|
PWS Articles PWS Research
Other |
[ Printable Page | Edit ]
Research Notes: Respiratory Disorders in Prader-Willi Syndrome (PWS)Note: This page collects research abstracts about respiratory issues in PWS such as obstructive sleep apnea, hypoventilation, etc. and their effects and treatment. Please see here for the article about the importance of early diagnosis and treatment of respiratory disorders in PWS. Pediatr Res. 2007 Jun 25. Prader-Willi syndrome (PWS) is a neurogenetic disorder with hypotonia, psychomotor delay, obesity, short stature, and sleep-related breathing disorders. The aim of this study was to evaluate the association between psychomotor development and sleep-related breathing disorders in PWS infants. Bayley Scales of Infant Development were performed in 22 PWS infants, with a median (interquartile range, IQR) age of 1.8 (1.1-3.4) y, and a body mass index SD score (BMISDS) of -0.5 (-1.3 to 1.6). We evaluated psychomotor development in relation to results of polysomnography. Median (interquartile range) mental and motor development was 73.1% (64.3-79.6%) and 55.2% (46.5-63.1%) of normal children, respectively. All infants had sleep-related breathing disorders, mostly of central origin. The apnea hypopnea index was not associated with psychomotor development. Only four infants had obstructive sleep apnea syndrome (OSAS). They had a significantly delayed mental development of 65.5% (60.0-70.3%) of normal. They had a median BMISDS of 1.4 (0.1-1.6), which tended to be higher than in those without OSAS. Our data indicate that psychomotor development in PWS infants is not related to central sleep-related breathing disorders, but infants with OSAS have more severely delayed mental development, suggesting that PWS infants should be screened for OSAS. Ann Otol Rhinol Laryngol. 2007 May. OBJECTIVES: We undertook to identify data that facilitate determination of an accurate diagnosis of the cause of stridor in infants and to develop a framework to conceptualize the problem. METHODS: We reviewed medical records of patients less than 1 year of age with the presenting symptom of stridor who were initially evaluated in the outpatient setting of a tertiary children's hospital. Infants with obvious congenital syndromes, cerebral palsy, or hypotonia were excluded. All infants underwent history-taking, physical examination, and when symptoms were mild, office flexible laryngoscopy. With moderate or severe stridor, a more complete endoscopic evaluation was undertaken in the operating room. RESULTS: Of 202 patients, 119 (59%) were boys and 83 (41%) were girls. Their ages ranged from 3 days to 11 months; 175 (87%) were 6 months of age or younger. Congenital anomalies were diagnosed as the cause of stridor in 170 (84%). Congenital laryngeal anomalies caused stridor in 157 (78%); congenital tracheal abnormalities were the cause in 13 (6%). The most common congenital laryngeal anomaly was laryngomalacia (94%). Forty-two (21%) of the 202 patients had at least 1 other anomaly that contributed to airway compromise. Half of all patients had laryngopharyngeal reflux, the most common associated condition. Of patients referred with a presumptive diagnosis by non-otolaryngologists, 28 of 94 (30%) were referred with erroneous presumptive diagnoses for which they were being treated, the most common of which was tracheomalacia. CONCLUSIONS: A standard, rational approach to the evaluation of stridor in infants facilitates management. A framework for evaluation is presented. Neuropsychol Rev. 2006 Nov 16. Prader-Willi Syndrome (PWS) is a rare genetic disorder characterized by a range of physical, psychological, and physiological abnormalities. It is also distinguished by the high prevalence of obstructive sleep apnea syndrome (OSAS), i.e., repetitive upper airway collapse during sleep resulting in hypoxia and sleep fragmentation. In non-PWS populations, OSAS is associated with a range of neurocognitive and psychosocial deficits. Importantly, these deficits are at least partly reversible following treatment. Given the findings in non-PWS populations, it is possible that OSAS may contribute to neurocognitive and psychosocial deficits in PWS. The present review examines this possibility. While acknowledging a primary contribution from the primary genetic abnormality to central neural dysfunction in PWS, we conclude that OSAS may be an important secondary contributing factor to reduced neurocognitive and psychosocial performance. Treatment of OSAS may have potential benefits in improving neurocognitive performance and behavior in PWS, but this awaits confirmatory investigation. Sleep Med. 2006 Oct 3. Background and purpose: Hypersomnia, sleep-disordered breathing and narcoleptic traits such as rapid eye movement (REM) sleep onset periods (SOREMPs) have been reported in Prader-Willi syndrome (PWS). In a group of young adult patients with genetically confirmed PWS we evaluated sleep and breathing polysomnographically, including cycling alternating pattern (CAP), and we analyzed the potential interacting role of sleep variables, sleep-related breathing abnormalities, hypersomnia, severity of illness variables and growth hormone (GH) secretory pattern. Patients and methods: Eleven males and 7 females (mean age: 27.5+/-5.5 years) were submitted to a full night of complete polysomnography and the multiple sleep latency test (MSLT). GH secretory pattern was evaluated by a standard GH-releasing hormone plus arginine test. Sixteen non-obese healthy subjects without sleep disturbances were recruited as controls. Results: Compared to controls PWS patients showed reduced mean MSLT score (P<0.001), reduced mean latency of sleep (P=0.03), increased REM sleep periods (P=0.01), and increased mean CAP rate/non-rapid eye movement (NREM) (P<0.001). Only four PWS patients had apnea/hypopnea index (AHI)>/=10. Conversely, significant nocturnal oxygen desaturation was frequent (83% of patients) and independent from apneas or hypopneas. In the PWS group, CAP rate/NREM showed a significant negative correlation with MSLT score (P=0.02) independently from arousals, respiratory disturbance variables, severity of illness measured by Holm's score or body mass index (BMI). PWS patients with CAP expression characterized by higher proportion of A1 subtypes presented less severe GH deficiency (P=0.01). Conclusions: Our study suggests a relationship between hypersomnia and CAP rate, and between CAP expression and GH secretory pattern in PWS, possibly reflecting underlying central dysfunctions. J Clin Endocrinol Metab. 2006 Sep 26. Context: Recently, several cases of sudden death in growth hormone (GH)-treated and non-GH-treated, mainly young Prader-Willi Syndrome (PWS) patients, were reported. GH-treatment in PWS results in a remarkable growth response, and an improvement of body composition and muscle strength. Data concerning effects on respiratory parameters, are however limited. Objective: To evaluate effects of GH on respiratory parameters in pre-pubertal PWS children. Design: Polysomnography (PSG) was performed before GH in 53 children and repeated after 6 months of GH-treatment in 35 of them. Patients: 53 pre-pubertal PWS children (30 boys), with median (interquartile range (iqr)) age of 5.4 (2.1-7.2) years and body mass index (BMI) of +1.0 SD score (-0.1-1.7). Intervention: Treatment with GH 1 mg/m(2)/day. Results: Apnea Hypopnea Index (AHI) was 5.1/h (2.8-8.7) (normal 0-1/h). Of these, 2.8/h (1.5-5.4) were central apneas and the rest mainly hypopneas. Duration of apneas was 15.0 sec (13.0-28.0). AHI did not correlate with age and BMI, but central apneas decreased with age (r= -0.34, P = 0.01). During 6 months of GH-treatment, AHI did not significantly change, from 4.8 (2.6 - 7.9) at baseline to 4.0 (2.7 - 6.2; P = 0.36). One patient died unexpectedly during mild upper respiratory tract infection (URTI), although he had a nearly normal PSG. Conclusions: PWS children have a high AHI, mainly due to central apneas. Six months of GH does not aggravate the sleep-related breathing disorders in young PWS children. Our study also shows that monitoring during URTI in PWS children should be considered. [Note: This study was funded by Pfizer and one of the study authors "has delivered lectures and received reimbursement of travel/accommodation expenses at meetings sponsored by Pfizer."] Excerpts from the full text article: Introduction [...] Several reports have demonstrated that GH-treatment results in a remarkable growth response, but also in an impressive improvement of body composition, with decline in fat-percentage and increment in lean body mass, muscle strength and agility (9-11). Preliminary studies suggested that GH might improve psychosocial development in PWS (12). Data on effects of GH on respiratory parameters in young, pre-pubertal PWS children are however very limited. Haqq et al found after 6 months of GH a slight reduction in sleep apnea incidence in 12 PWS children, aged 4.5 to 14.5 years (13). Lindgren et al found improved CO2-responsiveness in 12 children with PWS after 6-9 months of GH compared to baseline (14). Recently, several reports have been published on sudden death in children with PWS during GH-treatment (15, 16). Unexpected death, however, has also been described in non-GH-treated children with PWS (17, 18). In fact, Whittington reported an overall death rate of 3% per year for PWS patients in one UK Health Region (19). In our study we evaluated the occurrence of sleep-related breathing disorders (SRBD) in 53 young, pre-pubertal children with PWS and