Nocturnal Enuresis

Definition and Introduction

Image courtesy of MOJOE Opens in new window Enuresis Opens in new window is defined as the persistence of involuntary voiding of urine in inappropriate places beyond the age of anticipated control, mostly 5 years onwards, after ruling out organic causes.

According to the diagnostic criteria of ICD-10, wetting occurs at least either twice a month (age 5-7) or once a month (age>7) for at least 3 consecutive months. According to DSM-5, wetting occurs twice a week or leads to social incapacitation for at least 3 consecutive months.

According to the classification of the International Children’s Continence Society (ICCS), which is the gold standard in national and international research,

1.    Types of Nocturnal Enuresis

Nocturnal enuresis can be divided into different subtypes, as follows (see Table X1).

1.1     Primary nocturnal enuresis (PNE)

Primary nocturnal enuresis (PNE) denotes nocturnal incontinence in children who have never been dry for more than 6 months. Two subtypes can be differentiated:

1. Primary monosymptomatic nocturnal enuresis (PMNE) refers to nocturnal incontinence without a dry interval longer than 6 months and no longer urinary tract symptoms, e.g., daytime incontinence, urgency, voiding postponement, or interrupted flow. Children with this type of nocturnal enuresis often wet large amounts of urine and are very difficult to wake up.
   
   During the day, no lower urinary tract abnormalities exist. The micturition frequency is normal (4–7 times a day) and the amount of urine during daytime is appropriate for age. No urgency is present; the children do not show holding maneuvers, they can empty their bladder without any problems, and they do not soil>
2. Primary non-monosymptomatic nocturnal enuresis (PNMNE) refers to nocturnal incontinence without a dry interval longer than 6 months with disturbances of bladder function. For instance, these children can show urgency, voiding post-ponement, or interrupted flow.

1.2     Secondary nocturnal enuresis

Children with secondary nocturnal enuresis wet during the night after a dry period of at least 6 months. Again, two subtypes are differentiated:

1. Secondary monosymptomatic nocturnal enuresis (SMNE) is defined as nocturnal incontinence after a dry period of at least 6 months without any signs of bladder dysfunction.
2. Secondary non-menosymptomatic nocturnal enuresis (SNMNE) describes nocturnal incontinence after a dry period of at least 6 months with signs of bladder dysfunction – as in PNMNE.

The differentiation between monosymptomatic and non-monosymptomatic is more relevant for treatment. Disturbances of bladder function have to be treated first. Treatment is the same in primary as in secondary types. However, children with secondary nocturnal enuresis have a higher risk for comorbid psychological disorders, which, if necessary, have to be treated in addition to the incontinence.

1.3    Prevalence

Nocturnal enuresis occurs 2–3 more often than daytime (diurnal) urinary incontinence. The ratio is 1.5:1 to 2:1 (boys to girls). Thus nocturnal enuresis is more prevalent in boys than girls.

Depending on definition, prevalence rates are 43.2% in 3–year-old children and 20.2% in 4–year-old children. However, enuresis is not a formal diagnosis at this age (not until age 5 according to ICD-10, DSM-5, and ICCS). Of 5–year-old children, 15.7% are affected, of the 6–year-olds 13.1%. The prevalence rate decreases to 2.5% in children between 7 and 10 years of age.

In adolescence, 1–2% still wet during the night and in adulthood 0.3–1.7%. Here the high rate of spontaneous remission of nocturnal enuresis of approximately 13% per year becomes apparent (Hellström, Hanson, Hasson, & Jodal, 1990; von Gontard & Nevéus, 2006). According to the large epidemiological Avon Longitudinal Study of Parent and Children (ALSPAC, Golding, Pembrey, & Jones, 2001), at the age of 7¹/₂ years 15.5% (of 8,269 children) wet during the night (Butler, Golding, Northstone, & ALSPAC Team, 2005). Most of these children wet approximately once a week (82.9%).

