Nocturnal enuresis By Dr. Turky Al-Mouhissen R4 Urology

Outline: Introduction & definition Epidemiology & natural history Physiology of bladder maturation Causes Evaluation Management

Introduction & definition Enuresis defined as involuntary voiding When it occurs at night it is termed nocturnal enuresis daytime incontinence is termed diurnal enuresis 1ry : who never achieved peroid of dryness at night time 2ndry: who achieved period of dryness

At 5 yrs of age, 15 % of children remain incompletely continent of urine Most of these children have isolated nocturnal enuresis ( monosymptomatic enuresis ) Monosymptomatic enuresis divided into 1ry & 2ndry

1ry enuresis: who never achieved a satisfactory period of nighttime dryness 80 % of nocturnal Enuresis 2ndry enuresis: who had a period of dryness, usually for at least 6 mo. before the onset of wetting begins 20 % of noc. Enuresis Often associated with unusually stressful event

20 % of children who have nocturnal enuresis also have daytime symptoms Daytime symptoms may be limited to urgency and frequency, but often include incontinence (diurnal enuresis) Urologic and neurologic disorders (eg, detrusor instability, recurrent UTI, spinal dysraphism) more common among children with diurnal symptoms

Nocturnal enuresis + daytime symptoms = complex or complicated enuresis ( dysfunctional voiding ) [ Noc. Enuresis + Urinary & bowel symptoms = dysfunctional elimination syndrome

EPIDEMIOLOGY AND NATURAL HISTORY

5 years: 16 % 6 years: 13 % 7 years: 10 % 8 years: 7 % 10 years: 5 % 12 to 14 years: 2 - 3 % 15 years: 1 - 2 %

Boys = twice girls resolves spontaneously at a rate of 15 % / year The longer the enuresis persists, the lower the probability that it will spontaneously resolve

In a study by the college of medicine in Dammam, saudi arabia cross-sectional population-based study Data were collected using a self-administered questionnaire 644 school children aged 6-16 years were selected randomly Enuresis prevalence was 16.3% among boys and 13.8% among girls The overall prevalence was 15% The 83 children who had enuresis during sleep, 25 (30.1%) wet their beds during day time sleep : Acta Paediatr. 1996 Oct;85(10):1217-22. Links Enuresis: prevalence and associated factors among primary school children in Saudi Arabia Kalo BB, Bella H.

Bladder maturation Normal bladder function entails a complex interrelation btwn autonomic and somatic nerves They are integrated at various sites in spinal cord, brain stem, midbrain, and higher cortical centers The complex coordination permits urine storage at low pressure with high outlet resistance and voiding with low outlet resistance and sustained detrusor contraction

Central organization of mic. Reflex by centers in cerebrum, posterior hypothalamus, midbrain, pontine, sacral spinal cord Parasymp. Supply by pelvic nerve arising from S 2-4, to the detrusor muscle Symp. Supply by hypogastric n. from t 10-12 innervating bladder neck & urthral smooth m. Somatic supply. By pudendal n. innervating ext. urethral sphinter

At birth, bladder function is coordinated through the lower spinal cord and/or primitive brain centers Voiding at this stage is efficient but uncontrolled: uninhibited contraction is caused by progressive and sustained bladder filling Voiding in the newborn also may be initiated by neurologically stimulating activities such as feeding, bathing, tickling, etc.

The newborn voids approx. 20 times per day During the first 3 yrs, bladder capacity increases disproportionately relative to body surface area At 3 yrs, No. of voids per day decreases to approximately 11, while mean voided volume increases nearly fourfold At 4 years, most children void 5-6 times/day

Development of bladder control appears to follow a progressive maturation child first becomes aware of bladder filling subsequently develops the ability to suppress detrusor contractions voluntarily finally learns to coordinate sphincter and detrusor function These skills usually are achieved, at least during the day, by 4 yrs of age.

