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Purpose: The purpose of this study was to compare the differences in lower urinary tract function and treatment response between non-monosymptomatic nocturnal enuresis (NMNE) pediatric patients with and without constipation., Method: We retrospectively analyzed pediatric patients diagnosed as NMNE from our enuresis database. Inclusion criteria were children aged 5 years or older with a follow-up duration of at least one month. Basic evaluation included the Rome IV questionnaire, Dysfunctional voiding score questionnaire (DVSS), two-day voiding diary, one-week enuresis diary and uroflowmetry with post-void residual (PVR) measurement. Constipation was defined as a Rome IV score of ≥ 2. We compared the results of evaluations and treatment response between groups with and without constipation., Results: From July 2005 to December 2021, we enrolled 128 children who met the diagnostic criteria for NMNE. The median age was 7 years (interquartile range [IQR]: 6-9), and the median follow-up duration was 8.6 months (IQR: 3.5-15.6). NMNE patients with constipation had significantly higher scores on the daytime incontinence, holding maneuver, urgency, and total scores of the DVSS questionnaire. No significant differences were found between those with and without constipation in terms of daytime maximal voided volume and voiding frequency as recorded in the voiding diary. Although the group without constipation showed a relatively higher maximum flow rate, there was no significant difference observed in the PVR between the two groups. Patients in the constipation group exhibited a higher proportion requiring the combination of more medications for enuresis treatment. However, constipation did not affect the time to achieve partial or complete response in NMNE patients. The use of laxatives also did not affect the treatment response in the constipation group., Conclusion: Constipation in NMNE patients is associated with increased severity of daytime lower urinary tract symptoms and requires more medications to achieve treatment response. However, with proper treatment, the time to partial or complete response is comparable to those without constipation., Clinical Trial Number: Not applicable., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Institutional Review Board of Taipei Tzu Chi Hospital (No. 13-IRB028). The consent to participate in the study was waived by the Institutional Review Board of Taipei Tzu Chi Hospital due to the retrospective nature of the study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Sleep enuresis (SE), commonly known as bedwetting, refers to involuntary urination during sleep. It is a prevalent condition affecting approximately 15 % of children at age 5, 10 % by age 7, and 5 % by age 10. This condition can significantly impact both children and their families. The pathophysiology of SE is complex and not yet fully understood. There are several established treatment methods, but limited information on their sleep dynamics., Objective: This study aimed to evaluate differences in sleep structure before and after treatment in patients with monosymptomatic SE (MSE), focusing on alarm therapy, desmopressin, and a combination of both. The analysis compared pre- and post-treatment differences within each treatment arm. The analysis was conducted for both successful and unsuccessful treatment outcomes., Methods/results: This was a prospective study with MSE patients, aged 6-16 years, diagnosed by multidisciplinary assessment. Of the 140 initial applicants 75 were initially included in the study and randomized for therapeutic intervention in three treatment arms, namely: alarm, desmopressin and alarm + desmopressin. Therapeutic response was evaluated 12 months after treatment discontinuation. Polysomnographic evaluation pre and post treatment was carried out. 51/75 completed the entire protocol. 42/51 were successfully treated and had a median age of 10 [8-12] and the non-success, 8 [7-10]. Among the successful patients, the percentage of N2 sleep decreased from a median of 55.7 %-48.5 % (p = 0.0004) in the alarm arm, from 58.8 % to 50 % (p = 0.002) in the desmopressin arm, and from 54.7 % to 50.9 % (p = 0.044) in the combined arm. The percentage of N3 sleep increased from 25.7 % to 30.1 % (p = 0.004) in the alarm arm, from 21.6 % to 26 % (p = 0.032) in the desmopressin arm, and from 23.7 % to 28.3 % (p = 0.014) in the combined arm. The arousal index significantly increased from pre-to post-treatment in all arms: in the alarm arm, from 1.25 to 2.8 (p = 0.002); in the desmopressin arm, from 1.3 to 2.7 (p = 0.019); and in the combined treatment arm, from 1 to 4 (p = 0.003). No significant differences were observed in the non-successful arm or among those who experienced complete resolution of the enuresis without treatment., Conclusion: The observed increase in N3 sleep and arousal and decrease in N2 sleep following successful treatment, regardless of the specific interventions, underscores the role of sleep in the pathophysiology of enuresis. Conversely, the lack of sleep differences in the non-successful arm further highlights the importance of sleep, beyond developmental factors, in influencing the clinical outcomes of enuresis, especially since all children were assessed 12 months after the start of treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Nocturnal urine volume and bladder reservoir function are key pathogenic factors behind monosymptomatic nocturnal enuresis (MNE). We investigated the predictive value of these together with other demographic and clinical variables for response to first-line treatments in children with MNE., Materials and Methods: A randomized, controlled, international, multicenter study was conducted in 324 treatment-naïve children (6-14 years old) with primary MNE. The children were randomized to treatment with or without prior consideration of voiding diaries. In the group where treatment choice was based on voiding diaries, children with nocturnal polyuria and normal maximum voided volume (MVV) received desmopressin (dDAVP) treatment, and children with reduced MVV and no nocturnal polyuria received an enuresis alarm. In the other group, treatment with dDAVP or alarm was randomly allocated., Results: A total of 281 children (72% males) were qualified for statistical analysis. The change of responding to treatment was 21% higher in children where treatment was individualized compared to children where treatment was randomly selected (risk ratio = 1.21 [1.02-1.45], P = .032). In children with reduced MVV and no nocturnal polyuria (35% of all children), individualized treatment was associated with a 46% improvement in response compared to random treatment selection (risk ratio = 1.46 [1.14-1.87], P = .003). Furthermore, we developed a clinically relevant prediction model for response to dDAVP treatment (receiver operating characteristic curve 0.85)., Conclusions: The present study demonstrates that treatment selection based on voiding diaries improves response to first-line treatment, particularly in specific subtypes. Information from voiding diaries together with clinical and demographic information provides the basis for predicting response., Clinical Trial Registration No.: NCT03389412.

Introduction and Objective: Desmopressin is well accepted as first-line medical therapy for enuresis. If ineffective, combination therapy of desmopressin + oxybutynin or desmopressin + imipramine has been used. This study assessed the efficacy of adjunct therapy with either imipramine or oxybutynin in the management of enuresis patients who failed desmopressin treatment., Study Design: A retrospective chart review of our database for patients with enuresis was performed. Patients who were prescribed desmopressin, oxybutynin, and imipramine over 14 years for enuresis were included. Two cohorts of patients were examined; group OXY was treated with desmopressin and oxybutynin, and group IMP received desmopressin and imipramine. Pretreatment measurement of Vancouver Symptom Scores (VSS) were used to compare groups using the VSS question "I wet my bed at night" where 4: every night, 3: 4-5 nights per week, 2: 1-2 nights per week, 1: 3-4 nights per month, and 0: never. International Children's Continence Society (ICCS) criteria for continence success was utilized to determine outcomes., Results: 2521 patients prescribed one of the 3 medications were identified. Among them, 81 patients (mean age: 10.5 ± 2.8 years) received combination therapy. Of which, 55 were male and 26 female. Specifically, 58 were prescribed both desmopressin and imipramine (group IMP), 23 desmopressin and oxybutynin (group OXY), and 4 transitioned from OXY to IMP. Mean pretreatment VSS showed no difference between groups. Both groups experienced minimal drops in wet nights with desmopressin alone. A comparison revealed that group IMP reduced wet nights significantly more than group OXY (VSS wet night score 0.7 ± 1.2 vs. 2.3 ± 1.1 respectively, p < 0.0001). Non-intent-to-treat complete response rate was 68% vs 5% (OR = 42.5, p < 0.001) (IMP vs. OXY respectively). Intent-to-treat response rates were 58%., Discussion: Although first-line desmopressin treatment for enuresis is effective, it does not work for all patients, and many parents and children desire nighttime dryness. Clinicians have combined desmopressin with oxybutynin or imipramine for improved results, but research comparing these modalities is scarce. Our study suggests that the desmopressin and imipramine combination is superior at reducing nights wet compared to desmopressin and oxybutynin, attributed to imipramine's probable central mechanism rather than its secondary anticholinergic properties. Limitations include a modest sample size, retrospective design, and subjective responses to the Vancouver questionnaire., Conclusion: A combination of desmopressin and imipramine was more effective in reducing wet nights and had a complete response rate that was 42.5 times greater than desmopressin and oxybutynin., Competing Interests: Conflicts of interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2024 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background: The first uninterrupted sleep period (FUSP, time up to the first episode of enuresis/nocturia after falling asleep) is a frequently investigated parameter in adults with nocturia, as it correlates with quality of life. However, it has not been included in pediatric enuresis studies., Aim: Investigate FUSP, circadian renal water and sodium handling, as well as sleep quality before and after desmopressin therapy in enuresis., Materials and Methods: We conducted a post hoc analysis of a prospective study in 30 treatment-naïve children with enuresis who underwent a video-polysomnography and a 24-h urine concentration profile before and after 6 months of desmopressin therapy. We analyzed FUSP, periodic limb movements in sleep (PLMS), and arousal indexes and their correlations with the urinary parameters., Results: Sixteen children with a mean age of 10.9 ± 3.1 years had full registrations and were included in this subanalysis. After therapy, FUSP was significantly longer (p < 0.001), and the PLMS index was lower (p = 0.023). Significant differences in the circadian rhythm of diuresis (night/day diuresis, p = 0.041), nocturnal urinary osmolality (p = 0.009), and creatinine (p = 0.001) were found, demonstrating the increase of urinary concentration overnight by desmopressin, as well as a significant antidiuretic effect (diuresis [p = 0.013] and diuresis rate (p = 0.008). There was no correlation between the difference of FUSP, PLMS index, and urinary parameters. Nevertheless, despite this study being underpowered, there are indications of a correlation between nocturnal diuresis and diuresis rate., Results: Our results support the need for further research regarding FUSP in children with enuresis, in accordance with nocturia studies in adults, as this parameter could be valuable in the follow-up and evaluation of therapeutic strategies for enuresis., (© 2023 Wiley Periodicals LLC.)