According to DSM-IV, 2.6% fulfilled the criteria for nocturnal enuresis, thus wetted at least twice a week. In their study of 2,856 children with a mean age of 7.3 years, Sureshkumar and colleagues (2009) found a prevalence rate for nocturnal enuresis of 18.2%. Of these children, 12.6% had nocturnal enuresis with a frequency of 1–6 times per month, 3.6% of them wet every night.

In an epidemiological study by two of the authors with 2,079 preschoolers (mean age of 6 years), a prevalence rate of 9.5% for nocturnal enuresis was found (Equit, Klein, Braun-Bither, Gräber, & von Gontard, 2013). Of these children, 2.7% wetted during the day at least once a month. In another population-based study of 1,391 6-year-old children, 13.4% showed daytime or nighttime wetting: 9.1% wetted at night and 4.4% during the day (von Gontard, Moritz, Thome-Granz, & Freitag, 2011).

In general, PNE occurs more often than SNE, but until the age of 7, SNE appears as often as PNE (5.2%; Fergusson, Horwood, & Shannon, 1986). SNE occurs the most often at the age of 7 (5.1%). Further epidemiological studies show that monosymptomatic nocturnal enuresis (MNE) occurs twice as often (68.5%) as non-monosymptomatic nocturnal enuresis (NMNE, 31.5%; Butler, Heron, & ALSPAC Team, 2006).

2.     Differential Diagnoses and Comorbid Disorders

2.1    Psychological Differential Diagnoses

Many children wet during the night without any psychological disorder. If additional psychological disorder exist, they are classified separately. Therefore, in general, the focus is more on identifying possible comorbid disorders. These should be diagnosed and treated in addition to the incontinence—not on a differential diagnosis per se. However, the same possible organic causes as in daytime urinary incontinence have to be ruled out.

2.2    Comorbid Psychological Disorders

Children with incontinence often have high psychological stress and reduced self-esteem Opens in new window. Subjective distress, however, is often a consequence of incontinence (Hägglöf, Andren, Bergström, Marklund, & Wendelius, 1996). These subclinical symptoms usually do not need additional treatment.

The most common comorbid disorder of nocturnal enuresis is the attention deficit hyperactivity disorder (ADHD). Of the children with ADHD 20.9% also wet at night (Robson, Jackson, Blackhurst, & Leung, 1997). In contrast, in an epidemiological study with 1,136 children between 8 and–11 years old, 12.5% of the children with nocturnal enuresis additionally fulfilled the criteria for ADHD in comparison to only 3.6% of children without nocturnal enuresis (Shreeram, He, Kalaydjian, Brothers, & Merikangas, 2009).

Comparably high prevalence rates of 10% in children with ADHD combined with nocturnal enuresis in primary care and up to 30% in tertiary care are described by Baeyens, Roeyers, D’Hase, and colleagues (2006).

Children with nocturnal enuresis and ADHD are more difficult to treat, show lower compliance, and have lower success rates in therapies that require compliance. For instance, children with ADHD more often refuse to get up at night during alarm treatment than children with nocturnal enuresis without ADHD (Baeyens, Roeyers, Demeyere, et al., 2005; Crimmins et al., 2003).

In a study by von Gontard, and colleagues (1999), the rate of comorbid disorders with PNE was 20%. Children who only wet at night without symptoms of bladder dysfunction showed a very low rate (10%) of comorbid psychological disorders. Children with MNE were thus not more disturbed than nonwetting children.

In children with signs of bladder dysfunction, such as urgency, the rate of psychological disorders was increased. These children especially need further assessment and therapy in addition to the treatment of nocturnal enuresis. Furthermore, many clinical epidemiological studies indicate that the rate of stressful life events is significantly increased in children with SNE, particularly preceding the relapse. Parental separation/divorce was described as an especially stressful event in the life of children (Järvelin, Moilanen, Vikeväninen-Tervonen, & Huttunen, 1990).

3.     Etiology

3.1     Genetics

Nocturnal enuresis can be considered a genetically determined maturation disorder of the central nervous system. The genetic predisposition is the same in primary and secondary enuresis. Genetics can be regarded as the most important etiological factor for the development of nocturnal enuresis, which has been shown by formal as well as molecular genetic analyses (von Gontard, Schaumburg, Hollmann, Eiberg, & Rittig, 2001).

