Overactive Bladder in Clinical Practice

Overactive Bladder in Clinical Practice

Alan J. Wein Christopher Chapple

Overactive Bladder in Clinical Practice

Authors Alan J. Wein Division of Urology University of Pennsylvania Health System Philadelphia USA

Christopher Chapple Department of Urology Royal Hallamshire Hospital Sheffield UK

ISBN 978-1-84628-830-2 e-ISBN 978-1-84628-831-9 DOI 10.1007/978-1-84628-831-9 Springer London Dordrecht Heidelberg New York British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Control Number: 2011944263 © Springer-Verlag London Limited 2012 Whilst we have made considerable efforts to contact all holders of copyright material contained in this book, we may have failed to locate some of them. Should holders wish to contact the Publisher, we will be happy to come to some arrangement with them. Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms of licenses issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms should be sent to the publishers. The use of registered names, trademarks, etc., in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Contents

1

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Socioeconomic Impact . . . . . . . . . . . . . . . . . . . . . . . . Who Seeks Treatment and Why? . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1 1 4 8 11 15 17

2

The Pathophysiology of Overactive Bladder . . . . . Anatomy and Pathophysiology of the Lower Urinary Tract . . . . . . . . . . . . . . . . Urinary Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . The Detrusor Muscle . . . . . . . . . . . . . . . . . . . . . . . . . Detrusor Overactivity . . . . . . . . . . . . . . . . . . . . . . Etiology of Detrusor Overactivity . . . . . . . . . . . . . . Neurogenic Factors . . . . . . . . . . . . . . . . . . . . . . . . Idiopathic Detrusor Overactivity . . . . . . . . . . . . Nocturia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21

Diagnosis and Assessment . . . . . . . . . . . . . . . . . . . . . Reasons for Visiting the Primary Care Physician . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . “Patient Flow”. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reasons for Visiting the Specialist . . . . . . . . . . . . . . Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . Abdomen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prostate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pelvic Floor Muscles . . . . . . . . . . . . . . . . . . . . . . .

41

3

21 23 26 27 29 31 33 34 37

41 43 43 45 45 46 46 v

vi

Contents

Female Genitourinary System . . . . . . . . . . . . . . . Importance of Good Communication. . . . . . . . . Patient Questionnaires. . . . . . . . . . . . . . . . . . . . . . . . Patient Diaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Urinalysis and Other Readily Available Studies . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

55 56

4

The Role of the Specialist . . . . . . . . . . . . . . . . . . . . . General Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Additional Investigations . . . . . . . . . . . . . . . . . . . . . Urodynamic Investigations . . . . . . . . . . . . . . . . . . . . Simple Urodynamic Investigations . . . . . . . . . . . Pressure/Flow Studies . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

59 59 60 61 62 62 63 66 73

5

Management of Overactive Bladder . . . . . . . . . . . . Principles of Management . . . . . . . . . . . . . . . . . . . . . The Role of the Primary Care Physician and the Specialist in Management . . . . . . . . . . Follow-Up Strategies . . . . . . . . . . . . . . . . . . . . . . . Self-care Practices and Lifestyle Changes . . . . . . . . Smoking Cessation. . . . . . . . . . . . . . . . . . . . . . . . . Weight Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Behavioral Modification . . . . . . . . . . . . . . . . . . . . . . Patient Compliance . . . . . . . . . . . . . . . . . . . . . . . . Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Combined Behavior Modification and Drug Therapy . . . . . . . . . . . . . . . . . . . . . . . Acupuncture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

75 75

6

Pharmacological Treatment of Overactive Bladder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Choosing a Drug Therapy for Overactive Bladder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

46 47 47 49

76 77 77 78 78 78 80 80 80 81 82

83 83

Contents

vii

Overview of Key Drugs . . . . . . . . . . . . . . . . . . . . . . . Darifenacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fesoterodine (Toviaz) . . . . . . . . . . . . . . . . . . . . . . Oxybutynin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Propiverine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Solifenacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tolterodine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Trospium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Current Recommendations . . . . . . . . . . . . . . . . . . . . Efficacy of Antimuscarinic Drug Therapy . . . . . . . . Long-Term Tolerability and Compliance with Antimuscarinic Drug Therapy . . . . . . . . . Patient-Perceived Outcomes with Antimuscarinic Drug Therapy . . . . . . . . . Intradetrusor Botulinum Toxin Injection Therapy . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85 85 87 89 91 92 93 95 96 97

105 110

7

Neuromodulation and Surgical Approaches . . . . . . Surgery for Overactive Bladder . . . . . . . . . . . . . . . . Augmentation Cystoplasty . . . . . . . . . . . . . . . . . . Autoaugmentation . . . . . . . . . . . . . . . . . . . . . . . . . Sacral Neuromodulation . . . . . . . . . . . . . . . . . . . . . . Percutaneous Posterior Tibial Nerve stimulation . . Pudendal Nerve Stimulation . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

115 115 116 119 120 122 122 123

8

Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . Overactive Bladder in the Male . . . . . . . . . . . . . . . . Postradical Prostatectomy . . . . . . . . . . . . . . . . . . Prostate Enlargement and Bladder Outlet Obstruction . . . . . . . . . . . . . . . . . . . . . . . Nocturia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Incidence of Urine Retention in the Male . . . . . Elderly People. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Neurogenic Group . . . . . . . . . . . . . . . . . . . . . . . The Mixed Incontinence Group . . . . . . . . . . . . . . . .

125 125 128

102 104

129 133 134 134 136 136

viii

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Contents

Pregnancy and OAB. . . . . . . . . . . . . . . . . . . . . . . . . . Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

137 137 138

Comorbid Conditions and Complications . . . . . . . . Prevalence of Comorbid Conditions . . . . . . . . . . . . Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sexual Dysfunction. . . . . . . . . . . . . . . . . . . . . . . . . . . Falls and Fractures . . . . . . . . . . . . . . . . . . . . . . . . . . . Cardiac Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gastrointestinal Disorders . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

143 143 144 144 145 145 146 146

Author Biographies

Alan J. Wein, MD, PhD (hon) is Professor and Chief of the Division of Urology in the Perelman School of Medicine of the University of Pennsylvania, Chief of Urology at the Hospital of the University of Pennsylvania and Director of the Residency Program in Urology at the University of Pennsylvania. He is a graduate of Princeton University and received his MD from the University of Pennsylvania School of Medicine. He completed training in surgery and urology at the University of Pennsylvania, including a fellowship at the Harrison Department of Surgical Research. He has been certified and recertified (voluntary) by the American Board of Urology. He was awarded an honorary PhD from the University of Patras, Greece in September 2005. Dr Wein’s affiliations and professional memberships include the American Association of Genitourinary Surgeons, Clinical Society of Genitourinary Surgeons, American Surgical Association, Society of Surgical Oncology, Society of Urologic Oncology, Society of Pelvic Surgeons, Society for Urodynamics and Female Urology, Société Internationale d’Urologie, American Urological Association (AUA) and the Royal Society of Medicine. He has served on the American Board of Urology (Vice President), the Examination Committee of the American Urological Association and the Residency Review Committee for Urology (Chair). He has held editorial positions on journals including the Journal of Urology, Neurourology and Urodynamics, Urology, British Journal of Urology International, International Urogynecology Journal, Current Urology Reports, Current Opinion in Urology and Nature Urology. He has been an editor of the textbook considered to be the gold standard in urology, Campbell-Walsh Urology, since 1992, and is currently the Editor-in-Chief. Dr Wein has authored or co-authored more than 880 articles and chapters and has edited or co-edited 28 books. His fields of interest are the evaluation and management of urologic cancer, the physiology and pharmacology of the lower urinary tract, the evaluation and management of voiding function and dysfunction, including problems related to prostate enlargement, urinary incontinence and neurologic disease. Christopher Chapple, MD, FRCS (Urol) is a Consultant Urological Surgeon at Sheffield Teaching Hospitals and visiting professor at Sheffield Hallam University, Sheffield, UK. He trained at the Middlesex

ix

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Author Biographies

Hospital where he subsequently completed his doctorate thesis on Pharmacological Control Mechanisms in the Lower Urinary Tract. His sub-specialist training was at the Middlesex Hospital and Institute of Urology in London and he provides a tertiary service in lower urinary tract reconstructive surgery. He has a particular interest in functional reconstruction of the lower urinary tract and the underlying pharmacological control mechanisms. He is Past Director of the European School of Urology and an Adjunct Secretary General to the European Association of Urology responsible for education. He is editor of the journal Neurourology and Urodynamics, and is on the editorial board of several other journals. Dr Chapple is a member of a number of urology societies including the American Association of Genitourinary Surgeons. He has co-authored over 300 articles in peer-reviewed journals and has written several books and a number of book chapters. He has chaired a number of guidelines initiatives including the recent UK male lower urinary tract symptoms (LUTS) guidelines report for the National Institute for Clinical Excellence (NICE). He was awarded the St Peter’s medal by the British Association of Urological Surgeons in 2011 and is an honorary member of several national urology associations.

Chapter 1 Introduction

Overactive bladder (OAB) is a prevalent condition that is chronic in its course and may be debilitating to those who have it [1–3]. Consequently, OAB can have a significant impact on an individual’s quality of life (QoL) and has significant costs for society [3]. It is therefore an important syndrome that has become a focus of research with respect to its basic and clinical science and the alleviation of symptoms [3].

Definition There remains a degree of debate as to what constitutes OAB, how the symptoms themselves should be defined, and the terminology used to describe patients’ experiences [4,5]. The term “overactive bladder” was first used in the International Continence Society (ICS) standardization of terminology report in 1988 to describe a chronic condition defined urodynamically as “detrusor overactivity” and characterized by involuntary bladder contractions during the filling phase of the micturition cycle [6]. The definition of OAB as a symptom syndrome was later refined by the ICS to serve as a symptomatic diagnosis that includes urinary urgency, with or without urgency incontinence, usually accompanied by urinary frequency (more than eight micturitions/24 hours) and nocturia (Figs. 1.1 and 1.2) [7]. For the diagnosis to be OAB, the symptoms must occur in the A.J. Wein, C. Chapple, Overactive Bladder in Clinical Practice, DOI 10.1007/978-1-84628-831-9_1, © Springer-Verlag London Limited 2012

1

2

Chapter 1. Introduction

Definitions of symptoms of overactive bladder Symptom

Definition

Urgency

Complaint of a sudden compelling desire to pass urine that is difficult to defer

Urgency urinary incontinence

Complaint of involuntary leakage accompanied by or immediately preceded by urgency

Increased daytime frequency

Complaint by patients who consider that they void too often by day

Nocturia

Complaint that the individual has to wake up at night one or more times to void

Figure 1.1 Definitions of symptoms of overactive bladder. Adapted from Abrams et al. [7, 8]

Diagram demonstrating the overlap between the different categories of storage symptoms

Mixed symptoms OAB symptoms

SUI Mixed incontinence UUI

Figure 1.2 Diagram demonstrating the overlap between the different categories of storage symptoms. Mixed symptoms represent overactive bladder (OAB) without urgency urinary incontinence (UUI) (OAB “dry”) plus stress urinary incontinence (SUI). Mixed incontinence represents OAB with UUI (OAB “wet”) plus SUI. Reproduced with permission from Wein and Rackley [2]

Definition

3

absence of pathological (eg, urinary tract infection, urinary stones, or interstitial cystitis) or metabolic factors (eg, diabetes mellitus) that would explain them. Although the symptoms are suggestive of detrusor overactivity (uro-dynamically demonstrable, involuntary bladder contractions), they can be due to other forms of storage or voiding dysfunction. Although OAB is therefore clearly distinct from urodynamically proven detrusor overactivity, most people with OAB are thought to have this underlying diagnosis. It should be noted that the standardized definition of OAB by the ICS is considered somewhat open to interpretation, particularly regarding whether “urgency” is a dichotomous or continuous variable and the utility of the word “sudden” [4,5,9]. In addition, the ICS definition of frequency as more than eight micturitions/24 hours may not always be accurate. A study of 284 asymptomatic US males aged 18–66 years indicated that the median void frequency was seven/24 hours, with 38% voiding eight or more times daily [10]. Convenience voids, when the bladder is emptied for solely social reasons, may also have an impact on voiding frequency, with 72% of 53 healthy volunteers in the UK reporting at least one convenience void per week, at an average of 4.6 and 3.4 convenience voids per week for men and women, respectively [11]. Moreover, it was found in a study of 1809 individuals aged ³18 years attending a tertiary referral center in the UK for urodynamics that OAB symptoms were better correlated with the urodynamic diagnosis of detrusor overactivity in men than in women [12]. Nevertheless, the ICS definition has facilitated rigorous examination of the prevalence, burden, and clinical management of the disorder. The concept of “urgency” as a subjective term for patients to describe their experience of OAB has also been called into question, because all individuals with sufficient bladder filling to capacity feel a compelling desire to pass urine, regardless of whether or not they have OAB [9]. What OAB patients do experience that sets them apart from other individuals is a “fear of leakage” [9]. It is helpful to consider urgency on a

4

Chapter 1. Introduction

Urgency: yes/no versus degree of sensation ON

or

or OFF

ON

OFF

Like a “dimmer”?

• Is the presence of a “sudden, compelling desire to void” similar to a light switch? − something (presumably a voiding reflex) gets triggered, then urgency occurs • Questioning the ICS definition of urgency − Seperation pathological sensation, or extreme form of a normal sensation? − Always suddenly, or gradual buildup of sensation?

Figure 1.3 Urgency: yes/no versus degree of sensation. ICS, International Continence Society

scale rather akin to what is seen with a rheostat. Bear in mind that urgency is a sensation and afferent impulses are transmitted to the central nervous system via the periaqueductal gray matter. When a threshold level is reached, there is a compelling desire to pass urine that will inevitably lead to voiding. This results in incontinence if the patient is unable to reach a toilet in time (urgency incontinence) [13]. This is illustrated in Fig. 1.3.

Epidemiology OAB increases in prevalence with age in both sexes (Fig. 1.4). Patients with stress incontinence can usually get to the toilet in time, but they are more likely to leak while taking exercise, coughing, or sneezing than those with OAB. Nocturia is less likely to be a prominent feature in patients with stress incontinence than in those with OAB or bladder outflow obstruction, for example. Nevertheless, nocturia occurs with increasing prevalence with age. Nocturia may occur as a consequence of either a bladder storage disorder (eg, detrusor overactivity) or increased production of urine at night (nocturnal polyuria), or from decreased functional bladder capacity caused by a

Epidemiology

5

Prevalence (%)

Prevalence of overactive bladder with age 40

Men*

35

Men† Women*

30

Women†

25 20 15 10 5

70 +

18 –2 9 30 –3 4 35 –3 9 40 –4 4 45 –4 9 50 –5 4 55 –5 9 60 –6 4 65 –6 9

0

Age (years)

Figure 1.4 Prevalence of overactive bladder with age. *Based on SIFO data from Milsom et al. [14]. †Based on data from Irwin et al. [15]

significant residual urine volume, or a combination of factors. Nocturnal polyuria increases with age in its prevalence and is identified as being a significant feature if the nocturnal urine output represents more than 33% of the total 24-hour urine production [7]. Nocturnal polyuria is often a result of cardiovascular or metabolic disorders (eg, diabetes) and may be associated with sleep apnea. Female patients, in particular, experience combined urgency and stress incontinence (socalled “mixed incontinence”). The differential diagnosis is aided by a careful medical history including a detailed assessment of symptoms and a targeted physical examination. The prevalence of OAB has been estimated in a wide range of countries. A cross-sectional, population-based survey of 19,165 men and women aged ³18 years from Canada, Germany, Italy, Sweden, and the UK conducted by Milsom et al., using the 2002 ICS definition of OAB, estimated the prevalence of OAB to be 10.8% in men and 12.2% in women [16]. In those aged ³40 years, the prevalence of OAB was 13.1% in men and 14.6% in women. Of OAB cases in individuals aged ³18 years, 28.0% of men and 44.5% of women

6

Chapter 1. Introduction Disposition of overactive bladder cases by sex, urinary incontinence, urinary status, troublesome symptoms, and initiation of conversation with healthcare provider OAB cases, n=1503

Bothered: 52.8%

Not bothered: 46.2%

Men with UI: 76.9%* Women with UI: 65.5%

Men with UI: 23.1% Women with UI: 33.1%

Men without UI: 44.0%* Women without UI: 35.2%

Men without UI: 55.4% Women without UI: 64.4%

Initiated conversation with healthcare provider: 51.4%†

Initiated conversation with healthcare provider: 21.2%

Men with UI: 66.7%† Women with UI: 52.6%†

Men with UI: 27.8% Women with UI: 30.9%

Men without UI: 45.5%† Women without UI: 41.9%†

Men without UI: 15.2% Women without UI: 17.3%

*P=0.05 bothered men vs bothered women by incontinence status †P=0.05 bothered vs not bothered within sex by incontinence status

Figure 1.5 Disposition of overactive bladder cases by sex, urinary incontinence, urinary status, troublesome symptoms, and initiation of conversation with healthcare provider. UI, urinary incontinence. Reproduced with permission from Milsom et al. [16]

experienced urinary incontinence (UI). Trouble from OAB was experienced by 52.8% of participants overall, at 76.9% and 66.5% of men and women, respectively, with UI, and 44.0% and 35.2% of men and women, respectively, without UI (Fig. 1.5). In those with and without UI, men were significantly more bothered than women [16]. The prevalence of OAB was also assessed in a large population-based survey in the USA: the National Overactive BLadder Evaluation (NOBLE) survey [17]. A sample of 5204 adults aged >18 years, and representative of the US population by sex, age, and geographical region, was assessed. The overall prevalence of OAB was similar between men (16.0%) and women (16.9%), and was quite similar to the results reported earlier from Europe [14].

Epidemiology

7

Recently, a study of the prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK, and Sweden, involving a total of 30,000 participants aged ³40 years in a crosssectional population-representative survey, revealed that 72.3% of men and 76.3% of women had more than one LUTS “sometimes,” whereas 47.9% and 52.5%, respectively, had one or more symptom(s) “often” [18]. The most common voiding symptom was terminal dribble, which was reported by 45.5% and 38.3% of men and women, respectively; whereas the most common storage symptom was one or more episodes of nocturia, noted by 69.4% and 75.8%, respectively [18]. Overall, from these studies it can be concluded that, of these patients with OAB, approximately a third are troubled by incontinence (OAB “wet”) and two-thirds are not (OAB “dry”). Incontinence is far more likely to occur in women than in men, with particular risk factors in men being advanced age and having had surgery on the prostate, especially for prostate cancer. More recent data from the EPIC (European Prospective Investigation into Cancer and Nutrition) study suggest that the prevalence of OAB symptoms (using the 2002 ICS definition) is closer to 12% in the community, and of these individuals approximately 50% experience significant trouble from their symptoms [19]. The prevalence of OAB has also been estimated in Japan, in which the responses of 4570 men and women aged ³40 years to a self-administered questionnaire were analyzed [20]. This revealed that the prevalence of OAB was 14% for men and 11% for women and increased with age, rising from 5% of respondents aged 40–49 years to 37% of those aged ³80 years. The prevalence of OAB with UI was 6.4% overall, whereas that of OAB without UI was 6.0% [20]. A study of 1827 community-dwelling adults in Taiwan indicated that the age-adjusted prevalence of OAB was 16.9%, whereas that of OAB plus UI was 4.5% [21]. The ageadjusted prevalence of OAB was significantly higher in women than in men, at 18.3% versus 16.0%, and the prevalence increased with age. Frequency was detected in 79.5% of individuals with OAB; 63.2% had nocturia and 37.6% of women with OAB also reported stress UI [21].

8

Chapter 1. Introduction

In Brazil, the prevalence of OAB was estimated in a population-based study in which 848 individuals aged 15–55 years completed a self-administered questionnaire [22]. The overall prevalence was found to be 18.9% [22]. Although the prevalence of OAB was significantly higher in women than in men, at 23.2% versus 14.0%, there were no significant differences between age groups [22]. UI, frequency, and nocturia were reported by 5.4%, 13.5%, and 48.2% of the participants, respectively [22]. Of those with OAB, 19.2% had urgency as the only symptom, whereas 80.8% had at least one other associated symptoms [22].

Quality of Life OAB symptoms often have a profound negative influence on QoL. Using data from the EPIC study of individuals from Canada, Germany, Italy, Sweden, and the UK, Coyne et al. compared 1434 OAB cases with 1434 age-, gender-, and country-matched controls [23]. Patients had, compared with controls, significantly greater levels of depression, at 11.4% versus 3.6%, and unemployment, at 42.0% versus 33.6% [23]. Furthermore, patients were significantly more likely to have any form of work impairment than controls, at 24.7% versus 12.2%; less likely to have been sexually active in the past 12 months, at 62.4% versus 68.2%; more likely to report decreased enjoyment of sexual activity, at 15.4% versus 2.8%, and more likely to have moderate-to-complete impotence, at 9.8% versus 5.6% [23]. EQ-5D health status scores were also significantly lower in patients than in controls, at 0.85 versus 0.90 [23]. Finally, the investigators found that patients with the most severe OAB symptoms had significantly worse health-related quality of life (HRQoL) and troublesome symptom scores in the Overactive Bladder Questionnaire Short Form than other patients [23]. In another study, data from the NOBLE program in the USA on 171 incontinent individuals was used to compare the

Quality of Life

9

impact of stress urinary incontinence (SUI), urgency urinary incontinence (UUI), and mixed incontinence (MI) on HRQoL [24]. MI patients had a significantly lower HRQoL and more troublesome symptoms than SI patients, whereas UUI patients had significantly more trouble and lower sleep HRQoL than SI patients [24]. There were no significant differences in HRQoL and troublesome symptoms between UUI and MI patients [24]. The findings of a study of 14 incontinent OAB patients, 14 family members of incontinent OAB patients, and 17 spouses/ partners of continent OAB patients also indicated that both continent and incontinent OAB syndromes have a significant impact on family members, even if they do not live with the patient [25]. Urinary frequency was the most bothersome symptom for family members because it limited activities, whereas nocturia caused sleep disruption and fatigue [25]. There was also an emotional impact on family members in terms of embarrassment and reduction in sexual interactions and intimacy [25]. Although the symptoms of urinary urgency and frequency alone have a significant negative impact on patients’ QoL, UUI is more disruptive. However, despite the negative impact of these symptoms on QoL, “wet” patients frequently fail to seek medical help and often endure the inconvenience and unpleasantness of symptoms for many years (Fig. 1.6), relying on coping strategies (eg, voiding frequently in an effort to avoid leakage episodes, mapping out the location of toilets, drinking less, or using incontinence pads) that can be maladaptive. This might be because of embarrassment or, possibly, because of the mistaken opinion that effective treatment is not available (Fig. 1.7). The UK Leicestershire MRC study [27] showed that, when patients do mention the condition to their general practitioner, 27% were prescribed antibiotics, 20% were reassured that it was acceptable to be incontinent, and 30% were told to return only if the condition developed. So it seems that there is currently a problem with physicians not feeling

10

Chapter 1. Introduction

Prevalence of medical consultation and current medication in men and women aged 40–74 years with chronic overactive bladder Overactive bladder (n=1916)

Spoken to a doctor, 60%

Not spoken to a doctor, 40%

Currently on medication, 27%

Currently not on medication, 73%

Never tried, 73%

Tried but failed, 27%

Likely to discuss with a doctor again, 54%

Not likely to discuss again, 46%

Likely to discuss with a doctor again, 65%

Not likely to discuss again, 35%

Figure 1.6 Prevalence of medical consultation and current medication in men and women aged 40–74 years with chronic overactive bladder. Reproduced with permission from Milsom et al. [14]

confident about managing urinary incontinence and storage disorders of the bladder (ie, OAB). Men and women frequently do not seek professional advice for LUTSs and when they do they often do not receive active treatment (Fig. 1.8). Possible reasons for this include the following: • Lack of sufficient trouble to cause them to seek treatment • Acceptance of the symptoms as a natural phenomenon related to aging, living habits, heredity, or gender • Negative attitudes regarding the availability of interested and knowledgeable healthcare providers • Availability of effective treatment.

Socioeconomic Impact

11

Overactive bladder symptom perception grouped according to gender Something you have to learn to live with

*

Something few people my age may have Ignored by the medical community

*

A result of the way I live * Hereditary, so it can’t be helped A sign of more serious medical condition

*

Natural part of aging * Can’t be cured or helped Not really a medical condition

*

Not worth bothering a doctor about

* *P≤ 0.005 vs men

Total Men

0

10

20

Women

30

40

50

60

70

80

90

subjects (%)

Figure 1.7 Overactive bladder symptom perception grouped according to gender. Reproduced with permission from Irwin et al. [26]

Socioeconomic Impact In addition to the incalculable costs associated with the negative effects of OAB on physical and emotional well-being, especially in the “wet” patient, the disorder imposes a considerable financial burden on individuals, their families, and society. This includes both the direct costs associated with diagnosis and treatment of the disorder and its complications, and the indirect costs of lost wages and productivity (see Fig. 1.9) [29,30].

