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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 5  |  Issue : 2  |  Page : 69-77

Evidence based management of primary monosymptomatic nocturnal enuresis


1 Division of Nephrology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
2 Department of Pediatrics, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India

Date of Submission16-Apr-2022
Date of Decision25-May-2022
Date of Acceptance19-Oct-2022
Date of Web Publication31-Dec-2022

Correspondence Address:
Girish Chandra Bhatt
Room No. 1023, 1st Floor, Academic Block, AIIMS Hospital, Saket Nagar, Bhopal - 462 020, Madhya Pradesh
India
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Source of Support: None, Conflict of Interest: None


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  Abstract 


Nocturnal enuresis refers to bedwetting at night or during sleep. It may be either primary or have a complex presentation due to secondary etiologies. It is essential to differentiate primary enuresis from secondary enuresis, and monosymptomatic enuresis from polysymptomatic monosymptomatic enuresis, to guide therapy. For primary monosymptomatic enuresis, bladder training, urotherapy, alarm therapy, and desmopressin have been the mainstay of treatment. Choosing a suitable therapy for nocturnal enuresis warrants a thorough review of symptoms and voiding diary. Additionally, certain pretreatment and posttreatment response predictors have been found useful in management. Subclassification of primary monosymptomatic enuresis through bladder diary or ultrasonography helps select suitable candidates for anticholinergic therapy, which was previously reserved for refractory enuresis. The aim of this review is to integrate newer approaches with conventional therapy in diagnosing, classifying, and selecting therapies for nocturnal enuresis. Search Strategy: MeSH analysis was done on NCBI Platform with “enuresis” as MeSH major topic with several subtopics. The input for search builder was: (”Enuresis/classification”[Mesh] OR “Enuresis/diagnosis”[Mesh] OR “Enuresis/diagnostic imaging”[Mesh] OR “Enuresis/diet therapy”[Mesh] OR “Enuresis/prevention and control”[Mesh] OR “Enuresis/therapy”[Mesh])) AND (”Enuresis/etiology”[Mesh] OR). Six hundred and fifty-seven results were found from 75 clinical trials, 28 systematic reviews, and 4 review articles that were used to synthesize this review.

Keywords: Enuresis, management, primary monosymptomatic nocturnal enuresis (PMNE)


How to cite this article:
Bohra A, Bhatt GC. Evidence based management of primary monosymptomatic nocturnal enuresis. Asian J Pediatr Nephrol 2022;5:69-77

How to cite this URL:
Bohra A, Bhatt GC. Evidence based management of primary monosymptomatic nocturnal enuresis. Asian J Pediatr Nephrol [serial online] 2022 [cited 2023 Feb 4];5:69-77. Available from: https://www.ajpn-online.org/text.asp?2022/5/2/69/366536




  Introduction Top


The International Children's Continence Society defines enuresis as a disorder characterized by episodes of intermittent bedwetting during sleep in children ≥5 years of age.[1] In contrast, incontinence is a broader term used to describe the involuntary passage of urine at a socially inappropriate place.[1]

Enuresis during sleep without any daytime symptoms and bladder dysfunction is termed monosymptomatic nocturnal enuresis. Monosymptomatic nocturnal enuresis has been attributed to polyuria, reduced arousal from sleep, or an exaggerated micturition reflex due to lack of supraspinal inhibition. Micturition reflex is normally controlled by supraspinal and somatic factors, which may be inherited or modulated by the environment.[1] Studies show that 65%–85% of children with nocturnal enuresis have a positive family history and that its relative risk (RR) is higher when the father had enuresis compared to the mother (RR 7.1 vs. 5.2).