Background: The voiding chart is part of the initial evaluation of enuresis, since the data gathered this way are assumed to carry predictive information. However, there is little evidence that the voiding chart actually does predict therapy response. Lundmark & Nevéus performed a pilot investigation in 2020 and found that anamnestic and voiding chart data did not predict response to second-line therapies. This study aims at evaluating whether these findings could be replicated., Patients and Methods: This is an evaluation of clinical practice. All patients in a tertiary outpatient clinic with enuresis resistant to first-line therapy (i.e. the enuresis alarm and desmopressin medication) during the evaluation period were included in the study. Baseline anamnestic data focused on bladder and bowel habits, were gathered and the families were instructed to complete a voiding chart including measurements of nocturnal urine production. The children were then treated in accordance with international guidelines, which are anticholinergics and antidepressants as second- and third-line treatment, respectively. Desmopressin was added if needed., Results: In total, 70 patients were included. At the end of the study 37 of these patients were dry, 11 patients were still wetting their beds and 22 patients were lost to follow-up. Of the dry patients 21 became dry on anticholinergics (and/or mirabegron, with or without desmopressin), five on tricyclic antidepressants (with or without desmopressin), seven after a new attempt with the alarm and five became dry spontaneously. The only statistically significant differences between responders and non-responders to the various treatments were that children responsive to anticholinergics had harder and more infrequent stools (p = 0.04 and p = 0.03, respectively)., Conclusion: This study found that anamnestic and voiding chart data do not predict response to treatment in children with therapy-resistant enuresis. Because of this and the fact that we lose some children who need our help by demanding that they complete a voiding chart before initiating treatment, we question the use of this instrument in the evaluation of therapy-resistant enuresis., Competing Interests: Conflict of interest None of the authors have any conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: This pooled analysis aims to demonstrate the clinical efficacy and safety of combined desmopressin and anticholinergic therapy in the treatment of pediatric nocturnal enuresis (NE)., Methods: A systematic search was conducted through PubMed, MEDLINE, EMBASE, ResearchGate, and Cochrane Library to identify all randomized controlled trials (RCTs) comparing monotherapy with desmopressin versus combined therapy with desmopressin and anticholinergic agents for the treatment of NE. Data analysis was performed using RevMan version 5.4.1., Results: This study included 8 RCTs involving a total of 659 patients. The frequencies of complete response (CR), partial response (PR), and nonresponse (NR) were computed for both short-term treatment (1 month) and long-term treatment (3 months). Additionally, alterations in the mean number of NE episodes, adverse events, and relapse were assessed. Our analysis indicates that, in comparison to the monotherapy group, the combination therapy group plays a pivotal role in augmenting the CR odds and diminishing the NR ratios in both short-term and long-term treatments (1 month CR ratio [risk ratio (RR): 1.84; 95% confidence interval (CI): 1.22-2.76; p = 0.003, I 2  = 72%]; 3 months CR ratio [RR: 1.48; 95% CI: 1.25-1.76; p < 0.00001, I 2  = 0%]; 1 month NR ratio [RR: 0.67; 95% CI: 0.55-0.82; p = 0.0001, I 2  = 0%]; 3 months CR ratio [RR: 0.37; 95% CI: 0.19-0.73; p = 0.004, I 2  = 0%]). Furthermore, in both short-term and long-term treatment, the combined therapy group exhibits a greater magnitude of change in the average number of NE episodes compared to patients receiving monotherapy (1 month, mean difference [MD] = -2.97; 95% CI: -4.23 to -1.71, p < 0.0001; 3 months, MD = -4.30; 95% CI: -7.18 to -1.43, p = 0.003). Moreover, the combination therapy group exhibits a significant reduction in the recurrence rate (RR: 0.36; 95% CI: 0.15-0.86; p = 0.02). There is no significant difference in the incidence of adverse events between the two groups (RR: 1.16; 95% CI: 0.58-2.31; p = 0.67)., Conclusion: Combining desmopressin with anticholinergic medications is more effective for NE than desmopressin alone, with lower recurrence and minimal adverse effects., (© 2023 Wiley Periodicals LLC.)

Objectives: To compare the efficacy and tolerability of Solifenacin plus Desmopressin and Desmopressin alone in the treatment of primary monosymptomatic nocturnal enuresis (PMNE)., Methods: A total of 88 children, 5-14 years old, diagnosed with PMNE were enrolled in this randomized control trial (RCT) from June 2017 to June 2020. After informed written consent patients were randomized to one of the two therapeutic groups. Group 1 received one puff of desmopressin nasal spray 1 h before bedtime every night. Group 2 received one pill of solifenacin 5 mg plus one puff of desmopressin nasal spray 1 h before bedtime every night. All patients were evaluated after three months for their response to treatment and drug side effects., Results: The mean age in desmopressin alone group and solifenacin plus desmopressin group was 8.1 ± 2.2 (5-14) and 7.9 ± 2.2 (5-14) years respectively (p-value >0.05). In group 2, 37/44 (84.09%) patients achieved complete response after three months of treatment in comparison to group 1 in which 27/44 (61.36%) patients showed complete response (p-value <0.05). In group 1, 8/44 (18.18%) patients developed treatment related side effects whereas in group 2, 12/44 (27.27%) patients developed side effects (p-value >0.05). No case of discontinuation of treatment due to side effects was observed in any of the two groups. The recurrence rate was also significantly lower in group 2 in comparison to group 1 (8.1% vs 33.3%, p-value <0.05)., Conclusion: Our study demonstrated that the combination of Solifenacin plus Desmopressin is more effective than desmopressin monotherapy in the treatment of PMNE with an acceptable tolerability profile., Level of Evidence: Level I., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Enuresis, defined as involuntary nocturnal urination without any underlying organic disorder in a child expected to control urination, poses a common problem. This study evaluated the effectiveness of Tolterodine and Oxybutynin in children presenting with primary desmopressin-resistant enuresis., Materials and Methods: A randomized clinical trial was undertaken involving 68 participants aged between 5 and 16 years, all suffering from primary enuresis. These patients were randomly assigned to one of two treatment groups for a three-month period: Group 1, treated with Oxybutynin and Desmopressin, and Group 2, treated with Tolterodine and Desmopressin. Data on demographics, clinical and laboratory findings, and subjective responses to treatment were gathered. The response was measured based on the frequency of wetting incidents per night and week and compared with pre-treatment data., Results: Patients were divided into two groups (30 patients in Group 1 and 38 patients in Group 2). The mean age of the patients was 88.97±27.09 months. In the first treatment group, 6 out of 30 patients (20%) experienced a complete treatment response, as did 5 out of 38 patients (13.2%) in the second treatment group. This difference between the groups was not statistically significant. Seven patients (23%) in the Oxybutynin group and 13 patients (34%) in the Tolterodine group reported a lack of response to treatment, a difference that also lacked statistical significance., Conclusion: For patients resistant to Desmopressin, the addition of anticholinergic drugs elicited a significant response in over half of the patients. However, no benefit was observed in using either Oxybutynin or Tolterodine in the treatment of Desmopressin-resistant enuresis., (© 2023 Neda E., et al.)