12

Chapter 1. Introduction

Healthcare-seeking behavior for and treatment of lower urinary tract symptoms Variable

V only

S only

Men, n

1704

1280

mean (SD) number of visits to a healthcare professional in past year†

3.5 (5.7)

3.6 (5.0)

n

1699

Sought treatment from a healthcare provider for urinary symptoms, n (%)† 95 (5.6)

140 (11.2)

n

1693

1250

• Prescription medications

50 (2.9)

75 (5.9)

• Physical therapy

1 (0.1)

11 (0.9)

• Self-treatment

31 (1.8)

32 (2.5)

• Coping strategies

53 (3.1)

96 (7.5)

• Surgery

19 (1.1)

42 (3.3)

• Other

19 (1.1)

23 (1.8)

Women, n

822

3545

mean (SD) number of visits to a healthcare professional in past year†

4.7 (7.0)

4.3 (7.1)

n

817

3526

Treatments for urinary symptoms, n (%)†

Sought treatment from a healthcare provider for urinary symptoms, n (%)† 66 (8.1)

274 (7.8)

n

810

3498

• Prescription medications

39 (4.8)

139 (3.9)

• Physical therapy

14 (1.7)

112 (3.1)

• Self-treatment

25 (3.1)

126 (3.5)

• Coping strategies

61 (7.4)

684 (19.3)

• Surgery

16 (2.0)

69 (1.9)

• Other

22 (2.7)

96 (2.7)

Treatments for urinary symptoms, n (%)

Figure 1.8 Healthcare-seeking behavior for and treatment of lower urinary tract symptoms.*All numbers presented are weighted; subgroups might or might not equal total number (n) because of rounding or weighted values. †Scheffe’s post-hoc pairwise comparisons indicated significant differences between the mean number of visits at P<0.001 for no LUTS vs V + S, no LUTS vs V + PM, no LUTS vs S + PM, no LUTS vs V + S + PM, V only vs V + S, V only vs V + S + PM, S only vs V + S, S only vs V + S + PM, PM only vs V + S, PM only vs V + S + PM, V + S vs V + S + PM, V + PM vs V + S + PM. For women: no LUTS vs V only, no LUTS vs S only, no LUTS vs V + S, no LUTS vs V + PM, no LUTS vs S + PM, no LUTS vs V + S + PM, V only vs V + S + PM, S only vs V + S + PM, V + S vs V + S + PM. †Missing responses not included in these frequencies and calculations. LUTS, lower urinary tract symptoms; V, voiding; S, storage; PM, postmicturition. Reproduced with permission from Sexton et al. [28]

Socioeconomic Impact

PM only

V+S

V+PM

S+PM

V+S+PM P

427

1449

1463

288

3433

3.1 (4.0)

4.5 (7.2)

3.8 (6.2)

4.4 (7.0)

5.4 (6.9)

1459

13

<0.001

3427

27 (6.3)

250 (17.5)

128 (8.9)

46 (15.9)

979 (29.1)

423

1424

1448

286

3368

8 (2.0)

162 (11.2)

90 (6.2)

22 (7.6)

603 (17.6)

<0.001

1 (0.2)

15 (1.1)

3 (0.2)

1 (0.3)

42 (1.2)

<0.001

11 (2.5)

60 (4.2)

44 (3.0)

11 (3.8)

253 (7.4)

<0.001

11 (2.7)

167 (11.5)

104 (7.1)

39 (13.4)

705 (20.5)

<0.001

9 (2.1)

52 (3.6)

22 (1.5)

5 (1.8)

118 (3.4)

<0.001

3 (0.7)

29 (2.0)

20 (1.3)

8 (2.9)

115 (3.4)

<0.001

143

2340

311

574

4120

4.0 (4.7)

4.7 (5.5)

5.0 (8.9)

5.2 (6.4)

6.4 (9.5)

2335

<0.001

<0.001

4112

21 (15.0)

316 (13.8)

44 (14.4)

97 (17.3)

1114 (27.5) <0.001

140

2292

308

562

4056

1 (0.4)

161 (6.9)

20 (6.5)

32 (5.6)

430 (10.4)

<0.001

2 (1.5)

102 (4.4)

7 (2.1)

19 (3.3)

346 (8.4)

<0.001

6 (4.0)

83 (3.5)

24 (7.8)

35 (6.2)

344 (8.4)

<0.001

13 (9.1)

590 (25.2)

58 (18.5)

170 (29.6)

1613 (39.2) <0.001

5 (3.2)

67 (2.8)

12 (3.9)

9 (1.5)

235 (5.7)

<0.001

3 (2.3)

72 (3.1)

7 (2.2)

14 (2.4)

216 (5.3)

<0.001

Figure 1.8 (continued)

In 2004 an update of the NOBLE program to incorporate more recent prevalence and cost information by Hu et al. revealed that, in the USA in 2000, the combined community and institutional cost of OAB was US$12.6 billion [31]. This incorporated diagnosis, treatment, routine care, consequence, and indirect costs for both community-dwelling adu lts aged ³18 years and institutionalized elderly people, aged ³65 years (Fig. 1.10) [31]. Using data derived from the EPIC study and healthcare resource-use data, Irwin et al. estimated the economic impact of OAB on the health sector in Canada, Germany, Italy, Spain, Sweden, and the UK [32]. The direct costs associated with diagnosis, treatment, medical consultations, and treatment of clinical depression linked to OAB ranged from €333 million in Sweden, €367 million in Spain, €379 million in Canada, and €572 million in Italy, to €1 billion in the UK and €1.2 billion in Germany, at an average cost per country of €3.9

14

Chapter 1. Introduction

Impact of overactive bladder on employment grouped according to gender and presence of overactive bladder incontinence symptoms 40 35

Subjects (%)

30 25 20 15 10 5 0 Worry about interrupting meetings

Changed jobs or terminated

men OAB with incontinence men OAB without incontinence

Factors in location and hours worked

Voluntary ternination or early retirement

Women OAB with incontinence Women OAB without incontinence Total

Figure 1.9 Impact of overactive bladder on employment grouped according to gender and presence of overactive bladder incontinence symptoms. Percentages are weighted. P<0.05 for men with OAB with incontinence in each scenario except “changed jobs or terminated.” Reproduced with permission from Irwin et al. [26] Overactive bladder costs for community-dwelling adults and institutionalized elderly people Factor

Community-dwelling adults(US$ millions)

Institutionalized elderly (US$ millions)

Diagnostic costs

77.38

25.97

Treatment costs

2777.75

3.68

Routine care costs

1554.27

3363.02

Consequence costs (including skin conditions, falls, urinary tract infections)

3860.27

78.87

Indirect costs (lost productivity)

826.88

Figure 1.10 Overactive bladder costs for community-dwelling adults and the institutionalised elderly. Adapted from Hu et al. [31]

Who Seeks Treatment and Why?

15

billion (about US$5.3 billion) [32]. The average total annual nursing home costs per country were calculated to be €4.7 billion (about US$6.3 billion), whereas the average total lost productivity costs per country were €1.1 billion (about US$1.5 billion), giving an average total cost for OAB per country of €9.7 billion (US$13.1 billion) [32]. In a previous cost estimate analysis, Milsom et al. noted that 79% of the respondents with OAB symptoms had experienced their symptoms for over a year, with 49% experiencing symptoms for more than 3 years, emphasizing that, because OAB is a chronic disorder, healthcare and other costs persist [14].

Who Seeks Treatment and Why? To develop integrated and comprehensive OAB treatment services, it is important that clinicians and policy-makers understand who seeks treatment for OAB and why. McGrother et al. conducted a cross-sectional and longitudinal population-based survey of 162,533 individuals aged ³40 years registered with 108 general practices in two counties in the UK [33]. The prevalence of the categories of moderate or severe incontinence, a storage disorder, storage symptoms with impact on QoL, healthcare need for OAB, and healthcare requirement for OAB were 16.1%, 28.5%, 30.4%, 37.1%, and 20.4%, respectively, whereas the annual incidence rates for storage disorder, healthcare need for OAB, and healthcare requirement for OAB were 6.3%, 14.1%, and 15.6%, respectively [33]. It was found that the use of any form of care was lower in men than in women, at 14% versus 20% [33]. Although help-seeking at consultation was similar in men and women, at 12% versus 13%, the use of pads and aids was substantially lower in men than in women, at 2% versus 11% [33]. An unmet healthcare need was more likely to be perceived by younger patients (at an odds ratio [OR] of 0.36 for patients aged ³80 years versus 40–49 years), by

16

Chapter 1. Introduction

male patients (at an OR of 0.68 for female versus male patients), by those with a higher symptom severity (at an OR of 1.19 per unit increase), and by those with a little or great impact from OAB on their QoL (at ORs of 47.60 and 188.50, respectively, versus no QoL impact) [33]. Consultation or treatment for OAB was associated with increasing age (with an OR for patients aged ³80 years versus those aged 40–49 years of 1.90, for male patients, and an OR of 0.66 for female versus male patients), with those who had a higher symptom severity (with an OR of 1.11 per unit increase), and with those who had a little or great QoL impact (at ORs of 5.30 and 18.90, respectively), versus no QoL impact [33]. A Taiwanese study of 1827 communit y-based adults aged ³30 years revealed that 13.0% had consulted a doctor for one or more OAB symptom, with no significant difference in treatment seeking between men and women, at 10.4% versus 15.7%, respectively [21]. Individuals with OAB “wet” were significantly more likely than those with OAB “dry” to seek treatment, at 27.2% versus 7.6%, respectively [21]. Patients who perceived themselves as experiencing severe or moderate trouble were markedly more likely to seek treatment for OAB than those who reported mild or no trouble, at 46.1% and 29.7% versus 3.3% and 0.0%, respectively [21]. Patients report that UI is the most potent stimulus to seeking treatment. The response to this symptom depends on the degree of leakage and the circumstances in which it occurs; for example, it is considered less troublesome if the patient is able to void without embarrassment, as in the case of a farm worker versus an office worker. The other symptoms of urgency – nocturia and frequency – can be very disabling and also serve as potent stimuli for treatment seeking. Reinforcing the impact of OAB symptoms on QoL, a study comparing 611 female patients with urodynamic SUI, DO, MI, with control individuals revealed that patients with diagnoses of detrusor overactivity, MI, or SUI plus OAB had significantly worse incontinence-related trouble and HRQoL than patients with a diagnosis of SUI without OAB [34].

References

17

References 1. Tubaro A, Palleschi G (2005). Overactive bladder: epidemiology and social impact. Curr Opin Obstet Gynecol 17:507–11. 2. Wein AJ, Rackley RR (2006). Overactive bladder: a better understanding of pathophysiology, diagnosis and management. J Urol 175:S5–10. 3. Hashim H, Abrams P (2007). Overactive bladder: an update. Curr Opin Urol 17:231–6. 4. Abrams P (2007). Re: Overactive bladder and the definition of urgency – Dr Jerry Blaivas. Neurourol Urodynam 26:759. 5. Blaivas JG (2007). Overactive bladder and the definition of urgency. Neurourol Urodyn 26:757–8; discussion 759–60. 6. Abrams P, Blaivas JG, Stanton SL, et al (1988). Standardisation of terminology of lower urinary tract function. Neurourol Urodyn 7:403–27. 7. Abrams P, Cardozo L, Fall M, et al (2002). The standardization of terminology in lower urinary tract function: report from the Standardization Sub-committee of the International Continence Society. Am J Obstet Gynecol 187:116–26. 8. Abrams P, Artibani W, Cardozo, et al (2009). Reviewing the ICS 2002 terminology report; The ongoing debate in neurology and dynamics. Neurourol Urodyn 28:287. 9. Rosier PF, Bosch JR (2006). A prospective study to find evidence for the iCS definition of urgency. Neurourol Urodynam 25:517–18. 10. Latini JM, Mueller E, Lux MM, Fitzgerald MP, Kreder KJ (2004). Voiding frequency in a sample of asymptomatic American men. J Urol 172:980–4. 11. Darling R, Neilson D (2005). Convenience voids: an important new factor in urinary frequency volume chart analysis. J Urol 173:487–9. 12. Hashim H, Abrams P (2006). Is the bladder a reliable witness for predicting detrusor overactivity? J Urol 175:191–4; discussion 194–5. 13. Chapple CR, Artibani W, Cardozo LD, et al (2005). The role of urinary urgency and its measurement in the overac tive bladder symptom syndrome: current concepts and future prospects. BJU Int 95:335–40. 14. Milsom I, Abrams P, Cardozo L, et al (2001). How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 87:760–6. 15. Irwin D, Milsom I, Reilly K, et al (2006). Prevalence of overactive bladder syndrome: European results from the EPIC study. Abstract presented at: European Association of Urology, Paris, France, 6 April, 2006.

18

Chapter 1. Introduction

16. Milsom I, Irwin D, Coyne KS, et al (2006). Prevalence, symptom bother, and healthcare seeking among individuals with overactive bladder: Results from the EPIC Study. Neurourol Urodynam 25:575–6. 17. Stewart WF, van Rooyen JB, Cundiff GW, et al (2003). Prevalence and burden of overactive bladder in the United States. World J Urol 20:327–36. 18. Coyne KS, Matza LS, Brewster-Jordan J (2009). “We have to stop again?!”: The impact of overactive bladder on family members. Neurourol Urodyn 28:969–75. 19. Irwin DE, Milsom I, Hunskaar S, et al (2006). Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 50:1306–14. 20. Homma Y, Yamaguchi O, Hayashi K (2005). An epidemiological survey of overactive bladder symptoms in Japan. BJU Int 96:1314–18. 21. Yu HJ, Liu CY, Lee KL, Lee WC, Chen TH (2006). Overactive bladder syndrome among community-dwelling adults in Taiwan: prevalence, correlates, perception, and treatment seeking. Urol Int 77:327–33. 22. Teloken C, Caraver F, Weber FA, et al (2006). Overactive bladder: prevalence and implications in Brazil. Eur Urol 49:1087–92. 23. Coyne KS, Sexton CC, Irwin DE, et al (2008). The impact of overactive bladder, incontinence and other lower urinary tract symptoms on quality of life, work productivity, sexuality and emotional wellbeing in men and women: results from the EPIC study. BJU Int 101:1388–95. 24. Coyne KS, Zhou Z, Thompson C, Versi E (2003). The impact on health-related quality of life of stress, urge and mixed urinary incontinence. BJU Int 92:731–5. 25. Coyne KS, Sexton CC, Thompson CL, et al (2009). The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK and Sweden: results from the Epidemiology of LUTS (EpiLUTS) study. BJU Int 104:352–60. 26. Irwin DE, Milsom I, Kopp Z, et al (2006). Impact of overactive bladder symptoms on employment, social interactions and emotional well-being in six European countries. BJU Int 97:96–100. 27. Dallosso HM, Matthews RJ, McGrother CW, et al (2004). Leicestershire MRC incontinence Study Group. The association of diet and other lifestyle factors with the onset of overactive bladder: a longitudinal study in men. Public Health Nutr 7:885–91. 28. Sexton CC, Coyne KS, Kopp ZS, et al (2009). The overlap of storage, voiding and postmicturition symptoms and implications for treatment seeking in the USA, UK and Sweden: EpiLUTS. BJU Int 103(suppl):312–23.

References

19

29. Hu TW, Wagner TH (2000). Economic considerations in overactive bladder. Am J Manag Care 6(11 suppl):S591–8. 30. Kelleher CJ (2002). Economic and social impact of OAB. Eur Urol 1:11–16. 31. Hu TW, Wagner TH, Bentkover JD, et al (2004). Costs of urinary incontinence and overactive bladder in the United States: a comparative study. Urology 63:461–5. 32. Irwin DE, Mungapen L, Milsom I, et al (2009). The economic impact of overactive bladder syndrome in six Western countries. BJU Int 103: 202–9. 33. McGrother CW, Donaldson MM, Shaw C, et al (2004). Storage symptoms of the bladder: prevalence, incidence and need for services in the UK. BJU Int 93:763–9. 34. Haessler AL, Nguyen JN, Bhatia NN (2009). Impact of urodynamic based incontinence diagnosis on quality of life in women. Neurourol Urodyn 28:183–7.

Chapter 2 The Pathophysiology of Overactive Bladder

Anatomy and Pathophysiology of the Lower Urinary Tract The pathophysiology of overactive bladder (OAB) is poorly understood, but probably involves changes at multiple levels that control micturition (ie, brain, spinal cord, and smooth muscle of the bladder). Understanding the various pathways that lead to symptoms of OAB can help achieve an accurate diagnosis and realistic evidence-based treatment goals. It becomes more important when the risks and cost of treatment increase (eg, when surgical treatment of detrusor overactivity [DO] is considered) or when chronic use of medication, expensive programs of training, biofeedback, or implantation of devices is undertaken. The main components of the male and female lower urinary tracts are shown in Fig. 2.1, including the bladder, urethra, and external urethral sphincter (rhabdosphincter), which is integrated with the pelvic floor. In men, the prostate surrounds the proximal part of the urethra. The bladder is composed of three layers: 1. A mucosal layer on the luminal side. 2. A layer of smooth muscle (the detrusor muscle). 3. An adventitial layer of connective tissue on the outside, which is partly covered by the peritoneum.

A.J. Wein, C. Chapple, Overactive Bladder in Clinical Practice, DOI 10.1007/978-1-84628-831-9_2, © Springer-Verlag London Limited 2012

21

22

Chapter 2. The Pathophysiology of Overactive Bladder

Schematic diagram of the male and the female lower urinary tract Male

Female

D

D

D

D T

T

IS (SM)

SM

PS

PS

ES

SM

ES

Figure 2.1 Schematic diagram of the male and the female lower urinary tract. D, detrusor muscle; ES, external urethral sphincter; IS, internal urethral sphincter; PS, periurethral striated muscle; SM, smooth muscle; T, trigone. Adapted with permission from Dixon et al. [1]

The bladder fills with urine under normal circumstances over a period of 2–4 hours, and as it fills the individual becomes increasingly aware of the need to pass urine. Urination involves simultaneous relaxation of the muscles of the urethra and contraction of the muscle in the bladder; the prime effector of continence is the synergic accommodation of the smooth muscle of the bladder wall to increasing volumes of urine without a change in detrusor pressure, and closure of the bladder outlet. Urinary leakage occurs when the pressure of the bladder exceeds that within the urethra, either as a result of involuntary contractions of the detrusor muscle or decreased compliance (a gradual inappropriate rise in detru-sor pressure with respect to volume) or as a consequence of defective urethral closure (stress incontinence). DO is characterized by uncontrolled contractions of the detrusor muscle during the bladder’s filling phase, but it has to be borne in mind that up to 50% of OAB patients do not exhibit DO in a laboratory urodynamic setting. However, when stress incontinence occurs, as it commonly does, together with OAB symptoms in association with urgency

Urinary Symptoms

23

incontinence (OAB “wet”) in women, the condition is known as “mixed incontinence.” When stress incontinence occurs together with OAB “dry,” it is known as “mixed symptoms” (see Chapter 1). The lower urinary tract is innervated sympathetically, para-sympathetically, and somatically (Fig. 2.2), although the innervation and structure of the bladder neck are significantly different in men and women [3]. Parasympathetic nerves are present in both sexes, but the male bladder neck has rich sympathetic innervation, whereas the female bladder is only sparsely supplied with sympathetic nerves. The sympathetic nerve fibers originate from the T11 to the L2 segments of the spinal cord and innervate primarily smooth muscle fibers around the bladder neck and proximal urethra, causing these fibers to contract in response to stimulation. Some fibers may innervate smooth muscle bundles in the body of the bladder but cause a relaxation response when activated. As the bladder fills, sensory stimulation within the bladder wall triggers a central nervous system response. The parasympathetic fibers, as well as fibers responsible for somatic (voluntary) control of micturition, originate from the sacral plexus (the S2–4 segments of the spinal cord). The parasympathetic nervous system mediates contraction of the detrusor muscle, whereas the muscles of the pelvic floor and external sphincter relax. The somatic fibers innervate the external sphincter and are responsible for the voluntary control of continence when there is a pressing desire to void. Activation of these and contraction of the “external sphincter” inhibit the micturition reflex.

Urinary Symptoms The various terms applied to the symptoms of the OAB syndrome are as follows: • Urgency: a sudden, compelling desire to pass urine, which is difficult to defer, associated with a feeling of impending leakage. The desire to void because of pain is not urgency, but is suggestive of a bladder disorder (eg, painful bladder syndrome, urinary infection, bladder stone).

S3 S4

S2

T11 T12 L1 L2

Somatic pudendal nerves

ic

het pat sym rves a r Pa ic ne v pel

Pontine micturition center (PMC)

s

ve

ic er et th ic n pa astr m Sy pog hy

Somatic

Parasympathetic

Sympathetic

Contraction

Relaxation

Action

Muscle of floor the pelvic

“External” striated urethral sphincter

Detrusor muscle

Contraction

Contraction

Contraction

Smooth Contraction muscle of the bladder and proximal urethra (“internal” sphincter)

Trigone

Detrusor muscle

Structures innervated

Figure 2.2 Innervation of the lower urinary tract. Reproduced with permission from Newman and Wein [2]

Spinal cord

Brain stem

Cerebral cortex

Cerebral cortex exerts conscious and unconscious control of the PMC and spinal centers

Innervation of the lower urinary tract

24 Chapter 2. The Pathophysiology of Overactive Bladder

Urinary Symptoms

25

• Urgency incontinence: involuntary leakage of urine accompanied or immediately preceded by urgency. • Frequency: the need to void eight or more times daily. Frequency usually accompanies urgency, with or without urgency incontinence. • Nocturia: the need to void during the night, which wakens the person from sleep. Nocturia usually accompanies urgency in OAB, with or without urgency incontinence. Clearly, however, nocturia can occur for many other reasons, as discussed later. The symptom combinations used in the International Continence Society (ICS) definition of OAB are suggestive of urodynamically demonstrable DO (involuntary bladder contractions), but can be associated with other forms of urethrovesical dysfunction. If no infection or other obvious pathology is present, the term “OAB” can be used [4]. OAB is, therefore, clearly distinct from urodynamically proven DO, but most people with OAB are thought to have this underlying diagnosis. Interestingly, a study of OAB patients with (31 patients) and without (41 patients) urodynami-cally demonstrable DO found no difference in reported compelling desire to urinate, or sudden change in desire over 3 months, at 90.3% versus 82.9% and 0.9% versus 0.9%, respectively [5]. Urgency is an obligatory component of OAB and is considered to be the “driving force” behind the other components (urgency incontinence, frequency, and nocturia) mentioned in the ICS definition (Fig. 2.3). The term “urgency” (distinct from “urge” or the normal desire to void) is a sensory symptom produced by a central perception of increased afferent discharge from the bladder and, as such, is difficult to define, communicate to both patients and healthcare colleagues, and measure (quantify). It is not known: • whether the sensation is similar if there is an underlying disease process in patients with a neurological etiology, in contrast to idiopathic DO • where the sensation of urgency is located (eg, in the suprapubic area or the perineum)

26

Chapter 2. The Pathophysiology of Overactive Bladder

Urgency drives the other symptoms of the overactive bladder syndrome Urgency

Increased frequency and reduced intervoid interval

Nocturia*

Reduced volume voided per micturition

Incontinence*

Figure 2.3 Urgency drives the other symptoms of the overactive bladder syndrome. *Both of these symptoms may be influenced by other pathology: in the case of nocturia, cardiovascular or metabolic problems; in the case of incontinence, pelvic floor weakness or intrinsic urethral sphincter weakness. Reproduced with permission from Chapple et al. [6]

• whether there are differences in the symptom of urgency and its clinical features in men in contrast to women, which reflect the anatomical and physiological differences between the sexes. Patients report that an improvement in urgency, in terms of either frequency or severity, or both is the most noticeable response to therapy. It has proven difficult to measure but it is evident in the clinic when a patient states that he or she has more “control.” Despite the importance of urgency, urgency incontinence episodes and frequency are often used as primary endpoints because they are easier to quantify.

The Detrusor Muscle Low bladder pressure is required both to enable kidney drainage and to ensure continence. Under normal circumstances increasing amounts of urine can be stored in the bladder without significantly raising the pressure. A coordinated and sustained contraction of the detrusor muscle forces the urine out of the bladder during voiding.

The Detrusor Muscle

27

Detrusor Overactivity In any patient who fails to respond to initial therapy or in the presence of a complex picture, formal cystometry (measurement of detrusor pressures during filling and voiding) is important as the diagnostic study to demonstrate abnormal detrusor function and/or abnormal bladder sensation. DO is defined as the urodynamic observation of involuntary detrusor contractions during the filling phase, which may be spontaneous or provoked in a conscious cooperative patient who is trying to inhibit voiding [7]. Involuntary bladder contractions refer to increases of detrusor pressure during filling. These may or may not lead to incontinence. In the recent standardization report of the ICS, it is stated that DO may be qualified according to cause (eg, neurogenic DO when there is a relevant neurogenic condition) [4]. Previously, this was classified as detrusor hyperreflexia. In the absence of any specific cause, the term proposed is “idiopathic detrusor overactivity,” which replaces the previous term of “detrusor instability” [4]. If a tonic abnormal increase in detrusor pressure is found, the term used is “low compliance.” During cystometry, bladder sensation can also be evaluated, and can be judged at defined points during filling cystometry and must be interpreted in relation to both bladder volume at that specific moment and the patient’s symptomatic complaint or sensation. Many patients with OAB will present with an increased bladder sensation characterized by an early first sensation of bladder filling or an early desire to void. Another pattern may be an early strong desire to void, which occurs at low bladder volume and persists. This can be indicated by the patient as urgency or a sudden compelling desire to void. Under the prior ICS terminology, such individuals in whom involuntary contractions were demonstrable were said to have “motor urgency,” whereas individuals in whom these were not demonstrable were classified as having “sensory urgency.” The ICS, however, no longer recommends these terms because they are

28

Chapter 2. The Pathophysiology of Overactive Bladder

Updated terminology used in urodynamic evaluation Past

Present

Detrusor hyperreflexia

Neurogenic detrusor overactivity

Detrusor instability

Idiopathic detrusor overactivity

Motor urgency

None

Sensory urgency

None

Motor urge incontinence

Detrusor overactivity incontinence with urgency

Reflex incontinence

Detrusor overactivity incontinence without sensation

Genuine stress incontinence

Urodynamic stress incontinence

Figure 2.4 Updated terminology used in urodynamic evaluation

often misused and have little intuitive meaning. Furthermore, it may be simplistic to relate urgency just to the presence or absence of DO [7]. The relationship of urgency to both motor and sensory abnormalities of the bladder has recently been explored. Provocative maneuvers, such as rapid filling, use of cooled or acid medium, postural changes, and hand washing, may be used during cys-tometry to provoke DO. However, it should be realized that, with this type of provocation, DO should not be seen in a “normal” individual who is consciously trying to inhibit voiding. If there remains doubt as to the exact behavior of the bladder, ambulatory urodynamics can be used to monitor bladder activity for a prolonged period of time, although this remains a nonstandardized technique and is still best regarded as a research tool. Cystometry also permits measurement of the end-filling pressure at bladder capacity and allows this to be matched to the bladder diary data. This is the volume at which the patient feels that he or she can no longer delay micturition because of the strong desire to void. If there is uncontrollable urgency resulting in incontinence, this volume is the volume at which voiding starts. The terminology relating to urodynamic evaluation has been extensively revised and can best be summarized as in Fig. 2.4.

Etiology of Detrusor Overactivity

29

Etiology of storage symptoms suggestive of overactive bladder Overactive bladder (ICS definition) Idiopathic: no known cause Neurogenic: demonstrable neurological disorder thought to be affecting bladder Other known pathologic causes of symptoms suggestive of OAB Stone in bladder Infection: urinary infection, acute or chronic Neoplasm: bladder tumor or carcinoma in situ Inflammation: interstitial cystitis (painful bladder syndrome)

Figure 2.5 Etiology of storage symptoms suggestive of overactive bladder

Etiology of Detrusor Overactivity It is likely that DO has multiple causes, although in some cases a neurological abnormality can be demonstrated (neurogenic DO). In most, no cause can be identified, because either a neurogenic abnormality has not yet become manifest or it is due to some other etiology. The types of etiologies associated with symptoms suggestive of OAB can be found in Fig. 2.5. In 30–50% of cases there is no demonstrable DO underlying the storage symptoms of OAB. Although, in the past, attention has focused on the predominant muscarinic motor innervation of the human detrusor, mediated predominantly by the M3-receptors, in recent years it has been suggested that M3-receptors may be of some importance in disease states, as may noncholinergic mechanisms. More recently there has been increased interest in disordered sensory mechanisms at a peripheral level in the lower urinary tract. Although we usually label DO as idiopathic, this is because we have not identified a specific underlying pathophysiological cause in most cases. However, several recent studies have identified new candidate pathways and molecules for DO that may eventually lead to novel management strategies. One candidate molecule is the ion channel of the transient

30

Chapter 2. The Pathophysiology of Overactive Bladder

receptor potential vanilloid subfamily 1 (TRPV1). In a murine study, it was shown that animals lacking TRVP1 have significantly reduced afferent bladder responses to distension, whereas application of the TRPV1 antagonist capsazepine significantly attenuates afferent discharge in animals that have the ion channel [8]. In 28 patients with idiopathic DO refractory to anticholinergics, intravesical treatment with the vanilloid receptor activator resinferatoxin led to a response in 50% of patients [9]. Analysis revealed that responders had significantly higher TRPV1 mRNA expression than nonresponders, and higher TRPV1 expression levels than controls, demonstrating the potential role of TRVP1 in DO [9]. It has also been shown that intravesical administration of hydrogen peroxide to adult female rats induces DO in a dosedependent manner, but that the effect is almost abolished by catalase and significantly reduced by dimethylthiourea, deferoxamine, capsaicin pretreatment, indomethacin, and ketoprofen [10]. Taken together, the findings indicate that reactive oxygen species activate capsaicin-sensitive C-fiber afferent pathways, at least partly mediated by cyclooxygenase stimulation, to cause DO [10]. Another study of rats with DO revealed that the number of gap junctions between cells and the expression of connexin mRNA and Cx43 protein are increased compared with controls, whereas intercellular communication through gap junctions increases after 6 weeks of partial outflow obstruction, which may provide avenues for novel OAB treatments [11]. The amplitude of detrusor muscle contraction may also be reduced by transient colonic inflammatory insult, which appears, at least in part, to be due to changes in the balance between cholinergic and noncholinergic regulation of bladder contractility [12]. Although the effect is not permanent, because it is reversed after recovery from colitis [12], the findings emphasize the possibility of visceral organ pathology affecting detrusor activity and, hence, bladder control.

