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J Clin Endocrinol Metab. 2006 Sep 26. Abstract [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 Genotropinฎ (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 IGF-1, are involved in the physiologic regulation of breathing (37). IGF-1 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. |