the effects of 6 months of GH-treatment in 35 of them. Patients and Methods Patients In April 2002, a multicenter, randomised, controlled, prospective GH trial in PWS children was started investigating the effects of GH-treatment versus no GH on growth, body composition, activity level and psychosocial development. Participants fulfilled the following inclusion criteria: (1) genetically confirmed diagnosis of PWS by positive methylation test; (2) age between 6 months and 16 years; (3) bone age less than 14 years (girls) or 16 years (boys); (4) in children over 3 years: height standard deviation score (SDS) for age below zero (5) in children over 3 years: if height is > 0 SDS, weight-for-height SDS must be over +2 SDS, according to Dutch standards (20, 21). Patients with non-cooperative behaviour or patients receiving medication to reduce fat were excluded. All patients over 3 years started a diet and exercise program 3 months prior to start of the study. Children were enrolled in the study irrespective of their GH status. Patients received Genotropin® (Somatropin) in a dose of 1 mg/m2/day. The first 4 weeks of treatment, they received only 0.5 mg/m2/day in order to prevent fluid retention. In April 2003, we started a polysomnography (PSG) study in addition to the original protocol. For the PSG study we used the following inclusion criteria: (1) pre-pubertal at baseline and at repeated PSG (2) no upper respiratory tract infection (URTI) during PSG (3) no previous GH-treatment. On November 11, 2005, 83 patients had been included in the original study. Twenty-five were excluded from the PSG study, because they received GH-treatment, before start of the PSG study. For one patient, parents refused PSG, 3 were pubertal at repeated PSG and one was excluded because of treatment with nasal continuous positive airway pressure. As a result, 53 patients were eligible for analysis of baseline PSG. Thirty-nine children had a PSG repeated after 6 months of GH-treatment. Fourteen patients were followed in the control group of the original study. Their PSG will be repeated at 6 months after start of GH-treatment. As all patients were stratified for age and BMI before randomisation in the original study, these patients were not different from those who had repeated PSG. Of the 39 patients with repeated PSG, 4 had URTI during second PSG and were therefore excluded from group analysis. [...] Methods Anthropometry Supine length was recorded below the age of 2.5 years, and thereafter standing height, measured with a Harpenden stadiometer. Weight was assessed on an accurate scale, and body mass index (BMI) (kg/m2) was calculated. Height and BMI were converted into SDS according to Dutch references for age (20, 21). Calculations were performed with Growth Analyser Version 3.0 (www.growthanalyser.org). Polysomnography PSG was performed before and after 6.6 (6.1-7.3) months of GH-treatment. All PSG's were performed in one specialized sleep center (A.W., sleep specialist). Children were admitted to the sleep center at 5.00 p.m., accompanied by one parent. Patients underwent complete overnight PSG. Recordings included electroencephalogram, electro-oculogram, one channel derivation of electrocardiogram, and surface electromyography of the submental muscle and both anterior tibial muscles. Nasal-oral airflow was monitored by nasal pressure prongs fixed in the nose, respiratory effort by thoraco-abdominal strain gauges and oxygen saturation (SaO2) by pulse oximetry. All PSG studies were evaluated independently by two persons, both certified in PSG analysis. In case of major discrepancies between both assessments a third expert opinion was asked. The polygraphic records were scored according to standard criteria of Rechtschaffen and Kales (22). A period of apnea or hypopnea was defined as more than 90% (apnea) or 50% (hypopnea) reduction of airflow for 3 breaths or longer. For hypopneas, the additional criterion was a reduction of SaO2 of 4% or more. Periods of apnea and hypopnea were counted over the period of sleep during the night and calculated as mean per hour of sleep (apnea hypopnea index, AHI). An AHI above 1/hour is considered pathological (23). Apneas were considered obstructive when absence of airflow occurred without a decrease in respiratory effort and central, when thoracic movements were absent. Abnormal SaO2 was defined as SaO2 below 92% or more than 4% below baseline values during 3 breaths or longer. Otorhinolaryngologic examination consisted of 3-monthly tonsillar inspection according to Brodsky staging system (24). Snoring was recorded in a structured interview with parents. When snoring or obstructive sleep apnea (OSA) was diagnosed, fiberoptic endoscopy was performed by an ear-nose-throat (ENT) surgeon. If adenoid or tonsillar hypertrophy was found, adenotonsillectomy was performed. [...] Results Clinical characteristics at baseline Fifty-three pre-pubertal PWS children (30 boys) participated in the PSG study. The median (iqr) age was 5.4 years (2.1 – 7.2) and the median (iqr) BMI was 1.0 SDS (-0.1 – 1.7). Sixteen patients had paternal deletion, 21 had maternal disomy, 4 had an imprinting center mutation. In 12 patients diagnosis was confirmed by a positive methylation test for PWS, but was not yet further specified. Thirty-nine patients (23 boys) started GH at a dose of 1mg/m2/day. The first month of GH, they received only 0.5 mg/m2/day, to avoid fluid retention. Respiratory parameters at baseline At baseline, the median (iqr) AHI was 5.1 (2.8 – 8.7). Of these, 2.8/h (1.5 – 5.4) were identified as central apneas, 0.0/h (0.0 – 0.3) as obstructive apneas and 0.9 (0.0 - 2.7) as hypopneas. The longest median (iqr) duration was 15.0 sec (13.0 – 28.0). In all children, the AHI exceeded the normal range of 0-1/hr, indicating that SRBD do frequently occur, even in normal-weight pre-pubertal children with PWS. In the total patient group, no correlation was found between BMI SDS and AHI. Forty-five of our 53 patients were not obese. Of them, only 9% had OSA (4/45), defined as obstructive apnea index over 1/h. In contrast, in our 8 patients who were obese (i.e. BMI over +2SDS) 50% had OSA (4/8) (prevalence of OSA in normal weight versus obese patients, p=0.01). We found a negative correlation between both age and BMI and the number of central apneas (r=-0.34, p=0.01 and r=-0.33, p=0.017 respectively). There was no significant difference in AHI with regard to gender or genetic defect. Tonsil size as assessed by Brodsky staging system, was not associated with the AHI (data not shown). Respiratory parameters after 6 months of GH Thirty-five pre-pubertal children had PSG repeated after 6 months of GH-treatment. (Table 2) This group of 35 children had a median (iqr) age of 6.0 years (2.4 – 8.6), and median (iqr) BMI of 0.8 SDS (-0.1 – 1.5) before GH. At baseline, median (iqr) AHI in this group was 4.8/h (2.6 – 7.9), of which 2.9/h (1.5 – 5.2) were indicated as central and 0.0 (0.0 – 0.3) as obstructive. After 6 months of GH (1mg/m2/day), a non-significant decline in the AHI was found to 4.0 (2.7 – 6.2). This decline was mainly due to a reduction in central apneas to 2.2/h (0.8 – 4.1). In 5, adenoidectomy and/or tonsillectomy was performed because adenoidal and/or tonsil hypertrophy developed during the follow-up period. There was no association between changes in AHI and changes in number of awakenings or REM sleep-percentage (data not shown). Breathing disorders during illness Four patients were excluded from analysis because of URTI. The results of their PSG's during health and illness are listed in table 3. In one of them, PSG was repeated after recovery and adenoidectomy. In this particular patient, the AHI before GH-treatment was 7.9/h (100% central), during illness after 6 months of GH-treatment, the AHI had impressively increased to 38.6/h (1.2 central apneas/h, 12.4 obstructive apneas/h, and 25.1 hypopneas/h), whereas after recovery and adenoidectomy, AHI was 3.4/h (100% central). One patient in our study died unexpectedly. This 3-year old boy had GH-treatment for 13 months. He responded very well in terms of growth and body composition. In this particular patient, PSG was performed before (AHI 1.7/h, 100% central) and after 6 months of GH (AHI 1.4/h, 67% central, 33% hypopnea). Six weeks before his death, BMI was 1.6 SDS and tonsils were assessed as Brodsky I-II. He had mild URTI and was clinically evaluated by his paediatrician the day prior to his death. At that time he had URTI, but was in good condition, running around and not generally ill. During the night, he suddenly deteriorated and was found dead in the morning. Autopsy did not reveal the cause of death. Discussion We found an increased AHI in 53 young, pre-pubertal children with genetically confirmed diagnosis of PWS. The high AHI was mainly due to central apneas and hypopneas. In the total group of mainly non-obese PWS children, obstructive apneas were rare. In contrast, obstructive apneas were found in 4 of the 8 overweight patients. After 6 months of GH-treatment a non-significant decrease of AHI was found, mainly due to a decrease in central apneas. No significant change in obstructive apneas was found during GH. Illness or adenoid/tonsil hypertrophy, however did result into a marked increase in sleep-related breathing disorders, and particularly obstructive sleep apnea. Our study also shows that a relatively normal PSG does not exclude the possibility of unexpected death during mild URTI. The increased number of central apneas, in our young PWS children suggests a central