Etiology of Detrusor Overactivity

31

Neurogenic Factors Neural control of micturition is complex, involving communication between many parts of the central nervous system (cerebral cortex, limbic system, hypothalamus, thalamus, basal ganglia, cerebellum, brain stem, and spinal cord), and between the central and peripheral nervous systems. The higher centers exhibit a continuous inhibitory effect on the pontine micturition center. It is release of this that gives “permission to void.” Spinal reflex (autonomic) pathways are active during bladder filling and facilitate the storage of urine. By contrast, bladder emptying (voiding) is under parasympathetic (voluntary) control. Detrusor contractility is thought to be inhibited by a sympathetic reflex, increasing tension in the smooth muscle around the bladder neck and urethra, and inhibiting parasympathetic transmission through an action on either a spinal or a ganglionic level. Neurogenic DO is likely to represent an excess of sensory stimulation from the bladder, a pathologically lowered sensory central threshold for afferent stimulation from the bladder, or a dyssynchronous relationship between afferent signaling and central inhibition of bladder contraction. This has consequences in terms of increased frequency, a reduced between-void interval, and reduced volumes voided (Fig. 2.6). Functional magnetic resonance imaging in healthy female controls suggests that neurological responses increase steadily with bladder filling [13]. This includes responses in the insula, periaqueductal gray, anterior cingulate gyrus, and bilaterally in the prefrontal cortex. In contrast, imaging studies in females with poor bladder control indicates relatively weak responses at low bladder volumes and exaggerated responses at larger volumes, except for an area in the prefrontal cortex that remains weakly activated [13]. Consequently, it appears that increased bladder afferent activity cannot account solely for abnormal responses to filling, but rather it is a more complex picture in which the nature of afferent signals or the handling or the signals in the brain appears to be abnormal [13].

32

Chapter 2. The Pathophysiology of Overactive Bladder

Pathogenesis of overactive bladder A Micturition process in overactive bladder Presumed normal void volume

Reduction in volume voided due to urgency

Intensitiy

Bladder volume (mL)

Void (voluntary and/or involuntary)

Urge Reduction of time between voids

Urgency

B Voiding period in overactive bladder: refractory period/warning time Void (voluntary and/or involuntary)

Intensitiy

Bladder volume (mL)

Void

Urge Urgency

Warning time = period of urgency

Refractory (urgency-free) period

Intervoid interval

Etiology of Detrusor Overactivity

33

Neurological deficit (eg, multiple sclerosis, Parkinson’s disease, stroke, and spinal trauma) can, therefore, also cause DO; such cases are termed “neurogenic detrusor overactivity.”

Idiopathic Detrusor Overactivity Most cases of DO are classified as “without a demonstrable cause” and hence are idiopathic. This represents the vast majority of patients seen with DO and indeed no DO is seen in many patients with OAB. The term “idiopathic” can be applied to these individuals as well. Inevitably a number of theories have been suggested to explain the pathogenesis of patients falling into this category. Broadly speaking, these can be considered to be central or peripheral in nature. In view of the age-related increase in DO and OAB, it is very likely that there is an age-related abnormality in the central processing of peripheral afferent signals [13]. The mainstay of peripheral mechanisms has been the coexistence of DO and OAB symptoms in patients with bladder outlet obstruction. In this context, it has been suggested that bladder outlet obstruction leads to morphological changes in the detrusor muscle, which cause DO. In addition, there is a denervation supersensitivity of the obstructed detrusor muscle. Other explanations for the coexistence of DO and obstruction range from ischemic effects on the detrusor muscle associated with obstruction [14] to more recent theories suggesting altered peripheral afferent mechanisms. It must not be forgotten, however, that indeed it may be an incidental coexistence that there is an association of DO with obstruction in men, and in fact it is an age-related phenomenon. More work needs to be done in this area to clearly identify the true relationship. A major troublesome symptom of OAB is urgency urinary incontinence, which is defined as involuntary leakage accompanied by or immediately preceded by urgency [4]. Incontinence may also be classified as stress urinary Figure 2.6 Pathogenesis of overactive bladder. Adapted from Chapple et al. [6]

34

Chapter 2. The Pathophysiology of Overactive Bladder

incontinence (SUI), which is involuntary leakage on effort or exertion, or on sneezing or coughing, or as mixed urinary incontinence, with involuntary leakage associated with urgency and also with exertion, effort, sneezing, or coughing [4]. One study of 2753 American women indicated that urgency, stress, and mixed incontinence each account for approximately a third of incontinence cases, at 31.8%, 33.8%, and 34.4%, respectively [15]. In another study of 609 women and men in a urology unit inpatient database, of the 52% of patients who had incontinence, 82.6% had both frequency and urge, whereas 59.6% had stress SUI [16]. To compare the impact of stress, urgency, and mixed incontinence, Coyne et al. studied 171 patients from the National Overactive Bladder Evaluation (NOBLE) program with incontinence, of whom 62 had stress incontinence, 69 had urgency incontinence, and 40 had mixed incontinence [17]. There were no significant differences between the groups in terms of the frequency of voids per day or nocturia episodes per night [17]. However, urge and mixed incontinence groups had significantly higher urinary urge intensity than SUI patients, mixed incontinence patients reported significantly more incontinence episodes than SUI patients, and mixed and urgency incontinence patients were significantly more likely than SUI patients to have “lost more than a few drops” per incontinence episode [17]. Both mixed and urgency incontinence patients had a worse health-related quality of life and more trouble than SUI patients [17].

Nocturia Nocturia, which is defined as waking at night to void, is a common condition and distinct from nocturnal enuresis, which refers to voiding at night while asleep. In a study of 2081 community-dwelling Swedish individuals aged ³65 years, 65% reported one or more void per night, whereas 29% reported two or more voids per night [18]. The prevalence of nocturia increased with age, to a prevalence of 43% in participants aged =85 years, and men reported significantly more voids per

Nocturia

35

Possible causes of nocturia

Polyuria Excess intake Diuretic drugs (eg, caffeine, lithium) Peripheral edema (caused by, for example, congestive heart failure, low albumin states,peripheral vascular disease, venous insufficiency, or drugs such as nonsteroidal anti-inflammatory drugs and nifedipine) Endocrine and metabolic factors (eg, diabetes, hypercalcemia)

Storage-related factors (often associated with age) Small bladder capacity Detrusor overactivity Prostate related Overflow incontinence Elevated post-void residual Decreased bladder compliance Sensory urgency Infection/inflammation Pelvic pain syndromes

Sleep-related factors Insomnia obstructive sleep apnea Pain Dyspnea Depression Anxiety Drugs Environmental factors

Figure 2.7 Possible causes of nocturia. Adapted from Drake [19]

night than women, at 1.3 versus 1.1, and had a higher prevalence of nocturia, at 31% versus 26% [18]. Increase in the number of nocturnal voids correlated significantly with incontinence, daytime urgency, and nocturnal thirst, and correlated negatively with good sleep and feelings of good health [18]. Some common causes of nocturia are listed in Fig. 2.7. The physiological changes associated with age, including reduced functional bladder capacity, are a major cause of nocturia. Although there has been no significant association

36

Chapter 2. The Pathophysiology of Overactive Bladder

of diabetes mellitus with nocturia, both poorly controlled diabetes mellitus and diabetes insipidus can lead to nocturnal polyuria (excessive volume of urine) and hence to an increased number of awakenings [20,21]. There are three proposed definitions of nocturnal polyuria: absolute (a defined volume of urine); relative (a certain proportion of the 24-hour volume of urine voided at night); and functional (a “nocturia index,” derived from dividing nocturnal urine volume by the largest single voided volume from a 24-hour diary) [22,23]. Sleep disorders are a major cause of nocturia and are also caused by it. The constant awakenings due to nocturia can lead to insomnia and other sleep disorders, whereas those who wake frequently because of apnea, noise, or other sleep disturbances often find themselves needing to urinate often [24,25]. To examine the trouble experienced by individuals with nocturia, Fiske et al. [26] reviewed the charts of 1214 neurologically healthy women with an average age of 54.6 years attending a female urology office, 87.3% of whom reported one or more void per night and 60.0% two or more voids per night. Troublesome symptoms, as measured using the Symptom Problem Index, increased significantly with the number of nocturnal voids, at an odds ratio of 2.7 for each additional night-time void, independent of age and continence status [26]. As the number of night-time voids increased to two or more, compared with no or one void, the increase in the degree of troublesome symptoms experienced was significant [26]. This finding was reinforced by a survey, conducted by Tikkinen and colleagues, of 6000 adults aged £79 years (equally divided between men and women) who were randomly chosen from the Finnish Population Register. The percentage of those reporting moderate or major troublesome symptoms greatly increased with the number of nighttime voids, from 17% of people with two night-time voids to 55.9% and 81.7% of people with three or four or more voids, respectively [27]. Generally, the greater the number of nocturia episodes a person has, the lower their reported quality of life tends to be [27,28].

References

37

Approach to differential diagnosis of patients with nocturia

Nocturia Is it bothersome? Advice

Sleep disturbance

Bladder storage problems

Establish cause

Polyuria

Nocturnal polyuria

Psychological

Behavioral

24-hour polyuria

Figure 2.8 Approach to differential diagnosis of patients with nocturia. Adapted from Wein et al. [29]

Figure 2.8 provides an algorithm suggesting a practical approach to the evaluation of nocturia.

References 1. Dixon JS, Gosling JA (1994). The anatomy of the bladder, urethra and pelvic floor. in: Mundy AR, Stephenson T P, Wein AJ (eds), Urodynamics: Principles, Practice and Application, 2nd edn. New York: Churchill Livingstone, pp 3–14. 2. Newman DK, Wein AJ (2009). Managing and Treating Urinary Incontinence, 2nd edn. Baltimore, MD: Health Professions Press. 3. de Groat WC, Downie JW, Levin RM, et al (1999). Basic neurophysiology and neuropharmacology. in: Abrams P, Khoury S, Wein AJ (eds), Incontinence: First International Consultation on Incontinence. Plymouth: Plymbridge Distributors Ltd, pp 105–54. 4. Abrams P, Cardozo L, Fall M, et al (2002). The standardization of terminology in lower urinary tract function: report from the Standardization Sub-committee of the International Continence Society. Am J Obstet Gynecol 187:116–26.

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Chapter 2. The Pathophysiology of Overactive Bladder

5. Rosier PF, Bosch JLHR (2007). No difference in “urgency” during urodynamic investigation between patients with overactive detrusor and others. Eur Urol 6(suppl 2):167. Abstract 578. 6. Chapple CR, Artibani W, Cardozo LD, et al (2005). The role of urinary urgency and its measurement in the overactive bladder symptom syndrome: current concepts and future prospects. BJU Int 95:335–40. 7. Abrams P, Cardozo L, Fall M, et al, and Standardisation Subcommittee of the International Continence Society. (2002). The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 21:167–78. 8. Daly D, Rong W, Chess-Williams R, Chapple C, Grundy D (2007). Bladder afferent sensitivity in wild-type and TRPv1 knockout mice. J Physiol 583:663–74. 9. Liu H-T, Kuo H-C (2007). increased expression of transient receptor potential vanilloid subfamily 1 in the bladder predicts the response to intravesical instillations of resinferatoxin in patients with refractory idiopathic detrusor overactivity. BJU Int 100:1086–90. 10. Masuda H, Kihara K, Saito K, et al (2008). Reactive oxygen species mediate detrusor overactivity via sensitization of afferent pathway in the bladder of anaesthetized rats. BJU Int 101:775–80. 11. Li L, Jiang C, Hao P, et al (2007). Changes of gap junctional cell-cell communication in overactive detrusor in rats. Am J Physiol Cell Physiol 293:C1627–35. 12. Noronha R, Akbarali H, Malykhina A, Foreman RD, Greenwoodvan Meerveld B (2007). Changes in urinary bladder smooth muscle function in response to colonic inflammation. Am J Physiol Renal Physiol 293:F1461–7. 13. Griffiths D (2007). imaging bladder sensations. Neurourol Urodyn 26:899–903. 14. Greenland JE, Brading AF (2001). The effect of bladder outflow obstruction on detrusor blood flow changes during the voiding cycle in conscious pigs. J Urol 165:245–8. 15. Stewart WF, van Rooyen JB, Cundiff GW, et al (2003). Prevalence and burden of overactive bladder in the United States. World J Urol 20:327–36. 16. Currie CJ, McEwan P, Poole CD, et al (2006). The impact of the overactive bladder on health-related utility and quality of life. BJU Int 97:1267–72. 17. Coyne KS, Zhou Z, Thompson C, versi E (2003). The impact on health-related quality of life of stress, urge and mixed urinary incontinence. BJU Int 92:731–5. 18. Rembratt A, Norgaard J P, Andersson K-E (2003). Nocturia and associated morbidity in a community-dwelling elderly population. BJU Int 92:726–30.

References

39

19. Drake M. Nocturia. in Wein AJ, Kavoussi LR, Novick AC (eds). Campbell-Walsh Urology, 10th edn. New York; Elsevier; 2011. 20. Robertson GL, Norgaard JP (2002). Renal regulation of urine volume: potential implications for nocturia. BJU Int 90(suppl 3):7–10. 21. Wagg A, Andersson K-E, Cardozo L, et al (2005). Nocturia: morbidity and management in adults. Int J Clin Pract 59:938–45. 22. Weiss J P, Blaivas JG, Stember DS, Chaikin DC (1999). Evaluation of the etiology of nocturia in men: the nocturia and nocturnal bladder capacity indices. Neurourol Urodyn 18:559–65. 23. Rembratt A, Norgaard J P, Andersson K-E (2002). What is nocturnal polyuria? BJU Int 90(suppl 3):18–20. 24. Lose G, Alling-Møller L, Jennum P (2001). Nocturia in women. Am J Obstet Gynecol 185:514–21. 25. Jennum P (2002). Sleep and nocturia. BJU Int 90(suppl 3):21–4. 26. Fiske J, Scarpero HM, Xue X, Nitti VW (2004). Degree of bother caused by nocturia in women. Neurourol Urodyn 23:130–3. 27. Tikkinen KAO, Johnson TM ii, Tamella TLJ, et al (2010). Nocturia frequency, bother, and quality of life: how often is too often? A population-based study in Finland. Eur Urol 57:488–98. 28. Yu H-J, Chen F-Y, Huang P-C, Chen TH-H, Chie W-C, Liu C-Y (2006). impact of nocturia on symptom-specific quality of life among community-dwelling adults aged 40 years and older. Urology 67:713–18. 29. Wein A, Lose GR, Fonda D (2002). Nocturia in men, women and the elderly: a practical approach. BJU Int 90(suppl 3): 28–31.

Chapter 3 Diagnosis and Assessment

Reasons for Visiting the Primary Care Physician Overactive bladder (OAB) is a highly prevalent condition, has a considerable impact on a patient’s quality of life, and is associated with adverse outcomes [1]. However, it often remains underrecognized and under-treated in primary care [2]. It is estimated that only 45% of female patients have talked to a doctor about their symptoms, 65% of whom have talked to a primary care physician. Interestingly, 37% of women would feel more comfortable discussing their symptoms if the conversation were initiated by the healthcare provider, yet only 28% of women report having been asked about urinary symptoms [3]. Although there is a range of patient questionnaires that could assist with screening and be used as a starting point for discussion, it is clear that there is a communication gap between patients with OAB symptoms and healthcare providers [3]. This may be due partly to the chronic nature of OAB, and the consequent need for repeat visits, or the high healthcare costs, with one study estimating an annual total cost for OAB per developed country of approximately US$13 billion in the USA [4]. In addition, strategies such as behavioral modification can be laborintensive and time-consuming for both the patient and the physician, with successful treatment relying on motivation

A.J. Wein, C. Chapple, Overactive Bladder in Clinical Practice, DOI 10.1007/978-1-84628-831-9_3, © Springer-Verlag London Limited 2012

41

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Chapter 3. Diagnosis and Assessment

and commitment from the patient [2]. Whatever the reason, it is important that there is greater communication between patients and providers, and improved identification of OAB. Few patients present in primary care complaining specifically of OAB. People typically wait 6–12 months after their first symptoms start before seeking help, and their first visit to a physician tends to be triggered by a particularly distressing incident, worsening symptoms (in particular incontinence), sleep disturbance, or concern that it could be something more serious. On presentation at the surgery, many patients mention “waterworks problems” or something vague. Clinicians should, therefore, discuss the patient’s urinary health during appropriate routine visits or at a minimum during annual physical examinations. With patients who could be at risk, the use of basic screening questions, such as the following, can be very helpful in this context: • Are you bothered by going to the toilet too frequently? • Are you bothered by a sudden, compelling need to go to the toilet? • Are you bothered by getting up at night to go to the toilet? • Are you bothered by leakage of urine? Primary care physicians are in the optimal position to initiate these discussions with patients. A good starting point would be with the simple question of whether the patient is having trouble with urine control or has any other problems with the bladder or when urinating. However, in the HertNet study [5], 25% of general practitioners surveyed said that they had had no previous training in diagnosing bladder problems, nearly 40% of general practitioners (GPs) felt that their training was inadequate, and two-thirds felt that guidelines would be helpful. Diagnosis should, therefore, include: • history taking — questionnaires, frequency/volume chart • urinalysis • basic physical examination.

Reasons for Visiting the Specialist

43

“Patient Flow” Primary care physicians (PCPs)/GPs are the most common first point of contact for patients with OAB, but indications for referral to continence care services are variable and very subjective, and patients are often inappropriately directed to secondary care [6]. GPs commonly manage patients by prescribing drug therapy; however, patient drop-out from treatment regimens is high. Clearly, whenever possible, it is appropriate that patients with lower urinary tract symptoms (LUTSs) are initially diagnosed and treated in the community setting, with referral to secondary care being restricted to complex cases. Community practitioners have the advantage of knowing their patient’s full history and of being able to provide holistic management and continuity of care. They are also ideally placed to recognize and understand the impact of concurrent medication and to ensure that the balance of benefits and risks of treatment remains in the patient’s favor. At a community level, the core dilemma is to identify the pathophysi-ology underlying the predominant problem so that the most appropriate treatment can be given. Certainly, there may be a tendency to classify all female incontinence as stress incontinence, and to overlook urgency incontinence, so difficulty will inevitably arise with the management of mixed incontinence in identifying the predominant component, whether it is OAB or SUI, in each patient. In addition there is a tendency in male patients, particularly the older male, to attribute storage symptoms to prostate or bladder overflow release problems.

Reasons for Visiting the Specialist In most cases, OAB may be diagnosed and managed in the primary care setting using conservative behavioral interventions and/or pharmaco-therapy. However, for patients in whom these measures do not achieve an acceptable level of improvement, specialist referral may be required. See Chapter 4 for further detail on specialist referral.

44

Chapter 3. Diagnosis and Assessment

When should a patient be referred by the primary care physician to a specialist? Hematuria Recurrent febrile urinary tract infections Complicated neurological disease Large post-void residual Prostatic nodule or induration, elevated prostate-specific antigen, or recurrent bouts of prostatitis Associated symptomatic pelvic prolapse or exterior prolapse (beyond the introitus) Refractory symptomatology (to initial conservative management) History of prior pelvic or vaginal surgery with the onset or worsening of symptoms afterward Renal dysfunction Pelvic, bladder, urethral, or vaginal pain

Figure 3.1 When should a patient be referred by the primary care physician to a specialist?

For most patients, the patient history, physical examination, self-reported questionnaires, and urinalysis are sufficient to establish a working diagnosis of OAB. A symptom-based approach to the diagnosis of OAB bypasses the need for invasive and expensive investigations that require referral to a specialist in a hospital setting, which many patients, particularly older patients, find distressing. In the female patient the differential diagnosis is aided by a careful history. Once the diagnosis has been made, the patient might be treated empirically for a 2- to 3-month period. Specialist referral is not routinely required before initiating therapy unless complicating factors are present, including, for example, suspected bladder outlet obstruction (BOO), failure to respond to conservative measures, previous incontinence surgery, risk factors for malignancy (eg, smoking), and hema-turia, or if a neurological etiology is suspected. Although a number of indications may warrant a referral from the GP or PCP to the specialist, Fig. 3.1 lists those indications that the authors feel best warrant referral to the specialist; however, these remain the opinion of the authors.

Physical Examination

45

Most patients with OAB can be successfully treated with conservative behavioral therapy and/or pharmacotherapy in the primary care setting; however, a general practitioner will encounter refractory patients for whom such conservative measures fail to provide satisfactory improvement, in which case specialist referral is warranted.

Physical Examination The physical examination should include a general examination, assessment of any neurological abnormalities, and an abdominal, pelvic floor, and rectal assessment: • A general assessment should identify important factors such as obesity and problems with mobility. • The abdomen should be checked for gross abnormalities, such as surgical scars. • A general assessment of the patient’s demeanor, facial symmetry, speech, and gait should be performed; observation of the patient’s walking into the consulting room aids this assessment. • A brief neurological assessment of the perineum and lower extremities (including the presence of edema) should also be performed to detect any sensory or motor loss. The community practitioner should identify neurological diseases that affect cognition, dexterity, and mobility (eg, multiple sclerosis), which could have an effect on toileting. • Rectal tone, as an assessment of sacral reflex arc integrity and perineal sensation, should be assessed.

Abdomen An abdominal examination should be performed to check for scars (eg, resulting from previous incontinence surgery or trauma) and possible contributors to intra-abdominal pressure or storage bladder symptoms (eg, a palpable bladder). Flank tenderness should also be assessed.

46

Chapter 3. Diagnosis and Assessment

Prostate In men, prostatic enlargement and consistency can all be checked by a digital rectal examination. Up to two-thirds of men with BOO consequent upon benign prostatic enlargement due to benign prostatic hyperplasia have detrusor overactivity that results in OAB symptoms. The obstruction can be associated with OAB symptoms; relief of this by prostate surgery can, in many instances, improve the storage symptoms, although there is evidence that these symptoms may recur in the longer term.

Pelvic Floor Muscles Measurement of squeeze pressure is the most commonly used method to measure pelvic floor muscle maximum strength and endurance. The patient is asked to contract the pelvic floor musculature as hard as possible (maximum strength), sustain a contraction (endurance), and repeat as many contractions as possible (endurance). The measurement can be done in the urethra, vagina, or rectum using manual muscle testing with vaginal palpation, pressure manometry, or dynamometry.

Female Genitourinary System During the female genitourinary examination, it is important to look for evidence of hormonal deficiency (eg, atrophic vaginitis). Having the patient perform Valsalva’s maneuver during a pelvic examination enables the physician to assess urethral mobility, muscle tone, prolapse, and/or evidence of leakage. Symptomatic patients with at least grade 2 cystoceles (bladder descent to the introitus with straining) require evaluation by a specialist.

Patient Questionnaires

47

Importance of Good Communication It is important to note when assessing the patient with suspected OAB that the medical terminology for LUTSs is poorly understood and misinterpreted by many patients [7]. In a survey of 50 women attending urodynamic clinics, just 37.5% identified the correct definition for stress urinary incontinence. The corresponding figures for urgency urinary incontinence, frequency, urgency, nocturia, and hesitancy were 55%, 21%, 57%, 59%, and 27%, respectively [7]. Examples of errors included 18% of patients defining urge urinary incontinence as leakage when you sneeze and cough, whereas 24% described frequency as voiding >11 times a day, and 22% defined nocturia as nocturnal enuresis [6]. Furthermore, in a study of 757 women with one or more bladder control symptom, 30% of respondents felt uncomfortable talking to their doctor about their condition, and only 28% of OAB “wet” and 16% of OAB “dry” patients strongly agreed with the statement that their bladder control symptoms constitute a medical condition [8].

Patient Questionnaires There are generic quality-of-life and disease-specific questionnaires. The generic scoring systems are insensitive when dealing with specific conditions such as OAB and, hence, are relatively poor at picking up differences between patients and grading responses to treatment precisely because they are not condition specific. Disease-specific scales include those in Fig. 3.2. In addition, the International Consultation on Incontinence Questionnaire Advisory Board has produced a modular questionnaire [20], which is a straightforward quality-of-life questionnaire with additional modules relating specifically to

48

Chapter 3. Diagnosis and Assessment

Disease-specific instruments

Instrument

Reference

OAB symptom and health-related questionnaire (OAB-q) Coyne et al. [9] OAB-V8 King’s Health Questionnaire (KHQ)

Kelleher et al. [10]

Bristol Female Lower Urinary Tract Symptoms (BFlUTS) Jackson et al. [11] Urogenital Disease Inventory (UDI)

Shumaker et al. [12]

Severity Index for Female Incontinence

Sandvik et al. [13]

Incontinence Impact Questionnaire (IIQ)

Shumaker et al. [12]

Incontinence QoL instrument (IQoLI)

Renck-Hooper et al. [14]

York Incontinence Perception Scale (YIPS)

Lee et al. [15]

Incontinence QoL (IQoL)

Wagner et al. [16]

Danish LUTS

Bernstein et al. [17]

SEAPPI QMM Incontinence Classification

Raz et al. [18]

Symptom Impact Index

Black et al. [19]

Figure 3.2 Disease-specific instruments. LUTS, lower urinary tract symptoms; OAB, overactive bladder; QoL, quality of life

prolapse, rectal dysfunction, sexual dysfunction, stress incontinence, and OAB (Fig. 3.3). These disease-specific questionnaires dealing with aspects of the disease process, by virtue of their length and detailed nature, tend to be research tools and, although these are used in some interested centers at secondary care level, they are rarely used within primary care. To address this issue a disease-specific questionnaire has been developed for more detailed assessment of patients in primary care — the V8 questionnaire (Fig. 3.4) [9]. The OABV8 has been evaluated in a primary care study in which a total of 1299 patients were enrolled, and where 1260 provided complete data. Patients were aged 51.6 ± 17.0 years, 62% were female, most (89%) were white, 22% experienced urinary urgency, and 18% experienced urgency incontinence. The prevalence of probable OAB was 12%. The questionnaire had a sensitivity and specificity of 98.0% and 82.7% for probable OAB. For OAB-V8 scores >8, the odds ratio for

Patient Diaries

49

probable OAB was 95.7 (95% confidence interval 29.3; 312.4). The OAB-V8 performed well in helping clinicians identify patients with troublesome OAB symptoms in a primary care setting and will assist clinicians in identifying patients who may benefit from treatment.

Patient Diaries It is not possible to completely assess LUTSs without using a bladder diary, which should ideally be used in all patients presenting with LUTSs.

International Consultation on Incontinence Questionnaire on overactive bladder (OAB) Overactive bladder Many people experience urinary symptoms some of the time. We are trying to find out how many people experience urinary symptoms, and how much they bother them. We would be grateful if you could answer the following questions, thinking about how you have been,on average, over the PAST FOUR WEEKS. 1. Please write in your date of birth: DAY 2. Are you (tick one): Female

MONTH

YEAR

Male

3a. How often do you pass urine during the day? 1 to 6 times

0

7 to 8 times

1

9 to 10 times

2

11 to 12 times

3

13 or more times

4

3b. How much does this bother you? Please ring a number between 0 (not at all) and 10 (a great deal) 0

1

Not at all

2

3

4

5

6

7

8

9

10 A great deal

Figure 3.3 International Consultation on Incontinence Questionnaire on overactive bladder (OAB). Questionnaire available from on request from www.iciq.net

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Chapter 3. Diagnosis and Assessment

International Consultation on Incontinence Questionnaire on overactive bladder (OAB) (continued) 4a. During the night, how many times do you have to get up to urinate,on average? None

0

One

1

Two

2

Three

3

Four or more

4

4b. How much does this bother you? Please ring a number between 0 (not at all) and 10 (a great deal) 0

1

2

3

4

5

6

7

8

9

Not at all

10 A great deal

5a. Do you have to rush to the toilet to urinate? Never

0

Occasionally

1

Sometimes

2

Most of the time

3

All of the time

4

5b. How much does this bother you? Please ring a number between 0 (not at all) and 10 (a great deal) 0

1

2

3

4

5

6

7

8

Not at all

9

10

A great deal

6a. Does urine leak before you can get to the toilet? Never

0

Occasionally

1

Sometimes

2

Most of the time

3

All of the time

4

6b. How much does this bother you? Please ring a number between 0 (not at all) and 10 (a great deal) 0

1

2

3

Not at all

Figure 3.3 (continued)

4

5

6

7

8

9

10

A great deal

Patient Diaries

51

The OAB-V8 questionnaire

A very great deal

A great deal

Quite a bit

Some what

A little bit

Not at all

The questions below are about how bothered you may be by some bladder symptoms. Some people are bothered by bladder symptoms and may not realise that there are treatments available for their symptoms. Please circle that number that best describes how much you have been bothered by each symptom. Add the numbers together for a total score and record the score in the boxes provided at the bottom.

How bothered have you been by... 1. Frequent urination during the daytime hours?

