Congenital Hypoventilation Research Articles

Genetic identification of medullary neurons underlying congenital hypoventilation.

Mutations in the transcription factors encoded by PHOX2B or LBX1 correlate with congenital central hypoventilation disorders. These conditions are typically characterized by pronounced hypoventilation, central apnea, and diminished chemoreflexes, particularly to abnormally high levels of arterial PCO2. The dysfunctional neurons causing these respiratory disorders are largely unknown. Here, we show that distinct, and previously undescribed, sets of medullary neurons coexpressing both transcription factors (dB2 neurons) account for specific respiratory functions and phenotypes seen in congenital hypoventilation. By combining intersectional chemogenetics, intersectional labeling, lineage tracing, and conditional mutagenesis, we uncovered subgroups of dB2 neurons with key functions in (i) respiratory tidal volumes, (ii) the hypercarbic reflex, (iii) neonatal respiratory stability, and (iv) neonatal survival. These data provide functional evidence for the critical role of distinct medullary dB2 neurons in neonatal respiratory physiology. In summary, our work identifies distinct subgroups of dB2 neurons regulating breathing homeostasis, dysfunction of which causes respiratory phenotypes associated with congenital hypoventilation.

1028 Congenital Central Hypoventilation in a patient with MCEP2 duplication syndrome

Abstract Introduction Congenital central hypoventilation (CCHS) is a rare disorder due to impairment of autonomic nervous system clinically defined by a significantly reduced or abolished ventilatory response to hypercapnia and hypoxemia in the absence of pulmonary, neuromuscular, or cardiac disease. There is limited knowledge on associated respiratory manifestations and sleep-disordered breathing in children with the MECP2 duplication syndrome. Although sleep-disordered breathing and nocturnal hypoventilation are currently not well recognized in these children, we present a case of a patient with MECP2 mutation and congenital hypoventilation syndrome. Report of case(s) 24-week-old male born full-term via c-section presented with recurrent respiratory problems, laryngeal cleft, dysphagia, snoring and apneic episodes. Previous genetic work up showed chromosome 15q11.2 microdeletion. Past medical history was significant for neonatal ICU stay for respiratory distress immediately following birth. Tonsils are 1+ on exam. PSG showed profound central sleep apnea (CAI 300/h) with average apneic episodes lasted for 7 seconds and very significant periodic breathing (88%) and mild obstructive apnea. Mild hypoxemia was also seen with SpO2 in low 90s without any significant hypercapnia. Bradypnea with resp rate 10-20/m was seen. PHOX2B gene testing was negative. Genetic testing with SNP array showed MECP2 duplication syndrome. His development is delayed, currently at the age of 20 months, including cognitive, speech and motor function for which he is on therapy. Tracheostomy was recommended, however family preferred to continue with non-invasive ventilation while awaiting diaphragmatic pacing. Conclusion Respiratory manifestations in MECP2 duplication syndrome patients are common, with important impact and even a possible fatal outcome. Although sleep-disordered breathing and nocturnal hypoventilation is currently not cited as an important symptom in these children, there have been several case reports of CCHS associated with this. PSG should be considered in patients with MCEP2 duplication syndrome for timely diagnosis. Different treatment modalities (ENT surgery, CPAP and NIV) can be applied successfully to treat respiratory conditions associated with MECP2 duplication syndrome. Support (if any)

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.

