Central Hypoventilation Syndrome Research Articles

Congenital Central Hypoventilation Syndrome in Israel-Novel Findings from a New National Center.

Congenital central hypoventilation syndrome (CCHS) is a rare autosomal-dominant disorder of the autonomic nervous system that results from mutations in the PHOX2B gene. A national CCHS center was founded in Israel in 2018. Unique new findings were observed. All 27 CCHS patients in Israel were contacted and followed. Novel findings were observed. The prevalence of new CCHS cases was almost twice higher compared to other countries. The most common mutations in our cohort were polyalanine repeat mutations (PARM) 20/25, 20/26, 20/27 (combined = 85% of cases). Two patients showed unique recessive inheritance while their heterozygotes family members were asymptomatic. A right-sided cardio-neuromodulation was performed on an eight-year-old boy for recurrent asystoles by ablating the parasympathetic ganglionated plexi using radiofrequency (RF) energy. Over 36 months' follow-up with an implantable loop-recorder, no bradycardias/pauses events were observed. A cardiac pacemaker was avoided. A significant benefit and new information arise from a nationwide expert CCHS center for both clinical and basic purposes. The incidence of CCHS in some populations may be increased. Asymptomatic NPARM mutations may be much more common in the general population, leading to an autosomal recessive presentation of CCHS. RF cardio-neuromodulation offers a novel approach to children avoiding the need for permanent pacemaker implantation.

Control of Breathing and Central Hypoventilation Syndromes.

Control of breathing in children varies with age and sleep state. There is overlap between central hypoventilation, autonomic dysfunction, and hypothalamic dysfunction in the rare disorders (congenital central hypoventilation syndrome and rapid-onset obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysregulation). Other, more common disorders that typically present in childhood also include central hypoventilation and disordered ventilatory responses.

Neurogenic hypertension characterizes children with congenital central hypoventilation syndrome and is aggravated by alveolar hypoventilation during sleep.

Autonomic nervous system (ANS) dysfunction characterizes congenital central hypoventilation syndrome (CCHS). The objectives were to describe ambulatory blood pressure monitoring (ABPM) of children with CCHS, to assess cardiac ANS dysfunction as compared with control participants and to search for relationships between ANS dysfunction and blood pressure (BP) or night-time PCO 2 measurements. Retrospective study of ABPM of children with CCHS and case (CCHS)-control (healthy children) study of heart rate variability (HRV) indices obtained during polysomnography (wakefulness, nonrapid eye movement sleep, rapid eye movement sleep, and whole night). The HRV indices analyzed were low, high-frequency powers, low frequency/high frequency, and for the whole night, SD1/SD2. Twenty-four children with CCHS (14 girls) who underwent 81 ABPM (2-6/patient, 74 after 4 years) were included in the longitudinal study. Hypertension was evidenced in 29 of 45 (64%) ABPM made between 5 and 9 years of age as compared with 12 of 36 (33%) ABPM made between 10 and 17 years of age ( P = 0.005). In the case-control study (12 pairs), as compared with control children, children with CCHS were characterized by a decreased HRV while awake, which was aggravated at night. In children with CCHS, at daytime, SBP percentiles positively correlated with low-frequency power ( R = -0.82; P = 0.001), while at night-time, SBP percentiles negatively correlated with SD1/SD2 ( R = -0.79; P = 0.010). The SD1/SD2 ratio also negatively correlated with median PCO 2 under mechanical ventilation ( R = -0.69; P = 0.013). Neurogenic hypertension is frequent in CCHS and correlates with ANS dysfunction, which also correlates with alveolar ventilation during mechanical ventilation.