0

1

2

3

4

5

2. An uncomfortable urge to urinate?

0

1

2

3

4

5

3. A sudden urge to urinate with little or no warning

0

1

2

3

4

5

4. Accidental loss of small amounts of urine?

0

1

2

3

4

5

5. Nighttime urination?

0

1

2

3

4

5

6. An uncontrollable urge to urinate?

0

1

2

3

4

5

7. Urine loss associated with a strong desire to urinate? 0

1

2

3

4

5

Are you a male? If male, add 2 points to your score Please add up your responses to the questions above Please hand this page to your doctor when you see him/her for your visit. If your score is 8 or greater, you may have overactive bladder. There are effective treatments for this condition. You may want to talk with a healthcare professional about your symptoms.

Figure 3.4 The OAB-V8 questionnaire. Reproduced with permission from Coyne et al. [9]

Self-monitoring by the patient using a bladder diary provides the clinician with a valuable source of information on voiding behavior [20]. Furthermore, the act of keeping a daily bladder diary may well be therapeutic in itself, because it allows patients to make the connection themselves between fluid intake and urinary symptoms. When patients can see clearly the link between, say, two or three cups of coffee at breakfast and mid-morning voiding, they often take the decision themselves to moderate intake [21]. The bladder diary provides objective information on the time of each void, subjective information about leakage and

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Chapter 3. Diagnosis and Assessment

urgency, and details about any events that the patient believes triggered these episodes [21]. Urgency, in particular, is a very troublesome OAB symptom and having the patient record its frequency and degree of severity in the daily diary can be helpful in assessing improvement during treatment [21]. Bladder diaries are normally segmented into 24-hour intervals which are further subdivided into shorter time blocks to allow assessment of the frequency of voiding at different times of the day and night [21]. Patients record urinary output, average voided volume, frequency of voiding, and incontinent episodes. In addition, the type and volume of fluid intake can be included. They are a useful way of objectively quantifying symptoms — both before and after treatment — and pertinent information is acquired quickly. Furthermore, the act of keeping a diary can aid the patient’s behavioral modification when following nonpharmacological regimens (eg, bladder training). Bladder diaries can be kept by the patient for 3 days or for longer periods of time, although shorter diaries, such as 3 days, are associated with significantly better compliance than those lasting for 7 days, without compromising efficacy [22]. Figure 3.5 is a sample diary page of a 62-year-old man 6 months after a prostatectomy. It shows mild leakage in response to physical effort. Urinary frequency is within normal limits, with increased evening frequency triggered by alcohol intake. Fluid intake is inadequate, suggesting the patient may be limiting intake to control urinary leakage [21]. There is no standardized diary design and lay-out; it should be adapted to the needs and abilities of the patient; for example, the diary it could include the time at which the patient goes to bed and wakes up. This simple evaluation can be very helpful in revealing habits that contribute to urinary symptoms (eg, large intake of caffeine in the evenings or infrequent voids during working hours). Some diaries use a frequency–volume chart to measure voided volume in a 24-hour period to help determine bladder capacity. Figure 3.6 is a sample 24-hour frequency–volume chart for a 70-year-old woman with mixed urinary

Patient Diaries

53

Sample diary page of a 62-year-old man 6 months after a prostatectomy 1

2

3

4

Time interval

Urinated in toilet

Amount of Reason urine leakage for urine L M S leakage

5

6

Changed wet pad

Type/amount of liquid intake

D

W

S

6 am 7 am 8 am 9 am 10 am 11 am Noon 1 pm 2 pm 3 pm 4 pm 5 pm 6 pm 7 pm 8 pm 9 pm 10 pm to midnight Midnight to 2 am 2–4 am 4–6 am

Figure 3.5 Sample diary page of a 62-year-old man 6 months after a prostatectomy. L/M/S, large/ medium/small; D/W/S, damp/wet/ soaked. Reproduced with permission from Newman and Wein [21]

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Chapter 3. Diagnosis and Assessment

Sample 24-hour frequency–volume chart for a 70-year-old woman with mixed urinary incontinence and overactive bladder

Time

Amount voided

Type of pad:

Activity

Urine leakage (Yes/No)

Urgency present (Yes/No)

Fluid intake type/amount

No. pad used:5–6

Comments:

Figure 3.6 Sample 24-hour frequency–volume chart for a 70-yearold woman with mixed urinary incontinence and overactive bladder. Reproduced with permission from Newman and Wein [21]

incontinence and OAB. Frequent voiding of small volumes is typical of OAB, where the bladder tends to contract before it is fully distended [21]. To provide a normative picture for bladder diary assessment, Amundsen et al. [23] collected 3-day bladder diaries from 161 asymptomatic women with a median age of 46.6 years and no history of conditions or treatment affecting urological function. This showed that there was wide variation between individuals, at an average 24-hour urine volume of 1730 mL (range of 437–3861 mL), an average voiding frequency (F24) of 7.1

Urinalysis and Other Readily Available Studies

55

(range 2.0–13.0), and an average maximum volume per void of 514 mL (range 150–1000 mL) [23]. Increasing voided volume was associated with significant increase in both functional bladder capacity (FBC) and reduced frequency [23]. Voiding frequency increased significantly with increased age, and FBC appeared to decrease slightly [23]. There appear to be gender differences in the 24-hour urinary diaries between asymptomatic men and women. A study involving 141 matched pairs of male and female North American adults, at an age range of 18–68 years, revealed that 24-hour urinary frequency was significantly greater in women than in men, at 8 versus 7, whereas the average voided volume was lower, at 205 mL versus 231 mL, and the number of voids per liter intake was greater, at 4.2 versus 2.8 [24]. Men had a significantly higher fluid intake than women, at 2400 mL versus 1980 mL [24]. There were no significant differences in terms of body mass index, total urine volume, and night-time/daytime diuresis rates [24]. In addition, a study in which the bladder diaries from 535 women who underwent a suburethral sling operation were compared with medical records, physical examination, and urodynamics indicated that only 47% of women were accurate about their daytime voiding frequency, with 51% overestimating the frequency [25]. The overestimation was most marked in women reporting a daytime frequency >10, leading to a weak correlation between medical histories and diaries, with an r value of 0.31 for the correlation coefficient [25]. However, 93% of the participants were accurate on the nighttime estimate, giving a highly significant correlation between medical histories and diaries on this measure [25].

Urinalysis and Other Readily Available Studies A routine urine sample should be checked with a dipstick for infection, hematuria, and the presence of glucose or other contributing causes.

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References 1. Coyne KS, Sexton CC, Irwin DE, et al (2008). The impact of overactive bladder, incontinence and other lower urinary tract symptoms on quality of life, work productivity, sexuality and emotional wellbeing in men and women: results from the EPIC study. BJU Int 101:1388–95. 2. Sussman DO (2007). Overactive bladder: treatment options in primary care medicine. J Am Osteopath Assoc 107:379–85. 3. MacDiarmid S, Rosenberg M (2005). Overactive bladder in women: symptom impact and treatment expectations. Curr Med Res Opin 21:1413–21. 4. Irwin DE, Mungapen L, Milsom I, et al (2009). The economic impact of overactive bladder syndrome in six Western countries. BJU Int 103:202–9. 5. Kirby M, Artibani W, Cartozo L, Chapple C, Wagg A et al. (2006) Overactive bladder: the importance of new guidance. Int J Clin Pract 60:1263–71 6. Raphael H, Getliffe K (2004). Care pathways for overactive bladder. Presented at: Wessex Primary Care Research Network 10th Annual Research Day, Southampton, UK. 7. Khullar V, Basra R, Teague S, Hendricken C, Kelleher C (2006). What do patients understand by lower urinary tract symptoms? Neurourol Urodyn 25:603–4. 8. Diokno AC, Sand PK, Macdiarmid S, Shah R, Armstrong RB (2006). Perceptions and behaviours of women with bladder control problems. Fam Pract 23:568–77. 9. Coyne KS, Zyczynski T, Margolis MK, et al (2005). Validation of an overactive bladder awareness tool for use in primary care settings. Adv Ther 22:381–94. 10. Kelleher CJ, Cardozo LD, Toozs-Hobson PM (1995). Quality of life and urinary incontinence. Curr Opin Obstet Gynecol 7:404–8. 11. Jackson S, Donovan J, Brookes S, et al (1996). The Bristol Female Lower Urinary Tract Symptoms questionnaire: development and psychometric testing. Br J Urol 77:805–12. 12. Shumaker SA, Wyman JF, Uebersax JS, et al (1994). Health-related quality of life measures for women with urinary incontinence: the Incontinence Impact Questionnaire and the Urogenital Distress inventory. Continence Program in Women (CPW ) Research Group. Qual Life Res 3:291–306. 13. Sandvik H, Hunskaar S, Seim A, et al (1993). Validation of a severity index in female urinary incontinence and its implementation in an epidemiological survey. J Epidemiol Community Health 47:497–9. 14. Renck-Hooper U, McKenna SP, Whalley D (1997). Measuring the quality of life in female urinary urge incontinence: development and psychometric properties of the IQoLI. J Outcome Res 1:1–8.

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15. Lee PS, Reid DW, Saltmarche A, Linton L (1995). Measuring the psychosocial impact of urinary incontinence: the York incontinence Perceptions Scale (YIPS). J Am Geriatr Soc 43:1275–8. 16. Wagner TH, Patrick DL, Bavendam TG, et al (1996). Quality of life of persons with urinary incontinence: Development of a new measure. Urology 47:67–72. 17. Bernstein I, Sejr T, Able I, et al (1996). Assessment of lower urinary tract symptoms in women by a self-administered questionnaire: testretest reliability. Int Urogynecol J Pelvic Floor Dysfunct 7:37–47. 18. Raz S, Erickson DR (1992). SEAPI QMM incontinence classification system. Neurourol Urodyn 11:187–99. 19. Black N, Griffiths J, Pope C (1996). Development of a symptom severity index and a symptom impact index for stress incontinence in women. Neurourol Urodyn 15:630–40. 20. Abrams P, Avery K, Gardener N, et al; for the ICIQ Advisory Board (2006). The international Consultation on Incontinence Modular Questionnaire: www.iciq.net. J Urol 175:1063–6. 21. Newman DK, Wein AJ (2009). Managing and Treating Urinary Incontinence, 2nd edn. Baltimore, MD: Health Professions Press. 22. Dmochowski RR, Sanders SW, Appell RA, Nitti VW, Davila GW (2005). Bladder-health diaries: an assessment of 3-day vs 7-day entries. BJU Int 96:1049–54. 23. Amundsen CL, Parsons M, Tissot B, et al (2007). Bladder diary measurements in asymptomatic females: functional bladder capacity, frequency, and 24-hr volume. Neurourol Urodyn 26:341–9. 24. Mueller E, Latini J, Lux M, et al (2005). Gender differences in 24-hour urinary diaries of asymptomatic North American adults. J Urol 173:490–2. 25. Stav K, Dwyer PL, Rosamilia A (2009). Women overestimate daytime urinary frequency: the importance of the bladder diary. J Urol 181:2176–80.

Chapter 4 The Role of the Specialist

General Assessment A general assessment of the patient will reveal important factors, such as obesity and poor mobility. Specific systemic examination should include abdominal examination to reveal bladder distension and evidence of previous surgery. In women, a vaginal examination can be carried out with the patient lying either supine with the hips abducted or in the left lateral position using a Sims speculum and asking the patient to “bear down” or “cough” to objectively demonstrate stress leakage of urine and assess the degree of bladder neck mobility and cystourethrovaginal prolapse. If a neurological cause is suspected, tone, power, sensation, and reflexes of the lower limbs should be assessed. Rectal examination allows assessment of anal tone and anal reflex, and detection of prostate abnormalities in men. In addition to routine tests, such as a urine examination, further investigation should utilize urodynamic assessment, which strictly speaking includes any test of lower urinary tract function. In any patient who fails to respond to initial therapy or in the presence of a complex picture, formal cystometry is important as the diagnostic study to define the abnormal detrusor function and/or abnormal bladder sensation and voiding pathology. The Oxford Grading System can be used to evaluate pelvic floor muscle strength. Laycock developed the modified Oxford Grading System to measure pelvic floor muscle A.J. Wein, C. Chapple, Overactive Bladder in Clinical Practice, DOI 10.1007/978-1-84628-831-9_4, © Springer-Verlag London Limited 2012

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strength using vaginal palpation of the pelvic floor muscle [1,2]. This is a 6-point scale where 0 = no contraction, 1 = flicker, 2 = weak, 3 = moderate, 4 = good (with lift), and 5 = strong. This measurement scale is commonly used by physical therapists because it can be incorporated with vaginal palpation in the clinical assessment, its use is considered a physical therapist’s core manual skill, it is simple to use, and it does not require expensive equipment. A simple method of assessment is the Kegel squeeze, which involves performing a quick (1 s) squeeze and a prolonged (>3 s) squeeze. Absence of this squeeze can indicate neuropathy or severe pubococcygeal muscle atrophy. In addition, pelvic examination should assess atrophic vaginitis (in women), pelvic mass, and pelvic organ prolapse. Kegel used a vaginal pressure device connected to a manometer (the perineometer), showing the pressure (in millimeters of mercury) as a measure of pelvic floor muscle strength [3]. He did not report any data about responsiveness, reliability, or validity for his method. The term “perineometer” is somewhat misleading because the pressure-sensitive region of the probe of the manometer is not placed at the perineum, but in the vagina at the level of the levator ani muscles. Currently, several types of vaginal pressure devices are available to measure vaginal squeeze pressure.

Differential Diagnosis A clear diagnosis depends on identifying the underlying pathophysiology in patients presenting with lower urinary tract symptoms (Fig. 4.1), thereby differentiating between storage and voiding disorders in both male and female patients. There is an increased recognition of the importance of storage symptoms represented by the OAB symptom complex and of the individual importance of sphincteric weakness, possible detrusor overactivity (DO) or underactivity, and bladder outlet obstruction (BOO). The key symptom of OAB that differentiates it from other storage disorders, such as painful bladder syndrome, is

Differential Diagnosis

61

Differential diagnosis for overactive bladder, stress incontinence, and mixed incontinence Symptoms

OAB

Stress Mixed Incontinence incontinence

Urgency (strong, sudden desire to void)

Yes

No

Yes

Frequency with urgency (more than eight times/24 hours)

Yes

No

Yes

Leaking during physical activity (eg, coughing, sneezing, lifting)

No

Yes

Yes

Amount of urinary leakage with episode of incontinence

Large (if present)

Small

Variable

Ability to reach the toilet in time following the urge to void

Often no

Yes

Variable

Waking to pass urine at night

Usually

Seldom

Maybe

Figure 4.1 Differential diagnosis for overactive bladder, stress incontinence, and mixed incontinence. Reproduced with permission from Abrams and Wein [4]

urgency (or fear of leakage). In painful bladder syndrome there is a sensation of discomfort that prompts voiding. Patients can be asked to record in their bladder diaries whether they: • are able to finish their active task before going to the toilet; this is not urgency in some cases • have to go to the toilet as soon as they feel the need (urgency) • are unable to prevent urination, with resultant incontinence.

Symptoms History-taking focuses on the four major symptoms of OAB: urgency, urgency incontinence, frequency, and nocturia. This is facilitated by use of a frequency–volume chart, which can also help identify risk or contributory factors for OAB, such as abnormal drinking habits or excessive alcohol or caffeine intake.

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Many patients develop coping mechanisms to reduce the impact of their symptoms on their daily lives. They may drink less, empty their bladder before they need to, or avoid going far from a toilet. However, because they appear to be coping reasonably well does not mean that their quality of life is satisfactory, so the severity of symptoms and their effect on the patient need to be investigated fully. There is evidence that depression increases the likelihood of urological symptoms [5], whereas urinary frequency, urgency, and nocturia are all associated with childhood and adolescent/adult sexual, physical, and emotional abuse, increasing the odds of each symptoms by factors of 1.6–1.9, 2.0–2.3, and 1.3–1.5, respectively [6]. So clearly, a thorough investigation of urinary incontinence requires tact and sensitivity.

Additional Investigations Urine cytology: In order to rule out carcinoma in situ or bladder cancer, as well as dysplasia, patients with OAB and persistent severe symptoms or pain for which no cause has been identified should have a urine sample sent for cytological examination [7,8]. Urine microscopy and culture: To identify microscopic hematuria and infection, urinalysis and midstream urine specimen should be obtained from patients with OAB [9].

Urodynamic Investigations Urodynamic studies (UDS) are tests that allow direct assessment of lower urinary tract function by the generation of quantitative data relevant to the filling/storage and voiding/ emptying phases of the micturation cycle [10]. It has been stated that “the immediate aim of urodynamic testing is to reproduce the symptom(s) of the patient under controlled and measurable conditions, so that the cause of the

Urodynamic Investigations

63

symptoms can be determined” [11]. These authors go on to list the following specific roles for urodynamic testing in the clinic: • to identify or to rule out factors contributing to the LUT dysfunction (eg, urinary incontinence) and assess their relative importance • to obtain information about other aspects of LUT dysfunction • to predict the consequences of LUT dysfunction for the upper urinary tract • to predict the outcome, including undesirable side effects, of a contemplated treatment • to confirm the effects of intervention or understand the mode of action of a particular type of treatment; especially a new one • to understand the reasons for failure of previous treatments for urinary incontinence, or for LUT dysfunction in general. Simple UDS include pad testing, uroflowmetry and/or ultrasound residual, and ultrasound cystodynamogram. Pressure/ flow studies, used in more complex or equivocal cases, include cystometry, leak point measurements, video urodynamics, and ambulatory urodynamics. Complex UDS include urethral pressure measurement, neurophysiological investigation, and upper tract urodynamics (Whitaker test) [12].

Simple Urodynamic Investigations Pad Testing This involves weighing a perineal pad before and after use. It is intended to determine the amount of urine leaked during a specified period, so demonstrating the severity of incontinence to both clinician and patient. It is especially useful for confirming the presence of incontinence when other tests have failed to demonstrate any urinary leakage [12].

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Chapter 4. The Role of the Specialist

Uroflowmetry With a full bladder, the patient voids into a flowmeter. This noninvasive and inexpensive test gives a great deal of information regarding voiding function. It is a valuable screening tool for BOO and is often the first investigation for patients with suspected voiding dysfunction [12]. However, it is limited by its relative inability to distinguish between poor detrusor function and BOO, and there is no evidence linking urodynamic diagnosis and uroflowmetry pattern [13]. It is therefore impossible to determine from a flow rate alone if voiding dysfunction is due to a detrusor pathology or bladder outlet/urethral pathology or from a combination of problems [12]. Furthermore, there is also a large variation in maximal flow rate in the same individual due to different voided volumes, and the relationship between maximal flow rate and voided volume varies substantially between patients [13]. Pressure/flow cystometry is necessary to accurately diagnose the degree of obstruction and detrusor contractility [12,13].

Post-Void Residual Uroflowmetry may be combined with simple post-void residual (PVR) estimation using a handheld ultrasonic scanner to ascertain the completeness of bladder emptying [12]. This is because poor emptying may lead to recurrent urinary tract infections and, in the context of retention with large residuals and high bladder pressures, upper urinary tract damage [14]. Residual urine should always be related to the functional capacity of the bladder. The functional capacity is the volume voided on a frequency volume chart plus the measure residual. While there is no generally agreed value for what represents a ‘significant’ residual urine volume, the majority of those working in this field would agree that a residual urine volume of more than 40% of the functional capacity of the bladder estimated in this fashion is significant and deserves appropriate long term follow up, as these patients are at

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65

Which patients should be assessed for post-void residual volume? Patients with complicated neurological disease Patients who feel that they don’t empty well Patients with significant hesitancy or a poor stream Patients with what seems to be a palpable bladder Patients with what seems to be a relatively fixed small bladder capacity Patients with symptoms suggestive of “overflow incontinence”

Figure 4.2 Which patients should be assessed for post-void residual volume?

increased risk of developing complications or experiencing voiding difficulty. Accurate estimation of PVR relies on catheterization or bladder ultrasound [15]. There remains little doubt though that the most accurate way of assessing a residual is catheterization, as most of the ultrasound techniques using the simple devices have a significant measurement error associated with them. A study of 201 women with urinary frequency, urgency and/or incontinence aged ³20 years revealed that 19% had an elevated PVR of ³100 mL [15]. On multivariate analysis, independent predictors of elevated PVR were age ³55 years, a history of incontinence surgery, a history of multiple sclerosis, and pelvic organ prolapse at stage 2 or higher, at respective odds ratios of 3.71, 4.32, 15.32, and 3.61 [15]. Figure 4.2 lists those patients with OAB symptoms who should be assessed for PVR volume.

Ultrasound Cystodynamogram Ultrasound cystodynamogram (USCD) is a combination of ultrasound examination of the bladder and uroflowmetry that provides more detailed information than uroflowmetry alone, including the structure of the bladder (shape, presence of diverticula), distal ureteric anatomy (presence of hydroureteronephrosis), completeness of bladder emptying, and prostate size (Fig. 4.3).

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Chapter 4. The Role of the Specialist

Ultrasound cystodynamogram

Prevoid bladder volume Outflow obstruction Normal Hydronephrosis Empty bladder

Thickened bladder wall

No residual Flow rate (Q) (ml/s)

Normal flow

Incomplete emptying

Raised residual Flow rate (Q) (ml/s)

Prolonged reduced flow

Figure 4.3 Ultrasound cystodynamogram. The additional ultrasonic data, on the right showing incomplete emptying, thickened bladder wall and bilateral hydronephrosis associated with chronic poor voiding. Reproduced with permission from Chapple et al. [12]

USCD is particularly valuable for assessing patients with raised PVR, poor detrusor function, or suspected compromised voiding after a repair procedure for stress incontinence [12].

Pressure/Flow Studies Cystometry The main advantage of cystometry compared with simple urodynamic procedures is that the simultaneous measurement of bladder pressure and voiding function allows localization of the site of dysfunction to either the bladder or the bladder outlet/urethra. It also provides useful information on the function of the lower urinary tract during storage and voiding phases, and in many instances can provide a definitive pathophysiological diagnosis [12].

Urodynamic Investigations

67

Cystometry apparatus Sterile water or saline EMG Pabd

EMG

Pves Pdet Qura

Rectal transducer

Vol.

Bladder transducer

Pump

Flow meter

Computer

CD storage

Transducer

Computer storage and analysis

Figure 4.4 Cystometry apparatus

Simple cystometry, in which only the intravesical (total bladder) pressure is measured, is inaccurate and is rarely performed. Subtraction cystometry, which involves simultaneous measurement of both the intra-vesical and intraabdominal pressure, enables the detrusor pressure component of the intravesical pressure to be calculated and analyzed. This allows accurate determination of detrusor pressure and is used in urodynamic units worldwide [12]. The bladder is filled with saline or sterile water via catheters placed in the urethra and the bladder pressure is measured. The intensity of the patient’s desire to void can be directly correlated with objectively measured pressure [10]. Pressures are measured with transducers attached to fluidfilled lines inserted into the rectum or vagina (abdominal pressure) and bladder (vesical pressure) (Fig. 4.4). This allows the calculation of the detrusor pressure (vesical–abdominal pressure). Urodynamics is important in the differential diagnosis of DO and urodynamic stress incontinence. It is only by

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Chapter 4. The Role of the Specialist

Patterns of detrusor behavior

Detrusor pressure

Normal filling cystometrogram Low compliance Systolic overactivity Nonsystolic overactivity

Bladder volume

Figure 4.5 Patterns of detrusor behavior

measuring changes in detrusor pressure that impaired compliance and DO can be diagnosed, but it is essential that these findings be correlated with reported symptoms and leakage. Under normal circumstances during cystometry, there should be no intrinsic rise in detrusor pressure in a conscious cooperative patient who is attempting to inhibit voiding. Examples of different patterns of detrusor behavior are shown in Fig. 4.5 and a trace from a patient with detrusor overactivity is shown in Fig. 4.6. Specific indications for cystometry include: • after treatment failure • before invasive therapy • complicated incontinence • long-term surveillance of lower urinary tract dysfunction associated with neurological disorders. Cystometric bladder capacity is the bladder volume at the end of the cystometry filling when the patient is given permission to void. If the patient has uncontrollable voiding (incontinence), this volume is documented as the volume at which voiding starts. Maximum cystometric bladder capacity can also be determined, which is the volume at which patients feel that they cannot delay urination any longer because of the strong desire to void. In DO, peaks of increased bladder pressure are recorded during the filling phase, which result from involuntary detrusor contractions (see Fig. 4.5).

Urodynamic Investigations

69

Detrusor pressure measured during bladder filling in a patient with overactive bladder OAB contraction Detrusor pressure

Urgency Pabd (cm H20) 50 0 Pves (cm H20) 50

Pdet (cm H20)

0 50 0 Cough

Hand wash event

Urge

Bladder volume

Figure 4.6 Detrusor pressure measured during bladder filling in a patient withoveractive bladder. Note the effect of handwashing in precipitating an OAB contraction. Pabd (abdominal pressure); Pves (bladder pressure); Pdet (detrusor pressure)

Sensation can be evaluated at defined points during the filling phase and should be judged according to the bladder volume at that specific point and in relation to the patient’s symptoms. Patients with DO may experience urgency, which is a compelling desire to void that is difficult to defer. In approximately half to two-thirds of cases urodynamically demonstrable DO is present. The bladder capacity measured using cystometry should be interpreted in the context of the findings from the patient’s bladder diary and in discussion with the patient to correlate the findings with the symptoms experienced by the patient during the study.

Leak Point Pressures During the storage phase leak point pressures can also be assessed. Two leak point pressures have been defined by the ICS: abdominal leak point pressure (ALPP) and valsalva leak

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Chapter 4. The Role of the Specialist

point pressure (VLPP). ALPP is the intravesical pressure at which urine leakage occurs due to increased abdominal pressure in the absence of a detrusor contraction. It acts as a measure of the ability of the bladder neck and the urethral sphincter mechanism to resist intra-abdominal pressure. It may also help identify sphincter deficiency, which may lead to stress urinary incontinence. VLPP and cough leak point pressure (CLPP) are terms sometimes used to describe the methods of increasing the intra-abdominal pressure. A CLPP is the more clinically relevant, but the rapidity of the event makes measurement difficult [12]. Detrusor leak point pressure (DLPP) is the lowest detrusor pressure at which urine leakage occurs in the absence of either a detrusor contraction or increased abdominal pressure. DLPP can predict upper tract dysfunction in patients with neurological conditions affecting bladder compliance and voiding. It measures the capacity of the bladder neck and urethral sphincter mechanism to resist increased pressure. High detrusor pressure combined with high DLPP may be dangerous to the upper urinary tracts [12].

Videourodynamics Multichannel fluoroscopic visualization of the bladder and urethra during the study (Fig. 4.7) increases the quality of the data derived from all the above UDS [10]. It provides information on the anatomy of the bladder, the presence of any vesicoureteric reflux, the degree of bladder neck and urethral mobility, and the presence and level of any outflow obstruction. This is certainly a useful diagnostic option in the preoperative evaluation of complicated/urinary incontinence or suspected obstruction. Ideally, UDS should reproduce the patient’s symptoms to minimize the occurrence of falsepositive and false-negative results. Even then the results must be interpreted in the context of patient history and other tests and examinations [10]. Several studies have identified a lack of correlation between subjective symptoms of voiding difficulties and objective

Urodynamic Investigations

71

Videourodynamic apparatus

Contrast

X-ray EMG

Synchronous imaging

Pabd

EMG

Pves Pdet Qura

Rectal transducer

Vol.

Bladder transducer

Pump

Flow meter

Computer

CD storage

Transducer

Computer storage and analysis

Figure 4.7 Videourodynamic apparatus. The study can also be performed without fluoroscopic imaging

urodynamic data. There is now clear evidence that DO correlates better with storage symptoms than voiding symptoms do with BOO. A further complicating factor is that the definition of obstruction in the human is based on a cohort of male patients in whom the pressure–flow relationship was studied, leading on to a definition of obstruction versus equivocal voiding versus normal voiding. In women the situation is more complex because of the presence of the vagina and the development of pelvic floor prolapse with rotational descent of the pelvic viscera. As a consequence of this, although a number of normograms have been produced over the years, there is no clear consensus on whether obstruction as such can be clearly defined in women because of these confounding variables. The presence of a pelvic floor weakness and prolapse leads to very variable and confounding factors, as seen, for example, in the context of a cystourethrocele leading to kinking of the

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urethra. Once this is replaced, a degree of “obstruction” can be resolved. In one study, 206 female patients attending a urogynecological clinic underwent detailed clinical evaluation, including a general, obstetric, and urogynecological questionnaire, urinary diary, urine culture, neurological and pelvic examinations, and a full urodynamic evaluation [14]. In all, 61.7% of women reported voiding difficulty symptoms, whereas the remainder said that they were symptom free. In contrast, 19.4% of the women were diagnosed on urodynamic analysis with voiding difficulty, at 21.2% of symptomatic and 16.5% of asymptomatic women [14]. Voiding difficulties were associated with BOO in one case, whereas the remainder were due to impaired detrusor contractility [14]. Another study involving 116 women aged ³25 years revealed that 50% reported one or more voiding difficulty symptoms: 13.7% had to strain to void, 18.1% reported double voiding, 27.5% post-micturition dribbling, 8.6% poor stream, and 29.3% incomplete emptying [16]. On urodynamic analysis, just 6.9% of patients had abnormal voiding, whereas 11% were equivocal and 82.1% were normal [16]. Only poor stream and strain were able weakly to predict a residual volume of >100 mL and >150 mL [16]. However, there were no other associations and no cut-off values against which symptoms, as they became more prevalent, could be determined [16].

