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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.)

Background: We investigated the effect of combining indomethacin and desmopressin in treating children with monosymptomatic nocturnal enuresis (MNE) and desmopressin-resistant nocturnal polyuria., Methods: Twenty-three children with MNE, nocturnal polyuria, and partial or no response to desmopressin were recruited from incontinence clinics of our tertiary referral center. We used a randomized single-arm crossover placebo-controlled study design consisting of two 3-week treatment periods with a combination of desmopressin (0.4 mg) and indomethacin (50 mg) or desmopressin and placebo at bedtime. Home recordings at baseline and for the final 2 weeks of each treatment period were performed and included nocturnal urine output measurements. The number of dry nights achieved and reduction in the nocturnal urine output were the main effect parameters. Student's t test and Pearson's correlation coefficient were used for statistical analysis., Results: The addition of indomethacin to desmopressin significantly reduced nocturnal urine output (from 324 ± 14 ml to 258 ± 13 ml, p < 0.001). This did not lead to more dry nights in all children, and we found no statistically significant reduction in enuresis frequency (from 68 % ± 0.1 to 56 % ± 0.1, p = 0.24)., Conclusions: Addition of indomethacin to desmopressin can further reduce nocturnal urine output in children with MNE and desmopressin-resistant nocturnal polyuria. The combination treatment does not, however, improve outcome in terms of frequency of nights with enuresis. The dissociation of antidiuretic and antienuretic effect may reflect nocturnal bladder reservoir dysfunction in children who present with normal daytime bladder function.

Most patients with monosymptomatic nocturnal enuresis can be effectively treated with an enuresis alarm or antidiuretic therapy (desmopressin), depending on the pathophysiology of the condition in the individual patient. Desmopressin is first-line therapy for enuresis caused by nocturnal polyuria, an excessive urine output during the night. However, in a recent study, around one-third of patients thought to be resistant to desmopressin were subsequently treated effectively with desmopressin monotherapy in a specialist centre. The aim of this article is to review best practice in selecting patients for desmopressin treatment, as well as outline eight recommendations for maximizing the chances of treatment success in patients receiving desmopressin. The roles of formulation, dose, timing of administration, food and fluid intake, inter-individual variation in response, body weight, adherence, withdrawal strategies and combination therapies are discussed in light of the most recent research on desmopressin and enuresis. Possible reasons for suboptimal treatment response are explored and strategies to improve outcomes in patients for whom desmopressin is an appropriate therapy are presented. Through optimization of the treatment plan in primary and specialist care centres, the hope is that fewer patients with this distressing and often embarrassing condition will experience unnecessary delays in receiving appropriate care and achieving improvements., Competing Interests: Compliance with ethical standards Financial disclosure KK has acted as a speaker for Ferring Pharmaceuticals. SR has acted as advisor/consultant to, and has research collaboration with, Ferring Pharmaceuticals. CVH has acted as a speaker for Ferring Pharmaceuticals. JVW has acted as advisor/consultant to, and has research collaboration with, Ferring Pharmaceuticals. Conflict of interest statement All authors declare that they have no conflicting interests involving this work.

Background: There is a high comorbidity between nocturnal enuresis, sleep disorders and psychological problems. The aim of this study was to investigate whether a decrease in nocturnal diuresis volume not only improves enuresis but also ameliorates disrupted sleep and (neuro)psychological dysfunction, the major comorbidities of this disorder., Methods: In this open-label, prospective phase IV study, 30 children with monosymptomatic nocturnal enuresis (MNE) underwent standardized video-polysomnographic testing and multi-informant (neuro)psychological testing at baseline and 6 months after the start of desmopressin treatment in the University Hospital Ghent, Belgium. Primary endpoints were the effect on sleep and (neuro)psychological functioning. The secondary endpoint was the change in the first undisturbed sleep period or the time to the first void., Results: Thirty children aged between 6 and 16 (mean 10.43, standard deviation 3.08) years completed the study. The results demonstrated a significant decrease in periodic limb movements during sleep (PLMS) and a prolonged first undisturbed sleep period. Additionally, (neuro)psychological functioning was improved on several domains., Conclusions: The study demonstrates that the degree of comorbidity symptoms is at least aggravated by enuresis (and/or high nocturnal diuresis rate) since sleep and (neuro)psychological functioning were significantly ameliorated by treatment of enuresis. These results indicate that enuresis is not such a benign condition as has previously been assumed.

