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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 6  |  Issue : 1  |  Page : 4-14

A clinical review of enuresis and its associated psychiatric comorbidities


1 Consultant Psychiatrist, Saarathi Mind Care, Aurangabad, India
2 Department of Psychiatry, Parul Institute of Medical Sciences and Research, Parul University, Vadodara, Gujarat, India
3 Consultant Psychiatrist, Manoday Mansopchar Clinic, Akot, Akola, Maharashtra, India

Date of Submission06-Aug-2021
Date of Decision14-Sep-2021
Date of Acceptance14-Nov-2021
Date of Web Publication10-Feb-2022

Correspondence Address:
Dr. Ajinkya Sureshrao Ghogare
Manoday Mansopchar Clinic, In Front of City Police Station, Above Sable Medical Store, Akola Road, Akot, Tehsil - Akot, District - Akola, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aip.aip_102_21

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  Abstract 


Enuresis is a common childhood condition treated by pediatricians and psychiatrists. Enuresis is also commonly referred as bedwetting. It is more prevalent among boys than girls. Enuresis is an involuntary voiding of urine continuing after an anticipated age of control in the absence of any organic abnormality. This review summarizes the current knowledge about epidemiology, diagnosis, etiological factors, psychiatric comorbidities, and behavioral (enuresis alarm and star charts) as well as pharmacological (desmopressin and imipramine) management of enuresis. It is important to understand the epidemiology, etiology, behavioral as well as pharmacological management, and screening for psychiatric comorbidities for the better outcome among the children with enuresis. Enuresis can be stressful physically as well as mentally for both child and parents. Many times, parents of children with enuresis either do not show willingness or hesitate to report the bedwetting behavior of their children due to perceived stigma related to enuresis. Hence, there is a paucity of data in this field that the detailed evaluation of the prevalence, causative factors, and risk factors is needed and of great value to understand the psychiatric comorbidities associated with enuresis for the better outcome. Psychological support and motivation are needed for both children and their parents for improving their treatment-seeking behavior and for an effective management of enuresis.

Keywords: Alarm, enuresis, children, comorbidities, desmopressin, imipramine, parents, psychiatry


How to cite this article:
Pole R, Vankar GK, Ghogare AS. A clinical review of enuresis and its associated psychiatric comorbidities. Ann Indian Psychiatry 2022;6:4-14

How to cite this URL:
Pole R, Vankar GK, Ghogare AS. A clinical review of enuresis and its associated psychiatric comorbidities. Ann Indian Psychiatry [serial online] 2022 [cited 2022 Aug 9];6:4-14. Available from: https://www.anip.co.in/text.asp?2022/6/1/4/337518




  Introduction Top


What is enuresis?

Enuresis or bedwetting is common condition affecting children. It is defined as involuntary or intentional voiding of urine into cloths/bed continuing after anticipated age of control in the absence of organic abnormality.[1] Although Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) has incorporated both the terms “involuntary” and “intentional,” majority of children do not exhibit wetting behavior intentionally or on subconscious motivation.[2] According to the DSM-5, chronological age of 5 years is required to establish diagnosis of enuresis.[1],[2] Enuresis can be distressing for suffering children and for parents/guardians. Enuresis can cause poor self-esteem among children.[3]

Epidemiology of enuresis

Incidence of enuresis

Incidence varies according to gender and age. [Table 1] sums up gender, age, and frequency of incontinence-wise incidence of enuresis (Isle of Wight Studies).[2],[4]
Table 1: Distribution of incidence of enuresis based on gender, age, and frequency of incontinence

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Prevalence of enuresis

Prevalence among 7-year-old children was found to be 9.8%, out of which 6.4% had nocturnal enuresis, 1.8% had diurnal enuresis, and 1.6% had mixed nocturnal plus diurnal enuresis.[2] Prevalence of nocturnal enuresis among 8-year-old children was found to be 7.4%, out of which 3.3% had primary enuresis and 4.1% had secondary enuresis.[2] [Table 2] sums up point prevalence of enuresis according to gender and age.[2]
Table 2: Distribution of point prevalence rates of enuresis based on the gender and age

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[Table 3] presents age-wise prevalence of enuresis based on the DSM-5 diagnostic criteria.[1]
Table 3: Age-wise prevalence of enuresis as per Diagnostic and Statistical Manual of Mental Disorders Fifth Edition diagnostic criteria

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Spontaneous remission of enuresis

Enuresis is mostly self-limiting disorder with spontaneous remission. After age of 5 years, spontaneous remission rate is 5%–10% per year.[2]