1046 Severe hypoventilation in a child with rapid onset weight gain

Abstract Introduction Pediatric sleep-related hypoventilation is a clinical pattern in which ventilatory insufficiency occurs in the setting of either severe OSA (obstructive hypoventilation) or obesity hypoventilation (sleep related hypoventilation). We are reporting a case describing the management of overlapping obstructive hypoventilation due to uncontrolled severe OSA and pediatric obesity hypoventilation syndrome. Report of case(s) The patient is a full term African American 5 y/o male with past medical history of obesity and prediabetes who was referred to discuss sleep related problems after rapid onset of weight gain.He gained 76 lbs over 8-month period; during this time his aunt noticed apneic events with the development of loud snoring.Initial workup was negative for abnormal findings,MRI w/w/o was unremarkable and TSH, cortisol, GH, IGF-1 and prolactin were all within normal limits. X-ray bone age study showed skeletal age appropriate for patient's chronologic age.Upper airway exam showed severe tonsillar hypertrophy 3+ with Mallampati class 4.The diagnostic PSG demonstrated the presence of 12 obstructive, 151 central, and 61 mixed apneas.There were 214 hypopneas resulting in an Apnea\Hypopnea Index of 60.5 events per hour.Mean oxygen saturation was 91.3%.The lowest oxygen saturation during sleep was 64.0%.Time spent ≤88% oxygen saturation was 119.7 minutes (26.2%). End tidal CO2 range was between 50-100 mmHg for 30% of study.The titration study revealed that the optimal treatment modality was BiPAP ST. Conclusion This case focuses on a five-year-old male who experienced rapid onset weight gain and presented with snoring, excessive daytime sleepiness and apneic events and was found to have profound hypoventilation with hypopnea predominant severe obstructive sleep apnea.The initial differential diagnosis of pediatric sleep-related hypoventilation includes ROHHAD, congenital central hypoventilation syndrome, primary central sleep apnea and obesity hypoventilation syndrome.The most common cause of hypoventilation during sleep in children remains OSA.The stepwise approach to management in such a case includes tonsillectomy with adenoidectomy,along with use of BiPAP. After the T&A the patient should have repeat PSG with capnography, if hypercarbia persists on post procedure PSG, he will need to continue BiPAP therapy with appropriate weight loss program. Early recognition evaluation, and treatment of obstructive sleep apnea in the pediatric population is imperative to prevent long-term consequences. Support (if any)

0901 An odd presentation of a hidden curse

Abstract Introduction Congenital central hypoventilation syndrome (CCHS) is a rare disorder of respiratory deficiency due to a mutation in the PHOX2B gene. Clinical presentation may be mild in certain individuals due to different levels of ventilatory dysregulation. Methods We present the findings of exogenous ventilatory challenge testing and polysomnography (PSG) performed on a normocapnic adult female with late-onset (LO) CCHS patient. Results The patient was exposed to four separate ventilatory challenges. During exposure to hyperoxia using 100% oxygen (O2) administration, patient showed an inconsistent ventilatory response with a blunted and delayed increase in regional tissue oxygen saturation (rSO2). During hyperoxic hypercapnia with 5% carbon dioxide (CO2) and 95% O2, she demonstrated a reduced ventilatory response based on respiratory rate and tidal volume. During hypoxic hypercapnia, 7% CO2 and 14% O2, patient demonstrated a delayed and markedly attenuated ventilatory response. Hypoxia; 100% nitrogen inhalation did not result in increased ventilation. Ve slope, change in minute ventilation/change in end-tidal CO2 (EtCO2), with hypercapnia challenges was 4.88, which is lower than normal. Ventilatory EtCO2 threshold was 36 mmHg. PSG showed apnea-hypopnea index 3.3 with hypoxemia during rapid eye movement (REM), with an oxygen saturation nadir of 84%. EtCO2 baseline was around 36, peak was 50 and was associated with REM-related apnea events. Arterial blood gas was unremarkable. Conclusion CCHS is characterized by abnormal respiratory response to exogenous ventilatory challenge testing. Hyperoxia silences peripheral chemoreceptors (PC) responsible for stimulating ventilation in normal individuals. Hyperoxic hypercapnia silences PC but stimulates central chemoreceptors (CC). Hypoxic hypercapnia stimulates hyperventilation via both PC and CC. Our patient demonstrated inconsistent and reduced ventilatory responses to all four challenges. As expected, the classic chemosensory parameter, Ve slope, for hypercarbia challenge was markedly reduced. However, the ventilatory EtCO2 threshold fell well below threshold typically observed in CCHS. PSG noted greater alveolar hypoventilation during REM compared to non-REM, which is also atypical for CCHS. In conclusion, exogenous ventilatory challenge testing demonstrated derangements in ventilatory control typical in CCHS. Despite this, our patient had no evidence of daytime hypoventilation with normal CO2 threshold. This case illustrates the phenotypic variability present in LO-CCHS. Support (if any)

