Enuresis

The International Children’s Continence Society (ICCS) restricts the term enuresis to wetting that occurs at night. Enuresis can be divided into primary enuresis (PE) and secondary enuresis (SE). A child who has never been dry is considered to have PE; a child who has been continent for at least 6 months before the onset of the bedwetting is considered to have SE. It is felt that the pathogenesis of PE is similar to that of SE.[2, 3]

In PE, psychological problems are almost always the result of the condition and only rarely the cause. In SE, however, psychological problems are a possible cause, albeit not a common one. The comorbidity of behavioral problems is two to four times higher in children with enuresis.

The emotional impact of enuresis on a child and family can be considerable. Children with enuresis are commonly punished and are at risk for emotional and physical abuse. Numerous studies of children with enuresis report feelings of embarrassment and anxiety, loss of self-esteem, and effects on self-perception, interpersonal relationships, quality of life, and school performance.[4] A substantial negative impact on self-esteem is reported even in children whose enuretic episodes occur as infrequently as once per month.

Diagnostic criteria (DSM-5)

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), classified both enuresis and encopresis under the heading of elimination disorders.[5]  DSM-5 criteria for enuresis are as follows:

• Repeated voiding of urine into bed or clothes, whether involuntary or intentional
• The behavior either (a) occurs at least twice a week for at least 3 consecutive months or (b) results in clinically significant distress or social, functional, or academic impairment
• The behavior occurs in a child who is at least 5 years old (or has reached the equivalent developmental level)
• The behavior cannot be attributed to the physiologic effects of a substance or other medical condition

Enuresis can be further divided into the following three subtypes on the basis of the time of occurrence[5] :

• Nocturnal (ie, during sleep)
• Diurnal (ie, during waking hours)
• Nocturnal and diurnal (also known as nonmonosymptomatic enuresis)

Normal achievement of continence

Dryness at night usually follows achievement of continence by day (see Table 1 below). During the second year of life, children start to develop the ability to relax the external urethral sphincter voluntarily and to initiate voiding, even in the absence of the desire to void. By approximately age 4 years, most if not all children with normal bladder function should have acquired this ability.

Table 1. Percent of Children Dry by Day and Night at Various Preschool Ages (Open Table in a new window)

Genetics

Numerous studies report varying but high prevalence of the condition in other family members of patients with enuresis. According to the highest reported familial prevalence rates, 56% of fathers, 36% of mothers, and 40% of siblings experience a problem with enuresis. Enuresis is reported in 43% of children of enuretic fathers, 44% of children of enuretic mothers, and 77% of children when both the mother and father had enuresis. A family history of bedwetting is found in approximately 50% of children with SE.

Enuresis is usually transmitted in an autosomal dominant fashion. Chromosome 22 was identified as the site of enuresis locus in a Danish family in 1995.[6] Subsequent reports link enuresis in other families to loci chromosomes 8, 12, and 16.[7] Identified genes cannot control for enuresis per se. Rather, an identified gene would have to control a pathophysiologic factor such as arousal, nocturnal polyuria, or bladder capacity.

A family history of enuresis does not seem to influence the outcomes of any of the various treatments.

Possible causes of PE and SE are summarized in Table 2 below.

Table 2. Possible Causes of Primary and Secondary Enuresis (Open Table in a new window)

Idiopathic

If no cause can be identified, the important pathophysiologic factors include a disorder of sleep arousal, nocturnal polyuria, and a low nocturnal bladder capacity.

Disorder of sleep arousal

Sleep studies reveal that children with enuresis do not wake up normally in response to an auditory signal; this finding confirms a problem in arousal.

Arousal to the sensation of a full or contracting bladder involves interconnected anatomic areas, including the cerebral cortex, the reticular activating system (RAS), the locus ceruleus (LC), the hypothalamus, the pontine micturition center (PMC), the spinal cord, and the bladder. The RAS controls depth of sleep, the LC controls arousal, and the PMC initiates the command for a detrusor contraction. Various neurotransmitters are involved, including norepinephrine, serotonin, and antidiuretic hormone (ADH).

Nocturnal polyuria

Studies reveal nocturnal polyuria in some but not all children with enuresis. Although nocturnal polyuria is important in the pathophysiology of enuresis, overproduction of urine per se cannot be the sole causal factor. Nocturnal polyuria does not explain why children with enuresis do not wake up to the sensation of a full or contracting bladder or why enuresis can occur during daytime naps.

Nocturnal polyuria in children with enuresis may be multifactorial. Possible causes include the following:

• Increased fluid ingestion from the time a child arrives home from school through the afternoon and evening to bedtime
• Reduced fluid ingestion from the time a child wakes through the school day
• Food consumption from the time a child arrives home from school through the afternoon and evening to bedtime
• Low nocturnal secretion of ADH
• Increased nocturnal solute excretion

Ingestion of fluids from the time a child arrives home from school through to bedtime is a common cause. Solid food ingestion is also a cause because excretion of solute by the kidney is accompanied by an obligate amount of water.