Sindrom kongenitalne centralne hipoventilacije - heterogenost kliničke prezentacije, modaliteti ventilatorne potpore i ishodi

Introduction/aim: Central congenital hypoventilation syndrome (CCHS) is a rare genetic disorder characterized by autonomic dysregulation and alveolar hypoventilation with ventilatory support being the cornerstone of long-term survival. The aim was to present different ventilatory strategies in CCHS. Material and methods: The study included retrospectively analyzed medical records of five patients diagnosed with CCHS in a national pediatric center. Alveolar hypoventilation was evidenced by noninvasive continuous transcutaneous capnometry and central sleep-disordered breathing documented by polygraphy. Clinical evaluation included cardiac evaluation, rectal biopsies, and urinalysis of catecholamine levels. Life-threatening cardiac arrhythmias were indications for pacemaker implantation. Genetic analyses of alanine residues in paired-like homeobox 2B gene (PHOX2B) confirmed the diagnosis. Results: A range of pathogenic changes in the PHOX2B gene resulted in varying clinical outcomes. 3/4 (75%) of patients with an early onset were ventilated continuously through a tracheostomy tube, while one patient was successfully treated with noninvasive ventilation (NIV) as the preferred option. Additionally, NIV was applied in one child with early-onset disease after decannulation. Finally, NIV was also feasible in a case with late-onset disease presented by the time of four years with symptoms of pulmonary hypertension. There were no serious side effects of ventilation, and one patient died due to cardiac arrhythmias. Conclusion: Invasive mechanical ventilation remains the treatment of choice in most children with early-onset disease. However, the indications for NIV have been widened from overnight ventilation in the late-onset course to selected cases with early-onset disease. The timely switch from IMV to NIV has been popularized in recent years worldwide.

Hirschsprung Disease.

Hirschsprung Disease.

Non-invasive Ventilation and CPAP Failure in Children and Indications for Invasive Ventilation.

Non-invasive ventilation (NIV) and continuous positive airway pressure (CPAP) are effective treatments for children with severe sleep disordered breathing (SBD). However, some patients may present too severe SDB that do not respond to NIV/CPAP or insufficient compliance to treatment. A careful revaluation of the interface and of ventilator settings should be performed before considering alternative treatments. In patients with obstructive sleep apnea (OSA), alternatives to CPAP/NIV rely on the underlying disease. Ear-nose-throat (ENT) surgery such as adeno-tonsillectomy (AT), turbinectomy or supraglottoplasty represent an effective treatment in selected patients before starting CPAP/NIV and should be reconsidered in case of CPAP failure. Rapid maxillary expansion (RME) is restricted to children with OSA and a narrow palate who have little adenotonsillar tissue, or for those with residual OSA after AT. Weight loss is the first line therapy for obese children with OSA before starting CPAP and should remain a priority in the long-term. Selected patients may benefit from maxillo-facial surgery such as mandibular distraction osteogenesis (MDO) or from neurosurgery procedures like fronto-facial monobloc advancement. Nasopharyngeal airway (NPA) or high flow nasal cannula (HFNC) may constitute efficient alternatives to CPAP in selected patients. Hypoglossal nerve stimulation has been proposed in children with Down syndrome not tolerant to CPAP. Ultimately, tracheostomy represents the unique alternative in case of failure of all the above-mentioned treatments. All these treatments require a multidisciplinary approach with a personalized treatment tailored on the different diseases and sites of obstruction. In patients with neuromuscular, neurological or lung disorders, non-invasive management in case of NIV failure is more challenging. Diaphragmatic pacing has been proposed for some patients with central congenital hypoventilation syndrome (CCHS) or neurological disorders, however its experience in children is limited. Finally, invasive ventilation via tracheotomy represents again the ultimate alternative for children with severe disease and little or no ventilatory autonomy. However, ethical considerations weighting the efficacy against the burden of this treatment should be discussed before choosing this last option.