Nighttime bladder control is achieved months to years after daytime control, but is not expected until 5 – 7 yrs of age Incomplete development of bladder control results in more complex wetting problems that almost always associated with diurnal enuresis uninhibited bladder of childhood bladder sphincter dyssynergy recurrent UTI some cases of vesicoureteral reflux

Causes: Maturational delay Genetics Functional small bladder capacity Abnormal diurnal secretion of vasopressin (antidiuretic hormone, ADH) Nocturnal polyuria Detrusor instability Sleep disorders Psychological issues

Maturational delay In almost all cases, monosymptomatic nocturnal enuresis resolves spontaneously This suggests that delayed maturation of a normal developmental process plays a role Some studies have demonstrated increased incidence of delayed language & gross motor development and slowed motor performance among children with enuresis

Genetics Monozygotic twins twice that among dizygotic twins (68 versus 36 %) One parent have h/o prolonged nighttime wetting, ½ of the offspring are affected Both parents affected, ¾ the offspring are affected When neither parent has a history of nocturnal enuresis, only 15 % of offspring are affected An autosomal dominant form was identified in Danish families and linked to a locus on chr. 13q13-q14.3 Additional genetic loci for enuresis have been identified on chr. 12q and 22q11 [

Small bladder capacity At birth, bladder volume approx. 60 mL it increases with age at a relatively steady rate of approximately 30 mL per year Children with noc. enuresis, even who do not have daytime symptoms, have noted to have smaller bladder capacity than age-matched children who do not have nocturnal enuresis

In a study showed, the reduced bladder capacity appears to be functional rather than anatomical In another study, the maximal bladder capacity during the daytime was similar between children with enuresis and controls However, among children with enuresis, the maximal voided vol. during night was significantly smaller than the maximal daytime bladder capacity

Nocturnal polyuria and ADH It has been suggested that increased nighttime U.O.P may play a role in nocturnal enuresis In children who don`t have enuresis, U.O.P. during the night bcs the secretion of ADH and other regulatory hormones follows a circadian pattern, with increased secretion at night

studies have indicated that nocturnal enuresis children have decreased nocturnal secretion of ADH increased U.O.P. One of the reasons may be small bladder capacity, since ADH secretion is thought to increase with bladder distension The relationship between ADH secretion and nighttime urinary flow rates remains controversial

Abnormalities in ADH secretion appear to play a role in at least some pts with noct. enuresis. However, whether these abnormalities are primary or secondary (eg, to bladder capacity or maturational delay) is not clear

Detrusor instability   Urodynamics in children who have diurnal incontinence demonstrates significant functional detrusor abnormalities No clear pattern of UDN abnormality demonstrated in children with primary monosymptomatic noct. Enuresis Most studies suggest that the incidence of uninhibited bladder activity in children with 1ry monosymptomatic noct. enuresis is similar to the incidence in normal children ( 3-5% )

bladder dysfunction should be considered in children who have refractory monosymptomatic primary nocturnal enuresis When UDN studies performed during sleep, the only difference between enuretic and nonenuretic children is the increased rate of bladder contractions in enuresis

Sleep disorders Parents often describe their children with enuresis as excessively deep sleepers Excessively deep sleep appears to contribute to nocturnal enuresis in adolescents and adults Sleep studies show that sleep patterns among children with and without enuresis are similar

Nocturnal sleep and bladder monitoring studies by Robert and others (1993) have been able to distinguish 3 types of enuretic episodes: Type 1: Gradually elevations in bladder pressure culminate in wetting; . associated with prominent somatic and visceral reactions tachycardia, body movements, increasing respirations, and progressive awakening. The awakening reaction is strong, and the child struggles to keep from wetting.

Type 2 A very quick micturition is associated with minimal body movement and visceral signs. The awakening reaction is very brief, and the struggle to keep from wetting is very limited Type 3 Complete parasomnia, a total lack of CNS reaction and response to bladder contraction, occurs neither bladder filling nor bladder contraction registers on the EEG involuntary voiding occurs without any modification of sleep.

These three patterns appear to reflect the various stages in the normal development of nocturnal urinary control and suggest wetting during sleep is to a great extent determined by CNS maturation.

These findings suggest sleep patterns of enuretics are not different from those of normal children most enuretics neither have a disorder of arousal nor wet as a consequence of sleeping too deeply Enuresis is related to delay in CNS development or, more accurately, a dual delay in the development of the perception and inhibition of bladder filling and contraction by the CNS (Koff, 1995).

