Nocturnal enuresis (NE) is a common voiding problem among children. Treatment is considered when NE persists in children over 5 years of age [1]. Several guidelines, including those of the International Children’s Continence Society (ICCS), suggest that nonmonosymptomatic enuresis (NME) can be diagnosed when NE is associated with lower urinary tract dysfunction (LUTD) [2,3]. LUTD should be addressed prior to the treatment of enuresis per se. However, details regarding the evaluation and management of LUTD in patients with NME have been vaguely described. For example, such decisions depend on the physician’s discretion regarding the severity of LUTD that warrants treatment prior to addressing enuresis, the hierarchical order of instituting each treatment modality for LUTD, and the timing of ceasing LUTD treatment and starting enuresis management. The diagnosis and management of constipation for the treatment of LUTD or enuresis have likewise not been fully clarified. A simple question such as “Do you think your child has constipation?” may not be helpful for identifying the presence of constipation due to frequent inconsistencies among parental perceptions, symptoms, and the real amount of fecal loading [4,5]. Moreover, it is difficult to determine the severity of constipation that warrants treatment for LUTD. Given that adequate bowel decompression may take a long time, it is important to establish criteria for how much constipation should improve in order to address LUTD. Postponing treatment for enuresis until full decompression of the bowel may take several months to years, which may lead to reduced compliance and loss to follow-up.

Anticholinergics have been the mainstay for the treatment of overactive bladder (OAB) [2,6]. Since OAB is a common cause of LUTD in children, it is safe to say that anticholinergics are likely to play a major role in the treatment of NME. Although the use of anticholinergics is not recommended for the management of monosymptomatic enuresis (ME) [1], several studies have reported the successful use of anticholinergics to ameliorate or cure enuresis [7-10].

To understand the clinical course and results of NME treatment, we treated patients with NME as recommended by most guidelines [2,3], including standard urotherapy, constipation treatment (if present), and anticholinergics. The use of desmopressin was deferred until the occurrence of partial response (PR) of OAB. The analysis of our data is expected to provide helpful insights into the results of treatment when the principle of “addressing LUTD first” is strictly followed. Thus, the main purpose of our study was to characterize the course of treatment for NME with OAB in a real clinical setting.

This analysis may provide additional insights about which patients might show resistance to this treatment. The reason for treating LUTD prior to enuresis control is the perception that LUTD might be associated with a prolonged treatment period and resistance to treatment [2,10,11]. By understanding which patients may not respond to treatment, the treatment strategy could be tailored to obtain better results.

With approval from the Institutional Review Board, and following human subject guidelines, we reviewed the medical records of 176 children aged 5–15 years who were diagnosed and treated with primary NE between July 2010 and July 2015. Twenty-one patients who were diagnosed with ME were excluded from the review. Hence, data from 155 children who were treated for NME were eligible for review. None of these children had anatomical urinary tract abnormalities or neurological disorders. According to the ICCS definition, children who exhibited urgency or frequency or diurnal urgency incontinence were diagnosed with OAB [12].

All patients underwent a medical history and physical examination, completed a bladder diary, and were assessed using the modified Korean version of the Dysfunctional Voiding and Incontinence Symptom Score (DVISS) [13], the ROME III criteria for functional constipation [14], uroflowmetry, and postvoid residual urine measurement. Abnormal uroflow curves and elevated postvoid residual urine were seen in 23 patients. These patients were regarded to have other forms of voiding dysfunction, such as dysfunctional voiding. They were excluded from the review. Data regarding maximal and average voided volume and voiding frequency were extracted from bladder diaries. The average voided volume was determined after excluding the first morning voided volume. Expected bladder capacity was estimated following ICCS recommendations [12]. Simple plain radiography was performed routinely for the kidneys, ureters, and bladder before treatment to identify abnormalities in the spine and stool retention. Stool impaction was assessed based on the definitions presented by Marks et al. [4]. Rectal stool and total stool length (RSL and TSL, respectively) were measured as surrogate markers.

After the initial evaluation, standard urotherapy and treatment of constipation were first attempted. Standard urotherapy included demystification, education about urinary tract function, and advice regarding sound voiding habits, including lifestyle modifications such as timed voiding and adequate postvoid water consumption. In patients with a positive history of constipation according to the ROME III criteria, an RSL more than 6 cm, or a TSL longer than 34 cm, polyethylene glycol (10 g) or lactitol syrup (15 mL) was prescribed to decompress the bowel, depending on which was more palatable. Following a 1-month trial of standard urotherapy and/or laxatives, the further need to use anticholinergics was determined based on whether patients showed at least PR in daytime symptoms and complied with urotherapy. Treatment efficacy was measured in accordance with ICCS recommendations [12]. No response (NR) and PR were defined as reductions in enuresis of <50% and 50%–99%, respectively. Complete response (CR) was considered to have occurred when there was 0–1 episode of enuresis during 3 months of follow-up. Patients who showed at least PR in urgency, were compliant on more than 80% of occasions based on their anamnesis, and were well-motivated continued nonpharmacological treatment. Anticholinergic treatment was reserved for those who did not meet those criteria. Based on the patient’s ability to swallow tablets, a 5-mg tablet of solifenacin or 10 mg of powdered propiverine was initially prescribed. All patients were followed regularly every 3 months. The use of desmopressin was deferred until they showed at least PR in control of urgency. At each follow-up, they were asked to provide information regarding the modified DVISS and a bladder diary.