Contribution of retrotrapezoid nucleus and carotid bodies to asphyxia‐induced arousal in rats

Arousal in response to asphyxia is a life‐saving reflex that helps restore normal breathing and blood gas homeostasis. The carotid bodies (CB) are essential to hypoxia‐induced arousal whereas CNS serotonergic neurons and the lateral parabrachial nucleus contribute to CO2‐induced arousal. Here we wished to test whether the retrotrapezoid nucleus (RTN) is also implicated in CO2‐induced arousal. Our hypothesis was that RTN contributes to arousal elicited by hypercapnia but not hypoxia. The rationale is as follows. RTN is an important pluricellular CO2 detector that mediates the bulk of the hypercapnic ventilatory reflex (HCVR). RTN is likely absent since birth in central congenital hypoventilation syndrome, CCHS, a developmental disease in which the HCVR and asphyxia‐induced arousal are both greatly reduced. To test our hypothesis, we studied four groups of adult Sprague‐Dawley rats. In one group, we nearly completely destroyed RTN (“RTN lesion” group; n=8) with microinjections of saporin conjugated with substance‐P (2.4 ng/injection). The cognate control group (“RTN control”; n=7) received saline. The CBs were ablated in a third rat cohort (“CBx rats”; n=7). The fourth group (“CB control rats”; n=7) underwent sham surgery. Four weeks later, rats were placed in a plethysmograph chamber where breathing frequency and amplitude, EEG and EMG were recorded. Using mass flow controllers, the gas mixture perfusing the chamber was intermittently changed for exactly 1 min from normoxia (21% O2/balance N2) back to normoxia (control for flow interruption), from normoxia to hypercapnia (15% CO2/21% O2/balance N2), or from normoxia to hypoxia (10% O2, balance N2). Sleep survival curves representing the cumulative probability for SWS to persist after onset of the gas change were obtained. Two‐way ANOVA for repeated measures was used for statistical analysis of these curves. Sleep architecture was assessed by measuring the proportion of time the rats spent in SWS, REM sleep or quiet waking and the number of sleep stage transitions. Based on these measurements, sleep was unaffected by CBx or RTN lesion. However, the probability of SWS to persist 20 sec after the beginning of stimulus was significantly higher in RTN lesion rats compared to control (73.6 ± 14% vs. 54.8 ± 18 % at 20 sec from the beginning of stimulus). The corresponding figures at the 30 s time‐point were 57.8 ± 12 vs. 9.6 ± 13% and, at 40 sec, 40.1 ± 11 vs. 0 %. By contrast, RTN lesion had no detectable effect on hypoxia‐induced arousal. The arousal deficits elicited by CBx were different. CBx‐rats exposed to hypoxia had a significantly probability of SWS to persist compared to CB Control rats (89.9 ± 9 vs. 67.1 ± 9 % at 20 sec; 81.5 ± 15 vs. 56.4 ± 14 % at 30 sec, and 70.8 ± 16 vs. 39.9 ± 11 at 40 sec after the beginning of stimulus). In summary, we confirm the importance of the CBs to hypoxia‐induced arousal and demonstrate that arousal to hypercapnia is selectively reduced after RTN lesion. Neither CBx nor RTN lesions eliminated the arousal elicited by hypoxia or hypercapnia, however. Additional O2 and CO2 sensors (peripheral or central) therefore likely contribute to asphyxia‐induced arousal.Support or Funding InformationNational Institutes of Health (HL074011 and HL28785 to P.G.G.)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Dissecting the Contribution of Specific Hindbrain Cell Populations in the Phenotypic Characterization of a Mouse Model of Central Congenital Hypoventilation Syndrome