Empirical family studies show that 60–80% of all children with nocturnal enuresis have relatives with wetting problems. The prevalence of enuresis in children is 44% if one parent was affected and 77% if both parents were affected (Barkwin, 1961, 1973).

Twin studies compared concordance rates of mono– and dizygotic twins and showed significantly higher rates for monozygotic (46%–68%) compared to dizygotic twins (19–36%) (Barkwin, 1973).

Segregation analyses showed an autosomal dominant mode of inheritance with reduced penetration of 90% in 44% of the cases. This means that only one parent with possible enuresis genes would be sufficient to induce enuresis in a child (dominant inheritance; Arnell et al., 1997). Reduced penetration means that if the relevant gene exists, only 90% actually develop enuresis. In contrast, in only one third of the cases enuresis develops sporadically, i.e., no relatives are incontinent or have been affected by wetting. Linkage studies have identified different ‘loci’ on chromosomes 4, 8, 12, 13, and 22, on which possible genes for nocturnal enuresis could be localized (von Gontard, Schaumburg, et al., 2001).

Thus, nocturnal enuresis is a predominantly genetic disorder influenced by environmental factors. The environmental impact is less in PNE as genetic factors lead directly to wetting (delay in getting dry). Children with SNE have an increased genetic disposition for relapse, which is activated by environmental conditions, e.g., stressful life events or psychological disorders.

3.2     Neurobiological Results

Neurobiological findings are comparable in PNE and SNE. Unspecific signs for involvement of the central nervous system are lower birth weight, lower body length, and delayed bone age.

In one third of all children fine neurologic coordination disorders (soft-signs) were found that additionally emphasize the involvement of the central nervous system. Children with nocturnal enuresis show slower motor performance (von Gontard, Freitag, Seifen, Prukop, & Röhling, 2006) and exhibit a slightly higher rate of abnormalities in early acoustic evoked potentials (Freitag, Seifen, Pukrop, & von Gontard, 2006).

In sleep studies with EEG monitoring, children with nocturnal enuresis revealed no abnormalities. Wetting is not an equivalent of dreaming, as wetting rarely occurs in rapid eye movement (REM) phases. Instead, wetting is independent of sleep stage and occurs in every non-REM phase (non-dreaming phase). However, the majority of wetting episodes occur in the first third of the night (Nevéus, Läckgren, et al., 2000).

Neurobiological factors of nocturnal enuresis are not located in the cerebral cortex, as measured by EEG, but in deeper brain structures.

A full bladder can lead to wetting during the night if the micturition reflex is not inhibited (Nevéus, Läckgren, et al., 2000). This function, i.e., the inhibition of the micturition reflex, is mediated by the pontine micturition center in the brainstem.

Additionally, wetting occurs when sensations of the full bladder are not registered and do not lead to arousal, which is regulated by the locus coeruleus. Both structures are anatomically close and functionally connected.

Many parents of children with nocturnal enuresis report difficulties in waking their children up, which could be demonstrated in standardized waking trials. Wolfish, Pivik, & Busby (1997) showed that only 9% of enuretic children could be woken up by acoustic stimuli of up to 120 decibel.

3.3     Neuroendocrinological Results

Many children with PNE or SNE have increased urine production (polyuria) during the night as well as a shift of the circadian day-night rhythm of the antidiuretic hormone (ADH). Due to increased production of urine, the capacity of the bladder can be exceeded so that wetting results if the children do not awake (Nevéus, Läckgren, et al., 2000).

The amount of urine is regulated by ADH leading to a decreased production of urine. Usually, during daytime less ADH is secreted so that more urine is produced. During the night, ADH secretion increases, whereby less and more concentrated urine is produced.

For some children with nocturnal enuresis, ADH secretion is the same during night and day (i.e., leading to nocturnal polyuria). Therefore, changes of the day-night rhythm can be associated with nocturnal enuresis (Norgaard, Pedersen, & Djurhuus, 1985; Rittig, Knudsen, Norgaard, Pedersen, Djurhuus, 1989).