origin of SRBD. A hypothalamic origin of SRBD in PWS was already postulated 20 years ago (25). A decreased number of oxytocin neurons in the hypothalamic paraventricular nucleus was reported, which might also be involved in reduced neural modulation of breathing (26,27). Recently, Ren et al (28) proposed that necdin (neurally differentiated embryonal carcinoma-cell derived factor) deficiency may contribute to the observed respiratory abnormalities in individuals with PWS as Necdin is one of the protein-coding genes that are deficient in PWS (29). Deficiency of Necdin in mice results in neonatal hypoventilation, which is usually fatal (30). We found a negative association of both age and BMI, with number of central apneas. Because in PWS children, age and BMI are highly correlated, we cannot distinguish whether this is an effect of age or BMI. From a pathophysiological point of view, we consider it more likely to be an effect of age. In fact, our data are in line with a previous report, indicating that central apneas are more common in younger, healthy children, although within the normal range (31). The mechanism is unclear, and might be related to a relatively more immature respiratory control in younger children. However, we cannot exclude that underweight in young PWS infants might contribute to as well. OSA was uncommon in normal-weight PWS patients. However, 4 of the 8 overweight (defined as BMI over +2 SDS) patients (50%) had signs of OSA. Increased BMI has been associated with decreased SaO2 and higher AHI in older PWS children and adults (32). Harris et al reported an improvement of OSA and hypoventilation after weight-loss in children and adults with PWS (33). Tonsillar hypertrophy may also play a role in OSA. Children with PWS might have a smaller naso- and oropharynx, which could contribute to obstruction (3). Recently an improvement in AHI and oxygen saturation was reported after adenotonsillectomy in 5 PWS children with OSA (34). After 6 months of GH-treatment, a non-significant decline in AHI was found compared to baseline, mainly due to a lower number of central apneas. Thus, our study indicates that GH had no adverse effects on the respiration of PWS children. Several publications reported sudden death in infants and children with PWS during GH treatment (15, 16, 35). Several ones suggested a causal relationship between GH and sudden death in PWS. Until now only limited data were available on the effects of GH on PSG. Miller et al recently reported an improvement of AHI after 6 weeks of GH in most of her PWS patients. She performed PSG in children and adults of which 12 were children under the age of 12 years. A subset of patients, however, had an increased AHI after 6 weeks of GH. Most of these patients had URTI during the second evaluation (36). Haqq et al reported in a cross-over study a decrease in AHI after 6 months of GH in 12 PWS children, aged 4.5 to 14.5 years, although not statistically significant (13). Myers et al demonstrated that inspiratory and expiratory muscle strength improved in 20 children with PWS, aged 4 to 16 years after 12 months of GH compared to 10 controls (11). Lindgren et al found improved CO2-responsiveness in 12 children with PWS after 6-9 months of GH compared to baseline (14). A number of hormones, including GH and IGF1, are involved in the physiologic regulation of breathing (37). IGF1 receptors are located around the central chemoreceptors in the brainstem, and also in the cerebellum where the inputs from chemoreceptors are integrated (38). GH may therefore theoretically improve breathing via a direct mechanism. In our study we found only a small number of obstructive apneas both before and during GH-treatment. There was no increase in obstructive apneas during GH treatment. Five children had adenotonsillectomy before the second PSG was performed, because of adenoid and/or tonsillar hypertrophy. Unfortunately this might confound our results, but for obvious safety reasons we could not avoid this. The AHI of these patients during both PSG's was not different compared to the rest of the study group. We found no significant association between tonsil size or snoring and the AHI. Sleep apnea, both obstructive and central, occurs more frequently in adults with GH excess (acromegaly)(39) and is associated with thickening of the pharyngeal wall in the acromegalic patients (40). We cannot rule out that GH might have resulted in some adenoidhypertrophy, as we only performed fiberoptic endoscopy when indicated by snoring or OSA during PSG. It has been suggested that GH-treatment might increase tonsil size, however, to our knowledge, no controlled, prospective study has been performed. One of our patients died unexpectedly during an episode of URTI. One of the most alarming findings is that this patient had near-normal sleep-related breathing during PSG, both before and during GH-treatment. This points out that a near-normal PSG in a healthy PWS child does not guarantee he/she won't die during mild URTI. It might be related to a rise of apneas (both central and obstructive) during illness as shown in 4 of our patients who had a PSG during an episode of mild URTI. Unexpected deaths have been described in PWS children both without and during GH and have been attributed to several possible causes, such as respiratory dysfunction, cardiomyopathy, temperature instability and adrenal insufficiency or combinations of these. We recommend monitoring of SRBD by PSG and regular ENT-evaluation in all PWS children, both before and during GH-treatment. If adenoidhypertrophy or tonsillar hypertrophy occurs, adenotonsillectomy should be considered. It is important to mention that a relatively normal PSG does not exclude the possibility of unexpected death during mild URTI. Based on our results cardiorespiratory monitoring during URTI in children with PWS before and during GH-treatment should be considered. Future studies are required for evaluating SRBD in PWS during URTI in order to give recommendations with regard to monitoring during URTI. In conclusion, our study shows that many pre-pubertal children with PWS have sleep-related breathing disorders, mainly due to central apneas. BMI or age cannot explain the variability in the severity of the SRBD, although OSA was more prevalent in children with obesity than in normal weight children. After 6 months of GH, a nonsignificant decrease in AHI was found. Thus our data are reassuring with respect to the effects of GH on SRBD. Our study also shows that a normal PSG does not exclude the possibility of unexpected death during mild upper respiratory tract infections. During URTI, AHI may rise and obstructive apneas may occur. Arch Dis Child. 2006 Apr. Recombinant human growth hormone (rhGH) therapy in Prader-Willi syndrome (PWS) causes increased basal metabolic rate and oxygen consumption, and hence increased ventilatory load. The case of an adolescent with PWS who experienced respiratory deterioration with an increase in rhGH and improvement with cessation of therapy is reported. J Clin Endocrinol Metab. 2006 Feb. Context: GH was approved for Prader-Willi Syndrome (PWS) in 2000. Fatalities in individuals with PWS soon after beginning GH treatment prompted concern about GH worsening sleep apnea. Objective: We sought to determine whether GH affects sleep apnea in individuals with PWS. Design: Twenty-five patients with PWS had overnight polysomnography (PSA) at baseline and 6 wk after starting GH. Setting: The study was conducted in a sleep lab using a standardized procedure. Patients: The patients studied had genetically confirmed PWS. Main outcome measures: PSA results were analyzed for frequency and severity of central and obstructive apnea/hypopnea events and total apnea/hypopnea index. Results: As a group, GH improved apnea/hypopnea index by a mean of 1.2 events per hour (P = 0.02) and central events by a median of 1.7 events per hour (P < 0.001). Fourteen patients had improvement in obstructive events by a mean of 1.7 events per hour. Six patients had worsening of obstructive events on GH. Four of these patients had upper respiratory tract infections at the time of the second PSA and had tonsil/adenoid hypertrophy on otorhinolaryngological evaluation. Two patients with high serum IGF-I levels had increased obstructive events. Conclusions: Most of our PWS patients had improvement after short-term GH treatment, but 32% had worsening of sleep disturbance. A subset of PWS patients are at risk during this window of vulnerability shortly after initiation of GH. Because it is difficult to predict who will worsen with GH, patients with PWS should have PSA before and after starting GH and should be monitored for sleep apnea with upper respiratory tract infections. Otorhinolaryngological evaluation is warranted if sleep apnea worsens on GH. IGF-I levels should be monitored, with the goal being physiological levels. Excerpts from (02/24/06) Science Daily: Growth Hormone, Obesity Can Trigger Sleep Apnea In Some Kids Growth hormone helps hundreds of children with a rare disorder that causes them to gorge on food, but for some, starting treatment can worsen a dangerous nighttime breathing problem, University of Florida researchers have found. Sleep apnea disrupts breathing during sleep and is common among morbidly obese children, including those with Prader-Willi syndrome, a disease that compels them to eat nonstop. Researchers say that uncovering how to treat obesity and related problems in children genetically wired to be overweight could help them better