Many children with bedwetting drink very modest amounts of fluids at breakfast and throughout the school day. Accordingly, they arrive home from school hungry and thirsty, and most of their fluid intake often occurs in the few hours between arriving home and bedtime. Children who engage in strenuous physical activities will also become dehydrated and will drink large amounts of fluids in the evening.These patterns favor nocturnal polyuria.

Production of urine is controlled by several factors, including ADH, which directly controls water absorption, and atrial natriuretic peptide (ANP) and aldosterone, which control solute and thus indirectly affect water excretion.

Norgaard et al first reported the absence of the expected nocturnal increase in ADH secretion in adults with enuresis.[8] Subsequent reports suggested that low nocturnal secretions of ADH are present in some but not all children with enuresis.[9] Urine sodium and potassium excretion are increased in some children with enuresis, but the reasons for these increases are not clear. Rittig et al reported that secretion of ANP in children with enuresis shows a normal circadian rhythm and that the renin-angiotensin-aldosterone system is intact.[10]

Bladder distention may influence nocturnal secretion of ADH. Some studies report that ADH secretion is increased in response to bladder distention and reduced with bladder emptying. If ADH secretion falls with bladder emptying, the observed low nocturnal blood levels of ADH may be a consequence of enuresis rather than a cause.

Small nocturnal bladder capacity

Small functional bladder capacity (FBC) is now known to play a role in the pathogenesis of enuresis. For some time, it was considered a less likely explanation for enuresis in children without daytime symptoms, but studies confirmed that children without daytime symptoms may have a low nocturnal bladder capacity and that this is a very common factor in enuresis.

In a study by Mattsson and Lindstrom, FBC was positively correlated with nighttime urine output.[11] It has been theorized that children with enuresis may maintain a smaller nocturnal bladder volume and that this situation may condition the detrusor muscle to contract at a lower volume. According to this theory, the low nocturnal bladder capacity is a consequence of enuresis rather than a cause.

Bloom et al suggested a problem with the external urethral sphincter as a possible cause of low nocturnal bladder capacity,[12] noting that the control of voiding rests at the external urethral sphincter, where constant activity is present as a guarding reflex to preserve continence. They speculated that the activity of the external urethral sphincter might fall below a critical level during sleep and thereby trigger a detrusor contraction.

Chronic constipation may also lead to reduced bladder capacity due to accumulation of stool in the distal colon.

Overactive bladder or dysfunctional voiding

Overactive bladder or dysfunctional voiding is more common among girls in preschool or elementary school, usually presenting with urinary frequency, urgency, squatting behavior, daytime wetting, and enuresis.

Squatting behavior, a common and distinct symptom of overactive bladder or dysfunctional voiding, is a learned response and an attempt to suppress an unexpected and unwelcome detrusor contraction. The squatting posture elicits a bulbar detrusor inhibitory reflex. In some children, a period of normal voiding occurs, and the onset of the bedwetting is compatible with SE. If enuresis is present, the cause is presumed to be a low nocturnal bladder capacity, but a disorder of arousal must also be present. Squatting is commonly associated with a history of cystitis.

Symptoms tend to improve or resolve with time and are less common after puberty. Vesicoureteral reflux is more common in these children, and cystitis and constipation are frequent complicating problems. Urodynamic studies reveal unstable detrusor contractions early in the filling phase.

Cystitis

Cystitis is a common cause of enuresis and an aggravating factor associated with other causes; cystitis associated with enuresis may present at any age. Cystitis causes uninhibited detrusor contractions that can lead to episodes of daytime and nighttime wetting.

If cystitis is the only cause of enuresis, other symptoms of infection are usually present, and the wetting resolves with an appropriate antibiotic. Cystitis is more common in children with overactive bladder or dysfunctional voiding, neurogenic bladder, urethral obstruction, ectopic ureter, or diabetes mellitus. In these conditions, daytime symptoms do not resolve completely with antibiotic treatment.

Psychological causes

Various common situations predispose to a psychological cause of enuresis, including birth of a new sibling, parental divorce or separation, death in the family, child abuse, or any other cause of social dysfunction at home or school.

A study by von Gontard et al found that children with SE have a significantly higher rate of behavioral disorders, life events, and continuous psychosocial stress than those with PE.[13] Stressful life events and psychiatric diagnoses are reported to precede the diagnosis of SE. The later the onset of SE, the greater the likelihood of preceding psychological stress.

Constipation

Constipation can cause both PE and SE and is a common aggravating factor that should be considered when other causes are present.

Although the mechanism is not clear, the pressure effect of stool in the descending or sigmoid colon likely restricts bladder capacity, and colonic movements at night might trigger an uninhibited detrusor contraction. Constipation is usually present in children with neurogenic bladder and is more common in those with overactive bladder or dysfunctional voiding.

Sleep-disordered breathing

Sleep-disordered breathing (SDB) is a disorder associated with both an abnormality in arousal and enuresis. The most common cause of SDB in childhood is adenotonsillar hypertrophy, which has a peak incidence in children aged 2-5 years. Nocturnal polyuria is reported in individuals with obstructive sleep apnea (OSA). A decrease in nocturnal secretion of ADH and an increase in ANP secretion are possible explanations for nocturnal polyuria.