These ADH hypotheses of enuresis do not apply to all children as many wetting children do not have polyuria. Other children are dry during the night despite polyuria because they wake up and go to the toilet. Furthermore, polyuria does not explain why children do not wake up during the night or do not suppress the micturition reflex (Hunsballe et al., 1995; Mattson, 1994; Nevéus, 2011).

In summary, polyuria does indeed increase the risk of nocturnal enuresis, but is not the main cause. Arousal difficulty or the lacking suppression of the micturition reflex are also needed to explain the pathophysiology of nocturnal enuresis. Polyuria and variations of ADH can therefore be considered additional aspects of general maturation delay of the central nervous system.

3.4     Psychosocial Factors

Two longitudinal Swiss studies of the 1950s and 1960s showed that potty training does not have an impact on becoming dry during the night.

In the 1950s, 96% of all parents began potty training Opens in new window before their child reached the age of 1 year; in the 1970s training shifted to the median age of 19-21 months due to different child-rearing practices and the availability of disposable diapers.

However, these differences did not have an impact on becoming dry during the night (Bloom, Seeley, Ritchey, & McGuire, 1993; Largo, Molinari, von Siebenthal, & Wolfensberger, 1996).

In a longitudinal study of more than 8,000 children, Joinson et al. (2009) could demonstrate that children who began potty training at the age of two took longer to get dry during the day and had more relapses in bladder control during the day compared to children who began potty training with 15–24 months of age. However, no differences were found between these groups concerning the age of continence at night.

Psychological risks (e.g., stressful life events, existing psychiatric disorders) can trigger a relapse. Enuresis can lead to high psychological stress and decrease self-esteem. After successful therapy, subclinical psychological signs decrease. However, problems in self-esteem can reinforce already existent psychological disorders.

Also, psychosocial risks and wetting can coexist without any causal relation, i.e., by chance. In a study by Sureshkumar and colleagues (2009) of 2,856 Australian children, associations were demonstrated between the existence of emotional stressors and mild nocturnal enuresis.

Children with PMNE do not exhibit a highly increased rate of psychological disorders or psychosocial risk factors. These results support the predominantly genetic-biologic etiology of PMNE.

For children with PNMNE, emotional and behavioral symptoms are more common compared to healthy children or children with PMNE, however, these symptoms are less common than in children with daytime urinary incontinence (Zink et al., 2008).

Butler and colleagues (2006) compared children with MNE and NMNE in respect to abnormalities in micturition, voiding frequency, etc., but also in respect to psychological variables such as social anxiety, general anxiety, unhappiness/depression, and ADHD. Although the rates of psychological disturbances were higher in the group of children with NMNE, no statistically significant differences could be shown.

The rate of stressful life events and preceding psychiatric disorder is increased in children with SNE and can function as a trigger for relapse.

There are two main peaks for relapse: in infancy (2–3 years) and at preschool age (5–6 years). The most important life event was the separation or divorce of the parents (Järvelin et al., 1990). Fergusson and colleagues (1990) demonstrated that the risk for SNE was increased in children who were exposed to four or more stressful life events in a year.

In one study, 75% of children with secondary enuresis had a comorbid psychological disorder. Additionally, 62% of the parents reported stressful life events, such as a separation or divorce, in the environment of 19% of the children (von Gontard, Plück, et al., 1999).

4.     Treatment

Practical management for nocturnal enuresis is presented in Table X1. Studies suggest that only a minority of children with enuresis is ever assessed and treated and that many of those who are referred do not receive adequate treatment. Many families, and clinicians, seem to accept bed-wetting as part of normal childhood.

4.1     Standard Treatment

About 10% of children have a reduction in the number of wet nights after a single visit to a clinician in which the only intervention was the recording of baseline wetting frequency and simple reassurance. Such reassurance should make clear that enuresis is a biological condition that is made worse by stress and that may be associated in a noncausal way with other psychiatric disorders.

Younger children can be told that their problem is shared by many others of the same age. The excellent prognosis for patients who comply with therapy should be stressed. Recording the frequency of enuresis can be achieved by using a simple star chart. This is most effective if performed the child, who records each dry night with a star. The completed chart is then shown to the parents on a daily basis, and they can provide appropriate praise and reinforcement.