Ambulatory Urodynamics Conventional pressure/flow cystometry has a number of shortcomings, such as nonphysiologically high filling rate and an unfamiliar environment for the patient. It may therefore not always give an accurate representation of lower urinary tract function in “real life” conditions. Nevertheless, it remains the gold standard investigation of lower urinary tract dysfunction and is used far more commonly than ambulatory urodynamics (AUM). AUM overcomes some of the problems associated with conventional urodynamics at the expense of introducing other artifacts and difficulties. The equipment

References

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is portable, allowing the patient to move freely and void in private. In addition, the patient fills his or her bladder spontaneously after drinking a fluid load. As the technique is not adequately standardized and there are no internationally accepted diagnostic criteria, it is best regarded as a research tool at present, particularly as some studies have reported involuntary detrusor contractions in up to 70% of apparently normal individuals. The technique is best used when conventional pressure/studies have failed to explain or reproduce the symptoms and when further understanding of lower urinary tract function may aid subsequent management [12].

References 1. Laycock J (1994). Clinical evaluation of the pelvic floor. in: Schussler B, Laycock J, Norton Pet al (eds), Pelvic Floor Re-education. London: Springer-verlag, pp 42–8. 2. British Medical Research Council War Memorandum (1943). Aid to the Investigation of Peripheral Nerve Injuries. London: HMSO, pp 11–46. 3. Kegel AH (1948). Progressive resistance exercise in the functional restoration of the perineal muscles.Am J Obstet Gynecol 56:238–49. 4. Abrams P, Wein AJ (1998). The Overactive Bladder: A Widespread but Treatable Condition. Stockholm, Sweden: Erik Sparre Medical AB. 5. Fitzgerald MP, Link CL, Litman HJ, Travison TG, McKinlay JB (2007). Beyond the lower urinary tract: the association of urologic and sexual symptoms with common illnesses. Eur Urol 52:407–15. 6. Link CL, Lutfey KE, Steers WD, McKinlay JB (2007). Is abuse causally related to urologic symptoms? Results from the Boston Area Community Health (BACH) Survey. Eur Urol 52:397–406. 7. Wein AJ (2003). Diagnosis and treatment of the overactive bladder. Urology 62:20–7. 8. Duckett J, Aggarwal I, Basu M, Vella M, Patil A (2007). The value of cystoscopy and bladder biopsy taken at the time of tension-free vaginal tape insertion. J Obstet Gynaecol 27:297–9. 9. Freeman RM, Adekanmi OA (2005). Overactive bladder. Best Pract Res Clin Obstet Gynaecol 19: 829–41. 10. Newman DK, Wein AJ (2009). Managing and Treating Urinary Incontinence, 2nd edn. Baltimore, MD: Health Professions Press. 11. Hosker G, Rosier P, Gajewski J, et al (2009). Dynamic testing. in: Abrams P, Cardozo L, Khoury S, Wein AJ (eds), Incontinence: Fourth

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12. 13. 14.

15.

16.

Chapter 4. The Role of the Specialist International Consultation on Incontinence. Plymouth, UK: Health Publication Ltd; pp 413–522. Chapple C, MacDiarmid S, Patel A. (2009) Urodynamics Made Easy. Oxford: Churchill Livingstone:(2009):38–42. Takeda M, Araki I, Kamiyama M, et al (2003). Diagnosis and treatment of voiding symptoms. Urology 62:11–19. Groutz A, Gordon D, Lessing JB, et al (1999). Prevalence and characteristics of voiding difficulties in women: are subjective symptoms substantiated by objective urodynamic data? Urology 54:268–72. Milleman M, Langenstroer P, Guralnick ML (2004). Post-void residual urine volume in women with overactive bladder symptoms. J Urol 172:1911–14. Jeffery ST, Doumouchtsis SK, Vlachos IS, Fynes MM (2008). Are voiding symptoms really associated with abnormal urodynamic voiding parameters in women? Int J Urol 15:1044–8.

Chapter 5 Management of Overactive Bladder

Principles of Management After diagnosing overactive bladder (OAB), simple and straightforward treatment options can be employed. These options include both non-pharmacological and pharmacological approaches, which can be used separately or in combination (Fig. 5.1). It is reasonable to empirically initiate behavioral modification and pharmacological treatment in patients presenting with OAB symptoms who show no evidence of infection, hematuria, or other physical findings suggestive of known pathologies, reserving more aggressive therapies for patients who do not respond. It is worth noting that 49% of all women with self-reported urinary symptoms and 51% of those with urge urinary incontinence (UI) desire a reduction in leakage episodes of >70% to consider a prescription therapy effective, whereas 26% desire a reduction in leakage episodes of 90% [1]. However, only a minority of women report symptom relief from treatment: 26% of those given panty liners, 33% of those using pads, 11% performing pelvic exercises, 45% of those receiving prescription medications, and 16% of those undergoing bladder training [1].

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Cascade of increasingly more aggressive possible treatment interventions for idiopathic and neurogenic overactive bladder Intervention Behavioral

Lifestyle modification, bladder training, pelvic floor muscle exercises

Pharmacotherapy

Muscarinic receptor antagonists, intradetrusor botulinum toxin A or B*

Neuromodulation

Peripheral and sacral nerves

Bladder augmentation

Autoaugmentation, enterocytoplasty

Supravesical urinary diversion

Figure 5.1 Cascade of increasingly more aggressive possible treatment interventions for idiopathic and neurogenic overactive bladder. *Not approved by regulatory authorities in the USA or Europe/ the UK.

The Role of the Primary Care Physician and the Specialist in Management Early management strategies in primary care may consist of behavioral modification and/or pharmacological therapy, for which the best evidence is for anticholinergics in general and antimuscarinics in particular [2]. A patient should be referred for specialist care if he or she is a poor responder to noninvasive therapy, which should be assessed based on a combination of efficacy, tolerability, and compliance [2]. At that point, the therapeutic options available to the specialist include [2]: • reassurance • more intense behavioral modification • increase in the drug dose • addition of another drug • changing the agent prescribed • adding or initiating a change of therapy. If adaptation of the pharmacological and behavioral regimens does not yield improvements in outcomes, then nonpharmacological approaches may have to be considered. Urodynamic studies may be helpful and are mandatory before other invasive and irreversible therapies [2].

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Follow-Up Strategies Expectations of treatment should be outlined to patients, and patient satisfaction with treatment should be routinely assessed as part of follow-up care in order to optimize clinical outcomes for patients with OAB [1]. Patients receiving behavioral treatment and physiotherapy for OAB also require outpatient treatment sessions in the preliminary phase to ensure efficacy [3].

Self-care Practices and Lifestyle Changes There are a number of techniques that the patient with UI can use to lessen symptom severity. These interventions work by countering lifestyle habits and behaviors that have been identified as triggering urinary symptoms [4]. The following are key components of this approach: • Adjust daily fluid intake to approximately 2500 mL or 30 mL/kg per day. OAB patients may exhibit excessive or restrictive fluid intake, both of which can exacerbate urinary symptoms. Drinking water is the preferred method of meeting fluid needs, and most adults can obtain adequate hydration by letting thirst be their guide [4]. • Reduce the intake of potential bladder irritants. Carbonated drinks, artificial sweeteners, spicy foods, and citrus fruits and juices are known bladder irritants and may influence continence status, and alcohol intake is associated with OAB symptoms [4]. • Reduce caffeine intake to <400 mg/day. Caffeine occurs naturally in coffee, tea, and chocolate, and is added to many beverages, medications, and diet supplements. It has been shown to have an excitatory effect on detrusor muscle contraction. A 12-oz mug of brewed coffee contains about 200 mg caffeine, whereas tea has about 30–50 mg caffeine per cup. “Caffeine Count” education tools are available that list the caffeine content of many products, helping OAB patients keep within limits. Caffeine reduction should be tapered gradually to avoid severe headache [4].

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• Regulate bowel function. Chronic constipation can contribute to UI, so affected patients should be encouraged to improve bowel function through use of dietary fiber, fluid intake, and exercise [4]. • Address the problem of nocturia. Nocturia can be a problem for older adults. Affected patients should be advised to limit fluid intake after 6 pm and shift intake to the morning and afternoon. Patients with peripheral edema should elevate the lower limbs for several hours in the afternoon to stimulate natural diuresis. Those taking shortacting diuretics may benefit from taking the pm dose in the afternoon rather than the evening [4].

Smoking Cessation Smoking increases the risk of developing UI, and coughing due to smoking and smoking-related diseases may promote urgency. Nicotine may contribute to large phasic bladder contractions [4].

Weight Loss Obesity, defined as a body mass index (BMI) of ³30, has been identified as a risk factor for the severity of stress UI or mixed UI. The effect of weight loss on urinary symptoms has been shown to be significant in stress UI [5].

Behavioral Modification Inexpensive, low-risk, noninvasive, nonpharmacological (physical) therapies are clearly most appropriate as primary or adjunctive therapy for patients with OAB. In many cases, they aim to help the patient regain control of the bladder by increasing its effective capacity, thereby reducing the symptoms of OAB. Methods include the following:

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• Pelvic floor muscle (PFM) rehabilitation (first devised by Arnold Kegel in the 1940s [6] and often termed “Kegel exercises”), which aim to strengthen the musculature of the pelvic floor and reinforce the pelvic floor reflex, causing inhibition of detrusor contraction in urgency incontinence. During digital vaginal examination, the patient should be instructed to isolate the pubococcygeus without using other muscles, and advised to perform the exercises several times a day in sets of 10–15 to avoid muscle fatigue. To be effective, PFM rehabilitation requires regular, intensive work over several months, with gradual increases in the quantity and intensity of exercises [4,7]. PFM exercises are useful in stress, urgency, and mixed incontinence, reducing incontinence episodes in most patients who practice them. They are most effective in women with mild-tomoderate symptoms of OAB. • Bladder retraining, with timed or prompted voiding. The goal of bladder-training techniques, such as timed voiding, is to increase the amount of urine that the bladder can hold, thereby increasing the interval between voids and reducing urgency and incontinence [4,7]. Infrequent voiders are instructed to void every 2–3 hours while awake, and frequent voiders are encouraged to start at intervals of every 30 min and then gradually increase the voiding interval toward an acceptable duration that provides minimal interference with quality of life. Keeping a bladder diary has a central role in bladder retraining, in addition to an assessment of the patient’s fluid intake compared with urine output. Bladder retraining necessitates significant effort and behavioral modification on the part of the patient and carers, and one meta-analysis found that there was not sufficient evidence to recommend timed voiding as a general strategy in all patients [8]. • Behavioral strategies for dealing with urgency and urgency incontinence. Behavioral “urgency” strategies include trying to prevent urgency-associated leakage by practicing timely relaxation and deep-breathing exercises. In addition, as strong muscle contraction reflexively inhibits

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bladder overactivity, performing several successive short PFM contractions, each lasting less than a second (so-called “quick flicks”), suppresses or inhibits urgency, giving more time to void.

Patient Compliance Adherence to behavior modification can be problematic because the exercises are burdensome and it often takes months for symptomatic improvements to appear. To improve patient compliance, the clinician should review progress on a regular basis and provide positive feedback where deserved. A patient–doctor “contract” setting out personal treatment goals can help reinforce motivation, as can the use of patient diaries [4,7].

Efficacy Most patients experience significant symptom reductions and improvements in quality of life with behavior modification programs [7]. However, most do not gain complete control with behavior modification alone [7]. In an attempt to improve these results, some clinicians prescribe behavior modification with other nonpharmacological modalities, such as electrical stimulation, but this has not been shown in clinical studies to provide a significant improvement compared with behavior modification alone [7].

Combined Behavior Modification and Drug Therapy Some clinicians prescribe a combination of behavior modification and drug therapy (see Chapter 6 for a full discussion of pharmacological treatment options) because they believe that such inhibition of bladder activity makes it easier for the

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patient to control detrusor contraction, or alternatively because they feel that good bladder control is necessary to enable drugs to provide complete continence [7]. There have been a number of clinical trials of combined behavior modification and drug therapy, with some encouraging results, particularly in the areas of patient perception and satisfaction [7]. For example, a study in which 307 women with urgency-predominant incontinence were randomized to 10 weeks of open-label, extended-release tolterodine alone, or combined behavioral training followed by treatment discontinuation and follow-up at 8 months, showed that significantly more patients on combination therapy than drug therapy alone achieved ³70% reduction in incontinence at 10 weeks, at 69% versus 58%, respectively [9]. In addition, combination therapy patients achieved significantly better patient satisfaction and perceived improvement scores at both 10 weeks and 8 months than drug therapy alone. However, there were no differences in terms of health-related quality of life, or the rate of successful discontinuation of therapy at 8 months, which was 41% in both groups [9].

Acupuncture The goal of acupuncture for OAB is to reduce UI, frequency, and urgency, and the psychological distress of OAB [10]. To test the outcomes, 85 women who had OAB with urgency incontinence were randomized to either acupuncture treatment expected to improve bladder symptoms or placebo acupuncture designed to promote relaxation, with assessments performed at baseline and after 4-weekly acupuncture treatments. In the 74 women who completed the study, there was a nonsignificant difference in the reduction of incontinent episodes between active and placebo treatments [10]. However, women given OAB-directed acupuncture experienced significant improvements over placebo in urinary frequency, voids associated with urgency, maximum voided volume, and maximum cystometric capacity [10]. In addition,

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OAB acupuncture also led to significant improvements over placebo in terms of Urinary Distress Inventory and Incontinence Impact Questionnaire scores, at respective reductions of 57% and 52% with active treatments versus 32% and 23% with placebo [10].

References 1. MacDiarmid S, Rosenberg M (2005). Overactive bladder in women: symptom impact and treatment expectations. Curr Med Res Opin 21:1413–21. 2. Wein AJ (2003). Diagnosis and treatment of the overactive bladder. Urology 62:20–7. 3. Tubaro A, Palleschi G (2005). Overactive bladder: epidemiology and social impact. Curr Opin Obstet Gynecol 17:507–11. 4. Newman DK, Wein AJ (2009). Managing and Treating Urinary Incontinence, 2nd edn. Baltimore, MD: Health Professions Press. 5. Subak LL, Wing R, West DS, et al (2009). Weight loss to treat urinary incontinence in overweight and obese women. N Engl J Med 360: 481–90. 6. Kegel AH (1948). Progressive resistance exercise in the functional restoration of the perineal muscles. Am J Obstet Gynecol 56:238–49. 7. Burgio KL (2009). Behavioral treatment of urinary incontinence, voiding dysfunction, and overactive bladder. Obstet Gynecol Clin North Am 36:475–91. 8. Ostaszkiewicz J, Johnston L, Roe B (2009). Timed voiding for the management of urinary incontinence in adults. Cochrane Database System Rev (2):CD002802. 9. Burgio KL, Kraus SR, Menefee S, et al (2008). Behavioral therapy to enable women with urge incontinence to discontinue drug treatment: a randomized trial. Ann Intern Med 149:161–9. 10. Emmons SL, Otto L (2005). Acupuncture for overactive bladder: a randomized controlled trial. Obstet Gynecol 106:138–43.

Chapter 6 Pharmacological Treatment of Overactive Bladder

Choosing a Drug Therapy for Overactive Bladder Acceptable efficacy, documented in randomized controlled trials, has been demonstrated for the antimuscarinics tolterodine, trospium, solif-enacin, darifenacin, and fesoterodine, and drugs with mixed actions, oxybutynin and propiverine; all have been found to fulfill the criteria for level 1 evidence according to the Oxford assessment system and were given grade A recommendations by the International Continence Society (ICS). Antimuscarinic agents are, therefore, the cornerstone of medical treatment for overactive bladder (OAB) [1–4]. Antimuscarinic drugs reduce urgency urinary incontinence (UUI) episodes by 60–80%, compared with 35–40% with placebo. They reduce the frequency of urgency episodes by approximately 50% compared with 25% for placebo, and frequency over 24 hours by approximately 20% compared with 10–12% for placebo. Antimuscarinics do not improve OAB nocturia episodes to a clinically significant degree. Muscarinic receptors are not found exclusively in the urinary tract, but are also present in the brain (M1-, M3-, M4-, and M5-receptor subtypes), salivary glands (M1- and M3-receptor subtypes), heart (M2-receptor subtype), gastrointestinal smooth muscle (M2- and M3-receptor subtypes), and eyes (M3- and M5-receptor subtypes). This widespread distribution of muscarinic receptors within the body accounts for the A.J. Wein, C. Chapple, Overactive Bladder in Clinical Practice, DOI 10.1007/978-1-84628-831-9_6, © Springer-Verlag London Limited 2012

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commonly observed side effects of these agents, including cognitive problems, dry mouth, tachycardia, constipation, and blurred vision [5]. Antimuscarinic agents are contraindicated in patients with urinary retention, gastric retention, or untreated glaucoma [6]. As in all conditions, the choice of pharmacological therapy for the patient with OAB relies on a balance between efficacy and tolerability/ safety, and the cost of treatment. In the assessment of suitability of one drug over another for a particular patient, the clinician seeks advantages, or “edges.” These may be “real” edges, in which case the basis of distinction would be evidence based, or “theoretical” edges, which are valuable when real edges either do not exist or are disputed [7]. In the treatment of OAB with antimuscarinics, the possible theoretical edges include [7] the following: • the muscarinic receptor profile of the drug (ie, M1 + M2 + M3, M2 + M3, or relatively selective for M3) • uroselectivity (ie, for bladder over other cholinergically innervated organs) • half-life • dose titratability or flexibility • the potential for cognitive dysfunction, which is related to blood—brain barrier issues and receptor blockade profile • the potential for cardiac effects • the potential for drug—drug interactions • the urinary concentration of the pharmacologically active drug • pharmacological activity of metabolites. If these edges do not translate into real edges, either they do not exist or the proper studies have not been conducted [7]. It is likely that there is a continuum between theoretical and real edges, and each drug may have an edge profile that is more compatible with one patient type than another. It is up to the individual practitioner to decide on a “first choice” drug based on his or her assessment of an individual patient’s characteristics and a judgment as to the advantages/disadvantages of one agent over another in that particular patient.

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Overview of Key Drugs There are many antimuscarinic preparations available for the treatment of OAB; none is clearly more effective in all patients than the others and all can cause bothersome side effects [8]. Nevertheless there are a number of differences between these drugs, but whether this makes one more appropriate than another for the individual patient is inconclusive. In the final analysis, the clinician has to make a choice based on knowledge of the products available and an understanding of how individual patients may respond favorably or react badly to various product characteristics [8]. The following overview and Fig. 6.1 is based on the EMEA summaries of prescribing characteristics (SmPCs) for the drugs discussed. Physicians should refer to the full SmPC for detailed advice on prescribing these drugs, including contraindications.

Darifenacin Mechanism of Action Darifenacin is a relatively selective muscarinic M3-receptor antagonist (M3 SRA) in vitro. The M3-receptor is the major subtype that controls detrusor contraction, although outnumbered 3:1 by the M2-receptor. Cystometric studies performed with darifenacin in patients with involuntary bladder contractions showed increased bladder capacity, increased volume threshold for unstable contractions and diminished frequency of unstable detrusor contractions.

Licensed Indications Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in adult patients with overactive bladder syndrome.

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Treatment options for overactive bladder Drug

Available formulations

Recommended dosage*

Darifenacin (Esmelex®, Enablex®)

7.5 mg ER tablet

7.5–15 mg once daily

Fesoterodine (Toviaz®)

4 mg ER tablet

15 mg ER tablet 4–8 mg once daily

8 mg ER tablet Oxybutynin (Lyrinel®, Ditropan®, Kentera®, Oxytrol®, Gelnique®)

2.5 mg IR tablet 5 mg IR tablet 5 mg ER tablet 10 mg ER tablet Liquid

2.5–5 mg two to three times daily (IR); 5–30 mg once daily (ER); once patch applied twice weekly, providing 3.9 mg per day (transdermal patch); 1 g unit dose containing 100 mg oxybutynin applied once daily (gel)

Transdermal patch Topical gel (not currently available in europe) Propiverine (Detrunorn®, Detrunorm® Xl)

15 mg IR tablet 30 mg ER tablet

15 mg twice or three times daily (IR); 30 mg once daily (ER)

Solifenacin (Vesicare®)

5 mg ER tablet

5–10 mg once daily

10 ER mg tablet Tolterodine (Detrusitol®, Detrusitol® XL, Detrol®, Detrol® LA)

1 mg IR tablet 2 mg IR tablet

2 mg twice daily (IR); 4 mg once daily (ER)

2 mg ER tablet 4 mg ER tablet Trospium (Regurin®, Regurin® XL, Flotros®, Sanctura®, Sanctura® XR)

20 mg IR tablet 60 mg ER tablet

20 mg twice daily IR); 60 mg once daily (ER)

Figure 6.1 Treatment options for overactive bladder. IR, immediaterelease; SR, sustained-release. *Please refer to the main text and SmPCs for details on titration and special dosing considerations in different patient groups

Dosage The recommended starting dose is 7.5 mg daily. After 2 weeks of starting therapy, patients should be reassessed. For those patients requiring greater symptom relief, the dose may be increased to 15 mg daily, based on individual response. The tablets should be taken once daily with liquid. They can be taken with or without food, and must be swallowed whole and not chewed, divided or crushed.

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The recommended starting dose for the elderly is 7.5 mg daily. After 2 weeks of starting therapy, patients should be reassessed for efficacy and safety. For those patients who have an acceptable tolerability profile but require greater symptom relief, the dose may be increased to 15 mg daily, based on individual response. Darifenacin is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy. No dose adjustment is required in patients with impaired renal function. However, caution should be exercised when treating this population. Patients with moderate hepatic impairment should only be treated if the benefit outweighs the risk, and the dose should be restricted to 7.5 mg daily. Darifenacin is contraindicated in patients with severe hepatic impairment. In patients receiving substances that are potent CYP2D6 inhibitors, such as paroxetine, terbinafine, quinidine and cimetidine, or moderate CYP3A4 inhibitors, such as fluconazole, grapefruit juice and erythromycin, treatment should start with the 7.5 mg dose. The dose may be titrated to 15 mg daily to obtain an improved clinical response provided the dose is well tolerated. However, caution should be exercised.

Adverse Events The only very common adverse effects are dry mouth and constipation. Common adverse effects include nausea, dyspepsia, abdominal pain and headache.

Fesoterodine (Toviaz) Mechanism of Action Fesoterodine is a competitive, specific muscarinic receptor antagonist. It is rapidly and extensively hydrolyzed by nonspecific plasma esterases to the 5-hydroxymethyl derivative,

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its primary active metabolite, which is the main active pharmacological principle of fesoterodine.

Licensed Indications Treatment of the symptoms (increased urinary frequency and/or urgency and/or urgency incontinence) that may occur in patients with OAB.

Dosage The recommended starting dose in adults including the elderly is 4 mg once daily. Based upon individual response, the dose may be increased to 8 mg once daily. The maximum daily dose is 8 mg. Fesoterodine is not recommended for use in children and adolescents below 18 years of age due to lack of data on safety and efficacy. Tablets are to be taken once daily with liquid and swallowed whole. Fesoterodine can be administered with or without food. Fesoterodine is contraindicated in patients with severe hepatic impairment, or in patients with moderate hepatic impairment or moderate or severe renal impairment in the presence of potent CYP3A4 inhibitors. In subjects with normal renal and hepatic function receiving concomitant administration of potent CYP3A4 inhibitors, the maximum daily dose of fesoterodine should be 4 mg once daily. During concomitant administration of a moderate CYP3A4 inhibitor, a dose increase to 8 mg should be preceded by an evaluation of the individual response and tolerability.

Adverse Events The only very common adverse effect is dry mouth. Common adverse effects inclide dizziness, headache, dry eye, dry throat, abdominal pain, diarrhea, dyspepsia, constipation, nausea, dysuria, and insomnia.

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Oxybutynin Mechanism of Action Oxybutynin acts as a competitive antagonist of acetylcholine at post-ganglionic muscarinic receptors, resulting in relaxation of bladder smooth muscle. In patients with OAB characterized by detrusor overactivity, cystometric studies have demonstrated that oxybutynin increases maximum urinary bladder capacity and increases the volume to first detrusor contraction. Oxybutynin thus decreases urinary urgency and frequency of both incontinence episodes and voluntary urination.

Licensed Indications In adults, oxybutynin is indicated for the symptomatic treatment of urge incontinence and/or increased urinary frequency associated with urgency as may occur in patients with unstable bladder. In children it is indicated for the symptomatic treatment of detrusor overactivity secondary to a neurogenic condition.

Dosage Oxybutinin IR In adults the usual dose is 5 mg two or three times a day. This may be increased to a maximum of 5 mg four times a day to obtain a clinical response provided that the side effects are tolerated. In the elderly, a dose of 2.5 mg twice a day is likely to be adequate. Oxybutinin ER In adults, the recommended starting dose is one 5 mg tablet once daily. In order to achieve a maintenance dose giving an optimal balance of efficacy and tolerability, after at least 1 week on 5 mg daily, the dose may be increased to 10 mg once daily, with subsequent incremental increases or decreases of

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5 mg/day. There should be an interval of at least 1 week between dose changes and the total daily dose should not exceed 20 mg. In children over 6 years, the initial dose of 5 mg once a day can be increased in 5-mg increments up to a maximum of 15 mg once a day. Tablets must be swallowed whole with the aid of liquid, and must not be chewed, divided, or crushed. They may be administered with or without food. Oxybutynin Liquid In adults, the usual dose is 5 mg (10 mL) two or three times a day. This may be increased to a maximum of 5 mg four times a day to obtain a clinical response provided that the side effects are tolerated. In the elderly, a dose of 2.5 mg (5 mL) twice a day, particularly if the patient is frail, is likely to be adequate. This dose may be titrated upwards to 5 mg two times a day to obtain a clinical response provided the side effects are tolerated. In children (over 5 years of age) with neurogenic bladder, the usual dose is 2.5 mg (5 mL) twice a day. This dose may be titrated upward to 5 mg (10 mL) two or three times a day to obtain a clinical response provided that the side effects are tolerated. In children (over 5 years of age) with nocturnal enuresis, the usual dose is 2.5 mg (5 mL) twice a day. This dose may be titrated upwards to 5 mg (10 mL) two or three times a day to obtain a clinical response provided that the side effects are tolerated. The last dose should be given before bedtime. Transdermal Patch The patch should be applied to dry, intact skin on the abdomen, hip, or buttock immediately after removal from the protective sachet. A new application site should be selected with each new patch to avoid reapplication to the same site within 7 days. The recommended dose is one 3.9 mg transdermal patch applied twice weekly (every 3 to 4 days). There is no experience in children.

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Topical Gel The contents of one sachet should be applied once daily to dry, intact skin on the abdomen, upper arms/shoulders, or thighs. Application sites should be rotated. Application of oxybutynin topical gel should not be made to the same site on consecutive days.

Adverse Events As with other antimuscarinic agents, dry mouth is very common with oral forms of oxybutynin. Other common adverse effects of oxybutynin ER include urinary tract infection, upper respiratory tract infection, somnolence, headache, dry eyes, dry throat, and GI symptoms. For the transdermal patch, the only very common adverse effect is application site pruritis. Common adverse effects include urinary tract infection, blurred vision, dizziness, dry mouth, constipation, diarrhea, nausea, abdominal pain, application site erythema, application site reaction, application site rash, headache, and somnolence. For topical gel, there are no very common adverse effects. Common adverse effects include dry mouth, application site reactions (occasionally of severe intensity), dizziness, headache, constipation, pruritus, application site pruritus, and application site dermatitis.

