1. Nocturia and Nocturnal Enuresis Chun-Hou Liao Chief, Division of Urology, Cardinal Tien Hospital Associate Professor, Fu-Jen Catholic University Adjunct Attending, Department of Urology, NTUH Secretary-General, Taiwanese Continence Society (TCS) and Taiwanese Association of Andrology (TAA)

3. Nocturia Definition ◦a bothersome condition, defined by the ICS as ‘‘the complaint that the individual has to wake at night one or more times to void  van Kerrebroeck P 2002 Nocturia that occurs twice or more per night can have a substantial negative impact on the patient’s quality of life (QOL), mood and overall health Nocturia can be caused by ◦reduced bladder capacity ◦increased nocturnal urine volume Multiple factors can contribute to nocturia, including polyuria, nocturnal polyuria, advanced age, sleep disorder, and bladder storage disorder including benign prostatic hyperplasia, overactive bladder, chronic pelvic pain syndrome.

4. 1. Weiss et al. J Urol 2011;186:1358–1363; 2. Van Kerrebroeck et al. Neurourol Urodyn 2002;21:179–183  NP is a major cause of nocturia (76–88% of patients in 2 large cohorts) 1  Defined as production of an abnormally large volume of urine during sleep: 2 –Young: >20% of daily total output –Elderly: >33% of daily total output NOCTURNAL POLYURIA

5. Mean variation in urinary excretion rate ml/hour P<0.001 Adapted from Rittig et al. Am J Physiol 1989 Apr;256(4 Pt 2):F664-71. Circadian Urine Production Normal Enuresis 8AM-12AM 12AM-4PM 4PM-10PM 10PM-8AM

6. Circadian ADH Production Mean variation in plasma antidiuretic hormone (ADH) P avp (pg/ml) P<0.001 Adapted from Rittig et al. Am J Physiol 1989 Apr;256(4 Pt 2):F664-71. Normal Enuresis 8AM-12AM 12AM-4PM 4PM-10PM 10PM-8AM

7.  NP is a major underlying factor which is often overlooked  NP is a disease created by an impairment of natural circadian rhythms of Arginine Vasopressin (AVP)  NP may occur with other urological conditions, such as OAB and BPO  If NP is not treated when it occurs with OAB/BPO, nocturia will persist Myth: ‘Nocturia is only a symptom of some other underlying disorder, and is attributable to OAB in women, and BPO in men’ BUT NOCTURIA TREATMENT OFTEN FAILS DUE TO QUESTIONABLE DIAGNOSTIC ASSUMPTIONS

8. Poor results are observed with OAB/BPO therapy for nocturia treatment 1. Johnson et al. J Urol 2003;170:145–148; 2. Djavan et al. Eur Urol Suppl 2005;4:61–68; 3. Johnson et al. J Urol 2007;178:2045–2050; 4. Yamaguchi et al. BJU Int 2007;100:579–587; 5. Brubaker & FitzGerald. Int Urogynecol J Pelvic Floor Dysfunct 2007;18:737–741; 6. Nitti et al. BJU Int 2006;97:1262–1266; 7. Rackley et al. J Urol 2006;67:731–736; 8. Kaplan et al. JAMA 2006;296:2319–2328

9. TURP FAILS TO IMPROVE NOCTURIA IN MEN TURP is not the answer – other mechanisms (eg NP) involved Reproduced from Urology, 61, Yoshimura et al. Nocturia and benign prostatic hyperplasia, 786–790. Copyright 2003, with permission from Elsevier

10. UNDERLYING NOCTURAL POLYURIA (NP) IS THE REASON WHY α1-BLOCKER TREATMENT OFTEN FAILS TO TREAT NOCTURIA 85% of patients unresponsive to α1-blocker treatment are found to have NP Yoong et al. Med J Malaysia 2005;60;294–296 Global polyuria (10%) Normal nocturnal output (5%) NP (85%)

11. EVALUATION Clinicians should be alert to the potential reluctance of patients to present their nocturia1 Patients should be evaluated for underlying disease states, cardiovascular conditions, consumption of beverages Urine analysis, urine culture and cytology should be performed1 Questionnaires can quantify the effect of nocturia on daily functioning Frequency–volume charts (FVCs) are a key tool for diagnosis of NP

12. VALUE OF FVCS FOR APPROPRIATE DIAGNOSIS AND TREATMENT FVCs provide valuable information regarding voiding frequency and urinary volumes for 24–72 hours Chart can also include record of volume and type of fluid ingested, time of retiring to bed and time of rising If nocturnal urine volume >20–33% of total 24-hour urine volume, NP is present

13. Patient 1Patient 2Patient 3 24-hour volume1900 mL (no global polyuria) 5000 mL2500 mL (no global polyuria) Nocturnal urine volume (includes first morning void) 1200 mL1500 mL Nocturia episodes337 Nocturnal urine volume/24-hour volume 63% (NP) 30% (normal) 60% (NP) Maximum voided volume 400600200 DiagnosisNPGlobal polyuriaMixed aetiology (NP and reduced voided volumes) VOIDING DIARY ANALYSIS: CASE STUDIES

