Clinical manifestations

Presentation and course

Sleep enuresis is characterized by recurrent involuntary urination during sleep. Primary sleep enuresis refers to failure to attain urinary control from infancy; secondary enuresis denotes a relapse after control has been achieved. Sleep enuresis typically is diagnosed when involuntary bedwetting occurs after 5 years of age in girls and 6 years of age in boys. A minority of children with sleep enuresis also have daytime (waking) enuresis.

Primary sleep enuresis is continuous from infancy, with wetting from once or twice a week to nightly, and often several times a night. In secondary sleep enuresis, the child has been dry for at least 3 months.

Approximately 25% of all children have some relapse of bedwetting after a period of initial dryness. This bedwetting generally is self-limiting and associated with illness or stress. Sleep enuresis usually disappears spontaneously at a rate of 15% per year after 5 years of age.

Sleep enuresis also occurs in the elderly: about 3% of women and 1% of men over the age of 65 years have the disorder (15).

Prognosis and complications

Sleep enuresis is often kept secret when it persists beyond childhood, as it causes embarrassment and inconvenience. Daily changing of sheets and concerns about odor are typical. Primary sleep enuresis restricts the child's range of activities, such as spending the night with a friend, going on trips, or camping. The psychological trauma is often the most serious complication. When children and families wait for resolution without therapy or counseling, the social and emotional hardships associated with incontinence can result in developmental problems, conduct problems, and child abuse.

With increased age and duration of symptoms, the self-esteem domain of quality of life worsens. Also, there seems to be a significant correlation between sleep quality parameters from the Pittsburgh Sleep Quality Index and the physical well-being domain of the Quality of Life questionnaire (27).

There seems to be a strong association of enuresis with attention-deficit hyperactivity disorder (ADHD); a 16.9% prevalence of enuresis was described in an ADHD cohort where the likelihood of inattentive symptoms was higher than in the nonenuretic group (25). Deficits in arousal could probably contribute to both enuresis and ADHD. Another study found an odds ratio of 2.88 for ADHD and enuresis comorbidity and advocated a routine ADHD evaluation for enuresis and vice versa (70).

Clinical vignette

A 10-year-old boy was referred for evaluation of bedwetting. He had never been dry at night for a substantial period and was enuretic between 3 and 7 times weekly, but he did not have daytime enuresis or urgency. His parents described him as a deep sleeper who was difficult to awaken.

Intravenous pyelogram, urinalysis, and urine cultures performed previously were normal. Treatments with fluid restriction and oxybutynin had been unsuccessful. Imipramine had produced modest benefits but was discontinued because of sleep disruption and daytime behavioral problems.

He had a history of allergic asthma. Family history was positive for sleeptalking in both parents but was negative for enuresis. His father was a physician, and his mother was active in community affairs. The patient, the second of 2 children, was an excellent student. There were no major family conflicts, but the parents had differing parenting styles; the father was considered distant and occasionally hostile by the mother, whereas the mother was considered overly protective by the father. Physical and mental status examinations were normal.

The impression was primary sleep enuresis. Treatments with bladder retention exercises and sphincter exercises were prescribed along with the bell-and-pad method. Family counseling was also recommended, but the father was unwilling to consider this approach.

At follow-up 3 months later, the patient had used the bell-and-pad regularly but had performed the bladder and sphincter exercises only occasionally. The frequency of enuresis dropped initially to 1 to 3 times weekly but then increased again to 5 to 7 times weekly. The patient was encouraged to continue with the bell-and-pad and was prescribed desmopressin 20 µg intranasally at bedtime. Over the next 3 months, he was enuretic only 3 times. He continued to do well with the combined treatment for 5 more months. During this time, marital difficulties worsened, and the parents separated. Desmopressin was then discontinued, but enuresis returned and the medication was restarted and continued for another 6 months. Following discontinuation of the medication, he continued to do well, despite the divorce of his parents, with only occasional enuretic episodes over the next 6 months.