Status of enuresis in India

South Indian study observed that among 8–12-year-old children, 18.6% and 4.3% had an episode of enuresis in the last year and in the last week, respectively. The same study found that enuresis was associated poor academic achievement, parental educational status, psychiatric and physical symptoms in child, and insufficiently careful attitude of parents regarding toilet training.[5] Western Indian study by De Sousa et al. observed that the prevalence of enuresis was 7.61%. The same study observed that enuresis was common among boys, 28.57% had family history of enuresis, 14.29% had diurnal enuresis, and only 24.11% of parents had consulted doctor for enuresis in their children. The same study observed that factors such as scholastic backwardness, presence of family stressors, lower socioeconomic status, and eventful/significant birth history were found among children with enuresis.[6] North Indian study observed that the prevalence of enuresis was 12.6% among school-going children. The same study also observed that enuresis was associated with factors such as familial conflicts, parental history of enuresis, parental scolding, enuresis-induced stress in children, having single parent, and poor academic performance. The same study also observed that the prevalence of enuresis was 17.9% among children who were not exclusively breastfed by mothers for initial 6 months of their lives.[7]

Subtypes of enuresis

Subtypes according to duration of continence

  1. “Primary” type: Child who has never maintained urinary continence for more than 1 year.[1],[2]
  2. “Secondary” type: Child who has gained urinary continence for 1 year or longer and then resume bedwetting.[1],[2] It may occur at any age but most commonly occurs between 5 and 8 years of age.[2]


Subtypes according to timing of episodes of incontinence throughout the day

  1. Nocturnal-only subtype: It is also known as “monosymptomatic nocturnal enuresis” (MNE). It is the most common clinical subtype that involves urinary incontinence that occurs only during the nighttime sleep. It typically happens during first one-third of nighttime sleep[1]
  2. Diurnal-only subtype: This subtype is simply known as “urinary incontinence” and it occurs in the absence of episode(s) of nocturnal enuresis. Those who suffer from this subtype can be divided into two classes namely “urge incontinence” and “voiding postponement.” Individuals with “urge incontinence” tend to have sudden urge symptoms and bladder detrusor muscle instability, while individuals with “voiding postponement” tend to postpone micturition urges consciously until incontinence occurs[1]
  3. Nocturnal and diurnal subtype: It is also known as “nonmonosymptomatic enuresis.” In this type, child wets the bed during sleep as well as when awake.[1]


Etiology of enuresis

Majority of children with enuresis wet involuntarily. Voluntary bed wetting mostly points toward the diagnosis of underlying psychosis or oppositional defiant disorder (ODD).[2] Few children who originally have involuntary enuresis may sometimes exhibit behavior on voluntary-learned basis as well.[2] Factors such as psychosocial stress and socially difficult situations tend to have higher correlation with enuresis.[2] Enuresis can occur due to abnormal or dysfunctional urinary bladder or due to behavioral disturbance. Children with enuresis due to behavioral disturbance tend to have history of developmental delays.[2] Excessive intake of fluids at bedtime may precipitate enuresis in children who otherwise do not have history of enuresis.[2]

Maturational delay

Children with enuresis tend to have more developmental delays and more minor neurological dysfunction than those who do not have enuresis.[2] Children with enuresis may exhibit delayed development of bones, which hints at general maturational delay in them.[2] Literature has shown evidence that the use of evoked potentials and electromyographic recordings of startle eye-blink response has reflected delayed maturation of brainstem functions.[2] A study observed that enuresis was associated with lower intelligence quotient (IQ) levels. In that study, Wechsler Intelligence Scale for Children–Third Edition (WISC-III) was used to assess IQ, and authors observed that children with enuresis scored lower on performance section of WISC-III. Based on observation, authors conclude that enuresis may be related to maturational deficit of central nervous system.[8] Another study found similar finding that boys with enuresis from low socioeconomic status had lower IQ level than the controls.[9] A study assessed motor function among 37 children with nocturnal enuresis and found that on Zurich Neuromotor Assessment, children with nocturnal enuresis had slower motor performance than controls regarding repetitive finger and hand movements, thus providing the proof that children with enuresis tend to have maturational deficit. The same study proposed that children with enuresis might have maturational deficits in brainstem, motor cortex circuitry, and related cortical areas.[10]

Comorbid psychiatric disorders

Attention-deficit hyperactivity disorder (ADHD) is a psychiatric disorder commonly seen in children.[11] ADHD is the most common psychiatric comorbidity associated with primary nocturnal enuresis (PNE).[2] Co-occurrence rate of ADHD and PNE is about 30%.[2] A study observed that ADHD was significantly associated with enuresis (odds ratio = 2.88). The same study also observed that only 36% of children with enuresis received treatment for enuresis.[12] Enuresis is frequently noted in premorbid childhood histories among early adolescent bipolar I disorder patients.[2] In the available literature, it has been evident that behavioral disturbance and secondary enuresis have strong association.[2]