14. Simple Algorithm for Classification and Treatment of Nocturia Medical history Examination Laboratory tests FVC Dietary advice Lifestyle advice Exclusion/treatment of OSA Desmopressin (<65 years) Endocrinologist Poly- dipsia DI/DM/ other Urologist, uro-gynaecologist, geriatrician, sleep expert 24h - polyuria (24-hour voided volume >40 mL/kg) NP (nocturnal urine volume >20–33%, including first morning voided volume) Apparent bladder storage problems BPO OAB Bladder dysfunction Other Sleep problems Cardiac Gynaecological α 1 - blockers anticholinergics FVC, frequency–volume chart; DI, diabetes insipidus; DM, diabetes mellitus; OSA, obstructive sleep apnoea

15. Management Lifestyle modification Lifestyle modification is recommended as the first-line option ◦van Kerrebroeck P 2010 These recommendations include ◦preemptive voiding immediately before going to bed ◦nocturnal ‘‘dehydration,’’ ◦dietary and fluid restrictions (avoidance of caffeinated beverages and alcohol) ◦medication timing (taking diuretics in the afternoon) ◦evening leg elevation to mobilize fluids, and use of sedatives ◦Weiss JP 2011

16. Management Lifestyle modification A prospective study of 56 patients of nocturia managed by nondrug lifestyle measures including restriction of fluid intake, refraining from excess hours in bed, moderate daily exercise and keeping warm in bed  Their results showed mean nocturnal voids and nocturnal urine volume decreased significantly from 3.6 to 2.7 (p <0.0001) and from 923 to 768 ml (p = 0.0005), respectively.  More than 50 % patients showed an improvement of more than 1 episode  Soda T 2010

17. Management Lifestyle modification Pelvic floor exercises are thought to be effective to treat urgency at night [Johnson II TM 2005].  However, no randomized control trials (RCT) evaluating behavioral therapy to treat nocturia as a primary outcome is available. One trial enrolled 49 men with nocturnal polyuria and compared furosemide intake 6 hour before bedtime with placebo  Using 7-day FVC, administration of 40 mg of furosemide 6 hour before bedtime was superior to placebo in reducing the numbers of nocturnal voids, but not the nocturnal voided volume. ◦Reynard JM 1998

18. WHAT IS DESMOPRESSIN? Desmopressin is a synthetic analogue of AVP Natural AVP is secreted from the pituitary gland and acts on the distal renal tubules and collecting ducts to promote water reabsorption Insufficient AVP in the kidneys or renal AVP resistance can increase urine production and cause NP/nocturia Desmopressin increases water reabsorption in the distal and collecting tubules of the kidney, concentrating urine and decreasing urine output and nocturia Van Kerrebroeck et al. Eur Urol 2007;52:221–229

19. Desmopressin has Level 1b-Evidence and Grade A-Recommendation

20. Weiss et al. BJU Int 2011;108:6–21 COMBINATION THERAPY  Daytime LUTS are treated with anticholinergics and α1 blockers.  Night-time LUTS (nocturia) may have multiple underlying causes  If patients have more than one cause underlying nocturia, all must be treated  Desmopressin is only agent which addresses aetiology of nocturia due to NP  Combination therapy can address daytime and night-time LUTS

21. DesmopressinAnticholinergic α 1 -blocker ++ DesmopressinAnticholinergic + Desmopressinα 1 -blocker + Anticholinergicα 1 -blocker + Further investigational studies of these strategies are warranted Possible therapy combinations 21

22. Poor results are observed with OAB/BPO therapy for nocturia treatment BPO/OAB therapyNet advantage vs placebo (reduction in number of voids or % reduction) BPOTerazosin 1 0.3 voids Tamsulosin OCAS 2 0.3 voids Doxazosin + finasteride 3 ~0.2 voids OABSolifenacin 4 0.16 voids Solifenacin 5 0.08 voids (NP) 0.18 voids (No NP) Tolterodine ER 6 ~0.75 voids/week (severe urgency nocturnal voids only) Tolterodine ER 7 4% BPO + OABTolterodine ER + tamsulosin 8 Combination therapy 0.2 voids 1. Johnson et al. J Urol 2003;170:145–148; 2. Djavan et al. Eur Urol Suppl 2005;4:61–68; 3. Johnson et al. J Urol 2007;178:2045–2050; 4. Yamaguchi et al. BJU Int 2007;100:579–587; 5. Brubaker & FitzGerald. Int Urogynecol J Pelvic Floor Dysfunct 2007;18:737–741; 6. Nitti et al. BJU Int 2006;97:1262–1266; 7. Rackley et al. J Urol 2006;67:731–736; 8. Kaplan et al. JAMA 2006;296:2319–2328 OCAS, oral-controlled absorption system; NP, nocturnal polyuria; ER, extended release 22