Congenital central hypoventilation syndrome (Ondine’s curse)

Pediatricians and neonatologists often deal with a variety of causes of respiratory failure. Most algorithms for the diagnosis and treatment of such conditions are well developed. However, the diagnosis of some rare causes of respiratory disorders is still challenging. The aim of this review is to present current literature data on a very rare autosomal dominant disorder – congenital central hypoventilation syndrome (Ondine’s curse). This syndrome is manifested by the absence of spontaneous breathing due to a congenital genetic defect, namely the expansion of the polyalanine tract in the PHOX2B gene on chromosome 4p12. Conclusion. Issues of pathogenesis, diagnosis, clinical variants, treatment, and prognosis of this disease are discussed.

Ondine's curse: clinical presentation with diaphragmatic pacing and spontaneous respiratory recovery. Illustrative case.

The complexity of posterior fossa surgery can often lead to rare complications due to the anatomy involved. Vestibular schwannoma resection is a common pathology in the posterior fossa, often requiring surgical intervention. Given the proximity of this space to the brainstem, cranial nerve VII/VIII complex, and posterior inferior cerebellar artery (PICA), neurovascular complications are not infrequent. A rare vascular complication from this surgical approach is a lateral medullary infarction from injury to the lateral medullary segment of the proximal PICA, leading to central hypoventilation syndrome (CHS). This report presents a unique case of a 51-year-old man who underwent a retrosigmoid craniectomy for resection of a vestibular schwannoma. Following surgery, the patient was unable to be weaned off the ventilator and was noted to become apneic while he slept, a clinical picture consistent with Ondine's curse. This report discusses the anatomical considerations of this surgical corridor leading to this complication and the management of a patient with acquired Ondine's curse and reviews the scarce literature on this uncommon cause of acquired CHS.

Сongenital central hypoventilation syndrome. Experience Almazov National Medical Research Centre

The article provides a brief review of the etiopathogenetic aspects of congenital central hypoventilation syndrome with an emphasis on genotype-phenotypic correlations, and highlights approaches to ventilatory support. Based on the data of the local register, the experience of Almazov National Medical Research Centre is summarised. A systematic multidisciplinary approach to the treatment and rehabilitation of children with congenital central hypoventilation syndrome that has been implemented provides the most favorable results in preserving neurological and intellectual potential and quality of life.

Clinical Features of COVID-19 in Patients with Congenital Central Hypoventilation Syndrome.

Background: The clinical course of COVID-19 in patients with congenital central hypoventilation syndrome (CCHS) is unknown. Methods: We conducted a cross-sectional questionnaire study in 43 patients with CCHS who had COVID-19. Results: The median age of patients was 11 [interquartile range (IQR) 6-22] years and 53.5% required assisted ventilation (AV) through tracheostomy. Disease severity ranged from asymptomatic infection (12%) to severe illness with hypoxemia (33%) and hypercapnia requiring emergency care/hospitalization (21%), increased AV duration (42%), increased ventilator settings (12%), and supplemental oxygen demand (28%). The median duration to return to baseline AV (n = 20) was 7 (IQR 3-10) days. Patients with polyalanine repeat mutations required increased AV duration compared with those with nonpolyalanine repeat mutations (P = 0.048). Patients with tracheostomy required increased oxygen during illness (P = 0.02). Patients aged ≥18 years took longer to return to baseline AV (P = 0.04). Conclusions: Our study suggests that all patients with CCHS should be vigilantly monitored during COVID-19 illness.