Hindbrain respiratory neuron networks undergo critical developmental maturation during the late embryonic, perinatal and post‐natal periods in mammals. Thus, abnormalities in neuron network development may contribute to autonomic respiratory dysfunction. Central Congenital Hypoventilation Syndrome (CCHS) is a rare genetic disorder characterized by an inability to sense and respond to altered levels of CO2 or O2 (Chemosensation). CCHS patients present with a spectrum of central respiratory control pathophysiologies, ranging from deficiency in chemosensation, to most severe manifestations of neonatal apnea that requires life‐sustaining mechanical ventilation. Heterozygous Mutations of the transcription factor PHOX2B, classified as either poly‐alanine repeat (PARM) and non‐poly‐alanine repeat (NPARM), have been linked to the development of CCHS. In order to explore CCHS pathophysiology, a novel transgenic mouse expressing an inducible NPARM Phox2b mutation (Phox2bΔ8) was developed and characterized by Nobuta and collaborators (Nabuta et al. 2015). Following this study and aiming to reveal the contribution of specific hindbrain populations to CCHS, we have generated two additional mouse models in which of Phox2bΔ8 expression is restricted to cell populations derived from either NKX2.2+ or OLIG3+ progenitors. Expression of Phox2bΔ8 on NKX2.2+ derived cells resulted in a strong apneic phenotype on newborn pups. Detail examination of this mouse model hindbrains showed deficiencies in a spectrum of rhombomeric nuclei not developmentally derived from NKX2.2+‐expressing progenitors, indicating that the developmental neuropathologies identified result through non‐cell‐autonomous mechanisms. Additionally, we find that these pathologies result from early rhombomeric patterning defects in embryonic ventral neural progenitor zones, which showed reduced endogenous PHOX2B expression. On the other hand, preliminary results indicate that expression of Phox2bΔ8 on OLIG3+ derived cells result in a subtle deficit in chemosensation, but we have been unable to find any neuropathological change in the hindbrain. Together, our results help to dissect the contributions of different cell populations in the hindbrain and to further clarify the different manifestations and severity of chemosensation and respiratory deficits seen in human CCHS patientsSupport or Funding InformationNIH R01HL132355This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Mutation in LBX1/Lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice

The respiratory rhythm is generated by the preBötzinger complex in the medulla oblongata, and is modulated by neurons in the retrotrapezoid nucleus (RTN), which are essential for accelerating respiration in response to high CO2 Here we identify a LBX1 frameshift (LBX1FS ) mutation in patients with congenital central hypoventilation. The mutation alters the C-terminal but not the DNA-binding domain of LBX1 Mice with the analogous mutation recapitulate the breathing deficits found in humans. Furthermore, the mutation only interferes with a small subset of Lbx1 functions, and in particular with development of RTN neurons that coexpress Lbx1 and Phox2b. Genome-wide analyses in a cell culture model show that Lbx1FS and wild-type Lbx1 proteins are mostly bound to similar sites, but that Lbx1FS is unable to cooperate with Phox2b. Thus, our analyses on Lbx1FS (dys)function reveals an unusual pathomechanism; that is, a mutation that selectively interferes with the ability of Lbx1 to cooperate with Phox2b, and thus impairs the development of a small subpopulation of neurons essential for respiratory control.

Current Perspectives for the use of Gonane Progesteronergic Drugs in the Treatment of Central Hypoventilation Syndromes.

Background: Central alveolar hypoventilation syndromes (CHS) encompass neurorespiratory diseases resulting from congenital or acquired neurological disorders. Hypercapnia, acidosis, and hypoxemia resulting from CHS negatively affect physiological functions and can be life-threatening. To date, the absence of pharmacological treatment implies that the patients must receive assisted ventilation throughout their lives.Objective: To highlight the relevance of determining conditions in which using gonane synthetic progestins could be of po-tential clinical interest for the treatment of CHS.Methods: The mechanisms by which gonanes modulate the respiratory drive were put into the context of those established for natural progesterone and other synthetic progestins.Results: The clinical benefits of synthetic progestins to treat respiratory diseases are mixed with either positive outcomes or no improvement. A benefit for CHS patients has only recently been proposed. We incidentally observed restoration of CO2 chemosensitivity, the functional deficit of this disease, in two adult CHS women by desogestrel, a gonane progestin, used for contraception. This effect was not observed by another group, studying a single patient. These contradictory findings are probably due to the complex nature of the action of desogestrel on breathing and led us to carry out mechanistic studies in rodents. Our results show that desogestrel influences the respiratory command by modulating the GABAA and NMDA sig-naling in the respiratory network, medullary serotoninergic systems, and supramedullary areas.Conclusion: Gonanes show promise for improving ventilation of CHS patients, although the conditions of their use need to be better understood