23. DESMOPRESSIN + α1 ANTAGONISTS DECREASE NOCTURIA AND IMPROVE IPSS SCORES IN PATIENTS WITH LUTS Observational study of patients with LUTS suggestive of BPH and nocturia Treated with desmopressin tablets for 3 months 34 patients with diagnosed NP receiving an α1 antagonist at least 4 weeks prior to desmopressin treatment Addition of desmopressin associated with: ◦50% reduction in median nocturia episodes (from 4 to 2) ◦Reduced median IPSS score (from 18 to 14) Berges et al. ICS/IUGA, 23–27 August 2010, Toronto, Canada. Abstract 75 Desmopressin provided additional benefit to patients with LUTS suggestive of BPH and nocturia already receiving α1 antagonist

24. DESMOPRESSIN + LUTS AGENTS ARE AN EFFECTIVE TREATMENT FOR NOCTURIA IN PATIENTS WITH BPH Patients with BPH >65 years with nocturia and NP All treated with α-blocker; ~33% on anticholinergics Clinical response (decrease ≥2 voids) was achieved by 61.4% patients (p<0.001 relative to placebo) Reprinted from J Urol, 185, Wang et al, Low dose oral desmopressin for nocturnal polyuria in patients with benign prostatic hyperplasia: a double-blind, placebo controlled, randomized study, 219–223., Copyright 2011, with permission from Elsevier Reduction in number of nocturnal voids over time Increase in duration of first sleep period over time 0 4 Mean number of nocturnal voids 1 6 8 2 36 Time (month) Baseline12 Placebon=58 Desmopressinn=57 0 Mean duration of first sleep period (min) 1 100 150 50 36 Time (month) Baseline12 Placebon=58 Desmopressinn=57

25. DESMOPRESSIN + LUTS AGENTS ARE A WELL TOLERATED TREATMENT FOR NOCTURIA IN PATIENTS WITH BPH No serious systemic complications were found during medication Serum sodium level of desmopressin group was always lower than the placebo group, but no clinically significant symptoms seen Wang et al. J Urol 2011;185:219–223 Adverse eventPlacebo (% patients) Desmopressin (% patients) Headache6.95.3 Dizziness6.97.0 Nausea1.70 Serum sodium <130 mmol/L without clinical symptoms 17.215.8

26. Practical Considerations for Desmopressin Use Initiate at low dose (0.1 mg/day – before sleeping) Increase dose weekly until maximal efficacy reached Maximum recommended dose: 0.4 mg/day Patients should avoid drinking fluids 1 hour before and 8 hours after administration In men ≥65 years, desmopressin should be avoided if serum sodium concentration below normal In other men ≥65 years, measure serum sodium at day 3 and 7, and 1 month. If all readings normal, then monitor every 3–6 months

27. SUMMARY: CURRENT DIAGNOSIS AND TREATMENT RECOMMENDATIONS Nocturia is a condition which requires careful diagnostic evaluation FVCs are a valuable diagnostic tool Desmopressin is recommended as first-line treatment for nocturia related to NP ◦Mono- or combination therapy A significant treatment effect should be an improvement in all symptoms clinically associated with nocturia Further research is needed to validate and clarify clinical relevance of definition of nocturia and NP ◦Definitive, relevant sleep endpoints for nocturia studies are required

28. Nocturnal Enuresis

29. Enuresis – piss-a-beds (Greek) 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 Monosymptomatic with a familial tendency

30. Quantification of Nocturnal Enuresis 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 Amount of wetting: The bed is soaking wet or smaller amounts Arousibility: To wake up to a full bladder

31. Subtypes of Nocturnal Enuresis Primary nocturnal enuresis: mono-symptomatic bedwetting never have been dry for uninterrupted period >6months Onset nocturnal enuresis Familial nocturnal enuresis Nocturnal polyuria enuresis : urine production > functional bladder capacity on wet nights, nocturia on dry nights

32. 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 Enuresis has a 15% per year spontaneous resolution rate Bed wetting is the cause of significant psychosocial stress, especially in older children

33. Balance between Bladder capacity and Nocturnal urine vol

34. Causes of Enuresis Urine Volume Bladder Contractions Sleep Arousal ENURESIS Adapted from Wolfish et al., J Urol 2001; Vol. 166, 2444–7. Causes of Enuresis: A Triad 1

35. Treatment of Nocturnal Enuresis 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%) (2) anti-cholinergics (3) desmopressin (DDAVP) Side effect in combination medical therapy

36. DDAVP Therapy in Nocturnal Enuresis in Children 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 20 ug is adequate in treating PNE, in children not responded to 20ug, 40ug did not effective No serious adverse effect

37. Thanks for your attention