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Introduction

  1. Top of page
  2. Introduction
  3. Understanding of nocturnal enuresis
  4. Monitoring progress
  5. Preventing relapse
  6. Conclusion
  7. Acknowledgements
  8. Authors

Nocturnal enuresis (NE) is a multifactorial condition with various aetiologies [1,2]. There are compelling arguments in favour of offering treatment for children who wet the bed beyond 7 years of age. NE is remarkably prevalent in childhood, with 9–13% of 9-year-olds and 1–2% of adolescents and young adults still affected by the problem [3]. Children may become socially isolated, emotionally distressed and have a low self-esteem as a result of enuresis [4–6]. An improvement in psychological functioning, including self-esteem, has been reported after successful treatment [6,7]. Although most parents are supportive, there is a significant number, reportedly up to 30%, who become intolerant towards the NE and their child [8,9]. Finally, the cost of enuresis can have a marked effect on the family economy and therefore treatment of this condition cannot be ignored [10].

Understanding of nocturnal enuresis

  1. Top of page
  2. Introduction
  3. Understanding of nocturnal enuresis
  4. Monitoring progress
  5. Preventing relapse
  6. Conclusion
  7. Acknowledgements
  8. Authors

The ‘three-systems’ model, comprising three causes of NE (low arginine vasopressin, AVP, bladder instability and lack of arousal from sleep) has been proposed to offer a better understanding of NE and enhance the possibility of selecting the most effective treatment for the child or young person [2]. Current treatment modalities generated from the three-systems model suggest using desmopressin to supplement a lack of AVP release, bladder training exercises coupled with oxybutynin for bladder instability, and the enuresis alarm to encourage the child to wake in response to full bladder sensations. The following variables are important when considering the most appropriate treatment for any given child.

Selecting effective treatment interventions

Alarm therapy is proclaimed to be amongst the most effective interventions for treating childhood NE. Several reviews of studies, using unselected populations of children with NE, report success rates of 65–70%, with a treatment duration of 5–12 weeks and stated relapse rates of 15–30% in the 6 months after treatment [11–13]. Furthermore, there appears to be no difference between types of enuresis alarm (bed or body-worn) in terms of success rates [14].

Controlled studies report that desmopressin is effective in the immediate cessation of wetting [15–18], whether administered nasally or orally [19]. Moffatt et al.[20] comprehensively reviewed many published papers on randomized clinical trials of desmopressin and found, compared with placebo, that desmopressin was significantly better in 13 of the 14 studies. With a more selected population of children with primary NE, Caione et al.[21] found a 79% success rate after the administration of desmopressin. Devitt et al.[22] showed that the response to desmopressin was closely related to the level and variability of AVP. The treatment was successful in children who had suboptimal levels of AVP and unsuccessful in children with either normal or very low levels of AVP.

Oxybutynin, when used with no bladder training exercises and in unselected populations of children with NE, has not been effective in randomized controlled studies [23]. However, recent work suggests that oxybutynin is effective in reducing unstable bladder contractions and increasing the urine volume at first desire to void [24]. In more selected groups of children with bladder instability as a cause of their NE, Watanabe et al.[25] claimed a 67% success rate with oxybutynin; Kass et al.[26] reported a 90% success rate and in a study of dose escalation, Kosar et al.[24] reported complete success after administering 15–20 mg oxybutynin in a selected group of 17 children.

Comparisons between pharmacological intervention and alarm treatment have been difficult because of different philosophical goals [27]. Behavioural interventions, e.g. alarm treatment, have typically sought to encourage the cessation of wetting, with the criteria for success based on consecutive dry nights [28], whereas pharmacological treatment has emphasized managing the enuresis and aims to reduce the frequency of wetting [1].

Linking treatment to the child's needs

Some have argued that the type of treatment intervention advocated should be based on the cause of the child's NE [2]. An appropriate assessment will highlight which of the three systems is affected; thus desmopressin is a logical treatment for low AVP release, oxybutynin plus bladder training for bladder instability and the enuresis alarm when the child indicates the potential to wake from sleep [2].