Primary enuresis is defined when a child has never achieved bladder control or has never had satisfactory period of night-time dryness. In contrast, secondary enuresis refers to that which is noted after achieving a dry period of at least 6 months, without an identifiable cause.[2] Primary enuresis has been linked to insufficient secretion of antidiuretic hormone (ADH) at night or decreased renal responsiveness to ADH, lack of control of micturition reflex, lack of arousal, and lower than expected bladder capacity for age [Figure 1]. Diabetes mellitus and diabetes insipidus may cause nocturnal polyuria and secondary monosymptomatic nocturnal enuresis.[3] Sleep-disordered breathing secondary to obesity or adenotonsillar hypertrophy impairs arousal and can cause enuresis.[3] Secondary enuresis may be associated with attention-deficit-hyperactivity disorder, psychological stress, and child abuse. A secondary cause should be ruled out and managed alongside therapy for enuresis.[2],[4]
Figure 1: Etiopathogenesis of primary monosymptomatic nocturnal enuresis. *As assessed by maximum voided volume compared to expected capacity for age. ADH antidiuretic hormone

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Nonmonosymptomatic enuresis is characterized by the presence of daytime incontinence and/or lower urinary tract symptoms, such as increased frequency, daytime incontinence, urgency, hesitancy, and genital or lower urinary tract pain.[2],[4] Bladder dysfunction can be a storage abnormality or voiding abnormality. Bladder capacity is reduced in patients with constipation, cystitis, and neurogenic bladder.[3] Daytime incontinence is often associated with constipation or encopresis.[1]

Children with nocturnal enuresis are prone to isolation, low self-esteem, and poor academic performance.[5] Children with enuresis may have internalizing psychopathologies like anxiety and depression.[6] Internalizing psychopathologies may be a cause as well as consequence of enuresis, and may precede, succeed, or coexist with enuresis.[6] Externalizing psychopathologies like attention deficit hyperactivity disorder (ADHD) and ADHD symptoms at age 9 are associated with remitted or life-long enuresis.[6] As ADHD does not overtly present at age 3 or 6, the presence of enuresis should raise suspicion for underlying ADHD.[6]

The diagnosis of nocturnal enuresis involves a thorough physical examination, detailed history-taking to rule out comorbidities that suggest nonmonosymptomatic nocturnal enuresis. [Figure 2] outlines an approach to nocturnal enuresis.
Figure 2: Approach to diagnosis and treatment of child with enuresis. BVWI bladder volume wall index

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  Voiding Diary Top


A voiding dairy is a method of studying urodynamic parameters noninvasively. A 3-day voiding diary, as described in [Figure 3], is a useful aid in diagnosis. [Table 1] details important parameters that can be assessed using a voiding diary.
Figure 3: Outline of a bladder diary

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Table 1: Parameters assessed from voiding diary and ultrasonography

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The “3 systems” model classifies primary monosymptomatic nocturnal enuresis into subclasses on the basis of voiding diary.[7] These include night-time polyuria, enuresis due to overactive or small bladder capacity, and enuresis due to lack of arousal.[7] Children with lack of arousal tend to have frequent voids in the morning, whereas those with nocturnal polyuria void more often before or at midnight and have large night-time voided volume.[7] Children with bladder capacities lower than that expected for age present with variable voiding pattern throughout the night.[7] Refractory MNE is associated with low normalizing bladder capacity (NBC) for age. Children who achieve NBC for their age by adolescence are the ones who become dry after treatment.

The South African guidelines on enuresis use this classification to guide therapy. An approach to decision-making as per voiding pattern is outlined in [Figure 3].


  Polysomnography Top


While the role of polysomnography in managing children with enuresis is less well defined, it has potential for personalized therapy. Patients with nocturnal enuresis have lower sleep quality and quantity, with reduced total sleep time, reduced sleep efficiency, lighter sleep, and higher rates of waking up. Prominent sleep-wake changes before enuresis, increased delta power, decreased cortical arousal index during nonrapid eye movement (NREM) sleep, and increased cyclical alternating pattern during NREM sleep stage 3 are reported.[8] In contrast, nonmonosymptomatic nocturnal enuresis is linked to deeper sleep.[8] Children with refractory monosymptomatic nocturnal enuresis have deeper sleep, high cortical arousal index, and sleep fragmentation.[8]