Biological basis

Etiology and pathogenesis

The pathologic basis of uncomplicated primary enuresis is unknown. Proposed causes or contributors include central nervous system immaturity, primary disorder of arousal, excess fluid intake, impaired ability to concentrate urine, psychosocial factors, and such bladder abnormalities as small size or increased contractility. Other risk factors include male gender, stress and psychosocial problems within the family, attention-deficit hyperactivity disorder, maternal smoking, and maternal age less than 20 years at the time of the child’s birth (64; 67). Causes of secondary enuresis can be structural, pathological, or psychological.

The biological basis for primary sleep enuresis is unclear. An interaction of genetic psychological, neurologic, urologic, endocrinologic, autonomic, sleep-related, and developmental factors is suspected, but the relative importance of these factors varies across individuals and is often multifactorial. Some children have enuretic episodes following normal cystometrogram activity whereas others have uninhibited contractions of the bladder during deep NREM sleep (41). Similarly, some children have brief arousals prior to bedwetting whereas others do not (41). Autonomic nervous system studies suggest parasympathetic hyperactivity in some children (88).

Psychological factors such as posttraumatic stress contribute to enuresis in some children, and parental anxiety and expectation play a role in others. Children who are bullied are more likely to have enuresis, and in a study of 134 children before and after a flood in Bangladesh, one third developed a new problem with enuresis after the disaster (22; 85). However, psychosomatic complaints are not increased in enuretic children, and there are no major emotional or behavioral differences between children with enuresis, children who have outgrown enuresis, and children who have never had enuresis (83; 84; 38; 30).

Although there are no major group differences in sleep patterns between enuretic and nonenuretic children, obstructive sleep apnea appears to contribute to enuresis in some children and adults (77; 43; 81). In addition, boys with sleep enuresis are more difficult to arouse from sleep than boys without enuresis (83; 86). Nevus and colleagues studied children with primary sleep-related enuresis polysomnographically prior to and following treatment with desmopressin. Approximately half responded to treatment and half did not. Interestingly, children who responded to desmopressin therapy spent more time in REM sleep than those children who were nonresponders (57). Although sleep of enuretic children does not seem to differ significantly from that of nonenuretic children, those who suffer from primary sleep-related enuresis spend a slightly longer time in bed and have an increased number of sleep cycles. Children who void during REM sleep are found to have more REM sleep than others. Tachycardia is often seen to precede the enuretic event. Although sleep of enuretic children seems to be polysomnographically normal, the children can exhibit signs of autonomic arousal prior to voiding (05).

Nocturnal mean arterial pressure was found to be significantly higher in children with enuresis and polyuria than in children without polyuria, with no significant difference between wet and dry nights within this sample (44).

Studies have analyzed sleep quality of enuretic children by means of Pittsburg Sleep Quality Index (PSQI) questionnaire and found a poor quality of sleep, successively improved by a month with desmopressin (desmopressin acetate) therapy (36; 27). In particular, anxiety and fear seem to play a negative role in sleep perception. PSQI subscales relating to excessive daytime sleepiness (p< 0.003) and daytime behavior (p< 0.000) were significantly worse in enuretic children, whereas snoring subscale scores were significantly higher only in female enuretic subjects, suggesting a link between enuresis and sleep-disordered breathing in girls (72). Sleep-disordered breathing should be ruled out in all enuretic children with excessive daytime sleepiness who do not respond to standard treatment.

Genetic factors may play a role in some cases. Enuresis is more common in children of enuretics than in the general population, and in some families, the pattern of involvement is consistent with an autosomal dominant inheritance with high penetrance. Genetic studies suggest linkage of primary sleep enuresis to markers on chromosome 12, 13, and 22 (Eiberg et al 1995; 04; 79; 24). Associations between genotype and phenotype are complex and susceptible to environmental influences. Exact assessment of the clinical phenotype and identification of intermediary phenotypes or traits of enuretic children are necessary (80). Nonetheless, expectations by enuretic parents that their children will be enuretic probably contribute to some degree to the familial clustering of sleep enuresis.

