1. WELCOME TO A TALK ABOUT ENURESIS Old Pew By N.C. Wyeth
From Robert Louis Stevenson’s Treasure Island

2. Primary Nocturnal Enuresis a survey 1. title
J.P. Nørgaard MD DMSC
Executive Director Clincal Sciences Urology
Ferring International Centre
Copenhagen

3. What is nocturnal enuresis?
Benign condition with bedwetting as single symptom
In a healthy child
Older than 5 years
Complete emptying of the bladder
No other symptoms
Nijman et al. 2nd Intl. Consultation on Incontinence In: Incontinence 2002

4. Bedwetting is not…. A primary psychological condition
A self-healing disease
Normal after age 7
Caused by excessive drinking
Untreatable
…………

5. Terminology Monosymptomatic nocturnal enuresis
Primary nocturnal enuresis
Non-monosymptomatic nocturnal enuresis
Enuresis
Bedwetting
Nighttime overactive bladder
………………

6. Primary Nocturnal enuresis (Bedwetting)
Very common problem in most western countries
About 7-15% children aged 7 yrs
Significant adverse behavioral and psychological impact on affected children

7. Prevalence of nocturnal enuresis
100%
Prevalence of NE
50%
Adults 0.5–1% 0% 4 8 12 16 20
Age (years)

8. Prevalence of primary nocturnal enuresis among different countries35
Japan 30
U.S.A.
Sudan 25
Holland 20
Prevalence (%) 15 10 5 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Age (years)

9. Hong Kong: where East meets West

10. Prevalence of primary nocturnal enuresis among different countries (1996)
Hong Kong 35
Japan 30
U.S.A.
Sudan 25
Holland 20
Prevalence (%) 15 10 5 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Age (years)

12. Prevalence of primary nocturnal enuresis among different countries (2000)
Hong Kong 5 10 20 30 35
Age (years)
Prevalence (%) 6 7 8 9 11 12 13 14 15 16 17 18 19 25
Japan
U.S.A.
Sudan
Holland

13. Prevalence of primary nocturnal enuresis among different countries
(1996)
(2000) 35
Hong Kong 30
Japan
U.S.A. 25
Sudan 20
Holland
Prevalence (%) 15
1996
2000 10 5 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Age (years)
Age (years)

14. Primary nocturnal enuresis (Bedwetting)
Lesson to learn:
Prevalence figures at times can be deceptive!
Patients will turn up ONLY if they can see new hope!!

15. Pathophysiology of PNE: Genetics
75% risk where both parents had been enuretics as a child
45% risk where only one parent had been enuretic as a child
15% risk where there is no parental history of enuretics
40% siblings also had PNE
75% risk where both parents have been enuretics as children

16. Nocturnal enuresis: Pathophysiology
Nocturnal urine output volume
Nocturnal bladder capacity
>> +
Failure to awaken in response to bladder fullness
Nocturnal enuresis (a heterogeneous disorder!)

17. Diurnal variation of antidiuretic hormone (ADH) secretion in normal versus enuretic children
Plasma ADH
Day
Night
Urine osmolality
Day
Night
Urine volume
Day
Night
Normal
Enuretic
Rittig, Norgaard 1985, 1987

18. Primary nocturnal enuresis: Pathophysiology
2 main subgroups:
1. Children with large nocturnal urine production (nocturnal polyuria)
in general have normal bladder function but a deranged circadian rhythm of AVP (ADH) secretion
2. Children with a small nocturnal functional bladder capacity
due to various types of bladder dysfunction, either only after sleep at night, or both during daytime and nighttime

21. Primary nocturnal enuresis
Summary
PNE comprises of a diverse spectrum of conditions resulting in a mismatch of nocturnal urine production in excess of nocturnal functional bladder capacity, together with a disturbance of conscious awakening response to sensation of bladder fullness

22. historical aspects
This slide illustrates some of the early treatments used for enuresis. Treatment of children with urinary incontinence dates back to 1500 BC, indicating that enuresis has been a problem for many years. Many of the older treatments for urinary incontinence are unpleasant, for example, biting the head off a frog, and are not comparable with the advanced treatment interventions used today.

23. The role of desmopressin in PNE

24. Reduced bladder capacity
Nocturia and nocturnal enuresis
Polyuria during sleep
Reduced bladder capacity
Full bladder
Waking up?
YES NO
Nocturnal enuresis
Nocturia
ICI 2001

25. PNE: Pathophysiology & treatment
Polyuria
(nocturnal)
Bladder
overactivity
(nocturnal)
Arousal
disorders
Genetics

26. > normal bladder volume
Nocturnal polyuria and PNE
PNE with nocturnal
polyuria =
nocturnal diuresis
> normal bladder volume

27. What is desmopressin? Analogue of vasopressin (antidiuretic hormone)
Potent antidiuretic
Concentrates urine
No direct bladder effect
No direct cardiovascular action

28. Indication for MINIRIN treatment
Primary nocturnal enuresis (PNE)
where nocturnal urine output exceeds bladder capacity

29. Desmopressin function
Urine volume
Functional
bladder capacity I II
III
Time
I: No medication given. Early enuresis
II: Insufficient antidiuresis. Late enuresis (or nocturia)
III: Sufficient antidiuresis. Dry night.

