Enuresis

# Overview
Enuresis is involuntary urination beyond the age of anticipated control. The two major forms of enuresis are diurnal enuresis (or daytime wetting), and nocturnal enuresis (bedwetting or nighttime wetting). This condition adversely affects the whole family. Enuresis impacts the child's overall development and is mostly associated with poor scholastic performance. It also has a major psychosocial burden on the parents, resulting in poorer quality of life.  Treatment of enuresis should be holistic, targeting the management of enuresis in children as well as psychoeducation of the parents.

# Historical Perspective
- Enuresis has been a major social problem since ancient times.
- The term enuresis is derived from the Greek word 'enourein' that means to void urine.
- Initially, enuresis was considered a psychiatric disturbance. It has been followed by the clearer theory of maturation delay along with the major role of hereditary factors. 
- After multiple studies, it has been found that enuresis may be the cause and not the result of a psychiatric disorder.
- As early as 1550 BC, the problem of childhood incontinence was described in the Ebers papyrus.
- Prayers were an important component of the treatment options in the middle ages.
- Belladonna, camphor, opium, and ergot were administered to enhance the bladder muscle tone in the eighteenth century.
- In 1948, a direct conditioning-based treatment modality called the alarm or bell-and-pad system was introduced.
- Initially, psychotherapy was accepted as the only possible method to treat enuresis, and there was a lot of skepticism about the conditioning treatment. 
- Gradually, the alarm system became one of the most efficacious non-pharmacological management options worldwide.

# Classification
- According to International Childrens Continence Society (ICCS), enuresis consists of wetting by a child who has passed his or her fifth birthday.
- Enuresis is considered significant if it occurs more than once a month and at a frequency of at least three times per three months. Enuresis is termed frequent if there are more than three episodes a week.
- Enuresis is broadly divided into two types: daytime wetting and nighttime wetting.
- Primary enuresis is the condition used for a child that was never continent. On the other hand, the term secondary enuresis is used for new-onset symptoms after a dry period of at least six months.
- If bedwetting and nocturia are the only symptoms, the condition is known as monosymptomatic enuresis (MEN). If there are concomitant daytime voiding symptoms such as incontinence, frequency, urgency, or low voided volume, the condition is termed nonmonosymptomatic enuresis (NMEN).
- MEN occurs without any other symptoms of bladder dysfunction whereas NMEN is associated with dysfunction of the lower urinary tract with or without daytime incontinence.

# Pathophysiology
- Some of the underlying pathophysiological mechanisms for enuresis are:
Altered antidiuretic hormone profile
Sleep arousal failure
Delayed bladder maturation
Abnormal bladder function
Detrusor instability
Excess urine production during sleep
- Altered antidiuretic hormone profile
- Sleep arousal failure
- Delayed bladder maturation
- Abnormal bladder function
- Detrusor instability
- Excess urine production during sleep
- Nocturnal enuresis may be associated with lower urinary tract symptoms such as urgency, and frequency, with an overactive bladder. These may be further associated with constipation.
- Nocturnal enuresis mostly occurs early in the night, mainly in sleep stage 2 and deep sleep. Children with nocturnal enuresis and nocturnal polyuria differ in hemodynamics and autonomic activation at night compared to controls.
- Children with nocturnal enuresis often have sleep-disordered breathing and disturbed sleep due to awakenings and arousal.
- Periodic limb movements (PLM) have also been seen in children with refractory enuresis.

# Differential Diagnosis
Enuresis should be differentiated from other causes
- Medication side effects
- Neurogenic bladder
- Renal diseases
- Constipation
- Diabetes Mellitus
- Detrussor areflexia or overactivity
- Urinary tract infection
- Posterior urethral valve
- Emotional disturbances
- Underlying conditions resulting in polyuria such as sickle cell disease, and diabetes insipidus
- Spinal dysraphism
- Nephronopthisis
- Psychogenic polydipsia
- Pinworm infection
- Upper airway tract obstruction
- Other urological dysfunction
- Other neurological diseases

# Epidemiology and Demographics

## Prevalence
- The prevalence of enuresis is
5,000-10,000 per 100,000 (5%-10%) among children 5 years of age
3,000-5,000 per 100,000 (3%-5%) among children 10 year of age
1,000 per 100,000 (1%) among individuals 15 years of age or older
- 5,000-10,000 per 100,000 (5%-10%) among children 5 years of age
- 3,000-5,000 per 100,000 (3%-5%) among children 10 year of age
- 1,000 per 100,000 (1%) among individuals 15 years of age or older

## Age
- Enuresis is found to be more prevalent in first-born children.
- If enuretic symptoms persist into adulthood, they are less likely to resolve with time.
- Primary nocturnal enuresis in adults may represent a more pronounced form and have a more serious social and psychological effect on affected individuals.

## Gender
- Most studies show a predominance of enuresis in males, whereas some others show no gender predominance.

## Race
- Sickle-cell anemia (SCA) is the most common inherited hemoglobinopathy in the African population. It has been found that children and adolescents with SCA are at increased risk of nocturnal enuresis.

# Risk Factors
- The risk factors for the development of enuresis are 
Delayed or lax toilet training
Genetic predisposition
Encopresis
Psychosocial stressors
Family history of enuresis (such as maternal history, and sibling history of bedwetting)
Low socioeconomic status
Snoring
Heavy and late supper
Deep sleeper
Sleepwalking
Being introverted and shy
- Delayed or lax toilet training
- Genetic predisposition
- Encopresis
- Psychosocial stressors
- Family history of enuresis (such as maternal history, and sibling history of bedwetting)
- Low socioeconomic status
- Snoring
- Heavy and late supper
- Deep sleeper
- Sleepwalking
- Being introverted and shy

# Natural History, Complications, and Prognosis

## Natural History
- Most children with enuresis eventually attain bladder control.
- It has been found that the prevalence of nocturnal enuresis gradually decreases with increasing age and many may achieve spontaneous resolution.
- The link between childhood enuresis and adult detrusor instability is observed to be stronger for men than women.