battle childhood obesity in general. Growth hormone has shown to be one of the most effective ways to treat children and adults with Prader-Willi. But UF researchers found that starting treatments can worsen or trigger sleep apnea in obese children exposed to colds, potentially leading to death, according to findings published online recently in The Journal of Clinical Endocrinology and Metabolism. "Every kid we studied had abnormal sleep at the beginning, before growth hormone," said Jennifer Miller, M.D., a UF assistant professor of pediatrics and the study's lead author. "On growth hormone, most of them got better but not all of them. The ones that got worse tended to be school age. Some of them were just entering school and then they were coming home with upper-respiratory infections. "The combination of starting growth hormone, still having weak muscle tone, having an illness and/or being obese tends to put you at risk for having really bad obstructive sleep apnea." The researchers urge doctors to monitor patients' sleep before and during treatment for signs of obstructive sleep apnea, such as loud snoring or abnormal daytime sleepiness. Sleep studies are recommended for all obese children, not just those with Prader-Willi, Miller added. [...] Obesity also can lead to severe respiratory problems as fat accumulates in the upper body and throat, and these effects cause the most problems for obese patients, including those with Prader-Willi, said [Bryan E. Hainline, M.D., Ph.D., an Indiana University associate professor of pediatrics who specializes in pediatric metabolism and genetics]. The UF study highlights this, he added. Growth hormone was approved in the United States to treat Prader-Willi in 2000, but several children with the disease died after beginning the treatments. All died in their sleep and had been battling infections. To understand the problem, UF researchers decided to study how growth hormone affected sleep, monitoring patients on the therapy closely and performing sleep studies before and during treatment, Miller said. The researchers studied 25 children and adults with Prader-Willi syndrome, a large sample for such a rare disorder. Four school-age children had increased difficulty breathing at night shortly after the treatment began. All began having problems after they were exposed to upper respiratory infections in school, the findings show. The children's muscles were so weak at the beginning of the treatment they couldn't breathe with a stuffed-up nose, Miller said. Growth hormone worsened the problem, causing the tonsils to swell and exacerbating their sleep apnea. "We realized it was an infection issue," Miller said. "They didn't have the strength to overcome any resistance." To keep patients safe, the researchers suggest doctors perform sleep studies on children before and during treatment. Some children may also need to have their tonsils removed if necessary. This helps, but because of their poor muscle tone and obesity, Prader-Willi patients have more risks to anesthesia, Miller said. "The important part is for parents to realize that being on growth hormone, while it's good for most people, there is a subset that's vulnerable to having problems during sleep," she said. "That's why the sleep study should be done, because we don't know who it's going to be." J Pediatr. 2005 Dec. Objectives: To determine the prevalence and type of sleep-disordered breathing among patients with Prader-Willi syndrome (PWS) and its relationship to such neurobehavioral abnormalities as mental retardation, obsessive-compulsive behavior, and conduct disorders. Study design: Polysomnography (PSG) studies were conducted in 13 unselected subjects with PWS (age 1.5 to 28 years). PSG results were compared with tests of behavior and cognition (Development Behavior Checklist [DBC], Auditory Continuous Performance Test [ACPT], and Wechsler Intelligence Scale appropriate for age). Results: Nine of 13 (69%) subjects had > 10 apneas and hypopneas per hour of sleep. Apart from a 2-year-old subject with normal body weight who demonstrated severe central hypopnea in rapid eye movement sleep, the sleep-breathing disturbance was due to upper airway obstruction. Age-adjusted body mass index was associated with more severe hypoxemia during sleep (min SaO2, r = -.87, P < .005) and more sleep disruption (arousals/hour of sleep, r = .62, P < .05; sleep efficiency, r = -.66, P < .05). Increasing severity of obstructive sleep apnea (OSA) or sleep disturbance was associated with daytime inactivity/sleepiness and autistic-relating behavior (DBC) and with impulsiveness (ACPT). Unexpectedly, sleep hypoxemia appeared to be predictive of increased performance IQ. Conclusions: OSA is prevalent among subjects with PWS and is associated with increased body mass, daytime inactivity/ sleepiness, and some behavioral disturbances. J Clin Endocrinol Metab. 2005 Oct. CONTEXT: Adult patients with Prader-Willi syndrome (PWS) are prone to develop obesity, GH deficiency (GHD), and their related complications, with cardiopulmonary failure explaining more than half of PWS fatalities. OBJECTIVE AND STUDY PARTICIPANTS: This study was undertaken to examine the effect of GHD and sleep breathing disorders on cardiovascular risk factors and heart features of 13 PWS (age 26.9 +/- 1.2 yr) and 13 age-, gender-, and body mass index-matched obese individuals (age 26.2 +/- 0.8 yr). RESULTS: Compared with controls, PWS patients had lower GH response to arginine+GHRH, IGF-I levels, triglycerides, total and LDL-cholesterol, insulin, and insulin resistance measured by a homeostatic model approach. Dual-energy x-ray absorptiometry, abdominal computed tomography scans, and polysomnography revealed a greater fat mass, similar abdominal fat, but greater sleep breathing disorders in PWS than obese subjects. Echocardiography showed no systolic or diastolic alteration, although PWS had lower left ventricle (LV) mass (135.7 +/- 7.7 vs. 163.5 +/- 8.4 g, P < 0.05) and near significantly lower values of LV end-diastole diameter (P = 0.08), compared with obese controls. Baseline radionuclide angiography documented comparable values of systolic and diastolic values between groups. However, adrenergic stimulation with dobutamine caused a lower increase of LV ejection fraction (71.9 +/- 1.9 vs. 76.3 +/- 1.2%, P < 0.05) and heart rate (103 +/- 6.9 vs. 128 +/- 2.8 beats/min, P < 0.05) in PWS than obese individuals. By multivariate analysis, nocturnal oxygen desaturation and IGF-I levels were main significant predictors of LV mass and heart rate in PWS patients. CONCLUSIONS: PWS differs from simple obesity by a healthier metabolic profile, impaired nocturnal breathing, decreased heart geometry, and systolic and chronotropic performance. GHD and the predictive role of IGF-I on structural and functional heart parameters suggest a GH/IGF-I-mediated control of cardiac risk in PWS. From the full text article: Polysomnography revealed a greater prevalence of sleep breathing disorders in PWS compared with obese subjects, consisting of greater AHI (P < 0.05) and lower oxygen saturation during nocturnal sleep, a longer time spent at SaO2 <90%, and lower average minimum SaO2 during desaturations as well as higher desat SaO2/h (P < 0.01 for all) (Table 1). [...] One potential contributor to cardiovascular alterations in PWS is sleep apnea, which is mixed in most patients and includes a central component caused by a defect in the central ventilatory drive response to hypercarbia as well as a peripheral obstructive component caused by deficient pharyngeal patency associated with obesity. The significant correlations herein obtained between nocturnal breathing and cardiovascular features in PWS patients are thus of potential interest and claim for a tight relationship between sleep breathing disorders and either left cardiac mass and output or HR. In the general population, sleep apnea is an independent risk factor for arrhythmias, sympathetic hyperactivity, hypertension, diastolic and systolic dysfunction, pulmonary congestion, and cardiac hypertrophy. Am J Med Genet A. 2005 Jul 1. Patients with Prader-Willi syndrome (PWS) are recognized to have a tendency of sudden, unexpected death (SED), but its exact cause is unknown because of paucity of such case reports. Since growth hormone (GH) treatment was applied to PWS patients worldwide, several cases of death have been reported. However, whether the therapy is directly related to their SED remains unknown, too. We collected 13 deceased PWS patients (Group A, aged 9 months to 34 years) who had never received GH therapy, and seven deceased patients (Group B, all boys aged 0.7-15 years) having received the therapy from the registration in PWS-patient-support associations and from the literature, respectively. We then compared the cause of SED between the two groups. Irrespective of GH therapy, SED of infants under age 1 year was associated with milk aspiration or hypothalamic dysregulation of respiration, while SED of patients in early childhood or adolescence occurred at sleeping in association with preceding viral infections. In contrast, SED of four adult (>20 years of age) patients who never received GH therapy was associated with complications, such as leg cellulites and pulmonary embolism, secondary to massive obesity and diabetes mellitus (DM). Two Group-B patients (aged 14 and 20 years) without any obesity-related or diabetes-related complications died of drowning in a bath tub, and their drowning death could be related to poor respiratory control [or cataplexy?]