1. 排尿障礙治療中心 版權所有 Nocturnal Enuresis Hann-Chorng Kuo Department of Urology Buddhist Tzu Chi General Hospital

2. 排尿障礙治療中心 版權所有 Nocturnal Enuresis Enuresis – piss-a-beds (Greek) Enuresis – piss-a-beds (Greek) Enuresis – A normal void occurring at an inappropriate or socially unacceptable time or place Enuresis – A normal void occurring at an inappropriate or socially unacceptable time or place Nocturnal enuresis – Children void in bed while asleep and are generally not aroused by the wetting Nocturnal enuresis – Children void in bed while asleep and are generally not aroused by the wetting Monosymptomatic with a familial tendency Monosymptomatic with a familial tendency

3. 排尿障礙治療中心 版權所有 Quantification of Nocturnal Enuresis Age: children over the age of 5 years Age: children over the age of 5 years Frequency: number of wet nights per week or month; the time of wetting at early (first 2 hours) or late (2 hours before arising) or randomly timed Frequency: number of wet nights per week or month; the time of wetting at early (first 2 hours) or late (2 hours before arising) or randomly timed Amount of wetting: The bed is soaking wet or smaller amounts Amount of wetting: The bed is soaking wet or smaller amounts Arousibility: To wake up to a full bladder Arousibility: To wake up to a full bladder

4. 排尿障礙治療中心 版權所有 Subtypes of Nocturnal Enuresis Primary nocturnal enuresis: mono- symptomatic bedwetting never have been dry for uninterrupted period >6months Primary nocturnal enuresis: mono- symptomatic bedwetting never have been dry for uninterrupted period >6months Onset nocturnal enuresis Onset nocturnal enuresis Familial nocturnal enuresis Familial nocturnal enuresis Nocturnal polyuria enuresis : urine production > functional bladder capacity on wet nights, nocturia on dry nights Nocturnal polyuria enuresis : urine production > functional bladder capacity on wet nights, nocturia on dry nights

5. 排尿障礙治療中心 版權所有 Epidemiology of Nocturnal Enuresis 15 – 20% of 5-year-olds, 5% of 10-year- olds, 2-3 % of all adolescents wet the bed at least 1/month 15 – 20% of 5-year-olds, 5% of 10-year- olds, 2-3 % of all adolescents wet the bed at least 1/month Enuresis has a 15% per year spontaneous resolution rate Enuresis has a 15% per year spontaneous resolution rate Bed wetting is the cause of significant psychosocial stress, especially in older children Bed wetting is the cause of significant psychosocial stress, especially in older children

6. 排尿障礙治療中心 版權所有 Genetic Factors for Nocturnal enuresis Family history: Increased incidence of enuresis in children whose parents were enuretic, 77% in both parents enuretic, 43% in only one parent enuretic, 15% no parental history of enuresis Family history: Increased incidence of enuresis in children whose parents were enuretic, 77% in both parents enuretic, 43% in only one parent enuretic, 15% no parental history of enuresis Among boys 70% monozygotic and 31% dizygotic, among girls 65% vs 44% were enuretic Among boys 70% monozygotic and 31% dizygotic, among girls 65% vs 44% were enuretic

7. 排尿障礙治療中心 版權所有 Genetic Defects in NE Vasopressin-neurophysin II (VPNP II) gene is defective in familial nephrogenic diabetic insipidus (FNDI), but not in familial mono- symptomatic NE, on chromosome 20 Vasopressin-neurophysin II (VPNP II) gene is defective in familial nephrogenic diabetic insipidus (FNDI), but not in familial mono- symptomatic NE, on chromosome 20 Disease phenotype of nocturnal enuresis was associated with 2 markers, 13q13 & 13q14.2, locating at long arm of chromosome 13 (ENUR 1) Disease phenotype of nocturnal enuresis was associated with 2 markers, 13q13 & 13q14.2, locating at long arm of chromosome 13 (ENUR 1)

8. 排尿障礙治療中心 版權所有 Genetic factors and Response to Vasopressin Therapy 91% of enuretic patients with family history had good response to vasopressin vs only 7% of no family history 91% of enuretic patients with family history had good response to vasopressin vs only 7% of no family history Response is confined to those with nocturnal polyuria Response is confined to those with nocturnal polyuria ENUR 1 cannot be responsible for the enuretic phenotype in all affected families ENUR 1 cannot be responsible for the enuretic phenotype in all affected families

