Approach to nocturnal enuresis in children

Opening Vignette

Ashley, a 7-year-old girl, was attending your clinic for bedwetting. She had never been dry at night before. She did not have any daytime urinary incontinence or frequency. Apart from allergic rhinitis and constipation, Ashley was well. On examination, she was cheerful, but her nasal turbinates were engorged and tonsils were enlarged. Abdominal, genitourinary, spine and neurological examinations were normal. You explored the history of bedwetting and planned to start treatment for allergic rhinitis and constipation.

WHAT IS NOCTURNAL ENURESIS?

Nocturnal enuresis (NE) is a common condition seen in children aged ≥ 5 years and is defined by the occurrence of intermittent incontinence during sleep, at least once a month for a minimum duration of 3 months. Frequent enuresis is defined as more than four times per week and infrequent enuresis as less than four times per week.[1]

Nocturnal enuresis can be classified into (a) monosymptomatic (MNE) or non-monosymptomatic (NMNE), and (b) primary or secondary. The distinguishing factor between MNE and NMNE is the presence of daytime lower urinary tract symptoms (LUTS). Non-monosymptomatic NE involves an underlying bladder dysfunction causing daytime LUTS. Nocturnal enuresis can also be subdivided based on its onset. Children with secondary NE have had a previous dry period of more than 6 months, while children with primary NE have not been dry for more than 6 months.

HOW RELEVANT IS THIS TO MY PRACTICE?

Epidemiology

The estimated prevalence of NE at 5 years of age is approximately 15%. Without treatment, NE typically resolves spontaneously at a rate of 15% per year with persistence at higher ages. The prevalence among teenagers is around 3% and in adults, it is 0.5%–1%.[2,3] The chance of becoming dry without treatment is markedly lower if enuresis is frequent. Enuresis seems to be twice more common in boys, in whom the problem is often more difficult to treat.[4] Primary enuresis is also twice more common than secondary enuresis. Of note, less than 3% of children referred to enuresis clinic have an identifiable organic cause. Such organic causes must be evaluated if history suggests their presence.

Pathophysiology

Nocturnal enuresis tends to run in the family. Up to 75% of affected children have affected first-degree relatives (77% incidence when both parents have NE and 44% incidence when one parent is affected). It is also twice as common in monozygotic twins as compared to dizygotic twins. Two genetic loci on chromosomes 6 and 13 coding for the genes PRDM13, SIM1 and EDNRB have been recently reported. These genes were found to be important in central nervous system (CNS) development, regulation of antidiuretic hormone (ADH), and salt and water homeostasis in the body.[5] Due to clinical and genetic heterogeneity, the presence or absence of enuresis in the child’s family history may sometimes be limited in clinical applicability. The current understanding is that NE is a result of the interplay of the following three factors:[6] (a) nocturnal bladder capacity (nocturnal detrusor overactivity and small functional bladder capacity);[7,8] (b) nocturnal polyuria due to alteration of ADH secretion and response;[7,9] and (c) decreased sleep arousal and maturation delay of CNS.[10]

WHAT CAN I DO IN MY PRACTICE?

Common comorbidities

Constipation can exacerbate NE, but the association is not as strong as between constipation and daytime incontinence. This association is probably due to distortion of the bladder from a full rectum, leading to secondary detrusor overactivity. A child with bladder dysfunction may often have concomitant faecal impaction with or without gastrointestinal symptoms. Treatment of NE should not be started before constipation has been assessed or successfully treated.[11]

Certain urinary tract malformations may cause enuresis. Children with posterior urethral valves can have abnormal bladder function. There may also be concomitant renal tubular damage leading to polyuria and increased intravesical pressure.[12]

Obstructive sleep apnoea (OSA) is also associated with NE. Approximately 50% of enuretic children with sleep-disordered breathing will become dry after undergoing adenotonsillectomy.[13] It has been postulated that OSA results in constant arousal stimuli from the obstructed airways, causing paradoxical high sleep arousal threshold. The negative intrathoracic pressure created during snoring can cause polyuria via increased secretion of the atrial natriuretic polypeptide.[14]

Furthermore, NE can cause significant adverse outcomes on the psychological development of the child and stress on the child’s caregivers. The child is often embarrassed by it, resulting in low self-esteem and poor social adjustments. Affected children also have difficulties participating in outdoor activities like overnight camping and travelling. The chronicity of NE can often lead to resentment and anxiety in parents and other family members. Among children with enuresis, approximately 15% have attention-deficit hyperactivity disorder (ADHD) and vice versa.[15] It has been suggesed that both enuresis and ADHD might be related to delays in CNS maturation. Children with NMNE, secondary NE or therapy-resistant enuresis are at the highest risk for psychosocial comorbidities.

