Continuing Education Activity

Enuresis refers to the involuntary loss of urine during sleep that occurs at least twice a week in children older than 5 years of age (or the developmental equivalent) for at least 3 months, and it is the most common urologic complaint in pediatric patients. Primary enuresis is that which occurs in a child who has not been dry for at least 6 months, whereas secondary enuresis is the one that has an onset after a period of nocturnal dryness of at least 6 months. Also, the enuresis is classified as monosymptomatic or non-monosymptomatic, with the latter correlating with daytime incontinence or other lower urinary tract symptoms like urgency. This activity reviews the definition, pathophysiology, evaluation, and management of enuresis and reviews the role of the interprofessional team in identifying and managing patients with this condition.

Objectives:

• Describe the epidemiology of enuresis.
• Review the appropriate history, physical, and evaluation of enuresis.
• Summarize the treatment and management options available for enuresis.
• Outline interprofessional team strategies for improving care coordination and communication to advance enuresis and improve outcomes.

Introduction

Enuresis refers to the involuntary loss of urine during sleep that occurs at least twice a week in children older than 5 years of age (or the developmental equivalent) for at least 3 months, and it is the most common urologic complaint in pediatric patients.[1][2][3][4]. Primary enuresis is when it occurs in a child who has not been dry for at least 6 months, whereas secondary enuresis is the one that has an onset after a period of nocturnal dryness of at least 6 months [2], [3]. Also, the enuresis classifies as monosymptomatic or non-monosymptomatic, with the latter correlating with daytime incontinence or other lower urinary tract symptoms like urgency.[5] Moreover, the enuretic episodes are considered frequent if they occur 4 or more times per week.[6]

To avoid confusion, the International Children’s Continence Society has defined enuresis as wetting that occurs at night, whereas they no longer refer to daytime incontinence as diurnal enuresis.[2]

Nocturnal enuresis is not a benign disorder; it has severe repercussions for the child and the family. Children are often punished and are at risk for physical and emotional abuse. Many children become isolated, lack self-esteem, and have poor academic performance. This activity highlights a detailed understanding of this very common yet misdiagnosed condition.

Etiology

Enuresis is considered a multifactorial entity with a strong genetic component that may be influenced by comorbidities and immaturity of the central nervous system bladder control mechanisms.[7] Although specific genes remain unidentified,[7] studies suggest that inheritance of the condition is in an autosomal dominant pattern with 90% penetrance.[3] Studies show a 44% chance of enuresis in children with one affected parent and 77% in those with two affected parents.[2][3]

Once thought to play a causal role, psychological or psychiatric factors are now considered to be either a consequence of enuresis or comorbidity.[8]

Other Conditions associated with nocturnal enuresis include:

• Constipation
• Urethral obstruction
• Ectopic ureter
• Cystitis
• Diabetes insipidus
• Disorders of sleep arousal
• Small bladder capacity
• Overactive bladder

Epidemiology

The prevalence of enuresis is similar across cultures.[2] The prevalence varies with age, with 15% of 7-year-olds,[2] 10% of 10-year-olds,[3] 2% of adolescents,[7] and 0.5 to 1% of adults being affected by the condition.[9][5] Enuresis is more common in boys when compared to girls, with a ratio of 3 to 1, but this difference tends to decrease after age 10.[3][5]

Additionally, 20 to 30% of patients with enuresis also suffer from at least one psychological, behavioral, or psychiatric disorder, a rate twice as high as that of the general population.[8] The most common of these comorbidities is attention deficit and hyperactivity disorder,[8] and the postulate is that a common sleep disturbance could link both conditions.[9] Other comorbid conditions in this category include autism spectrum disorder, oppositional defiant disorder, and mood disorders.[3]

Also, there is an association between sleep-disordered breathing and enuresis.[4][2] These patients have high levels of atrial natriuretic peptide leading to inhibition of the renin-angiotensin-aldosterone pathway and increased diuresis,[2] but other proposed links between both entities are an inadequate arousal response secondary from sleep fragmentation due to disordered breathing and bladder stimulation from elevated abdominal pressure resulting from an increased respiratory effort to compensate for an obstructed airway. Enuresis tends to be cured, or its frequency drastically diminished, after tonsillectomy and adenoidectomy in these patients.[2][10]

Patients with sickle cell disease also show a higher incidence of enuresis.[11]

Pathophysiology

Researchers suspect several factors to be involved in the pathophysiology of enuresis, with each patient exhibiting different combinations of these, thus explaining why some individuals respond to specific therapies that are unsuccessful in others.[9] As a result, the understanding of enuresis is now a group of disorders rather than a single entity.