Neuroanatomical Analysis of a Conditional Knockin Mutant PHOX2B Mouse Model

BackgroundCentral Congenital Hypoventilation Syndrome (CCHS) is a rare disorder characterized by autonomic dysfunction, including abnormal respiration. Symptoms of CCHS include the inability to establish a regular respiratory rhythm, inadequate responses to hypoxemia and hypercapnia, heart rate abnormalities, and impaired bowel function. Mutations in paired‐like homeobox 2b (PHOX2B) are known to be causative for CCHS. We previously demonstrated that mice harboring an eight‐nucleotide deletion in PHOX2B (d8‐PHOX2B) displayed diffuse hindbrain pathology and perinatal lethality due to lack of spontaneous respiration. In this study, we are further exploring which brainstem circuits are required at birth for proper respiratory function and whether specific circuits are lost or insufficiently matured in mice expressing d8‐PHOX2B.MethodsWe are crossing several Cre driver mice with d8‐PHOX2B mice to selectively express d8‐PHOX2B in hindbrain neural nuclei known to be affected by mutant PHOX2B expression. Histological examination of brainstems from these mice along with unbiased quantification will allow us to determine how the morphology and number of cells within these neural populations is altered.Preliminary resultsAtoh1‐cre; d8‐PHOX2B mice were generated and assessed for perinatal viability, as Atoh1 is a transcription factor known to be involved in the development of medullary respiratory centers. At birth Atoh1‐cre; d8‐PHOX2B pups appeared healthy and displayed spontaneous respiration. Histological examination of hindbrains from these pups revealed no neuropathology, with evident intact locus coeruleus, facial nucleus, and retrotrapezoid nucleus. These preliminary results suggest that the expression of Phox2b in the Atoh1 lineage is not required for normal hindbrain development and respiration at birth.Support or Funding Information1R01HL132355‐01A1

Pathogenesis of central and complex sleep apnoea.

Central sleep apnoea (CSA) - the temporary absence or diminution of ventilatory effort during sleep - is seen in a variety of forms including periodic breathing in infancy and healthy adults at altitude and Cheyne-Stokes respiration in heart failure. In most circumstances, the cyclic absence of effort is paradoxically a consequence of hypersensitive ventilatory chemoreflex responses to oppose changes in airflow, that is elevated loop gain, leading to overshoot/undershoot ventilatory oscillations. Considerable evidence illustrates overlap between CSA and obstructive sleep apnoea (OSA), including elevated loop gain in patients with OSA and the presence of pharyngeal narrowing during central apnoeas. Indeed, treatment of OSA, whether via continuous positive airway pressure (CPAP), tracheostomy or oral appliances, can reveal CSA, an occurrence referred to as complex sleep apnoea. Factors influencing loop gain include increased chemosensitivity (increased controller gain), reduced damping of blood gas levels (increased plant gain) and increased lung to chemoreceptor circulatory delay. Sleep-wake transitions and pharyngeal dilator muscle responses effectively raise the controller gain and therefore also contribute to total loop gain and overall instability. In some circumstances, for example apnoea of infancy and central congenital hypoventilation syndrome, central apnoeas are the consequence of ventilatory depression and defective ventilatory responses, that is low loop gain. The efficacy of available treatments for CSA can be explained in terms of their effects on loop gain, for example CPAP improves lung volume (plant gain), stimulants reduce the alveolar-inspired PCO2 difference and supplemental oxygen lowers chemosensitivity. Understanding the magnitude of loop gain and the mechanisms contributing to instability may facilitate personalized interventions for CSA.

How to Understand Sleep and Sleep Problems in Patients with Prader-Willi Syndrome?