Adenotonsillar hypertrophy is associated with both primary enuresis and enuresis associated with obstructive sleep apnea. While both conditions have high apnea-hypopnea index, the REM stage of sleep is prolonged in patients with enuresis alone, while the cyclical alternating pattern is increased in patients with apnea and enuresis.[8] It is important to differentiate between these two conditions, as the response to treatment differs between the two. A systematic review (18 studies, 890 patients) concluded that surgical intervention reduced symptoms in 60% of patients, and led to complete resolution of enuresis in >50% of patients;[9] however, surgery was ineffective in patients with concurrent obstructive sleep apnea, and associated with continued dependence on desmopressin.[10]


  Management Top


Patients should be counseled that enuresis is common in children. Almost 15% of children may void in sleep at least once a week until they are older than 5 years, followed by spontaneous resolution. Therapy is usually considered if enuresis persists >7 years of age, or when children appear to be able to take responsibility and are motivated to stay dry by night. Patients with psychological distress due to enuresis should receive treatment.[1],[11]

End goals of therapy include reduction in the frequency of wet nights, staying dry on specific occasions (e.g., sleepover, night camps), positive impact on the child and family, and lack of recurrence.[12] The International Children's Continence Society has defined initial and long-term outcomes to assess response to intervention.[2] Initial outcomes categorize the response to intervention as no response or failure to therapy if the frequency of symptoms shows <50% decline from baseline, partial response if the decline is 50%–99%, and complete response if symptoms resolve entirely. A voiding diary is maintained and the frequency of dry and wet nights recorded.[4] Signs of response include fewer wet nights, fewer episodes of bedwetting per night, and a reduction in the size of wet patches.[4] On the other hand, the NICE guidelines define complete response as having achieved 14 consecutive dry nights or at least 90% reduction in the number of wet nights per week, and partial response as improvement that does not meet these criteria.[4] Response is typically evaluated 1–2 weeks after therapy initiation.[2],[4] Signs of early response include reduction in the area of wet patches, awakening after the alarm, fewer early morning voids and alarms, fewer alarms per night, and fewer wet nights.[4]

Long-term outcomes assess the success of therapy as continued success, complete success, and relapse. Relapse is defined as recurrence of more than one symptom per month. A child is said to have achieved continued success if there are no relapses in the 6 months following cessation of therapy, while complete success is the absence of relapses in the two years following therapy cessation. The management is summarised in [Table 2].
Table 2: Summary of drug regimens for nocturnal enuresis

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Urotherapy

Urotherapy includes all nonpharmacological and nonsurgical approaches used to resolve lower urinary tract symptoms. Behavioral therapy is pivotal and should be emphasized adequately before the start of therapy. Behavioral therapy should be tried in children who are 5–7 years old, do not wet the bed every night, and are motivated to take responsibility.[4],[13],[14] Caregivers should ensure that the child voids 4–7 times a day.[11] Caffeinated or sugary drinks should be avoided, especially at night.[11] Fluid intake is reduced in the evening to 20% of the daily intake, while ensuring patients drink 40% each of their total daily fluid intake in the morning and afternoon.[15] Routine use of diapers interferes with motivation and subsequent habit development, and is discouraged.[11] Caregivers should ensure hygiene and regularly clean bedding and clothes.[11] To decrease the distress of bedwetting, caregivers may use bed protection, disposable linen, and washable linen or mattresses.

A systematic review concluded that rewarding children, compared to no treatment or control interventions, is associated with fewer wet nights (mean difference 4.6 per week; 95% confidence interval [CI] 2.9–6.4) and higher rates of complete response, i.e., 14 consecutive dry nights (32% vs. 19%).[13] However, the review was limited by the inclusion of smaller and fewer studies and inclusion of comparisons of dissimilar interventions. Initially, small rewards should be given on counseled behavior like going to the toilet before bedtime, and larger rewards are reserved for prolonged dry periods.[4] In order to reinforce good behavior, rewards are increased as and when child shows gradual improvement. These rewards should be according to child's preferences and be discussed beforehand. Punishment is associated with poor outcomes and is discouraged.[2],[4] Surveys indicate that punishment turns into physical abuse in 1 out of 4 cases.[16],[17] Hence, penalizing, and negative reinforcement through removal of previously gained rewards, is discouraged.[18]

Enuresis alarm therapy

Enuresis alarms work through the mechanism of positive punishment, which is based on the principle of gradual removal of aversive consequence on achieving desired behavior [Textbox 1]. Alarm therapy is useful only if the child is motivated and is arousable by sound or touch.[19] Alarm therapy is generally recommended in children >6 years old.