Where children appear to have difficulty in more than one of the systems, combined therapy (using more than one treatment intervention) might reasonably be considered. Butler reviewed the methodological issues associated with combined treatment [29]. The most common combined cause of NE is lack of AVP plus a lack of arousability.

Three studies reported on combined desmopressin and the enuresis alarm on unselected groups of children. Sukhai et al.[30], with a crossover design, randomized children into two treatment groups, i.e. alarm plus desmopressin (A+D) or alarm with placebo (A+P). The results suggested that A+D was better (P = 0.05) than A+P in treating NE. However, the sample population was both small (28 children) and not homogeneous (29% of the children having learning difficulties). However, the most problematic methodological issue was the treatment duration. Children were only treated for 2 weeks before crossover, which is sufficient time to assess the effect of desmopressin but clearly insufficient to test the effectiveness of the alarm, as 5–12 weeks has been suggested as the mean treatment duration with an enuresis alarm [11,12]. Thus treatment success in the A+D group was arguably caused by a response to desmopressin, whereas insufficient duration of treatment in the A+P group must have contributed to the failure rate in this group.

Bradbury [31] randomly allocated 71 children to either the alarm plus desmopressin (40 µg) or alarm monotherapy for 6 weeks; the combined therapy was more effective than the alarm alone, particularly where the child had severe NE and behavioural problems. However, the samples were not homogenous for severity, as before allocation 20% were dry more than four times per week, which raises questions about treatment eligibility. Furthermore, no information was provided on the rates of primary/secondary, non-mono or monosymptomatic NE, diurnal enuresis, previous alarm therapy or parental intolerance. The absence of a placebo suggests a lack of methodological equivalence, with the combined group receiving a more ‘enhanced’ treatment package than the alarm monotherapy group.

Leebeek-Groenewegen et al.[32], in a double-blind placebo-controlled study, examined 93 children with monosymptomatic NE. Children were allocated to treatment with alarm plus desmopressin 40 µg (A+D) or alarm plus placebo (A+P) for 9 weeks. During the treatment period the desmopressin dose was titrated three times (40, 20 and 0 µg). There were significant differences between the groups only at 3 weeks, which suggests that the effect was largely the result of desmopressin rather than the combination. The response rate over 9 weeks suggested that two separate treatment effects could account for the results. In the A+D group the immediate reduction in the number of wet nights, which reached a plateau, is a typical treatment response with desmopressin, whereas with A+P the profile showed a gradual reduction in the number of wet nights through to week 9, a response suggestive of alarm treatment. Although the study used unusual success criteria (cure defined as geqslant R: gt-or-equal, slanted90% reduction and success as geqslant R: gt-or-equal, slanted50% reduction) the authors concluded that desmopressin does not result in higher cure rates and that combined treatment is not justified in all enuretic children from the outset of treatment.

These studies suggest that the success with combined alarm plus desmopressin is caused by the desmopressin intervention and not the combination. It might be argued that when a child is responsive to desmopressin the alarm becomes redundant, as it will not be triggered. Using combined treatment without first assessing the cause in terms of the three systems [2] may be considered inadvisable, and potentially overloads both child and parents with unnecessary treatment interventions.

A more appropriate combination theoretically might include anticholinergic medication plus desmopressin, where bladder instability and a lack of AVP are indicated [33]. Two studies report the effectiveness of such a combination [34,35]. An Italian multicentre trial reported significantly more success with oxybutynin plus desmopressin (79%) than with oxybutynin monotherapy (54%), where children had NE with daytime urgency and frequency [35]. The study concluded that the reduced urinary output and bladder filling, as a consequence of desmopressin, decreased the onset of uninhibited bladder contractions and thus enhanced the effect of oxybutynin.