. These findings indicated that the cause of SED is not essentially different between PWS patients with and without GH treatment. Deceased PWS patients may have had underlying respiratory dysregulation and hypothalamic dysfunction, and GH therapy might have led to certain obstructive respiratory disturbances that exacerbated the respiratory conditions. This will call clinicians' attention when using GH in PWS patients, for example, careful determination of the dose of GH and careful monitoring of patient's respiratory conditions, especially in male obese patients with respiratory problems. Pediatr Pulmonol. 2002 Sep. Prader-Willi syndrome (PWS) is a genetic disorder, with hypotonia being the predominant feature in infancy, and developmental delay, obesity, and behavioral problems becoming more prominent in childhood and adolescence. Children with this disorder frequently suffer from excessive daytime sleepiness and have a primary abnormality of the circadian rhythm of rapid eye movement sleep. They also have primary abnormal ventilatory responses to hypoxia and hypercapnia, and these abnormalities may be exacerbated by obesity. Children with PWS are at risk of a variety of abnormalities of breathing during sleep, including obstructive sleep apnea and sleep-related alveolar hypoventilation. Clinical evaluation should include a careful history of sleep-related symptoms and assessment of the upper airway and lung function. Polysomnography should be considered for those with symptoms suggestive of sleep-disordered breathing. Treatment options depend on the underlying problem, but may include behavioral interventions, weight control, adenotonsillectomy, and nocturnal ventilation. Clin Neurophysiol. 2001 May. Objective: Excessive daytime sleepiness is a common symptom in Prader Willi syndrome (PWs). Sleep disordered breathing (SDB) and narcoleptic traits such as REM sleep onsets (SOREMPs) have been reported in these subjects. We evaluated nighttime and daytime sleep patterns in patients with PWS in order to clarify the nature of their hypersomnia. Design and methods: We performed overnight continuous EEG-polysomnographic studies (with breathing monitoring included) in 14 subjects (6 M,8 F; mean age 17 years, range 8-37) affected by PWs unselected for sleep disturbances. Ten patients underwent a Multiple Sleep Latency Test (MSLT) the day following the nocturnal sleep studies. Patients assessment was completed by means of immunogenetic characterization. Results: Nocturnal polysomnographic investigation documented sleep related breathing abnormalities such as central apneas, hypopneas or hypoventilation which mainly occurred during REM sleep in 8 subjects and did not cause sleep disruption. Only 4 subjects presented an increase in the Respiratory Disorder Index (RDI) slightly above the normal limits. In 8 subjects out of 10, with and without SDB, the mean daytime sleep latency could be considered abnormal according to the Tanner staging of pubertal development. Five patients showed at least two SOREMPs at MSLT. Subjects with and without SOREMPs had, respectively, a mean age of 18.6 SD 7.9 (4 M, 1 F) and 14.5 SD 2.9 (4 F, 1 M). The paternal deletion:uniparental dysomy ratio at genotypic characterization was 4:1 and 3.5:1 in subjects with and without SOREMPs, respectively. No patient presented DR-15 nor Dq-6. Conclusions: Excessive sleepiness is a frequent disturbance in PWs. Subgroups of PW patients show hypersomnolence and SOREMPs. Sleep disordered breathing appears to have a limited role in the genesis of hypersomnia which seems on the other hand attributable to the coexistence of narcolepsy phenotype. Hypersomnia in PW syndrome is likely to mainly be attributable to a primary hypothalamic dysfunction. The potential interacting role of other factors such as subjects age, sex and genetic pattern is suggested and deserve further investigation. Indian J Chest Dis Allied Sci. 2001 Jan-Mar. We report a case of a 3-year-old child with Prader-Willi syndrome who had severe sleep disordered breathing with daytime hypersomnolence. His daytime blood gases showed type II respiratory failure. He was effectively treated with continuous positive airway pressure (CPAP) and has used this form of therapy for 2 years now with improvement in daytime somnolence, improved mental acuity and normalisation of daytime blood gases. Psychiatry Clin Neurosci. 2000 Jun. To assess whether hypersomnia in Prader-Willi syndrome (PWS) patients is related to the respiratory disorder during sleep (RDDS), we made a systematic evaluation regarding the relationship between the two disorders in three patients. All patients showed hypersomnia manifested as the long duration of night sleep and shortened sleep latencies of multiple sleep latency test. Although magnetic resonance imaging and laboratory studies revealed obstruction of the upper airway and mild increase of esophageal pressure during sleep, the number of other apneic episodes or awakenings was not as frequent. From the above results, we speculate that the mechanism of excessive daytime sleepiness in PWS is not caused by RDDS and quite resembles that of essential hypersomnia. Eur J Pediatr. 1999 Nov. Abnormal ventilatory control in patients with Prader-Willi syndrome when awake and sleeping include abnormal responses to hyperoxia, hypoxia and hypercarbia. Lindgren et al., report similar results regarding response to hypoxia; however, they have demonstrated significant minute ventilation and carbon dioxide responses in their patients treated with growth hormone irrespective of body mass index. It is possible that the explanation for the abnormal respiratory control in this syndrome is located in central rather than peripheral structures. The hypothalamus stands out as the possible location that links their abnormal ventilatory control with the other features. Further investigations to correlate this finding are warranted. Neurophysiol Clin. 1998 Dec. The association of Prader-Willi-syndrome with breathing disturbances such as sleep apnea syndrome and/or hypoxemia during REM sleep, REM sleep abnormalities and excessive daytime sleepiness is well known. We report the case of an 11-year-old boy who presented with Prader-Willi syndrome, obesity (body mass index [BMI] = 45.6), severe obstructive sleep apnea syndrome and significant daytime sleepiness on multiple sleep latency test. Behavioral disorders did not allowed the use of continuous positive pressure in this patient. Therefore, clomipramine (20 mg per day) was administered. Sleep examination over 8 months showed: slight weight loss (BMI = 44.4), persistence of severe obstructive sleep apnea syndrome, slight improvement in nocturnal hypoxemia, and disappearance of excessive daytime drowsiness with mean sleep latency of 15 min 37 s (less than 2 min before treatment) and no diurnal REM sleep periods. However, clomipramine had no effect on hyperphagia. Eur Respir J. 1998 May. Hypercapnic respiratory failure is a common cause of death in the Prader-Willi syndrome. Its relationship to sleep-disordered breathing has not been established and there are no reports of its successful treatment. We have retrospectively reviewed the records of four patients with the syndrome, who developed ventilatory failure. Daytime arterial blood gas tensions and overnight oximetry traces before and during treatment were compared. Each patient had severe sleep-disordered breathing in association with daytime ventilatory failure. The median overnight mean arterial oxygen saturation (Sa,O2) was 82% and the median minimum was only 41.5%. Initial treatment was with nasal intermittent positive pressure ventilation, and in each case the daytime arterial blood gas tensions were normalized. The patients were maintained on nasal continuous positive airway pressure at night after discharge. Compliance has been good, and at last follow-up (after a median of 4.8 yrs) the daytime arterial gas tensions remained normal, while the median overnight mean arterial oxygen saturation was 95.5% and the median minimum was 84.5%. This study of patients with the Prader-Willi syndrome shows that daytime ventilatory failure is associated with sleep-disordered breathing. It can be reversed with nocturnal noninvasive ventilation and maintenance treatment with continuous positive airway pressure is well tolerated, with no deterioration in respiratory parameters. Eur J Pediatr. 