9. 排尿障礙治療中心 版權所有 Normal Micturition Bladder capacity is reached Bladder capacity is reached Stimulating stretch receptors in bladder wall Stimulating stretch receptors in bladder wall Bladder neck descent and open Bladder neck descent and open External sphincter reflexly opens External sphincter reflexly opens Detrusor contraction starts Detrusor contraction starts Urine is expelled from the urethra under pressure Urine is expelled from the urethra under pressure

10. 排尿障礙治療中心 版權所有 Bladder Control Under 6 month old, frequent reflex voiding day and night Under 6 month old, frequent reflex voiding day and night 6 to 12 month old, bladder empty is less frequent because of CNS inhibition 6 to 12 month old, bladder empty is less frequent because of CNS inhibition 1 to 2 years, child recognizes when the bladder is full and can communicate verbally 1 to 2 years, child recognizes when the bladder is full and can communicate verbally 3 to 4 years old, child can postpone urination 3 to 4 years old, child can postpone urination The awareness of bladder fullness increases up to age 5, when the child can delayed voiding on command The awareness of bladder fullness increases up to age 5, when the child can delayed voiding on command

11. 排尿障礙治療中心 版權所有 Night time Bladder Control In children aged 2 to 12 months, voided 1 to 8 times during 4 hours observation In children aged 2 to 12 months, voided 1 to 8 times during 4 hours observation 78% of children voided within 10minutes of waking (arousal in response to bladder fullness) 78% of children voided within 10minutes of waking (arousal in response to bladder fullness) More than 50% of children aged 3 years & >81% of 4 years are reported generally is dry at night More than 50% of children aged 3 years & >81% of 4 years are reported generally is dry at night

12. 排尿障礙治療中心 版權所有 Development and N E Increased incidence of developmental delay in enuretic children Increased incidence of developmental delay in enuretic children Delayed motor development is associated with a delay in bladder control Delayed motor development is associated with a delay in bladder control Nocturnal enuresis is more prevalent in boys than girls, which is associated with maturation delay Nocturnal enuresis is more prevalent in boys than girls, which is associated with maturation delay Small bladder capacity is controversial Small bladder capacity is controversial

13. 排尿障礙治療中心 版權所有 Delay in Bladder Control Detrusor instability is an important pathogenic factor in NE children Detrusor instability is an important pathogenic factor in NE children Day time incontinence, urgency, frequency, small bladder capacity might be associated with a dyssynergic pelvic floor muscle during voiding Day time incontinence, urgency, frequency, small bladder capacity might be associated with a dyssynergic pelvic floor muscle during voiding Recent studies indicated enuretic children do not have daytime DI, not respond to oxybutynine Recent studies indicated enuretic children do not have daytime DI, not respond to oxybutynine

14. 排尿障礙治療中心 版權所有 Night time Bladder Control Functional bladder capacity is smaller than non-enuretic children Functional bladder capacity is smaller than non-enuretic children Bladder capacity is less important than perception of bladder contractions Bladder capacity is less important than perception of bladder contractions A smaller bladder capacity may be a consequence rather than a cause of NE A smaller bladder capacity may be a consequence rather than a cause of NE 70% of NE children had a stable bladder, 30% had DI when asleep although a stable bladder was detected in daytime 70% of NE children had a stable bladder, 30% had DI when asleep although a stable bladder was detected in daytime

15. 排尿障礙治療中心 版權所有 Balance between Bladder capacity and Nocturnal urine vol Nocturnal urine production Nocturnal urine production Functional bladder capacity Functional bladder capacity Enuresis will only result if nocturnal bladder capacity is exceeded Enuresis will only result if nocturnal bladder capacity is exceeded Enuretic children only experienced wet nights when nocturnal urine volume exceeded bladder volume Enuretic children only experienced wet nights when nocturnal urine volume exceeded bladder volume

16. 排尿障礙治療中心 版權所有 Balance between Bladder capacity and Nocturnal urine vol

17. 排尿障礙治療中心 版權所有 CNS Control of Bladder Function A developmental delay in CNS control of bladder function might be a cause of NE A developmental delay in CNS control of bladder function might be a cause of NE A defect in efferent (failed to inhibit detrusor contraction) or afferent (failed to respond to bladder fullness or contraction) pathways might produce NE A defect in efferent (failed to inhibit detrusor contraction) or afferent (failed to respond to bladder fullness or contraction) pathways might produce NE Enuretic children failed to contract pelvic floor muscles (silent EMG) in response to bladder filling during sleep Enuretic children failed to contract pelvic floor muscles (silent EMG) in response to bladder filling during sleep