The main pathophysiological mechanisms involved are nocturnal polyuria, bladder dysfunction, and high arousal thresholds.[9] Nocturnal polyuria may be associated with vasopressin deficiency or alterations in its circadian release.[2] Bladder dysfunction is more common in patients who also have daytime incontinence, and it can manifest as diminished functional bladder capacities or abnormal urodynamics,[2] as in nocturnal detrusor hyperactivity, which could be associated with constipation, probably through bladder distortion from a full rectum.[9] High arousal thresholds are now seen as either a contributing factor or a consequence of enuresis, given that disturbed sleep from an obstructed airway or a contracting bladder can lead to this difficult arousal.[9] Furthermore, the maturational delay hypothesis also merits consideration, and it has support from the finding of a higher prevalence of motor clumsiness, perceptual dysfunction, and speech disturbances in children with enuresis.[2]

History and Physical

The history and detailed physical examination are key to diagnosing this condition. The initial step in the evaluation of nocturnal enuresis is obtaining a history. It is essential to determine whether the enuresis is primary or secondary, its pattern (number of episodes in one night and number of nights per week), and caffeine and evening fluid intake. Also, it is just as important to determine the presence of nocturnal polyuria (elicited by asking the parents if the enuretic episodes involve large amounts of urine), polydipsia, dysuria, urgency, frequency, daytime incontinence, abnormal urinary stream, and constipation.[2] The child that has multiple voiding episodes of variable amounts of urine throughout the night can be presumed to have a component of an overactive bladder or one of small capacity. Other pertinent questions include family history of enuresis,[2] history of recurrent urinary tract infections (which may point to underlying bowel or bladder dysfunction), sleep disorders, snoring or a diagnosis of sleep-disordered breathing, and the use of chronic medications, since some drugs, may be associated with secondary enuresis.[3] Patients should have screening for psychological or behavioral disturbances, including attention deficit and hyperactivity disorder and learning disabilities, and obtaining a developmental history is also necessary.[8][2]

The physical exam is unremarkable in most affected children. Clinicians should look for distended bladder, rectal exam consistent with fecal impaction,[2] phallic or meatal anomalies in boys and labial adhesions or urethral anomalies in girls, abnormal muscle tone, sensation, or deep tendon reflexes, and skin changes suggestive of occult spinal dysraphism (tuft of hair or sacral dimples).[2]

Evaluation

The laboratory tests besides a urinalysis are usually unnecessary since this test will show alterations in specific gravity in diabetes insipidus, glycosuria in case of diabetes mellitus, and the presence of nitrites leukocyte esterase, leukocytes, or bacteria in case of infection.[2] Moreover, the non-monosymptomatic enuresis and lack of response to therapy may warrant additional workups,[2] like renal and bladder ultrasound, including measurement of post-void residual volume, measurement of urine flow rate, urodynamics studies, and anorectal manometry.

Treatment / Management

The treatment of this common condition can be tailored according to the patient's underlying cause, and monitoring of treatment plays a crucial role in a successful response. After identifying the term, it should ideally be treated early, preferably no later than age 6 years.[7] The treatment choice should be tailored to the patient’s most likely underlying pathophysiology and coexisting disorders,[9] and it is essential to take into account that the patient’s and family’s motivation is a significant factor in the success of the intervention.[7] If the patient suffers from constipation, this problem should be treated first [12], and any behavioral or psychological comorbidities should be addressed as well since their presence negatively affects treatment adherence leading to lower success rates.[12][8][13] The initial approach is to try behavioral modifications, including restriction of fluid intake 2 hours before bedtime and of dairy 4 hours before bedtime (to avoid osmotic diuresis) and voiding before going to bed.[2]

By a slight difference over desmopressin, the most effective therapeutic modality is the alarm system.[7] Estimates of cure rates are at 66% to 70% and, even though it takes longer and requires strict daily usage to achieve results, it offers a much lower relapse rate after discontinuation than pharmacological options.[2] It is believed to work through conditioned response.[14] Parents are advised to make the patient wear underwear instead of diapers and to wake the patient up when the alarm goes off (i.e., when the device senses moisture) if the child does not wake on his own, and the patient should go to the bathroom when this happens.[2] This treatment works best in monosymptomatic enuresis and in older children who are motivated to achieve dryness.[5] Therapy is considered successful if the patient uses the device without triggering the alarm for one month, which usually requires 3 to 4 months of use.[2]

Pharmacologic therapy is used to help treat the disorder while awaiting natural resolution rather than as a curative measure.[2] It is considered in case of failure to improve with behavioral modifications and alarm therapy or if the clinical scenario is highly suggestive of specific underlying pathophysiology that receives targeted medication therapy.

The initial choice is desmopressin acetate,[2] a synthetic ADH analog, which works by reducing urine production, and thus the presence of nocturnal polyuria is a predictor for an excellent response to desmopressin,[6] while patients with associated bladder dysfunction or daytime incontinence usually show no response or only a partial one. Desmopressin is also useful for camps or sleepovers.[15] The favorable response, defined as a 50% decrease in the number of wet nights, is achieved in 60% to 70% of patients, but relapses after discontinuation of therapy are frequent.[2]

