Impact of Adenotonsillectomy on Nocturnal Enuresis in Children With Sleep-Disordered Breathing: A Prospective Study

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1 The Laryngoscope VC 2016 The American Laryngological, Rhinological and Otological Society, Inc. Impact of Adenotonsillectomy on Nocturnal Enuresis in Children With Sleep-Disordered Breathing: A Prospective Study Sungchan Park, MD, PhD; Jung Min Lee, MD; Chang Sun Sim, MD, PhD; Jae Gi Kim, MD; Jung Gwon Nam, MD, PhD; Tae-Hoon Lee, MD, PhD; Myung Woul Han, MD, PhD; Joong Keun Kwon, MD, PhD; Jong Cheol Lee, MD, PhD Objectives/Hypothesis: To investigate the relationship between sleep-disordered breathing (SDB) and nocturnal enuresis (NE) in children and to prospectively evaluate the effectiveness of adenotonsillectomy on resolving enuresis in indicated SDB patients with NE. Methods: We prospectively collected data from 183 children (121 males, mean age years) who underwent adenotonsillectomy to treat SDB between July 2011 and July 2013, and analyzed the prevalence of NE. Before and 3 months after surgery, all parents were requested to answer a self-reported SDB scale questionnaire (22 questions, 0 22 points) and a NE questionnaire (episodes of enuresis per month). Paired t test, Student t test, and Chi-square test were used to analyze the data. Results: Overall prevalence of NE was 9.3% (17 patients) preoperatively and 1.5% postoperatively (four patients). After adenotonsillectomy, prevalence of NE and the mean SDB scale were significantly decreased (both P values < 0.001). After adenotonsillectomy, 13 of the 17 NE patients (76.5%) showed complete resolution. There was significantly higher prevalence of NE in patients with obstructive sleep apnea (OSA) than those without OSA (13.1%, 14 of 107 vs. 3.9%, 3 of 76; P ). Conclusion: There is strong association between NE and SDB, and adenotonsillectomy can markedly improve enuresis in the majority of children with NE and SDB. Key Words: Sleep-disordered breathing, nocturnal enuresis, adenotonsillectomy. Level of Evidence: 4. Laryngoscope, 126: , 2016 INTRODUCTION Nocturnal enuresis (NE) is intermittent involuntary voiding during sleep in the absence of physical disease in a child older than 5 years. A minimum of one episode per month for at least 3 months is required for diagnosis. At present, NE is the most common pediatric urologic complaint and the second most common chronic health problem in children following allergy. It occurs worldwide, with an estimated prevalence of 8% to 20% for 5 year olds, 1.5% to 10% for 10 year olds, and 0.5% to 2% for adults. The interplay of three physiological factors are thought to cause NE: defective sleep arousal; nocturnal polyuria; and bladder factors such as lack of inhibition of bladder emptying during sleep, reduced bladder capacity, and/or bladder overactivity. 1,2 From the Department of Urology (S.P.); the Department of Otorhinolaryngology (J.M.L., J.G.K., J.G.N., T-H.L., M.W.H., J.K.K., J.C.L.); and the Department of Occupational and Environmental Medicine (C.S.S.), Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea. Editor s Note: This Manuscript was accepted for publication January 27, This work was supported by Priority Research Center Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology ( ). The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Jong Cheol Lee, MD, PhD, Department of Otorhinolaryngology, Ulsan University Hospital, 877 Bangeojinsunhwandoro, Ulsan 44033, Republic of Korea. jclee898@gmail.com DOI: /lary Immediate cessation of bedwetting after adenoidectomy was described in 1978; since then, upper airway obstruction has been proposed to be one etiologic factor of NE. 3 Many studies have subsequently shown that sleepdisordered breathing (SDB) causes a small percentage (5% 10%) of NE. SDB which is a condition characterized by repeated episodes of hypopnea and apnea during sleep, encompasses the spectrum of sleep disorders ranging in severity from primary snoring to obstructive sleep apnea (OSA). This condition is increasingly being recognized, and the estimated prevalence is between 1.0% and 3.0% among school-aged children. Although polysomnography is the gold standard for diagnosing and quantifying SDB, it is expensive, time-consuming, and not widely available. Consequently, in the majority of cases, a clinical diagnosis of SDB is based on adenotonsillar hypertrophy in a child with daytime and nighttime symptoms of a sleep disorder. 