30. Canadian Enuresis Study (CESE)
Objective: to evaluate the long-term (1-year) efficacy and safety of MINIRIN tablets in children with PNE
Open, continuous, multicentre trial
256 children (203 boys, 53 girls)
Mean age 9.6 years (6–18 y)
Wolfish et al. Scand J Urol Nephrol 2003; 37:22–27

31. CESE study design Titration period 0.2 mg and 0.4 mg for 2 or 4 weeks
< 50% reduction in wet nights Excluded from the study
> 50% reduction in wet nights
12 weeks treatment
< 2 wet nights
Treatment free period
Repeat until treatment period 4
> 2 wet nights
12 weeks treatment
4 weeks MINIRIN on half the dose

32. Response after cessation of treatment
Results – CESE
Response after cessation of treatment
Total
Period 3
Period 2
Period 1
Full response (no. pts) 27 12 9 6
Accumulated full response (%) –
37.5%
17% 6%

33. Swedish Enuresis Trial (SWEET)
Objective: To study the long-term (1-year) efficacy and safety of MINIRIN nasal spray in children with PNE
Open, continuous, multicentre trial
399 children (298 boys, 101 girls)
Mean age 7.9 years (5 – 12 y)
Hjälmås K, et al. BJU.1998;82:704–709.

34. SWEET study design
Titration period 20 µg intranasal for 2 weeks. Increase dose by 10 µg to max. 40 µg if >2 wet nights
< 50% reduction in wet nights
Excluded from the study
> 50% reduction in wet nights
12 weeks treatment
No wet nights
1 week treatment free period
Repeat until
treatment
period 4
wet nights
12 weeks treatment
Stop medication

35. Response after cessation of treatment
Results – SWEET
Response after cessation of treatment
13% 32
Period 1
Period 2
30% 13
Period 3
31.4% 1
Period 4
31.4% 77
Total
Accumulated full response (%)
Full response (no. pts) 30
25%

36. Efficacy of long-term MINIRIN for PNE
*Initial response rate
**Response rate during treatment
**Dry with no medication after 1 year’s treatment
Wolfish (oral)
The Canadian Enuresis Study and Evaluation
50%
74%
37.5%
Hjälmås (nasal)
The Swedish Enuresis Trial
61%
100%
31.4%
* Response rate: > 50% reduction of wet nights
** Based on the responding group

37. Cure rate after long term treatment on oral desmopressin in adolescents
Dry patients 90 83
Observed cure rate 78 80 74 70 65 62 61 57 55 60 47 50
Cure rate (%) 38 40 35 27 30 15 20
7.5 10 1 2 3 4 5 6
Years after treatment
Läckgren et al, BJU 1998

38. Efficacy of MINIRIN for PNE Evidence-based results
MINIRIN vs placebo
4.5 (1.4 to 15) times more likely to become dry
2.2 (-0.7 to -3.7) fewer wet nights per week
Evans BMJ. 2001;323:1167
Level of evidence: 1
ICI 2001

39. MINIRIN safety – CESE study
2 patients (0.8%) drug-related adverse events
(headache, abdominal pain)
No changes in:
Serum electrolytes
Heart rate
Blood pressure
ALT, AST, BUN, creatinine

40. MINIRIN safety – SWEET study
No serious drug related adverse events:
14 patients (4%) reported adverse events (common cold, rhinitis, headache, gastro-enteritis)
5 children had decreased serum sodium without clinical symptoms
No influence on:
Body weight or height
Blood pressure
Serum creatinine or urine analysis

41. MINIRIN safety – van Kerrebroeck review
1083 patients receiving long-term desmopressin treatment (> 6 months)
53 patients (5%) adverse events: headache (2%), abdominal pain (1%), hyponatraemia with no clinical symptoms in 1%
No changes in:
Body weight
Serum electrolytes
Heart rate
Blood pressure
ALT, AST, BUN, creatinine
Van Kerrebroeck BJU 2002;89:420–425

42. MINIRIN Safety: Medline search 1966–94
Investigated hyponatraemia events in 23 studies
In 717 patients with nocturnal enuresis treated with desmopressin:
10 cases of hyponatraemia in patients 5–15 years
Excessive water intake was a contributing factor in 5/10
All of the patients who developed neurological symptoms recovered
Robson WLM, et al. Eur J Pediatr 1996;155:

43. MINIRIN treatment regimen
Fluid intake must be limited to a minimum from one hour before until eight hours after administration
In case of fever and / or diarrhea MINIRIN treatment should be stopped until the patient has fully recovered

44. Self-esteem in different populations
Western: Self-concept significantly improved after conditioning treatment 1
Western: Significant improvement in self-concept after 6 months’ treatment 2
Chinese: Significant improvement in self-esteem can be achieved after appropriate treatment 3
1. Moffat, Kato, Pless. J Pediatr. 1987;110(4):647–52
2. Longstaffe, Moffat, Whalen. Pediatrics 2000;105:935–40
3. Sit et al. ICCS/APAPU Joint Meeting, Hong Kong 2002 Abstract 2.06

45. Will Minirin always stop bedwetting ?

46. Desmopressin non-response
Evidence of bladder dysfunction
Abnormal renal sensitivity to ADH and desmopressin (Nørgaard, BJU, 79:825,1997)

47. Nocturnal vasopressin levels ‘Dry’ vs. ‘Wet’ nights
1.8 *
1.6
1.4
1.2 1 *
0.8
0.6
Responders
0.4
dDAVP non-responders
0.2
Dry night
Wet night
* p = 0.004
Hansen et al, J Urol 2001

48. Treatment of non-responders
”By adopting an individualized approach, using either high-dose desmopressin or combination treatment with desmopressin and oxybutynin, the majority of enuretic children resistant to conventional treatment can achieve dryness or become greatly improved”
Neveus et al 2000

49. Let’s initiate medical treatment
Choise of treatment?
Let’s talk
Let’s train
Let’s initiate medical treatment
R. Butler
Urotherapists MD
Different attitudes are dependent on different studies by different investigators in different study populations

50. In summary, there are no small problems
In summary, there are no small problems. Problems that appear small are large problems that are not understood.
Santiago Ramón y Cajal, 1897