Understanding the treatment rationale

The perceived mode of action of desmopressin is in mimicking AVP through reducing urine production and increasing urine concentration, and as such desmopressin has been construed as a replacement or supplementation. Hansen and Jorgensen [36] confirmed this by finding reduced night-time urine production during desmopressin treatment. However, some work suggests that desmopressin has an additional effect, i.e. in increasing arousability. Lackgren et al.[37] found that > 70% of individuals treated with desmopressin became dry by waking from sleep to void. This raised the question as to whether, by reducing urine volume, desmopressin shifts the point at which the bladder becomes full to the early morning, when arousal from sleep is easier for the child [38].

Interestingly, the mode of action of the alarm is ill understood, but several explanations have been suggested:

  • An increased expectation of success [39].

  • Alteration of social reinforcement to a point close to the wetting [40].

  • ‘Avoidance conditioning’, whereby the child seeks to avoid the unpleasantness of the noise by spontaneous waking or by contraction of the pelvic floor muscles [41].

  • Increased functional bladder capacity [42].

  • Increased production of AVP in response to the stress of waking to the alarm, which might explain why ≈ 80% of children who become dry with the enuresis alarm are able to sleep through the night [43].

  • A conditioned response whereby waking after urination serves as an unconditioned stimulus, whilst the ‘startle response’ of pelvic floor contractions which stops urination is the unconditioned response. With repeated triggering, it is argued, the alarm produces a conditioned response of inhibition of urination in the presence of detrusor contractions during sleep [44].

Acceptability of treatment

With oxybutynin the reported side-effects include dry mouth, constipation and, in some individuals, flushing [24]. With desmopressin there are very few side-effects reported [18,45,46]. Klauber [47] reported no serious adverse reactions in 516 cases. In an exhaustive review of randomized clinical trials of desmopressin, Moffatt et al.[20] found that eight of the 18 studies reported no side-effects. Headaches were reported in four children (of a total of 689) and stomach ache in three. Even during long-term treatment with desmopressin, side-effects are rarely reported [19,48,49]. However, there are rare reported cases of hyponatraemia with desmopressin treatment [50]. Robson et al.[51] reviewed 11 case reports and found excess fluid intake contributed to six cases. They suggested that to prevent hyponatraemia, children should be encouraged not to drink > 240 mL on any night that desmopressin is taken.

A primary concern with alarm therapy is parental intolerance [8,39]. Several parents become angry, annoyed and intolerant of bedwetting, particularly with an older child and where the family are functioning under stress. Parents often seek to blame their child, believing the bedwetting is somehow under their control, and resort to punitive means of coping. Up to a third of parents resort to punitive measures in seeking to cope with the problem [8,9,52].

There is ample evidence indicating a close association between parental (usually maternal) intolerance and discontinuation or early withdrawal from alarm treatment [53–55]. Enuresis alarms are time-consuming and complicated to set up, notoriously temperamental, tend to disrupt the sleep of everyone in the household and often take weeks of use before there are positive signs of progress. Alarms therefore potentially increase parental annoyance and may place the child at greater physical and emotional risk [39].

Considering pretreatment predictors of outcome

An understanding of the variables under which a treatment is likely to succeed or fail is an important clinical tool; it improves the choice over available treatment options and enhances the likelihood of success [56]. Moffatt and Cheang [57] also argue that research design should incorporate known prognostic indicators to ensure comparison groups are matched against variables known to enhance success or increase failure rates across treatment interventions.

Pre-treatment predictors of success for desmopressin include:

  • The older child [58–62].

  • Less severe NE in terms of number of wet nights/week [58,63,64].

  • Normal functional bladder capacity [61,62,65–67].

  • Primary as opposed to secondary NE [20].

  • When enuretic incidents occur during the first 2 h of sleep which may reflect an increase in urine production due to lack of vasopressin release [66].