Neurogenic bladder

A neurogenic bladder can result from a lesion at any level in the nervous system, including the cerebral cortex, the spinal cord, and the peripheral nerves. As many as 37% of children with cerebral palsy have enuresis. Patients with myelomeningocele almost always have enuresis. Other spinal cord abnormalities, such as caudal regression syndrome, tethered cord, tumors, anterior spinal artery syndrome, and spinal cord trauma, can cause enuresis.

Specific dysfunction in the external urethral sphincter can develop after pelvic extirpative surgery, radiation therapy for pelvic malignancy, pelvic fracture, or incontinence surgery. Sacral agenesis can be associated with a neurogenic bladder. As many as 5% of patients with an imperforate anus have a neurogenic bladder, and most patients also have a lumbosacral anomaly.

Urethral obstruction

Urethral obstruction can be congenital (as with posterior urethral valves (PUVs), congenital stricture, or urethral diverticula) or acquired (as with a traumatic or infectious stricture or with meatal stenosis after circumcision). Traumatic strictures may develop after a traumatic urethral catheterization, a foreign body in the urethra, or pelvic trauma. Infectious strictures are a complication of purulent urethritis due to bacteria such as Neisseria gonorrhoeae.

Meatal stenosis is a common cause of distal urethral obstruction in circumcised males, but it is not considered a cause of enuresis. It may, however, be associated with bladder overactivity and may be a contributing factor for enuresis.

Seizure disorder

SE may be a symptom of an unobserved overnight major motor convulsion in a child with a known seizure disorder. New-onset seizures rarely occur only at night; consequently, bedwetting is a rare manifestation.

Ectopic ureter

Ectopic ureter is due to the insertion of the ureter in a location other than the lateral angle of the bladder trigone. The most common site of the ectopic orifice is adjacent to the external urethral meatus and is below the external sphincter in females. Children with ectopic ureter tend to wet constantly. Enuresis results when the insertion is distal to the external urethral sphincter. Ectopic ureter is three to four times more common in girls than in boys and causes incontinence only in females.

Diabetes mellitus

Enuresis usually is not the presenting complaint in a child with new-onset diabetes mellitus. Conventional symptoms of insulin deficiency usually overshadow the presence of bedwetting.

SE in a child with established diabetes mellitus may be a symptom of suboptimal control, with nocturnal polyuria due to hyperglycemia. Although nocturnal polyuria is presumed to be the cause of the bedwetting, a disorder of arousal is also likely to be present because most school-aged patients develop nocturia but maintain a dry bed. Diabetes mellitus is also associated with abnormalities in the afferent sensory pathways to the bladder, which may contribute to enuresis.

Diabetes insipidus

Diabetes insipidus is a very rare cause of enuresis. Although nocturnal polyuria is often presumed to be the cause of bedwetting, a disorder of arousal may also be present. Diabetes insipidus may be either central or nephrogenic. Central diabetes insipidus may result from an intracranial tumor, head trauma, encephalitis, or meningitis; nephrogenic diabetes insipidus may result from any cause of renal failure, diffuse renal cortical or medullary damage, hypokalemia, hypercalcemia, or nephrotoxic drugs.

United States and international statistics

In the United States, the prevalence of PE varies by age. At age 4 years, 25% of children frequently wet the bed, but by age 7 years, only 5-10% still wet the bed, and by age 10 years, fewer than 5% of children do so.

The resolution rate of PE is approximately 15% per year; by the late teenaged years, very few patients have the condition. The resolution rate is often used as a justification for waiting and not treating PE. However, it probably is not applicable to children who wet every night and likely applies only to those children who have already started to have dry nights.

Worldwide, the prevalence of PE seems to be approximately the same, though no standardized evaluation of the prevalence of bedwetting has been made on a global basis.

Age-, sex-, and race-related demographics

The prevalence of enuresis gradually declines during childhood. Of children aged 5 years, 23% have enuresis. During elementary school years, 10% of 7-year-old children and 4% of 10-year-old children still experience enuresis. In adults, however, the reported prevalence of enuresis is 0.5-2%. A Korean epidemiologic study found that the overall prevalence of nocturnal enuresis in subjects aged 16-40 years was 2.6%.[14]

When PE and SE are reported, a secondary onset accounts for about 25% of cases. The prevalence of SE as a percentage of all cases increases with age. In a cohort of New Zealand children, 7.9% developed SE by the age of 10 years.[15]

Enuresis is more common in males. The reported prevalences of enuresis at the ages of 7 and 10 years are 9% and 7%, respectively, in boys and 6% and 3%, respectively, in girls. No racial predisposition has been documented.

Mortality attributable directly to enuresis has not been reported, but children with enuresis have been fatally abused by parents and other caregivers, and bedwetting was considered a “trigger” for the abuse in some situations. The morbidity, in terms of psychosocial stress, has been recognized in the psychology literature.[16] Enuresis can also be associated with significant family stress. Punishment should be considered a potential morbid consequence of enuresis.