Also, combining the desmopressin and alarm system can lead to response rates close to 100%.[3] Desmopressin is taken 30 minutes before bedtime at a starting dose of 0.2 mg, which can be titrated up after 14 days without an adequate response to a maximum of 0.6 mg until achieving the desired effect.[1][2] Treatment should be discontinued for 2 weeks after 6 months to see if enuresis has resolved.[2] In its oral presentation, it is well-tolerated and adverse effects are rare,[2] but it is still advised to avoid fluid intake or restrict it to 250 mL,[1] one hour before and 8 hours after taking the medication to prevent hyponatremia.[6] Due to a higher incidence of severe adverse effects (mainly those consistent with “water intoxication”), the intranasal formulation does not have approval for use in the treatment of enuresis.[2] It is crucial to keep in mind that treatment with desmopressin should temporarily cease during periods when the patient is at increased risk for electrolyte abnormalities, such as when experiencing fever, gastrointestinal losses, or after vigorous exercise.[2]

Anticholinergic agents are suggested as an add-on therapy to non-responders to desmopressin.[2] Patients with non-monosymptomatic enuresis, overactive bladder, or with small bladder capacity are more likely to respond.[2] Oxybutynin is the most commonly used one, while tolterodine is not FDA-approved for pediatric patients.[1] The adverse reactions of this group of medications include dry mouth and eyes, constipation, flushing, sedation, and cognitive effects.[15]

Furthermore, imipramine, a tricyclic antidepressant, is another pharmacological option that should be reserved for older non-responders to first and second-line treatments. Its mechanism of action has been proposed to involve a central effect at the brainstem level promoting arousal and inhibiting urination, a weak anticholinergic and detrusor antispasmodic effect, increasing ADH release, and suppressing REM sleep.[2] Its response rate is close to 50%, but only 25% of initial responders remain dry long-term after discontinuation, with lower chances if the medication stops abruptly.[2] Adverse effects are uncommon at therapeutic doses but include cardiac arrhythmia, liver toxicity, central nervous system depression, drug interactions, and accidental overdose.[2][1] Some experts suggest screening for long QT syndrome with an electrocardiogram before initiation of therapy.[1] Parents should be advised to store and lock this medication in a safe place out of reach of children.[15]

Differential Diagnosis

The most important to exclude conditions before diagnosing enuresis include

• Bladder dysfunction from infection or neurological conditions,
• Incontinence due to anatomical abnormalities, and
• Polyuria secondary to diabetes mellitus, diabetes insipidus, excessive fluid or diuretic intake, or drugs.

Staging

DSM 5 Criteria

• Recurrent episodes of enuresis, whether intentional or involuntary
• The behavior occurs at least twice a week for a minimum of 3 consecutive months
• The enuresis is associated with significant social distress and poor functioning in school
• The behavior occurs in a child who is at least 5 years
• Behavior is not attributed to any medical condition or medication

Prognosis

Enuresis tends to self-resolve spontaneously, with 15% of affected individuals becoming continent per year.[2]

However, the condition is associated with enormous morbidity. The children are susceptible to emotional and physical abuse. The child often has low self-esteem and has poor academic performance.

Of all the treatments, alarm therapy and treatment with imipramine and desmopressin have the highest success. However, the response is slow and as many as 20% will continue to have enuresis as adults.

Complications

Enuresis has been found to negatively impact the child’s and family’s quality of life,[8][5] lead to low self-esteem,[8][7] mood problems,[3] and high levels of stress.[8] The condition also impairs the patient’s ability to socialize with peers normally. Additionally, evidence that effective treatment of enuresis leads to improvement in the quality of life of patients.[8]

Consultations

Referral to a specialist should be a strong consideration for patients with non-monosymptomatic enuresis since they are more likely to fail standard therapy. Suggestions are that patients who do not respond to treatment after three months should obtain a referral to a specialist.[15]

Deterrence and Patient Education

Families should receive counseling on what are the appropriate and inappropriate behavioral interventions for enuresis. Caregivers should also be informed about the natural history of the condition, the different therapeutic options, and the complications associated with delaying treatment.

Enhancing Healthcare Team Outcomes

Nocturnal enuresis is a very common problem in children, leading to embarrassment, social isolation, and loss of self-esteem. Because many people do not admit to the problem for fear of embarrassment, the exact incidence remains unknown. Because of its significant negative repercussions on the child, the condition is best diagnosed and managed by an interprofessional team. Nurses can assess the effectiveness of therapy, medication compliance and counsel the family or caregivers. Pharmacists can verify dosing and counsel on proper administration. Concerns in these areas require communication with the rest of the healthcare team. Only through this type of interprofessional collaboration can patient outcomes achieve their optimal potential. [Level V]

Healthcare providers should actively ask about enuresis during well-child visits since many families still see it as a disciplinary issue instead of a medical condition. Parents need to understand that punishment has no role in the treatment of this condition and may make the enuresis worse.  The nurse should educate the caregiver on alarm therapy, and the pharmacist should provide information about the drugs, their benefits, and their adverse effects.

The children should be evaluated every few months to monitor progress.

An interprofessional approach involving the primary care provider, a urologist in the setting of refractory or non-monosymptomatic cases, nurses, and different specialists in case of comorbidities, including mental health professionals, is the ideal line of action to achieve better outcomes.[8] [Level 4]