Approach
Initial management includes educational, behavioural, and lifestyle measures. This may be followed by additional treatments aimed at improving arousal thresholds, and/or matching nocturnal urine production to bladder storage capacity.
Education, motivation, and lifestyle changes
Usually children under 7 years of age are not actively treated, and the family is reassured. Active management is offered for children ≥7 years. It is very important that the family and patient are willing participants in what is likely to be a long treatment course. Education on the natural history of the disease is also important, emphasising that resolution occurs at a rate of 5% to 10% per year.[1] From this point on, the patient must be supported emotionally and encouraged when positive progress is made, but not embarrassed or punished for any set-backs. A star chart recording the patient's days and nights of dryness with a star or reward can be useful.
Regular voiding habits must be developed for the daytime, as well as instructing the patient to limit the amount of fluid intake, specifically caffeinated fluids, in the hours before sleep; this can be supplemented by voiding immediately before bed. These educational, behavioural, and lifestyle measures continue, even if other therapies are commenced.
Bladder training therapy (urotherapy) may be used as part of these initial behavioural measures. It involves a combination of education, rigorous scheduling of diet and voiding habits, and psychological support. It is most helpful in children who show signs and symptoms of daytime voiding dysfunction such as urgency, frequency, or infrequent voiding. The child is shown that they can take control of their bladder and that by doing this they can avoid the night-time accidents. This should be done under the supervision of a trained urotherapist and has been shown to cure bedwetting in up to 90% of appropriately selected patients.[32] With such a high success rate, some have proposed that all enuretic children start their therapy with bladder training before any pharmacotherapy or alarm regimens. This has yet to be studied rigorously and its wide use is still considered investigational.[33]
There have been historical recommendations for lifting or taking the child to the toilet during the night to void to pre-empt enuresis; however, this has poor efficacy in resolving the underlying enuresis. It may temporarily solve the problem and keep bedding dry until the child grows out of enuresis spontaneously.
Evaluation and treatment of other conditions
Many of these children will also have constipation, and by resolving this alone as many as 60% of children will see their enuresis improve.[34] Any signs or symptoms of upper airway obstruction should be evaluated, and if appropriate, the patient referred to the ear, nose, and throat department or a sleep-disordered breathing specialist.
Treatments
Initial therapy (after educational, behavioural, and lifestyle measures have been employed) is alarm therapy. An enuresis alarm is a device that makes a loud sound or vibrates as soon as a moisture sensor detects a small amount of urine. This rouses the sleeping child so that he or she can be walked to the toilet to urinate. This treatment is the best studied of all therapies for nocturnal enuresis, and the literature shows a significant increase in bladder capacity in these patients after alarm treatment.[35]
The data for success on alarm therapy are strong, with multiple meta-analyses generally concluding that alarm therapy may be more effective than no treatment in reducing enuresis in children and probably has a lower risk of adverse events than desmopressin.[36]
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Signs of successful treatment with alarm therapy may be slow to appear, especially when compared with desmopressin.[37] It is vital that families are told at the outset that alarm therapy needs to be continuous for up to 12 weeks before re-evaluation. Frustration over a lack of immediate success can lead to a high percentage of patients dropping out, thus making analysis of the literature on alarm therapy difficult.[37] The other downside of alarm therapy is that it is socially awkward, especially during overnight events; in this case desmopressin therapy can be used as an adjunct.
Patients who are difficult to rouse may sleep through the alarm and will need a parent to come and wake them and take them to the toilet. If a child does not get up to void every time the alarm sounds, they are not likely to improve with alarm therapy. Alarm therapy is superior to all other therapies as about half of children will have a durable response after therapy is completed.[36] All other therapies have much higher relapse rates.