Phox2ba: The Potential Genetic Link behind the Overlap in the Symptomatology between CHARGE and Central Congenital Hypoventilation Syndromes.

CHARGE syndrome typically results from mutations in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7). CHD7 is involved in regulating neural crest development, which gives rise to tissues of the skull/face and the autonomic nervous system (ANS). Individuals with CHARGE syndrome are frequently born with anomalies requiring multiple surgeries and often experience adverse events post-anesthesia, including oxygen desaturations, decreased respiratory rates, and heart rate abnormalities. Central congenital hypoventilation syndrome (CCHS) affects ANS components that regulate breathing. Its hallmark feature is hypoventilation during sleep, clinically resembling observations in anesthetized CHARGE patients. Loss of PHOX2B (paired-like homeobox 2b) underlies CCHS. Employing a chd7-null zebrafish model, we investigated physiologic responses to anesthesia and compared these to loss of phox2b. Heart rates were lower in chd7 mutants compared to the wild-type. Exposure to tricaine, a zebrafish anesthetic/muscle relaxant, revealed that chd7 mutants took longer to become anesthetized, with higher respiratory rates during recovery. chd7 mutant larvae demonstrated unique phox2ba expression patterns. The knockdown of phox2ba reduced larval heart rates similar to chd7 mutants. chd7 mutant fish are a valuable preclinical model to investigate anesthesia in CHARGE syndrome and reveal a novel functional link between CHARGE syndrome and CCHS.

Analysis and comparisons of gene expression changes in patient- derived neurons from ROHHAD, CCHS, and PWS.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome is an ultra-rare neurocristopathy with no known genetic or environmental etiology. Rapid-onset obesity over a 3-12 month period with onset between ages 1.5-7 years of age is followed by an unfolding constellation of symptoms including severe hypoventilation that can lead to cardiorespiratory arrest in previously healthy children if not identified early and intervention provided. Congenital Central Hypoventilation syndrome (CCHS) and Prader-Willi syndrome (PWS) have overlapping clinical features with ROHHAD and known genetic etiologies. Here we compare patient neurons from three pediatric syndromes (ROHHAD, CCHS, and PWS) and neurotypical control subjects to identify molecular overlap that may explain the clinical similarities. Dental pulp stem cells (DPSC) from neurotypical control, ROHHAD, and CCHS subjects were differentiated into neuronal cultures for RNA sequencing (RNAseq). Differential expression analysis identified transcripts variably regulated in ROHHAD and CCHS vs. neurotypical control neurons. In addition, we used previously published PWS transcript data to compare both groups to PWS patient-derived DPSC neurons. Enrichment analysis was performed on RNAseq data and downstream protein expression analysis was performed using immunoblotting. We identified three transcripts differentially regulated in all three syndromes vs. neurotypical control subjects. Gene ontology analysis on the ROHHAD dataset revealed enrichments in several molecular pathways that may contribute to disease pathology. Importantly, we found 58 transcripts differentially expressed in both ROHHAD and CCHS patient neurons vs. control neurons. Finally, we validated transcript level changes in expression of ADORA2A, a gene encoding for an adenosine receptor, at the protein level in CCHS neurons and found variable, although significant, changes in ROHHAD neurons. The molecular overlap between CCHS and ROHHAD neurons suggests that the clinical phenotypes in these syndromes likely arise from or affect similar transcriptional pathways. Further, gene ontology analysis identified enrichments in ATPase transmembrane transporters, acetylglucosaminyltransferases, and phagocytic vesicle membrane proteins that may contribute to the ROHHAD phenotype. Finally, our data imply that the rapid-onset obesity seen in both ROHHAD and PWS likely arise from different molecular mechanisms. The data presented here describes important preliminary findings that warrant further validation.

