|Year : 2015 | Volume
| Issue : 4 | Page : 258-263
Polysomnography and antidiuretic hormone secretion pattern in children with primary nocturnal enuresis
Hanan M Hamed MD 1, Amany M Abd Al-Aziz1, Ayat A Motawie1, Amany A. A. Fatouh1, Mona A. M. Awad2, Lamia Afifi3
1 Department of Pediatric, National Research Centre, Cairo, Egypt
2 Department of Clinical Pathology, National Research Centre, Cairo, Egypt
3 Department of Clinical Neurophysiology Unit, Faculty of Medicine, Cairo University, Cairo, Egypt
|Date of Submission||15-Jan-2015|
|Date of Acceptance||01-Mar-2015|
|Date of Web Publication||27-Nov-2015|
Hanan M Hamed
Department of Pediatric, National Research Centre, El-Buhouth Str., Dokki, 12311 Cairo
Source of Support: None, Conflict of Interest: None
Nocturnal enuresis (NE) is one of the most common pediatric sleep-related problems. Data on sleep patterns in children with NE are conflicting.
We aimed at studying the sleep architecture, associated breathing problems, and its relation to antidiuretic hormone (ADH) in children with primary NE.
Patients and methods
This study included 31 children aged 6-18 years with primary monosymptomatic NE and 16 healthy matched controls. They were subjected to a single overnight polysomnography and assessment of ADH levels at 9-11 a.m. and 9-11 p.m.
Enuretic children had significantly prolonged sleep latency and higher stage N1 percentage, less total sleep time, lower sleep efficiency, and lower rapid eye movement sleep percentage compared with the control group. Ten (32.2%) NE children had nocturnal arrhythmia, whereas six (19.35%) had a respiratory distress index more than 5. Reversed ADH secretion pattern was present in 82% of the NE children. Children with reversed ADH secretion had lower stage N1 and respiratory distress index, and higher sleep efficiency, compared with NE children with normal ADH rhythm.
Primary NE is associated with disturbed sleep architecture. NE could be a presenting symptom for hidden sleep disordered breathing. The association of NE with cardiac arrhythmia is an interesting finding that requires further research. Most NE children have a reversed pattern of ADH secretion.
Keywords: antidiuretic hormone, polysomnography, primary nocturnal enuresis, sleep disordered breathing
|How to cite this article:|
Hamed HM, Abd Al-Aziz AM, Motawie AA, Fatouh AA, Awad MA, Afifi L. Polysomnography and antidiuretic hormone secretion pattern in children with primary nocturnal enuresis. Egypt J Neurol Psychiatry Neurosurg 2015;52:258-63
|How to cite this URL:|
Hamed HM, Abd Al-Aziz AM, Motawie AA, Fatouh AA, Awad MA, Afifi L. Polysomnography and antidiuretic hormone secretion pattern in children with primary nocturnal enuresis. Egypt J Neurol Psychiatry Neurosurg [serial online] 2015 [cited 2017 Aug 22];52:258-63. Available from: http://www.ejnpn.eg.net/text.asp?2015/52/4/258/170658
| Introduction|| |
Nocturnal enuresis (NE) is one of the most common pediatric sleep-related problems, with different studies citing a prevalence of 16.1% in 5-year-old children and of 9.8% in 7-year-old children  . Prevalence decreases with age, as the prevalence at age 9 and 19 years falls to 3.14 and 2.2% of children, respectively  . Boys are reported to be more commonly affected than girls  . In Egypt the prevalence of primary nocturnal enuresis (PNE) was reported to be 14.7% in children aged 6-13 years  .
Three major factors are hypothesized to be behind enuresis: increased nocturnal urine production, detrusor hyperactivity, and impaired arousability  . Both bladder filling and detrusor contractions are recognized as powerful arousal stimuli; yet, it is not clearly known why the imminent voiding does not awaken the NE children. Children with NE are generally believed to be more difficult to arouse than normal children  . However, this may be a characteristic and not a cause for NE. Both the arousal process and the micturition reflex are mediated by nuclei in the brain stem. It is postulated that functional immaturity of CNS may lead to decreased sensory perception of the bladder filling, inability to inhibit bladder emptying, and poor arousal mechanism  . There are conflicting results from studies assessing sleep using polysomnography (PSG) in children with enuresis, as some studies have reported that PSG results of enuretic children are similar to those of control children, whereas other studies have shown significant differences between the two groups , . Also the relationship between NE and obstructive sleep apnea (OSA) is controversial , . Therefore, we aimed to study the sleep architecture, associated breathing problems, and its relation to antidiuretic hormone (ADH) in children with PNE.