4 Previous studies, including a systematic analysis of the literature published between 1980 and 2010, showed that there was a positive correlation between the prevalence of NE in children and that of OSA compared to the normal population, and that NE improved after treatment of sleep apnea by surgical intervention or continuous positive airway pressure. However, these previous studies were mostly retrospective studies involving a small number of patients rather than large-scale prospective studies. 5 9 This limits the external validity of these studies. Furthermore, although it is well accepted 1241

2 TABLE I. General Characteristics of Subjects Variables Mean 6 SD Age (year) Boys: girls 121:62 (1.95:1) Mean operation time (min) Variables Preoperative Postoperative *P Value Prevalence of nocturnal enuresis 9.3% (17/183) 2.2% (4/183) < Sleep-disordered breathing scale (mean 6 SD) *Calculated by Student t test. min 5 minutes; SD 5 standard deviation < 0.001* hyperactivity disorder, and four questions about other behaviors (Table II). Each question was scored 0 or 1 (yes 5 1, no 5 0); a commonly used clinical threshold is a total score of 8 of 22 or above, which has a sensitivity of 0.85 and a specificity of 0.81 for diagnosis of OSA. 11 To evaluate NE, parents were asked about their child s birth, past medical and family history, current medical conditions, and medications. We also recorded age at toilet training, presence of daytime urinary symptoms (such as urgency, increased urinary frequency, etc.), past or current use of an alarm and/or medications to treat NE, and fluid restriction at bedtime (Table III). To differentiate NE from other voiding disorders, questions about daytime urinary incontinence and bowel habits were also added. Adenotonsillectomy was performed by electrocautery, adenoidotome, and adenoid curette under general anesthesia following routine protocols. Mean operation time was minutes. that adenotonsillectomy has excellent results in resolving SDB, 10 much less is known about the effectiveness of adenotonsillectomy at resolving NE. Our aim in this study was therefore to investigate the relationship between SDB and NE in children and to prospectively evaluate the effectiveness of adenotonsillectomy at resolving enuresis in indicated SDB patients with NE. Statistical Analysis Statistical analyses were performed using Excel 2010 (Microsoft; Redmond, WA) and SPSS 21 software (IBM; Armonk, NY). The paired t test, Student t test, and Chi-square test were used to evaluate the significance of differences in values between groups. All statistical analyses were two-sided, and P < 0.05 was considered statistically significant. MATERIALS AND METHODS Patient Characteristics This study was approved by the Institutional Review Board of Ulsan University Hospital (UUH), University of Ulsan College of Medicine, Ulsan, Korea (UUH-IRB ). All clinical data in this study were obtained by prospective review of medical records of all included patients after obtaining informed consent from their parents or guardians. Among 251 children who underwent adenotonsillectomy at one tertiary hospital in Ulsan, Republic of Korea, between July 2011 and July 2013 to treat SBD, 183 patients (121 males, mean age years) were prospectively included in the current study (Table I). Fifty-three children below age 5, 10 children with a preoperative SDB score of zero, and five children whose parents or guardians did not give permission for them to participate in this study were excluded per our exclusion criteria. None of the subjects had daytime incontinence or bowel symptoms. Mean operation time was minutes (Table I). Sleep-Disordered Breathing and Nocturnal Enuresis Questionnaires and Operation Method Before and 3 months after surgery, all parents of the participating children were requested to answer a self-reported SDB questionnaire (22 questions, 0 22 points), and the presence of NE was assessed using the NE questionnaire (episodes of nocturnal enuresis per month; this questionnaire has not yet been validated). A phone survey was performed at the postoperative 3-month time point. Information about snoring and its severity, breathing difficulty during sleep, daytime sleepiness, and mouth breathing were investigated by the SDB questionnaire, which is used as a screening test for OSA. The SDB scale consists of a total of 22 questions: four questions related to snoring, four questions related to daytime sleepiness, two questions related to breathing problems, two questions related to open mouth breathing, six questions related to attention deficient 1242 TABLE II. Questionnaire on Pediatric Sleep-Disordered Breathing. Question Yes 5 1, No Does your child snore for more than half the time he or she sleeps? 2. Does your child always snore? 3. Does your child have problems breathing? 4. Does your child snore loudly? 5. Does your child have ragged breathing? 6. Does your child have sleep apnea? 7. During the daytime, does your child breathe through his or her mouth? 8. When your child wakes up in the morning, do they complain that their mouth is dry? 9. Does your child have nocturnal uresis? 10. When your child wakes up in the morning, does he or she complain of discomfort? 11. Is your child sleepy during the daytime? 12. Do you know if your child has daytime sleep apnea? 13. Is your child difficult to wake up in the morning? 14. Does your child have a headache when he or she wakes up in the morning? 15. Does your child have a developmental disability? 16. Is your child overweight? 17. Does your child pay attention when you tell him or her something? 18. Does your child find it difficult to perform complex work? 19. In response to external stimuli, does your child become easily agitated? 20. Does your child move his or her hands or feet continuously? 21. Is your child constantly moving? 22. Does your child interfere with or disturb others?

3 TABLE III. Questionnaire on Nocturnal Enuresis. 1. Age at toilet training (months) 2. Nocturnal enuresis (1) Number of wet nights w every nights w 5 6/week(wk) w 3 4/wk w 1 2/wk w 1 3/month (2) Has your child ever attained nighttime dryness for 6 months or longer? 3. Daytime urinary symptoms (1) Does your child wet during the day? (2) Does your child void frequently: (3) Does your child have a sudden feeling of having to urinate immediately? (4) Does your child leak urine on the way to the toilet? (5) Does your child habitually postpone micturition? 4. Bowel habits (1) Does your child have fecal soiling? (2) Is your child constipated? 5. History of previous treatments If yes, w alarm w medication w behavior therapy (fluid restriction or timed voiding, etc.) 6. Have any of the members of your child s family ever had childhood wetting? If yes, w father w mother w father s family w mother s family w brothers or sisters 7. Has your child ever had a pediatric or neurological problem? RESULTS The overall prevalence of NE preoperatively was 9.3% (17 of 183 patients) compared to 1.5% (4 of 183 patients) postoperatively. Mean preoperative SDB was , and mean postoperative SDB was After adenotonsillectomy, prevalence of NE and the mean SDB scale were significantly decreased (both P values < 0.001) (Table I). Among 17 NE patients, eight patients were male, and the prevalence according to age was as follows: 15.0% in 5 year olds (6 of 40), 3.2% in 6 year olds (1 of 31), 9.1% in 7 year olds (2 of 22), 31.6% in 8 year olds (6 of 19), 7.7% in 10 year olds (1 of 13), and 9.1% in 13 year olds (1 of 11) (Fig. 1). Compared to the alleged prevalence of 6% to 10% in the general population, the prevalence at age 8 in this study was significantly higher. After adenotonsillectomy, 13 of 17 NE patients (76.5%) showed complete resolution, and the other four children (23.5%) showed partial improvement. Among these four children, in three children the frequency of NE decreased from more than 12 times to 1 to 2 times per month, whereas in the last child the frequency decreased from more than 12 times to four to eight times per month (Fig. 2). In patients without NE, mean preoperative SDB scale was 8.87 en, r., and mean postoperative SDB scale was In those with NE, mean preoperative SDB Fig. 1. Age distribution and prevalence of nocturnal enuresis in children. NE 5 nocturnal enuresis. Fig. 2. Frequency distribution of nocturnal enuresis before and after adenotonsillectomy. Three of four patients with postoperative NE showed a significant improvement from over 12 episodes of NE to one or two episodes per month. Preop NE 5 preoperative nocturnal enuresis; postop NE 5 postoperative nocturnal enuresis. 1243

