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

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

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 2001. In: Incontinence 2002

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

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

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

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

Prevalence of primary nocturnal enuresis among different countries 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)

Hong Kong: where East meets West

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)

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

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)

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!!

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

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

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

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

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

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.

The role of desmopressin in PNE

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

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

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

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

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

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.

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

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

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%

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.

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

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%

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

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

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

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

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

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

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;155:959-962

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

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

Will Minirin always stop bedwetting ?

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

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

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

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

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