1997 Jan. Physiological parameters of infants and children with Prader-Willi syndrome were examined in order to clarify whether there were indicators of disturbed respiratory control mechanisms in the pre-obesity stage of the syndrome. From January 1993 to March 1995 in eight patients with Prader-Willi syndrome (five boys, three girls, aged 6 weeks-12.5 years), polysomnography was performed and compared with 28 children matched for gestational age, sex, birth weight and age at sleep study. The recordings included thoracic and abdominal breathing movements, nasal airflow, tcPO2, tcPCO2, oxygen saturation, EEG, EOG and ECG. Respiratory responses to hypercapnia during quiet sleep were obtained from five Prader-Willi patients and ten peers. The Prader-Willi group showed an increased number of apnoeas per hour of sleep, a decreased nadir of oxygen saturation, increased maximum of the instantaneous heart rate and decreased respiratory responses to hypercapnia during quiet sleep. CONCLUSION: These findings indicate a primary disturbance of central respiratory control in patients with Prader-Willi syndrome which may be worsened by the development of obesity. Arch Pediatr Adolesc Med. 1996 Dec. Objectives: To assess nighttime and daytime sleep patterns in patients with Prader-Willi syndrome and to examine the effects of weight change on excessive daytime sleepiness in patients with this disorder. Design: Case series (within-subject design). Setting: A university sleep disorders center. Patients: Eight patients (5 males and 3 females), ranging in age from 5.5 to 21 years, who met the diagnostic criteria for Prader-Willi syndrome. Interventions: Overnight sleep polysomnographic recording and daytime Multiple Sleep Latency Test. Four of the 8 patients were restudied after their weight had changed. Main outcome measures: Changes in the sleep disordered breathing rate and Multiple Sleep Latency Test measures. Results: Sleep-disordered breathing occurred in all patients and was principally characterized by obstructive hypoventilation or episodes of apnea that occurred primarily during rapid eye movement sleep. After weight reduction, 3 patients had respiratory values that were within the broad normal range (disordered breathing rate, < 15 breaths per hour). Statistically significant (P < .05) weight loss effects occurred during nonrapid eye movement sleep (decrease with weight loss, F = 6.243). Excessive daytime sleepiness was documented in 6 of 7 patients who completed the Multiple Sleep Latency Test. Excessive daytime sleepiness was not consistently correlated with body weight or any of the nocturnal sleep variables. Conclusions: A sleep-related breathing disorder occurred during rapid eye movement and nonrapid eye movement sleep and improved with weight change in patients with Prader-Willi syndrome, emphasizing the importance of weight reduction in clinical management. However, excessive daytime sleepiness persisted despite a reduction in sleep-disordered breathing after weight loss, suggesting a primary disturbance of sleep. Our findings provide additional support for the view that primary hypersomnia is a characteristic feature of the Prader-Willi syndrome. Am J Med Genet. 1996 Sep 20. To assess whether sleep abnormalities are related to the genetic abnormalities in Prader-Willi Syndrome (PWS), we performed polysomnographic studies (nighttime and daytime) and determined the chromosome 15 genotypes in eight patients with PWS. Four patients demonstrated sleep onset REM periods (SOREM), and five met the objective polysomnographic criteria for severe or moderate excessive daytime sleepiness (EDS). Three of the four patients with SOREM displayed a paternally derived deletion of chromosome 15q11-q13, whereas the fourth exhibited maternal uniparental heterodisomy in this chromosomal region (UPD). Two of the four patients that did not display SOREM carried paternally derived deletions; the remaining two demonstrated UPD. Four of the five patients with EDS displayed paternal deletions, and the fifth exhibited UPD. One of three patients without evidence of EDS demonstrated paternal deletion; the remaining two showed UPD. Although neither EDS nor SOREM was not consistently associated with a specific genetic abnormality, these phenotypes may be more common in patients with paternal deletions than in those UPD. Sleep abnormalities in PWS cannot be explained by a single genetic model. Eur Respir J. 1996 Jul. The clinical course and changes in hypercapnic ventilatory drive over time were serially assessed before and after tracheostomy placement in a 14 year old, morbidly obese female patient with Prader-Willi syndrome, severe obstructive sleep apnoea, and obesity-hypoventilation syndrome. A tracheostomy became necessary after supplemental oxygen and continuous positive airway pressure (CPAP) had failed to improve the severity of nocturnal hypoventilation. Continued improvement in the slope to rebreathing hyperoxic hypercapnia occurred from 2-10 weeks after tracheotomy in conjunction with night-time bilevel pressure ventilation, and remained unchanged thereafter. In contrast, increases in mean resting minute ventilation at an end-tidal carbon dioxide tension (PET,CO2) of 8 kPa (60 mmHg) were documented even after 30 weeks. This case study illustrates the time-frame of dynamic ventilatory changes occurring after removal of upper airway resistance and normalization of nocturnal alveolar ventilation. From the full text article: In adult patients with severe obstructive sleep apnoea syndrome (OSAS), a beneficial effect is observed 3 months after the reversal of upper airway resistance by tracheostomy placement. Both improved resting breathing pattern and hypercapnic ventilatory responses (HCVR) were reported in seven patients who were hypercapnic during wakefulness [1–3]. However, such beneficial effect has not yet been demonstrated in children with severe OSAS in whom tracheotomy may be required. Prader-Willi syndrome (PWS) is the most common genetic disorder leading to obesity [4]. Hypogonadism, short stature with small hands and feet, behavioural disorders, as well as compulsive eating are characteristic of this syndrome [4]. However, with strict dietary intake restrictions, obesity may be prevented in PWS patients. Whilst absent or markedly reduced ventilatory response both to transient and isocapnic hypoxia during wakefulness [5, 6] are universally found both in obese and nonobese PWS patients, HCVR is blunted only in obese PWS patients [5, 7]. Furthermore, abnormal sleep patterns, including daytime somnolence, hypoventilation, oxygen desaturations during rapid eye movement (REM) sleep and abnormal sleep architecture, tend to occur more frequently in obese PWS [8], suggesting that additional obesity-related respiratory loads may contribute to modification of hypercapnic responsivity over time. We report the case of a 14 year old obese female PWS patient with severe OSAS and obesity-hypoventilation syndrome, in whom resting ventilatory measures and HCVR were assessed prior to and serially after tracheotomy and nocturnal ventilatory support. Case report A 14 year old female previously diagnosed with PWS was urgently admitted following the insidious onset of fever, and diminished mental and physical activity levels over a 3 day period. Her past medical history was positive for recurrent urinary tract infections, uncontrollable appetite and feeding schedules, as well as obsessive compulsive behaviours, such as skin-pinching and hair-pulling. In addition, marked weight gain, loud snoring and daytime somnolence had been observed to develop since institution of trimonthly hormonal therapy with medroxyprogesterone for aggressive verbal behaviour. The patient's weight was 77 kg, height 143 cm, and calculated body mass index (BMI) 37.6 kg·m-2. Physical examination disclosed a markedly obese patient, in no apparent distress, with a rectal temperature of 38.3 °C, a respiratory frequency (fR) of 14 breaths·min-1, pulse rate 114 breaths·min-1, and blood pressure of 117/77 mmHg. The patient was somnolent, although easily arousable on verbal command. No lymphadenopathy, icterus, cyanosis or clubbing were found. The head and neck were normal. Decreased breath sounds and diffuse rales were present over both lungs. The remainder of the examination revealed only physical stigmata characteristic of Prader-Willi syndrome, such as small hands and feet, sparse pubic, axillary and body hair, and small clitoris and labia minora. Arterial blood gas values obtained whilst awake and breathing room air revealed a pH of 7.38, an arterial oxygen tension (Pa,O2) of 8.7 kPa (65 mmHg), and an arterial carbon dioxide tension (Pa,CO2) of 6.9 kPa (52 mmHg). A radiograph of the chest disclosed bilateral interstitial infiltrates, and therapy was instituted with intravenous antibiotics (cefuroxime and erythromycin), and supplemental oxygen at 2 L·min-1 delivered via nasal cannula. However, during sleep, loud snoring, and marked oxygen desaturations to the low 60s % were noted, and arterial blood gas measurements at this time revealed a pH of 7.25, a Pa,O2 of 5.1 kPa (38 mmHg), and a (Pa,CO2) of 10.4 kPa (78 mmHg). The patient was intubated and mechanically ventilated for several days, with rapid clearing of chest infiltrates and auscultatory findings, as well as normalization of arterial blood gas values. However, although minimal ventilatory support requirements (continuous positive airway pressure (CPAP) 6 cmH2O; inspiratory oxygen fraction (FI,O2, 24%) were necessary during wakefulness, increasing support was necessary during sleep due to worsening hypercapnia and hypoxaemia (assist/control mode; fR 14 breaths·min-1; positive endexpiratory pressure (PIP) 40 cmH2O; positive end-expiratory pressure (PEEP) 6 cmH2O; FI,O2 28%). The patient was finally extubated on Day 5 after 12 h of CPAP, and 2 days later, an overnight polysomnogram was performed which confirmed the presence of severe OSAS (table 1). On Day 9 of hospitalization, the patient developed cyanosis and bradycardia (45 beats·min-1) during sleep. Arterial blood gas measurements on supplemental oxygen by mask revealed a pH of 7.07 and Pa,CO2 of 12.1 kPa (91 mmHg), and the patient was intubated and mechanically ventilated. In the following 12 days, despite minimal ventilatory settings, several attempts to extubate the patient were unsuccessful due to development of severe alveolar hypoventilation (Pa,CO2 9.3 kPa (>70 mmHg)) during sleep. On day 20, rebreathing ventilatory responses to hypercapnia were first assessed (see below), and 2 days later, a tracheostomy was performed. The patient was gradually weaned from daytime ventilation over the next 14 days. Arterial