| Patients and methods|| |
Thirty-one children aged 6-18 years, 20 boys and 11 girls, complaining of primary monosymptomatic NE were recruited from the Pediatric Outpatient Clinic, National Research Centre. The patients were subjected to full history taking (especially number of wetting episodes per week, difficulty to awaken at night, respiratory problems, and snoring) and clinical examination. Abdominal and pelvic ultrasounds were taken to exclude anomalies in the urinary tract. Exclusion criteria were as follows: age younger than 6 years; presence of attention deficit hyperactivity disorder; secondary NE; having undergone spinal, brain, or pelvic surgery; presence of congenital anomalies of the urological tract; urinary tract infection; diabetes mellitus; and diabetes insipidus. Sixteen matched healthy children were included as the control group. Written informed consent was taken from the guardians of all children. The study was approved by the local institutional ethical committee.
A single attended overnight PSG study was performed at the clinical Neurophysiology Unit of Cairo University Hospitals. Children were studied in a quiet, darkened room with one of their guardians present. No medications were used to induce sleep. All participants underwent 1 night of laboratory-based PSG carried out using a Schwarzer Epos 32 GmpH Amplifier (Schwarzer, Essen, Germany) and Somnologica software (Broomfield, CO, USA). The following procedures and tools were used to obtain electrophysiological data: electroencephalography (C3/A2, C4/A1, O2/C3, and O1/C4); left and right electro-oculography; mentalis and tibial electromyography; ECG; respiratory airflow; respiratory effort; finger pulse oximetry; snoring neck microphone; and body position sensors. Sleep measures obtained for each patient included total sleep time, sleep efficiency (SE), percentage of different sleep stages, sleep onset latency, respiratory distress index (RDI), oxygen saturation, and periodic limb movement index. The PSG was carried out by an experienced PSG technologist and was scored by a sleep disorder physician in accordance with the American Academy of Sleep Medicine guidelines  . Assay of ADH levels was performed at 9-11 a.m. and 9-11 p.m. in 28 patients with NE and controls using an enzyme immunoassay kit (Assay Design Inc., Ann Arbor, Michigan, USA). The kit uses polyclonal antibody to vasopressin to bind in a competitive manner.
Statistical package for the social sciences (SPSS, version 15.0 for Windows; SPSS Inc., Chicago Illinois, USA) was used for statistical analysis. Data were represented as mean ± SD, frequency, and percentages. We used the independent t-test to compare between two independent means. To compare between three or more independent means one-way ANOVA was used. To compare between independent proportions the χ2 test was used.
| Results|| |
Thirty-one children with NE aged 6-18 years (11.64 ± 3.08 years) and 16 healthy matched children aged 7-18 years (11.5 ± 3.27 years) participated in this study.
Comparison between PSG findings in NE patients and controls showed that sleep latency and stage N1 percentage were significantly increased in our cases than in controls. In contrast, total sleep time, SE, rapid eye movement (REM) sleep percentage, and lowest oxygen saturation were significantly reduced in NE patients than in controls ([Table 1]). Five NE children had enuretic events during the PSG: three events occurred during stage N2 sleep and two events occurred during stage N3 sleep.
|Table 1 Comparison of polysomnographic parameters between nocturnal enuresis children and controls |
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Comparison between male and female nocturnal enuresis patients
Our results showed that female patients were significantly older than male patients, with no significant PSG differences between them ([Table 2]).
|Table 2 Comparison between males and females enuretic patients as regards polysomnography |
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Comparison between nocturnal enuresis patients with and without elevated apnea-hypopnea index
The RDI was similar in the NE and control groups. We were interested in finding out whether any of the NE patients carried the diagnosis of sleep-related disordered breathing. Different RDI abnormality cutoff values were previously used, including a cutoff of an apnea index more than 1  , obstructive apnea-hypopnea index (AHI) more than 1.4  , and RDI more than 5  . [Table 3] shows the PSG results using cutoffs of 1 and 5 for AHI abnormality. Six NE children had an AHI more than 5, and those children showed more frequent snoring and lighter sleep than the other NE patients.
