Overactive Bladder E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 528

Veröffentlichungsjahr: 2015

Beschreibung

Overactive Bladder: Practical Management provides urologists, gynecologists and other health practitioners with a comprehensive clinical guide to this very common problem, resulting in a perfect resource to consult time and time again.

Beginning with an introductory section covering the definition and pathophysiolgy of OAB, it then moves on to cover evaluation, first-line management, second-line management and finally surgery.

Well-illustrated throughout, each chapter begins with a key points box outlining the most important take-home messages.  Also included are clear management algorithms to aid decision-making, 'Do's and Don't' boxes to help avoid errors made, key references to the top journal articles, and the very latest guidelines from the EAU, AUA and other major urology societies. 

Chapters are written by the top names in the field and the entire book is expertly edited by Jacques Corcos, John Heesakkers and Scott MacDiarmid.  The result is a consistent, comprehensive and fully up to date approach to OAB, providing urologists managing patients with this condition with rapid access, specialist clinical guidance.

Leseprobe

CONTENTS

Overactive Bladder

Practical Management

EDITED BY

Jacques Corcos MD, FRCS(S)

Professor of UrologyDepartment of UrologyMcGill UniversityMontreal, QC, Canada

Scott MacDiarmid MD, FRCPSC

DirectorBladder Control and Pelvic Pain CenterAlliance Urology SpecialistsGreensboro, NC, USA

John Heesakkers MD, PhD

UrologistDepartment of UrologyRadboud University Medical CenterNijmegen, The Netherlands

Contributors

Karl-Erik Andersson, MD, PhDFaculty of Health, Institute for Clinical MedicineUniversity of ArhusArhus, Denmark

Apostolos Apostolidis, MD, PhD, FEBUAssistant Professor of Urology-NeurourologySecond Department of Urology,Papageorgiou General Hospital, AristotleUniversity of ThessalonikiThessaloniki, Greece

Kari Bø, PhDProfessor of Exercise ScienceNorwegian School of Sport Sciences,Department of Sports MedicineOslo, Norway

Mathieu Boudes, PhDLaboratory of Experimental UrologyDepartment of Development and RegenerationKU Leuven, Leuven, Belgium

Christopher R. Chapple, BSc, MD, FRCS (Urol), FEBUConsultant Urological Surgeon, Department of Urology, Royal Hallamshire HospitalHonorary Senior Lecturer of Urology,University of SheffieldVisiting Professor of UrologySheffield Hallam UniversitySheffield, UK

Jacques Corcos, MD, FRCS(S)Professor of UrologyDepartment of UrologyMcGill UniversityMontreal, QC, Canada

Jill Danford, MDVanderbilt UniversityMedical Center, Nashville, USA

G.W. Davila, MDCleveland Clinic FloridaWeston/Fort Lauderdale, FL, USA

Dirk De Ridder, MD, PhD, FEBULaboratory of Experimental UrologyDepartment of Development and RegenerationKU LeuvenLeuven, Belgium

Roger Dmochowski, MD, FACSProfessor of Urology / GynecologyVanderbilt University Medical CenterNashville, TN, USA

Jerzy B. Gajewski, MD, FRCSCProfessor of Urology & PharmacologyDalhousie UniversityHalifax, NS, Canada

Lara C. Gerbrandy-Schreuders, MDDepartment of UrologyAMC University HospitalAmsterdam, The Netherlands

Barry G. Hallner Jr, MDFemale Pelvic Medicine and Reconstructive SurgeryDepartment of Obstetrics & Gynecology Louisiana State University Health Sciences CenterNew Orleans, LA, USA

John Heesakkers, MD, PhDDepartment of UrologyRadboud University Medical CenterNijmegen, The Netherlands

Sender Herschorn, BSc, MD, FRCSCSunnybrook Health Sciences CentreUniversity of TorontoToronto, ON, Canada.