Psychological Although psychologic abn. have been considered to play a role in noct. enuresis, this relationship has not been proven perceived adjustment problems tend to improve after resolution of enuresis, suggesting behavioral abnormalities are a result, rather than a cause of the enuresis

Deferential diagnosis: Unrecognized underlying medical disorders (eg, SCD, seizures, DM, DI , hyperthyroidism) Encopresis or constipation Dysfunctional voiding (usually associated with daytime symptoms) Urinary tract infection Chronic renal failure Spinal dysraphism Psychogenic polydipsia

Evaluation: History Presence of daytime wetting or symptoms Any prolonged period of dryness Family history of nocturnal enuresis Frequency and trend of nocturnal enuresis

Fluid intake diary Voiding diary Stooling diary Medical history ( diabetes, sickle cell disease or trait, urinary tract infection, gait or neurologic abnormalities) Social history ( important in secondary enuresis) Effect of problem on child & family which interventions the family has tried

Physical examination Usually normal

Conditions which reflect medical etiology for enuresis include: Palpation of stool in the abdomen suggests constipation or encopresis. Perianal excoriation or vulvovaginitis may indicate pinworm infection Poor growth and/or hypertension may indicate renal disease. Presence of abnormalities of the lower lumbosacral spine or neurlolgical abnormalities Detection of incomplete bladder emptying

Urinalysis  screen for diabetic ketoacidosis, diabetes insipidus, water intoxication, and/or occult urinary tract infection Imaging —  Urologic imaging is reserved for who have significant daytime complaints h/o UTI not previously evaluated signs and symptoms of structural urologic abnormalities Neurologic imaging (MRI spine) is indicated in children who have abnormalities of the lower lumbosacral spine on neurologic examination of the perineum and lower extremities

Management of nocturnal enuresis in children GENERAL PRINCIPLES —  age at which enuresis is considered to be a "problem" varies depending upon the family For the child, nocturnal enuresis usually becomes significant only when it interferes with his or her ability to socialize As a general rule, children younger than seven years of age may be managed expectantly, as the majority will resolve spontaneosly

Parents must clearly understand that nocturnal wetting are involuntary on the part of the child Parent education that Rx may be prolonged, associated with relapses, and may fail in the short term The parents must be willing to participate, and the family environment must be supportive The child must be highly motivated to participate in a treatment program

Treatment modalities Motivational therapy Bladder training Fluid management Behavioral alarms Pharmacological agents

Rx is rarely indicated in a child younger than 7yrs motivational therapy, bladder retention exercises, fluid management are usually tried for 3-6 mo. in motivated family & child More active intervention (eg, arousal alarm systems, pharmacotherapy) should be considered as the child gets older, social pressures increase, and self-esteem is affected Pharmacologic agents can be effective in the short-term (eg, for sleepovers or camp attendance), but enuresis alarms are the most effective long-term therapy

Motivational therapy Rewards given to a child for longer period of dryness leads to significant improvement > 70 % relapse rate (more than two wet nights in two wks ) is 5 % Motivational therapy is a good 1st line of therapy for 1ry noct. enuresis, particularly in younger children If motivational therapy fails to lead to improvement after 3-6 mo., other methods should be tried

Bladder training children with noct. enuresis have a functionally small bladder capacity Bladder retention training exercises may be undertaken to increase bladder capacity Bladder training therapy leads to significant improvement 60 % Successful in 35 % a trial of this simple behavioral method is recommended before alarms and pharmacologic agents are tried

Some authors recommend Fluid management  Some authors recommend to drink 40 % of their total fluid in the morning 40 % in the afternoon only 20 % in the evening beverages consumed in the evening caffeine-free Isolated nighttime fluid restriction, should be compensated in daytime fluid consumption

Enuresis alarms Enuresis alarm is the most effective means of controlling nocturnal enuresis Enuresis alarms are activated when a sensor, placed in the undergarments or on a bed pad, detects moisture; the arousal device is usually an auditory alarm and/or a vibrating belt or pager

Alarm works through conditioning: the patient learns to wake or inhibit bladder contraction in response to the neurologic conditions present before wetting The child should F/U 1-2 wks after starting the alarm and then at the end of an 8 -week trial Therapy with the alarm can be reinitiated for relapse (more than two wet nights in two weeks). 30 % of pts discontinue the alarm for various reasons

Alarms appeared to be less immediately effective than desmopressin, but more effective in preventing relapse Alarms were more effective than tricyclic antidepressants during and after treatment Relapse rate after stopping therapy is much lower with alarms than with desmopressin

Many authors concluded that an ordinary alarm clock is Alarm clocks It may be possible to condition some children to wake to void by using an alarm clock Many authors concluded that an ordinary alarm clock is safe Effective noncontact treatment that does not require an episode of bedwetting to initiate a conditioning

PHARMACOLOGIC THERAPY desmopressin acetate (DDAVP) tricyclic antidepressants (TCAs) Other drugs may be beneficial