Stress and trauma

Stress is defined as internal state which can be result of physical demands on the body (such as diseases, extremes of temperature, and exercise) or caused by social and environmental situations which are evaluated as potentially harmful, uncontrollable, or exceeding resources of coping.[13] Environmental, physical, and social causes of stress are known as stressors.[13] Anecdotal report and controlled study demonstrated that significant association exists between onset of enuresis and loss of parent by either death or divorce.[2] Delayed mastery over nocturnal continence and exposure to four or more stressful life events in a year may act as risk factors for occurrence of secondary enuresis.[2] Psychological trauma can occur when person experiences threat or serious loss. Early life or childhood traumas may involve subtypes such as emotional abuse, emotional neglect, physical abuse, physical neglect, and sexual abuse.[14],[15],[16] Significant association exists between traumatic events and development of secondary enuresis.[2] A study observed similar finding that among school-aged children, significant association existed between exposure to stressful events during childhood and frequently persistent bedwetting for at least twice per week till an age of 9 years. The same study concluded that parents and treating physicians must recognize that attaining continence is developmental process that may be affected by greater stress level in family.[17]

Genetic cause

It has been well known that enuresis has genetic etiology.[2] Risk of enuresis is 7.1 times higher if there is positive family history of enuresis in father, whereas risk is 5.2 times higher if there is positive family history of enuresis in mother.[2] Literature has shown that genetic transmission of enuresis is significantly seen in families with polygenerational histories of enuresis.[2] A study observed that 8.8% of mothers had a history of nocturnal enuresis and 0.7% of mothers had a history of daytime urinary incontinence. The same study also observed that 9.6% of fathers had a history of nocturnal enuresis and 0.3% had a history of daytime urinary incontinence. The same study found significant association between child and parental nocturnal enuresis and between child and parental daytime urinary incontinence.[18] A study assessed the pattern of inheritance in PNE and found that 43% of cases had dominant transmission and 9% had recessive inheritance pattern. The same study concluded that pedigree analysis and linkage study revealed involvement of gene located on chromosome 12q in causation of enuresis.[19] Genetic linkage had shown involvement of other genes located on chromosomes 13q, 4p, 8, 12q, and 22.[2] Genetic linkage also suggested possibility of mutation in aquaporin-2 water channel locus among families with dominant inheritance of primary enuresis.[2]

Biological cause

A study observed that majority of children with nocturnal enuresis had smaller urinary bladder capacities and also tend to pass more quantity of urine than children without enuresis during daytime, in addition to nocturnal bedwetting. The same study conclude that majority of children with enuresis were mentally normal and free from any neurological disability, and main underlying cause for enuresis was small urinary bladder capacity.[20]

Sleep disorders

Available literature has shown that children with enuresis are difficult to arouse from sleep than controls.[2] In some children, obstructive sleep apnea (OSA) may act as risk factor for development of PNE.[2] A study observed that sleep disturbance was significantly associated with development of nocturnal enuresis. The same study also observed that factors such as sweets intake, drinking beverages rich in sugars, family history of nocturnal enuresis, and consuming little plain water during day time were also significantly associated with nocturnal enuresis.[21] A study observed that children with lower respiratory disturbance index (RDI) of 1 or <1 had lower prevalence of enuresis (17%) and children with RDI of >1 had higher prevalence of enuresis (47%). The same study conclude that enuresis might be effect of OSA on arousal response, urinary hormone secretion, or urinary bladder pressure.[22] Another study observed that nocturnal enuresis was significantly associated with moderate-to-severe OSA after adjustment for obesity, age, gender and hypertrophy of tonsils (P = 0.03; adjusted odds ratio = 1.92 [1.08–3.43]).[23] Another study found that strong association existed between primary nocturnal enuresis and upper airway obstruction. Hence, the same study conclude that upper airway obstruction should be considered as potential cause for primary nocturnal enuresis.[24]

Refractory enuresis

Some cases of enuresis may persist into adolescence and adulthood periods are known as refractory enuresis, and they do not respond to desmopressin due to primary pathophysiology at receptor level.[2]

Risk factors for enuresis

Environmental factors

These factors include lax or delayed toilet training and psychosocial stress that may act as predisposing factor for development of enuresis.[1]

Cultural factors

The condition is well known and documented from Asian, European, and African countries apart from the United States. Nationwide, the prevalence and spontaneous remission rates have shown high similarity. Rates of enuresis in residential institutions and orphanages are very high and are most likely to be related to environment and mode in which toilet training takes place.[1]

Gender-related factors

Diurnal urinary incontinence is more common among girls, while nocturnal enuresis is commonly seen among boys. Likelihood of development of enuresis in children is more when family history was present in father than in mother.[1]

Diagnosis of enuresis

Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Diagnostic Criteria for enuresis