18. 排尿障礙治療中心 版權所有 Arousal and Nocturnal enuresis Locus coeruleus in brain stem is responsible for cortical arousal of stimuli, releasing noradrenaline, which in turn regulates vasopressin secretion from hypothalamus Locus coeruleus in brain stem is responsible for cortical arousal of stimuli, releasing noradrenaline, which in turn regulates vasopressin secretion from hypothalamus Deficit in vasopressin secretion results in polyuria and impair cortical arousal Deficit in vasopressin secretion results in polyuria and impair cortical arousal Vasopresin can increase alertness in rats Vasopresin can increase alertness in rats Abnormal vasopressin secretion pattern in enuretics withnocturnal polyuria Abnormal vasopressin secretion pattern in enuretics withnocturnal polyuria

19. 排尿障礙治療中心 版權所有 Arousal Dysfunction in PNE

20. 排尿障礙治療中心 版權所有 Arousal Defects in Enuretics Enuretic children are heavier sleepers compared with non-enuretics Enuretic children are heavier sleepers compared with non-enuretics Arousal was successful on only 9.3% of attempts in enuretics, compared with 39.7% in the controls Arousal was successful on only 9.3% of attempts in enuretics, compared with 39.7% in the controls Sleep pattern of the enuretics is similar to that of normal children Sleep pattern of the enuretics is similar to that of normal children Enuresis occurs in all sleep stages Enuresis occurs in all sleep stages

21. 排尿障礙治療中心 版權所有 Categories of Enuresis Type I: detectable EEG response to bladder distension and a stable CMG, 58% Type I: detectable EEG response to bladder distension and a stable CMG, 58% Type IIa: no EEG response to bladder distension, stable CMG, 10% Type IIa: no EEG response to bladder distension, stable CMG, 10% Type IIb: no EEG response to bladder distension, unstable CMG during sleep, 32% Type IIb: no EEG response to bladder distension, unstable CMG during sleep, 32% Type I & II: mild to severe arousal defects Type I & II: mild to severe arousal defects

22. 排尿障礙治療中心 版權所有 Arousal and Bladder Function in Nocturnal enuresis

23. 排尿障礙治療中心 版權所有 Lack of Diurnal Rhythmicity of Plasma Vasopressin in Enuretics Normal children have a diurnal rhythm of plasma vasopressin and urinary output with a nocturnal increase in plasma vasopressin, decrease in urinary excretion rate, and increase in urine osmolarity Normal children have a diurnal rhythm of plasma vasopressin and urinary output with a nocturnal increase in plasma vasopressin, decrease in urinary excretion rate, and increase in urine osmolarity Enuretics have an abnormal rhythm of plasma vasopressin and urinary output with nocturnal low vasopressin, large urinary excretion rate, and lower urinary osmolarity Enuretics have an abnormal rhythm of plasma vasopressin and urinary output with nocturnal low vasopressin, large urinary excretion rate, and lower urinary osmolarity

24. 排尿障礙治療中心 版權所有 Lack of Diurnal Rhythmicity of Plasma Vasopressin in Enuretics

25. 排尿障礙治療中心 版權所有 Plasma vasopressin level in NE

26. 排尿障礙治療中心 版權所有 Urine Osmolarity in NE

27. 排尿障礙治療中心 版權所有 Nocturnal urine volume in NE

28. 排尿障礙治療中心 版權所有 Treatment of Nocturnal Enuresis Primary nocturnal enuresis (PNE or MNE) Primary nocturnal enuresis (PNE or MNE) with or without nocturnal polyuria with or without nocturnal polyuria desmopressin responder or non-responder desmopressin responder or non-responder arousal dysfunction or bladder dysfunction arousal dysfunction or bladder dysfunction Secondary nocturnal enuresis Secondary nocturnal enuresis dysfunctionalvoiding dysfunctionalvoiding neurogenic voiding dysfunction neurogenic voiding dysfunction psychological distress psychological distress

29. 排尿障礙治療中心 版權所有 Nocturnal Urine Control In normal subjects, urine production decreases during night time In normal subjects, urine production decreases during night time Nocturnal urine production is about half of that in the daytime Nocturnal urine production is about half of that in the daytime A significant proportion of MNE patients lost the circadian rhythm of vasopressin secretion and produce large volume of diluted urine A significant proportion of MNE patients lost the circadian rhythm of vasopressin secretion and produce large volume of diluted urine Polyuria is an important factor in ¾ of the enuretic children Polyuria is an important factor in ¾ of the enuretic children