History taking

In the evaluation of NE, detailed history taking to confirm and identify the type of NE is the most important step [Table 1]. The history should focus on the voiding habits and enuresis history. Specific questions about daytime LUTS must be explored, as they imply the presence of NMNE. The critical aspects of history should include the following: (a) general health and development, (b) enuresis history and fluid intake, (c) daytime LUTS, (d) bowel habits, (e) sleep history, and (f) psychological impact.

Table 1.

History taking in nocturnal enuresis (NE).

History	Relevance
General health and development
• Has growth been normal? Was there any nausea or weight loss?	• Renal disease
• Any excessive thirst with polyphagia?	• Diabetes mellitus
• Are there any developmental delays, particularly gross and fine motor?	• Underlying neurological condition
Enuresis history and fluid intake
• How frequent is NE per week?	• Nightly NE is associated with poor prognosis
• Are there changes in the frequency of NE over time?	• Natural history of NE is spontaneous resolution
• Has there been a prolonged dry period beyond 6 months?	• Secondary NE is more often associated with psychological comorbidities
• What is the overall and type of fluid intake and the relation of fluid intake to the time of day?	• Timing of fluid intake (increased afternoon or evening fluid intake) may suggest an aetiology of nocturnal polyuria (e.g. diabetes mellitus, diabetes insipidus)
Daytime symptoms	Dysfunctional voiding or anatomical abnormality
• How often does the child void (normal voiding: four to seven times per day)?
• Does the child experience daytime wetting or urgency?
• Any holding manoeuvres (legs crossing, pressing the heel into the perineum) or voiding difficulties (interrupted or weak stream or straining)?
• Any previous urinary tract infection?
Bowel habits	Constipation may reduce the bladder capacity
• Are the bowel frequency and habits suggestive of constipation?
Review of systems
• Does the child snore at night?	• Obstructive sleep apnoea
• Any gait abnormalities?	• Spinal dysraphism
• Any staring spells?	• Seizure disorder
• Any perianal itching or vulvovaginitis?	• Pinworms
Family history	Genetic factors may contribute to NE
• Is there a family history of NE?
Behavioural problems • How has bedwetting affected the child (at home or in school)?	Severe behavioural problems may need to be addressed concomitantly with
• How are caregivers coping or supporting the child?	NE therapy

Clinical examination

In most cases (particularly in MNE), the physical examination is completely normal. A focused examination [Table 2] should always include general health, abdominal, spine (check for signs of occult spinal dysraphism) and external genitalia examination.

Table 2.

Key findings from physical examination in children with nocturnal enuresis.

Physical examination	Examination findings	Possible significance
General appearance	Poor growth	Renal disease
Blood pressure	Hypertension	Renal disease
Ear, nose, throat	Large tonsils Swollen nasal turbinates	Tonsillar hypertrophy which may contribute to OSA Allergic rhinitis which may contribute to OSA
Developmental assessment	Delayed development	Possible neurological conditions
Abdomen	Palpable faecal masses Palpable bladder	Constipation Urological abnormality
Perineum	Wetness in undergarments Perianal excoriation or vulvovaginitis Observation of slow urinary stream, straining, dribbling, intermittent stream	Daytime incontinence Natural history is spontaneous resolution Urological abnormality
Neurological exam	Abnormal neurological examination of the perineum and lower extremities	Spinal lesions which may result in neurogenic bladder/bowel
Spine	Cutaneous stigmata of spinal dysraphism (sacral dimple, naevus, lipoma, tufts of hair over the midline, abnormal or asymmetric gluteal cleft)	Underlying spinal cord abnormalities (spina bifida, tethered cord, cord lipoma, persistent dural sinus)

OSA: obstructive sleep apnoea

INVESTIGATIONS

For MNE, urine dipstick should suffice as an initial laboratory evaluation. If there is pyuria, urine culture should be obtained. The presence of proteinuria or glycosuria hints at chronic kidney disease or diabetes mellitus and would warrant further investigations. If history taking is not suggestive of NMNE or other organic conditions and physical examination findings and urine dipstick are normal, no further workup is usually necessary.