Objective: To compare the efficacy of desmopressin plus tolterodine (D+T) with desmopressin plus indomethacin (D+I) for treating enuresis in children., Design: Open-label randomized controlled trial., Setting: Bandar Abbas Children's Hospital, a tertiary care children's hospital in Iran, from March 21, 2018, to March 21, 2019., Participants: 40 children older than five years with monosymp-tomatic and non-monosymptomatic primary enuresis resistant to desmopressin monotherapy., Intervention: Patients were randomized to receive either D+T (60 µg sublingual desmopressin and 2 mg tolterodine) or D+I (60 µg sublingual desmopressin and 50 mg indomethacin) every night before bedtime for five months., Outcome: Reduction in the frequency of enuresis was evaluated at one, three, and five months, and response to treatment at five months. Drug reactions and complications were also noted., Results: After adjustment for age, consistent incontinence from toilet training, and non-monosymptomatic enuresis, D+T was significantly more efficacious than D+I; mean (SD) percent in nocturnal enuresis reduction at 1 [58.86 (7.27)% vs 31.18 (3.85) %; P<0.001], 3 [69.78 (5.99) % vs 38.56 (3.31) %; P<0.000], and 5 [84.84(6.21) % vs 39.14 (3.63) %; P<0.001] months showing a large effect. At 5 months, complete response to treatment was only observed with D+T, while treatment failure was significantly higher with D+I (50% vs 20%; P=0.047). None of the patients in either group developed cutaneous drug reactions or central nervous system symptoms., Conclusion: Desmopressin plus tolterodine appears to be superior to desmopressin plus indomethacin for treating pediatric enuresis resistant to desmopressin.

Background: Monosymptomatic enuresis (MNE) results from a pathogenic triad that may include lack of vasopressin secretion during sleep, reduced functional bladder capacity and inability to wake up during sleep. The treatment of MNE can be performed through behavioral therapy, use of alarms or medications such as desmopressin and imipramine., Objective: To compare the effectiveness of different treatments of MNE., Study Design: Prospective and randomized study comparing different intervention and a control group (receiving only behavior therapy) for MNE., Inclusion Criteria: age between 5 and 16 years old, with MNE, evaluated at the pediatric urology outpatient clinic of Hospital Infantil Menino Jesus. At first visit children were submitted to behavior therapy (urotherapy) for 3 months, children were subsequently characterized according to the ICCS as non-responders, partial responders, or full responders. Those partial responders or non-responders received a patient ID and were randomized to four groups: Alarm Group (G1), Desmopressin Group - DDAVP (G2), Imipramine Group (G3) and Control (G4). All groups were monitored monthly, for a period of 6 months. After 6 months, the children were reevaluated for MNE., Results: 93 patients were enrolled. Mean age was 10.96 years with a standard deviation of 2.28 years, 59,1% were male. All groups had improvement in the number of dry nights (Table). Taking in account success the population full responders and partial responders: Alarm Group (G1) achieve success in 100% of cases, Desmopressin Group - DDAVP (G2) in 63.6% of cases, Imipramine Group (G3) in 73.7% of cases (Table 3). No drugs side effects were observed in both groups (G2 and G3), there was no dropout in patients who used alarms., Discussion: Our data suggests that the use of alarms is the most effective treatment of ENM with superior results when compared to imipramine and DDAVP. The small number of participants is a weakness of the study, as well as the lack of a voiding diary at the end of the study., Conclusion: All therapeutics options utilized in the treatment of MNE are safe, effective and has a low rate of abandonment., (Copyright © 2023 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background and Aim: Two central problems with the enuresis alarm are the family workload and the lack of predictors of therapy response. We wanted to look at predictors of alarm response in a setting reflecting clinical reality., Methods: An alarm linked to a smartphone app was provided to enuretic children managed at pediatric outpatient wards. Baseline data (sex, age, daytime incontinence, urgency, previous therapies, arousal thresholds and baseline enuresis frequency) were recorded. Further information, such as enuretic episodes and actual alarm use, was gathered via the app during therapy. Therapy was given for 8-12 weeks or until 14 consecutive dry nights had been achieved., Results: For the 196 recruited children the outcome was as follows: full responders (FR) 18.4%, partial responders (PR) 20.4%, nonresponders (NR) 22.4% and dropouts 38.8%. We found no clear predictors of response or adherence among baseline data. But as treatment progressed responders reduced their enuresis frequency as compared to NR (week two P = 0.003, week three and onwards P < 0.001). This is further illustrated in the Figure below. Furthermore, the children unable to complete the full treatment had more non-registered nights already from the second week (week two P = 0.005, week three P = 0.002 and so on)., Discussion: Anamnestic data give little predictive information regarding enuresis alarm response or adherence. Contrary to common belief neither daytime incontinence nor previous alarm attempts influenced treatment success. But after 2-4 weeks of therapy the children with a good chance of treatment success could be discerned by decreasing enuresis frequency, and the families that would not be able to comply with the full treatment showed incomplete adherence already during the first weeks., Conclusions: Maybe the enuresis alarm strategy should be changed so that the treatment is reassessed after one month and only children with a high chance of success continue. This way, unnecessary frustration for the families of therapy-resistant children may be reduced., Competing Interests: Conflicts of interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Combination therapy (CT) (desmopressin plus oxybutynin) has been considered for the treatment of monosymptomatic nocturnal enuresis (MNE). We designed our study with the aim to evaluate the response rate to CT compared with desmopressin alone (primary outcome) and to identify factors associated with the response to CT (secondary outcome). We prospectively enrolled children with MNE with absent/partial response after 3 months of evening treatment with 240 mcg of desmopressin. We defined the response rate to CT compared with desmopressin alone according to the standardization of terminology document of the International Children's Continence Society: no-response, < 50% reduction; partial response, 50 to 99% reduction; and complete response, 100% reduction of wet nights. Both partial response and complete response to CT were clustered for the analyses of this manuscript. The enrolled children treated with 240 mcg/evening of desmopressin had also an additional evening administration of 0.3 mg/kg oxybutynin. A follow-up was scheduled at 3 and 6 months after the beginning of CT. At 3 months, oxybutynin dose was augmented to 0.5 mg/kg in case of absent/partial response to CT. Nocturnal diuresis was measured in 5 wet nights prior the beginning of therapy with desmopressin. Nocturnal polyuria (NP) was defined as nocturnal urine production > 130% of the expected bladder capacity. All patients with constipation were treated with macrogol. We enrolled 81 children (35.8% females) with a mean age of 8.4 ± 2.3 years. Seventy-eight patients completed the follow-up. After the CT, 59/78 (75.6%) patients showed an improvement of the response with CT compared with desmopressin alone. At multivariate analysis, both NP in more than 1 night (OR = 8.5; 95% CI, 1.4-51.6; p = 0.02) and absence of constipation (OR = 7.1; 95% CI, 1.6-31.0; p = 0.009) resulted significant after Bonferroni correction., Conclusions: CT determines an improvement of response compared to therapy with desmopressin alone in 75.6% of patients. Significant predictive factors of response to CT were presence of NP and absence of constipation., What Is Known: • Combination therapy (CT) (desmopressin plus anticholinergic drug) has been described as a therapeutic option for patients with monosymptomatic nocturnal enuresis (MNE) not responding to desmopressin alone as first-line treatment. • Variable protocols and variable combination of drugs have been described with a response rate ranging from 44 to 76%., What Is New: • We found that 59 patients (75.6%) treated with evening administration of 240 mcg of sublingual desmopressin plus 0.3-0.5 mg/kg of oxybutynin had an improvement of response compared to treatment with desmopressin alone. • We add evidence that presence of frequently recurring nocturnal polyuria and absence of constipation are predictors of response to CT., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Evidence about the negative caffeine effect on enuresis in children remains understudied or poorly understood. The study aimed to investigate the effect of caffeine restriction on the improvement and severity of primary monosymptomatic nocturnal enuresis (PMNE)., Design: Randomised clinical trial., Setting: Two referral hospitals in Tehran, Iran, from 2021 to 2023., Patients: Five hundred and thirty-four PMNE children aged 6-15 years (each group 267)., Interventions: Amount of caffeine consumption was recorded by the feed frequency questionnaire and was estimated by Nutrition 4 software. Caffeine consumption per day in the intervention group was <30 mg, and in the control group, 80-110 mg. All children were asked to return 1 month later to check the recorded data. The ordinal logistic regression analysis was used to assay the effects of caffeine restriction on PMNE by relative risk (RR) at a 95% CI., Main Outcome Measures: The effect of limited caffeine consumption on the improvement and severity of PMNE., Results: The mean age of the intervention and control groups was 10.9±2.3 and 10.5±2.5 years, respectively. The mean number of bed-wetting before caffeine restriction in the intervention and control group was 3.5 (SD 1.7) times/week and 3.4 (SD 1.9) times/week (p=0.91) and 1 month after intervention were 2.3 (SD 1.8) times/week and 3.2 (SD 1.9) times/week, respectively (p=0.001). Caffeine restriction significantly reduced the severity of enuresis in the intervention group. Fifty-four children (20.2%) improved (dry at night) in caffeine restriction and 18 children (6.7%) in the control group with RR 0.615 at 95% CI 0.521 to 0.726, p=0.001. The caffeine restriction significantly reduced the enuresis in children with a number-needed-to-treat benefit 7.417. It means you must treat 7.417 PMNE children with caffeine limitation to improve one child with enuresis (become dry)., Conclusion: Caffeine restriction can be helpful in reducing PMNE or its severity. Constructive limitation of caffeine is suggested as one of the first-line treatments in the management of PMNE., Trial Registration Number: IRCT20180401039167N3., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Standard urotherapy in children with nocturnal enuresis (NE) is first-line treatment according to the current International Children's Continence Society (ICCS) guidelines. ICCS defines standard urotherapy as information and demystification, instruction in how to resolve lower urinary tract dysfunction, lifestyle advice, registration of symptoms and voiding habits, and support and encouragement. These interventions often are time consuming and some aspects of urotherapy, such as fluid restrictions, can be a frustrating process for a child, which emphasizes the importance of clarifying their relevance. The purpose of this review is to perform a systematic search in literature to evaluate the use of standard urotherapy in the treatment of children with primary NE (PNE)., Study Design: A systematic literature search was conducted in MEDLINE, Embase, and CENTRAL based on the key concepts of standard urotherapy and NE. We identified 2,476 studies. After a systematic selection process using the Covidence tool, 39 studies were included. The quality of the studies was assessed by the QualSyst Checklist. Our protocol adheres to the PRISMA statement and was registered in PROSPERO database (CRD42020185611)., Results: Most of the 39 included studies scored low in quality. All studies combined several urotherapy interventions and studied different study populations. Twenty-two randomized controlled trials (RCTs) were included, which reported 0-92% of children being dry after urotherapy treatment. Three RCTs, all individualizing and optimizing drinking and voiding during the day and practicing optimal toilet posture, scored higher in quality based on the QualSyst score, and reported few children experiencing complete resolution of NE (5-33%). Eight studies compared the efficacy of urotherapy to a control group, however, conflicting results were found., Discussion: This systematic review presents available literature in the field of standard urotherapy in the treatment of children with PNE. One possible explanation for low efficacy rates of urotherapy in NE is the large heterogeneity of the study populations and interventions. Additionally, the intervention period and the intensity of intervention can have an impact on the outcome., Conclusion: The number of clinical studies on standard urotherapy in children with NE is limited and many of them are of poor quality. High quality research in a well-defined NE population is needed to establish the role of standard urotherapy in first-line treatment of children with NE or as an add-on to other first line treatments. We conclude that at present there is insufficient evidence for recommending standard urotherapy to children with PNE as a first line treatment modality., Competing Interests: Conflict of interest The authors declare that there is no conflict of interests regarding the publication of this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: One of the main medical treatment options for monosymptomatic nocturnal enuresis (MNE) is the vasopressin analog desmopressin. But not all children respond to desmopressin treatment, and no reliable treatment predictor has yet been established. We hypothesize that plasma copeptin, a surrogate marker for vasopressin, can be used to predict treatment response to desmopressin in children with MNE., Design/methods: In this prospective observational study, we included 28 children with MNE. At baseline, we assessed the number of wet nights, morning, and evening plasma copeptin, and plasma sodium and started treatment with desmopressin (120 µg daily). Desmopressin was increased to 240 µg daily if clinically necessary. The primary endpoint was reduction in the number of wet nights following 12 weeks of treatment with desmopressin using plasma copeptin ratio (evening/morning copeptin) at baseline., Results: Eighteen children responded to desmopressin treatment at 12 weeks, while 9 did not. A copeptin ratio cutoff of 1.34 (sensitivity 55.56%, specificity 94.12%, area under the curve 70.6%, P = .07) was best at predicting treatment response, with a lower ratio indicating a better treatment response. In contrast, neither the number of wet nights at baseline (P = .15) nor serum sodium (P = .11) alone or in combination with plasma copeptin improved outcome prediction., Conclusions: Our results indicate that, of our investigated parameters, plasma copeptin ratio is the best predictor for treatment response in children with MNE. Plasma copeptin ratio could thus be useful to identify children with the highest benefit of desmopressin treatment and improve individualized treatment of MNE., Competing Interests: Conflicts of interest: M.C.-C. has received speaker honoraria from Thermofisher AG, the manufacturer of the copeptin assay. M.C.-C. is on the editorial board of EJE. She was not involved in the review or editorial process for this paper, on which she is listed as an author. All other authors report no conflict of interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We aimed to investigate if there was any relationship between screen time (ST) and the severity of primary monosymptomatic nocturnal enuresis (PMNE) and treatment success., Methods: This study was conducted in urology and child and adolescent phsychiatry clinic in Afyonkarahisar Health Sciences University Hospital. After diagnosis patients were seperated by the ST for exploring causation. Group 1 > 120, Group 2 < 120 (min/day). For the the treatment response, patients were grouped again. Group 3 patients were administered 120 mcg Desmopressin Melt (DeM) and were requested < 60 min ST. Patients in Group 4 were given 120 mcg DeM solely., Results: The first stage of the study included 71 patients. The ages of the patients ranged from 6 to 13. Group 1 comprised 47 patients, 26 males and 21 females. Group 2 comprised 24 patients,11 males and 13 famales. Median age was 7 years in both groups. The groups were similar in respect of age and gender (p = 0.670, p = 0.449, respectively). A significant relationship was determined between ST and PMNE severity. Severe symptoms were seen at the rate of 42.6% in the Group 1, and at 16.7% in the Group 2 (p = 0.033). 44 patients completed the second stage of the study. Group 3 comprised 21 patients, 11 males and 10 females. Group 4 comprised 23 patients,11 males and 12 famales. Median age was 7 years in both groups. The groups were similar in respect of age and gender (p = 0.708, p = 0.765, respectively). Response to treatment was determined as full response in 70% (14/20) in Group 3 and in 31% (5/16) in Group 4 (p = 0.021). Failure was determined in 5% (1/21) in Group 3 and in 30% (7/23) in Group 4 (p = 0.048). Recurrence was determined at a lower rate in Group 3 where ST was restricted (7% vs. 60%, p = 0.037)., Conclusion: High screen exposure may be a factor for PMNE aetiology. And also reducing ST to a normal range can be an easy and beneficial method for treatment of PMNE. Trial Registration ISRCTN15760867( www.isrctn.com ). Date of registration: 23/05/2022. This trial was registered retrospectively., (© 2023. The Author(s).)