Rs6313 polymorphism in 5-hydroxytriptamine receptor 2A (5HTR2A) gene has been associated with polysymptomatic primary nocturnal enuresis (PPNE) (82). Previous evidence of SSRIs efficacy in PPNE prompted the search for a possible genetic receptor link. The study revealed that TT and TC genotypes were both associated with higher risk for PPNE compared with CC (OR 10.71 and 2.68 respectively, p= 0.0002). Also allele T alone compared with allele C (OR= 3.7, p=0.000015) had a higher frequency in PPNE, this evidence suggesting that genetic variance of 5HTR2A transmission may influence therapeutic response of PPNE.

Some enuretic children lack a normal nighttime peak in antidiuretic hormone levels, with resultant high overnight urine output (59; 01). In these children, the amount of urine produced during the night may exceed the maximum daytime functional capacity, thereby leading to enuresis. However, studies have confirmed the established fact that arginine vasopressin secretion is a function of plasma osmolality, contracting the hypothesis that enuretic children are deficient in arginine vasopressin. Results of investigations in children with nocturnal enuresis compared to normal controls pointed to central action of desmopressin, a defect at the central arginine vasopressin receptor level or the signal transduction pathway (23).

In children with primary enuresis, structural abnormalities of the urinary tract are uncommon, and little evidence supports a proposed association between a small functional bladder capacity and sleep enuresis (42).

Among elderly adults with sleep enuresis, congestive heart failure and regular use of sleep medications appear to be contributing factors (15).

Epidemiology

The reported prevalence of sleep enuresis varies according to its definition; sleep enuresis may be defined by a range of frequencies, from bedwetting at least once per week to bedwetting at least once in 3 months. Using a definition based on bedwetting at least once per month, sleep enuresis has a prevalence of approximately 80% in 2 year olds, 30% in 4 year olds, 18% in 5 year olds, 10% in 6 year olds, 8% in 8 year olds, 3% to 4% in 12 year olds, and 1% in 15 year olds (10; 17; 73). With enuresis defined as at least 1 wet night in 3 months, it has a prevalence of 8% in healthy children aged 7 to 15 years (49). Boys at all ages are affected more often than girls. Approximately 15% of bed-wetters achieve nocturnal control each year.

A study of 656 Yemen school children (via questionnaires completed by parents) found a total of 17.2% experienced nocturnal enuresis, which decreased by age from 31.5% at 6 to 8 years to 8.7% at 15 years and older (p< 0.05); 76.% of those experienced primary nocturnal enuresis with nightly bedwetting (89).

Primary enuresis accounts for 75% to 80% of enuretic cases, with secondary enuresis representing the remaining 20% to 25%. By 12 years of age, 50% of all cases of enuresis are of the secondary type. Fifteen percent to 20% of sleep enuretics have diurnal enuresis, a prevalence that rapidly decreases after 5 years of age.

A high correlation exists between a family history of enuresis and enuresis in children. Studies suggest an incidence of 77% when both parents were enuretic as children and a rate of 44% in children when 1 parent has a history of enuresis. In approximately 70% of families with an enuretic child, at least 1 other sibling also has had the problem.

Prevalence figures are similar in all societies, whether industrialized or primitive. However, the prevalence of sleep enuresis is higher in lower socioeconomic groups, where parenting skills or expectations may be less developed and toilet training may not be encouraged or achieved. Enuresis also is more prevalent among developmentally delayed youngsters, institutionalized children, and those with sickle cell anemia, attention-deficit hyperactivity disorder, or obstructive sleep apnea syndrome (63; 64; 81). The prevalence rate of ADHD is increased in an enuretic population compared to community samples (3% to 5%) (06). Several studies have indicated a greater frequency of enuresis in black than in white children (67). Among older adults, the risk of sleep enuresis is increased with Graves disease, congestive heart failure, and the use of sleeping medications (15; 35).