PRINCIPLES OF MANAGEMENT

Treatment of NE should always begin with educating the child and family about the condition. It is critical to spend time reassuring, setting goals and explaining the prognosis. The goals of intervention for NE include the following: (a) to stay dry on particular occasions (e.g. camping); (b) to reduce the number of wet nights; (c) to reduce the impact of enuresis on the child and family; and (d) to prevent recurrence. Figure 1 illustrates the algorithm for the management of NE.

Figure 1.

Algorithm for management of children with nocturnal enuresis. LUTS: lower urinary tract symptoms

The main treatment options for NE are urotherapy, enuresis alarm and medications. The choice of treatment depends on the child’s age and motivation, the frequency and severity of enuresis and the caregiver’s ability to cope. A child should be offered active treatment (i.e. enuresis alarm and pharmacotherapy) if (a) the child’s age is ≥ 6 years, (b) the condition affects the child’s normal social and emotional development, and (c) the condition affects the child’s schoolwork, indicating significant functional impairment. All enuretic children should receive counselling on lifestyle changes, urotherapy and treatment for comorbid conditions, if present. Pharmacotherapy can be started by physicians who are able to provide counselling for NE and are equipped with adequate knowledge of the indications and contraindications of these treatments.

Lifestyle changes and urotherapy

Urotherapy involves education on normal bladder function and voiding habits, fluid intake, avoidance of constipation, as well as support for the child and caregivers. The family should be reassured that primary MNE usually resolves spontaneously. Advice should be given on good fluid intake, specifically the adjustment of fluid intake to two-thirds of normal total daily fluids during the morning to early afternoon and the remaining one-third to the remainder of the day. Fluids that promote diuresis or irritate the bladder (caffeinated drinks, excessive fruit juices, fizzy drinks) should be reduced. Physicians should keep in mind the rule of ‘twos’. Consumption of fluids 2 h before bedtime should be minimised. When awake, the child should pass urine every 2 h. Double voiding should be encouraged, whereby the child attempts voiding two times with each toilet visit (i.e. after emptying completely the first time, count 10 s and attempt to pass any remaining urine for a second time before leaving the toilet), to ensure complete emptying of the bladder. Food and fluids should be minimised 2 h before bedtime. All children should also be reminded to maintain a good posture when micturating and to void immediately before bedtime. If parents have the habit of waking the child at night to void, they should be informed that this is allowed but not needed and it would only help for that specific night, if at all. Constipation should be treated with dietary measures and stool softeners (e.g. lactulose or macrogol) to achieve daily passage of soft stools without straining. Urotherapy is more beneficial in NMNE to normalise daytime bladder function, which will then improve function at night. A bladder and bowel diary can be used to facilitate monitoring for such cases.

Behavioural therapy

Motivational therapy (positive reinforcement), where the child is rewarded for dry nights, is another intervention that appears to be more effective than no treatment. Rewarding agreed behaviour (e.g. voiding before sleep and engaging in management) may be more efficacious than simply rewarding dry nights, which is out of the child’s conscious control. The child should be reassured that enuresis is a common problem and is not his/her fault. Supportive counselling for the enuretic child and family is also important, providing reassurance that help is available. Many families still believe that enuresis is a result of poor parenting skills or due to psychological factors. This misconception should be addressed if present. Punishment (negative reinforcement) is not an acceptable treatment option, as it may result in stress-related accidents. In general, clinicians can allow 6 weeks to evaluate the effectiveness of behavioural therapy before implementing other treatment strategies.