|Table 3 Polysomnographic pattern comparison between enuretic children regarding different apnea-hypopnea index cutoffs |
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Nocturnal enuresis patients with heart arrhythmia
Ten (32.2%) patients showed heart beat arrhythmia as follows: six patients had tachycardia; one had extrasystole; two had atrial fibrillation; and one had sinus arrhythmia. The last three patients underwent echocardiography and were found to suffer from mitral valve prolapse. None of the controls showed any arrhythmia. The PSG results in NE patients with and without arrhythmia did not show any significant differences ([Figure 1]).
|Figure 1 Polysomnographic pattern comparison between enuretic children with normal heart beat versus those having arrhythmia. REM, rapid eye movement|
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Antidiuretic hormone pattern
Reversal of circadian rhythm of ADH secretion was present in 82% of cases, and normal rhythm was present in 18%. The morning mean ± SD levels of ADH of the reversed group versus the normal rhythm group was 69.3 ± 60.2 versus 30 ± 14.1, respectively (P = 0.2), whereas their evening ADH was 30.5 ± 20.05 versus 56.3 ± 38.3 (P = 0.05). PSG revealed that children with reversed ADH rhythm showed less stage N1 percentage and RDI, and higher SE than did the group with normal ADH rhythm ([Table 4]).
|Table 4 Comparison between enuretic children with normal antidiuretic hormone versus reversed rhythm |
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| Discussion|| |
The pathogenesis of enuresis could be considered on the basis of a mutual balance of three basic mechanisms: bladder capacity, nocturnal production of urine, and abnormally deep sleep  . Our team had previously studied bladder capacity in PNE  and ADH levels (nocturnal urine production)  . In this work we focused on sleep architecture, associated breathing problems, and its relation to ADH.
Few studies are available that have objectively assessed the sleep patterns of children with NE using PSG, and even fewer studies have included a control group in their evaluation ,, . Furthermore, the results from these studies are conflicting , .
Five NE children had enuretic events during the PSG, and all events occurred during non rapid eye movement (NREM) sleep. This is consistent with other studies that found that enuretic events were predominantly NREM phenomena , . This could be explained by the high parasympathetic tone that characterizes non-REM sleep, as this high tone increased detrusor muscle contractions. The PSG results revealed that our patients had prolonged sleep latency compared with controls. We suggest that this finding might be due to heightened anxiety in NE children who may worry about wetting the bed at night, especially outside their home, which can expose them to criticism and threaten their self-esteem. Our study showed that enuretic children have longer light stage (stage N1), normal deep sleep (N3), and less REM sleep compared with the control group. Although a previous study by Yeung  reported that children with enuresis had more light sleep, less deep sleep, and REM sleep than did controls, other studies have found that sleep stage percentages were similar in NE children and controls , . The theory of a dysfunction in pontine reticular formation as one of the causes of enuresis was supported by the loss of REM-related phasic chin muscle activity in some NE patients  . A dysfunction in the pontine reticular formation might explain the decrease in REM sleep in our patients compared with controls.
SE was significantly reduced in our NE patients compared with controls. This is consistent with previous studies that reported a higher number of awakenings or arousals in NE patients , . Night-time awakenings in NE children can be due to spontaneous awakening following bed-wetting  . It is possible that a vicious circle thus arises as the sleep fragmentation due to night-time awakenings leads to an increased arousal threshold that consequently leads to failure to respond to full-bladder signals and thus repeated bed-wetting. Although PSG cannot assess arousal thresholds, a study using auditory stimuli found that stimuli that resulted in full behavioral arousal in 40% of controls were able to awake only 9% of NE boys  . It was suggested that the high arousal threshold of enuretic patients may be linked to the autonomous nervous system and/or disturbances in the upper pons as both control micturition and arousal mechanisms  .