0994 Neuroblastoma as the Initial Manifestation of Familial PHOX2B NPARM Positive Congenital Central Hypoventilation Syndrome

Abstract Introduction Congenital Central Hypoventilation Syndrome (CCHS) is a genetic disorder of the autonomic nervous system caused by mutations in the PHOX2B gene. Children with CCHS often present as neonates in hypoxemic, hypercarbic respiratory failure. Most causative mutations are de novo Polyalanine Repeat Mutations (PARMs). Non-Polyalanine Repeat Mutations (NPARMs) have been associated with more severe disease, specifically the need for 24-hour ventilatory support, Hirschsprung disease, and neural crest tumors; however, NPARMs may have variable expressivity and incomplete penetrance, resulting in delayed or atypical presentations. We report a toddler with maxillary sinus neuroblastoma, which led to the diagnosis of familial PHOX2B NPARM positive CCHS. Report of case(s) A two-year-old boy presented with right-sided facial swelling. A facial CT uncovered a right maxillary sinus lytic lesion, and biopsy confirmed neuroblastoma. After full recovery from the procedure, he had persistent nocturnal hypoxemia and hypercapnia requiring bilevel positive airway pressure (PAP) during sleep, raising concern for CCHS. Genetic testing revealed a novel PHOX2B NPARM, c.428dup, which likely causes a frameshift and premature protein termination (p.Val144Glyfs*34). His maternal grandfather, mother and brothers tested positive for the same mutation. Family history revealed that his maternal grandfather and maternal great-uncles had frequent childhood apneic spells associated with syncope, his maternal grandfather is currently on nocturnal bilevel PAP, and his mother almost drowned as a younger child while having a breath-holding contest under water. His six-year-old brother underwent polysomnography which showed hypoventilation, now managed with bilevel PAP. His five-year-old brother also underwent polysomnography and does not require nocturnal ventilatory support at this time. Conclusion We report a rare case of familial PHOX2B NPARM positive CCHS which initially presented as maxillary sinus neuroblastoma. Additionally, the child and his family display varying disease severity despite having the same NPARM, highlighting the variable expressivity in this novel NPARM. Support (if any) None

PO-02-232 CARDIONEURAL ABLATION IN THE MANAGEMENT OF LONG QT SYNDROME, TYPE 7

Vasovagal syncope is a complex interaction of neurologic and cardiovascular mechanisms resulting in cardiac inhibition by the parasympathetic nervous system via the vagus nerve and associated ganglionic plexi. Some types of tachycardia may be induced by bradycardia, LQT type 3 being the most common example. In these patients, a pacemaker is sometimes indicated to avoid the bradycardia trigger for tachycardia. Cardioneural ablation (CNA) is an emerging therapy that offers the potential of abolishing vagal-induced bradycardia. It is most commonly used to treat vasovagal syncope but it may also provide benefit to patients with bradycardia-induced tachyarrhythmias. We present a case of a patient with Long QT type 7 with vasovagal syncope who had an asystolic pause which induced a run of nonsustained VT. Cardioneural ablation was utilized to avoid bradycardia, with the intention of avoiding future triggering of VT. An 8-year-old female with a past-medical history of Andersen-Tawil Syndrome (Long QT Syndrome type 7). She had two syncopal events which suggested a vagal etiology. After loop monitor placement, she had a third syncopal event, which recorded a period of sinus bradycardia, culminating in a 6.3 second asystolic pause, followed by a 6 beat run of VT, with cycle length of 200-260 msec. Cardioneural ablation was considered as a means of avoiding future bradycardic events. Procedure was performed under general anesthesia. Electroanatomic mapping (Ensite Precision) was used to create 3D cardiac geometry. The same system, coupled with transthoracic ultrasound, was also used to guide transseptal puncture. Sinus bradycardia could be induced at baseline with vagal stimulation. Areas of fractionated signals were mapped to the high atrial septum between the right upper pulmonary vein and the fossa ovalis; and also in the roof of the coronary sinus. Patient was known to have a persistent left SVC to the coronary sinus. These areas were targeted for ablation. Post ablation, she had no bradycardia inducible with vagal stimulation. She tolerated the procedure well, without complication. CNA shows potential promise in the treatment of vasovagal syncope. However, there may be other clinical settings in which it finds utility. Conditions which might benefit include Andersen-Tawil syndrome, Long QT type 3, Brugada syndrome, and possibly Congenital Central Hypoventilation syndrome. Further investigation is needed to elucidate the safety and efficacy of CNA in these settings.