Sleep problems occur frequently among patients with Prader-Willi syndrome (PWS). The most common problem is excessive daytime sleepiness (EDS) that are closely related to of sleep-related breathing disorder (SRBD) such as obstructive sleep apnea (OSA) and congenital hypoventilation syndrome. Obesity, craniofacial dysmorphism and muscular hypotonia of patients with PWS may increase the risk of SRBD. Sleep apneas can interrupt the continuity of sleep, and these disruptions result in a decrease in both the quality and quantity of sleep. In addition to SRBD, other sleep disorders have been reported, such as hypersomnia, a primary abnormality of the rapid eye movement (REM) sleep and narcolepsy traits at sleep onset REM sleep. Patients with PWS have intrinsic abnormalities of sleep-wake cycles due to hypothalamic dysfunction. The treatment of EDS and other sleep disorders in PWS are similar to standard treatments. Correction of sleep hygiene such as sufficient amount of sleep, maintenance of regular sleep-wake rhythm, and planned naps are important. After comprehensive evaluation of sleep disturbances, CPAP or surgery should be recommended for treatment of SRBD. Remaining EDS or narcolepsy-like syndrome are controlled by stimulant medication. Bright light therapy might be beneficial for disturbed circadian sleep-wake rhythm caused by hypothalamic dysfunction.

A Phox2b BAC Transgenic Rat Line Useful for Understanding Respiratory Rhythm Generator Neural Circuitry.

The key role of the respiratory neural center is respiratory rhythm generation to maintain homeostasis through the control of arterial blood pCO2/pH and pO2 levels. The neuronal network responsible for respiratory rhythm generation in neonatal rat resides in the ventral side of the medulla and is composed of two groups; the parafacial respiratory group (pFRG) and the pre-Bötzinger complex group (preBötC). The pFRG partially overlaps in the retrotrapezoid nucleus (RTN), which was originally identified in adult cats and rats. Part of the pre-inspiratory (Pre-I) neurons in the RTN/pFRG serves as central chemoreceptor neurons and the CO2 sensitive Pre-I neurons express homeobox gene Phox2b. Phox2b encodes a transcription factor and is essential for the development of the sensory-motor visceral circuits. Mutations in human PHOX2B cause congenital hypoventilation syndrome, which is characterized by blunted ventilatory response to hypercapnia. Here we describe the generation of a novel transgenic (Tg) rat harboring fluorescently labeled Pre-I neurons in the RTN/pFRG. In addition, the Tg rat showed fluorescent signals in autonomic enteric neurons and carotid bodies. Because the Tg rat expresses inducible Cre recombinase in PHOX2B-positive cells during development, it is a potentially powerful tool for dissecting the entire picture of the respiratory neural network during development and for identifying the CO2/O2 sensor molecules in the adult central and peripheral nervous systems.

The cerebral cost of breathing: an FMRI case-study in congenital central hypoventilation syndrome.

Certain motor activities - like walking or breathing - present the interesting property of proceeding either automatically or under voluntary control. In the case of breathing, brainstem structures located in the medulla are in charge of the automatic mode, whereas cortico-subcortical brain networks - including various frontal lobe areas - subtend the voluntary mode. We speculated that the involvement of cortical activity during voluntary breathing could impact both on the “resting state” pattern of cortical-subcortical connectivity, and on the recruitment of executive functions mediated by the frontal lobe. In order to test this prediction we explored a patient suffering from central congenital hypoventilation syndrome (CCHS), a very rare developmental condition secondary to brainstem dysfunction. Typically, CCHS patients demonstrate efficient cortically-controlled breathing while awake, but require mechanically-assisted ventilation during sleep to overcome the inability of brainstem structures to mediate automatic breathing. We used simultaneous EEG-fMRI recordings to compare patterns of brain activity between these two types of ventilation during wakefulness. As compared with spontaneous breathing (SB), mechanical ventilation (MV) restored the default mode network (DMN) associated with self-consciousness, mind-wandering, creativity and introspection in healthy subjects. SB on the other hand resulted in a specific increase of functional connectivity between brainstem and frontal lobe. Behaviorally, the patient was more efficient in cognitive tasks requiring executive control during MV than during SB, in agreement with her subjective reports in everyday life. Taken together our results provide insight into the cognitive and neural costs of spontaneous breathing in one CCHS patient, and suggest that MV during waking periods may free up frontal lobe resources, and make them available for cognitive recruitment. More generally, this study reveals how the active maintenance of cortical control over a continuous motor activity impacts on brain functioning and cognition.