Propiverine Mechanism of Action Propiverine inhibits calcium influx and modulation of intracellular calcium in urinary bladder smooth muscle cells in vitro, causing musculotropic spasmolysis and inhibition of the efferent connection of the nervus pelvicus due to anticholinergic action. In animal models propiverine hydrochloride causes a dose-dependent decrease of the intravesical pressure and an

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increase in bladder capacity. The effect is based on the sum of the pharmacological properties of propiverine and three active urinary metabolites as shown in isolated detrusor strips of human and animal origin.

Licensed Indications The treatment of urinary incontinence, as well as urgency and frequency in patients who have idiopathic detrusor overactivity (OAB).

Dosage As a standard dose in adults and the elderly, one 30-mg capsule once a day is recommended. Due to a lack of data, this product should not be used in children. There is no clinically relevant effect of food on the pharmacokinetics of propiverine. Accordingly, there is no particular recommendation for the intake of propiverine in relation to food.

Adverse Events The only very common adverse effect is dry mouth. Common adverse effects include abnormal vision and accommodation.

Solifenacin Mechanism of Action Solifenacin is a competitive cholinergic-receptor antagonist. Of the muscaranic receptors it acts predominantly on the M3receptor and displays low or no affinity for the nonmuscarinic receptors and ion channels tested.

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Licensed Indications Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in patients with OAB syndrome.

Dosage The recommended dose is 5 mg solifenacin succinate once daily. If needed, the dose may be increased to 10 mg solifenacin succinate once daily. Safety and effectiveness in children have not yet been established. Therefore, solifenacin should not be used in children. Patients with severe renal impairment or moderate to severe hepatic impairment should be treated with caution and receive no more than 5 mg once daily. In patients subjects with normal renal and hepatic function receiving concomitant therapeutic doses of ketoconazole or other potent CYP3A4 inhibitors, the maximum dose of solifenacin should be restricted to 5 mg.

Adverse Events The only very common adverse effect is dry mouth. Common adverse effects are constipation, nausea, dyspepsia, abdominal pain, and blurred vision.

Tolterodine Mechanism of Action Tolterodine is a competitive, specific muscarinic receptor antagonist with selectivity for the urinary bladder over salivary glands in vivo.

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Licensed Indications Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in patients with OAB syndrome.

Dosage The recommended dose is 4 mg once daily except in patients with impaired liver function or severely impaired renal function for whom the recommended dose is 2 mg once daily. In case of troublesome side effects the dose may be reduced from 4 mg to 2 mg once daily. Dosage should be reviewed after 2 or 3 months. The prolonged-release capsules can be taken with or without food and must be swallowed whole. Tolterodine is not recommended in patients receiving substances that are potent CYP3A4 inhibitors, such as erythromycin, clarithromycin, ketoconazole, itraconazole, and antiproteases, due to increased serum concentrations of tolterodine in poor CYP2D6 metabolizers and subsequent risk of overdosage. Tolterodine is not currently recommended for children.

Adverse Events The only very common adverse effect is dry mouth. Common adverse effects include sinusitis, dizziness, somnolence, headache, dry eyes, abnormal vision (including abnormal accomodation), dyspepsia, constipation, abdominal pain, flatulence, diarrhea, dysuria, fatigue, and peripheral edema. Night time dosing may be associated with a lower incidence of adverse effects, particularly dry mouth, while maintaining 24-hour efficacy [8].

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Trospium Mechanism of Action Trospium chloride is a quaternary amine derivative of nortropane and therefore belongs to the class of parasympatholytic or anticholinergic active drugs, as it competes concentrationdependently with acetyl—choline, the body’s endogenous transmitter at postsynaptic, parasym-pathic binding sites. Trospium chloride binds with high affinity to muscarinic receptors of the M1, M2 and M3 subtypes and demonstrates negligible affinity to nicotinic receptors. Consequently, the anticholinergic effect of trospium chloride exerts a relaxing action on smooth muscle tissue and organ functions mediated by muscarinic receptors. In both preclinical and clinical experiments, trospium chloride diminishes the contractile tone of smooth muscle in the gastrointestinal and genitourinary tract.

Licensed Indications Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in patients with OAB.

Dosage The dose in adults and the elderly is one extended-release capsule once daily (equivalent to 60 mg/day of trospium chloride) or 20 mg IR twice daily Trospium is not recommended for use in children and adolescents below 18 years due to lack of data on safety and efficacy. Trospium ER should be taken with water on an empty stomach 1 hour before a meal.

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ICI assessments: Oxford guidelines Levels of evidence Level 1:

Systematic reviews, meta-analyses, good quality randomized controlled clinical trials (rcts)

Level 2:

RCTs, good quality prospective cohort studies

Level 3:

Case–control studies, case series

Level 4:

Expert opinion

Grades of recommendation Grade A:

Based on level 1 evidence (highly recommended)

Grade B:

Consistent level 2 or 3 evidence (recommended)

Grade C:

Level 4 studies or “majority evidence” (optional)

Grade D:

Evidence inconsistent/inconclusive (no recommendation possible) or the evidence indicates that the drug should not be recommended

Figure 6.2 ICI assessments: Oxford guidelines. ICI, International Consultation on Incontinence. Reproduced with permission from Abrams et al. [9].

Data on the use of trospium ER are not available for patients with renal impairment or hepatic impairment and so these patients should be treated with caution.

Adverse Events The only very common adverse effect is dry mouth. Common adverse effects include dry eyes, dyspepsia, constipation, constipation aggravated, abdominal pain, abdominal distension, nausea, and nasal dryness.

Current Recommendations Clinical drug recommendations were made by the International Consultation on Incontinence (ICI) based on evaluations made using a modification of the Oxford system (Fig. 6.2), in which emphasis was given to the quality of the trials assessed (Fig. 6.3).

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Drugs used in the treatment of overactive bladder/detrusor overactivity Level of evidence

Grade of recommendation

Antimuscarinic drugs Tolterodine

1

A

Trospium

1

A

Solifenacin

1

A

Darifenacin

1

A

Fesoterodine

1

A

Propantheline

2

B

Atropine, hyoscyamine

3

C

Drugs acting on membrane channels Calcium antagonists

2

D

K+ channel openers

2

D

Oxybutynin

1

A

Propiverine

1

A

Flavoxate

2

D

Drugs with mixed actions

Antidepressants Imipramine

3

C

Duloxetine

2

C

Alfuzosin

3

C

Doxazosin

3

C

Prazosin

3

C

Terazosin

3

C

Tamsulosin

3

C

a-Adrenoceptor antagonists

Figure 6.3 Drugs used in the treatment of overactive bladder/ detrusor overactivity. Assessments according to the Oxford system (modified). *intrathecal; †intravesical; ‡bladder wall; §nocturia (nocturnal polyuria); caution hyponatremia, especially in elderly people. COX, cyclooxygenase; PDE, phosphodiesterase. Reproduced with permission from Andersson et al. [2].

Efficacy of Antimuscarinic Drug Therapy In a review of the evidence for antimuscarinic drugs versus nondrug active therapies for OAB, involving 13 trials with a total of 1770 participants and a treatment duration of

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Drugs used in the treatment of overactive bladder/detrusor overactivity (continued) Level of evidence

Grade of recommendation

b-Adrenoceptor antagonists Terbutaline (β2)

3

C

Salbutamol (β2)

3

C

YM-178 (β3)

2

B

2

B

Indomethacin

2

C

Flurbiprofen

2

C

Botulinum toxin (neurogenic)‡

2

A

Botulinum toxin (idiopathic)‡

3

B

Capsaicin (neurogenic)†

2

C

Resiniferatoxin (neurogenic)†

2

C

3

C

PDE-5 Inhibitors (Sildenafil, taladafil, vardenafil) COX inhibitors

Toxins

Other drugs Baclofen* Hormones Estrogen

2

C

Desmopressin§

1

A

Figure 6.3 (continued)

3–12 weeks, it was shown that patients treated with antimuscarinics were more likely to experience symptomatic improvements than those receiving bladder training, at a relative risk of 0.73 [10]. In addition, antimuscarinics combined with bladder training was associated with greater improvement than bladder training alone, at a relative risk of 0.55 [10]. Although anticholinergic therapy plus bladder training showed improvements over antimuscarinic therapy alone, the difference was not significant [10]. Rudy et al. [11] examined the time to onset in the improvement of OAB symptoms with antimuscarinic treatment in 658 patients with OAB randomized to placebo or trospium chloride 20 mg twice daily for 12 weeks. Compared with placebo, drug treatment had a significant onset of effect at 1 day

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for UUI episodes per day and for OAB symptom composite score, at a median of 3 days for urgency severity per void, 5 days for voids per day, and 6/7 days for volume per void [11]. The magnitudes of effect by 7 days were less than the 4- or 12-week end-of-study effects. The impact on UUI episodes per day with active treatment was 60%, compared with a 35% reduction with placebo [11]. The correlations between symptomatic improvement and health-related quality of life, as well as patient perception, were studied in 987 patients with OAB, urinary frequency, and UUI treated with tolterodine 4 mg extended release once daily or placebo for 12 weeks [12]. Patients treated with tolterodine experienced, compared with those given placebo, significantly greater reductions in UUI episodes per week, at −71% versus −33%; significantly greater improvement on the Patient Perception of Bladder Condition (PPBC) questionnaire, at 58% versus 45%; and significantly greater improvements in 7 of the 10 domains on the King’s Health Questionnaire (KHQ) [12]. Changes in scores on the PPBC and the seven improved KHQ domains were significantly correlated with median percentage changes in UUI episodes per week, although scores on PPBC and all KHQ domains were significantly correlated in patients taking tolterodine [12]. A study comparing fesoterodine ER and fesoterodine 4 mg and 8 mg with placebo [13] found that all doses were significantly better than placebo in improving the symptoms of OAB, with the mean number of micturitions per 24 hours being significantly reduced (−1.73, P=0.001 in fesoterodine ER; −1.76, P<0.001 in fesoterodine 4 mg; −1.88, P<0.001 in fesoterodine 8 mg). This 12-week study was followed up with an open label extension study [14] in which eligible subjects were given fesotero-dine 8mg over a 4 week period. After the initial 4 weeks, the subjects were given the option to reduce their dosage to 4 mg or maintain the 8 mg dose for up to 24 months. Of 341 subjects, 71% chose to maintain the 8mg dose and 61% continued treatment for the full duration of the study. Additionally, the study reported an overall treatment satisfaction rate of 84%, demonstrating that long-term

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use of the drug was well tolerated and associated with sustained improvements in OAB symptoms. The efficacy of solifenacin has also been examined. A trial in which 863 patients with OAB symptoms for ³3 months were randomized to solifenacin 5/10 mg or placebo for 16 weeks, showed that solifenacin treatment led to significantly greater reductions in the number of severe urgency episodes, with or without incontinence, per 24 hours, at −2.6 episodes versus −1.8 episodes for placebo, with the effect of solifenacin evident as early as day 3 [15]. Patients given drug treatment also experienced improvements in the average number of all urgency episodes and in maximum urgency intensity at 24 hours over those given placebo [15]. However, Wein et al. [16] warn that “dryness” rates (continence for 3–5 diary days) may not be a reliable measure of treatment efficacy. Their study of 1005 patients on an intention-to-treat (ITT) analysis and 772 patients on a per protocol (PP) analysis from 167 centers in Australia, Europe, and North America, randomized to tolterodine ER or placebo, showed that “total” dryness rates decreased with increasing diary duration and greater frequency of urinary incontinence at baseline [16]. The ITT population also had lower dryness rates than the PP population, although the average reductions in weekly urinary incontinence episodes were consistent across the populations [16]. Important, as well, is the comparison between the rates achieved with drug versus placebo. Another study comparing tolterodine 4 mg daily for 8 weeks with placebo in 743 women with urge-predominant mixed urinary incontinence found that, during trials, patients can become “unblinded” to their randomization, with an impact on outcomes [17]. Tolterodine significantly reduced the number of UUI episodes per day compared with placebo, at 78% versus 51%, respectively [17]. However, a substantial proportion of patients correctly identified their treatment, at 58% and 37%, respectively [17]. The effectiveness of tolterodine over placebo was lower among those who assumed that they were receiving the drug than in those who assumed that they were given placebo, at differences in the reductions in urgency episodes per day of −10.94 and −20.73, respectively,

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although the absolute efficacy of tolterodine was higher in those who assumed that they were given the drug than in those who assumed that they were given placebo, at reductions in urgency episodes of 88.9% and 30.7%, respectively [17]. Moderate-to-severe dry mouth was more common in women who assumed that they had been given tolterodine than those who thought that they had placebo, at 7.3% versus 0.0% [17]. Interestingly, the improvement in the KHQ domains of emotions, severe measures, and severity of urgency incontinence among women treated with tolterodine was significantly and substantially greater among those who assumed that they had been given the drug compared with those who received placebo [17]. Oxybutynin is an antimuscarinic drug that has been in use orally for over 20 years and is now available as a transdermal patch. In phase 3 trials, transdermal oxybutynin 3.9 mg/day reduced incontinence episodes by 75% compared with a 50% reduction in patients using a placebo patch. Urinary frequency decreased by 18% with transdermal oxybutynin compared with 8.7% with placebo (P=0.0023). Urinary voided volume increased by 15% with transdermal oxybutynin versus 3.6% with placebo (P<0.00001) [18]. When transdermal oxybutynin was compared with oral tolterodine long-acting formulation and placebo, mean daily urge incontinence episodes decreased, as did frequency [19]. Well-designed studies that compare the therapies for OAB head-to-head are somewhat scarce, but two recent studies, Fesoterodine Assessment and Comparison Versus Tolterodine (FACT) 1 and 2 [20,21], have demonstrated the superiority of fesoterodine 8 mg over tolterodine ER 4 mg in treating patients with OAB. In both of these head-to-head, randomized, placebo controlled studies, use of fesoterodine 8 mg proved to be more effective in reducing UUI episodes, as well as decreasing the number of micturitions, urgency episodes, severe urgency episodes and frequency-urgency sum. Notably, a 70% three-day diary dry rate was observed with fesoterodine in FACT 1. Accordingly, symptom bother and total HRQL (health-related quality of life) in subjects assigned to fesoterodine 8 mg showed significant improvement when compared with tolterodine ER

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4 mg. Marked improvements in OAB symptoms and HRQL measures were sustained throughout the full 24 months of the open-label studies.

Long-Term Tolerability and Compliance with Antimuscarinic Drug Therapy OAB is a chronic condition that usually requires long-term treatment to maintain control of symptoms; adherence to treatment is key. Methods of assessing adherence include patient self-report (via informal interview/ note taking or structured questionnaire), review of pharmacy claims, counting/weighing of unused medication, electronic packaging monitors, and biological assays [22]. These options offer varying degrees of accuracy and practicability. In spite of the fact that antimuscarinic therapy for patients with OAB is generally acknowledged to lessen symptoms and problems, improve quality of life, and have a wide margin of tolerability and safety, persistence rates (chronic continuation) are poor. Retrospective database studies of prescription refills estimate persistence rates as low as 5–22% with a generally acknowledged figure of no more than 20–35% within 6–12 months [23,24]. There are a number of possible factors behind therapy discontinuation or failure to take the therapy as directed [22]. Unmet efficacy expectations, side effects, and a combination of the two are cited as the most important causative factors [25]. An inconvenient dosage schedule or mode of delivery can affect compliance, and inadequate support and follow-up, and cultural attitudes to illness and treatment, can also be factors. Finally, cost (willingness to pay) doubtless plays a role in countries where prescription benefits are suboptimal or where initial choices are limited to agents with a higher adverse-event profile. In one study of 2496 patients with chronic OAB/urinary incontinence in California, compliance with antimuscarinic therapy at 6 months was 22.2%, falling to 11.4% at 12 months [26]. The median time to discontinuation of therapy

Long-Term Tolerability and Compliance

103

was 50 days, and 42.7% discontinued treatment after just 30 days [26]. Analysis revealed that factors linked to compliance were white ethnicity, length of previous hospitalization, beginning therapy with tolterodine or oxybutynin extendedrelease formulations, and previous use of topical drugs or antipsychotics, although discontinuation was linked to previous depression or lower urinary tract infection, and polypharmacy [26]. Treatment discontinuation increased the risk of a urinary tract infection by 37% [26]. A pharmacy claims study in 1117 managed care patients with OAB [24] focused on persistence with antimuscarinic therapy, switch rates between drugs, and adherence rates. In this study population, only 13.2% of patients persisted for 12 months of therapy with the initial antimus-carinic drug. This study, seemingly representative of patient behavior in realworld populations, highlights the compliance issues with these drugs. The authors concluded that these results underline the need for medication counseling in patients with OAB. Discontinuation rates in clinical trials are much lower, and rates estimated from these and from populations electing to continue or institute therapy at the termination of a study are, in the authors’ opinion, quite unrealistic and not representative of a “real-world” situation. The discrepancy between short-term clinical effectiveness (efficacy, toler-ability, and safety) and long-term persistence is puzzling. The authors believe that a partial answer may lie in better patient education about the nature and natural history of the condition, more realistic expectations regarding positive treatment results and side effects, and more enthusiastic and forceful instruction and encouragement about the value of a simultaneous self-help regimen program which is, in reality, a program of behavioral modification. With the development of novel drug delivery systems, and the availability of sustained-release formulations for the convenience of once-daily or twice-weekly dosing regimens of antimuscarinic agents, patient compliance should be improved and give further relief for the symptoms of OAB. Clinical studies with the sustained-release formulations demonstrated potential

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clinical advantages over their respective immediate-release formulations in terms of either efficacy or tolerability, or both, although the therapeutic index of sustained-release tolterodine seems to demonstrate a greater advantage over its immediaterelease counterpart compared with oxybutynin [27]. In a study with transdermal oxybutynin, the most common adverse events with the oxybutynin transdermal delivery system included local skin irritation such as erythema (5.6%) and pruritis (16.8%) [18]. There was no significant difference in anticholinergic side effects in the transdermal oxybutynin compared with patients using a placebo patch, with respect to dry mouth, constipation, dizziness, abnormal vision, somnolence, and nausea [18]. The rates of discontinuation due to adverse events were 11.2% versus 1.2% in the oxybutynin transdermal group versus the placebo group, respectively.

Patient-Perceived Outcomes with Antimuscarinic Drug Therapy Along with behavioral modification, pharmacotherapy with antimus-carinic agents forms the basis of therapy for the initial treatment of OAB. To better understand the overall benefits of OAB treatment, it is critical that randomized controlled trials, particularly head-to-head comparator trials, should include health-related quality-of-life (HRQoL) assessments using validated instruments, including for example the Incontinence Impact Questionnaire (IIQ) [28], KHQ [29], and Medical Outcomes Study Short Form-36 (SF-36 [30]), to assess HRQoL and relate any improvements in HRQoL to changes in OAB symptoms. The use of such measures in clinical practice has already shown that effective OAB treatment can lead to an increase in HRQoL benefits [31–36]. In a meta-analysis by Chapple et al. [3,4], the effects of antimus-carinics for OAB and detrusor overactivity on patients’ HRQoL were assessed using instruments such as the IIQ, KHQ, and SF-36, among others. The antimuscarinics were found to be both safe and efficacious in the trials that

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were included, and generally showed significant differences in HRQoL compared with placebo. More importantly, the data revealed that antimuscarinics improved several areas of HRQoL, including physical activities, sleep and energy, emotions, and relationships (Fig. 6.4), and that these improvements are likely to be clinically meaningful. Future studies should emphasize the need to incorporate patient-perceived outcomes while including existing tools to assess bother and HRQoL. In particular, four areas require additional research: 1. New and recently licensed products should be assessed in head-to-head trials with comparator agents and the most relevant established interventions (including adjunctive bladder retraining or biofeedback). 2. Study design should include outcome measures that are more meaningful to patients, such as return to bladder control, achievement of normal micturition frequency, and quality of life. 3. Variation in persistence rates between the drugs needs to be evaluated. 4. More studies of the effects of antimuscarinics are required in older patients. The need for studies to assess the interrelationships of improvements in HRQoL, improvements in OAB symptoms, and the minimally important difference (ie, the smallest change between two scores that is subjectively meaningful to patients) is vital.

Intradetrusor Botulinum Toxin Injection Therapy Botulinum toxin is a presynaptic neuromuscular-blocking agent, inducing selective and reversible muscle weakness for up to several months when injected intramuscularly in small amounts. There is evidence suggesting it acts on the afferent side as well.

Relationships

Self-image Emotions

Daily activities Physical limitations Travel Sleep and energy

Global HRQoL domains Overall HRQoL

Contilife: overall HRQoL IIQ: overall HRQoL ICIQ-SP: overall score KHQ: overall score KHQ: general health OAB-q: overall HRQL PISQ: overall score SQOl-F: overall score Contilife: daily activities KHQ: physical limitations IIQ: travel KHQ: sleep and energy OAB-q: sleep Basle: tired-fresh Contilife: self-image Contilife: emotional consequences OAB-q: concern KHQ: emotional problems HAD: anxiety IIQ: feelings IIQ: relationships KHQ: role limitations KHQ: personal relationships

Significant impact reported for: Solifenacin Oxybutynin TDS; tolterodine ER; trospium Fesoterodine; tolterodine ER Oxybutynin IR; propiverine ER, IR Solifenacin; propiverine Darifenacin; tolterodine ER; solifenacin Tolterodine ER Tolterodine ER Solifenacin; tolterodine ER Tolterodine IR, ER; darifenacin; solifenacin; propiverine Oxybutynin TDS; tolterodine ER; trospium Tolterodine IR, ER; solifenacin; propiverine Solifenacin Propiverine IR Solifenacin Solifenacin Tolterodine ER; solifenacin Tolterodine IR, ER; solifenacin; propiverine Tolterodine ER Trospium Trospium Tolterodine IR, ER; darifenacin; solifenacin; propiverine Tolterodine ER; solifenacin; propiverine

Summary of the effects of antimuscarinics on health-related quality-of-life

106 Chapter 6. Pharmacological Treatment

KHQ: symptom severity OAB-q: bother UDI: irritative symptoms OAB-q: symptom bother KHQ: incontinence impact GAQ: stress score UDAAQ: warning time UDAAQ: leakage GAQ: urge score

Contilife: sexuality KHQ: social limitations Basle: tacitum–talkative Basle: retiring–gregarious OAB-q: social interaction KhQ: severity (coping) OAB-q: coping Tolterodine IR, ER; darifenacin; solifenacin; propiverine Solifenacin Oxybutynin TDS; tolterodine ER Tolterodine ER Tolterodine IR, ER; darifenacin; solifenacin; propiverine Propiverine IR Darifenacin Darifenacin Propiverine IR

Solifenacin Tolterodine ER; solifenacin; propiverine Propiverine IR Propiverine IR Tolterodine ER Tolterodine IR, ER Tolterodine ER; solifenacin

Figure 6.4 Summary of the effects of antimuscarinics on health-related quality-of-life. All are significant differences between antimuscarinics and placebo reported in included trials. Basle, Basle Subjective Weil-Being Survey; Contilife, Quality of Life Assessment Questionnaire Concern ing Urinary Incontinence; ER, extended release; GAQ, Gaudenz Appraisal Questionnaire; HAD, Hospital Anxiety Depression Scale Questionnaire; HRQoL, health-related quality of life; ICIQ-SF. International Consultation on Incontinence Questionnaire-Short Form; IIQ, Incontinence Impact Questionnaire; IR, immediate release; KHQ, King’s Health Questionaire; OAB-q, Overactive Bladder Questionnaire; PISQ, Pelvic Organ Prolapse/Urinary Incontinence Questionnaire; SQOL-F, Sexual Quality of Life-Female; UDAAQ, Urinary Daily Activity Assesment Questionnaire; UDI, Urinary Distress Inventory. Reproduced with permission from Chappie et al. [4].

Urgency

Incontinence

Disease-specific domains Symptom severity

Coping

Sexuality Social limitations

Intradetrusor Botulinum Toxin Injection Therapy 107

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The toxin, usually of the A subtype (although there is a little work with the B subtype), has been used in a number of areas of medicine. Injections of botulinum toxin A into the detrusor muscle were first reported by Schurch and co-workers to treat neurogenic detrusor overactivity in patients with spinal cord injuries and in children with myelomeningocele [37,38]. Although the data on many of the indications for the use of this therapy remain preliminary, there is a rapidly accruing evidence base. Initial therapy with botulinum toxin A injection therapy has been used for neurogenic detrusor overactivity (injection into the detrusor) and detrusor—sphincter dyssynergia (injection into the striated sphincter). A retrospective European multicenter study from 10 sites of 231 patients has presented some of the most extensive experience to date with botulinum toxin A injections into the detrusor muscle to treat neurogenic incontinence due to detrusor overactivity [39]. This study has confirmed that this new treatment is a safe and valuable addition to the therapeutic armamentarium, with a significant improvement in bladder function corresponding to improvements in continence and the subjective improvement experienced by the treated patients; 300 units botulinum toxin A were injected cystoscopically into the detrusor muscle at 30 different locations, while sparing the trigone. By the time of the initial (mean 12 weeks after injection) as well as at the second urodynamic follow-up examinations (mean 36 weeks after injection), the mean cystometric bladder capacity (P<0.0001) and the mean reflex volume (P<0.01) increased significantly, although the mean voiding pressure (P<0.0001) decreased significantly [39]. The mean bladder compliance had increased significantly (P<0.0001) by the first follow-up examination and nonsignificantly by the time of the second follow-up [39]. No injection-related complications or toxin-related side effects were reported. The patients considerably reduced their intake or even stopped taking anticholinergic drugs and were satisfied with the treatment. A subsequent placebo-controlled study has investigated the safety and efficacy of each of two doses of botulinum

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toxin A (200 or 300 units) injected into the detrusor for urinary incontinence caused by neurogenic detrusor overactivity of predominantly spinal cord origin [40]. There were significant post-treatment decreases in incontinence episodes from baseline in the two botulinum toxin A groups (P<0.05) but not in the placebo group [40]. In addition, more patients who received botu-linum toxin A reported no incontinence episodes during at least one post-treatment evaluation period. Positive treatment effects were also reflected by significant improvements in bladder function in the botulinum toxin A groups, as assessed by urodynamics and patient quality of life. Benefits were observed from the first evaluation at week 2 to the end of the 24-week study [40]. No safety concerns were raised. These authors were able to conclude that intramuscular injections of botulinum toxin A into the detrusor can provide rapid, well-tolerated, clinically significant decreases in the signs and symptoms of urinary incontinence caused by neurogenic detrusor overactivity during a 24-week study period [40]. The excellent results of the use of botulinum toxin A injections into the detrusor in neurogenic detrusor overactivity have subsequently led to an expansion of therapeutic indications for this therapy to include the treatment of incontinence resulting from idiopathic detrusor overactivity causing OAB. The European Association of Urology recommends the use of botu-linum toxin A for the intractable symptoms of neurogenic or idiopathic detrusor overactivity in adults. Due to the risk of voiding difficulty, and as the duration of effect has not been accurately evaluated, caution is recommended in idiopathic detrusor overactivity. In neurogenic detru-sor overactivity, repeated treatment is recommended, and the depth and location for bladder injections should be within the detrusor muscle outside the trigone [41]. Although preliminary results have been promising, the most appropriate dosage of the toxin, the dilution at which it should be administered, and its precise site of injection, in terms of both the depth of injection in the bladder wall and the anatomical location in the bladder, remain to be adequately

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established. Preliminary reports in abstract form have suggested that lower doses of botulinum toxin A may be just as effective as those reported to date and, possibly, lower doses may be just as effective in non-neurogenic cases. This therapy should be used only after careful assessment of patients, because its use is still investigational. Clearly, patients who respond will require repeated injections over the years. They should be warned of the transient adverse events associated with injection therapy (urinary infection, hematuria) and, in particular, the risk of retention, which will require the installation of intermittent self-catheterization in up to 20% of cases. Although botulinum toxin is a successful and standard treatment in other areas of medicine, clinical experience with this technique in bladder overactivity remains small at present, but may be of significant future value in the management of idiopathic bladder overactivity and OAB cases resistant to pharmacotherapy, following on from the reported experience in neurogenic overactivity. There is great interest in this therapeutic modality at present, and a number of case studies are being reported. For the future, controlled trials are absolutely essential to clearly establish the potential role of botulinum toxin A injections in the fields of urology and neurology.