Background: Long-term nocturnal enuresis treatment leads to stress and lowered self-esteem for children and their parents. This study evaluated the short-term effectiveness and safety of vibegron (50 mg) for children with refractory nocturnal enuresis., Methods: A retrospective cohort study of children with therapy-resistant enuresis was conducted using data for July to December 2019. Enuresis frequency was recorded during 30 days before and after additional vibegron administration with prior treatment. We assessed the treatment effectiveness based on enuresis frequencies between before and after treatment with vibegron 50 mg. Statistical evaluation was performed using a paired t-test., Results: Among 29 children receiving vibegron, 14 (48.3%) exhibited a partial or complete response to the drug. Enuresis frequencies (mean ± standard deviation [SD]) were, respectively, 15.8 ± 9.2 and 9.5 ± 9.6 before and after treatment with vibegron during the observed 30 days. A statistically significant reduction in enuresis frequency was found (p < 0.001). Moreover, maximum mean±SD morning urine of 200 ± 62.9 mL before treatment with vibegron changed to 232 ± 76.6 mL after treatment. A significant increase in voiding volume in the early morning was found (p < 0.05). No drug-related severe adverse event was found., Conclusion: Short-term treatment with vibegron is safe and effective for children with refractory enuresis., (© 2022 Japan Pediatric Society.)

Nocturnal enuresis is defined as intermittent urinary incontinence during sleep in children 5 years of age and older, occurring at least once a month for at least 3 months. In Japan, pediatricians who do not specialize in nocturnal enuresis have become more proactive in treating the condition since 2016, when the guidelines for treating it were revised for the first time in 12 years. For monosymptomatic nocturnal enuresis, the first step is lifestyle guidance, with a focus on the restriction of fluid intake at night; however, if lifestyle guidance does not decrease the frequency of nocturnal enuresis, aggressive treatment should be added. The first choice of aggressive treatment is oral desmopressin, an antidiuretic hormone preparation, or alarm therapy. However, there remain patients whose wet nights do not decrease with oral desmopressin or alarm therapy. In such cases, it is necessary to reconfirm the method of desmopressin administration and check for factors that may decrease the efficacy of desmopressin. If alarm therapy does not increase the number of dry nights, it is possible that the patient is fundamentally unsuitable for alarm therapy. If dry nights do not increase with oral desmopressin or alarm therapy, the next treatment strategy should be considered immediately to keep the patient motivated for treatment., (© 2023 Japan Pediatric Society.)