Severe perineal, genital, and lower abdominal rash may also occur in patients with enuresis, potentially leading to skin breakdown and, rarely, cutaneous infections.

Relapse of the enuresis is the most common complication and necessitates restarting the treatment that resulted in an improvement or cure of the condition.

The most important reason to treat enuresis is to improve the loss of self-esteem and other secondary psychological or behavioral problems resulting from this behavior. Improvement in self-esteem is noted with all therapies, reaching levels comparable to those in children without enuresis after only 6 months of treatment.

Even without treatment, the reported spontaneous cure rate is reportedly about 15% per year. However, children who wet every night are unlikely to become dry in the short term, and many of these children continue to wet until adolescence.

When enuresis is the sole symptom, behavioral therapy or a bedwetting alarm can be curative. The only therapies that have been shown to be effective in randomized trials include alarm therapy and treatment with desmopressin and imipramine.

A Cochrane review of alarm therapy concluded that alarm therapy is beneficial; about two thirds of children on alarm therapy were dry.[17] A Cochrane review of desmopressin therapy concluded that it reduces bedwetting; treated children had an average of 1.3 fewer wet nights per week than those receiving a placebo.[18] A Cochrane review of imipramine therapy concluded that imipramine reduces bedwetting; treated children had an average of 1 fewer wet nights per week those receiving a placebo.[19]

When daytime symptoms are also present, the prognosis depends on the underlying cause. The prognosis is excellent when enuresis is due to cystitis, ectopic ureter, OSA, diabetes mellitus, diabetes insipidus, or seizure disorder. Enuresis due to cystitis should resolve with appropriate antibiotic therapy; ectopic ureter and OSA respond to specific surgical interventions; and diabetes mellitus and diabetes insipidus respond to specific medical interventions.

Enuresis due to overactive bladder or dysfunctional voiding usually resolves, but daytime symptoms continue after puberty and into adulthood in as many as 20% of patients. The prognosis for enuresis due to neurogenic bladder depends on the neurologic cause and on whether a surgical solution is available.

Punishment has no role in the treatment of enuresis. The impact of enuresis on the child’s self-esteem and emotional health is already sizable enough without the added insult of punishment for a problem beyond the child’s control.

Punishment is not always overt and intentional; it can be subtle and unrecognized by an otherwise well-meaning parent. A child easily interprets fluid restriction and requests to wear diaper training pants or to launder sheets and clothes as punishment. Accordingly, parents benefit from education regarding how to present such requests sensitively so as to minimize any sense of being punished on the part of the child.

For patient education resources, see the Children’s Health Center and the Kidneys and Urinary System Center, as well as Bedwetting, Bladder Control Problems, and Understanding Bladder Control Medications.

The best time to investigate and discuss enuresis is when the parent or patient first raises the issue in the physician’s office. However, the best time to treat the behavior might depend more on the motivation of the child and the degree of parental concern.

The most important aspect of the investigation is a meticulous history, which can establish the diagnosis, lead to more precise treatment recommendations, and minimize the need for invasive and costly investigations. The history should include the following:

• Hydration history
• Daytime voiding pattern
• Toilet training history
• Number and timing of episodes of bedwetting
• Sleep history
• Family history of nocturnal enuresis
• Nutrition history
• Behavior, personality, and emotional status

If the history is not clear, the family should be asked record fluid intake, daytime voiding, and episodes of bedwetting for at least a 2-week period.

A sleep history should include the times the child goes to bed, falls asleep, and awakens in the morning. Parents should be asked to make a subjective assessment of the child’s depth of sleep. The presence of restless sleep, snoring, and the type and frequency of nocturnal arousals (eg, nightmares, sleep terrors, or sleepwalking) should be determined. Whether the child has experienced periods of dryness and the circumstances of these episodes should also be determined.

A nutrition history should include the timing, quantity, and type of fluid and solid food intake during the entire day, not merely after supper. Many children with enuresis do not drink appreciable amounts of liquids during the school day, arrive home from school thirsty, and drink most of their daily fluids in the 4-5 hours before bedtime, a pattern that favors nocturnal production of urine.

An assessment of the emotional impact on the child is important. Information should be solicited from both the parents and the child. Basic and revealing information includes whether the child has experienced teasing by family or friends or has self-restricted participation in school, sleepovers, or trips.

Alertness to symptoms reflecting common underlying problems is important. Patients with overactive bladder or dysfunctional voiding usually present with frequency, urgency, squatting behavior, and daytime and nighttime wetting. Cystitis and constipation are common associated problems in patients with overactive bladder or dysfunctional voiding.

Symptoms of cystitis include dysuria; cloudy, foul-smelling urine; visible blood in the urine; frequency; urgency; and daytime and nighttime wetting. Symptoms of cystitis can be very subtle in some children.