References 1. Andersson KE (2004). Antimuscarinics for treatment of overactive bladder. Lancet Neurol 3:46–53. 2. Andersson KE, Chapple CR, Cardozo L et al (2009). Pharmacological treatment of overactive bladder: report from the International Consultation on Incontinence. Curr Opin Urol 19:380–94. 3. Chapple C, Khullar V, Gabriel Z, et al (2005). The effects of antimuscarinic treatments in overactive bladder: a systematic review and meta-analysis. Eur Urol 48:5–26. 4. Chapple CR, Khullar V, Gabriel Z, et al (2008). The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur Urol 54:543–62. 5. Burgio KL, Locher JL, Goode PS, et al (1998). Behavioral vs drug treatment for urge urinary incontinence in older women: a randomized controlled trial. JAMA 280:1995–2000.

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6. Drutz HP, Appell RA, Gleason D, et al (1999). Clinical efficacy and safety of tolterodine compared to oxybutynin and placebo in patients with overactive bladder. Int Urogynecol J Pelvic Floor Dysfunct 10:283–9. 7. Wein AJ, Rackley RR (2006). Overactive bladder: a better understanding of pathophysiology, diagnosis and management. J Urol 175:S5–10. 8. Newman DK, Wein AJ (2009). Managing and Treating Urinary Incontinence, 2nd ed. 2009; Health professions Press. 9. Abrams P, Khoury S, Grant A (2007). Evidence-based medicine overview of the main steps for developing and grading guideline recommendations. Prog Urol 17:681. 10. Alhasso AA, McKinlay J, Patrick K, Stewart L (2006). Anticholinergic drugs versus non-drug active therapies for overactive bladder syndrome in adults. Cochrane Database System Rev (4):CD003193. 11. Rudy D, Cline K, Harris R, et al (2006). Time to onset of improvement in symptoms of overactive bladder using antimuscarinic treatment. BJU Int 97:540–6. 12. van Kerrebroeck PE, Kelleher CJ, Coyne KS, et al (2009). Correlations among improvements in urgency urinary incontinence, healthrelated quality of life, and perception of bladder-related problems in incontinent subjects with overactive bladder treated with tolterodine or placebo. Health Qual Life Outcomes 7:13. 13. Chapple C, van Kerrebroeck P, Tubaro A et al (2007). Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol 52:1204–12. 14. van Kerrebroeck PE, Heesakkers J, Berriman S, et al (2010). Longterm safety, tolerability and efficacy of fesoterodine treatment in subjects with overactive bladder symptoms. Int J Clin Pract 64:584–93. 15. Cardozo L, Hessdörfer E, Milani R, et al (2008). Solifenacin in the treatment of urgency and othersymptoms of overactive bladder: results from a randomized, double-blind, placebo-controlled, risingdose trial. BJU Int 102:1120–7. 16. Wein AJ, Khullar V, Wang JT, Guan Z (2007). Achieving continence with antimuscarinic therapy for overactive bladder: effects of baseline incontinence severity and bladder diary duration. BJU Int 99:360–3. 17. DuBeau CE, Khullar V, Versi E (2005). “Unblinding” in randomized controlled drug trials for urinary incontinence: Implications for assessing outcomes when adverse effects are evident. Neurourol Urodyn 24:13–20. 18. Dmochowski RR, Nitti V, Staskin D, et al (2005). Transdermal oxybutynin in the treatment of adults with overactive bladder: combined results of two randomized clinical trials. World J Urol 23:263–70.

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19. Dmochowski RR, Sand PK, Zinner NR, et al (2003). Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine versus placebo in previously treated patients with urge and mixed urinary incontinence. Urology 62:237–42. 20. Herschorn S, Swift S, Guan Z, et al (2010). Comparison of fesoterodine and tolterodine extended release for the treatment of overactive bladder: a head-to-head placebo-controlled trial. BJU Int 105: 58–66. 21. Kaplan SA, Schneider T, Foote JE, Guan Z, Carlsson M, Gong J (2011). Superior efficacy of fesoterodine over tolterodine extended release with rapid onset: a prospective, head-to-head, placebocontrolled trial. BJU Int 107:1432–40. 22. Basra RK, Wagg A, Chapple C, et al (2008). A review of adherence to drug therapy in patients with overactive bladder. BJU Int 102:774–9. 23. Shaya FT, Blume S, Gu A, et al (2005). Persistence overactive bladder pharmacotherapy in a Medicaid population. Am J Manag Care 11:s121–9. 24. D’Souza AO, Smith MJ, Miller LA, Doyle J, Ariely RJ (2008). Persistence, adherence, and switch rates among extended-release and immediate-release overactive bladder medications in a regional managed care plan. Manag Care Pharm 14:291–301. 25. Benner JS, Nichol MB, Rovner ES, et al (2009). Patient reported reasons for discontinuing overactive bladder medication. BJU Int 105:1276–82. 26. Yu YF, Nichol MB, Yu AP, Ahn J (2005). Persistence and adherence of medications for chronic overactive bladder/urinary incontinence in the California Medicaid program. Value Health 8:495–505. 27. Weese DL, Roskamp DA, Leach GE, et al (1993). Intravesical oxybutynin chloride: experience with 42 patients. Urology 41:527–30. 28. Uebersax JS, Wyman JF, Shumaker SA, et al (1995). Short forms to assess life quality and symptom distress for urinary incontinence in women: the Incontinence Impact Questionnaire and the Urogenital Distress Inventory. Neurourol Urodyn 14:131–9. 29. Kelleher CJ, Cardozo LD, Khullar V, et al (1997). A new questionnaire to assess the quality of life of urinary incontinent women. Br J Obstet Gynaecol 104:1374–9. 30. Ware JE Jr, Sherbourne CD (1992). The MOS 36-item short-form health survey (SF-36). i. Conceptual framework and item selection. Med Care 30:473–83. 31. Ushiroyama T, Ikeda A, Ueki M (2000). Clinical efficacy of clenbuterol and propiverine in menopausal women with urinary incontinence: improvement in quality of life. J Med 31:311–319. 32. Burgio KL, Locher JL, Roth DL, et al (2001). Psychological improvements associated with behavioral and drug treatment of urge incontinence in older women. J Gerontol B Psychol Sci SocSci 56:46–51.

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33. Kelleher CJ, Reese PR, Pleil AM, et al (2002). Health-related quality of life of patients receiving extended-release tolterodine for overactive bladder. Am J Manag Care 8:S608–615. 34. Kelleher CJ, Cardozo L, Chapple CR, et al (2005). Improved quality of life in patients with overactive bladder symptoms treated with solifenacin. BJU Int 95:81–5. 35. Homma Y, Kawabe K (2004). Health-related quality of life of Japanese patients with overactive bladder treated with extendedrelease tolterodine or immediate-release oxybutynin: a randomized, placebo-controlled trial. World J Urol 22:251–6. 36. Zinner N, Gittelman M, Harris R, et al (2004). Trospium chloride improves overactive bladder symptoms: a multicenter phase III trial. J Urol 171:2311–5. 37. Schurch B, Stöhrer M, Kramer G, et al (2000). Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results. J Urol 164:692–7. 38. Elliott S P, Meng Mv, Anwar H P, et al (2002). Complete laparoscopic ileal cystoplasty. Urology 59:939–943. 39. Reitz A, Stohrer M, Kramer G, et al (2004). European experience of 200 cases treated with botulinum-A toxin injections into the detrusor muscle for urinary incontinence due to neurogenic detrusor overactivity. Eur Urol 45:510–5. 40. Schurch B, de Seze M, Denys P et al (2005). Botox Detrusor Hyperreflexia Study Team. Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study. J Urol174:196–200. 41. Apostolidis A, Dasgupta P, Denys P, et al (2009). Recommendations on the use of botulinum toxin in the treatment of lower urinary tract disorders and pelvic floor dysfunctions: a European consensus report. Eur Urol 55:100–19.

Chapter 7 Neuromodulation and Surgical Approaches

Surgery for Overactive Bladder Surgery remains the last resort in the management of overactive bladder (OAB) resulting from detrusor overactivity because of its associated risks and complications, including retention and the consequences of incorporating bowel segments into the urinary tract (ie, production of mucus, electrolyte imbalance, and potential for malignant change). Careful evaluation and specialist assessment, including urodynamic evaluation, is required before surgical intervention. Surgical management is reserved for severe cases of urgency incontinence that are refractory to conservative treatment. Surgery for detrusor overactivity should be reserved only for patients for whom all conservative treatment modalities have failed, as all surgical procedures bring with them associated risks and complications. The functional objective of surgery is to increase the functional bladder capacity and decrease the maximal end-filling detrusor pressure. The latter would help to increase bladder compliance and prevent incontinence in patients with neuropathic bladders, and thereby confer protection to the upper tracts as well. Numerous surgical approaches have been used to manage unwanted neuropathic and idiopathic bladder overactivity and thereby increase bladder capacity using the techniques of neuromodulation, and augmentation cystoplasty.

A.J. Wein, C. Chapple, Overactive Bladder in Clinical Practice, DOI 10.1007/978-1-84628-831-9_7, © Springer-Verlag London Limited 2012

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Cystoplasty involves remodeling of the bladder in order to disrupt its ability to contract and to increase its physical and functional capacity. In contrast, electrical stimulation of the bladder’s nerve supply, commonly termed “neuromodulation,” aims to suppress the reflexes responsible for causing involuntary bladder contractions. Preoperatively, patients should be counseled about the outcomes of operation, especially about voiding difficulty and the potential use of intermittent selfcatheterization. Numerous approaches have been used to try to overcome unwanted bladder contractions in both the idiopathic and the neuropathic populations. Many innovative procedures have enjoyed temporary popularity, but then fallen into disuse as unacceptable complications and long-term results emerged. The denervation procedures that have been utilized in the past are relatively ineffective and are not recommended for clinical use. Among the historical footnotes at the present time are bladder transection, prolonged bladder distension, transtrigonal phenol injection therapy, and selective sacral neurectomy. Another option is to completely bypass the bladder as a last resort (ie, a supravesical diversion).

Augmentation Cystoplasty The principle underlying an augmentation cystoplasty is that, by bivalving a functionally overactive bladder and introducing a segment of intestine, it is possible to produce a bladder with an increased functional capacity and a lower end-filling pressure. Early attempts with a simple patch or cup augmentation enterocystoplasty resulted in a diverticulum. The “clam” technique, which almost completely bisects the bladder, was designed to avoid this problem [1]. The original technique [2] has not been surpassed and is still in use today. The major elements of the procedure can be seen in Fig. 7.1. The bladder is almost completely bivalved in the coronal plane, with an incision on each side carrying to

Urethra

Figure 7.1 Bladder augmentation using a bowel segment

Detubularized bowel

Bladder augmentation using a bowel segment

Bladder wall

New bladder wall

Surgery for Overactive Bladder 117

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within 1.5 cm of the internal urethral meatus in order to deactivate the unstable detrusor muscle. At this point the bladder has the appearance of an open clam, which is how the procedure got its name. A length of pre-terminal ileum of the appropriate size is isolated with its blood supply intact and detubularized by incising the antimesenteric border. This patch is then sutured into the bladder with a single layer of continuous Vicryl [1] The two most commonly used intestinal segments are ileum and sigmoid. The sigmoid is usually used in patients where a short small bowel mesentery renders the procedure difficult, but it has been suggested that ileum is preferable in that it produces lower reservoir pressures and better compliance. Colon is not used because it has a greater risk of malignant change [1]. Modifications to the clam method include opening the bladder in the sagittal plain, which appears equally effective, and opening the bladder as a “star.” Most workers find coronal or sagittal bivalving of the bladder to be effective and acceptable provided that adequate opening of the bladder is performed right down to the ureteral orifices, both to adequately open the bladder and also to prevent “diverticulation” of the cystoplasty segment. There have been recent reports of successful laparoscopic enterocystoplasty. This remains the province of the enthusiastic pioneer at present [3]. It must be remembered that this is major surgery and, despite adequate preoperative counseling, many patients take some months to adapt to their new bladder and learn to void effectively by abdominal straining. It is important to check on postoperative residuals, and intermittent self-catheterization is necessary for a number of these patients, particularly those with neurogenic bladder dysfunction. It is of interest to review the reported incidences of intermittent self-catheterization, the requirement for which varies from 15% to 85% of cases. Other problems encountered with augmentation cystoplasty include difficulty in voiding, mucus production, infections, and metabolic disorders, which are usually mild and

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subclinical. Persistent urinary infection can be troublesome, particularly in female patients, and it has been reported to occur in up to 30% of cases, with the need for long-term antibiotic therapy in a number of these. There can be a bowel disturbance with increased frequency and looseness of bowel actions, and a tendency to episodes of incontinence, which occurs in up to a third of patients. Bowel dysfunction after augmentation cystoplasty is thought to be related to the interruption of the normal enterohepatic circulation. Bladder perforations do occur in up to 10% of patients in reported series (mostly in patients on intermittent catheterization). At present, lifelong follow-up of these patients is recommended not only because of the above complications, but also in view of the suggestion that augmentation cystoplasty predisposes to the subsequent development of malignancy [4]. Tissue engineering technology may well prove to be useful in developing viable alternatives to the currently used bowel segments [5]. At present, these techniques remain experimental. However, initial laboratory studies have shown that it is realistic to believe that such technology holds genuine potential for future advances in the field of reconstructive urology.

Autoaugmentation The principle of this surgical technique is that the detrusor muscle over the entire dome of the bladder is excised, leaving the underlying bladder urothelium intact. A large epithelial “bulge” or wide-mouthed diverticulum is created, which functions by augmenting the storage capacity of the bladder, referred to as autoaugmentation. After excision of the dome detrusor muscle the lateral margins of the detrusor are fixed bilaterally to the psoas muscles. At present, although autoaugmentation has a number of attractive features to recommend it, it is clear that the increase in bladder capacity and reduction in detrusor overactivity that result from this procedure are far less pronounced than that achieved with an augmentation cystoplasty.

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The number of cases reported in the literature is small, with short-term follow-up. Although the definite advantage of this technique is the lower incidence of morbidity compared with conventional augmentation cystoplasty, the question must be posed as to whether this is adequately counterbalanced by the limited efficacy of the procedure and the possibility that the response achieved may not be maintained in the longer term. Although a definite advantage of this procedure is the fact that it is less interventional than augmentation cystoplasty, with a lower morbidity, the search for less invasive techniques has led to widespread acceptance of both sacral neuromodulation and botulinum toxin injection therapy, providing the opportunity for an organ-preserving and reversible treatment option to standard augmentation cystoplasty.

Sacral Neuromodulation The principle of sacral neuromodulation is to directly stimulate the sacral plexus, usually the S3 nerve root. The unit consists of a small device surgically implanted in the buttocks. The device stimulates the appropriate nerves by using mild or moderate electrical impulses. For patients with OAB this involves a three-stage process of acute stimulation, peripheral nerve evaluation (PNE) with a temporary electrode, and finally a permanent implant. The first implant for human sacral nerve stimulation was performed in 1986 by Tanagho and Schmidt [6], through research into sacral anterior root stimulation in patients with severe neuropathic voiding problems. Since then, a number of conditions refractory to conservative therapy have been treated by neuromodulation, with varying degrees of success. These include motor and sensory detrusor dysfunction, chronic retention in women, and pelvic pain, but treatment of detrusor overactivity has been the most widely studied. The exact mechanism of action of this therapy is, as yet, poorly defined in view of our relative lack of knowledge

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relating to the exact neurological control of the lower urinary tract, but theories include modulation of brain networks and/ or spinal cord reflexes via somatic sensory afferent fibers [7]. It is well established that efferent and afferent autonomic and synaptic pathways are interlinked to provide coordinated storage and voiding of urine in conjunction with central nervous control. A likely explanation is that stimulation of the sacral plexus results in afferent stimulation reflexly inhibiting the bladder. An alternative secondary mode of action is that electrical stimulation of the sacral nerve results in contraction of the pelvic floor, which further contributes to the afferent feedback [7]. The phenomenon of longer-lasting effects, and the use of the same modality for some cases of idiopathic urinary retention, serve to emphasize that there are a number of aspects of the mechanism of action of this therapy that still remain obscure, no doubt reflecting our limited knowledge in this field. Neuromodulation is generally considered, in patients with refractory OAB symptoms but without a small-capacity fibrotic bladder, to be a surgical treatment, and all the treatment options, risks, and benefits need to be explained. It does have the advantage of being reversible and does not affect further treatment if unsuccessful. Although its mechanism of action is unclear, it has a low morbidity. A disadvantage of the technique is that only 40–50% of patients respond to temporary stimulation. The technique for temporary stimulation is inaccurate due to movements of the temporary electrode, and developments in this area include modifications to the electrode and a trend toward placement of a permanent electrode for the PNE that facilitates the second-stage procedure. Sacral neuromodulation is well tolerated by patients, and initial surgical complications are rare. However, there is a significant initial failure rate (despite successful preoperative nerve testing) and some patients experience rapid or gradual accommodation to the stimulation and thus lose any lasting benefit. The equipment is costly, an experienced team is necessary to follow up the patients, and, overall, probably only

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30–50% out of the original patient cohort submitted to PNE get a worthwhile final long-term result. If initial benefit is lost then reoperation can be considered with a view to placing an electrode in the contralateral foramen. Pain at the site of the generator, dislodgement of the electrodes, and infection may also occur and may require revision surgery. These problems account for the relatively high reoperation rate of 33%. Despite this, it is an interesting and innovative approach to the management of bladder overactivity.

Percutaneous Posterior Tibial Nerve Stimulation Recently, another nerve stimulation device has been developed for use in bladder overactivity. The PercSANS technique utilizes a thin needle to apply stimulation to the posterior tibial nerve. Multiple visits are required to the healthcare facility or office. Stimulation is applied via the needle, which is inserted 5 cm cephalad from the medial malleolus and just posterior to the margin of the tibia. Correct positioning is confirmed by flexion of the great toes on stimulation [8]. Stimulation is given on an intermittent basis with the needle being reinserted for each treatment period. Clinical use of the technique has shown early promise, with reported success rates of 67–81%. This technique has not proven to be widely applicable thusfar because patients appear to require ongoing treatment if they are to maintain benefit.

Pudendal Nerve Stimulation Another alternative approach appropriate to the neurogenic bladder is stimulation of the pudendal nerve using neurophysiological guidance to ensure accurate stimulation. This is a logical route, because many of the sensory afferent fibers of the sacral nerves originate in the pudendal nerve.

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References 1. Bramble FJ (1990). The clam cystoplasty. Br J Urol 66:337–341. 2. Bramble FJ (1982). The treatment of adult enuresis and urge incontinence by enterocytoplasty. Br J Urol 54:693–6. 3. Elliott SP, Meng MV, Anwar HP, et al (2002). Complete laparoscopic ileal cystoplasty. Urology 59:939–43. 4. Filmer RB, Spencer JR (1990). Malignancies in bladder augmentations and intestinal conduits. J Urol 143:671–678. 5. Atala A (2000). New methods of bladder augmentation. BJU Int 85(suppl):24–34. 6. Cartwright PC, Snow BW (1989). Bladder autoaugmentation: early clinical experience. J Urol 142:505–507. 7. Oerlemans DJ, van Kerrebroeck PE (2008). Sacral nerve stimulation for neuromodulation of the lower urinary tract. Neurourol Urodyn 27:28–33. 8. Govier FE, Scott L, Nitti V, et al (2001). Percutaneous afferent neuromodulation for the refractory overactive bladder: results of a multicentre study. J Urol 165:1193–1198.

Chapter 8 Special Populations

Overactive Bladder in the Male The term “prostatism” has been replaced in favor of “lower urinary tract symptoms” (LUTSs) in recent years (Fig. 8.1), because LUTSs are associated with both the bladder and the prostate (Fig. 8.2) and the term describes the patient’s complaints without implying the cause. In addition, it is neither age nor gender specific. The National Overactive BLadder Evaluation (NOBLE) Terms for prostatic conditions Prostatism is no longer used Benign prostatic hyperplasia (BPH) means histopathologically confirmed hyperplastic changes in the prostate Benign prostatic enlargement (BPE) is prostatic enlargement caused by BPH that has not been histologically confirmed Benign prostatic obstruction (BPO) may be caused by BPE and is diagnosed by urodynamic pressure-flow studies Bladder outlet obstruction (BOO) means obstruction during voiding characterized by increased detrusor pressure and reduced urine flow rate Lower urinary tract symptoms (LUTSs) suggestive of BOO implies that BOO has not been confirmed with pressure-flow studies

Figure 8.1 Terms for prostatic conditions. Note that terms should be used only after confirmation of the condition using the appropriate diagnostic procedures. Reproduced with permission from Chapple and Roehrborn [1] A.J. Wein, C. Chapple, Overactive Bladder in Clinical Practice, DOI 10.1007/978-1-84628-831-9_8, © Springer-Verlag London Limited 2012

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Male lower urinary tract symptoms can be associated with the bladder, the prostate, or both Bladder conditions

Male lower urinary tract system Prostate conditions

Detrusor overactivity Urodynamic observation of incoluntary detrusor contractions during the filling phase, which may be spontaneous or provoked

Overactive bladder Symptomatic diagnosis of urgency, with or without urgency incontinence, usually with frequency and nocturia

Benign prostatic hyperplasia Histology Benign prostatic enlargement (BPE) Size

Prostate

Benign prostatic obstruction Obstruction due to BPE (size or shape) characterized by increased detrusor pressure and reduced urine flow rate, during voiding

Bladder outlet obstruction Generic urodynamic term

Figure 8.2 Male lower urinary tract symptoms can be associated with the bladder, the prostate, or both. Adapted from Abrams et al. [2]

survey [3], the SIFO study conducted by Milsom et al. [4] in six European countries, and the European Prospective Investigation into Cancer and Nutrition (EPIC) study in four European countries and Canada [5], which employed the most recent International Continence Society (ICS) diagnostic criteria, indicated that the overall prevalence of overactive bladder (OAB) is similar in men and women (Fig. 8.3). This finding runs counter to those of earlier studies, most of which included only women or focused on the presence of urinary incontinence, which is more prevalent among women than men. The NOBLE survey found that “wet” OAB is far more

Figure 8.3 Prevalence of overactive bladder in men compared with women. (A) European Union (EU) SIFO data from Milsom et al. [4]; (B) National Overactive BLadder Evaluation (NOBLE) data from Stewart et al. [3]; and (C) European Prospective investigation into Cancer and Nutrition (EPIC) data from irwin et al [5]

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Prevalence of overactive bladder in men compared with women

a

EU SIFO study 45

Men

40

Women

Prevalence (%)

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45–49

50–54

55–59

60–64

65–59

70–74

75+

Age (years)

Prevalence (%)

b

US NOBLE study 40

Men

35

Women

30 25 20 15 10 5 0 18–24

25–34

35–44

45–54

55–64

65–74

Age (years)

Prevalence (%)

c

EPIC study 20

Men

15

Women

10 5 0 ≤39

40–59 Age (years)

≥60

75+

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prevalent in women and “dry” OAB is more prevalent in men; nevertheless, incontinence is reported by up to 20% of the male responders. A study of a random sample of 2369 men aged ³18 years from 11 Asian countries indicated that the prevalence of OAB was 29.9%, with the most common symptoms being frequency (37%), urgency (34%), and frequency and urgency (10%) [6]. OAB was more common in older men, professional workers, high-income individuals, and urban dwellers [6]. Although 32% of patients with OAB reported some degree of troublesome symptoms, only 5.9% received treatment [6]. It is clear that the presence of OAB in men, although more common in men with LUTSs and benign prostatic enlargement, causing bladder outlet obstruction (BOO) may occur independently of prostate pathology (see Fig. 8.2). In fact it is the storage symptoms that usually stimulate men to seek help for their clinical problem.

Postradical Prostatectomy The reported incidence of persistent urinary incontinence after radical prostatectomy varies considerably, from 1–2% to 74%, which may include the development or persistence of detrusor overactivity and/or OAB symptoms. Urinary incontinence after prostatectomy is generally due to sphincteric insufficiency and can present as stress, urge, or mixed incontinence. Although sphincteric incontinence is a common urodynamic finding in patients with postradical prostatectomy incontinence, other pathophysiological findings, such as OAB, might coexist. OAB may be the sole cause of post-prostatectomy incontinence, although this is very uncommon. To treat patients with urinary incontinence after radical prostatectomy most effectively, it is important to know the cause. A good candidate for OAB treatment is one who can sense involuntary detrusor contractions as an urge to void and who has voluntary control of the external sphincter and pelvic floor muscles.

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Prostate Enlargement and Bladder Outlet Obstruction There is a significant age-related incidence of benign prostatic enlargement, which is often associated with BOO and LUTSs. By the age of 60 years, about 40% of men have enlarged prostates; this figure rises to 75% at 80 years. As the prostate enlarges, it can obstruct the outlet so that the detrusor muscle has to work harder during voiding. This strain on the bladder muscle causes dysfunction and, if the bladder is unable to contract adequately to overcome the outlet resistance, this may lead to the development of residual urine left in the bladder after voiding. An increased residual is not therefore an absolute marker for obstruction but for the detrusor’s inability to overcome the outlet resistance. If symptoms of OAB are present, which may occur to some extent in up to three-quarters of men with BOO, then an involuntary contraction may result, which produces urgency incontinence (leakage). Usually, of course, this is associated with the other symptoms of OAB, namely urgency, frequency, and nocturia. Although there appears to be a causal relationship between detrusor overactivity and BOO, this has been challenged in recent years and it is equally or more likely that detrusor overactivity is an age-related phenomenon. The overlap between LUTSs and OAB was determined using data on 19 165 adults from the EPIC study [7]. Among the 7210 men in the sample, 62.5% reported one or more LUTSs, with 8.8% reporting all three LUTS subtypes. In contrast, 7.0% of the sample had OAB, of whom 100% reported urgency and 29.3% only storage symptoms [17]. Of men with OAB symptoms, 37.3% had all three LUTS subtypes, which was a significantly greater proportion than the general population [7]. Nocturia was reported by 48.6% of the overall sample and 75.3% of OAB patients [7]. Moderate or severe LUTSs were reported by 6.1% of the overall sample versus 29.9% of OAB patients [7]. The proportion of OAB patients reporting troublesome symptoms increased with urgency severity, as well as the severity and number of LUTSs [7].