Enuresis alarm

Enuresis alarm is currently the most effective treatment available and is considered the first-line therapy for MNE. The use of enuresis alarm is usually combined with motivational therapy. Many alarms are available in the market, with no specific type being deemed the best. The enuresis alarm includes a moisture sensor, placed under the child’s underwear or as a pad beneath the child, which is connected via a wire or wirelessly to an alarm that delivers a loud, acoustic stimulus when it detects wetness. In this way, the enuresis alarm serves as a conditioning device that uses a sound to link the stimulus of a full bladder beginning to void with the desired behaviour of inhibiting micturition and waking. The response is more gradual and sustained than for medications. The success rate is between 50% and 80%. About 70% of children with NE who completed 16 weeks of enuresis alarm therapy remain dry 3 months after treatment.[15] It is generally recommended to continue enuretic alarm training for a maximum of 16 weeks or until 14 consecutive dry nights are achieved.[16] If there is no improvement after 6 weeks, it is reasonable to review this therapy and consider other options. A relapse can occur in 12%–30% of cases within the first 6 months after treatment, but the child often responds to another course of alarm therapy.[16]

Although effective, it must be highlighted that compliance to enuresis alarm can be difficult if parents have sleep problems or the child shares a room with siblings. Proper instructions on its use must be given. During alarm training, children will need adequate support from their family, as parents need to help the child wake up completely. In addition, the alarm should be used every night without interruptions. Alarm therapy may not be appropriate for children who have: (a) infrequent bedwetting, (b) severe problems interacting with their parents, (c) marked psychological disorders such as oppositional defiant disorders, and (d) untreated LUTS, especially from an overactive bladder.[16]

Pharmacotherapy

Desmopressin

Desmopressin is a synthetic analogue of the pituitary hormone, arginine vasopressin. It increases water reabsorption by the collecting tubules, thereby reducing urine production. Besides enuresis alarm, desmopressin is another recommended first-line therapy in MNE. Desmopressin is especially effective in children with nocturnal polyuria. Thirty percent of children with NE are full responders to desmopressin and 40% have a partial response. Desmopressin is usually well tolerated, and side effects such as headaches, emotional disturbances and abdominal pain are uncommon. Water intoxication and hyponatraemia, although rare, can be avoided by restricting fluid intake within 2 h of desmopressin administration. The child and caregiver must be informed of this before treatment.

Oxybutynin

Oxybutynin is an anticholinergic drug and its main action lies in relaxation of the smooth muscles of the bladder, thus being effective in children with detrusor overactivity. In the absence of constipation and postvoid residual urine in an enuretic child, oxybutynin can be considered as a second-line therapy, often in combination with desmopressin.

Imipramine

Imipramine can be used as a third-line alternative if desmopressin, enuresis alarm and oxybutynin have all been unsuccessful or contraindicated. While its mechanism of action is not fully understood, the postulated beneficial effect of imipramine is due to a combination of its noradrenergic, serotonergic and anticholinergic action on the bladder, urine production and arousal mechanisms. Although around 20% of children become dry while being treated, this effect is not sustained with cessation of treatment. Cardiotoxicity has limited the use of imipramine in NE. Other problems include risk of overdose, concomitant constipation and black box warning of increased suicidality. Therefore, imipramine is not recommended unless instituted by specialists in a tertiary centre.

WHEN SHOULD I REFER TO A SPECIALIST?

Red flags in NE can be divided into significant symptoms, past medical history and physical examination findings [Box 1]. The presence of daytime LUTS is more indicative of the diagnosis of NMNE, warranting specialist evaluation. Constitutional symptoms like loss of weight with failure to thrive may suggest renal disease. Patients with developmental or learning difficulties and those with marked behavioural symptoms may benefit from referral to a tertiary centre, as a multidisciplinary approach in treatment may be beneficial. All patients with previous febrile or recurrent urinary tract infections, previous pelvic or urological surgeries and potential renal malformations should be assessed further. The presence of abnormal physical examination findings [Table 2] is also concerning for an organic cause for NE. Other considerations include patients who have failed therapy after 6 months and patients with comorbidities (e.g. severe constipation, OSA).

Box 1.

Red flags in nocturnal enuresis.

Daytime symptoms

• Daytime incontinence • Voiding>7 or <4 times per day

• Sudden and urgent need to urinate

• Straining to void

• Holding manoeuvres (leg crossing, pressing the heel into the perineum)

• Interrupted or weak stream of urine

Significant history

• Secondary nocturnal enuresis

• Encopresis

• Marked behavioural symptoms

• Loss of weight, failure to thrive

• Previous febrile or recurrent urinary tract infections

• Previous pelvic/urological surgery/interventions

• Abnormal antenatal scans of kidneys or urinary tract

Significant findings on physical examination

• Refer to Table 2

TAKE HOME MESSAGES

1. Nocturnal enuresis is a common condition seen in children aged ≥ 5 years, and is defined by the occurrence of intermittent incontinence during sleep, at least once a month for a minimum duration of 3 months.