blood gases and oxygen saturation measured during wakefulness were within normal limits. To maintain adequate oxygenation and Pa,CO2 6 kPa (<45 mmHg) ventilatory support was provided during night-time sleep with bilevel positive airway pressure (BiPAP), ventilation (Respironics, Murrysville, PA, USA) at the following settings: assist/control mode; PIP 20 cmH2O; PEEP 6 cmH2O; and fR 10 breaths·min-1. On Day 47, the patient was discharged on nighttime bilevel ventilation at the above settings, and underwent two additional sleep studies at 4 and 9 weeks after tracheostomy placement (table 1). ... Results The results of hypercapnic ventilatory tests are shown in figures 1 and 2. Improvements in the slope of HCVR occurred within 2 weeks of tracheotomy and nocturnal bilevel pressure ventilatory support and plateaued at 10 weeks after surgery (fig. 1). Ongoing increases in resting V'E as well as in V'E measured at PET,CO2 of 8 kPa (60 mmHg) were still noticed 30 weeks after surgery (fig. 2). Discussion The present case documents the time course for recovery of hypercapnic ventilatory drive after removal of upper airway obstruction and night-time ventilatory support. Although no weight reduction occurred in our patient over time, marked increases in spontaneous ventilation during wakefulness, at PET, CO2 of 8 kPa (60 torr), as well as in the HCVR slope occurred during the initial 10 weeks following tracheotomy, and the latter remaining unchanged thereafter (figs. 1 and 2). Thus, analogous to studies in adults [12], reduction of upper airway resistance, normalization of alveolar gas exchange during sleep, and prevention of sleep fragmentation due to apnoea resulted in gradual improvement of waking ventilatory measures, finally allowing for discontinuation of daytime ventilatory support 2 weeks after tracheotomy. However, although improved, persistent hypoventilation during sleep was still present after 9 weeks of treatment. GUILLEMINAULT and CUMMISKEY [1] reported significant increases in the slope of HCVR after 12–16 weeks in five tracheotomized adult patients with OSAS, and comparable findings in three additional patients were documented within similar postoperative periods [2, 3]. The time course of such improved hypercapnic drive was not serially assessed. More recently, increased ventilatory measures at a PET,CO2 of 8 kPa (60 mmHg) were found in daytime hypercapnic OSAS patients as early as 48 h following institution of CPAP therapy, and continued to improve with continuing CPAP treatment for 2 weeks [13]. However, the slope of the HCVR remained unchanged over time [13]. Improvements in daytime ventilatory measures and chemosensitivity evolved slowly in our patient, despite normalization of alveolar ventilation during sleep with bilevel pressure ventilatory support. The absence of further improvement in this patient could indicate that she may have reached her "normal" HCVR, or that no further improvements would occur unless other therapeutic measures, such as weight loss or respiratory stimulants, were instituted. Evaluation of control of breathing in awake, adult OSAS patients suggests that in patients with normocapnia during wakefulness, normal hypercapnic ventilatory and mouth occlusion pressures are found [14]. In contrast, in hypercapnic patients, the ventilatory CO2 response is usually depressed [15]. In nonobese children with OSAS, ventilatory responses to hypercapnia and hypoxia are similar to those found in healthy controls [16], suggesting that abnormal central respiratory drive is not a frequent component in the pathophysiology of OSAS in childhood. The additional contribution of obesity to respiratory drive in our patient is unclear. Obesity leads to decreased chest wall compliance due to deposition of adipose tissue, and such elastic load may elicit early enhancement of neuromuscular respiratory output [17]. However, with prolonged mass loading, hypoventilation may develop over time [18]. In a recent study, we found that obese PWS patients had significantly diminished hypercapnic ventilatory slopes, whilst nonobese PWS patients demonstrated comparable slopes to those found in age-, gender and BMI-matched controls [5]. Thus, the absence of continued HCVR improvement after 10 weeks following tracheotomy in our patient may represent the net effect of daytime mass loading due to obesity, which may impinge on the complete recovery of HCVR to normal values [19], or an unrelated, diminished inborn hypercapnic ventilatory drive. Also worthy of mention was the relative bradypnoea recorded on admission in the presence of fever. We are uncertain of the exact significance of this sign, which could underlie either the absence of peripheral chemoreceptor response [6], or indicate disturbances in feedforward mechanisms originating in hypothalamic structures [5, 6]. In summary, the temporal improvements in waking ventilation and hypercapnic drive occurring after tracheotomy and bilevel pressure ventilation are reported in a Prader-Willi Syndrome patient over a period of 30 weeks. This interesting case emphasizes the contribution of sleep-disordered breathing to blunted ventilatory responses to carbon dioxide and respiratory failure, and the potential for partial reversibility of such changes by therapeutic measures leading to adequate gas exchange. Am J Respir Crit Care Med. 1996 Jan. Ventilatory responses to peripheral chemoreceptor stimuli are absent in patients with Prader-Willi syndrome (PWS) during wakefulness. Because arousal from sleep after rapidly developing hypoxia may require intact peripheral chemoreceptor function, we hypothesized that blunted hypoxic arousal responses during sleep Stage 3/4 would be present in PWS. Thirteen patients with PWS (mean age, 23.4 +/- 3.7 +/- SEM yr; 46% male; body mass index [BMI], 28.9 +/- 1.6 kg/m2) and 11 matched control subjects (mean age 28.0 +/- 5.4 yr; 54% male; BMI, 28.8 +/- 3.1 kg/m2) were studied. An abrupt decrease in inspired O2 tension to 80 mm Hg was introduced until arousal occurred or for a maximum of 3 min. One of the 13 patients with PWS and seven of the 11 control subjects were aroused by the hypoxic challenge (p < 0.02). During hypoxia, heart rate increased by 9 +/- 2% in the PWS group versus 22 +/- 4% in the control group (p < 0.005). Respiratory rate did not change in the PWS group (4 +/- 2%; p = NS), but it increased by 13 +/- 2% in the control group (p < 0.02). We conclude that abnormal arousal and cardiorespiratory responses to hypoxia are frequent in PWS. We postulate that intact peripheral chemoreceptor function is an important component underlying arousal mechanisms to rapidly developing hypoxia during sleep. Chest. 1995 Dec. Study objective: Prader-Willi syndrome (PWS) is characterized by a number of abnormalities of hypothalamic function, such as hyperphagia, short stature, temperature instability, hypogonadotropic hypogonadism, and neurosecretory growth hormone deficiency. Patients with PWS are reported to have sleep-disordered breathing and have blunted hypercapnic ventilatory responses secondary to abnormal peripheral chemoreceptor function. Thus, we hypothesized that hypercapnic arousal responses would be abnormal in PWS. Design: Hypercapnic arousal responses were tested in ten nonobese children and adults with PWS, aged 17.7 +/- 2.5 (SEM) years, 70% female, and nine control subjects, aged 14.2 +/- 2.6 years, 67% female. Hypercapnic challenges were performed during stage 3/4 non-rapid eye movement sleep. Results: The PWS subjects had a significantly higher arousal threshold to hypercapnia compared with the controls (53 +/- 1.0 vs 46 +/- 1.7 mm Hg; p < 0.01). The PWS subjects had significantly higher baseline end-tidal CO2 levels (42 +/- 0.8 vs 38 +/- 1.1 mm Hg; p < 0.01) and more central apneas greater than 15 s/h of sleep (1.5 +/- 0.3 vs 0.1 +/- 0.1; p < 0.01). Conclusions: Elevated hypercapnic arousal thresholds during sleep are found in PWS subjects; these may be a manifestation of abnormal peripheral chemoreceptor function and may further contribute to sleep-disordered breathing in PWS patients. Am J Med Genet. 1995 Mar 27. Polysomnographic recordings of 43 children and adults with Prader-Willi syndrome (PWS) were inspected and classified into 5 age groups. The effect of age and body mass index (BMI) on measures of breathing, oxygen saturation, and sleep efficiency were analyzed. Body mass index (BMI) increased significantly between early childhood and preadolescent groups. Subjecting the data to analysis of variance showed an overall significant effect of BMI but no age effect on breathing parameters and oxygen saturation. Increased BMI was associated with decreased oxygen saturation and with higher apnea/hypopnea index. Sleep efficiency index was significantly lower in adults than in young children, preadolescent, and adolescent groups. These findings emphasize the role of obesity in the development of sleep-related breathing abnormalities and nocturnal oxygen desaturation in patients with PWS. J Appl Physiol. 1994 Nov. Abnormalities of ventilatory control may play a significant role in the pathophysiology of sleep-disordered breathing in patients with the Prader-Willi syndrome (PWS). We measured rebreathing hypercapnic and hypoxic ventilatory responses (HCVR and HPVR, respectively) during wakefulness in 8 nonobese PWS (NOB-PWS) and 9 obese PWS (OB-PWS) patients and compared their results with those from 24 healthy nonobese control (NOB-CON) and 10 obese control (OB-CON) subjects. The slope of HCVR was similar in NOB-PWS patients and NOB-CON subjects (NS). However, HCVR was significantly lower in OB-PWS patients than in OB-CON subjects (P < 0.02). In PWS patients, the mean point of origin of the positive slope of HCVR occurred at a significantly higher end-tidal PCO2 than in either control group. During isocapnic hypoxic challenges, six PWS patients had no significant HPVR. In the remainder, mean slopes of HPVR were -0.80 +/- 0.06 l.min-1.