Prevention

The strongest predictor of sleep enuresis is a family history of the disorder (28). Other factors associated with sleep enuresis include adverse environmental circumstances (poor toilet training, emotionally traumatic events, fear of dark), psychological disturbances, and physiologic mechanisms (developmental delay, sleep patterns). Sleep enuresis is common in children with sickle cell anemia as a consequence of renal medullary infarction (63).

The frequency at any age varies inversely with the child's birth weight. A similar inverse correlation exists between sleep enuresis and height, bone age, and age of puberty (51).

Differential diagnosis

Patients with sleep enuresis, a normal physical examination, and negative urinalysis and urine culture findings have uncomplicated enuresis. Such children may have associated mild daytime urinary frequency or enuresis, a positive family history of enuresis, and slightly delayed developmental achievements.

Patients with a positive urine culture or history of urinary tract infection, abnormal neurologic examination, or history of significant voiding dysfunction have complicated enuresis, which may be caused by urinary infection, diabetes mellitus, diabetes insipidus, epilepsy, sickle cell anemia, or neurologic disorders. Sleep-related enuresis is often associated with obstructive sleep apnea syndrome. Brooks and colleagues have shown a high prevalence of enuresis in children with suspected sleep-disordered breathing. Children with a respiratory disturbance index greater than 1 event per hour of sleep were at higher risk for enuresis than children with a respiratory disturbance index of less than or equal to 1 event per hour. This may be due to the effects of obstructive sleep apnea on arousal response, bladder pressure, or urinary hormone secretion (13). Asthmatic children with wheezing in the last 12 months were found to be 2.33 times more likely to have had enuretic episodes at any time in their life according to questionnaires sent out to their guardians/parents (21). Whether this correlation, as it might be supposed, depends on obstruction of the airways remains to be seen. Sleep enuresis also commonly occurs in children who suffer from NREM sleep parasomnias, such as sleep terrors or sleep walking.

A pathologic process involving the urinary tract is likely if the child has daytime enuresis, abnormalities in the initiation of urination, or abnormal urinary flow. Secondary enuresis may be associated with obstructive sleep apnea or sexual abuse (26).

Diagnostic workup

Investigation of primary sleep enuretics should include urinalysis, complete enuresis history, and a comprehensive sleep history.

Urinalysis may help diagnose urinary tract infections and, in the presence of bacteriuria or hematuria, promote further radiological diagnoses. Glycosuria may indicate a diagnosis of diabetes, whereas concentration of first urine sample may inform on renal function (03). Ultrasonography, vesical sphincter electromyography, cystometry, and cystoscopy may be useful for some children who are still enuretic after 12 weeks of treatment. When radiographic and cystoscopic examinations are normal, persistent enuresis may be associated with detrusor or sphincter problems. In these cases, urodynamic studies may reveal either low bladder capacity or decreased bladder compliance and are especially useful to diagnose neurogenic bladder or obstruction. Up to 73% of adults with primary nocturnal enuresis have been found to have bladder dysfunction. Ultrasonography and voiding cystourethrography are specifically indicated to demonstrate renal or bladder structural abnormalities such as ureterocele, hydronephrosis, and increased bladder wall thickness. The latter condition may be an important component of bladder dysfunction, primarily in women with detrusor hyperactivity and some children with primary nocturnal enuresis (20; 19). Nocturnal polysomnography should be considered as part of the patient’s evaluation.

Management

Treatment must begin with a determination as to whether the child has uncomplicated or complicated enuresis. In most children, the disorder is uncomplicated and requires parental support, empathy, and patience. A common approach for otherwise normal children is to wait and see if the bedwetting problem is "outgrown." For most, it resolves spontaneously. The annual spontaneous cure rate between 5 and 19 years of age is about 15% per year.