The relationship between NE and sleep disordered breathing is also controversial, and studies reporting both positive and negative associations have been published , . The RDI difference was not significant between our NE patients and controls. Five (16.1%) NE children had AHI 1-5, whereas six (19.35%) NE children had AHI more than 5. The lack of a standard cutoff of abnormal RDI in children constitutes a major obstacle in defining 'normal' and 'abnormal' RDI with cutoff ranging from apnea index more than 1  to RDI more than 5  . NE was reported to affect ~40% of children with OSA  . Furthermore, adenotonsillectomy had been shown to have a favorable therapeutic effect on bed-wetting in children with snoring or OSA  . This association between NE and OSA can be attributed to the increasing sleep debt secondary to repeated hypoxic arousal stimuli in OSA that consequently leads to a high arousal threshold  . Another possible explanation is the polyuria caused by increased levels of natriuretic peptides due to cardiac distension by the negative pressure environment that is augmented in OSA  . Atrial natriuretic peptide hormone, in addition to increasing sodium and water excretion, inhibits other hormones that regulate fluid volume, mainly vasopressin and the renin-angiotensin-aldosterone complex  . This is consistent with our results, which showed that 82% of enuretic children had reversal of vasopressin circadian rhythm. Our previous results showed that reversal of ADH rhythm was present in 71.7% of NE cases, whereas normal rhythm was found in 28.3%  . Normally, production of more concentrated urine during nocturnal sleep occurs due to increased nocturnal plasma ADH levels. Decreased nocturnal ADH excretion leads to increased nocturnal urine production, which may lead to polyuria and NE. The high percentage of reversed ADH secretion in our NE patients supports this notion. Polyuria may be combined with impaired detrusor contractility in NE as it was shown that children with NE have larger postvoiding residual urine volume than do normal children, indicating that enuresis episodes may be related to incomplete bladder emptying and hypocontractility  .
We compared NE patients who had reversed ADH levels with those with normal ADH levels and found that patients with reversed ADH had less stage N1 and more REM sleep compared with those with normal rhythm. As polyuria is most probably due to ADH deficiency, the increase in REM sleep is consistent with the results of a previous study that reported that polyuric enuretic children spend more of their night in REM sleep than does the rest of the enuretic population  . These results are explained by the finding that ADH possesses REM depressant properties; therefore, its deficiency will be associated with increased REM sleep  . We found that children with normal ADH rhythm have a higher RDI than those with a reversed ADH rhythm. This finding can highlight the importance of searching for sleep disordered breathing in children who have normal ADH secretion rhythm as it can be another potential cause of NE.
Approximately a third of our patients showed nocturnal cardiac arrhythmia. This was rather a surprising finding. An unusual case report was described in which secondary NE occurred because of progressive bradycardia from complete heart block, and the secondary enuresis was cured by pacemaker implantation  . Tachycardia was often seen to precede the enuretic events in NE children undergoing PSG  . Another study reported that enuretic children exhibited more variability in heart beat compared with both dry controls and formerly enuretic children, possibly denoting a parasympathetic hyperfunction  . In contrast, Dundaröz et al.  assessed the heart rate variability using 24-h ECG, and their results suggested that sympathetic nervous system hyperactivity is present in enuretic children. They added that this finding may explain why some enuretic children do not respond to anticholinergic medications. We found no differences in PSG findings between NE children with and without arrhythmia. However, the association of NE with cardiac arrhythmia can shed light on the autonomic disturbances that can occur in NE and affect the management plans. Therefore, we consider this finding to be of utmost importance. Although there was no difference between boys and girls in terms of polysomnographic data, the girls in our work were older than boys, which could reflect late control of enuresis in female patients.
In conclusion, PNE is most likely a multifactorial disorder, associated with disturbed sleep architecture. It could be a presenting symptom for hidden sleep disordered breathing and/or arrhythmia. Studies that assess both sleep objectively and ADH levels are important in understanding the pathogenesis of this disorder. PSG is recommended in NE children to investigate previous hidden disorders. Further research incorporating the assessment of the autonomic nervous system and brain stem function, which is most likely the control center where dysfunction occurs, can be very fruitful.
This study was part of a project entitled 'Interplay between genetics, bladder, sleep and hormonal disorders in primary nocturnal enuresis', funded by National Research Centre (grant no. 8040511), Cairo, Egypt.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Yeung CK, Sreedhar B, Sihoe JD, Sit FK, Lau J. Differences in characteristics of nocturnal enuresis between children and adolescents: a critical appraisal from a large epidemiological study. BJU Int 2006; 97
El-Shereef E, Saleh M, Salah El-Deen G, Al-Attar T. Prevalence, risk factors and impact associated with nocturnal enuresis among children in some rural areas of Assiut governorate: a cross sectional study. Med J Cairo Univ 2011; 79
Neveus T, Läckgren G, Tuvemo T, Hetta J, Hjälmås K, Stenberg A. Enuresis - background and treatment. Scand J Urol Nephrol 2000; 206
Wolfish NM, Pivik RT, Busby KA. Elevated sleep arousal thresholds in enuretic boys: clinical implications. Acta Paediatr 1997; 86
Freitag CM, Robling D, Seifen S, Pukrop R, von Gontard A. Neurophysiology of nocturnal enuresis: evoked potential and prepulse inhibition of the startle reflex. Dev Med Child Neurol 2006; 48
Bader G, Nevéus T, Kruse S, Sillén U. Sleep of primary enuretic children and controls. Sleep 2002; 25
Yeung CK, Diao M, Sreedhar B. Cortical arousal in children with severe enuresis. N Engl J Med 2008; 358
Brooks LJ, Topol HI. Enuresis in children with sleep apnea. J Pediatr 2003; 142
American Academy of Sleep Medicine. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications
. Westchester: American Academy of Sleep Medicine; 2007.