2. The distinguishing factor between MNE and NMNE is the presence of daytime LUTS, while the difference between primary and secondary NE lies in the presence of a previous symptom-free interval of at least 6 months.

3. Medical history is the most important part in the evaluation of NE. In children with MNE, the physical examination is usually normal.

4. Constipation and OSA can be seen in children with NE, and treatment of these conditions can lead to improvement of NE.

5. For MNE with no red flags in evaluation, urine dipstick should suffice as an initial laboratory evaluation.

6. The main treatment strategies for NE include urotherapy and behavioural therapy, enuresis alarm and medications. Urotherapy and lifestyle changes should be advocated for all patients.

7. Enuresis alarm and desmopressin are the recommended first-line therapies in MNE.

8. Referral to a paediatrician should be made for children with NMNE, abnormal physical examination findings or significant urological history.

Closing Vignette

Urine dipstick test was performed and it was normal. Further history raised concerns for symptoms of OSA due to loud snoring and daytime somnolence. Ashley was referred to the paediatrician for her NE and OSA. Enuresis alarm, urotherapy and lifestyle changes were started. She was also started on intranasal steroids and oral antihistamines for her allergic rhinitis. Her constipation was managed with dietary changes and stool softener. Ashley was also evaluated by a sleep specialist and an ear, nose and throat surgeon in view of her OSA symptoms, with a plan for tonsillectomy and adenoidectomy if the OSA symptoms persisted. After 4 months of treatment, her NE, constipation, allergic rhinitis and OSA improved significantly.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

SMC CATEGORY 3B CME PROGRAMME

Online Quiz: https://www.sma.org.sg/cme-programme

Deadline for submission: 6 pm, 22 May 2024

Question: Answer True or False
1. Nocturnal enuresis (NE) is defined as intermittent incontinence for a duration of three consecutive months in a child aged ≥ 5 years.
2. Children with primary enuresis have had a previous dry period of more than 6 months.
3. The diagnosis of non-monosymptomatic NE can be made in a child with NE and daytime incontinence.
4. Nocturnal enuresis is equally common in boys and girls.
5. Urine dipstick is sufficient as a first-line investigation for most cases of NE.
6. Children with NE may have smaller functional bladder capacity.
7. Most children who present to the enuresis clinic have an identifiable organic cause.
8. Besides genetics as a cause, the following have been proposed for the pathophysiology of NE: (a) role of bladder with nocturnal detrusor overactivity and small functional bladder capacity; (b) nocturnal polyuria with alteration of vasopressin secretion; and (c) role of sleep with inefficient arousal and central nervous system (CNS) maturation delay.
9. Treatment of constipation and obstructive sleep apnoea can improve symptoms of NE.
10. Significant life events in the child’s life, such as parental separation and birth of another sibling, do not trigger recurrence of NE in children.
11. Constipation can lead to enuresis due to the distortion of the bladder as a result of a full rectum, leading to secondary detrusor overactivity.
12. Choice of treatment options is dependent on the age and motivation, the frequency and severity of enuresis and the caregiver’s ability to cope.
13. Children are recommended to consume two-thirds of normal total daily fluid intake between morning and early afternoon and one-third of daily fluids over the rest of the day.
14. Enuresis alarm is well tolerated by most patients and has no concerns of sleep disturbances.
15. The success rate for enuresis alarm is between 50% and 80%.
16. It is recommended that enuresis alarm should be continued for a maximum of 16 weeks or until seven consecutive dry nights are achieved.
17. Medical treatment of NE should be limited to children aged ≥ 5 years, and can be considered if initial non-pharmacological therapy is unsuccessful or if families prefer to initiate it as a first-line therapy.
18. Desmopressin is usually the medication of choice in NE, especially in children with nocturnal polyuria and normal bladder capacity.
19. Imipramine is not recommended as a first-line agent in view of side effects such as cardiac arrhythmias, hypotension, CNS depression, hepatotoxicity and potential accidental overdosing leading to intoxication.
20. Referral should be considered if non-monosymptomatic NE (enuresis with other lower urinary tract symptoms) is suspected.