Purpose: We investigated the efficacy and safety of fluoxetine, a selective serotonin reuptake inhibitor, for treating refractory primary monosymptomatic nocturnal enuresis in children., Materials and Methods: Children 8-18 years old with severe primary monosymptomatic nocturnal enuresis unresponsive to alarm therapy, desmopressin, and anticholinergics were screened for eligibility. After excluding children with daytime urinary symptoms, constipation, underlying urological, neuropsychiatric, endocrinological, or cardiac conditions, patients were randomly and equally assigned to 10 mg fluoxetine once daily or placebo for 12 weeks. The primary outcome was treatment response according to the International Children's Continence Society terminology. Treatment-related adverse effects and nighttime arousal were secondary outcomes., Results: A total of 150 children were enrolled, of whom 110 (56 in fluoxetine group and 54 in placebo group) with a mean age of 11.8 (SD 2.46) years were finally analyzed. After 4 weeks, 7.1% and 66.1% of the fluoxetine group achieved complete response and partial response (defined as 50%-99% reduction of the number of wet nights), respectively, versus 0% and 16.7% of the placebo group ( P < .001). At 12 weeks, complete and partial responses were achieved in 10.7% and 21.4% of the fluoxetine group, respectively (vs 0% and 14.8% of the placebo group, P = .023). Fluoxetine-treated patients had fewer wet nights (4.7 [SD 4.2] fortnightly vs 9.7 [SD 3.5] at 4 weeks, P < .001; 5.7 [SD 4.4] vs 9.9 [SD 3.4] at 8 weeks, P < .001; 7.5 [SD 4.6] vs 9.9 [SD 3.4] at 12 weeks, P = .003). Fluoxetine was associated with improved nighttime arousal ( P = .017), and minor and rapidly reversible adverse effects in 5 (8.9%) patients., Conclusions: Fluoxetine is safe treatment for refractory primary monosymptomatic nocturnal enuresis in children with good initial response that declines at 12 weeks.

Objectives: Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood. Although enuresis is a very common disorder in child diagnosed with ADHD, it may also develop because of methylphenidate., Methods: Authors report here on a child case of ADHD that developed a probable enuresis related to methylphenidate., Results and Conclusions: Clinicians should be aware that methylphenidate used in ADHD causes dose-dependent enuresis., Competing Interests: Conflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Japanese traditional (Kampo) medicine has been empirically used for nocturnal enuresis (NE). This study aims to investigate the efficacy of one of the most popular formulas, shokenchuto (SKT). We retrospectively analyzed 110 patients with NE who were referred to our department. Following the diagnosis of NE, treatment was started with either alarm or/and desmopressin (DDAVP) therapy. Patient refractory to DDAVP monotherapy or to combination therapy consisting of DDAVP and bedwetting alarm were selected. SKT (Tsumura Co., Tokyo, Japan) extract at a dose of 2.5 g was administered orally to all intractable cases twice daily before meals. The treatment outcomes and safety were assessed. In total, 24 cases were patient refractory to DDAVP monotherapy or to combination therapy consisting of DDAVP and bedwetting alarm. SKT was highly effective in 8, effective in 7, and ineffective in 9. A significant difference was observed between ages 10 and over (P = 0.031). SKT was significantly effective as a treatment for NE in patients aged ≥10 years and could be a good alternative if alarm or DDAVP therapies are ineffective. We proposed evaluating SKT prospectively for NE., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To conduct an overview of Cochrane systematic reviews about treatment alternatives for children and/or adolescents with enuresis., Sources: An overview of Cochrane systematic reviews about interventions for enuresis in children/adolescents was developed between September/2021 and December/2021. The protocol was registered on PROSPERO and the search was conducted only in the Cochrane Library database without any restriction. Reviews involving any type of intervention for the treatment of enuresis in children/adolescents were included. The risk of bias was assessed using Risk of Bias in Systematic Reviews (ROBIS) and the quality of reviews was assessed using A Measurement Tool to Assess Systematic Reviews (AMSTAR-2)., Summary of the Findings: Seven systematic reviews were identified. Based on the ROBIS assessment, all reviews were classified as low risk of bias. According to the AMSTAR-2 assessment, the three oldest systematic reviews were rated as critically low quality, one review was moderate quality, and the three most recent systematic reviews were rated as high quality. No difference was shown between alarm and desmopressin for a complete response to therapy after treatment (RR = 1.30; 95%CI: 0.92 to 1.84), but alarm use is related to a lower risk of adverse events (RR = 0.38; 95%CI: 0.20 to 0.71). There is a moderate certainty that the association between imipramine and oxybutynin is better than placebo to reduce the risk of children who do not achieve 14 consecutive dry nights after treatment (RR = 0.43; 95%CI: 0.23 to 0.78)., Conclusions: There is no difference between alarm and desmopressin for enuresis treatment. However, alarm therapy had fewer adverse events than desmopressin. Moreover, combination therapy between imipramine and oxybutynin is better than placebo., (Copyright © 2022 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Objectives: The purpose of our study was to assess the association between the winter season and desmopressin treatment failure in South Chinese children with monosymptomatic nocturnal enuresis (MNE)., Materials and Methods: A retrospective study was conducted to analyze the clinical data of children with monosymptomatic nocturnal enuresis who have visited our urology clinic from January to December 2019. All patients received desmopressin treatment. Final treatment outcomes were categorized as successful (complete response) or failed (absent and partial response). The relationship between winter season and treatment response to desmopressin was evaluated. Additionally, associated risk factors were investigated with both univariate and multivariate regression analysis., Results: In total, 393 patients diagnosed with MNE were included in the present study. There were no statistically significant differences in pretreatment variables at first visit between patients who visited the clinic in winter and those who did so in other seasons. However, the treatment failure rate of MNE in the winter season was higher than that of other seasons (77.50% vs. 52.74%). Multivariate logistic regression analysis demonstrated that the severity of symptoms and an initial clinic visit in the winter season were significantly related to desmopressin treatment failure in MNE patients., Conclusion: Winter season and severity of symptoms are two risk factors associated with desmopressin treatment failure in MNE patients., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Objectives: To investigate the efficacy of mebeverine for nocturnal incontinence in male patients with an ileal orthotopic bladder substitute (OBS)., Patients and Methods: A randomised controlled trial was carried out for adult male patients who were nocturnal incontinent. Patients were allocated to receive mebeverine 200 mg or placebo once a day in the evening for 3 months. The primary outcome was to compare the continence status between groups, assessed by the urinary domain of the Bladder Cancer Index (BCI) and pad usage. The secondary outcomes were to assess the safety of mebeverine., Results: There were 55 patients in the placebo group and 58 in mebeverine group who completed the follow-up. The median (interquartile range) interval between OBS surgery and starting treatment was 9 (4-13) years in the placebo group and 9 (6-13) years in the mebeverine group. The mean (SD) 3-month urinary domain score of the BCI was 70.8 (5.6) and 86.4 (14.2) in the placebo and mebeverine groups, respectively (P < 0.001). At 3 months, 54 (98.2%) and 26 (44.8%) patients required the use of a night-time pad in the placebo and mebeverine groups, respectively. Mebeverine reduced the risk of pad use by 53.4% (95% confidence interval 40.1-66.6; P < 0.001). Constipation occurred in one (2.1%) and three (5.8%) patients in the placebo and mebeverine groups, respectively; abdominal distention occurred in two (3.8%) of the patients in the mebeverine group (P = 0.25)., Conclusion: Mebeverine decreases night-time pad use and improves the quality of life in male patients with an ileal OBS and is associated with minimal adverse events., (© 2021 The Authors BJU International © 2021 BJU International Published by John Wiley & Sons Ltd.)

Background: One of the common pediatric issues is monosymptomatic nocturnal enuresis (MNE). MNE is involuntarily urine-voiding in night sleep without lower urinary tract symptoms, such as daytime frequency, incontinence, or urgency. Alarm therapy and desmopressin have been used for treating MNE, but there is no clear comparison of the effectiveness of the two modalities., Objective: This study aimed to compare the efficacy of alarm therapy and desmopressin and strategies to improve the therapy., Methods: Study searches were conducted on PubMed, Embase, and Cochrane with a time span of 2010 to 2021. The keywords used were desmopressin, alarm therapy, pediatrics, and monosymptomatic enuresis. The study included an RCT in English, and no subjects were dropped out. Studies without a definite number of subjects were excluded., Results: As many as 12 studies were included in the meta-analysis, 9 of which looked for response rates, and 3 were for desmopressin-withdrawal optimization strategy. Alarm therapy was superior to desmopressin in well-motivated parents and patients (p=0.02), with a combined risk ratio of 1.10 in the low heterogeneity population (Z-score = 2.31; I 2 = 32%). A strategy that could reduce the risk of desmopressin-withdrawal was a structured dose reduction rather than a sudden dose reduction (p=0.001; I 2 =0%; Z-score = 3.26). However, therapy discontinuation based on time did not differ the risk (p=0.24; I 2 =0%; Z-score = 1.17)., Conclusion: The meta-analysis shows that alarm therapy has a better response rate than desmopressin in proactive parents. However, desmopressin may be an option in the opposite subjects, and it is necessary to use structured strategies to optimize the treatment., Competing Interests: There are no conflicts of interest., (© 2021 Athaya Febriantyo Purnomo, Besut Daryanto, Pradana Nurhadi.)