As per the DSM-5, enuretic behavior must occur at least twice a week over a period of at least 3 consecutive months and must cause impairment/distress in functioning of child. For diagnosing enuresis, chronological or developmental age of a child must be at least 5 years.[1],[2] Rationale for age cutoff is that, by the age of 5 years, urinary continence is expected to be achieved by the children.[2] DSM-5 criteria also state that enuretic behavior should not be attributable to physiological effects of any substance (e.g., antipsychotic drugs, diuretic drugs) or any medical condition (e.g., spina bifida, seizure disorder, diabetes).[1],[2] Intentional bedwetting may be secondary to underlying psychological disturbance.[2] As mentioned earlier, children with primary enuresis have never maintained urinary continence for a period of more than 1 year.[2] Secondary enuresis refers to children who had achieved urinary continence for one year or longer and then again started bedwetting.[2]

Functional consequences of enuresis

Enuresis can cause functional impairment of suffering child. The child may have impairment in social activities such as not able to attend nighttime or sleep-away camps. The child may have negative impact on self-esteem, exclusion from peers, and punishment, rejection, or anger from caregivers/parents.[1]

Associated features that support diagnosis of enuresis

Occasionally, during nocturnal enuresis, urinary voiding may take place during rapid eye movement phase of sleep, following which the child may recall dream which involves act of voiding. In case of diurnal or daytime enuresis, the child tends to defer urinating unless and until incontinence takes place, which may be secondary to reluctant behavior to use toilet due to either preoccupation with activities related to play and school or due to social anxiety. Even after appropriate treatment of underlying cause such as infection or maladaptive behavior, enuresis often tends to persist commonly.[1]

Laboratory and imaging workup for diagnosis

[Table 4] sums up laboratory and imaging workup in children with bedwetting to arrive at diagnosis.
Table 4: Laboratory and imaging workup in case of enuresis

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Differential diagnosis of enuresis

Neurogenic bladder or another medical condition-induced urinary incontinence

In the presence of neurogenic urinary bladder or any medical condition causing urgency or polyuria (e.g., untreated diabetes insipidus, diabetes mellitus), diagnosis of enuresis cannot be made.[1] Further, diagnosis of enuresis cannot be made during acute urinary tract infection (UTI).[1] However, diagnosis of enuresis can be made with such conditions if urinary incontinence was present regularly before occurrence of another medical condition or urinary incontinence has persisted after administration of appropriate treatment of that medical condition.[1]

Medication-induced urinary incontinence

Many drugs including diuretics and antipsychotics can cause urinary incontinence that may lead to enuresis. In such case, diagnosis of enuresis can be made if continence was present regularly before initiating treatment with such medications.[1]

[Table 5] sums up differential diagnoses of enuresis.[2]
Table 5: Summary of differential diagnoses of enuresis

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Purpose of the study

This review was conducted with an exact purpose of helping the postgraduate residents as well as practicing clinicians to understand the link between enuresis and its various psychiatric comorbidities for the betterment in patient care and outcome.

Objectives of the present review

Objectives of the present study were (i) to review various domains such as epidemiology, etiology, types, diagnosis, differential diagnosis, laboratory workups, and different management strategies of enuresis in simplified way and (ii) to review psychiatric comorbidities associated with enuresis in simplified way.

Hypothesis

Based on various studies that were reviewed, we hypothesized that enuresis is associated with significant impairment and psychiatric comorbidities which warrants timely intervention.


  Methodology Top


Eligibility criteria

Eligibility/inclusion criteria adopted for the present study were (a) studies that were conducted on pediatric population with enuresis, (b) studies that were conducted on topics of etiology, epidemiology, diagnosis, and various methods of management of enuresis, and (c) studies that focused on psychiatric comorbidities of enuresis.

Information sources

Literature for the present study was collected online from databases such as PubMed, Google scholar, Scopus, Web of Science, and ResearchGate.

Search strategy

Research was restricted to original, review, and meta-analysis articles published in English language. Studies having participants aged above 5 years were included while studies with participants below the stated age group were excluded as diagnosis of enuresis requires the minimum age of 5 years. For this purpose, a literature search and review were planned by using keywords such as enuresis, bedwetting, nocturnal enuresis, primary enuresis, secondary enuresis, etiology, epidemiology, diagnosis, behavioral management, pharmacotherapy, and psychiatric comorbidities.


