Introduction

Enuresis is classified as an elimination disorder. It is frequently diagnosed in children who wet the bed or fail to establish continence of urine. It is a common disorder frequently seen in outpatient pediatric or urology clinics.[1][2]

Etiology

Many cases of enuresis lack an identifiable cause. Common etiologies in children are constipation and neurodevelopmental disorders. Various etiologies have been discussed, including poor arousal from sleep, delayed bladder maturation, decreased bladder capacity, and decreased vasopressin release. Enuresis has also been attributable to various medical conditions or medications listed in differential diagnoses seen below.[2][3]

Risk factors for enuresis include unusual stress, low socioeconomic status, parental divorce, sibling birth, and family history of enuresis. Enuresis has high genetic susceptibility, with children having a rate of 44% if one parent wet the bed and 77% if both parents had a history of wetting the bed. No specific gene has been linked to enuresis. Studies have found gene linkages on chromosomes 8, 12, 13, and 16.[4][5][6]

Constipation is also a cause of enuresis due to bladder pressure.[7][8]

Epidemiology

Enuresis is seen in 20% of 5-year-old children. It is most frequently diagnosed in children at 7 years old. The prevalence of enuresis in 7-year-old children is 5% to 10%. It is diagnosed in approximately 2% of adults. Enuresis occurs more frequently in boys than girls.[9]

Pathophysiology

A study of the pathophysiology of enuresis found decreased nocturnal antidiuretic hormone (ADH) production in patients with enuresis. Due to the reduced ADH production, the patient has increased urine volume at night, leading to increased voiding. With this underlying pathophysiology in mind, treatments like desmopressin, an ADH analog, are used. Other theories for the pathophysiology of enuresis have included decreased bladder capacity or reduced arousal from sleep.[10]

History and Physical

The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) classifies enuresis as an elimination disorder. The DSM-5 Diagnostic Criteria are as follows:[11]

1. Whether involuntary or intentional, repeated voiding of urine into bed or clothes.
2. The behavior should be clinically significant, with either:
   • Frequency of at least two times a week for at least three months consecutively
   • Clinically significant distress
   • Academic (occupational), social, or other areas of functioning are impaired.
3. A chronological age of at least 5 years or equivalent developmental level is required.
4. The behavior is not attributable to another medical condition (seizure disorder, diabetes, urinary tract infection, spina bifida, neurogenic bladder, etc.) or substance (diuretic, antipsychotic, etc.).

Specifiers include the following subtypes:

• Nocturnal-only is during nighttime sleep.[2][12]
• Diurnal-only is during waking hours.[13]
  • Diurnal-only, which is involuntary, is also called "urinary incontinence." The sub-groups include:
    • Urge incontinence (frequent urination due to increased urge to urinate)
    • Stress incontinence (during periods of intra-abdominal pressure increase, such as during Valsalva maneuvers)
    • Voiding postponement (situational delay in urination, such as in public places)
    • Giggling incontinence (during laughter)
• Nocturnal and diurnal

Classification of enuresis:

• Primary enuresis means continence was never established.[14]
• Secondary enuresis means continence was achieved and then lost. 

In addition to the standard medical, surgical, and family histories, it is important to obtain more details regarding toilet training, nutrition, and sleep histories. Ask about any family history of enuresis and specific detailed questions that rule out differential diagnoses, such as urinary tract infection, constipation, seizure, diabetes, or sleep apnea. 

Obtain a voiding diary that logs the wet days or wet nights (voiding pattern), the volume of urine, the volume of fluid intake (hydration history), and the urge to urinate on a provided scale. It can also include bed and wake times. Ideally, the diary should be done for at least three days consistently. Urine is collected using a collecting pan, also known as a "Texas Hat." The collecting pan can be obtained from the physician's office or medical supply stores. 

Physical exam should include vital signs, neurological exam, and examination of the tonsillar size, suprapubic area, abdomen, external genitalia, and lumbosacral spine. 

Evaluation

Urinalysis is often required to rule out urinary tract infection (UTI).[15]

Bladder scan, uroflowmetry, or ultrasonography with post-void is often required for cases of suspected underlying anatomical cause. Consider voiding cystourethrography, cystoscopy, or urodynamic studies if abnormalities are found on ultrasonography.[16][17][18][17] 

Sleep study is recommended in cases of suspected sleep disorder. In cases with decreased arousal from sleep, it is important to obtain a workup for obstructive sleep apnea (OSA).[4][19][3]

• Epworth Sleepiness Scale (EPS) should be completed prior to ordering a sleep study. 

Imipramine level from serum is recommended in patients on the medication to ensure the medication does not reach a toxic level or obtain a therapeutic level. The therapeutic index (TI) for imipramine is greater than 60 ng/ml.[20][21]

Seizure workup to assess for underlying epileptiform activity includes an MRI of the brain and an electroencephalogram (EEG). 

Abdominal X-ray if constipation is suspected. 

Treatment / Management

Treatment is rarely initiated if a child is less than 7 years old.