If alarm therapy is not improving the number of wet nights, desmopressin can be tried before instituting combined therapy, although patients with decreased bladder capacity tend not to respond as well to desmopressin therapy.[38][39]
Desmopressin is the treatment of choice following failure of educational, behavioural, and lifestyle measures alone and alarm therapy. Desmopressin is an analogue of arginine vasopressin (AVP) (also known as anti-diuretic hormone [ADH]) and acts on the V2 receptors in the collecting ducts and distal tubules to take up free water. Nocturnal diuresis in enuretic patients may be related to abnormalities in the nocturnal rise of AVP. The evidence for desmopressin therapy is fairly good but is clouded by variations in the definitions for cure and response throughout the literature.[40][41] Desmopressin is not a panacea, and in non-responders it is best to try other avenues of therapy to achieve a lasting cure. Intranasal desmopressin is no longer recommended in some countries (including the US) due to post-marketing reports of hyponatraemia-related seizures.
If treatment with desmopressin fails despite doubling of the dose, the recommended course of action is to use alarm therapy in combination with desmopressin. The factors predicting a good response to desmopressin are patients with decreased urine concentration, normal-capacity bladders, single episodes of enuresis at night, and prior response to a small dose of desmopressin.[38][42]
For children who have been shown to respond to desmopressin therapy (over the first 8 to 12 weeks of therapy) but who are only concerned about the potential of night-time symptoms occurring while away from home (e.g., while sleeping overnight at a friend's house), desmopressin may be used intermittently for these short periods when the need to be dry at night is considered more important for the child.
In children not responding to alarm therapy, desmopressin, or combination therapy, it is appropriate to investigate the possibility of a nocturnally overactive bladder. Detrusor-relaxing drugs such as oxybutynin or tolterodine are instituted empirically. These should not be used alone but as adjuvant therapy. Tolterodine is not yet approved for children in some countries but has been shown to be effective with few or no adverse effects.[43] Desmopressin plus oxybutynin have been used together in some children with success when oxybutynin alone did not work.
Imipramine is the oldest of the pharmacological therapies for nocturnal enuresis. However, given its adverse-effect profile and the development of better pharmacotherapy, it is not recommended except in specific instances. It is also used for the treatment of ADHD. In patients who are refractory to conventional therapies and have concomitant ADHD, imipramine may be prescribed. The main concerns are suicidality and cardiotoxicity. Because of this adverse-effect profile and its limited efficacy, it should be administered with assistance from colleagues in psychiatry who have more experience with its use. The mechanism of action is unclear but has been postulated to be related to reduction in detrusor activity and increased bladder capacity due to anticholinergic and sympathomimetic activity. Although it is prescribed at lower doses for enuresis than for psychiatric conditions, it can still pose a risk to both the patient and family members who may accidentally come across it.[44][45][46]
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One randomised placebo-controlled trial studied the short-term efficacy of a small dose of fluoxetine to treat children aged 8 to 18 years with no other urinary symptoms, constipation, or neuropsychiatric diagnosis.[47] It found that the group treated with fluoxetine had fewer wet nights when compared with the placebo group at the 4-, 8-, and 12-week marks of treatment. However, efficacy decreased after the 4-week mark and the study was limited to 12 weeks. This intriguing data supports the use of fluoxetine in the treatment of primary monosymptomatic nocturnal enuresis. Further studies may be needed to investigate long-term effects of fluoxetine, if increasing the fluoxetine dosage changes outcome, and if fluoxetine would be beneficial in patients with a neuropsychiatric diagnosis. It would also be worthwhile to see a multi-varied analysis that investigates if there is a change in stooling patterns in patients on fluoxetine as it does have a side effect of diarrhoea. Fluoxetine comes with a warning of suicidality in children, which needs to be considered when trialling with this medication.
Recurrence
With each treatment approach, recurrence is common, but spontaneous resolution does occur at a rate of 5% to 10% per year.[1] Management of recurrence is to reinstate therapy. Only alarm treatment has been shown to have durable effects significantly greater than the background resolution rate of 15% per year after treatment is withdrawn.
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