Jack C. Hou, MDUT Southwestern Medical CenterDallas, TX, USA

Vik Khullar, BSc, FRCOG, MD, AKCConsultant UrogynaecologistSt. Mary’s Hospital, NHS TrustImperial College LondonLondon, UK

Ryan M. Krlin, MDAssistant Professor of UrologyDepartment of UrologyLouisiana State University School of MedicineNew Orleans, LA, USA

Scott MacDiarmid, MD, FRCPSCDirectorBladder Control and Pelvic Pain CenterAlliance Urology SpecialistsGreensboro, NC, USA

Geneviève Nadeau, MD, M.Sc, FRCSCDivision of UrologyCentre Hospitalier de l’Université de QuébecQuébec, QC, Canada.

Diane K. Newman, DNP, ANP-BC, FAANResearch Investigator Senior and Adjunct Associate Professor of Urology in SurgeryPerelman School of Medicine, University of PennsylvaniaCo-Director of the Penn Center for Continence and Pelvic HealthDivision of Urology, University of Pennsylvania Medical Center, Philadelphia, PA, USA

Nadir I. Osman, MBChB (hons), MRCSDepartment of UrologyRoyal Hallamshire HospitalSheffield, UK

L.N. Plowright, MDCleveland Clinic FloridaWeston/Fort Lauderdale, FL, USA

Fadi Sawaqed, MDDalhousie UniversityHalifax, Canada

Anand Singh, MBBS, BScSpecialist Trainee in Obstetrics and GynaecologyClinical Research Fellow in UrogynaecologySt. Mary’s Hospital, NHS TrustImperial College LondonLondon, UK

Adrian Wagg, MBBS, FRCP, FRCP (E), FHEAResearch Chair in Healthy AgeingDepartment of Medicine,University of AlbertaEdmonton, AB, Canada

Hessel Wijkstra, MSc, PhDDepartment of UrologyAMC University HospitalAmsterdam, The Netherlands

J. Christian Winters, MD, FACSProfessor and Chairman, Department of UrologyLouisiana State University Health Sciences CenterNew Orleans, LA, USA

Philippe E. Zimmern, MDUT Southwestern Medical CenterDallas, TX, USA

Foreword

I had the chance to witness the conception of Overactive Bladder Syndrome as a product of two bright and leading brains as Paul Abrams and Alan Wein, with their ability to involve and ignite the experts network and coagulate their knowledge and expertise. I must admit – despite my reservations – that this has been a major advance in the communication with non-experts in functional urology and a tremendous instrument to raise the awareness of the clinical relevance of urinary urgency and related lower urinary symptoms. It has been a remarkable fruit of a magic period in which major revisions of lower urinary tract related terminology have been undertaken. Noticeably, while to describe the occurrence of urgency with/without frequency with/without urinary incontinence the wording target has been the bladder (OABs), almost simultaneously an organ-related wording such as prostatism or prostatic symptoms has been abandoned in preference of a more descriptive terminology that has became extremely popular and efficacious (Lower Urinary Tract Symptoms: LUTS). The continuously progressing knowledge about the physiopathology of badder dysfunctions by means of functional CNS imaging and basic research shows, with increased evidence, that in most instances the etiopathogenesis of bladder-related symptom syndromes relies on alterations of bladder control outside the target organ. Consequently I am convinced that a term such as “Altered Bladder Control” will be more adherent to our present knowledge, more open to future interpretations, and equally easy to understand for a non-expert. Others will witness a second magic period with bright changes of terminology such as those cleverly introduced with the wording of Overactive Bladder.

Walter ArtibaniProfessor and Chair of Urology at the University of VeronaGeneral Secretary of the International Continence Society (2005–2007)

Foreword: The impact of Overactive Bladder on Urogynecology

As providers of care to women with urogynecologic problems, our practice patterns have largely been determined by two main variables: (i) the identification and impact assessment of quality of life problems related to pelvic floor dysfunction, and (ii) development of new technology and innovations aimed at reducing the burden of these conditions. Overactive bladder certainly fits within this paradigm. That overactive bladder has a significant QOL impact on its sufferers is certain. A multiplicity of instruments have been developed to better quantify individual impact, and we – as clinicians – have developed disease classification schemes (and terminology) designed at better understanding the condition. In parallel, researchers and industry have developed innovative therapeutic modalities, from pharmacotherapy to rehabilitative and neuromodulation modalities. As a result, our patients have received significant benefit, and we can tell each OAB patient with certainty that we will be able to “make you better.”