4 TABLE IV. Treatment Outcomes of Sleep-Disordered Breathing According to Improvement of Nocturnal Enuresis. Variables (No) Without NE (166) P Value With NE (17) P Value SDB Preoperative < 0.001* < 0.001* Postoperative Tonsil size (cm) *Calculated by paired t test. NE, nocturnal enuresis; SDB 5 sleep-disordered breathing. scale was and mean postoperative SDB scale was A significant decrease in SDB scale preand postsurgery was found in both patient groups (P < 0.001). There was no significant difference in the mean size of the tonsil specimen after surgery between the two groups (Table IV). When comparing patients with and without NE, there was no significant difference in mean preoperative SDB scale (P ) or mean postoperative SDB scale (P ) (Fig. 3). Because a SDB score of 8 is interpreted as indicating the presence of obstructive OSA, we divided patients according to this threshold and analyzed the variables to evaluate the relationship between severe SDB and NE (Table V). As expected, the preoperative mean SDB scale was significantly higher in the OSA group (P < 0.001), as was the postoperative SDB scale. The prevalence of NE was significantly higher in patients with OSA than those without OSA (13.1%, 14 of 107 vs. 3.9%, 3 of 76; P ). DISCUSSION Remarkable progress often occurs spontaneously in NE; thus, this condition was often considered not to require treatment. However, a recent study showed that children who wet the bed are more nervous and anxious, tend to have more negative emotions and feel more depressed, and have developmental disabilities than non-bedwetting children. Moreover, a history of enuresis in childhood seems to increase the risk of having nocturnal polyuria syndrome in adult life. Therefore, enuresis in children requires aggressive treatment. 2,12,13 Fig. 3. Mean SDB scale before and after adenotonsillectomy. SDB 5 sleep-disordered breathing; NE 5 nocturnal enuresis; preop 5 preoperative; postop 5 postoperative. TABLE V. Comparison of Variables Between Severe and Mild SDB Scale Groups Variables Severe SDB Mild SDB P Value Criteria SDB 8 SDB < 8 Number Age (years) * Male: female 69:38 (1.82:1) 52:24 (2.16:1) Preoperative SDB < 0.001* Postoperative SDB * Preoperative NE 14/107 (13.1%) 3/76 (3.9%) Postoperative NE 3/107 (2.8%) 1/76 (1.3%) *Calculated by paired t test. NE, nocturnal enuresis; SDB 5 sleep-disordered breathing. We found that 9.3% of children with SDB had NE, and that the prevalence of NE was significantly higher in the severe SDB (OSA) group comprising children with a SDB scale 8 than the mild SDB group (13.1% vs. 3.9%). Because a wide range of prevalence rates of NE has been calculated using different cutoff values to define SDB and NE, a simple comparison of our results with those of previous studies is unlikely to be accurate. A systematic review of 12 studies published between 1998 and 2010 showed that a total of 1,113 (33%) children with SDB had a diagnosis of NE among 3,550 SDB subjects. 8 The high prevalence rate in this study was due to the inclusion of children under the age of 5 years. Because NE may be considered a physiological and developmental phenomenon, the inclusion of children with physiological enuresis elevates the prevalence of NE in most studies. The higher prevalence of NE in children with severe SDB is consistent with findings reported in previous publications, including a cohort study that reported children with SDB (respiratory disturbance index greater than one episode per hour) were more likely to have enuresis than children without SDB (11.3% vs. 6.3%). 5,14,15 However, in contrast to our findings, a cohort study of 6- to 11-year-old children in a community-based population showed that the prevalence of NE did not differ between children with OSA and those without OSA (9.7%, 25 of 258 vs. 8.8%, 30 of 339; P ). 