Constipation manifests as infrequent and painful passage of hard wide stool, encopresis, and colicky periumbilical pain. Some children with enuresis have bowel patterns that influence bladder control and capacity, but they are not constipated by conventional definitions. Thus, the history should include a careful assessment of the frequency and timing of bowel movements, whether the stool is easy to pass, and whether the child needs to push. Children who defecate later in the day, who miss days, and who need to push should be identified.

Bowel-related problems and gait abnormalities are often present in patients with neurogenic bladder.

Symptoms of sleep-disordered breathing (SDB) include snoring, mouth breathing, lack of restful sleep, and tiredness the following morning.

The hallmark symptoms of urethral obstruction are the need to wait or push to initiate voiding and a weak or interrupted stream.

When bedwetting is a feature of a major motor seizure, parents may hear nocturnal sounds associated with abnormal muscle movements.

Girls with ectopic ureter are “always” wet.

Symptoms of diabetes mellitus include polyuria, polydipsia, and weight loss despite a voracious appetite. Patients with diabetes insipidus present with polyuria, polydipsia, and symptoms related to the underlying hypothalamic or renal causes.

A comprehensive physical examination is important and should include the following:

• Measurement of blood pressure
• Inspection of external genitalia
• Palpation in the renal and suprapubic areas to look for enlarged kidneys or bladder
• Palpation of the abdomen to look for hard, wide stool in the left lower quadrant and up to the left upper quadrant or a hard stool mass in the suprapubic area
• Thorough neurologic examination of the lower extremities, including gait, muscle power, tone, sensation, reflexes, and plantar responses
• Assessment of the anal “wink”
• Inspection and palpation of the lumbosacral spine

Abnormal physical findings are usually absent in children when enuresis is the sole symptom and are not necessarily present in children with overactive bladder or dysfunctional voiding. Abnormal findings may be present in patients with cystitis, constipation, neurogenic bladder, urethral obstruction, ectopic ureter, or obstructive sleep apnea (OSA).

A spinal defect, such as a dimple, hair tuft, or skin discoloration, might be visible in approximately 50% of patients with an intraspinal lesion. Dimples above the cleft are especially suspicious.

Assessment of the anal wink or the ability of a patient to stand on the toes is a satisfactory test of the integrity of the S2-4 spinal reflex arc.

In some situations, observing the child void is helpful for assessing the urinary stream. If the child grunts audibly or uses the abdominal muscles to push, or if the stream is weak, interrupted, or deflected upward, a urethral obstruction may be present.

In girls with ectopic ureter, a constant moistness is observed in the introitus, and regular drying with tissue reveals the persistent leak of urine.

Tonsillar size in a child examined in the awake and sitting position may not correlate with OSA symptoms. Examination of the child in the prone position and during sleep may be necessary to visibly document obstruction. Referral to a pediatric otolaryngologist or a pediatric sleep specialist may be appropriate if OSA is suspected (see Treatment).

Urinalysis is the most important screening test in a child with enuresis. Blood tests are not needed. No imaging is needed if primary enuresis (PE) is suspected; however, radiologic evaluation might be warranted if other conditions are being considered.

Children with cystitis usually have white blood cells (WBCs) or bacteria evident in the microscopic urinalysis. Children with overactive bladder or dysfunctional voiding, urethral obstruction, neurogenic bladder, ectopic ureter, or diabetes mellitus are predisposed to cystitis. If the urinalysis findings suggest cystitis, a clean-catch urine specimen should be sent for culture and sensitivity.

Urethral obstruction may be associated with red blood cells (RBCs) in the urine. The presence of glucose suggests diabetes mellitus. A random or first-morning specific gravity greater than 1.020 excludes diabetes insipidus.

Failure to empty the bladder is a significant risk factor for cystitis and is common in patients with overactive bladder, dysfunctional voiding, neurogenic bladder, or urethral obstruction. Portable bladder ultrasonography (US) is available to assess residual urine when the patient is in the office. The residual volume of urine is normally less than 5 mL.

Diagnostic imaging studies are not routinely indicated; however, patients with coincidental daytime voiding symptoms should undergo US of the bladder and kidneys before and after voiding. In patients with significant daytime symptoms whose ultrasonograms are normal, more invasive investigations should be deferred for 3 months, during which period the voiding routine and emptying are improved, cystitis is treated or prevented, and bowel health is improved.

If the bladder wall is thickened or trabeculated on US or a significant postvoid residual volume (>50 mL) of urine is noted, voiding cystourethrography (VCUG) should be considered.

VCUG is warranted for patients in whom a neurogenic bladder is suspected. The lumbosacral spine should be visualized during the procedure to look for sacral agenesis or spinal dysraphism. The classic radiologic feature of a neurogenic bladder is a trabeculated bladder with a Christmas-tree or pine-cone configuration. VCUG is also warranted when urethral obstruction is suspected on the basis of an abnormal urinary stream or abnormal findings on US.

If obstructive sleep apnea (OSA) is suspected, lateral radiography of the neck or referral to a pediatric otolaryngologist for direct visualization of the nasopharynx should be considered. Referral to a pediatric sleep specialist should also be considered.