In early responders, the goal of therapy is to achieve full response by 12–16 weeks (range 5–24 weeks).[4],[20] After 3 months of alarm therapy, therapy is continued in patients with partial response;[4] however, a diagnosis of refractory enuresis is made in patients showing no improvement. Alarm therapy is re-initiated in children who relapse on therapy discontinuation.[4] Children who fail to show early response may be candidates for combination therapy with low-dose desmopressin and alarm therapy. Alternatively, alarm therapy can be reconsidered 6–12 months later when the child is more mature.

A lack of response in alarm therapy is attributed to failed arousal and higher wake thresholds. A modified approach may be used, with a prerecorded code along with an alarm. The premise is that if the child remembers the code word used after switching off the alarm, and can recall it the next morning, the child has higher levels of arousal and thus, better conditioning. However, in one study, complete response was observed in 54% (95% CI 47%–61%) patients on coded alarm therapy versus 47% (95% CI 40%–55%) on simple alarm therapy (P = 0.22).[21] Combining positive reinforcements through rewards along with alarm therapy is associated with higher response rates than alarm therapy alone (92% vs. 72%).[18] Negative reinforcement or giving penalties is counter-productive.[8],[20],[22]

A meta-analysis of 15 studies in patients with monosymptomatic nocturnal enuresis concluded that alarm therapy is superior to desmopressin on per per-protocol analysis, in terms of higher proportions with > 50% reduction in wet nights (odds ratio [OR] 1.53; 95% CI 1.05–2.23) and sustained response (OR 2.89; 95% CI 1.38–6.04), and lower rates of relapse (OR 0.25; 95% CI 0.12–0.50).[23] However, approximately 30% of patients discontinue alarm therapy owing to failure to wake up, skin irritation, and/or disturbance to family members.[24],[25] Hence, alarm therapy is associated with high drop-out rate compared to desmopressin, and on intention-to-treat analysis, therapy with alarm or desmopressin was associated with similar proportions of patients with >50% reduction in wet nights.[23]




  Pharmacological Treatment Top


Desmopressin

Nocturnal enuresis is associated with insufficient increase in nighttime release of ADH as compared to nonenuretic healthy subjects. Hence, vasopressin analogs have been tried as therapy, chiefly as DDAVP, which is available as an orally disintegrating lyophilizate (melt), solid tablet, and nasal spray. The nasal spray is avoided as it is associated with hyponatremia. In one meta-analysis, 47 of 54 cases of desmopressin-induced hyponatremia were with intranasal administration.[26]

Older age appears to be an independent positive response predictor for desmopressin therapy,[22] with patients between 6 and 7 years old being most responsive. The functional bladder capacity (FBC) at baseline was higher in responders than nonresponders (82% ± 22% vs. 56% ± 20% of the predicted bladder capacity for age; P < 0.001).[27] The best results with desmopressin were in children with nocturnal polyuria (nocturnal urine production >130%).[22] In a study of 103 patients with monosymptomatic enuresis, all patients with nocturnal polyuria on 3 out of 5 nights responded to desmopressin,[28] and a maximum voided volume >103% of FBC predicted response to desmopressin with high sensitivity (78.8%) but low specificity (47.5%).[28] Patients with low bladder capacity (MVV ≤70% of the estimated bladder capacity for age) are unresponsive to desmopressin therapy.[29] Prolonged therapy (≥3 months) is a predictor of good response. In one study, the ratio of baseline plasma copeptin levels in day/night was 120 among responders and 240 in nonresponders (P = 0.02), and can therefore be used as a pretreatment response predictor.[30] While the baseline day/night ratio of urinary aquaporin 2 did not differ significantly between desmopressin responders and nonresponders; there was a significant change in aquaporin 2 day/night ratio between baseline to complete remission among responders (P = 0.0004).[30]