Ophthalmologic Impairment during Adulthood in Central Congenital Hypoventilation Syndrome: A Longitudinal Cohort Analysis of Nine Patients

Background: Congenital central hypoventilation syndrome (CCHS) is a rare dysgenetic form of neurocristopathy associated with dysfunction of the autonomic nervous system. Ophthalmologic abnormalities are reported in CCHS children, and range from pupillary and iris abnormalities to ptosis, strabismus and convergence deficiency. Since earlier CCHS diagnosis and multidisciplinary management, combined with improved ventilatory support techniques, the lifespan of children with CCHS has been considerably lengthened. The oldest of them have now reached adult age and we report in this study the results of their ophthalmologic examination.Materials and methods: Nine CCHS adult patients were prospectively included during a 14-month period. Each patient underwent complete ophthalmologic examination, static pupillometry with scotopic and photopic pupillary diameter (PD) measures, Humphrey 24-2 visual field analysis, macular OCT and complete orthoptic assessment including a Hess-Lancaster test.Results: Ophthalmologic abnormalities were found in six of the nine patients (66%). The main features were strabismus in six patients (66%). Four patients (44%) displayed abnormal pupillary function, with a decrease in average scotopic PD (3.8 ± 1.4 mm), average photopic PD (3.5 ± 1.2 mm), and average percentage of pupillary constriction (7.6 ± 8.5%). Three patients (33%) exhibited iris abnormalities such as iris atrophy, smooth iris surface and atrophic sphincter.Conclusion: This study allowed the description of ophthalmologic abnormalities occurring in CCHS in a series of adult patients, thus improving current knowledge of the disease. The prevalence of pupillary and iris lesions were lower than those observed in a series of children, suggesting that they could be considered as systemic disease severity markers.

The progestin etonogestrel enhances the respiratory response to metabolic acidosis in newborn rats. Evidence for a mechanism involving supramedullary structures

Central congenital hypoventilation syndrome is a neuro-respiratory disease characterized by the dysfunction of the CO2/H+ chemosensitive neurons of the retrotrapezoid nucleus/parafacial respiratory group. A recovery of CO2/H+ chemosensitivity has been observed in some central congenital hypoventilation syndrome patients coincidental with contraceptive treatment by a potent progestin, desogestrel (Straus et al., 2010). The mechanisms of this progestin effect remain unknown, although structures of medulla oblongata, midbrain or diencephalon are known to be targets for progesterone. In the present study, on ex vivo preparations of central nervous system of newborn rats, we show that acute exposure to etonogestrel (active metabolite of desogestrel) enhanced the increased respiratory frequency induced by metabolic acidosis via a mechanism involving supramedullary structures located in pontine, mesencephalic or diencephalic regions.