Teaching NeuroImages: Ondine curse syndrome caused by dorsolateral medullary stroke

A 68-year-old man with an acute left dorsolateral medullary infarction (figure) had recurrent episodes of hypercarbic respiratory failure with sleep during hospitalization. While awake, the patient ventilated adequately, but when asleep, the patient developed a severe respiratory acidosis (pH 7.14, pCO2 >107) and became unarousable. He was intubated and his mentation improved rapidly. Eventually, he had a tracheostomy placed and continued to have prolonged apneic episodes with sleep during spontaneous breathing trials. The patient did not have central sleep apnea prior to the stroke.

Decannulation in congenital central hypoventilation syndrome.

Patients with congenital central hypoventilation syndrome (CCHS) require long-term ventilation to ensure gas exchange and to prevent deleterious consequences for neurocognitive development. Two ventilation modes may be used for these patients depending on their tolerance, one invasive by tracheostomy and the other noninvasive (NIV). For patients who have undergone a tracheostomy, transition to NIV is possible when they meet predefined criteria. Identifying the conditions favorable for weaning from a tracheostomy is critical for the success of the process. The aim of the study was to share our experience of decannulation in a reference center; we hereby describe the modality of ventilation and its effect on nocturnal gas exchange before and after tracheostomy removal. Retrospective observational study at Robert Debré Hospital over the past 10 years. The modalities of decannulation and transcutaneous carbon dioxide recordings or polysomnographies before and after decannulation were collected. Sixteen patients underwent decannulation following a specific procedure for transition from invasive to NIV. All decannulations were successful. The median age at decannulation was 12.6 [9.4; 14.1] years. Nocturnal gas exchange was not significantly different before and after decannulation, while expiratory positive airway pressure and inspiratory time increased significantly. An oronasal interface was chosen in two out of three patients. The median duration of hospital stay for decannulation was 4.0 [3.8; 6.0] days. Our study underlines that decannulation and transition to NIV are achievable in CCHS children using a well-defined procedure. Patient preparation is crucial to the success of the process.

Abstract Number ‐ 113: A Lateral Medullary Infarct Complicated by Central Hypoventilation Syndrome

Introduction A 43‐year‐old male with no known past medical history presented to a primary stroke center for sudden onset headache, nausea, vomiting, and dizziness while driving. A computed tomography angiogram of the head and neck revealed a left vertebral artery occlusion, and the patient was transferred to our comprehensive stroke center for further evaluation and treatment. Upon arrival at our facility, the patient was noted to have a national institute of health stroke scale score of 7 with left facial droop, dysarthria, and right upper extremity dysmetria. A cerebral angiogram revealed a tortuous left vertebral artery with dissection in the V4 segment. Subsequent brain diffusion weighted imaging revealed an acute infarct in the right lateral medulla measuring 1.4cm and several acute cerebellar infarcts. (fig. 1) In the postangiography period, the patient had dysphagia, sialorrhea, multiple aspiration episodes, and oral secretions requiring early tracheostomy and percutaneous endoscopic gastrostomy on hospital day (HD) #6. The subsequent hospital course was complicated by prolonged singultus lasting until HD #23 and repetitive vomiting requiring a transition from a gastric to a gastro‐jejunal feeding tube. Methods A central hypoventilation syndrome (CHS) prolonged ventilator weaning. Despite preserved ability to take large‐volume voluntary breaths, the patient experienced multiple episodes of sleep‐associated apnea and rapid shallow breathing pattern during daily spontaneous breathing trials (SBT). The apnea episodes were registered with ventilator apnea alarms set at 20 seconds. This pattern continued when attempting an SBT utilizing a T‐piece adaptor. The ability to maintain adequate minute ventilation in an asleep state subsequently improved, and the patient was able to tolerate 48 hours of spontaneous breathing with no apnea on HD #35. Results Few cases of CHS secondary to lateral medullary infarction (LMI) have been documented in the literature.(1‐3) As the respiratory drive originates from neurons in the latero‐rostro‐ventral medulla, infarcts in this brainstem region may lead to respiratory failure. More specifically to our patient, ataxic breathing may result from lesions in the rostro‐ventral medulla with yawning and hiccups being seen in lesions to the posterolateral medulla.(4) As our patient presented with a sizable 1.4cm lesion, likely impairing these brainstem centers, it is expected that his symptoms would account for multiple respiratory symptoms. The unique feature of the acquired CHS in the setting of LMI is its unilateral location implying lateralization of the respiratory control. In addition to the aforementioned symptoms, his lesion likely led to prolonged weaning from the ventilator as has been described previously.(5) Conclusions This case raises awareness regarding potentially disastrous complications of the lateral medullary syndrome like central hypoventilation syndrome. We urge caution and careful evaluation of patients with lateral medullary infarctions for disorders of the respiratory control system.