Background: The aim of this study was to compare the efficacy of combination therapy with desmopressin and an anticholinergic to desmopressin monotherapy for the first-line treatment of children with primary monosymptomatic nocturnal enuresis (PMNE)., Methods: A total of 98 children with PMNE (male:female 71:27) aged 5-16 (mean age 7.18 ± 1.8) years were retrospectively analyzed. The patients were divided into two groups: the monotherapy group (n = 49) was given oral desmopressin alone, and the combination therapy group (n = 49) was given desmopressin plus an anticholinergic (propiverine 10 mg) as a first-line treatment. The two groups were matched according to the following criteria: age, gender, and baseline frequency of nocturnal enuresis. The efficacy was evaluated by International Children's Continence Society criteria at 1 and 3 months after treatment initiation., Results: The combination therapy group showed a higher rate of complete response than the monotherapy group (20.4 vs. 6.1% at 1 month of treatment; 46.9 vs. 22.4% at 3 months of treatment). In terms of success (response and complete response), there was a significant difference between the two groups after 3 months of treatment (P = 0.002)., Conclusions: Our results indicate that combination therapy with desmopressin plus an anticholinergic is quicker and more effective than desmopressin monotherapy in reducing PMNE.

Background: Treating enuresis in children with attention deficit hyperactivity disorder (ADHD) has not been previously reported. This study aims to investigate the efficacy, tolerability, and adverse effects of nortriptyline for treating enuresis in children with ADHD., Methods: Forty-three children aged from 5 to 14 years old were randomized into two groups. The treatment group received methylphenidate plus nortriptyline, while the placebo group received methylphenidate plus placebo. Nortriptyline and placebo were administered for 30 days and methylphenidate was administered for 45 days. The major outcome measure was parent-reported frequency of enuresis for 2 weeks prior to the intervention, during the intervention, and for 2 weeks after stopping the adjuvant therapy. Adverse effects were also checked., Results: While nortriptyline statistically decreased the incidence of nocturnal enuresis during the intervention, the number of enuresis events did not significantly change in the placebo group. In addition, enuresis was not different from the baseline frequency of enuresis after stopping nortriptyline or placebo administration. Both nortriptyline and placebo were tolerated well., Conclusions: Administration of nortriptyline for treating enuresis in ADHD has not been investigated before. Nortriptyline is statistically superior to placebo. However, enuresis will relapse after stopping nortriptyline in children with ADHD who continue taking methylphenidate.

Purpose: Decreased nocturnal antidiuretic hormone (ADH) excretion has been suggested to be a causative factor for PNE in children. We investigate the demographic characteristics and nocturnal ADH levels of children with PNE who attended a tertiary referral center and to determine their response to treatment with desamino-D-arginine vasopressin (DDAVP)., Methods: We performed a retrospective study in 90 PNE children aged 6-12 years. We recorded the gender, height, weight, number of children per family, and psychosocial problems and compared these findings with the corresponding data obtained from a national survey. We also measured the nocturnal ADH levels and evaluated the response rate to DDAVP., Results: The number of PNE patients decreased with an increase in age. Enuresis was significantly associated with male gender (P = 0.044) and more number of children per family (P = 0.043). The rates of comorbidity with defecation problems, obesity, attention-deficit hyperactivity disorder (ADHD), and overweight were 36.7, 17.8, 12.2, and 10%, respectively. Although the prevalence of obesity and ADHD was higher among children with PNE, there was no significant difference between PNE patients and their prevalence in the community. The ADH levels at 2 a.m. and 8 a.m. were 0.87 ± 0.75 and 0.89 ± 0.76 pg/ml, respectively. In the 50 (55.5%) patients who received DDAVP treatment, the complete- and partial response rates were 86 and 14%, respectively., Conclusions: Our data confirmed that PNE was predominant in boys and larger family, and similar to the findings for disease prevalence, the number of children seeking treatment tended to decrease with increasing age. Low ADH levels were recognized as a possible cause of PNE, thereby explaining the good response to DDAVP treatment in Taiwanese children with PNE.

Nocturnal enuresis, or bedwetting, is the most common cause of urinary incontinence in children. It is known to have a significant psychosocial impact on the child as well as the family. Nocturnal enuresis typically presents as failure to become dry at night after successful daytime toilet training. It can be primary or secondary (developing after being successfully dry at night for at least 6 months). Children with nocturnal enuresis may have excessive nocturnal urine production, poor sleep arousal and/or reduced bladder capacity. Alarm therapy is the recommended first-line therapy, with treatment choices being influenced by the presence or absence of the abnormalities mentioned above. Children with nocturnal enuresis may also have daytime urinary urgency, frequency or incontinence of urine. This group (non-monosymptomatic nocturnal enuresis) requires a different clinical approach, with a focus on treating daytime bladder symptoms, which commonly involves pharmacotherapy with anticholinergic medications and urotherapy (including addressing bowel problems). This review discusses the current management of nocturnal enuresis using the terminologies recommended by the International Children's Continence Society.