16 In this study, adenotonsillectomy cured NE in 13 of 17 patients (76.5%). In addition, among the four remaining patients, three showed partial improvement; there was a significant improvement in NE episodes from more than 10 times preoperatively to one to three times per month. Overall, 94.1% of our patients (16 of 17) showed significant improvement within 3 months following surgical release of upper airway obstruction, indicating a good response rate of NE to adenotonsillectomy that cannot be attributed solely to spontaneous remission, which has been reported to occur at an annual rate of 14%. This is comparable to the rates reported in other studies in which adenotonsillectomy was associated with a significant improvement in NE of 84.2% (48 of 57), 63.9% (23 of 36), and 87.8% (29 of 33) of children with 1244

5 SDB. 6,7,9 In this context, Kovacevic et al. reported that lower response rate of NE to adenotonsillectomy was associated with prematurity, obesity, family history of NE, severe NE preoperatively, and arousal difficulties. 17 The dominant pathophysiological mechanism through which upper airway obstruction may cause enuresis is related to the increased work of breathing, which can lead to higher negative intrathoracic pressure during inspiration and hence caused cardiac wall distension and the release of atrial and brain natriuretic peptide. These peptide hormone increases sodium and water excretion and also inhibit other hormone systems that regulate fluid volume, vasopressin, and the reninangiotensin-aldosterone complex, resulting in diuresis. 9,18 A recent Childhood Adenotonsillectomy Trial (CHAT) revealed that adenotonsillectomy did reduce OSA symptoms and improve secondary outcomes of behavior, quality of life, and polysomnographic findings, thus providing evidence of the beneficial effects of early adenotonsillectomy for treatment of OSA syndrome. 10 Based on our results together with those of CHAT, although it is premature to assume that adenotonsillectomy is the sole indication of NE, the presence of SDB appears to play an important role in NE, and adenotonsillectomy might become the first-line treatment in this disorder. A possible limitation of our study was that patients were not evaluated by polysomnography. The SDB scale questionnaire, although is not an exact diagnostic tool for SDB because of its subjectivity, is a potential alternative screening test for SDB because it is easy to administer in the majority of children. Use of a phone interview at postoperative follow-up may have introduced recall bias regarding the severity of the child s NE. However, given the significant burden of NE on families, the study was meaningful in counseling parents regarding the probability of their child s NE responding to adenotonsillectomy, and we think it adds significant clinical information to this field. CONCLUSION We found that a strong association exists between NE and SDB, and that adenotonsillectomy could markedly improve enuresis in the majority of children with simultaneous NE and SDB. Therefore, SDB symptoms should be evaluated in children with NE. In addition, otolaryngologic evaluation is necessary if SDB symptoms are present. If adenotonsillar hypertrophy exists in combination with NE, adenotonsillectomy should be considered to treat both disorders. BIBLIOGRAPHY 1. Graham KM, Levy JB. Enuresis. Pediatr Rev 2009;30: ; quiz Caldwell PH, Deshpande AV, Von Gontard A. Management of nocturnal enuresis. BMJ 2013;347:f Weider DJ, Sateia MJ, West RP. Nocturnal enuresis in children with upper airway obstruction. Otolaryngol Head Neck Surg 1991;105: Alexander NS, Schroeder JW Jr. Pediatric obstructive sleep apnea syndrome. Pediatr Clin North Am 2013;60: Brooks LJ, Topol HI. Enuresis in children with sleep apnea. J Pediatr 2003;142: Basha S, Bialowas C, Ende K, Szeremeta W. Effectiveness of adenotonsillectomy in the resolution of nocturnal enuresis secondary to obstructive sleep apnea. Laryngoscope 2005;115: Firoozi F, Batniji R, Aslan AR, Longhurst PA, Kogan BA. Resolution of diurnal incontinence and nocturnal enuresis after adenotonsillectomy in children. 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