  • Where there is a family history of NE [35,68]. Hogg [68] defined a family history broadly, as any family member (including aunts, uncles and cousins) who had persistent enuresis beyond the age of 6 years, and found a positive family history in all desmopressin responders, with only 43% of those not responding having a positive family history. However, Hogg and Husmann [69] found a more striking discrepancy, with a 91% response to desmopressin in patients with a family history and only a 7% response in those with no family history. However, other studies have failed to find such a relationship [62,65,70–72].

  • Increased urine volume at night [73,74]. Rittig et al.[73] found patients who responded to desmopressin were able to reduce urine volume at night to the same as that of other children.

  • Increased urine production during the day [66].

  • Less concentrated urine during the day [66].

  • Frequent daytime micturition [62].

  • Increased birth-weight [63].

  • Higher dose [16,47,58,75].

Pre-treatment predictors with the enuresis alarm include:

(i) Discontinuation or early withdrawal from treatment when there is evidence of:

  • Parental intolerance and annoyance [53–55].

  • Children with low self esteem [76].

  • Children with behavioural problems [77].

  • Family history of bedwetting [78].

(ii) Failure is likely to occur:

  • When the bedwetting is severe before treatment & [57].

  • There is multiple wetting at night [57].

  • Children lack motivation or concern about the problem [79,80].

  • Children are perceived to have behavioural problems [57].

  • Children have a developmental delay [81].

  • Children have associated daytime wetting [82].

  • When the living conditions are unsatisfactory [83], although others, using a similar format for assessing housing and living conditions, failed to find such a relationship with alarm failure [80].

  • When there are family difficulties, disharmony and stress [80,83]. This refers to families where both natural parents are not present; marital discord with threatened or past separation; ‘other’ family disharmony; serious ‘handicap’ with parent or child; parental mental illness; bereavement in the family; and serious financial difficulties.

  • Parents adopt punitive reactions to the child's bedwetting [57].

  • There is previous lack of success with the enuresis alarm [82].

  • If the child voids early in the night when it is more difficult to arouse from sleep [38].

  • When maternal education is poor [57].

  • With higher socio-economic status [57].

To date, there are no reported pretreatment predictors with bladder training and anticholinergic medication.

Offering treatment choice

The importance of inviting children to choose the type of enuresis alarm (bed or body-worn), when this is considered to be the most appropriate treatment intervention, is being acknowledged clinically [14]. However, recent work suggests the importance of choice across the broader spectrum of treatment modalities. Monda and Husmann [71] undertook an intriguing study where children with NE chose the mode of treatment. Using a very strict success criterion (0–1 wet night/month) they found a 68% response with desmopressin, compared with a 32% response to imipramine and 63% with the enuresis alarm.

Using effective treatment adjuncts

Many behaviourally designed interventions have been used with the enuresis alarm. A fundamental principle might suggest that for an adjunct to be recommended it should add to the effectiveness of the alarm. In their exhaustive review, Houts et al.[27] failed to find support for the idea that adding behavioural procedures to alarm treatments improved overall effectiveness, yet later Houts [44] suggested that the incorporation of selected behavioural procedures tended to produce better outcomes than alarm monotherapy.

The most effective behavioural procedures include:

Arousal training which involves reinforcing appropriate behaviour (waking and toiletting) in response to alarm triggering. The aim of arousal training is to reinforce the child's rapid response to the alarm triggering, not on ‘learning to keep the bed dry’. van Londen et al.[84] reported a 98% success rate within 6 weeks with low relapse rates, finding 73% of children remained dry after 2.5 years.

Normalized voiding involves encouraging children to increase their fluid intake and void regularly during the daytime at predetermined times (e.g. 2-hourly or break times at school). In an attempt to increase cognitive control over voiding, Kruse et al.[85] reported 78% success in overcoming bedwetting, and when combined with the alarm a success rate of 80%, increasing to 100% when combined with desmopressin.