  Management of Enuresis Top


Management of enuresis has been divided into two parts, namely, behavioral management and pharmacological management. Success rate of behavior therapy in enuresis is found to be 75%.[2] Psychotherapy can be useful for behavioral problems, mainly in case of secondary enuresis. In case of primary enuresis, the success rate of psychotherapy has been found to be only 20%.[2]

Behavior therapy of enuresis

Bell and pad method of conditioning

Bell and pad method is also known as bedwetting alarm or enuresis alarm. It is a primary intervention in behavioral therapy of enuresis. In this treatment method, pad is placed on bed and the wire connects that pad with bell. When the child with enuresis exhibits bedwetting behavior, moisture triggers the circuit in the pad which leads to ringing of attached bell followed by waking of child from sleep. Due to repeated use of this method, the child gets up from bed before an act of voiding.[2] It is debatable whether this method works on principle of classical or operant conditioning. An author mentioned that it is not easy task to distinguish both types of conditioning as regards to bell and pad method of treating enuresis.[29] The same author tried to elaborate and mentioned that both types of conditioning could be applied for desired outcome of bell and pad method. Punishment of awakening from sleep is secondary to act of bedwetting. In classical conditioning, incontinence or voiding is a neutral stimulus and waking from sleep is aversive stimulus. Hence, bedwetting or voiding followed by awakening explains classical conditioning, whereas avoiding aversive stimulus of waking up from sleep by remaining awake explains operant conditioning.[29] The same author concludes that in most cases, bell and pad method operates on the basis of operant conditioning as most children with enuresis who were successfully treated by using bell and pad method slept throughout night without incontinence.[29]

Equal response was found between vibratory and audio alarm methods.[2] Desired outcome of behavior therapy for enuresis may be hampered by the presence of comorbid behavioral disturbances.[2] Systematic review and meta-analysis compared the efficacy of alarm therapy and desmopressin therapy and found that bell and pad alarm system had shown greater treatment response and lesser relapse rate in motivated children with enuresis than pharmacotherapy with the desmopressin.[30] Another strategy involves replacing bell and pad with alarm clock which rings 2–3 hours after child falls asleep when urinary bladder fills up to maximum capacity. Success rate of this strategy was found to be similar to bell and pad method.[2] A study assessed an effect of bell and pad alarm method on urinary bladder storage capacity among children with mono-symptomatic nocturnal enuresis and found that after 12 weeks treatment with alarm therapy, there was significant increase in urinary bladder storage capacity. The same study also found that maximum nocturnal urinary bladder capacity before alarm therapy was only 177.85 ± 84.95 ml, and after treatment, it was increased to 255.25 ± 124.52 ml (P < 0.0001).[31] Enuresis alarm therapy should be used as the first-line treatment among children under 8 years of age without nocturnal polyuria and with adequate support from the family.[32]

Biofeedback

Application of biofeedback technique as behavior therapy has been found to be useful in children with enuresis who have less urinary bladder storage capacities and unstable bladder detrusor muscles and who are refractory to other treatment methods.[2] In this latest behavioral therapy, external ultrasonic monitor is attached to waistband of child suffering from enuresis. Ultrasonic monitor reflects signals when urinary bladder reaches peak capacity. Success rates of biofeedback and bell and pad alarm techniques were found to be similar, and like that of bell and pad alarm therapy, there was also increase in storage capacity of urinary bladder with biofeedback therapy.[2] A study assessed efficacy of biofeedback method among children with enuresis who failed to show response to desmopressin treatment and found that biofeedback method was beneficial in 69% of the study participants. The same study also found that before biofeedback treatment, the frequency of enuresis was 25.1 ± 5.76 days/month, and after biofeedback treatment, it was reduced to 8.52 ± 10.07 days/month. The same study also observed that average urinary bladder capacity was increased from 215 mL to 257 mL after biofeedback treatment. At last, the same study also observed that the total bladder volume/age-adjusted normal bladder capacity (TBV/NBC) value was also increased from 0.66 to 0.77 after biofeedback treatment (P < 0.001).[33] This proves that biofeedback treatment is beneficial in the treatment of children with enuresis.

Evening fluid restriction/limitation of fluid intake

Avoidance of caffeine containing fluids with diuretic effect is advised to children with enuresis, but the effect is not evaluated sufficiently.[34],[35] Limiting nocturnal fluid intake is commonly advised to children with enuresis, but data about its efficacy are not sufficiently available.[36] [Table 6] sums up recommended daily consumption of drinks for children and young people according to the National Institute for Health and Care Excellence (NICE) guideline.[37]
Table 6: Recommended daily fluid intake for children and young people according to National Institute for Health and Care Excellence guideline[37]

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Urotherapy

Among children with enuresis, simple behavioral methods that correct voiding habits such as awakening child at night for urination, carrying child to toilet during night, motivating child for toilet training, and exercises to improve urinary bladder storage capacity must be primary basis of enuresis treatment.[38],[39] This method involves family education about enuresis and its management, limitation of fluid intake, giving suggestions regarding urinary voiding frequency and patterns, and treatment of concomitant constipation in children.[38] Untreated constipation may be the cause of refractory enuresis, and its early diagnosis and treatment may lead to improvement in treatment outcome of enuresis.[40]