Non-Pharmacologic Treatment

• Reassurance that the enuresis will improve is the first piece of education to be given to parents about their child's enuresis. When parents in a study were explained options of treatment versus no treatment, no treatment was selected by more (23%) as parents wanted reassurance.[22]
• the bell and pad method is the most effective first-line treatment, with a success rate of 75%. It is recommended that the method be continued until there are 21 to 28 dry nights. For the bell and pad method to be effective, a child must be able to wake to the pad alarm. In a 1-year follow-up study comparing outcomes of children whose parents chose various treatment modalities, those who chose the alarm were more likely completely dry at follow-up.[9][23][1][22]
• Planned nighttime awakenings are useful for patients who are unable to wake to an alarm.[1]
• Restricting fluids before bedtime is also helpful in decreasing nighttime enuresis.[1]
• Bladder training consists of teaching the patient to hold their urine for an increased amount of time. Bladder training is useful for patients with nocturnal and diurnal enuresis.[1]
• Motivational therapy for the patient and caregiver may be required before initiating the behavioral interventions listed. If a patient is not motivated for treatment, they can have motivational therapy or the treatment can be postponed until motivation improves.[24][25][26]

Pharmacologic Treatment 

• There is a higher rate of relapse with pharmacologic treatment compared to the bell and pad method. 
• It is important to treat underlying etiologies, such as constipation, as these patients may be less responsive to desmopressin or imipramine.[8]
• Desmopressin is an anti-diuretic hormone (ADH) analog FDA-approved for enuresis that decreases the production of urine. The oral form can be given in doses between 0.1 to 0.6 mg/day. The oral form should only be administered, as the intranasal formulation has an FDA alert for hyponatremia-induced seizures. Studies indicate that 50% of patients treated with desmopressin improve, and 25% obtain total dryness. The medication is given 1 hour before bedtime. Due to the risk of relapse with discontinuation of desmopressin, a gradual taper is recommended.[27][28][1]
• Imipramine is a tricyclic antidepressant (TCA) that is FDA-approved for the treatment of enuresis in children at least 6 years old. The medication causes relaxation of the detrusor muscle of the bladder due to its anticholinergic effects. Relaxation of the detrusor muscle leads to decreased bladder contractility and enuretic episodes. The medication also increases vasopressin. The starting dose is 25 mg, and the medication is increased every seven days to a goal dose between 75 to 125 mg/day. Studies indicate that 60% of patients treated with imipramine experience an effect. Once an effect is obtained, a taper should be tried every three months. The response is found in studies to correlate with the adverse effects of dry mouth. The medication is given 1 hour before bedtime.[9][27][1][20][21]
• Off-label treatments include oxybutynin, clonidine, propranolol, and other tricyclic antidepressants.[29][9][30]

A study of various treatment modalities (behavioral strategies, desmopressin) found that some participants improved in the first week of the study before treatment started. The study demonstrated that the process of obtaining medical help itself could improve enuresis in some cases.[31]

Differential Diagnosis

The following should be ruled out or considered in the differential diagnosis prior to diagnosing enuresis: 

Normal development is children meeting milestones of being dry by day around 2 years old, dry by night around 3 years old, and then able to toilet alone at 4 years old. At 5-years-old, 15% of the children remain incontinent of urine. Due to these normal development milestones, enuresis cannot be diagnosed in children under 5 years old.[1]

Medical Conditions

These include urinary tract infection (UTI), diabetes mellitus (DM), diabetes insipidus (DI), urethritis, seizure disorder, sickle cell disease, obstructive sleep apnea (OSA), neurogenic bladder, spina bifida, sleep disorder, genitourinary malformation, hyperthyroidism, constipation, central hormone abnormality, delayed bladder maturation, decreased bladder capacity, neurodevelopmental disorders [19][3]

• It is important to rule out seizures as a cause of enuresis or micturition, as enuresis may occur during the ictal period. [32] 

Medication-induced

Known causes include selective serotonin reuptake inhibitors (SSRI), bupropion, diuretics, and antipsychotics (risperidone).[13]

Comorbidities

• Attention deficit hyperactivity disorder (ADHD)[33]
• Neurodevelopmental disorders[33]
• Other psychiatric conditions are comorbid with secondary rather than primary enuresis.[33]

Prognosis

Younger children and girls achieve remission at higher rates than older children or boys. The prognosis is often poor if the patient has a comorbid mental health condition, language disorders, family stress, decreased bladder capacity, testicular disorders, or is a deep sleeper.[34][35]

Complications

Children with enuresis often experience increased stress, shame, and embarrassment due to enuresis. Other complications include genitourinary skin infections or rashes. Purchasing diapers, pull-ups, or replacing soiled linens or mattresses is also a financial burden. In some cases, enuresis can continue into adolescence and adulthood.[36]

Consultations

• Urology or nephrology referral is recommended when further workup is needed in cases that fail to respond to the bell and pad method or desmopressin.[23]
• Neurology referral is important in cases of expected underlying neurological or seizure disorders.[37]
• Endocrinology referral is recommended in cases of suspected diabetes mellitus (DM), hormone abnormality, or hyperthyroidism.[38][39][40]
• Otolaryngology referral is recommended if obstructive sleep apnea is suspected. 
• Psychiatry or psychology referral is useful in cases with comorbid psychiatric conditions or cases requiring motivational therapy before the bell and pad method. A psychiatrist can provide therapy and prescribe medications to treat enuresis.[23]

Deterrence and Patient Education

Patients and their families should direct questions to their interprofessional team. The team will provide information on the most likely etiology of the enuresis. Parents will be provided with the risks, benefits, and alternatives of various treatment options. 

Parents should be provided psychoeducation that enuresis is common, not volitional, and resolves with time. Parents should be aware that children can develop stress and lowered self-esteem due to punishment or shame from enuresis. Parents should avoid blaming their children for enuresis. Parents should limit the intake of fluids in the evening. Children should be encouraged to go to the bathroom frequently during the day and before bedtime.[2] 

Enhancing Healthcare Team Outcomes

Effective treatment of patients with enuresis requires interprofessional communication and collaboration to improve patient outcomes. Healthcare providers should monitor children longitudinally for resolution, along with monitoring for the potential for associated urological, endocrine, and neurological abnormalities.[2]