. METHODS: The clinical characteristics and PSG parameters were retrospectively analyzed. RESULTS: Pure or dominant CSA was rare (5% of all patients). Of all patients with CSA, 72% also exhibited other apnea subtypes that contributed to severe SAHS. Among patients with severe SAHS, those with CSA were more likely than others to be older; thinner; exhibit higher prevalences of comorbid coronary heart disease, arrhythmia, and heart failure; a higher apnea/hypopnea index (AHI); mixed apnea index (MAI); an elevated oxygen desaturation index (ODI); and more nighttime oxygen saturation levels < 90%. Multivariate logistic regression analysis revealed that older age, comorbid arrhythmia or heart failure, and an elevated ODI were independently associated with CSA. CONCLUSION: Patients who complain of snoring or apnea may be better evaluated by comprehensive PSG prior to treatment if they are old, show greater hypoxia, or suffer from arrhythmia and/or heart failure, because such patients are more likely than others to exhibit CSA.

Congenital central hypoventilation syndrome without hypoventilation: is it congenital central hypoventilation syndrome?

Congenital central hypoventilation syndrome (CCHS) is a rare condition caused by pathogenic variants of the PHOX2B gene. There have been case reports describing variable phenotypes and mutations of the PHOX2B gene, not commonly tested for, that may challenge the classic definition of CCHS. We report on 3 family members with a rare heterozygous deletion encompassing the entire PHOX2B gene with variable phenotypes, including sleep-disordered breathing and autonomic nervous system involvement, but an unexpected lack of alveolar hypoventilation, which is usually a defining feature of CCHS. Our cases highlight the dilemmas in making a diagnosis of CCHS and emphasize the need for expanded genetic testing, including for PHOX2B gene deletion. More patients with variable phenotypes of CCHS may be identified through comprehensive genetic testing and warrant surveillance as they are still at risk for high-risk complications of CCHS. CITATION: Wo LL, Itani R, Keens TG, Marachelian A, Ji J, Perez IA. Congenital central hypoventilation syndrome without hypoventilation: is it congenital central hypoventilation syndrome? J Clin Sleep Med. 2023;19(6):1161-1164.