Magnetic resonance imaging (MRI) of the spine is indicated in any patient with any of the following:

• An abnormal neurologic examination finding of the lower extremities
• A visible defect in the lumbosacral spine
• The triad of encopresis, gait abnormality, and daytime symptoms

MRI should be considered in patients with significant daytime voiding dysfunction that does not improve with treatment, even if neurologic and orthopedic examination findings are normal.

Urodynamic studies help clarify the diagnosis of neurogenic bladder. A video urodynamic study measures both filling-phase parameters (eg, bladder capacity, presence or absence of unstable detrusor contractions, bladder compliance, and the state of the bladder neck) and voiding-phase parameters (eg, voiding pressures, bladder emptying, and the state of the external urethral sphincter).

Urodynamic studies and cystoscopy should be reserved for patients with urethral obstruction and neurogenic bladder. They are not recommended in children who have bedwetting as their only symptom.

Uroflowmetry is a simple, noninvasive measurement of urine flow that is helpful in screening patients for neurogenic bladder and urethral obstruction. It is performed by having the child void into a special toilet with a pressure-sensitive device at the base.

A normal uroflow study shows a single bell-shaped curve with a normal peak and average flow rate for age and size. Children must be instructed to void when the bladder is full but not overfull; the uroflow curve in an overfull bladder can be tower-shaped or broad, and this can confuse the interpretation. Patients with dysfunctional voiding, urethral obstruction, or neurogenic bladder have prolonged curves or an interrupted series of curves and low peak and average urine flow rates.

The most important reason for treating enuresis is to minimize the embarrassment and anxiety of the child and the frustration experienced by the parents. Most children with enuresis feel very much alone with their problem, and they frequently have issues of low self-esteem.[20]  Family members with a history of enuresis should be encouraged to share their experiences and offer moral support to the child. The knowledge that another family member had and outgrew the problem can be therapeutic.

Preliminary management focusing on behavioral modification and positive reinforcement is often helpful. The only therapies that have been shown to be effective in randomized trials are alarm therapy and treatment with desmopressin acetate or imipramine. Nonmonosymptomatic enuresis may be more difficult and time-consuming to treat.[21, 22]

Bladder training has not been shown to be effective.[1] With this therapy, the child is asked to ingest large quantities of fluid and to hold the urine in the bladder without voiding until uncomfortable. A therapeutic approach that involves (a) teaching a child not to respond normally to the sensation of a full bladder and (b) prescribing a therapy that is inherently painful is fundamentally without merit. The results of studies that have reported on this therapy either have been methodologically flawed or have demonstrated no significant improvement.

Enuresis is not a surgically treated condition. Treatment usually is not recommended for children younger than 6 or 7 years. However, ectopic ureter and obstructive sleep apnea (OSA) may respond to specific surgical interventions.

Referral to a pediatric otolaryngologist or a pediatric sleep specialist may be appropriate if OSA is suspected.

Patients with primary enuresis (PE) are asked to keep a diary and should return for evaluation on a monthly basis to assess their progress.

A positive attitude and motivation to be dry are important components of treatment. Children with enuresis benefit from a caring and patient parental attitude; punishment has no role whatsoever. A positive approach by the physician is also important for instilling confidence and enhancing compliance. Many children have given up on achieving dryness, and an optimistic attitude must be encouraged. Behavioral modification with positive reinforcement may enhance treatment results. Consistent follow-up is important to assess therapeutic results.

An explanation of the probable cause of the enuresis is important for every family. If a child has no daytime symptoms or has experienced significant dry spells in the past, it is unlikely that a structural abnormality is causing the enuresis. This should be explained to the parents in order to allay any fears about other causes and to reassure them that invasive investigations are not necessary. Parents should be asked to provide specific examples of potential causes that have them worried, so that the physician can address and help relieve these often irrational fears.

Keen attention to a normal daytime voiding pattern is important. The child should be encouraged to void upon awakening, at common transition times and approximately every 1.5-2 hours, before leaving home or school for any reason, and always before bed. With voiding, the child should relax, use optimal posture, and take time to empty the bladder completely.

At school, children should be encouraged to void regularly, at least two or three times daily. A note for the teacher should be written to ensure that the child is allowed regular access to the bathroom. Children should not be expected to wait for scheduled breaks to void. Holding the urine to the last minute must be discouraged.

Children should be instructed to drink liberal amounts during the day and to maintain optimal hydration throughout the entire day. A well-hydrated child is not thirsty when he or she returns home from school and is not thirsty at bedtime. Thirst should be prevented so that a child does not drink excessive amounts in the evening hours before bed. Children who play sports or who are otherwise physically active in the evening after mealtime should be well hydrated for the activity.

Parents should be asked to take the child to the bathroom to void before bedtime. Because this therapeutic measure is designed only to minimize the quantity of fluid in the bladder, full wakefulness is neither necessary nor desirable. Careful monitoring by a parent is necessary for the trip from bed to bathroom and back. Children should go to bed at an hour calculated to offer the optimal number of sleep hours for their age.