Star charts/rewards

For the purpose of record and reward scheme, either alone or along with other treatments, star charts can be used. Star charts and reward systems involve giving some incentive or reward to child for dry night or for appropriate toileting behavior, irrespective of child actually being dry overnight.[41] Such incentives may range from stars on charts in child's room or in family room to pocket money or time earned by child for his/her preferred hobby such as gaming. On many occasions, star charts are commonly used to reward child for good behavior (e.g., educational settings). Hence, they are mostly familiar to children and their families which can be better utilized in management of enuresis.[41]

Retention control training

As method of behavioral therapy for enuresis, retention control training showed reduction in frequency of enuretic episodes, and patient commenced nocturnal voluntary and independent toileting.[42] In randomized controlled trial (RCT), children with enuresis in retention control training group were made aware of fact that “enuretic behavior is psychological mechanism that needs conscious control by self, and it can be resolved by willingness and responsibility on part children.” In RCT, children were taught sphincter muscle exercises and were asked to consume less than usual drink and to go to bed early. They were also taught about general physical exercises.[43] In the same RCT, the efficacy of retention control training and placebo was compared to desmopressin treatment. Number of children who remained dry for consecutive 14 nights periods with retention control training and placebo was lesser than desmopressin-treated children (16% vs. 40.8%, at 95% confidence interval and relative risk of 0.39 [0.22–0.7]).[43] Further, in the same RCT, the mean number of wet nights per week at the end of treatment and at follow-up was lesser in retention control and placebo group than in those who were treated with desmopressin (75 vs. 76 wet nights). The same study also observed that the relapse rate was higher in children who were treated with desmopressin (58.1%) than those who were treated with retention control training and placebo (50%). Risk of treatment drop-out was seen in 1.3% of cases treated with retention control training and placebo, and there was no treatment drop-out among desmopression-treated children.[43]

Pharmacological management of enuresis

Imipramine

Imipramine belongs to tricyclic antidepressant (TCA) group. Although imipramine is largely replaced by desmopressin, it is still recommended for treatment of children with enuresis who are resistant to other treatment methods. Imipramine is economically less costlier than desmopressin and may be the first pharmacological agent of choice for families with economical limitations.[2] Desipramine is metabolite of imipramine. Response to imipramine treatment may depend on its serum concentration either alone or in combination with desipramine. A study observed that combined serum concentration of imipramine and desipramine more than 80 ng/mL was associated with optimal response in children with enuresis. The same study conclude that monitoring serum imipramine levels leads to better treatment compliance.[44] Another study observed that the optimum treatment effect in enuresis was seen at steady-state levels of imipramine and desipramine of 60 μg/L, i.e., the effective plasma concentration for treatment of enuresis was 3–4 times lesser than that required for the treatment of depression.[45] In contrast to above two studies,[44],[45] another study observed that the assessment of plasma imipramine levels among children with enuresis during treatment did not have any significant value. The same study conclude that assessment of plasma imipramine levels can be carried out to avoid its toxicity.[46] A study observed that efficacy of imipramine was increased by increasing its dose as higher serum concentration was associated with better response. However, the same study also observed that there was about 700% variation in serum concentration between study participants at every dosage. The same study concluded that the assessment of serum imipramine concentration had limited but important usefulness in the management of enuresis.[47] Clinically, nonresponse to imipramine is commonly related to its dosing.[2] Starting dose of imipramine is 25 mg/day, and dose should be titrated upward by 25 mg every 4th–7th day.[2] Recommended maximal dose limit is 5 mg/kg body weight.[2] Imipramine may take 1–2 days to show response in children with enuresis.[2] Most of the children with enuresis exhibit positive response within dose range of 75–125 mg.[2] Imipramine is given orally 1 hour before sleep.[34] As regards age, imipramine is generally given in dose of 25 mg for children below 6 years of age and in dose of 50–75 mg for children above 11 years of age.[34] Electrocardiographic (ECG) monitoring is indicated at dose more than 3.5 mg/kg.[2] Before onset of treatment, baseline ECG should be carried out. Parents must be advised about supervised treatment of their children and to store imipramine safely away from children to avoid its toxicity/overdose. Moderate overdose of imipramine is generally managed symptomatically by taking care of adverse events such as seizures and arrhythmias. Severe overdose can be managed by treatment with physostigmine.[2] In children, dose of physostigmine is 0.02 mg/kg/dose via slow intravenous push administration with dose not crossing 0.5 mg/min. Dose can be repeated at interval of every 5–10 min PRN (Pro Re Nata/ when necessary/ as needed). Cumulative dose of physostigmine should not cross maximum 2 mg for given child with imipramine toxicity.[48] Doses of imipramine should be tapered downward at the interval of 3 months. Most children remain dry after 3–6 months of treatment with imipramine.[2] A study observed that after stopping imipramine at 3 and 6 months, about 90% children in the age range of 6–13 years maintained maximum response that was attained during treatment.[49] Adverse effects of imipramine are secondary to anticholinergic property and include dry mouth, sedation, blurring of vision, and constipation.[50] Imipramine also has side effects due to antihistaminic property which include weight gain and sedation.[50] By blocking alpha-1 adrenergic receptors, imipramine can cause hypotension, dizziness, and sedation.[50] At overdose, imipramine can induce seizures and arrhythmias secondary to blockade of ion channels.[50] Imipramine is cardiotoxic at high doses and cases of death due to arrhythmias have been reported.[51]