The ICCS recommends assessing response to desmopressin within 1–2 weeks of starting therapy.[2] In responsive patients, treatment is usually continued for 3 months after achieving response. Therapy with desmopressin is typically given for 3–6 months and then, tapered as per response.[19] A meta-analysis of 4 randomized controlled trials (RCTs) concluded that structured withdrawal was associated with reduced risk of relapse compared to abrupt withdrawal (pooled RR 1.38; 95% CI 1.17–1.63; P = 0.0001). Tapering the dose is associated with higher rates of sustained response than increasing the interval between doses (pooled RR 1.48; 95% CI 1.21–1.80; P = 0.0001).[31] However, one study on MELT did not find any difference between abrupt and structured withdrawal.[32] After 3 months of therapy, desmopressin is withdrawn for 1 week to check for relapse.[2],[4] In case of relapse, the therapy to which the child had responded previously is reinitiated. In children who relapse frequently upon stopping desmopressin, the dose is gradually tapered.

While adverse effects are rare, therapy with desmopressin carries risk of water intoxication leading to hyponatremia and seizures, especially in patients with high fluid intake. Hence, the evening intake of fluid should be ≤200 ml, there should be no intake during sleep hours.[11],[33] Fluid intake should be reduced between 1 h before to 8 h after the dose of desmopressin.[11] Routine measurements of blood pressure, serum electrolyte levels, and urine osmolality is not indicated during oral desmopressin therapy.[4] However, desmopressin should be discontinued during episodes of electrolyte imbalance like diarrhea, vomiting, or fever.


  Therapy for Refractory Enuresis Top


Anticholinergic agents

Nocturnal enuresis that is refractory to desmopressin (with or without alarm therapy) and is associated with significant nocturnal bladder instability (due to detrusor overactivity) or day-time incontinence is an indication for anticholinergic therapy.

Pretreatment response predictors for anticholinergic therapy for monosymptomatic nocturnal enuresis have not been determined clearly. One RCT found that bladder volume wall index (BVWI), calculated as bladder volume index by mean bladder wall thickness,[34] might predict response to anticholinergic treatment [Table 1]. In one study, patients were categorized into three groups based on BVWI measurements as group 1 (BVWI <70%), 2 (BVWI 70%–130%), and 3 (BVWI >130%). These patients were treated with oral desmopressin with oxybutynin (Group 1), oral desmopressin (Group 2), and oral desmopressin with double-voiding technique and scheduled voiding (Group 3).[35] Rates of complete response were 70%, 25%, and 20%, respectively (P < 0.05), indicating that oxybutynin monotherapy may suffice in patients with low BVWI.[35]

Another RCT found that patients responsive to oxybutynin had lower forced FBC than those responding to desmopressin (71% ± 25% vs. 88% ± 43%; P < 0.01).[36] Monosymptomatic enuresis associated with low bladder volumes for age tends to respond to oxybutynin.[36] Rates of complete or partial response are higher for a combination of desmopressin and oxybutynin than desmopressin alone (45% vs. 17%; P < 0.01).[37] A meta-analysis of four RCTs including 177 children with enuresis concluded that combination therapy of desmopressin with an anticholinergic agent is associated with higher response rates than desmopressin monotherapy in both treatment-resistant patients (RR 3.77; 95% CI 1.32–10.77) and treatment-naive ones (RR 1.74; 95% CI 1.20–2.52) and was well tolerated.[38] One RCT reported that combination therapy is also cost-effective. Overall, while combination therapy is better than desmopressin in both treatment-naive and refractory cases, combination therapy is not recommended as a first-line strategy since data is limited to few studies.[38]