American Thoracic Society. Standards and indications for cardiopulmonary sleep studies in children. Am J Respir Crit Care Med 1996; 153
Beck S, Marcus C. Pediatric polysomnography. Sleep Med Clin 2009; 4
Wing YK, Hui SH, Pak WM, Ho CK, Cheung A, Li AM, Fok TF. A controlled study of sleep related disordered breathing in obese children. Arch Dis Child 2003; 88
Nevéus T, Bader G, Sillén U. Enuresis, sleep and desmopressin treatment. Acta Paediatr 2002; 91
Fatouh A, Motawie A, Abd Al-Aziz A, Hamed H, Awad M, Abd El-Ghany A, et al.
Anti-diuretic hormone and genetic study in primary nocturnal enuresis. J Pediatr Urol 2013; 9
Abd Al-Aziz A, Hamed H, Motawie A, Abd Elbaky A, Fatouh A, El Bassyouni H, et al.
Post voiding residual urine volume and genetic assessment in Egyptian children with primary nocturnal enuresis. Res J Med Med Sci 2011; 6
Dhondt K, Baert E, Van Herzeele C, Raes A, Groen LA, Hoebeke P, Vande Walle J. Sleep fragmentation and increased periodic limb movements are more common in children with nocturnal enuresis. Acta Paediatr 2014; 103
Nevéus T, A Stenberg, G Läckgren, T Tuvemo, J Hetta. Sleep of children with enuresis: a polysomnographic study. Pediatrics 1999; 103
Reimão R, Pachelli LC, Carneiro R, Faiwichow G. Primary sleep enuresis in childhood. Polysomnographic evidences of sleep stage and time modulation. Arq Neuropsiquiatr 1993; 51
Yeung CK. Cortical arousal in children with severe enuresis. N Engl J Med 2008; 358
Kohyama J, Kumada S, Shimohira M, Araki S, Itoh M, Iwakawa Y. Nocturnal enuresis and the pontine reticular formation. Eur Urol 2000; 38
Cohen-Zrubavel V, Kushnir B, Kushnir J, Sadeh Avi. Sleep and sleepiness in children with nocturnal enuresis. Sleep 2011; 34
Nevéus T. The role of sleep and arousal in nocturnal enuresis. Acta Paediatr 2003; 92
Alexopoulos EI, Malakasioti G, Varlami V, Miligkos M, Gourgoulianis K, Kaditis AG. Nocturnal enuresis is associated with moderate-to-severe obstructive sleep apnea in children with snoring. Pediatr Res 2014; 76
El-Mitwalli A, Bediwy AS, Zaher AA, Belal T, Saleh AB. Sleep apnea in children with refractory monosymptomatic nocturnal enuresis. Nat Sci Sleep 2014; 13
Weissbach A, Leiberman A, Tarasiuk A, Goldbart A, Tal A. Adenotonsillectomy improves enuresis in children with obstructive sleep apnea syndrome. Int J Ped Otolaryngol 2006; 70
Umlauf MG, Chasens ER. Sleep disordered breathing and nocturnal polyuria: nocturia and nuresis. Sleep Med Rev 2003; 7
Berul CI, Murphy JD. Nocturnal enuresis secondary to heart block: report of cure by cardiac pacemaker implantation. Pediatrics 1993; 92
Fujiwara J, Kimura S, Tsukayama H, Nakahara S, Haibara S, Fujita M, et al
. Evaluation of the autonomic nervous system function in children with primary monosymptomatic nocturnal enuresis - power spectrum analysis of heart rate variability using 24-hour Holter electrocardiograms. Scand J Urol Nephrol 2001; 35
Dundaröz MR, Denli M, Uzun M, Aydin HI, Sarici SU, Yokuşoğlu M, Ulgen S. Analysis of heart rate variability in children with primary nocturnal enuresis. Int Urol Nephrol 2001; 32
[Table 1], [Table 2], [Table 3], [Table 4]