Desmopressin: mechanism of action unclear Suggested that DDAVP acts on a different receptor, possibly the vasopressin 1b receptor in the brain Dose given late evening to reduce urine production during sleep The drug is given either intranasally or orally It is relatively expensive A normal functional bladder capacity is necessary for response to desmopressin

Dose usually titrated to best effect, increasing the dose every 10 days to the maximum recommended dose The process usually takes a total of 30 days The oral tab. is given at 0.2 mg initially (1 tab.) and may be increased to 0.6 mg (3 tab.) as needed over a 2-week trial The nasal spray is usually begun at 20 micrograms at bedtime, and titrated to max. of 40 micrograms at bedtime

25 % achieves total dryness using desmo. 50 % had significant decrease in nighttime wetting Similar to TCAs, stopping the medication is associated with high rates of relapse 60-70 %

Desmopressin and TCA appear to be equally effective. systematic review of 41 randomized trials involving 2760 children comparing desmopressin to other drugs or alarms in the treatment of nocturnal enuresis Compared with placebo, desmopressin (20 microgram nasal spray) reduced bedwetting by 1.34 nights per week (95% CI 1.11-1.57). Compared with placebo, children treated with desmopressin (20 microgram nasal spray) were more likely to become dry (ie, no episodes for 14 nights) (RR 1.19, 95% CI 1.10-1.27). In contrast to arousal alarms, treatment effects were not sustained after discontinuation of therapy. Desmopressin and TCA appear to be equally effective.

Adverse effects of desmopressin uncommon Nasal form occasionally causes mild rhinitis The most serious adverse effect is dilutional hyponatremia, occurs when excess fluids are taken in the evening hours To prevent this complication, it is recommended that fluid intake be limited to 240 mL on any evening that desmopressin is given

Tricyclic antidepressants: Imipramine, Amitriptyline, and desipramine have been recognized as a useful adjunct in the Rx of enuresis since 1960 Although imipramine is the drug most often used, other TCAs are also effective TCAs decrease the amount of time spent in REM sleep, stimulate vasopressin secretion, and relax the detrusor muscle.

The dose of imipramine is 0.9 - 1.5 mg/kg per day, bedtime On average, the bedtime dose is 25 mg for children 5-8 years of age and 50 mg for older children The dose should not exceed 50 mg in children between 6 -12 yrs of age and 75 mg in children 12 years of age The Effect of imipramine is quick if the dose is adequate Imipramine should be discontinued if there is no improvement after a three-week trial (at an adequate dose); it may be discontinued abruptly

Adverse effects of TCA therapy are relatively uncommon 5 % develop neurologic symptoms including nervousness, personality change, and disordered sleep The most serious adverse effects of TCAs, involve CVS, including the risk of cardiac conduction disturbances and myocardial depression, particularly in cases of overdose.

Other drugs Indomethacin: Rarely used One small randomized controlled trial found that indomethacin suppository versus placebo significantly increased the number of dry nights in children with primary nocturnal enuresis who were treated for 3 wks Possible mechanisms of action include removal of the normal inhibitory effect of prostaglandins on the response to vasopressin

Anticholinergic drugs: such as oxybutynin, are not effective in treating monosymptomatic nocturnal enuresis May be useful in children who also present with significant daytime urgency combination of anticholinergic therapy and desmopressin may be used in these children in an attempt to increase bladder capacity during sleep

Other drugs, including phenmetrazine, amphetamine sulfate, ephedrine, atropine, furosemide, diclofenac, and chlorprotixine have been tried none of the drugs was better than desmopressin

Recommendations in the Rx of monosympotomatic nocturnal enuresis children < 7yrs therapy should consist primarily of reassurance that spontaneous resolution is likely Once the child is able to be partially responsible for Rx, motivation and simple behavior therapies are recommended include reinforcement for dry nights (eg, a sticker calendar) bladder training exercises, fluid management, as described above combination of these Enuresis alarms or pharmacologic therapy should be considered in children who failed to improve after 3-6 months of behavioral interventions

Enuresis alarms are preferred to pharmacologic therapy bcs their effects are sustained after discontinuation and bcs they are associated with fewer S/E Desmopressin is an effective short-term alternative to the enuresis alarm in patients who are unresponsive to the alarm

Similar to desmopressin, TCA are an effective short-term therapy for nocturnal enuresis their high relapse rate and potentially severe adverse effects make them less appealing than alarm or desmopressin therapy

Thank you

References www.uptodate.com www.pubmed.com Campbell`s Urology