Tricyclic antidepressants

There is some evidence to suggest that the combination of tricyclic antidepressants (TCA) and desmopressin or anticholinergic agents is beneficial in refractory cases. A meta-analysis found lower rates of failure to achieve full response in patients receiving the combination of imipramine and desmopressin compared to those on desmopressin monotherapy (15% vs. 40%; RR 0.38; 95% CI 0.17–0.83; 1 trial, 86 children).[39] Similarly, imipramine-oxybutynin combination had lower rate of failure to achieve full response than imipramine alone (48% vs. 74%; 1 trial, 63 children).[39] However, the combination of TCA and alarm therapy was no better than alarm therapy alone, the combination of alarm and desmopressin, or alarm-nortriptyline combination.[39] The addition of TCAs to behavioral therapies was not associated with better response rates.[39] Therapy with low-dose imipramine with synergistic uroselective anticholinergic solifenacin was associated with fewer wet nights as compared to placebo (<0.001) and was not associated with any serious adverse effect.[40]

As TCAs may have severe adverse events, they should be reserved for enuresis refractory to desmopressin and alarm therapy. The response to imipramine should be assessed after 1 month, and on achieving full response, the dose should be tapered to a minimum effective dose. Imipramine should be discontinued for 2 weeks after therapy for 3 months to decrease tolerance risk.

Other drugs

Drugs used in the treatment of ADHD, including atomoxetine and clonidine, have been tried in the treatment of children with enuresis. In one RCT, the additional use of clonidine was associated with partial or complete response in 56.1% of 148 patients refractory to alarm therapy, desmopressin, and anticholinergic therapy.[41] In another RCT on 87 patients with enuresis, therapy with atomoxetine was associated with reduction in symptoms by two wet nights per week, compared to placebo (P = 0.042).[42] The selective norepinephrine reuptake inhibitor, reboxetine, was associated with response in 4 of 18 patients with enuresis when used as monotherapy (P = 0.002).[43] Carbamazepine, an antiepileptic which is chemically similar to imipramine, increases bladder capacity and sensitizes renal tubule cells to ADH. In one study, therapy with carbamazepine was associated with 18.8 ± 8.8 dry nights per month compared to 3.9 ± 5.5 dry nights with placebo (P < 0.001).[44] A systematic review comparing drug therapies other than desmopressin and TCA found indomethacin, diclofenac, and diazepam to be better than placebo, but not comparable to desmopressin, in reducing the number of wet nights.[45]

Newer approaches

Patients with enuresis may have deranged melatonin profile. In a pilot study of 24 patients, exogenous melatonin supplementation was shown to improve melatonin levels but did not influence the number of wet nights.[46] Nocturnal enuresis is shown to be associated with insufficient levels of vitamin D and omega-3. In a double-blinded RCT, daily supplementation of Vitamin D (at 1000 IU/day), omega-3 (1000 mg/day), and both supplements was associated with cure rates of 44.4%, 28.2%, and 45%, respectively.[47] Therapy with fluvoxamine for anxiety associated with enuresis was found to be safe and effective. Using urinary 17-hydroxycorticosteroids and 17-ketosteroid sulfates as barometers of stress, fluvoxamine was shown to be effective in 93% of patients with stress, and 50% of children without stress.[48]

Laser acupuncture is proposed as a noninvasive and painless technique to improve urodynamic parameters in children with NE. Laser acupuncture is associated with superior cure rates and lower recurrence rates as compared to desmopressin at 3 months (P = 0.002). Extracorporeal magnetic innervation to strengthen the pelvic floor was found useful in refractory enuresis; the mean FBC increased 1.9 times and the frequency of awakening increased to 2.1 times.[49] In a group of 58 patients, transcranial magnetotherapy improved the inactivity of the subcortical nervous center in 24% of children.[50] Therapy increased volume of bladder 1.9 times, decreased urinary frequency 1.7 times, and voiding symptoms 1.3 times compared to placebo.[50]

Acknowledgment

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