## Complications
- If intranasal desmopressin is used in the treatment of enuresis, some patients may develop seizures or altered mental status within 14 days of starting the medication.
- The accidental poisoning of young children by medications (tricyclic antidepressants) prescribed for enuresis has been reported.

## Prognosis
- The prognosis of secondary nocturnal enuresis due to cystitis, constipation, diabetes mellitus, seizure disorder, acquired urethral obstruction, and hyperthyroidism, is excellent once the underlying cause has been treated successfully.
- Patients with nocturnal enuresis due to psychological causes generally improve over time with psychosocial alterations or psychotherapy.

# Comorbidities
- Enuresis exists with various conditions
Attention-deficit hyperactivity disorder (ADHD)
Obstructive sleep apnea syndrome
Sickle cell anemia
Childhood obesity
Oppositional-defiant disorder (ODD)
Tic disorder
Conduct disorder
Bipolar affective disorder
Post-traumatic stress disorder (PTSD)
- Attention-deficit hyperactivity disorder (ADHD)
- Obstructive sleep apnea syndrome
- Sickle cell anemia
- Childhood obesity
- Oppositional-defiant disorder (ODD)
- Tic disorder
- Conduct disorder
- Bipolar affective disorder
- Post-traumatic stress disorder (PTSD)

# Diagnostic Criteria

## DSM-5 Criteria for Enuresis
- Enuresis is included under the elimination disorders.
- The diagnostic guidelines are 
Repeated voiding of urine into bed or clothes, either involuntarily or intentionally.
The behavior is clinically significant manifested as either at least twice a week for a minimum of three consecutive months or with significant impairment of social, occupational, or other areas of functioning.
Chronological age is a minimum of 5 years.
The behavior is not attributable to the physiological effects of a substance (such as a diuretic, an antipsychotic ) or another medical condition (such as diabetes, spina bifida, or seizure disorder).
- Repeated voiding of urine into bed or clothes, either involuntarily or intentionally.
- The behavior is clinically significant manifested as either at least twice a week for a minimum of three consecutive months or with significant impairment of social, occupational, or other areas of functioning.
- Chronological age is a minimum of 5 years.
- The behavior is not attributable to the physiological effects of a substance (such as a diuretic, an antipsychotic ) or another medical condition (such as diabetes, spina bifida, or seizure disorder).
- Specify if:
Nocturnal only: Passage of urine only during nighttime sleep.
Diurnal only: Passage of urine only during waking hours.
Nocturnal and diurnal: A combination of the two subtypes.
- Nocturnal only: Passage of urine only during nighttime sleep.
- Diurnal only: Passage of urine only during waking hours.
- Nocturnal and diurnal: A combination of the two subtypes.

## ICD-10 Criteria
- The criteria for the diagnosis of nonorganic enuresis are described in the section 'F98.0'.
- It emphasizes that enuresis should not be diagnosed in a child under the age of five years or mental age of four years.
- This category includes urinary incontinence of nonorganic origin or functional enuresis.

# Treatment
- The patients are treated by behavioral modifications, medications, or a combination of both.
- Medications are usually avoided in children under seven years of age.
- Parents should be reassured about their child's health and psychoeducated about eliminating guilt, and punishment.
- It is extremely important that the psychosocial consequences of the symptom be addressed with sensitivity during the treatment of enuresis.

## Non-pharmacological management
- Enuresis alarms are effective in patients with primary nocturnal enuresis and should be considered for older, highly motivated children from cooperative families.
- In the long-term follow-up, it has been observed that the enuretic alarm device also provide a full response rate in children with primary nocturnal enuresis.
- Hypnotherapy is found to be an effective alternative or adjunctive treatment for enuresis in children.
- Acupressure administered by the parents could be an alternative non-pharmacological treatment. It has the advantages of being non-invasive, cost-effective, and painless.

## Pharmacological management
- Desmopressin, an antidiuretic hormone (ADH) analog, is also called as arginine vasopressin (AVP). It can resolve primary nocturnal enuresis by reducing urine production at the night.
- It has been found that a structured withdrawal program from sublingual formulation of fast-melting oral desmopressin lyophilisate (MELT) therapy doesn't offer advantages compared to abrupt discontinuation.
- Patients respond rapidly to desmopressin as compared to alarm systems. However, it has been observed that more children improve from psychological (urine alarm) than from pharmacological interventions. 
- Tricyclics and desmopressin are effective in reducing the number of wet nights while taking the drugs, but most children relapse after stopping active treatment. On the contrary, relapse rates are lower after alarm treatment.
- Imipramine is useful for enuresis when other treatment options such as desmopressin, alarm, and anticholinergics have failed in older children.
- Oxybutynin has shown partial response in the management of nocturnal enuresis.

## Combined therapy
- Combined pharmacological and non-pharmacological interventions are effective for resistant cases.
- Many studies have found that the combined therapy (enuresis alarm, bladder training, motivational therapy, and pelvic floor muscle training) is more effective than each component used alone.
- The combination of desmopressin and alarm is also helpful for severe cases with other behavioral problems.
- Pharmacotherapy can provide early relief, while behavioral intervention may lead to more long-term benefits. Therefore, the positive effect of achieving dry nights with pharmacotherapy can encourage the patient to sustain behavioral therapy.