If attention to the above preliminary management program for up to 3 months does not result in dryness, then either alarm therapy or pharmacologic therapy should be considered. Because neither therapy has been shown to be consistently superior to the other, the preliminary choice should be dictated by the clinical setting, the family preference, and the experience of the practitioner.

Alarm therapy offers the possibility of sustained improvement of enuresis and should be considered for every patient. It is reported to alleviate bedwetting by increasing nocturnal bladder capacity or by providing enhanced arousal; it does not reduce nocturnal urine output.

Numerous types alarms are available (eg, using sound, vibration, code words, or a combination of a sound and an electrical impulse). The alarm should be attached at bedtime to the underwear or pajamas in a position chosen to permit prompt sensing of wetness. Although most children with enuresis do not awaken to the alarm, they often stop emptying the bladder. When the alarm sounds, a parent must help the child wake to full consciousness and attend to the bathroom to finish voiding. After the sheets and underwear or pajamas are changed, the child should be returned to bed and the alarm reset.

Some successfully treated children replace enuresis with nocturia, and others sleep dry without the need to void at night. Some improve within the first 2 weeks of treatment, and others improve only after several months. A Cochrane review of 56 randomized trials involving 3257 children concluded that alarm therapy is beneficial.[17] About two thirds of children on alarm therapy were dry, but about half relapsed, so that only about a third remained dry at 6-month follow-up.

Optimal results occur when the child is well motivated. Older children usually have better developed motivation. Parental motivation and involvement are also important. The parent should believe that the approach is worthwhile and should be prepared to participate every night for at least 3 consecutive months. Close biweekly or monthly follow-up care is important to sustain motivation, troubleshoot technical problems, and otherwise monitor the therapy.

In successfully treated children, alarm therapy should be continued for at least 3 months and for 1 month after sustained dryness (at least 90% dry nights). Relapses are common, developing in 29-66% of children, and sometimes respond to further alarm therapy. If the child is still wet after a minimum of 3 months of consecutive use, alarm therapy can be discontinued and considered unsuccessful. Failure does not preclude future successful treatment once the child is older and more motivated.

Desmopressin acetate

Desmopressin acetate is the preferred medication for treating children with enuresis. A Cochrane review of 47 randomized trials concluded that desmopressin therapy reduces bedwetting; children treated with desmopressin had an average of 1.3 fewer wet nights per week.[18]

The tablet and the orally disintegrating tablet (melt) have similar efficacy. The orally disintegrating tablet is not approved for treatment of pediatric enuresis in the United States. The intranasal formulation carries a black box warning from the US Food and Drug Administration (FDA) and is no longer recommended for enuresis, because of the risk for severe hyponatremia that can cause seizures and death.[23]

Desmopressin acetate tablets or orally disintegrating tablets should be administered just before bedtime; the agent appears to be effective for about 8 hours. The recommended starting dose for the tablet is 0.2 mg, and the drug can be titrated as necessary to a maximum dose of 0.6 mg. The equivalent starting dose for the orally disintegrating tablet is 120 µg, and the maximum dose is 360 µg.

Desmopressin’s immediate onset of action allows the flexibility of choosing either intermittent administration for special occasions or long-term use to maintain dryness. For long-term use, desmopressin can be prescribed in 3-month quantities and discontinued between prescriptions to determine whether the wetting persists and thus whether continued use is justified.

The safety profile of desmopressin acetate is favorable, and many studies have documented low rates of adverse effects. For the tablet, the incidence of minor adverse events is not significantly different from that for a placebo.

The only serious adverse effect reported in patients with enuresis treated with desmopressin is the development of seizure or other central nervous system (CNS) symptoms due to water intoxication. A review of case reports of water intoxication associated with desmopressin confirmed that excess fluid intake was a feature in at least six of 11 individuals.[24]

This serious adverse effect can be prevented by educating the patient not to consume an excess of fluids on any evening in which desmopressin is administered. A maximum of 1 cup of fluid should be offered at the evening meal, no more than 1 cup between mealtime and bedtime, and no fluid at all within the 2 hours preceding bedtime. Early symptoms of water intoxication include headache, nausea, and vomiting. If these symptoms develop, the medication should be discontinued and the child promptly assessed by a physician.

Combination of alarm therapy with desmopressin therapy has been reported to result in dryness not achievable with either therapy alone.

Anticholinergic agents

An anticholinergic medication might be helpful in some patients, especially those with overactive bladder, dysfunctional voiding, or neurogenic bladder. These medications reduce uninhibited detrusor (bladder muscle) contractions, increase the threshold volume of the bladder  at which an uninhibited detrusor contraction occurs, and enlarge the functional bladder capacity.

Oxybutynin chloride and tolterodine are commonly prescribed in this setting. Oxybutynin chloride also has antispasmodic and analgesic properties. Anticholinergic adverse effects include dry mouth, blurred vision, facial flushing, constipation, poor bladder emptying, and mood changes. Constipation as an adverse event is especially problematic in that it might increase the risk for wetting.