4.2     Waking and Fluid Restriction

Although systematic studies have failed to show any effect of these interventions with enuretic inpatients, it may be that these strategies work for the majority of enuretic children who are not referred for treatment. If waking does appear to reduce the number of wet nights from baseline, a more systematic application may be indicated.

4.3     Surgery

Based on the premise that enuresis is casually associated with outflow tract obstruction, various surgical procedures have been advocated, for example urethral dilatation, meatotomy, cystoplasty, and bladder neck repair. These approaches cannot be supported because, in addition to the dubious concept of outflow tract obstruction per se, the surgery does not alter the urodynamics of the bladder.

4.4     Pharmacotherapy

Although it has been repeatedly demonstrated that temporary suppression rather than cure of enuresis is the usual outcome of drug therapy, it remains the most widely prescribed treatment in the United States. Four classes of drugs have principally been employed: synthetic antidiuretic hormones, tricyclic antidepressants, stimulants, and anticholinergic agents.

1. Synthetic antidiuretic hormone

The drug is usually administered intranasally, although oral preparations of equal efficacy have been developed (equivalent oral dose is 10 times the intranasal dose). It has been shown that almost 50% of children are able to stop wetting completely with a single nightly dose of 20–40 μg of DDAVP given intranasally. A further 40% are afforded a significant reduction in the frequency of enuresis with this treatment. As with tricyclic antidepressants, however, when treatment is stopped, the vast majority of individuals relapse.

2. Tricyclic antidepressants

The short-term effectiveness of imipramine and other related antidepressants has also been demonstrated via many randomized doubleblind, placebo-controlled trials.

Imipramine reduces the frequency of enuresis in about 85% of bed-wetters and eliminates enuresis in about 30% of these individuals. Nighttime doses of 1–2.5 mg/kg are usually effective, and a therapeutic effect is usually evident in the first week of treatment.

Relapse after withdrawal of medication is almost inevitable, so that three months after the cessation of tricyclic antidepressants nearly all patients will again have enuresis at pretreatment levels.

Side effects are common and include dry mouth, dizziness, postural hypotension, headache, and constipation. Toxicity after accidental ingestion or overdose is a serious consideration, causing cardiac effects, including arrhythmias and conduction defects, convulsions, hallucinations, and ataxia. Concern has been expressed about the possibility of sudden death (presumably caused by arrhythmia) in children taking tricyclic drugs.

3. Stimulant medication

Sympathomimetic stimulants such as dexamphetamine have been used to reduce the depth of sleep in children with enuresis; but because there is no evidence that enuresis is related to abnormally deep sleep, their lack of effectiveness is stopping bed-wetting is no surprise.

4. Anticholinergic drugs

Drugs such as propantheline, oxybutynin, and terodiline can reduce the frequency of voiding in individuals with neurogenic bladders, reduce urgency, and increase functional bladder capacity.

There is no evidence, however, that these anticholinergic drugs are effective in bed-wetting, although they may have a role in diurnal enuresis. Side effects are frequent and include dry mouth, blurred vision, headache, nausea, and constipation.

4.5     Psychosocial Treatments

The night alarm was first used in children with enuresis. The original system uses two electrodes separated by a device (e.g. bedding) connected to an alarm. When the child wets the bed, the urine completes the electrical circuit, sounds the alarm, and the child awakens.

All current night alarm systems are merely refinements on this design. A vibrating pad beneath the pillow can be used instead of a bell or buzzer, or the electrodes can be incorporated into a single unit or can be miniaturized so that they can be attached to night (or day) clothing. With treatment, full cessation of enuresis can be expected in 80% of cases.

The main problem with this form of enuretic treatment, however, is that cure is usually achieved only within the second month of treatment. This factor may influence clinicians to prescribe pharmacological treatments that, although more immediately gratifying, do not offer any real long-term benefit.

Relapse after successful treatment, if it occurs, will usually take place within the first six months after cessation of treatment.