30. 排尿障礙治療中心 版權所有 Nocturnal polyuria and Vasopressin Some enuretic children with NP (nocturnal polyuria) have good response to vasopressin Some enuretic children with NP (nocturnal polyuria) have good response to vasopressin A subgroup of enuretic children with NP have a normal rhythm of vasopressin secretion, and not respond to DDAVP A subgroup of enuretic children with NP have a normal rhythm of vasopressin secretion, and not respond to DDAVP A defect in renal sensitivity to vasopressin and DDAVP is likely A defect in renal sensitivity to vasopressin and DDAVP is likely Enuretic children without NP and have a normalvasopressin rhythm do not respond to DDAVP Enuretic children without NP and have a normalvasopressin rhythm do not respond to DDAVP

31. 排尿障礙治療中心 版權所有 Treatment of Nocturnal Enuresis Conditioning therapy: Alarm system or dry- bed training,effective in about 30-80% Conditioning therapy: Alarm system or dry- bed training,effective in about 30-80% Medcal therapy: (1) Tricyclic antidepressant (TCA), imipramine, amitriptyline effective in 10-50% (author 24%) Medcal therapy: (1) Tricyclic antidepressant (TCA), imipramine, amitriptyline effective in 10-50% (author 24%) (2) anti-cholinergics (2) anti-cholinergics (3) desmopressin (DDAVP) (3) desmopressin (DDAVP) Side effect in combination medical therapy Side effect in combination medical therapy

32. 排尿障礙治療中心 版權所有 DDAVP Therapy in Nocturnal Enuresis in Children DDAVP in dose of 10-20 ug intranasally is effective in 70% of children with PNE DDAVP in dose of 10-20 ug intranasally is effective in 70% of children with PNE After discontinuing DDAVP for 3months, 21% remained dry without medication After discontinuing DDAVP for 3months, 21% remained dry without medication 20 ug is adequate in treating PNE, in children not responded to 20ug, 40ug did not effective 20 ug is adequate in treating PNE, in children not responded to 20ug, 40ug did not effective No serious adverse effect No serious adverse effect

33. 排尿障礙治療中心 版權所有 DDAVP Experience in Hualien 34 patients aged 5 to 24 years (10+ 4 years) 34 patients aged 5 to 24 years (10+ 4 years) Responserate was 91% under active treatment with DDAVP 20 ug, and 39% off drug for 1 month Responserate was 91% under active treatment with DDAVP 20 ug, and 39% off drug for 1 month During treatment, 22/34 were dry(67%), 8/34(24%) improved to 3 wet nights/week and 3/34(9%) were wet >4/week During treatment, 22/34 were dry(67%), 8/34(24%) improved to 3 wet nights/week and 3/34(9%) were wet >4/week Dose of 20ug for 8 weeks is adequate Dose of 20ug for 8 weeks is adequate

34. 排尿障礙治療中心 版權所有 Double blind placebo control study of DDAVP in PNE

35. 排尿障礙治療中心 版權所有 The Effectiveness of DDAVP and Placebo in PNE DDAVPPlacebo DC drug 1 month Dry10(56%)3(17%)2(11%)2(11%) Gr I Improved7(39%)11(61%)10(56%)6(33%) N=18Failed1(5%)4(22%)6(33%)10(56%) Dry12(80%)1(7%)1(7%) Gr II Improved1(7%)8(53%)4(27%) N=15Failed2(13%)6(40%)10(66%)

36. 排尿障礙治療中心 版權所有 Secondary Nocturnal Enuresis Psychological factors: stress, anxiety, depression Psychological factors: stress, anxiety, depression Neurogenic detrusor underactivity and overflow incontinence Neurogenic detrusor underactivity and overflow incontinence Dysfunctional voiding Dysfunctional voiding Urinary tract infection Urinary tract infection Bladder outlet obstruction Bladder outlet obstruction Diurnal incontinence Diurnal incontinence

37. 排尿障礙治療中心 版權所有 Diurnal enuresis Detrusor instability is commonly found Detrusor instability is commonly found Urgency frequency and urge incontinence Urgency frequency and urge incontinence Pelvic floor spasticity and dysfunctional voiding Pelvic floor spasticity and dysfunctional voiding May associated with constipation or fecal incontinence May associated with constipation or fecal incontinence Urodynamic study in patients not respond to oxybutynine Urodynamic study in patients not respond to oxybutynine