Anticholinergic medications should not be administered during a fever, because one anticholinergic effect is a decrease in sweating. Similarly, they should be used with caution in children who exercise or play strenuously, especially on hot days.

Oxybutynin is given in a dose of 2.5-5 mg administered at bedtime. A long-acting preparation is available but has not been approved for use in children. Tolterodine is not approved for pediatric use. Flavoxate, a urinary spasmolytic, might be helpful in some patients with overactive bladder and dysfunctional voiding but is approved only for children older than 12 years.

The combination of desmopressin acetate and oxybutynin chloride might be efficacious in children with overactive bladder or dysfunctional voiding who respond to anticholinergic therapy with improved daytime symptoms but who continue to wet at night. Long-acting preparations of oxybutynin may be more efficacious for combined use with desmopressin and are thus recommended.

Imipramine

A Cochrane review of 64 randomized trials concluded that imipramine is effective in reducing bedwetting; children treated with imipramine had one fewer wet night per week.[19] The relapse rate is high when the medication is discontinued. The usual dose, taken 1-2 hours before bedtime, is 25 mg for patients aged 6-8 years and 50-75 mg for older children and adolescents.

Adverse effects include constipation, difficulty initiating voiding, irritability, drowsiness, reduced appetite, and personality changes. Imipramine overdose can be fatal, and a cautionary warning is necessary with every prescription. Because of the unfavorable adverse effect profile ( especially cardiac side effects) and the significant risk of death with overdose, the World Health Organization (WHO) does not recommend imipramine for the treatment of enuresis.

Children should be instructed to drink a liberal amount during the day, to maintain good hydration throughout the day, and to drink enough to prevent thirst when they arrive home from school and at bedtime. Children who play sports in the evening should be optimally hydrated prior to the activity.

Children should be assessed several months after the initial appointment to monitor progress and to fine-tune the treatment recommendations. Children who do not show any improvement, notwithstanding the best efforts of the child and family, should be referred to a pediatric urology or nephrology program for assessment and for determination of whether further investigations are required and whether other treatment options should be implemented.

Pharmacologic management plays an important role in the treatment of bedwetting. Three pharmacologic approaches are currently considered: desmopressin acetate, anticholinergic medications, and imipramine.

Class Summary

Secretion of vasopressin at night reduces urine output. Water is conserved and concentrated by increasing the flow in the kidney through the collecting tubules to the medullary interstitium.

Desmopressin acetate is a synthetic analogue of antidiuretic hormone (ADH). The mechanism of action is presumed to be a reduction in overnight production of urine.

It was later found that some children with bedwetting had lower nocturnal levels of ADH than children who were dry at night.

This finding provided a scientific rationale for desmopressin use; however, not all children with bedwetting have lower levels of ADH at night, overproduce urine at night, or respond to desmopressin. In addition, not all children who respond to desmopressin have lower levels of ADH or overproduce urine at night before being treated with the medication.

Desmopressin, oral (DDAVP)

Desmopressin increases the cellular permeability of collecting ducts, resulting in reabsorption of water by kidneys. It is formulated as a tablet, a disintegrating melt, and as a nasal spray. Because of the risk for severe hyponatremia, the intranasal formulation is no longer indicated for primary enuresis.

Class Summary

Most children with bedwetting have a small functional bladder capacity at night. Other children with bedwetting also have daytime symptoms of frequency and urgency. These children might benefit from treatment with an anticholinergic medication that allows the bladder to hold more urine. Outside of these situations, treatment with an anticholinergic medication is not likely to decrease the incidence of bedwetting.

Oxybutynin (Ditropan XL, Gelnique, Oxytrol)

Oxybutynin should be considered in children who are likely to have small functional bladder capacity either only at night or throughout the day. Daytime symptoms that might indicate potential for therapeutic benefit include frequency, urgency, and incontinence. Nighttime symptoms include wetting more frequently than once per night. It is not approved for children younger than 12 years.

Tolterodine (Detrol, Gelnique, Oxytrol)

Tolterodine is a competitive muscarinic receptor antagonist for overactive bladder; it differs from other anticholinergic drugs in that it has selectivity for the urinary bladder over salivary glands. Tolterodine is used in patients likely to have small functional bladder capacity either only at night or throughout the day. Daytime symptoms that may indicate potential for therapeutic benefit include frequency, urgency, and incontinence. Nighttime symptoms include wetting more frequently than once per night.

Flavoxate (Urispas)

Flavoxate is used for symptomatic relief of incontinence. It has anticholinergic effects and exerts a direct effect on muscle. It counteracts smooth muscle spasm of the urinary tract.

Class Summary

Imipramine was first prescribed for bedwetting in an era when psychological causes were considered common. The modern understanding is that psychological causes are not a cause of enuresis. The mechanism whereby imipramine improves bedwetting is not clear. Current theories include central nervous system (CNS)-related or local bladder-related effects.

Imipramine (Tofranil)

Imipramine facilitates urine storage by decreasing bladder contractility and increasing outlet resistance. It inhibits reuptake of norepinephrine or serotonin at the presynaptic neuron.