Serotonin and the ventilatory effects of etonogestrel, a gonane progestin, in a murine model of congenital central hypoventilation syndrome.

Congenital Central Hypoventilation Syndrome, a rare disease caused by PHOX2B mutation, is associated with absent or blunted CO2/H+ chemosensitivity due to the dysfunction of PHOX2B neurons of the retrotrapezoid nucleus. No pharmacological treatment is available. Clinical observations have reported non-systematic CO2/H+ chemosensitivity recovery under desogestrel. Here, we used a preclinical model of Congenital Central Hypoventilation Syndrome, the retrotrapezoid nucleus conditional Phox2b mutant mouse, to investigate whether etonogestrel, the active metabolite of desogestrel, led to a restoration of chemosensitivity by acting on serotonin neurons known to be sensitive to etonogestrel, or retrotrapezoid nucleus PHOX2B residual cells that persist despite the mutation. The influence of etonogestrel on respiratory variables under hypercapnia was investigated using whole-body plethysmographic recording. The effect of etonogestrel, alone or combined with serotonin drugs, on the respiratory rhythm of medullary-spinal cord preparations from Phox2b mutants and wildtype mice was analyzed under metabolic acidosis. c-FOS, serotonin and PHOX2B were immunodetected. Serotonin metabolic pathways were characterized in the medulla oblongata by ultra-high-performance liquid chromatography. We observed etonogestrel restored chemosensitivity in Phox2b mutants in a non-systematic way. Histological differences between Phox2b mutants with restored chemosensitivity and Phox2b mutant without restored chemosensitivity indicated greater activation of serotonin neurons of the raphe obscurus nucleus but no effect on retrotrapezoid nucleus PHOX2B residual cells. Finally, the increase in serotonergic signaling by the fluoxetine application modulated the respiratory effect of etonogestrel differently between Phox2b mutant mice and their WT littermates or WT OF1 mice, a result which parallels with differences in the functional state of serotonergic metabolic pathways between these different mice. Our work thus highlights that serotonin systems were critically important for the occurrence of an etonogestrel-restoration, an element to consider in potential therapeutic intervention in Congenital Central Hypoventilation Syndrome patients.

The Use of Caffeine Citrate for Respiratory Stimulation in Acquired Central Hypoventilation Syndrome: A Case Series.

Caffeine is commonly used as a respiratory stimulant for the treatment of apnea of prematurity in neonates. However, there are no reports to date of caffeine used to improve respiratory drive in adult patients with acquired central hypoventilation syndrome (ACHS). We report two cases of ACHS who were successfully liberated from mechanical ventilation after caffeine use, without side effects. The first case was a 41-year-old ethnic Chinese male, diagnosed with high-grade astrocytoma in the right hemi-pons, intubated and admitted to the intensive care unit (ICU) in view of central hypercapnia with intermittent apneic episodes. Oral caffeine citrate (1600mg loading followed by 800mg once daily) was initiated. His ventilator support was weaned successfully after 12 days. The second case was a 65-year-old ethnic Indian female, diagnosed with posterior circulation stroke. She underwent posterior fossa decompressive craniectomy and insertion of an extra-ventricular drain. Post-operatively, she was admitted to the ICU and absence of spontaneous breath was observed for 24 hours. Oral caffeine citrate (300mg twice daily) was initiated and she regained spontaneous breath after 2 days of treatment. She was extubated and discharged from the ICU. Oral caffeine was an effective respiratory stimulant in the above patients with ACHS. Larger randomized controlled studies are needed to determine its efficacy in the treatment of ACHS in adult patients.