Dry bed training incorporates the enuresis alarm; positive practice (mass practice of waking); cleanliness training (encouraging the child to take responsibility for removing wet sheets and re-making the bed); and two waking schedules to ease arousability from sleep [40]. High success and low discontinuation rates have been reported, although relapse rates are no different to alarm treatment [86]. Modifications have been advocated to remove some of the more punitive elements of the programme [55]; nonetheless it remains a complex, time-consuming and demanding procedure. Hirasing et al.[87] reported 80% success with group-administered dry-bed training, with girls responding better than boys. Although most parents were satisfied with the programme the opinions of the children were divided.

An important component analysis by Bollard and Nettelbeck [86] found the enuresis alarm accounted for most of the success achieved through dry-bed training. They suggested that a large proportion of the components of the procedure could be eliminated without sacrificing much of its overall effectiveness, and that the waking schedule, coupled with the enuresis alarm, was as effective as the complete dry-bed training programme.

Whelan and Houts [88] failed to substantiate this finding; they found that adding the waking schedule to their full-spectrum home training did not improve effectiveness, either in terms of the number becoming dry, speed of response or reduction in numbers of patients who relapsed after treatment. They cogently argued that this result does not suggest that the waking schedule is redundant, but that it may be useful only for certain individuals.

Monitoring progress

  1. Top of page
  2. Introduction
  3. Understanding of nocturnal enuresis
  4. Monitoring progress
  5. Preventing relapse
  6. Conclusion
  7. Acknowledgements
  8. Authors

The efficient recording of progress should enable the clinician to notice responsiveness to the treatment method quickly, even if the child is not immediately achieving dry nights. Recording progress should also enable the clinician to inform the child as to how he or she is improving. A progress chart, devised around the three-systems model, enables this [89]. For each night, irrespective of the treatment modality, the child is asked to record one of four events:

  • Dry by sleeping through, which indicates vasopressin release;

  • Dry by waking to toilet, which indicates arousability;

  • Waking after a wetting episode, which suggests the child is responding to the alarm (if used);

  • Discovery of the wet bed in the morning, which indicates both a lack of AVP and arousability.

Preventing relapse

  1. Top of page
  2. Introduction
  3. Understanding of nocturnal enuresis
  4. Monitoring progress
  5. Preventing relapse
  6. Conclusion
  7. Acknowledgements
  8. Authors

The relapse rate with alarm treatment is ≈ 30% and with medication, immediate and almost total relapse is inevitable [17,71]. Over-learning has been advocated as a method of preventing relapse with the enuresis alarm. It is designed to strengthen the detrusor muscles, and increase the bladder's maximum functional capacity, through gradually increasing night-time drinking in the last hour before bed, up to a maximum of 500 mL. Any increased wetting is construed as an opportunity for additional learning trials. Morgan [90] advocated over-learning at the point at which the child achieves the dryness criteria, although others begin the process at the start of alarm treatment [88]. Over-learning has been found to reduce relapse by 10–12% [44,90].

With desmopressin, a gradual reduction of dose has been advocated, yet it takes a long time (up to 3 years) and at best only half the children will remain dry [46]. The problem appears to be that in becoming dry the child attributes success to the treatment (alarm or medication) and in effect externalizes the success. Thus, removing the alarm or medication removes what the child believes to be the reason for success, and relapse consequently follows. Recently, Butler et al.[91] reported an 8-week withdrawal programme specifically designed for preventing relapse on removal of medication. The programme focuses on engaging the child in a process of internalizing success and highlighting the effective process by which this is accomplished, whether it be increased arousability or improved AVP release. Results using this programme suggest that ≈75% of children remain dry on completing the programme.

Conclusion

  1. Top of page
  2. Introduction
  3. Understanding of nocturnal enuresis
  4. Monitoring progress
  5. Preventing relapse
  6. Conclusion
  7. Acknowledgements
  8. Authors

Nocturnal enuresis is a distressing experience for children and young people, and successful treatment invariably improves their psychological functioning. A key clinical issue concerns the importance of ensuring that treatment interventions are effective. This paper reviews a series of variables as a framework for consideration when clinical decisions about treatment for NE are made.