%arterial O2 saturation-1 in five NOB-PWS patients and -0.68 +/- 0.15 l.min-1.%arterial O2 saturation-1 in six OB-PWS patients. These responses were significantly decreased compared with those in the control groups (P < 0.006). We conclude that NOB-PWS patients have normal HCVR, which is blunted in OB-PWS patients. Furthermore, isocapnic HPVR is either absent or markedly reduced in PWS patients. The severity of abnormality of the HPVR is independent of the degree of obesity. We postulate that the primary abnormality of ventilatory control in PWS affects peripheral chemoreceptor pathways. J Appl Physiol. 1994 Nov. Abnormalities in ventilatory control during wakefulness and sleep have been observed in patients with Prader-Willi syndrome (PWS). The role of peripheral chemoreceptors in the pathophysiology of abnormal ventilatory responses in PWS is unknown. We studied peripheral chemoreceptor function during wakefulness in 17 genetically confirmed PWS patients [age 27.0 +/- 2.5 (SE) yr; 7 males, 10 females; body mass index 31.1 +/- 1.4 kg/m2] and compared their responses with 17 control subjects matched for age, sex, and body mass index. All PWS and control subjects had normal resting end-tidal PCO2 and arterial O2 saturation while awake. Peripheral chemoreceptor function was assessed by the ventilatory responses to 100% O2 breathing, five tidal breaths of 100% N2, and vital capacity breaths of 15% CO2 in O2. Control subjects decreased minute ventilation (VE) by 15.5 +/- 3.6% during hyperoxia. However, PWS patients increased VE by 17.6 +/- 3.3%, indicating a paradoxical response to hyperoxia (P < 0.00001). After CO2 vital capacity breaths, PWS patients showed no significant change and control subjects showed a marked increase (P < 0.0001) in VE. During N2 breathing, again PWS patients showed no change and control subjects exhibited a marked increase (P < 0.00005) in VE. We conclude that PWS patients have absent peripheral chemoreceptor ventilatory responses. We speculate that the lack of ventilatory responses is due to primary peripheral chemoreceptor dysfunction and/or defective afferent pathways to central controllers. J Sleep Res. 1994 Jun. Seventeen children and young adults with the Prader-Willi syndrome were investigated. Twelve of 17 subjects had excessive daytime sleepiness as determined by their own or parental report, a high Epworth Sleepiness Scale score or a short mean sleep latency. Night sleep disturbances were reported in seven subjects with snoring, mouth-breathing, breath-holding and occasional nocturnal enuresis. Polysomnography showed abnormalities of sleep structure with rapid eye movements without reduction in muscle tone at sleep onset in 12 subjects, and a high respiratory event index with frequent brief apnoeas, particularly in REM sleep, in 16 subjects. Most apnoeas were not accompanied by arousals. Seven subjects, all of whom were obese, were considered to have symptomatic sleep apnoea and were treated with continuous positive airway pressure (CPAP) but this was poorly tolerated in two. Five subjects continued CPAP over a 6-month period resulting in subjective improvement in excessive daytime sleepiness in 3. Excessive daytime sleepiness occurs in approximately two-thirds of subjects with the Prader-Willi syndrome. It is mainly of central origin but obstructive sleep apnoea may increase sleepiness, particularly in obese subjects. Clin Otolaryngol Allied Sci. 1994 Jun. Obesity, short stature, hypotonia and excessive daytime sleepiness are characteristic features of the Prader-Willi syndrome. Excessive daytime sleepiness has been attributed to obstructive sleep apnoea (OSA). To investigate the role of anatomical factors in OSA in the Prader-Willi syndrome, clinical and ENT assessment, radiology of the upper airway and polysomnography including sleep oximetry were done in 14 subjects. Excessive daytime sleepiness was present in eight of 14 subjects as determined by a mean sleep latency to non-rapid eye movement stage I-II of < 5 min and/or self-rating sleepiness score > 9 (Epworth Sleepiness scale). Seven subjects were snorers or mouth breathers and dental abnormalities were present in 11. Sleep apnoea, as determined by a combined apnoea-hypopnoea index of more than 10 respiratory events per hour was present in 12 of 14 subjects. On clinical assessment, the nasopharynx, oropharynx and hypopharynx were small in one subject. No subject had redundant pharyngeal mucosa or an enlarged tongue. However, radiological studies performed in the awake supine posture showed a slight reduction in the cross-sectional area in nine subjects at the oropharyngeal level and in four subjects at the nasopharyngeal level as compared with normal control subjects. Sleep apnoea and minor radiological evidence of narrowing of the upper airway are common in the Prader-Willi syndrome, although clinical otolaryngological examination is often unremarkable. Excessive daytime sleepiness occurs in approximately 50% of all patients with Prader-Willi syndrome. Although obstructive sleep apnoea is one important factor related to sleepiness, an additional central disturbance of sleep mechanisms is present. J Intellect Disabil Res. 1993 Dec. The polygraphically recorded sleep-wake continuum of 21 Prader-Willi syndrome (PWS) patients was compared with that of 19 normal people. In the Prader-Willi group, excessive daytime sleepiness (EDS) is found in 95% of subjects, and rapid eye movement (REM) sleep disorders occur in 52%. These two features were significantly different from the normal group of subjects. No indications were found for the presence of the apnoea syndrome. The REM sleep disorders are: sleep onset rapid eye movements (SOREM), REM sleep in naps, many arousals during REM sleep, and a significant decrease in total REM sleep. These disturbances in the Prader-Willi group, combined with the presence of EDS and sometimes of cataplexy, are likely to be expressions of a narcoleptic syndrome although this was not sustained by the HLA-DR2 expression above normal. The quality of life of PWS subjects can be improved in some cases by treating them as narcoleptic patients. Sleep. 1993 Jun. Patients with Prader Willi syndrome (PWS) often complain of daytime hypersomnolence. Because of reported daytime sleepiness and high prevalence of morbid obesity, these patients have been considered at risk for sleep related disordered breathing, but polysomnographic studies have been limited. We evaluated sleep and breathing polysomnographically in 24 PWS patients including 15 adults and 9 children. All adult patients completed MSLT testing on the day following the nocturnal sleep study. Both adult and children groups showed little or no sleep apnea, but REM related oxygen desaturation was quite common, its severity significantly correlated with increased obesity. Sleep patterns in both groups showed abnormal REM sleep cycles with variable REM latency (at times significantly shortened) and fragmented REM sleep with multiple brief REM periods. REM sleep abnormalities were still present in some patients without REM related desaturation. As a group, patients with PWS demonstrated pathological somnolence as measured by MSLT, which correlated with nocturnal sleep efficiency but not with nocturnal REM latency. It is hypothesized that the abnormal sleep findings in PWS reflect an underlying hypothalamic dysfunction characteristic of this syndrome. Acta Paediatr Scand. 1991 Jan. This report describes the polysomnographic findings and the respiratory alterations during sleep in a 20-year-old patient with the Prader-Willi syndrome. Nocturnal recordings and a variant of the multiple sleep latency test showed excessive daytime sleepiness, sleep onset rapid eye movement episodes, snoring and sleep apnea. Treatment with nasal continuous positive airway pressure normalized the respiratory pattern and the sleep structure, except for rapid eye movement sleep onset. Whereas upper airway obstruction and obesity may explain the respiratory disorders, as shown by their resolution with continuous positive airway pressure treatment, hypothalamic dysfunction could play a role in the disruption of the normal nonrapid eye movement/rapid eye movement sleep periodicity. Arch Neurol. 1984 Mar. Nine patients with the Prader-Willi syndrome, ranging in age from 3 to 21 years, were examined clinically as well as studied in the sleep laboratory. They had striking disturbances of sleep-wakefulness patterns. All patients except one had the symptom of excessive daytime sleepiness. The most striking finding was the presence in five patients of rapid-eye-movement (REM) sleep occurring at sleep onset (SOREM). None of the patients had the condition of sleep apnea. One patient, however, demonstrated severe hypoventilation during REM sleep; the lowest value recorded for O2 saturation was 40%, with a consistent value below 50% for as long as ten to 15 minutes. Previous findings have indicated that the Prader-Willi syndrome is of hypothalamic origin. We hypothesize that both the SOREM and O2 desaturation findings in our patients with the Prader-Willi syndrome are also a result of hypothalamic changes. |