Desmopressin

At present, desmopressin has largely replaced imipramine as the first-line pharmacological agent. It is arginine vasopressin analog. A study observed that desmopressin was able to reduce frequency of enuresis, especially among children over 9 years of age. The same study observed that 71% of study participants responded to desmopressin.[52] Among most children with MNE, nocturnal polyuria is secondary to altered circadian release of vasopressin.[53] An RCT compared 30 mcg intranasal desmopressin with 0.9 mg/kg imipramine found that the number of children who attained dryness for 14 consecutive nights was higher with desmopressin than with imipramine (86.2% vs. 67.9%, at confidence interval of 95% and relative risk of 1.27 [0.95–1.7]). The same RCT also found that the mean number of wet nights per week after desmopressin treatment was higher than imipramine (29 vs. 28).[54] Another RCT found that the risk of treatment drop-out was higher among children treated with 25 mg tablet of imipramine (14.6%) than among children who were treated with 200 μg tablet of desmopressin (6.1%).[55] It was evident that 5.7% of children maintained dryness after cessation of desmopressin treatment.[2] Sudden and rapid discontinuation of desmopressin may result in high recurrence of enuresis[56] and planned gradual discontinuation tends to have lower risk of relapse.[57] Dose of desmopressin can be reduced by 10 μg per month until it is discontinued totally.[2] Combination of desmopressin and bell and pad alarm treatments was found to be superior in case of children with severe nocturnal enuresis.[2] A study observed that combined treatment with desmopressin and enuresis alarm was beneficial for children with severe nocturnal enuresis, family problems, and behavioral problems.[58] Response rate to desmopressin is 60%–70%, while relapse rate is 50%–90%.[43],[56] A study observed that combination of oxybutynin and desmopressin led to increased response rate and reduced relapse rate.[58] Desmopressin is available in nasal spray and tablet forms. Its effect lasts for about 12 hours after administration.[34] Adverse drug reactions to desmopressin include nasal congestion, nasal bleeding, headache, abdominal pain, water intoxication, hyponatremia, altered mouth taste, visual problems, nausea, and loss of appetite.[59] The reduced risk of hyponatremia was found with the oral desmopressin when compared with the intranasal desmopressin.[59] Intranasal desmopressin administration has been found to be associated with the risk of dilutional hyponatremia induced seizures.[59] Hence, children and/or their parents should be advised to avoid high fluid intake by the children with enuresis while they are on treatment with desmopressin.[59]

Oxybutynin

It is an anticholinergic and antispasmodic agent which is used for managing enuresis. It works by preventing or reducing uninhibited urinary bladder detrusor muscle contractions.[34],[60] It acts by complete antagonism of muscarinic M1, M2, and M3 receptors.[60] Oxybutynin can also act as calcium channel antagonist, thereby exerting direct spasmolytic effect on urinary bladder's smooth muscles.[61] It can be used in the treatment of neurogenic bladder and urge incontinence among children.[62] It is commonly used in children with problems such as detrusor hyperactivity and small urinary bladder storage capacity.[34],[39] Recommended dose ranges between 5 mg and 10 mg and it must be given at bedtime.[63] Success rate ranges between 47% and 71%.[34] Treatment with oxybutynin can be stopped 6 months after complete improvement.[34] Adverse effects of oxybutynin are dysphagia, dry mouth, blurring of vision, dryness of eyes, tachycardia, nausea, constipation, headache, and vomiting.[34],[60]

Transcutaneous parasacral electrical nerve stimulation

Transcutaneous parasacral electrical nerve stimulation (TCPSE) is an electrotherapy which has shown success rate of 63% by reducing symptoms of overactive urinary bladder.[64] A study found that cases of enuresis which were resistant to pharmacotherapy and biofeedback have shown success rate of 70.4% after 3 months of TCPSE treatment.[65]