Enuresis nocturna is a common problem. Numerous etiologic factors have been investigated, and various theories have been proposed. The objectives of our study were to establish the differences in the sleep quality of nocturnal enuretic patients from that of healthy voluntary subjects, and the changes after treatment with desmopressin acetate (DDAVP), among primary school children. The study comprised 19 children with primary nocturnal enuresis and 32 healthy children in the control group. Subjective assessment of sleep was determined with the Pittsburgh Sleep Quality Index (PSQI) questionnaire. PSQI scores for each patient and control subject were determined before the study was started and after a month time interval. The sleep quality of the nocturnal enuretic children was poor. We found lower scores after a month's treatment with DDAVP, and significant differences in two dimensions in the patient group: 'subjective sleep quality' and 'sleep disturbances'. When we asked the patients' group what caused the sleep disturbance, they replied 'the fear or the anxiety of bedwetting during sleep'. This anxiety or fear seemed to be a factor that probably affected their sleep quality. So, active treatment (medical or behavioral) should be started as soon as the child is ready to receive it or when the enuretic child wants to be dry when asleep.

The anticholinergic drug tolterodine has been suggested to be useful in therapy-resistant enuresis. Imipramine has a proven efficiency in unselected enuretic patients, but due to its side-effect profile it is only indicated, if at all, in therapy-resistant cases. We therefore compared these two drugs to placebo. Twenty-seven children with enuresis resistant to the alarm and to desmopressin in monotherapy were given placebo, tolterodine 1-2 mg, and imipramine 25-50 mg at bedtime for 5 weeks each in a randomised, double-blind, crossover fashion. The number of wet nights during the last 2 weeks of each treatment period was compared. One patient became spontaneously dry at the start of the study, and one dropped out due to side effects. Among the remaining 25 children, the number of wet nights during placebo, tolterodine and imipramine treatment were 11.0 +/- 3.9, 10.4 +/- 3.9 and 7.8 +/- 5.1, respectively (p < 0.001). Imipramine was significantly better than both placebo (p = 0.001) and tolterodine (p = 0.006). Nine children experienced side effects on imipramine and one on tolterodine (p = 0.001). This is the first study on anticholinergics or imipramine in children with therapy-resistant enuresis. Tolterodine, in monotherapy, had no proven effect. Imipramine was better than placebo, but side effects were common.

The aim of this trial was to compare the safety and efficacy of homotoxicological remedies versus placebo and versus desmopressin (dDAVP) in the treatment of monosymptomatic nocturnal enuresis (MNE). We conducted a randomised, double-blind, double-dummy, controlled trial in which 151 children with MNE were randomly assigned to receive oral homotoxicological remedies (n = 50), dDAVP (n = 50) or placebo (n = 51). The primary outcomes were: the reduction of wet nights per week after 3 months of therapy; the evaluation of the numbers and percentages of non-responders and responders; the number of children relapsing after initial response and the number of children attaining 14 consecutive dry nights during the treatment. The secondary outcome was the detection of adverse effects. Baseline clinical characteristics were similar in the three groups of patients. After the 3 months of therapy there was a significant difference between the three groups (P < 0.001) in the mean number of wet nights per week. The daily dose of dDAVP produced a statistically significant decrease (62.9%) in wet nights compared to placebo (2.4%) (P < 0.001) and compared to homotoxicological remedies (30.0%) (P < 0.001). There was a significant decrease in wet nights among the group treated with homotoxicological medications if compared with placebo (P < 0.001). The full response achieved with homotoxicological remedies (20%) was superior if compared with placebo (0%) (P < 0.001). Homotoxicology was superior to placebo (P < 0.001) with regard to the number of children attaining 14 consecutive dry nights during treatment. Our study demonstrates that homotoxicology is safe and effective when compared with placebo, even if it is significantly less effective than dDAVP in this clinical condition.

In this issue Ferrara et al. present an important placebo-controlled, three-arm, double-blind, double-dummy, study on the treatment of nocturnal enuresis, demonstrating that homotoxicology is superior to placebo but less effective than desmopressin. Nocturnal enuresis is a disease with a heterogeneous aetiology and complex pathophysiology. The fact that different therapies may result in a wide range of responses is, therefore, not surprising. Differences in success rate can, therefore, be largely attributed to selection bias in the sub-populations. This consideration must be taken into account for every study design, to avoid premature interpretation of the results. Positive results in a paper are only not subject for discussion if both methodology and study population fulfil the highest standards, because negative results are not likely to be reported. Several points of weakness are present in the majority of studies, such as (a) inappropriate subtyping of the patients (terminology) or (b) epidemiological data, (c) insufficient documentation of patients' characteristics, (d) lack of plausible explanation as to why the placebo effect might be absent, (e) the heterogeneity of the severity of bedwetting. All these may lead to false positive and/or false negative results. In this commentary we try to tackle these different issues which might be relevant for the interpretation even of placebo-controlled studies like that of Ferrara et al.