We analyzed the demographic and clinical features of the patient population. Patients’ response and disposition following initial nonpharmacological treatment were described. The clinical courses of urgency (as a surrogate marker of OAB) and enuresis were plotted against the changing proportions of treatment responses every 3 months. The overall outcomes of OAB and enuresis following treatment were also assessed, and the features of patients who showed persistent NR at 12 months of follow-up were identified.

All categorical and continuous variables were reported as proportions and mean±standard error, respectively. The distribution of patients’ responses was analyzed. Multivariate logistic regression analysis was performed to identify predictive factors for persistent NR. All statistical analyses were conducted using IBM SPSS Statistics ver. 21.0 (IBM Co., Armonk, NY, USA). P-values <0.05 were considered to indicate statistical significance.

In this study, we reviewed data regarding the treatment of enuretic patients with symptoms of OAB by standard urotherapy, constipation management, and subsequent anticholinergics. Following 12 months of treatment, 64% and 88% of patients experienced at least PR in enuresis and OAB, respectively. To the best of our knowledge, this is the first study to present the detailed clinical course and long-term outcomes of NME patients with features of OAB in the real world after treatment according to currently used guidelines. The response rates for enuresis (corresponding to the proportion of patients with CR or PR) were comparable to those of ME patients treated with desmopressin [15]. This suggests that NME with proper control of daytime symptoms could be successfully treated by desmopressin, with similar efficacy to the use of desmopressin for ME. The only notable difference was that the duration of treatment was longer in our cases than was the case for ME, as shown by the data of the Aarhus group [11]. This might be related to the need for time to stabilize the bladder prior to addressing enuresis. NME patients should receive counseling regarding this issue when considering such treatment. Without proper counseling, there may be problems in maintaining adequate compliance because some parents might take it for granted that enuresis is an easy-to-treat entity requiring only short-term pharmacological treatment.

Our results showed that anticholinergics alone were capable of controlling enuresis, as well as daytime symptoms, underscoring the role of bladder problems in the development of enuresis. Although the use of only anticholinergics was sufficient to control enuresis in some patients, more patients required combination therapy for enuresis to resolve. This supports the importance of other mechanisms that contribute to enuresis apart from bladder control. Since the optimal treatment for enuresis may vary according to patients’ characteristics, further efforts should be made to elucidate the characteristics related to the efficacy of a given combination of treatments.

An interesting finding from the subgroup comparison was that the patients who received combination therapy with laxatives appeared to show better control of enuresis than those who used anticholinergics alone. This is consistent with a previous report showing a 63% reduction in enuresis following constipation treatment alone [16]. Moreover, this tendency could partially explain the low response rate in the anticholinergics-only treatment group, because the 19 patients who did not consent to constipation treatment were managed using only anticholinergics.

As in a previous trial of polyethylene glycol [17], the refusal of constipation treatment in 19 patients reflected difficulties in addressing constipation in patients with enuresis. This is related to the fact that no criteria have been generally accepted regarding the institution or discontinuation of constipation treatment in patients with LUTD. Moreover, it is currently unclear which tests are suitable for diagnosing constipation responsible for enuresis. Our data showed an unacceptable concordance rate between the subjective ROME III criteria and objective assessments of fecal impaction. Nonetheless, we tried to treat all patients who showed signs of fecal impaction, as well as those who had subjective constipation, based on the assumption that fecal impaction by itself could be problematic, regardless of the presence of symptoms.

The multivariate analysis revealed that presentation with daytime incontinence and anticholinergics-only treatment were associated with the lack of CR after 12 months of treatment. Interpreting these results requires caution because these factors may not necessarily lead to eventual failure and refractoriness. Instead, the interpretation of these findings should be that more rigorous treatment of bladder and bowel problems is needed to accelerate the course of treatment and to achieve the resolution of enuresis. In this regard, the validity of the claim that combination treatment should be deferred until LUTD stabilizes may be questioned. However, this may result in the unnecessary treatment of those who show resolution of enuresis with anticholinergics alone.

The interpretation of our data requires careful scrutiny. First, it should be noted that the distinction of OAB from other voiding disorders was not based on uroflowmetry with simultaneous electromyography, which is the current standard [18]. Although only patients with bell/tower-shaped uroflow were selected, patients with other types of voiding disorders than OAB might have been included. Second, other treatment modalities, such as pelvic floor muscle exercise/biofeedback or an enuretic alarm, might be more effective for treating this condition. Applying different treatment modalities might be associated with different time courses in the improvement of enuresis and LUTD [19,20]. Third, this study was conducted in a tertiary care hospital. Therefore, inherent selection bias in patient recruitment may have been present. The retrospective nature of this analysis of real-world clinical data might have flaws. For example, the detailed treatment protocol may have varied across patients, even though the same treatment strategy was used. Finally, standard urotherapy was insufficiently applied to result in changes in enuresis despite its proven long-term efficacy in some patients [8]. However, the expectation of a prolonged time course and the modest efficacy inherent to standard urotherapy led us to avoid waiting for more than a month. In fact, 21 patients were lost within 3 months of treatment, implying that they were impatient for obtaining meaningful improvement of enuresis.

In conclusion, we acknowledge that a prolonged course of treatment is necessary to control NME and we confirm that OAB improves more quickly than enuresis. This supports the current guidelines that stress the need to treat daytime symptoms prior to treating enuresis per se. However, prolonged adherence to only anticholinergics to control daytime symptoms may lead to a protracted course of treatment. The proactive control of constipation and the early addition of desmopressin to anticholinergic therapy may facilitate the faster resolution of enuresis.