Background: Nocturnal enuresis or 'bedwetting', is a form of night-time urinary incontinence occurring in younger children. A diagnosis can be socially disruptive and psychologically stressful for a child. The most common strategies used by parents are waking the child during the night to use the bathroom and limiting the child's water intake before going to bed., Hypothesis/purpose: To determine if a herbal capsule formulation taken once daily can reduce incidence and frequency of nocturnal enuresis in children., Study Design: This randomised double-blind placebo-controlled trial evaluated the efficacy of an herbal medicine product to reduce the symptoms of nocturnal enuresis. Participants, aged between 6 and 14 years of age, were recruited from the community in Australia. They were randomised via computerised random-number generation at study enrolment to receive one or two oral capsules in the morning of either Urox® (Bedtime Buddy®) or placebo. The Paediatric Quality of life (Pin-Q) was used as a quality-of-life measure and waking wet, fluid intake and urinary urgency per week were monitored., Results: Forty-one children completed the trial with an attrition rate of 16%. There were more males (64.6%) compared to females (35.4%) and the mean age was 8.6 years. Forty-one point seven percentages (41.7%) of participants had improvements in bed wetting by two months which was a highly clinically relevant effect (Cohen's D = 0.98). The primary outcome found that there was a statistically significant reduction in NE (p = 0.034; CI 0.086-2.095) and between groups using longitudinal analysis (p = 0.04, Coefficient -1.12, CI 95% -2.20 - -0.04). In the secondary outcomes, urinary urgency reduced statistically significantly for the intervention (p = 0.002; a reduction of 18.3% difference for Bedtime Buddy compared to an increase of 3.7% for the placebo)., Conclusion: Urox® (Bedtime Buddy®) may assist children in reducing nocturnal enuresis compared to placebo. In addition, it may assist in reducing daily incontinence and urinary urgency., (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Introduction: To improve compliance with voiding diaries in children with primary monosymptomatic nocturnal enuresis (PMNE), a new modified 3-day weekend frequency-volume chart (FVC) was designed, and the compliance and validity of this modified FVC was evaluated by comparing with the International Children's Continence Society (ICCS) recommended voiding diary., Methods: A total of 1200 patients with PMNE were enrolled in the study from 13 centers in China and were randomly assigned to record this modified FVC or the ICCS-recommended voiding diary. The primary outcome measure was the compliance, assessed by comparing the completing index and the quality score of diaries between two groups. The secondary outcome measure was the validity, evaluated by comparing the constituent of subtypes, micturition parameters and response rate to desmopressin., Results: Among the 1200 participants enrolled in the study, 447 patients completed the ICCS-recommended voiding diary and 469 completed the modified diary. The diurnal completing index and the quality score of the modified FVC group were better than those of the ICCS group. In addition, there was no significant difference between these two groups in the subtype classification, or in the response rate to desmopressin., Conclusions: The modified FVC could be applied to obtain the voiding characteristics of children with PMNE as the ICCS-recommended voiding diary does and offers a reasonable and better choice for children with PMNE from the unselected population in the future., (© 2021. Children's Hospital, Zhejiang University School of Medicine.)

Background: Nocturnal enuresis is a common disease of childhood. It can be classified into monosymptomatic nocturnal enuresis (MNE) or nonmonosymptomatic nocturnal enuresis (NMNE). Imipramine is a tricyclic antidepressant used to treat enuresis with initial success rates are high as 50% but some studies record a high relapse rate and it has a cardiotoxic effect when overdosed. Anticholinergics may be effective in the treatment of children with bladder storage dysfunction, including daytime incontinence. However, anticholinergics monotherapy is not effective in treating MNE. In our study, we used a low dose (25 mg) of imipramine in order to avoid its potential side effects and combined it with the synergistic anticholinergic action of solifenacin. Our objective was to evaluate the efficacy and safety of the combination of solifenacin and imipramine compared with placebo in the treatment of desmopressin refractory MNE., Methods: One hundred children aged 6 years or more with primary MNE unresponsive to desmopressin treatment were included. The children were randomly divided into two equal groups. Group A received imipramine 25 mg and solifenacin 5-10 mg oral tablets and group B received placebo once 1 h before bedtime for 3 months. The primary end point was to investigate the efficacy of the combined treatment of solifenacin and imipramine and the secondary end point was the safety of the drugs., Results: Our study showed that the mean post treatment wet nights per month was significantly lesser in the treatment group than placebo group ( p  < 0.001) and cure rate was significantly higher in treatment group than placebo group ( p  < 0.001). The relapse rate was statistically significantly lower in treatment group than placebo group ( p  = 0.032). No significant side effects related to the drugs were reported., Conclusion: The combination treatment of solifenacin and imipramine is a useful and safe treatment for nocturnal enuresis after failure of everything else.

Background: The purpose of this study was to assess whether enuretic Japanese patients with nocturnal polyuria (NP) who met Hoashi's criteria (6-9 years: ≥200 mL; 10 years and older: ≥250 mL) met the International Children's Continence Society (ICCS; expected bladder capacity × 130%) and Rittig's criteria for nocturnal polyuria (>[age+9] × 20 mL). We also compared the effectiveness of 1-desamino-8-d-arginine vasopressin (DDAVP) with the three criteria., Methods: Fifty-four patients who had NP with normal bladder capacity were enrolled: 36 boys (67%); median age, 8 (interquartile range: 7-9). We compared the diagnostic differences between the Hoashi's criteria and international standards (ICCS and Rittig's) for NP and the short-term effects of DDAVP. The patients received DDAVP for 8 weeks; we evaluated the association between each evaluation method and the effects of therapy., Results: Only 17% of the patients met both Hoashi's and ICCS criteria, whereas 26% met both Hoashi's and Rittig's criteria. The therapeutic effect of DDAVP did not differ significantly between these two groups: there was an effective rate of 73% (Hoashi's criteria) versus 50% (ICCS criteria), P = 0.19, and an effective rate of 71% (Hoashi's criteria) versus 62% (Rittig's criteria), P = 0.84., Conclusions: Hoashi's criteria are widely used but, according to both the ICCS and Rittig's criteria, approximately 80% of the patients did not fulfill the definition of NP. However, 8 weeks after the DDAVP treatment began, no significant difference was observed in the therapeutic effect of DDAVP according to each set of criteria. The definition of NP should account for the physical disparities between Japanese people and Westerners., (© 2021 Japan Pediatric Society.)

Purpose: We analyzed the annual trends in and initial choice of pharmacotherapy for children with nocturnal enuresis (NE) using a large-scale medical claims database in Japan., Methods: A retrospective descriptive study performed using data from the Japan Medical Data Center between January 2005 and March 2019 involving 23,814 registrants under 16 years of age. In the first cohort of children with NE, we analyzed the comorbidities and associated annual pharmacotherapy prescribing trends. In the second cohort of only newly diagnosed cases, we analyzed the first prescribed age and initial choice of pharmacotherapy., Results: A total of 3494 children with NE were identified (mean age, 5.1 ± 3.6 years; male, 66.0%). An incremental increase in the proportion of children administered NE medications was observed. The proportion of children treated with desmopressin significantly increased, whereas the prescription of tricyclic antidepressants significantly decreased and that of anticholinergics did not significantly change. Among the newly diagnosed children, 1897 were treated with approximately 90% of the prescribed monotherapy. Sublingual desmopressin monotherapy accounts for more than half of the initial pharmacotherapy from 2016 onward. Regardless of the drug class, pharmacological therapy was commonly initiated at the age of 8.3 ± 2.1 years., Conclusions: In Japan, the proportion of children treated with pharmacotherapy has been increasing. Furthermore, since the introduction of desmopressin sublingual formulations in 2012, a paradigm shift has occurred and this form of medication is now the most commonly prescribed, both from the annual perspective and as an initial choice among the newly diagnosed., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To evaluate whether the efficacy of desmopressin differs between patients with and without nocturnal polyuria., Methods: A total of 65 treatment-naïve children with monosymptomatic nocturnal enuresis were enrolled (45 boys; median age 8.9 years). Patients received desmopressin as their first-line treatment. Four different standards were used (Akashi and Hoashi >0.9 mL/kg/sleeping hour; Hamano >[age + 2] × 25 × 130% mL; the International Children's Continence Society >[age + 1] × 30 × 130% mL; and Rittig >[age + 9] × 20 mL) to assess nocturnal polyuria. The effectiveness of desmopressin was compared between patients with and without nocturnal polyuria according to each standard. A response was defined as a reduction in wet nights of >50%., Results: The desmopressin treatment efficacy rate was 54% for polyuria and 67% for non-polyuria patients (P = 0.20), 45% for polyuria and 68% for non-polyuria patients (P = 0.08), 54% for polyuria and 59% for non-polyuria patients (P = 0.80), and 52% for polyuria and 61% for non-polyuria patients (P = 0.61), for the Akashi and Hoashi's, Hamano's, International Children's Continence Society and Rittig's standards, respectively., Conclusions: No difference was observed in the short-term clinical efficacy of desmopressin regardless of the presence of nocturnal polyuria. Thus, this might be a feasible treatment option for patients with nocturnal enuresis without nocturnal polyuria., (© 2021 The Japanese Urological Association.)