When the child or parents desire more rapid resolution, treatment also may involve behavioral techniques (behavior modification, wetness alarms, and retention control exercises), fluid restriction, medication, psychotherapy, hypnosis, surgery, biofeedback, or a combination of these (48). Behavioral techniques are more likely to be successful in children over the age of 6 than in younger children.

Systems that incorporate an alarm are commonly used behavioral techniques. Although medications were at one time the favored approach, physicians now appear to be more likely to recommend behavioral techniques, at least in some communities (78). The bell-and-pad method involves having the child sleep on a pad, which incorporates an alarm that sounds when the pad is wet. The alarm wakes the child, who stops voiding, turns off the alarm, and goes to the bathroom to finish voiding. Newer urine alarms, which attach to the child's pajamas, also condition the child to awaken when urinating at night and eventually to awaken at the sensation of bladder distention. The success rate for these devices is 65% to 80%, with relapses in 10% to 15% of cases (52). Comparative trials show that the urine alarm is superior to drug therapy and is the most effective treatment for enuresis, with increased nocturnal bladder capacity and higher rates of sustained continence (54; 61).

A study to determine the efficacy of bell and pad alarm therapy as initial and relapse treatment for nocturnal enuresis, and to explore risk factors for treatment failure and for relapse within 12 months of successful therapy, found an initial response rate of 84% and relapse rate of 30%, whereas effective therapy after relapse was 78%, with an average length of treatment of 10 weeks (32). Female gender, motivation, absence of diurnal symptoms, and shorter length of treatment were associated with successful therapy.

The enuresis alarm can be combined with positive reinforcement, nighttime awakenings, retention control (increasing urine retention before voiding), cleanliness training (cleaning up after an episode), and positive practice (imaging followed by voiding in a bathroom). Such combined approaches are sometimes superior to the use of an alarm alone.

Medications include antidepressants, antidiuretics, antispasmodics, and prostaglandin synthesis inhibitors.

Desmopressin (10 to 40 µg intranasally or 200 to 600 µg orally) is the primary antidiuretic prescribed for enuresis. This therapy is indicated in case of nocturnal polyuria due to free water diuresis linked to vasopressin deficiency (56). Although the medication usually reduces the frequency of wetting, only a small minority of patients obtain complete dryness (53; 29; 71). Treatment effects usually last only as long as the drug is taken. Side effects are uncommon. Hyponatremia and water intoxication with seizures are rare complications (74; 65). There does not appear to be a relationship between a positive family history of enuresis and response to desmopressin (69). Desmopressin with an alarm or other behavioral treatments may be the best overall therapy as the combined approach appears to be superior to either given alone (12; 11). Indication for the treatment of primary nocturnal enuresis was removed from all intranasal preparations of desmopressin in 2007. Within a few months, the proportion of oral tablet prescriptions increased to 80% (39). Anticholinergic agents can be combined with desmopressin for better efficiency in therapy-resistant enuresis (55).

A retrospective observational study explored the efficacy of desmopressin or anticholinergic treatment in nocturnal enuresis or daytime voiding symptoms in children with ADHD and autism spectrum disorder. The study showed a favorable trend toward efficacy of desmopressin and anticholinergic therapy in autistic children with an 8-month mean time to cure in 50% of children with an autism spectrum disorder and nocturnal enuresis (34).

The tricyclic antidepressant imipramine is frequently prescribed; its effectiveness appears to derive from increased alpha-adrenergic stimulation of proximal tubules of the kidney (31; 40). Typical doses are 25 mg 1 to 2 hours before bedtime for patients 6 to 8 years of age and 50 to 75 mg for older children and adolescents. Unfortunately, the long-term cure rate is only 25% and the relapse rate is high. Imipramine has become increasingly unfavorable as a primary treatment of sleep-related enuresis due to the high relapse rate, and fatal overdose is a significant possibility (37). Among modern antidepressants, reboxetine has been successfully used as an alternative to imipramine (Lundmark and 56). A review on the use of tricyclic and related drugs for nocturnal enuresis in children included over 64 trials involving 4071 children (18). The authors concluded that as a short-term outcome, tricyclics are better than placebo, but potentially harming serious adverse effects cannot be ruled out and do not justify a relatively small and transient effect size. Oxybutynin chloride (5 mg at bedtime for 8 year olds to 5 mg 3 times per day for teenagers), has a direct spasmolytic effect on the bladder and is helpful in controlling diurnal enuresis and uninhibited bladder contractions, but it has little or no effect on sleep enuresis.