In my various roles within the International Urogynecological Association (IUGA), I have been witness to this evolution of the role of OAB in our field. IUGA, like other large professional associations focused on pelvic floor dysfunction, has been able to better fulfill its mission in large part due to the expanded role of OAB within our field. Those of us who have been in practice more than 20 years will recall times when our annual meeting presentations and industry booths were largely focused on epidemiology, urodynamics techniques, and basic prolapse repair techniques. Our only OAB treatment modalities, besides physiotherapy, were anticholinergic meds that had been available for many years and were thus not actively marketed. The involvement of industry in our field led to the massive expansion in clinical and research activity we have recently witnessed. I can identify two main turning points responsible for the phenomenon: the launch of tolterodine by Pharmacia, and the launch of suburethral sling kits such as TVT by Gynecare and other companies. Industry involvement allowed IUGA to increase funding for educational programs, expand the scope and size of the annual meeting, and fund the organizational infrastructure required to maintain the association’s engine running. It has been a very exciting ride. The future brings about yet more technology and expanded therapeutic options. Will a neuromodulation or chemomodulation company be our next Pharmacia? Will stem cells or tissue modulation technology open doors to other novel therapeutic approaches? One thing is certain: we will have new options to offer our OAB and urogynecologic patients. And, that will continue to fuel our research, education, and organizational efforts.

As our knowledge on pelvic floor problems expands, this book on Overactive Bladder provides the reader with an up-to-date source of data and information that will allow him/her to better care for OAB patients. Congratulations and thanks to Jacques Corcos, Scott MacDiamid, and John Heesakers for this very timely text.

G. Willy Davila, MDPresident, International Urogynecological Association (IUGA)

Foreword

Overactive bladder syndrome remains an enigma that significantly affects the health and wellbeing of 12–17% of adult men and women throughout the world. The development of this term to describe the symptom complex of urgency, frequency, and nocturia with or without urgency urinary incontinence became a necessity 16 years ago with the introduction of the first new medication to treat this constellation of symptoms in over two decades. North American trials of tolterodine failed to show that it worked better than placebo to reduce urinary incontinence episodes, and thus it could not be marketed to treat urgency urinary incontinence. This seemingly bad news for a pharmaceutical company turned out to be a bonanza for all parties involved. Admitting to having urgency urinary incontinence was a marked deterrent to patients seeking care for these symptoms. However, patients had far less embarrassment in seeking care for their overactive bladder syndrome. The direct to consumer marketing efforts for tolterodine and the seven branded products that followed in the next decade have dramatically increased the number of patients willing to seek care for their overactive bladders from about 1 in 13, 15 years ago, to 1 in 5 more recently. Along with this has come increased attention from the industry and the investment community, which has helped to dramatically increase funding and research into new technologies and compounds to address the treatment of overactive bladder syndrome and related conditions over the last decade. This financial bounty has also spilled over into supporting the activities of our professional societies and increased grant funding for young investigators. While I and many academicians resented the introduction of this term, it has greatly benefitted all involved in the care of these men and women; but mostly it has benefitted our patients. This has also served as an excellent model of how industry and the academic community can work together to help promote our mutual goals and to help further the care of our patients.

What does the future hold for the treatment of overactive bladder syndrome? With changes in healthcare delivery systems and funding in North America will we see continued innovation and spending on new therapies for our patients with overactive bladder syndrome? These questions remain to be answered, but as this excellent textbook attests, there are still great minds that remain dedicated to answering the important questions that remain for those affected by overactive bladder syndrome. The editors have assembled a great group of authors who represent some of the best minds in our field. Hopefully, reading this text will inspire other young investigators to take on the challenge of innovating and seeking out the important answers that will lead to a complete understanding of the pathophysiology of the overactive bladder syndrome and its cure.