  Psychiatric Comorbidities in Enuresis Top


Those children who have enuresis often have developmental delays in domains such as language, speech, learning, and motor skills. They may have other issues such as sleepwalking, sleep terror, and encopresis.[2] Gizli Çoban et al. assessed psychiatric comorbidities among children with elimination disorders by using Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version. They found that the most common psychiatric comorbidity was ADHD, followed by social anxiety disorder and ODD.[66] The same study found that higher rate of psychiatric comorbidities was among enuresis + encopresis subgroup (61.9%), followed by nocturnal enuresis (48%) and encopresis (38.4%) subgroups. The same study highlighted importance of screening all children with elimination disorders for comorbid psychiatric disorders.[66] [Table 7] sums up distribution of psychiatric comorbidities among children with enuresis.[66]
Table 7: Distribution of psychiatric comorbidities among children with nocturnal enuresis

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Amiri et al. found that lifelong incidence of psychiatric disorders among children and adolescents with enuresis was 79.23%. The same study found that the highest incidence was of ADHD (74.9%), followed by ODD (53%) and tic disorders (12%) with predominant motor tics. The same study found that only 5% of children with enuresis had other psychiatric comorbidities such as conduct disorder, post traumatic stress disorder (PTSD), and bipolar affective disorder. The same study also found that although boys outnumbered girls, there was no clinically significant difference between both genders in terms of comorbid psychiatric disorders (P > 0.5).[67] Niemczyk et al. found that 8.5% of preschool children had nocturnal enuresis, 1.9% had daytime urinary incontinence, and 0.8% had fecal incontinence. The same study found that 6.4% children had ADHD, 6.2% had ODD, and 2.6% had both ADHD and ODD. The same study found that those children with both ADHD and ODD had higher rates of enuresis than children who had either of the psychiatric comorbidities.[68] Amiri et al. found that 17.5% of children and adolescents with ADHD had nocturnal enuresis.[69] Ghanizadeh concluded that the presence of comorbid ODD among children with ADHD predicted the occurrence of nocturnal enuresis.[70] Niemczyk et al. observed that screening for comorbid psychiatric disorders among children with nocturnal enuresis was valuable. The same study found that children with ADHD had delayed nighttime as well as daytime urinary bladder and bowel control than the controls. The same study inferred that delayed continence among children with ADHD could hint at maturational deficits or delay in the central nervous system. The same study finally concludes that treatment of children with ADHD may be associated with beneficial outcome regarding incontinence. The same study also concludes that children with ADHD must be screened for comorbid incontinence and vice versa.[71] Birdal et al. observed that compared to controls, children with enuresis had more behavioral problems. The same study found that from control group, only 23% of children had internalizing behavioral problem while none of them had externalizing behavioral problem. The same study also found that from case group, i.e., from group of children with enuresis, 56.6% children had internalizing behavioral problems and 10% had externalizing behavioral problems.[72] Amiri et al. based on their clinical experience realized that parents of children with nocturnal enuresis were not willing to report bedwetting behavior of their children due to perceived stigma related to it. Hence, there is a paucity of data in this field that detailed evaluation of the prevalence, causative factors, and risk factors is needed and of great value to understand psychiatric comorbidities associated with enuresis for better outcome.[67]

Strengths

This review was carried out on studies from databases such as PubMed, Scopus, and Web of science. It has summarized important aspects at one place such as detailed etiology, epidemiology, differential diagnosis, diagnostic workups, various methods of management (behavioral, pharmacological, and TCPSE), and psychiatric comorbidities of enuresis in concise manner that will be helpful for postgraduate psychiatric and pediatric residents for their study on this topic.

Limitations

There are few limitations to this review. Extent of perceived stigma among children suffering from enuresis and among their parents is not addressed in detail. Effects of behavioral and/or pharmacological interventions for enuresis on course of psychiatric comorbidities are not studied.

New knowledge added by this study

Apart from routine behavioral and pharmacotherapy, this study attempted to address other modes of managing enuresis such as biofeedback, urotherapy, star charts, retention control training, role of oxybutynin, and the electrotherapy in the form of TCPSE in a concise manner. This review also stated mechanisms of action of various pharmacological agents and management of imipramine/TCA toxicity with physostigmine which can occur among few children taking Imipramine for enuresis management. Apart from ADHD which is most common comorbidity with enuresis, this review has also thrown light on other psychiatric comorbidities of enuresis.

Summary of results and future clinical as well as research implications

This review concludes that combined behavioral therapy and pharmacotherapy is more useful for managing enuresis. Enuresis is associated with stigmatic attitude and belief among children and parents. Enuresis is also associated with psychiatric comorbidities. Hence, children and their parents should be motivated to improve their treatment-seeking behavior regarding enuresis for better outcome and for preventing or treating psychiatric comorbidities. All children with enuresis should be screened for coexisting psychiatric disorders for better outcome. Future research must concentrate on assessing stigma related to enuresis and ways to tackle it. Future research must also concentrate on assessing effects of behavioral and pharmacological therapies for enuresis on prognosis of psychiatric comorbidities related to enuresis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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