Nocturnal enuresis (NE) is a common problem among 10% school-aged children. The etiologies underlying childhood NE is complex and not fully understood nowadays. Nevertheless, increasing evidence suggests a potential link between neurobehavioral disorders and enuresis in children. In this study, we aimed to explore novel metabolomic insights into the pathophysiology of NE and also, its association with pediatric psychiatric problems. Urine collected from 41 bedwetting children and 27 healthy control children was analyzed by using 1 H-nuclear magnetic resonance spectroscopy from August 2017 to December 2018. At regular follow-up, there were 14 children with refractory NE having a diagnosis of attention deficient hyperactivity disorder (ADHD) or anxiety. Eventually, we identified eight significantly differential urinary metabolites and particularly increased urinary excretion of betaine, creatine and guanidinoacetate linked to glycine, serine and threonine metabolism were associated with a comorbidity of neurobehavioral disorders in refractory bedwetting children. Notably, based on physiological functions of betaine acting as a renal osmolyte and methyl group donor, we speculated its potential role in modulation of renal and/or central circadian clock systems, becoming a useful urinary metabolic marker in diagnosis of treatment-resistant NE in children affected by these two disorders., (© 2021. The Author(s).)

Introduction: Enuresis is identified as voluntary or involuntary leakage of urine for at least three consecutive months in the daytime and/or nighttime on clothes for children older than five. Monosymptomatic nocturnal enuresis (MNE) describes nighttime wetting without daytime leakage of urine in children with no pathology in the urinary system and it is 80% more common than enuresis. Desmopressin is the most common medical treatment for MNE. The aim of this study is to retrospectively compare the effectiveness of desmopressin as monotherapy and desmopressin + oxybutynin as a combination therapy in the treatment of nocturnal enuresis., Material and Method: This study retrospectively evaluated 183 patients who applied to pediatrics, pediatrics surgery and urology clinics with the complaint of nocturnal enuresis and diagnosed with primary monosymptomatic nocturnal enuresis between January 2014 and December 2019. The patients were divided into two groups (91 patients) who only received desmopressin therapy (Group 1), and those (92 patients) who received desmopressin and oxybutynin combination therapy (Group 2). Response to treatment, compliance and recurrence ratios were determined in the evaluation. Complete response was accepted as 90-100% decrease in the number of nighttime wetting, partial response was accepted as 50-90% decrease in the number of nighttime wetting and those below 50% were regarded as non-response. The 1st, 3rd, and 6th months of control data of treatment effectiveness of both groups were evaluated and their responses to treatment and the side effects of drugs were examined., Results: The mean age 183 patients of whom 103 were male and 80 were female was 10 (6-16) year. In the first month of control of Group 1, 71.4% had a complete cure, 8.8% had a partial cure and 19.8% had no response to treatment. In the third month of control of Group 1, 74.73% gave a complete response and were cured, 5.5% gave a partial response and 19.78% had no response. In the sixth month of Group 1, 70 patients were evaluated as complete response (79.5%), and 5 patients were evaluated as partial response (5.6%). In the first month of control of Group 2, 75% gave a complete response, 10.9% gave a partial response, 14.1% had no response to treatment. In the third month of control of Group 2, 86.9% gave a complete response, 6.52% gave a partial response, and 6.52% had no response. In the sixth month of the control of Group 2, the number of patients who did not come for control and could not be reached was 2, 83 patients out of 90 patients were evaluated as complete response (92.2%), 6 patients were evaluated as partial response (6.6%)., Conclusion: Desmopressin is the only FDA approved pharmacologic treatment for nocturnal enuresis. Desmopressin reduces urine production and the anticholinergic agent allows the bladder to store more urine. Therefore, combined therapy can be recommended in the MNE treatment for specially selected cases., Competing Interests: Conflict of interest None., (Copyright © 2021 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Objective: To study the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of desmopressin (dDAVP) oral lyophilisate in children below the age of 8 years with special emphasis on age-related and size-related differences in bioavailability., Design: Open label, non-randomised, interventional PK and PD trial., Setting: Single-centre study., Patients: Children (age: 6 months to 8 years) with nocturnal polyuria, including both children with uropathy or nephropathy (glomerular filtration rate >60 mL/min/1.73 m²) and children (age: 5-8 years) with severe monosymptomatic nocturnal enuresis, who were unresponsive to treatment with 400 µg of the dDAVP tablet for at least 1 month., Interventions: After a water load, dDAVP was administered sublingually as a single dose of oral lyophilisate. Subsequently, blood and urine samples were collected until 7 hours post-administration., Main Outcome Measures: Non-compartmental analysis of PK parameters was performed based on dDAVP concentrations in both plasma and urine. To evaluate the effect of dDAVP lyophilisate (PD parameters), the urinary concentration capacity (urine osmolality (mOsm/kg)) and antidiuretic effect (diuresis rate (mL/kg/h)) were calculated., Results: The PK data support the need for size-dependent dosing in children. Body weight was shown to be a significant covariate for apparent clearance (CL/F) and apparent volume of distribution (V d /F). A double absorption peak of dDAVP lyophilisate in the first 2 hours post-administration was demonstrated., Conclusions: For the first time, a double absorption profile of dDAVP lyophilisate was found in children, questioning extrapolation of bioequivalence from adults towards children. Moreover, the need for size-adapted dosing regimens of dDAVP lyophilisate in young children is indicated., Trial Registration Number: NTC02584231., Competing Interests: Competing interests: LD, CVH, EG and PDB received a travel reimbursement from Ferring Pharmaceuticals for a presentation at the Ghent-Aarhus Springschool. SR and JvdW received consulting fees and travel reimbursements from Ferring Pharmaceuticals. AV is an employee of Johnson & Johnson and holds stock/stock options from J&J. RM has no potential conflicts of interest that might be relevant to this manuscript., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To evaluate the impact of compliance on the therapeutic effects of Desmopressin, as well as the importance of establishing the voiding school for low-compliance children in primary monosymptomatic enuresis treatment., Methods: Eighty-nine patients with primary monosymptomatic enuresis treated with Desmopressin were observed during the 2017-2020 at University Children's Hospital Belgrade, Serbia. The average patients age was 7.7 ± 2.4 years; 65 (73%) were boys and 24 (27%) % were girls. After the 3 months of Desmopressin treatment, the effect of therapy was evaluated according to the compliance. After the treatment, low-compliance patients and their parents were suggested to visit a voiding school., Results: A significant decrease in the median enuresis frequency was noticed during the Desmopressin treatment (25.0 (20.0-26.0) vs 10.0 (2.0-17.0) per month, before vs after treatment, respectively) (p < 0.001). Patients with low compliance had a poorer response to Desmopressin (p < 0.001). An median enuresis reduction in the good compliance group was 92.3% (86.7 -95%), while in the low compliance group was 28.6% (16.7-43.3%). After attending voiding school, there was a significant increase in compliance (p < 0.001), associated with an median percent decrease in enuresis of 84.0% (75.0-95.5%) (p < 0.001)., Conclusion: Compliance considerably influences the beneficial effects of Desmopressin. Patients with poor therapeutic effects should be evaluated for compliance and introduced to voiding school.

Background: Monosymptomatic enuresis nocturna patients are shown to have disrupted blood-pressure regulation accompanying polyuria. In our study, we aimed to research the desmopressin response of enuresis patients with blood-pressure regulation problems., Methods: The study included 175 patients, aged from 6-15 years, with a diagnosis of monosymptomatic enuresis nocturna. Before treatment, 24 h ambulatory blood-pressure monitoring (ABPM) was used to identify 52 non-dipper patients and 73 patients with normal results. The responses to desmopressin treatment and clinical and demographic characteristics affecting response were compared., Results: The response to desmopressin treatment was found to be significantly low in the patients who were non-dippers on 24 h ABPM before treatment compared to those with normal ABPM results (P < 0.05). Similarly, the waking problems in the non-dipper group were found to be high by a significant degree (P < 0.05). In the non-dipper group, the systolic non-dipping rate was higher., Conclusions: Before desmopressin use, assessment of patients with a 24 h ABPM may be beneficial to select the method to be used for treatment., (© 2020 Japan Pediatric Society.)

Desmopressin plays a major role in the treatment of monosymptomatic enuresis but has the drawback of a high relapse rate after medical treatment. This study investigated the effect of the type of treatment termination on relapse in a large population of patients. A total of 1013 patients who were admitted with bedwetting to our paediatric urology clinic between October 2016 and April 2018 were evaluated retrospectively. Four hundred forty-seven monosymptomatic enuresis patients were treated with 120 μg/day oral desmopressin lyophilisate for 3 months, after which the treatment was terminated in one of two ways: immediate cessation of desmopressin (group 1; N = 209) and structured withdrawal (group 2; N = 238). In the structured withdrawal group, the patients continued to take desmopressin every other day for 15 days. All the patients were followed up 1 month after the drug was withdrawn, and the relapse rates were recorded. One month after cessation of treatment with oral desmopressin lyophilisate, the relapse rate in group 1 was 42.5% (89/209), and that in group 2 was 41.1% (98/238) (p > 0.05).Conclusion: This study, with the highest number of patients among reports in the literature, revealed that the methods used to terminate desmopressin treatment are not significantly different in monosymptomatic enuresis management. What is Known: • It is still unclear how to end the treatment in patients who are started desmopressin because of the complaint of monosymptomatic nocturnal enuresis. • Although there are papers in the literature suggesting that the drug should be discontinued gradually or by reducing the dose, there are also authors stating the opposite. What is New: • This study including vast amount of patients managed with desmopressin reveals that withdrawal strategy has no impact on relapse.