1177

Case Reports: A 50 year old African-American male presented with recurrent hypercapnic respiratory failure. Past medical history included hypertension, hypothyroidism and central sleep apnea on home BiPAP, with a BMI of 26. He presented in 2009 and 2010 with episodes of hypercapnia requiring intubation and normal pulmonary compliance and resistance. There was no history of sedative or narcotic medication ingestion. CT angiography, spirometry and neurological examination were normal. A brain MRI showed T2 and flair signal hyperintensities in the white matter and pons but no acute infarcts. On both occasions the patient briefly required mechanical ventilation and was discharged home. In 2012 he returned with lethargy and hypercapnic respiratory failure requiring intubation, room air ABG of 7.15/128/110/44/98%. CXR and CT head were negative and he had not received any sedation or narcotics. He had a mild erythrocytosis. Pulmonary mechanics were normal and he was able to comfortably draw 8-10 mL/Kg of ideal body weight on pressure support of 8/5, so he was extubated to BiPAP. Within a few hours he became lethargic and hypercapnic, with a room air ABG of 7.19/103/115/39/98% and was reintubated. Neurological examination was normal. EMGs were suspicious for demyelinating polyneuropathy, however he did not respond to a 3 day course of intravenous immunoglobulin. A sonographic “sniff test” revealed normal diaphragmatic excursion. Tracheostomy was performed. He tolerated tracheal collar during the day but required pressure support at night due to frequent periods of apnea. Genetic testing for central congenital hypoventilation syndrome (CCHS), also known as “Ondine’s curse”, was performed and returned positive for a heterozygous PHOX2b gene mutation. He was transferred to a university center for diaphragmatic pacemaker placement. Late-onset congential hypoventialation (LO-CHS) is rare, with fewer than 20 cases reported. Awareness of and evaluation for LO-CHS in patients with unexplained hypercapnic respiratory failure may help to diagnose future cases.

Syndrome d’Ondine à révélation tardive : revue de la littérature à propos d’un cas

Ondine syndrome is the central congenital hypoventilation syndrome (CCHS) caused by the mutation of the PHOX2B gene. In late onset cases, the symptomatology often appears after an acute event (infection, general anesthesia, drug intake), increasing hypoventilation. We report a case of late onset Ondine curse in a 9-year-old girl. The diagnosis was made based on a hypercapnic coma complicating a respiratory infection caused by Mycoplasma pneumoniae and was confirmed by genetic testing. In the patient's history we found symptoms that had not been noted (e.g., enuresis, morning headache, adynamia), attesting to chronic hypoventilation. Through this observation, we review the literature on CCHS, notably late onset cases, which are rare and insidious, emphasizing the pre-existing hypoventilation symptoms in this child. This case underlines the need for all practitioners not to trivialize these symptoms so as to decrease the current delay in diagnosis for late onset CCHS and to introduce optimal care as soon as possible.

Prenatal development of central rhythm generation

Foetal breathing in mice results from prenatal activity of the two coupled hindbrain oscillators considered to be responsible for respiratory rhythm generation after birth: the pre-Bötzinger complex (preBötC) is active shortly before the onset of foetal breathing; the parafacial respiratory group (e-pF in embryo) starts activity one day earlier. Transcription factors have been identified that are essential to specify neural progenitors and lineages forming each of these oscillators during early development of the neural tube: Hoxa1, Egr2 (Krox20), Phox2b, Lbx1 and Atoh1 for the e-pF; Dbx1 and Evx1 for the preBötC which eventually grow contralateral axons requiring expression of Robo3. Inactivation of the genes encoding these factors leads to mis-specification of these neurons and distinct breathing abnormalities: apneic patterns and loss of central chemosensitivity for the e-pF (central congenital hypoventilation syndrome, CCHS, in humans), complete loss of breathing for the preBötC, right-left desynchronized breathing in Robo3 mutants. Mutations affecting development in more rostral (pontine) respiratory territories change the shape of the inspiratory drive without affecting the rhythm. Other (primordial) embryonic oscillators start in the mouse three days before the e-pF, to generate low frequency (LF) rhythms that are probably required for activity-dependent development of neurones at embryonic stages; in the foetus, however, they are actively silenced to avoid detrimental interaction with the on-going respiratory rhythm. Altogether, these observations provide a strong support to the previously proposed hypothesis that the functional organization of the respiratory generator is specified at early stages of development and is dual in nature, comprising two serially non-homologous oscillators.