Tolterodine can also be used alternatively in children with detrusor instability alone or in association with desmopressin (66). Even diuretic treatment has been considered (furosemide 1 mg/Kg in the afternoon) as an alternative of desmopressin for treatment of nocturnal polyuria (58). Results showed, however, only a mild therapeutic response in nocturnal enuresis especially for children unresponsive to desmopressin.

In a randomized, double-blind, placebo-controlled cross-over design investigation, Al-Waili has shown carbamazepine to be useful in treatment of primary enuresis (02). However, prior to randomization, comprehensive evaluation of sleep using polysomnography or EEG was not done.

Psychotherapy is of value when sleep enuresis is related to posttraumatic stress, emotional disturbances, or family conflicts. Improvements have also been reported with hypnotherapy, and in some studies, the benefits were more enduring than with imipramine (07). Bjorkstrom and colleagues have investigated electro-acupuncture in the treatment of children with monosymptomatic nocturnal enuresis and found that there were more dry nights in 65% of the children (08). However, only 5 of 23 children were considered responders (greater than 90% reduction in the number of wet nights at the 6-month follow-up evaluation). Interestingly, according to the parents, the sleep arousal threshold had decreased in about 50% of the children.

The success of any of these approaches may be attributed in part to the spontaneous cure rate or to the patient's response to increased attention to the problem. Emotional support of the child is probably the most critical element of any treatment program.

Acupuncture as part of a traditional Chinese medicine approach is rated superior to the efficacy rate of alarm therapy, whereas it would be less effective when used as a monotherapy. Electro-acupuncture enhances treatment outcome and allows standardization of the intervention (09).

A report on the efficacy of acupuncture noticed the need of 78 treatment sessions to achieve results and more in older children as they were all deep sleepers (90). A systematic review and metaanalysis of randomized and nonrandomized studies found an overall favorable, but not significant, effect of acupuncture compared with conventional care and placebo, with minor and rare side effects (68).

Sleep architecture parameters predict postoperative nocturnal enuresis resolution in children with obstructive sleep apnea undergoing adenotonsillectomy (75). In children with severe obstructive sleep apnea and prolonged stage 2 sleep on polysomnography, 51.4% of 37 pediatric patients undergoing adenotonsillectomy were 3.4 times more likely to resolve their primary nocturnal enuresis postoperatively, even if they had an elevated BMI. Resolution of sleep fragmentation and increased arousal were thought to be key to explain such improvement.

An additional article from Japan reported improvement of nocturnal sleep in enuretic children following yokukansan, a partial D2 agonist, 5-HT1A agonist, and 5-HT2A antagonist (60). Following bedtime administration, 10 of 18 patients achieved a full response.

Among the ultimate treatment proposals, transcutaneous parasacral electric stimulation has been used in patients with an overactive bladder, with a complete response rate as monotherapy of 43% in one study and 70.4% in the most recent report on this option (Lordelo el al 2010; 76). Functional magnetic stimulation is also regarded as a promising treatment modality in girls and in children with cortical arousal dysfunction, where the periaqueductal area might be deactivated in response to bladder dysfunction (16; 87).

A synopsis of systematic reviews indicates that alarms, desmopressin, and some tricyclics (imipramine, desipramine, viloxazine, and amitriptyline) may be efficacious in the management of nocturnal enuresis (47). Some simple behavioral interventions, such as managing fluid intake, retention control training, and motivation by rewards, also seem beneficial, whereas complex behavioral interventions or combinations of treatment modalities are not supported by definitive data.