Staying alert with polyhydramnios; an Ondine syndrome case

Abstract Objectives Amniotic fluid is essential for proper fetal development. In the case of severe polyhydramnios associated with low fetal growth, a number of different underlying disorders must be considered. One such condition is congenital central hypoventilation syndrome (CCHS) or Ondine’s curse, a rare genetic disease caused by mutation of the PHOX2B gene. The incidence of CCHS is estimated to be 1 case in 200,000 live births. No publications have been made to date on the intrauterine period findings. This precludes an early intrauterine diagnosis and impedes ethically responsible therapeutic options. Case presentation A 37-year-old patient presented in her second pregnancy with a small for gestation fetus and severe polyhydramnios evidenced in the third trimester ultrasound (US) study. There were no previous signs of maternal diabetes or fetal abnormalities at US. During the immediate postpartum period, the newborn presented repeated apneas with cyanosis and hypo-responsiveness. Neonatal arterial blood gas testing revealed severe respiratory acidosis requiring orotracheal intubation and admission to the Neonatal Intensive Care Unit. Over the following days, all imaging and functional test findings were within normal ranges. A de novo pathogenic PHOX2B variant was identified. Conclusions Despite a high mortality rate, no neurological sequelae or other systemic diseases were recorded, thanks to multidisciplinary and coordinated follow-up.

Ventilatory and Orthostatic Challenges Reveal Biomarkers for Neurocognition in Children and Young Adults With Congenital Central Hypoventilation Syndrome

Children and young adults with congenital central hypoventilation syndrome (CCHS) are at risk of cognitive deficits. They experience autonomic dysfunction and chemoreceptor insensitivity measured during ventilatory and orthostatic challenges, but relationships between these features are undefined. Can a biomarker be identified from physiologic responses to ventilatory and orthostatic challenges that is related to neurocognitive outcomes in CCHS? This retrospective study included 25 children and young adults with CCHS tested over an inpatient stay. Relationships between physiologic measurements during hypercarbic and hypoxic ventilatory challenges, hypoxic ventilatory challenges, and orthostatic challenges and neurocognitive outcomes (by Wechsler intelligence indexes) were examined. Independent variable inclusion was determined by significant associations in Pearson's analyses. Multivariate linear regressions were used to assess relationships between measured physiologic responses to challenges and neurocognitive scores. Significant relationships were identified between areas of fluid intelligence and measures of oxygen saturation (SpO2) and heart rate (HR) during challenges. Specifically, perceptual reasoning was related to HR (adjusted regression [β] coefficient, -0.68; 95%CI, 1.24 to -0.12; P= .02) during orthostasis. Working memory was related to change in HR (β, -1.33; 95%CI, -2.61 to -0.05; P= .042) during the hypoxic ventilatory challenge. Processing speed was related to HR (β, -1.19; 95%CI, -1.93 to -0.46; P= .003) during orthostasis, to baseline SpO2 (hypercarbic and hypoxic β, 8.57 [95%CI, 1.63-15.51]; hypoxic β, 8.37 [95%CI, 3.65-13.11]; P= .002 for both) during the ventilatory challenges, and to intrachallenge SpO2 (β, 5.89; 95%CI, 0.71-11.07; P= .028) during the hypoxic ventilatory challenge. In children and young adults with CCHS, SpO2 and HR-or change in HR-at rest and as a response to hypoxia and orthostasis are related to cognitive outcomes in domains of known risk, particularly fluid reasoning. These findings can guide additional research on the usefulness of these as biomarkers in understanding the impact of daily physical stressors on neurodevelopment in this high-risk group.