There are few demonstrably effective interventions for NE; with unselected samples of children with NE, the enuresis alarm has good success rates. In more selected populations pharmacological therapy is beginning to reach equivalent success rates. There is good evidence for differentiating treatment according to the child's needs. The three-systems model [2] is useful in this regard, suggesting desmopressin for low vasopressin release, oxybutynin coupled with bladder training for bladder instability, and the enuresis alarm to enhance arousability from sleep.

Combined therapy is limited to those individuals who have difficulties with all three systems. Desmopressin coupled with oxybutynin is successful with those who have low AVP release, bladder instability and who are unable to wake to bladder signals. As yet there are no studies examining the combination of alarm and oxybutynin. There is no good evidence for combining desmopressin with the enuresis alarm and there are theoretical objections to such an approach.

Many adjuncts to the primary treatment intervention, usually the alarm, have been described and two intensive programmes (dry-bed training and home-spectrum training) incorporating many behavioural procedures, have been developed. The only effective adjuncts that enhance the alarm are arousal training and scheduled waking, both of which seek to improve waking to full bladder sensations, and both need replication. Normalized voiding, which aims to improve bladder instability, has enhanced desmopressin treatment in a small sample and again requires replication before its potential can be accurately assessed.

There are several findings about pretreatment factors and their effect on outcome. Many need replication but those links which consistently emerge include early discontinuation from alarm treatment when the parents react intolerantly to the child's wetting, and enhanced success with desmopressin in older children, those with less severe enuresis and those with a normal functional bladder capacity. There are as yet no investigations of pretreatment factors with oxybutynin. Awareness of such factors can lead to improved decision making over treatment for any particular child or young person.

A full explanation of the treatment process, including possible side-effects and sleep disruption, will enable both parents and children to determine acceptability. Informed choice has been shown to be important in influencing treatment compliance and success rates [71]. During treatment some method of monitoring progress has anecdotally and generally been regarded as important. An understanding of spontaneous waking, time of alarm triggering, functional bladder capacity and dry nights by sleeping through the night, enables the clinician to both feed back to the child which of the three systems are developing, and help to unravel the mode of action of each treatment intervention.

Finally, relapse is a problem with both desmopressin and alarm treatment. Arguably the most crucial measure of treatment effectiveness concerns how many children remain dry once the treatment is discontinued. Over-learning has reportedly been effective in reducing relapse with the alarm, although this requires replication. A structured withdrawal programme is showing promise in reducing relapse rates with desmopressin. The important issue in maintaining dryness, once either the alarm or desmopressin is discontinued, revolves around encouraging the individual to attribute the success to themselves, rather than to the treatment process.

The identification of the principles that influence the effectiveness of treatment can assist the clinician in developing interventions to suit the individual's particular circumstances and consequently enhance the likelihood of success.

Acknowledgements

  1. Top of page
  2. Introduction
  3. Understanding of nocturnal enuresis
  4. Monitoring progress
  5. Preventing relapse
  6. Conclusion
  7. Acknowledgements
  8. Authors

This work was undertaken with the support of Leeds Community & Mental Health NHS Trust.

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Authors

  1. Top of page
  2. Introduction
  3. Understanding of nocturnal enuresis
  4. Monitoring progress
  5. Preventing relapse
  6. Conclusion
  7. Acknowledgements
  8. Authors

R. Butler, PhD, Consultant Clinical Psychologist.

A. Stenberg, MD, Associate Professor.

Abbreviations
NE

nocturnal enuresis

AVP

arginine vasopressin.

R.J. Butler, Department of Clinical Psychology, High Royds Hospital, Menston, Nr Ilkley, Leeds LS29 6AQ, UK.e-mail: drbutler-lcmh@cwcom.net