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A Swedish study of 39 928 men indicated that 18.5% and 4.8% had moderate and severe LUTSs, respectively, with severity highly correlated with quality of life [8]. Just 29% of symptomatic individuals had been previously diagnosed with urinary problems and only 11% received medication [8]. Mariappan and Chong discovered, in a population-based study of 353 Malaysian men aged ³40 years, that the prevalence of mild, moderate, and severe LUTSs was 80.6%, 6%, and 0.3%, respectively [9]. Men with moderate and severe LUTSs had 1.4 times the risk of erectile dysfunction, whereas men who were overweight had an increased risk of moderateto-severe LUTSs [9]. Surgical therapy for BOO has been considered the reference standard for treatment, but pharmacological therapy is increasingly common, as reflected by fewer surgical interventions for BOO during the last 20 years. The National Institutes for Health and Clinical Excellence [10] guidance on the management of LUTSs in men recommends the following: • an a blocker (alfuzosin, doxazosin, tamsulosin, or terazosin) for men with moderate-to-severe symptoms • an anticholinergic in men with symptoms of an OAB • surgery should be offered only if voiding symptoms are severe or if drug treatment and conservative management options have been unsuccessful or are not appropriate. Determining the presence of incomplete bladder emptying by obtaining a post-void residual (PVR) volume is not necessary for all patients with OAB. However, in men with concomitant benign prostatic enlargement, the physician might want to refer the patient for a flow rate and PVR test to determine complete bladder emptying and assess whether BOO due to the benign prostatic enlargement is contributing to LUTSs. As OAB and benign prostatic enlargement often coexist, the combination of antimuscarinic therapy for OAB with pharmacotherapy for benign prostatic enlargement would appear to be a logical approach. However, the use of antimuscarinics

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in older men has traditionally been avoided because of the possibility of aggravating voiding difficulties, raising PVR, or precipitating acute urinary retention (AUR), especially in men with BOO [11]. Nevertheless, there is a growing body of research into the role of antimuscarinic treatment for men with persistent OAB symptoms after adequate treatment with an a blocker or a 5a-reductase inhibitor. Tolterodine has been reported to be safe and effective in men with benign prostatic enlargement who have associated OAB symptoms of urgency and frequency [12]. Combining tolterodine with doxazosin has been reported to be effective in three-quarters of men with BOO and OAB due to detrusor overactivity [13], although, in patients with BOO and detrusor overactivity, combination therapy with tamsulosin and tolterodine improved quality of life and was also found to be an effective and relatively safe treatment [14]. The combination of tolterodine extended release and tamsulosin resulted in significantly more patients reporting treatment benefit compared with placebo + tamsulosin in men with LUTSs including OAB [15]. Treatment with tolterodine extended release in men with benign prostatic hyperplasia (BPH) and LUTSs significantly reduced daytime and night-time frequency and PVR where treatment with a blockers failed [15]. When tolterodine was added to an a blocker in men with persistent OAB symptoms, there was no significant difference between tolterodine + a blocker and placebo + a blocker in the primary endpoint (improvement in PPBC score), but tolterodine was associated with significant improvements in a range of secondary endpoints, including International Prostate Symptom Score (IPSS) for storage symptoms, and numbers of micturitions and urgency episodes [11]. In one large, randomized, double-blind study [16], men with LUTSs who did not demonstrate complete symptom remission with tamsulosin alone experienced significant improvement with the addition of 10 mg/ day of oxybutynin extended release compared with placebo, particularly with respect to storage symptoms. Finally, propiverine was also shown to be effective in patients with storage and voiding symptoms who had been nonresponsive to a blockade [17].

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Duration (months)

Pdet Qmax (cm H2O)

PVR (mL)

Inc. AUR

QoL score

60

Do + To

3

Decreased NA >3 points in 63%

NA

NA

3.3%

NA

Athanasopoulos et al.[14]

50

Ta vs Ta + To

3

NA

+1.2

–8

–4.2

0

Increased

Kaplan et al.[18]

43

To

6

–6

+1.9

NA

–22

0

NA

Okada et al. [17]

35

Pro + a-blocker

3

–4.6

+0.8

NA

NS

0

Increased

Kaplan et al. [14]

662

To vs Ta + 3 To vs Ta + placebo

–1.83 (Ta + To vs Ta + placebo)

NA

NA

NA

0.4% (Ta + To)

–0.44 (Ta + To vs Ta + placebo)

Chapple et al. [11]

652

a-blocker vs a-blocker + To

3

NS

NA

NA

+13.6 6 % (both Oxy + Ta, treatment +1.0 Ta + groups) placebo

NS

MacDiarmid 420 et al. [16]

Oxy + Ta

3

–6.9 Oxy + NA Ta, –5.2 Ta + placebo

NA

NS

+1.3 Oxy + Ta, +0.8 Ta + placebo

Qmax (ml/sec)

Study design

Lee et al. [13]

Authors

IPSS

Cases

Summary of the data on the effect of antimuscarinic drugs in male patients with LUTSs/BPH

0

Figure 8.4 Summary of the data on the effect of antimuscarinic drugs in male patients with LUTSs/BPH. AUR, incidence of acute urine retention; BPH, benign prostatic hyperplasia; Do, doxazosin; ER, extended release; IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptom; NA, not assessed; NS, not statistically significant; Oxy, oxybutynin; Pdet Qmax¢ detrusor pressure at maximum urinary flow; Pro, propiverine; PvR, post-void residual urine; Qmax¢ maximum urinary flow rate; QoL, quality of life; Ta, tamsulosin; To, tolterodine

These studies, which are summarized in Fig. 8.4, suggest that antimuscarinics may be helpful for storage symptoms after previous a-blocker therapy, provided that the patient

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has a residual of less than 150–200 mL. However, the following must be considered: (1) patient selection; (2) short duration of therapy (only 3 months in most of these studies), with no truly long-term data regarding efficacy persistence and effect on detrusor function; and (3) clinical versus statistical significance. The most recent guidelines of the American Urological Association [19] recommend for the first time that anticholinergic agents are “an appropriate and effective treatment alternative for the management of LUTSs secondary to BPH in men without an elevated post-void residual and when LUTS are predominantly irritative.” It is evident that randomized controlled trials assessing the long-term safety and efficacy of combination therapy should be ongoing. It will be interesting to see whether the doses for these larger studies suggest an additive or synergistic effect of combination therapy.

Nocturia The prevalence of nocturia is positively correlated with age and is higher in men than in women aged >60 years [20]. In men aged 50–80 years, the incidence rate of nocturia increases over time, rising from a crude incidence rate of 75 new cases per 1000 men in the first 5 years of follow-up to 126 new cases per 1000 men during the second 5 years, and from 9 new cases per 1000 men to 14 new cases per 1000 men for moderate or severe nocturia [21]. This leads to an increase in the prevalence of nocturia, from 56% to 74% 10 years later, and from 39% among men aged 50 years at baseline to 87% among those aged 80 years at 10-year follow-up [21]. An increase in the frequency of nocturnal micturition is a well-established LUTS suggestive of benign prostatic obstruction [22], and this in itself is an independent risk factor for nocturia [23]. Increases in the number of voids per night have further negative effects on sleep, troublesome symptoms, and healthrelated quality of life (HRQoL) [24]. Older adults with severe

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sleep-disordered breathing have a greater number of nocturia episodes, so sleep-disordered breathing is an important differential diagnosis in the evaluation of older patients with nocturia [25]. Elderly obese men with urgency at night should be questioned about snoring (a sign of possible sleep apnea); micturition frequency and volume charts should be completed before deciding to operate [26], because nocturnal polyuria and essential hypertension may share some of the same pathophysiological determinants. The causes and assessment of nocturia are discussed in more detail in Chapter 2.

Incidence of Urine Retention in the Male Although retention of urine is a significant presenting problem, it is relatively uncommon, with an incidence of 0.2–0.7% per year in the general public. Even if one considers the rates of retention reported from studies conducted on patients entered in “benign prostatic hyperplasia” studies examining the efficacy of pharmacology with significant levels of symptoms and signs of BOO, the incidence of retention remains relatively low at 0.6–2% per year. To date, studies in male patients, both with LUTSs/BPH (see Fig. 8.4) and in trials of drug therapy for OAB, have not demonstrated an increased incidence of retention after treatment with antimuscarinics used at clinically recommended therapeutic doses.

Elderly People Elderly patients with OAB have been shown to have smaller average functional bladder capacity and briefer warning time than elderly individuals without OAB, although those who

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could prevent leakage for ³2 min were significantly more likely to be continent at home than other patients [27]. Antimuscarinic agents should be used with caution in elderly people, especially frail elderly people. Although the efficacy of antimuscarinic agents is well demonstrated in adult populations (including patients aged >65 years), few clinical studies have been reported in geriatric populations specifically, and antimuscarinic drugs are often underused in elderly people despite the marked increase in the prevalence of OAB in this age group. One explanation for this apparent underuse of an effective treatment option could be concerns about the frequency of anticholinergic adverse events, the probability of adverse effects on the central nervous system, including cognitive impairment and sleep disturbance, and the potential for harmful drug interactions. When selecting an antimuscarinic agent for the management of an elderly patient with OAB, safety issues specific to the elderly population should be considered in addition to the evidence of clinical efficacy and tolerability, such as: • slower metabolism and elimination of the drug • changes in the blood–brain barrier • changes in the activity and distribution of muscarinic receptors • age-related deficits in neurotransmission (aging and dementing disorders) • polypharmacy (including multiple anticholinergic agents). In particular, adverse effects on the central nervous system should be kept in mind, including cognitive impairment and sleep disturbances, secondary to anticholinergic load. Treatments such as bladder training, pelvic floor exercise, and behavioral therapy can be effective in elderly patients [28], whereas desmopressin decreases the number of nocturnal voids and increases the time to the first nocturnal void [29]. However, sodium concentrations should be monitored carefully when using desmopressin [29].

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The Neurogenic Group As neurogenic detrusor overactivity is thought to be due to stimulation of C-fibers, C-fiber endotoxins such as capsaicin and resinferatoxin have been used intravesically, producing encouraging results and minimal long-term complications [30]. Unfortunately both agents produce initial stimulation with discomfort and bladder spasm, and are not commercially available owing to limited data over efficacy of this compound as therapy. There have been promising results with botulinum toxin injections into the detrusor muscle, and with cannabinoids in multiple sclerosis patients, who experience benefits in terms of urgency incontinence with minimal adverse effects [30]. In experimental neurogenic detrusor overactivity, dopaminergic antagonists increase bladder capacity, whereas patients experience improvements in urodynamic parameters with gabapentin [31].

The Mixed Incontinence Group Mixed incontinence accounts for approximately a third of incontinence cases [3], and has a significant impact on HRQoL and troublesome symptoms [24]. Initial treatment for mixed incontinence should be conservative, with a combination of behavioral and drug therapies, plus pelvic floor exercises to combat the stress incontinence [32]. Electrical stimulation is a potential treatment for mixed incontinence, although it is associated with relatively poor cure rates, and surgery should be used only in patients who fail first-line treatment [32]. Pharmacological agents for mixed incontinence include antimuscarinic drugs, and dopamine, serotonin, and norepinephrine reuptake inhibitors [32]. A study of the antimuscarinic tolterodine extended release versus placebo in 854 women with urge-predominant mixed incontinence showed that, after 8 weeks, tolterodine was associated with a significant decrease in weekly urgency incontinence episodes, at −12.3 versus −8.0

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with placebo, although there was no impact on stress incontinence [33]. Significantly (P< 0.001) more tolterodine than placebo patients had improvements in bladder condition and treatment benefit, at 61% versus 46% and 76% versus 55%, respectively, and tolterodine patients had significant improvements over placebo in 9 of 10 quality-of-life domains [33]. After a complete history and physical exam, which includes a voiding diary, an acceptable initial conservative approach is to select what seems to be the most prominent set of symptoms (OAB or stress urinary incontinence [SUI]), primarily treat these, and observe the results.

Pregnancy and OAB At 12 and 36 weeks’ gestation, approximately 45% of women have “dry” OAB, which declines to 7.8% 3 months after delivery [34]. In contrast, the prevalence of “wet” OAB increased from 3.5% at 12 weeks’ gestation to 14.6% at 36 weeks’ gestation, falling again to 3.5% 3 months after delivery. Although “dry” OAB appears to have less impact on quality of life than “wet” OAB, the latter has a substantial effect on quality of life during and after pregnancy, particularly on mobility and embarrassment domains, and particularly due to urgency urinary incontinence [34].

Children A survey of 5282 Japanese schoolchildren aged 7–12 years, of whom approximately half were boys, showed that the prevalence of OAB was 17.8% and almost the same in both genders [35]. The prevalence of OAB decreased with increasing age in both girls and boys [35]. OAB was significantly more common in children with a history of cystitis, at 41.7% versus 17.1% in children without such a history [35]. The most common symptom was increased daytime frequency, followed by urgency incontinence, constipation, night-time bedwetting,

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and increased daytime frequency plus urgency incontinence, experienced by 73.8%, 33.8%, 20.4%, 13.3%, and 7.5%, respectively [35]. Childhood urinary symptoms may also predict adult OAB. Women aged 40–69 years who report having had childhood daytime frequency are significantly more likely to report adult urgency than other women, at an odds ratio of 1.9 [36]. Frequent childhood nocturia is also significantly associated with adult nocturia, at an odds ratio of 2.3, whereas both childhood daytime incontinence and nocturnal enuresis are linked to adult urgency incontinence, at respective odds ratios of 2.6 and 2.7 [36]. Outcomes of conservative treatment for childhood OAB using behavioral modification and/or pharmacological therapy with antimuscarinic agents are good, with up to 90% of patients experiencing complete or partial resolution of symptoms [37–39]. Significant improvements in all OAB symptoms have been reported with tolterodine, with an optimal dose of 1 mg identified for children aged 5–10 years [40,41]. Interestingly, children with the lowest frequency of wetting episodes are most likely to achieve daytime continence [42]. Among children refractory to pharmacotherapy, transcutaneous electrical nerve stimulation treatment twice daily for 20 min used for an average of 8 months appears to be safe and well tolerated, and leads to resolution or significant improvement of symptoms in 73% of cases [43].

References 1. Chapple CR, Roehrborn CG (2006). A shifted paradigm for the further understanding, evaluation, and treatment of lower urinary tract symptoms in men: focus on the bladder. Eur Urol 49:651–9. 2. Abrams P, Cardozo L, Fall M, et al (2003). The standardisation of terminology in lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Urology 61:37–49. 3. Stewart WF, van Rooyen JB, Cundiff GW, et al (2003). Prevalence and burden of overactive bladder in the United States. World J Urol 20:327–36.

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4. Milsom I, Abrams P, Cardozo L, et al (2001). How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 87:760–6. 5. Irwin DE, Milsom I, Hunskaar S, et al (2006). Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 50:1306–14. 6. Moorthy P, Lapitan MC, Quek PL, Lim PH (2004). Prevalence of overactive bladder in Asian men: an epidemiological survey. BJU Int 93:528–31. 7. Irwin DE, Milsom I, Kopp Z, et al (2009). Prevalence, severity, and symptom bother of lower urinary tract symptoms among men in the EPIC study: impact of overactive bladder. Eur Urol 56:14–20. 8. Andersson SO, Rashidkhani B, Karlberg L, et al (2004). Prevalence of lower urinary tract symptoms in men aged 45–79 years: a population-based study of 40 000 Swedish men. BJU Int 94:327–31. 9. Mariappan P, Chong WL (2006). Prevalence and correlations of lower urinary tract symptoms, erectile dysfunction and incontinence in men from a multiethnic Asian population: Results of a regional population-based survey and comparison with industrialized nations. BJU Int 98:1264–8. 10. National institutes for Health and Clinical Excellence (2010). The Management of Lower Urinary Tract Symptoms in Men. Clinical guideline 97. Available at: http//www.nice.org.uk/CG97. 11. Chapple C, Herschorn S, Abrams P, et al (2009). Tolterodine treatment improves storage symptoms suggestive of overactive bladder in men treated with alpha-blockers. Eur Urol 56:534–41. 12. Burnett AL, Wein AJ (2006). Benign prostatic hyperplasia in primary care: what you need to know. J Urol 175:S19–24. 13. Lee JY, Kim HW, Lee SJ, et al (2004). Comparison of doxazosin with or without tolterodine in men with symptomatic bladder outlet obstruction and an overactive bladder. BJU Int 94:817–20. 14. Athanasopoulos A, Gyftopoulos K, Giannitsas K, et al (2003). Combination treatment with an alpha-blocker plus an anticholinergic for bladder outlet obstruction: a prospective, randomized, controlled study. J Urol 169:2253–6. 15. Kaplan SA, Roehrborn CG, Rovner ES, et al (2006). Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. JAMA 296:2319–28. 16. MacDiarmid SA, Peters KM, Chen A, et al (2008). Efficacy and safety of extended-release oxybutynin in combination with tamsulosin for treatment of lower urinary tract symptoms in men: randomized, double-blind, placebo-controlled study. Mayo Clin Proc 83:1002–10.

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17. Okada H, Shirakawa T, Muto S, et al (2004). Propiverine hydrochloride relieves irritative symptoms of benign prostatic hyperplasia. J Urol 171(4, suppl):357–8. 18. Kaplan SA, Walmsley K, Te AE (2005). Tolterodine extended release attenuates lower urinary tract symptoms in men with benign prostatic hyperplasia. J Urol 174:2273–6. 19. American Urological Association Guideline: Management of Benign Prostatic Hyperplasia (BPH) (2010). Available at: http//www.auanet. org/content/guidelines-and-quality-care/clinical-guidelines. cfm?sub=bph 20. Kageyama T, Kabuto M, Nitta H, et al (2000). Prevalence of nocturia among Japanese adults. Psychiatry Clin Neurosci 54:299–300. 21. Häkkinen JT, Hakama M, Shiri R, et al (2006). Incidence of nocturia in 50 to 80-year-old Finnish men. J Urol 176(6 Pt 1):2541–5. 22. Johnson TM 2nd, Jones K, Williford WO, et al (2003). Changes in nocturia from medical treatment of benign prostatic hyperplasia: secondary analysis of the Department of veterans Affairs Cooperative Study Trial. J Urol 170:145–8. 23. Blanker MH, Bohnen AM, Groeneveld F P, et al (2000). Normal voiding patterns and determinants of increased diurnal and nocturnal voiding frequency in elderly men. J Urol 164:1201–5. 24. Coyne KS, Zhou Z, Bhattacharyya SK, et al (2003). The prevalence of nocturia and its effect on health-related quality of life and sleep in a community sample in the USA. BJU Int 92:948–54. 25. Endeshaw YW, Johnson TM, Kutner MH, et al (2004). Sleepdisordered breathing and nocturia in older adults. J Am Geriatr Soc 52:957–60. 26. Kinn AC, Harlid R (2003). Snoring as a cause of nocturia in men with lower urinary tract symptoms. Eur Urol 43:696–701. 27. Rosenberg LJ, Griffiths DJ, Resnick NM (2005). Factors that distinguish continent from incontinent older adults with detrusor overactivity. J Urol 174:1868–72. 28. Okamura K, Hasegawa T, Nojiri Y, et al (2008). Diagnosis and treatment of lower urinary tract symptoms in the elderly by general practitioners. Geriatr Gerontol Int 8:119–25. 29. Appell RA, Sand PK (2008). Nocturia: etiology, diagnosis, and treatment. Neurourol Urodyn 27:34–9. 30. Freeman RM, Adekanmi OA (2005). Overactive bladder. Best Pract Res Clin Obstet Gynaecol 19:829–41. 31. Kumar V, Cross RL, Chess-Williams R, Chapple CR (2005). Recent advances in basic science for overactive bladder. Curr Opin Urol 15: 222–6. 32. Chaliha C, Khullar V (2004). Mixed incontinence. Urology 63(3 suppl 1):51–7.

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33. Khullar V, Hill S, Laval KU, et al (2004). Treatment of urge-predominant mixed urinary incontinence with tolterodine extended release: a randomized, placebo-controlled trial. Urology 64:269–74. 34. van Brummen HJ, Bruinse HW, van de Pol G, et al (2006). What is the effect of overactive bladder symptoms on woman’s quality of life during and after first pregnancy? BJU Int 97:296–300. 35. Kajiwara M, Inoue K, Kato M, et al (2006). Nocturnal enuresis and overactive bladder in children: an epidemiological study. Int J Urol 13:36–41. 36. Fitzgerald MP, Thom DH, Wassel-Fyr C, et al (2006). Childhood urinary symptoms predict adult overactive bladder symptoms. J Urol 175(3 Part 1):989–93. 37. Curran MJ, Kaefer M, Peters C, et al (2000). The overactive bladder in childhood: long-term results with conservative management. J Urol 163: 574–7. 38. Hellerstein S, Zguta AA (2003). Outcome of overactive bladder in children. Clin Pediatr 42:553–6. 39. Sarica K, Yagci F, Erturhan S, Yurtseven C (2006). Conservative management of overactive bladder in children: evaluation of clinical and urodynamic results. J Pediatr Urol 2:34–9. 40. Hjälmås K, Hellström AL, Mogren K, et al (2001). The overactive bladder in children: a potential future indication for tolterodine. BJU Int 87:569–74. 41. Raes A, Hoebeke P, Segaert I, et al (2004). Retrospective analysis of efficacy and tolerability of tolterodine in children with overactive bladder. Eur Urol 45:240–4. 42. van Arendonk KJ, Knudson MJ, Austin JC, Cooper CS (2006). Improved efficacy of extended release oxybutynin in children with persistent daytime urinary incontinence converted from regular oxybutynin. Urology 68:862–5. 43. Malm-Buatsi E, Nepple KG, Boyt MA, et al (2007). Efficacy of transcutaneous electrical nerve stimulation in children with overactive bladder refractory to pharmacotherapy. Urology 70:980–3.

Chapter 9 Comorbid Conditions and Complications

Prevalence of Comorbid Conditions Comorbid conditions of all types are common among patients with OAB. The European Prospective Investigation into Cancer and Nutrition (EPIC) study was a telephone survey conducted in a random sample of 19165 adults in Canada, Germany, Italy, Sweden, and the UK between April and December 2005. Of those surveyed, 11% of men and 13% of women had at least one symptom of OAB [1]. A follow-up survey was conducted among this subpopulation and an equal number of controls to ascertain troublesome OAB symptoms. Nearly 49% of the subgroup with OAB had at least one comorbidity (defined as asthma, diabetes, high blood pressure, bladder/prostate cancer, stroke, Parkinson’s disease, multiple sclerosis, or depression), compared with 35% of the control group [2]. A similar survey of adults in the USA aged ³40 years, the Epidemiology of Lower Urinary Tract Symptoms II (EpiLUTS II), found an OAB prevalence rate of 26.1% in men and 41.2% in women (defined as having OAB symptoms at least “sometimes”). Survey participants who reported no or minimal OAB symptoms had a significantly lower rate of comorbid conditions than patients who reported that they had OAB sometimes or more often [3].

A.J. Wein, C. Chapple, Overactive Bladder in Clinical Practice, DOI 10.1007/978-1-84628-831-9_9, © Springer-Verlag London Limited 2012

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Depression OAB is associated with depression, but the precise nature of this relationship is deceptively complex. The question as to whether depression is a cause or a consequence still remains obscure. Patients with an altered mental status often present with detrusor overactivity or overflow incontinence. Mental status can be screened in an informal manner by noting the patient’s orientation, recent and past memory, speech and comprehension, sensory and motor function, and deep and sacral reflexes. In the EPIC study’s follow-up survey, both the respondents with OAB and controls were asked to complete the Center for Epidemiologic Studies Depression Scale (CES-D) to assess how depressed they felt during the past week. Over 11% of those with OAB, versus only 3.6% of controls, reported a point score of ³21 on a scale of 0–60, indicating major depressive symptoms (P<0.001) [4]. Similar results were noted in the earlier National Overactive Bladder Evaluation Program (NOBLE) survey, where 43.4% of those reporting urinary urgency had CES-D scores ³21 [5].

Sexual Dysfunction OAB can affect sexual identity, function, and relationships. Clinical experience suggests that women with OAB are specifically at risk of leaking during orgasm; however, further study with validated questionnaires is needed to discover which phases of the sexual response are more affected in patients with OAB, both continent and incontinent. OAB-related sexual dysfunction also appears to be associated with depression and anxiety. The EPIC study’s follow-up survey noted above also assessed sexual activity and rate of sexual enjoyment. Although the OAB group had only a slightly lower percentage of people who were sexually active over the past 12 months than the control group, they had a much higher rate of decreased enjoyment of sexual activity (15.4% versus

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2.8%; P<0.001). Those who reported the greatest number of OAB-related symptoms had the highest rates of depression and decreased enjoyment of sexual activity [4]. When the investigators studied just the sexually active men, they found that 25.2% of those with OAB had erectile dysfunction, versus 15.6% of controls (P£0.05). Fewer men with OAB had overall satisfaction with their sexual lives as well [6].

Falls and Fractures There is a proposed causal link between fractures and OAB in the elderly population [7]. The proposed rationale is that, if patients get the sudden urgency to void, they need to rush to the toilet, which, if they are unsteady on their feet, can precipitate a fall, particularly if it occurs at night (ie, nocturia). Asplund found, in a survey of 6103 senior citizens, of whom 39.5% were male, that hip fracture occurred in 3.9% of men and 4.6% of women [8]. The risk of hip fracture was greater in patients with three or more nocturia episodes versus two or more episodes, at an odds ratio of 1.8, and in those who frequently passed large nocturnal urine volumes versus very seldom or never passing large volumes, at an odds ratio of 3.5 [8]. Another study of 6000 elderly women found that urge incontinence led to a 26% greater chance of having a fall and a 34% greater chance of fracture, and more frequent incontinence was associated with increased risk, with women experiencing daily urge incontinence having a 35% greater risk of sustaining a fall and a 45% greater risk of sustaining a fracture [9].

Cardiac Disorders Cardiac disorders are an often-cited comorbidity of OAB. The autonomic imbalance that is often linked to the development of OAB could also be associated with the development of cardiovascular disease [10–12].

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In one study, the US-based HealthCore Integrated Research Database was used to locate adults with at least one medical or pharmaceutical claim related to OAB. Patients with OAB were matched with controls, and both groups were assessed for the prevalence of cardiovascular (CV) conditions. Overall, 38.8% of those with OAB had at least one pre-existing CV morbidity, versus 20.8% of controls (P<0.001). Hypertension was the most prevalent CV condition. Patients with OAB also had a greater use of antimuscarinic agents compared to controls (32.8% versus 16.8%, P<0.001), which have the potential to increase heart rate. Therefore, it is important to monitor patients with both OAB and pre-existing CV disorders who are prescribed antimuscarinics [12].

Gastrointestinal Disorders There is evidence for a relationship between OAB and both chronic constipation and fecal incontinence. In the EpiLUTS II survey, both men and women with OAB were more likely to have either constipation or fecal incontinence, or both conditions, than those without OAB [13]. An earlier study noted that patients with idiopathic detrusor instability had a higher rate of anal incontinence, frequency of bowel movements, passage of loose stools, and anorectal pain than asymptomatic patients [14]. However, this link between OAB symptoms and gastrointestinal disorders has yet to be adequately studied [13].

References 1. Irwin DE, Milsom I, Hunskaar S, et al (2006). Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 50:1306–15. 2. Irwin DE, Milsom I, Kopp Z, Abrams P, on behalf of the EPIC Study Group (2008). Symptom bother and health care–seeking behavior among individuals with overactive bladder. Eur Urol 53:1029–39.

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3. Coyne KS, Cash B, Kopp Z, et al (2010). The prevalence of chronic constipation and faecal incontinence among men and women with symptoms of overactive bladder. BJU Int 107:254–61. 4. Coyne KS, Sexton CC, Irwin DE, Kopp ZS, Kelleher CJ, Milsom I (2008). The impact of overactive bladder, incontinence and other lower urinary tract symptoms on quality of life, work productivity, sexuality and emotional well-being in men and women: results from the EPIC study. BJU Int 101:1388–95. 5. Coyne KS, Payne C, Bhattacharyya SK, et al (2004). The impact of urinary urgency and frequency on health-related quality of life in overactive bladder: results from a national community survey. Value Health 7:455–63. 6. Irwin DE, Milsom I, Reilly K, et al (2008). Overactive bladder is associated with erectile dysfunction and reduced sexual quality of life in men. J Sex Int 5:2904–10. 7. Freeman R, Bridge SM, Dooley JA (2004). Falls and overactive bladder: the need for a prevention strategy. Presented at the 20th International Conference on Pharmacoepidemiology and Therapeutic Risk Management, Bordeaux, France, August 22–25, 2004. 8. Asplund R (2006). Hip fractures, nocturia, and nocturnal polyuria in the elderly. Arch Gerontol Geriatr 43:319–26. 9. Brown JS, McGhan WF, Chokroverty S (2000). Comorbidities associated with overactive bladder. Am J Manag Care 6(suppl):S574–9. 10. Choi JB, Kim YB, Kim BT, Kim YS (2005). Analysis of heart rate variability in female patients with overactive bladder. Urology 65:1109–13. 11. Hubeaux K, Deffieux X, Ismael SS, Raibaut P, Amarenco G (2007). Autonomic nervous system activity during bladder filling assessed by heart rate variability in women with idiopathic overactive bladder syndrome or stress urinary incontinence. J Urol 178:2483–7. 12. Andersson K-E, Sarawate C, Kahler KH, Stanley EL, Kulkarni AS (2009). Cardiovascular morbidity, heart rates and use of antimuscarinics in patients with overactive bladder. BJU Int 106:268–74. 13. Cukier JM, Cortina-Borja M, Brading AF (1997). The prevalence of chronic constipation and faecal incontinence among men and women with symptoms of overactive bladder. Br J Urol 79:865–78.