38. 排尿障礙治療中心 版權所有 Nocturnal enuresis in Adults Monosymptomatic PNE exists in 0.5- 1% Monosymptomatic PNE exists in 0.5- 1% Desmopressin 200 – 400 micro g for 3 months Desmopressin 200 – 400 micro g for 3 months 35% of patients became dry after desmopressin remained dry without therapy 35% of patients became dry after desmopressin remained dry without therapy Nocturia occurred in 75% of enuretics, but in only 5% of the healthy controls Nocturia occurred in 75% of enuretics, but in only 5% of the healthy controls

39. 排尿障礙治療中心 版權所有 Secondary Nocturnal Enuresis in Adults Bladder outlet obstruction in elderly men (progressive BPH obstruction) Bladder outlet obstruction in elderly men (progressive BPH obstruction) Detrusor underactivity and overflow incontinence in women (after radical hysterectomy or APR) Detrusor underactivity and overflow incontinence in women (after radical hysterectomy or APR) Detrusor overactivity in neurogenic voiding dysfunction (stroke, Parkinson’s disease) Detrusor overactivity in neurogenic voiding dysfunction (stroke, Parkinson’s disease) Idiopathic (urethral instability ?) Idiopathic (urethral instability ?)

40. 排尿障礙治療中心 版權所有 Treatment of Adult Nocturnal Enuresis DDAVP in patients proven to have nocturnal polyuria (nocturnal urine volume > 35% daily urine volume, or >900ml/N) DDAVP in patients proven to have nocturnal polyuria (nocturnal urine volume > 35% daily urine volume, or >900ml/N) Oxybutynine in patients proven to have DI Oxybutynine in patients proven to have DI Imipramine or methylephedrine in patients suspicious to have urethral incompetence Imipramine or methylephedrine in patients suspicious to have urethral incompetence Pelvic floor muscle exercises or functional electrostimulation might be helpful Pelvic floor muscle exercises or functional electrostimulation might be helpful

41. 排尿障礙治療中心 版權所有 Psychological Factors in MNE Psychological distress in not significantly higher in enuretics than clinical controls Psychological distress in not significantly higher in enuretics than clinical controls Psychological distress is more common in secondary enuresis and day wetting than primary enuretics and bed wetting Psychological distress is more common in secondary enuresis and day wetting than primary enuretics and bed wetting Enuretic girls had higher risk in developing psychological distress Enuretic girls had higher risk in developing psychological distress

42. 排尿障礙治療中心 版權所有 Psychological symptoms Feel bewildered and humiliated and are different from peers Feel bewildered and humiliated and are different from peers Often teased and bullied because of enuresis Often teased and bullied because of enuresis Decline to participate activities and overnight stay or invite friends to visit Decline to participate activities and overnight stay or invite friends to visit Worry their bedroom smells unclean andnot allow friends to enter it Worry their bedroom smells unclean andnot allow friends to enter it Aware enuresis results in extra work and expense for their parents Aware enuresis results in extra work and expense for their parents

43. 排尿障礙治療中心 版權所有 Impact of Psychological Stress Enuresis occurs in mental retardation, autism, attention deficit disorder, dysfunction in motor control or perception Enuresis occurs in mental retardation, autism, attention deficit disorder, dysfunction in motor control or perception Enuresis is more common in lower socio- economic groups, in large overcrowded family, and in children living in institution Enuresis is more common in lower socio- economic groups, in large overcrowded family, and in children living in institution Enuresis is associated with short stature, reflecting deficiency of growth hormone secretion and vasopression deficiency Enuresis is associated with short stature, reflecting deficiency of growth hormone secretion and vasopression deficiency

44. 排尿障礙治療中心 版權所有 Conclusions Nocturnal enuresis has a multifactorial etiology Nocturnal enuresis has a multifactorial etiology It may be best regarded as groups of conditions It may be best regarded as groups of conditions A 15% annual spontaneous cure rate A 15% annual spontaneous cure rate Treatment should match to etiologies Treatment should match to etiologies Balance between bladder functional capacity and nocturnal urine output appear to be the most important Balance between bladder functional capacity and nocturnal urine output appear to be the most important

45. 排尿障礙治療中心 版權所有 No More Bed Wetting