Purpose: To assess the efficacy of desmopressin plus anticholinergic combination therapy as first-line treatment for children with primary monosymptomatic nocturnal enuresis (PMNE) and to analyze this combination's effect on functional bladder capacity (FBC)., Materials and Methods: A total of 99 children with PMNE were prospectively enrolled from 2015 to 2019 and randomly allocated to a monotherapy group (n=49), with oral desmopressin lyophilisate (MELT) only; and a combination group (n=50), with desmopressin plus an anticholinergic (propiverine 5 mg). Efficacy and FBC were evaluated at 1 and 3 months after treatment initiation; the relapse rate was assessed at 6 months after treatment cessation., Results: The combination therapy group showed a higher rate of complete response than the monotherapy group after 3 months of treatment (44.0% vs. 22.4%, p=0.002). A significant increase in mean FBC was observed only in the combination group, from 88.72±26.34 mL at baseline to 115.52±42.23 mL at 3 months of treatment (p=0.024). Combination therapy was significantly associated with treatment success at 3 months after treatment initiation (odds ratio [OR], 3.527; 95% confidence interval [CI], 1.203-6.983; p=0.011) and decreased risk of relapse at 6 months after treatment cessation (OR, 0.306; 95% CI, 0.213-0.894; p=0.021), by multivariable analysis., Conclusions: This study represents the first prospective, randomized controlled trial showing higher response rates and lower relapse rates with desmopressin plus anticholinergic combination therapy compared with desmopressin monotherapy as first-line treatment for children with PMNE., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association, 2021.)

Abstract: Aripiprazole is an atypical antipsychotic commonly used in the treatment of psychiatric disorders, such as schizophrenia, bipolar disorder, and irritability associated with autism spectrum disorder. Common adverse effects associated with aripiprazole usage in children and adolescents are nausea, vomiting, extrapyramidal adverse effects, akathisia, sedation, tremor, and increased appetite. Enuresis is one of the least expected adverse effects during aripiprazole use. The pathophysiology of aripiprazole-induced enuresis has not been fully clarified. To our knowledge, our report presents enuresis related to aripiprazole use at the lowest dose in the literature. In this report, we present the case of a 9-year-old boy who developed nocturnal enuresis after the beginning of low-dose aripiprazole treatment., Competing Interests: Conflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Aripiprazole is a third-generation atypical antipsychotic drug that acts as a stabilizer of the dopaminergic and serotonergic system. As partial agonist of the dopamine (D2) and serotonin (5-HT1A) receptors, it appears to be effective in reducing mania in patients with bipolar disorder, tics in Tourette Syndrome, aggression in schizophrenia and autism spectrum disorder. Enuresis has been reported among its side effects. Only a few studies, with conflicting results, have investigated the relationship between aripiprazole and enuresis., Case Presentation: We report the disappearance of enuresis in a Caucasian girl with intellectual disability and oppositional defiant disorder and in a Caucasian boy with intellectual disability and early-onset psychosis, both following initiation of treatment with aripiprazole., Conclusion: The aim of this study was to contribute to the literature on the use of aripripazole in subjects with enuresis. Our findings lead us to suggest that aripiprazole is less burdened with side effects, including bedwetting, than other antipsychotic drugs.

Little is known about sleep-based approaches to the treatment of nocturnal enuresis (NE). This report is the first to describe the successful use of suvorexant, an orexin receptor antagonist, in a 12-year-old boy with intractable NE. With suvorexant, the frequency of NE gradually decreased from 14 of 14 days (100%) to 5 of 14 days (35.7%). Sleep polysomnography indicated that rapid eye movement (REM) sleep increased from 101.5 min (19.9%) before suvorexant to 122.1 min (24.9%) with suvorexant. Furthermore, N2 increased from 233 min (45.6%) to 287.5 min (58.7%) during non-REM sleep. In contrast, N3 decreased from 160 min (31.3%) to 65 min (13.3%) during non-REM sleep. Suvorexant appeared to lighten the depth of sleep and alter sleep architecture. Although the application of an insomnia medication for treating NE seems paradoxical, suvorexant reduced the frequency of NE in patients with severe intractable NE. Thus, this treatment strategy warrants further examination., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Nocturnal enuresis (bedwetting) is a common disorder affecting 10-16% of 7-year-old children globally. Nocturnal enuresis is highly heritable, but its genetic determinants remain unknown. We aimed to identify genetic variants associated with nocturnal enuresis and explore its genetic architecture and underlying biology., Methods: We did a genome-wide association study (GWAS) of nocturnal enuresis. Nocturnal enuresis cases were identified in iPSYCH2012, a large Danish population-based case cohort established to investigate mental disorders, on the basis of 10th revision of the International Statistical Classification of Diseases (ICD-10) diagnoses and redeemed desmopressin prescriptions in Danish registers. The GWAS was done in a genetically homogeneous sample of unrelated individuals using logistic regression with relevant covariates. All genome-wide significant variants were analysed for their association with nocturnal enuresis in an independent Icelandic sample from deCODE genetics. Standardised polygenic risk scores for attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder were constructed from summary statistics of large GWASs and analysed for association with nocturnal enuresis., Findings: The GWAS included 3882 nocturnal enuresis cases and 31 073 controls. We found two loci at chromosome 6 and chromosome 13 significantly associated with nocturnal enuresis. Six genetic variants at the two loci (five variants at chromosome 6q16.2 and one variant at chromosome 13q22.3) surpassed the threshold for genome-wide significance (p<5 × 10 -8 ). There were two lead variants: rs9376454 (chromosome 6q16.2), with an odds ratio (OR) of 1·199 (95% CI 1·135-1·267; p=9·91 × 10 -11 ), and rs60721117 (chromosome 13q22.3), with an OR of 1·149 (1·095-1·205; p=1·21 × 10 -8 ). All associated variants in the chromosome 6 locus were replicated (p<8 × 10 -3 ) in the independent Icelandic cohort of 5475 nocturnal enuresis cases and 303 996 controls, whereas the associated variant in the chromosome 13 locus showed nominal significant association (p=0·031). The percentage of nocturnal enuresis phenotypic variance explained by the common genetic variants was 23·9-30·4%. Polygenic risk for ADHD was associated with nocturnal enuresis (OR 1·06, 95% CI, 1·01-1·10; p=0·011). Among the potential nocturnal enuresis risk genes mapped, PRDM13 and EDNRB have biological functions associated with known pathophysiological mechanisms in nocturnal enuresis, and SIM1 regulates the formation of the hypothalamic neuroendocrine lineage that produces arginine vasopressin, a well known nocturnal enuresis drug target., Interpretation: This study shows that common genetic variants contribute considerably to nocturnal enuresis, and it identifies potential nocturnal enuresis risk genes with roles in sleep, urine production, and bladder function. Given that available treatments target these mechanisms, any of the identified genes and their functional gene networks are potential drug targets., Funding: The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Stanley Foundation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Nocturnal enuresis (enuresis) is one of the most common developmental problems of childhood, which has often a familial basis, causes mental and psychological damage to the child and disrupts family solace., Objectives: In this study, we compared therapeutic efficacy and tolerability of treating primary nocturnal enuresis (PNE) with solifenacin plus desmopressin, tolterodine plus desmopressin, and desmopressin alone. Because we don't have enough information about this comparison especially about solifenacin plus desmopressin., Patients and Methods: This clinical trial study was performed on 62 patients with enuresis aged 5-15 years who referred to the urology clinic of Imam Khomeini Hospital in Ahwaz in 2017-2018. Patients were randomly assigned to one of the three different therapeutic protocols and any participants were given a specific code. After that, we compared the therapeutic response and the level of satisfaction of each therapeutic group in different months. Data were analyzed using SPSS 22 software and descriptive and analytical statistics., Results: The mean age of patients was 8.70±66 years. In the therapeutic group with desmopressin and solifenacin, 19 of 20 patients (95%) achieved complete remission (1) after a 3-month treatment in comparison with monotherapy group in which 14 of 22 patients (63.63%) achieved complete remission; and in the combination therapy group of desmopressin and tolterodine, in the study and the evaluation of the consequences of 3-month treatment of this group, it was found that 17 of 20 patients (85%) had complete remission. Overall, the therapeutic response in combination therapy groups of desmopressin plus anticholinergic was higher than the monotherapy group of desmopressin alone., Conclusion: Our results demonstrate that the combination of desmopressin and an anticholinergic agent is highly effective in treatment of children with PMNE. Although desmopressin has long been a first - line treatment for PMNE, desmopressin monotherapy often fails to achieve a successful response in patients with PMNE., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)