Peter K. Sand, MDProfessor of Obstetrics & GynecologyDirector, Evanston Continence CenterNorthShore University HealthSystemUniversity of Chicago, Pritzker School of Medicine

Preface

Two years ago, the publisher approached me with the suggestion that I become the editor of a textbook about OAB. Initially, I was reluctant to accept this invitation because I was starting my editorial duties for the third edition of the Textbook of the Neurogenic Bladder. While considering my options, it became apparent that there was a crucial need for such a book, due to recent developments in the understanding of this specific topic. General interest in a non-life-threatening disease is directly proportional to the interest shown by the pharmaceuticals industry. OAB is a good example of this equation. Industry supported research has allowed us to produce good epidemiological studies and well-developed basic research to better understand the pathophysiology as well as new molecules and techniques to treat the condition. The sum of this recent knowledge serves as the foundation of this book.

My co-editors are two individuals with advanced expertise in the field: one living and practicing in North America and one living and practicing in Europe. Each continent has its own particularities in the practice of medicine, resulting in a diverse variety of approaches. Scott and John bring different perspectives as co-editors, which allows for thorough reviews of each chapter.

Together, we have designed the table of contents, trying to be as didactic as possible in the divisions of our book. After a short introduction to the topic, there is a review of current knowledge on pathophysiology. The book continues with chapters about evaluation practices, including the timing of evaluation, which may vary for each patient depending on where the medical practice is located. The interview and physical examination are considered, including questionnaires, which are extremely useful in the initial assessment of OAB cases. Urodynamics is essential in the evaluation of neurogenic detrusor overactivity but has become optional in primary OAB evaluation.

Treatment chapters follow, divided into first-line, second-line, and third-line therapies, as well as surgery. Behavioral and lifestyle modifications are extremely important in primary and secondary OAB treatments and a significant addition to any other form of treatment. Physiotherapy is another treatment option for OAB, although it is not widely used for this purpose in North America at the present time. A review of the currently available and potential future medications is an important part of this book, considering that most of our patients use at least one drug to control symptoms at varying stages of the disease. Co-medication is the focus of an entire chapter because we think that it is under-used. Other forms of non-invasive, frequently forgotten techniques are the basis of the next chapter, which reviews knowledge on bladder training, acupuncture, naturopathic and herbal remedies, magnetic stimulation, catheters, and tissue engineering. Three other important chapters cover the role of two neuromodulation modalities and botulinum toxin injections, approaches in which significant progress has been made over the last decade. It is important to note that these approaches can be employed differently, one before the other one, depending on physician experience and place of practice. Finally, the surgical approach, used frequently in neurogenic conditions, completes the treatment section of the book. The last part of the book addresses important considerations regarding special populations: older people and men with outlet obstruction. In conclusion, a synthesis chapter provides a practical clinical summary of the principal themes of the book.

The contributor selection process was exceedingly difficult, since we have so many highly competent colleagues and friends with expertise in OAB. We apologize to those who are not participating in this venture and congratulate all the authors for the high quality of their work and for their efforts in (almost) respecting the deadlines. We are proud of the end result of this collaboration and we believe that this book will be very useful for learners at all stages: medical students, residents, and established physicians. This book will be practical for other healthcare professionals, with first-hand involvement in treating the potentially debilitating symptoms of OAB. Additionally, members of the industry can gain a better understanding of the condition and an overview of what their peers can offer to treat OAB.

May this book provide inspiration to present and future medical professionals in this field!

Jacques Corcos MD

Left to right: Dr. Scott MacDiarmid, Dr. Jacques Corcos, and Dr. John Heesakkers

SECTION 1Introduction

CHAPTER 1Overactive bladder: terminology and problem spectrum

John Heesakkers

Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands

KEY POINTS

The key symptom in the OAB syndrome is urgency, which can be interpreted in many different ways.

Urgency is difficult to appreciate by patients and caregivers.

Therefore incidence and prevalence data have to be looked at with caution.

It is a challenge to really appreciate the exact terminology introduced to describe the symptoms and suffering from overactive bladder complaints.

In the last part of the 20th century the term urge incontinence was used frequently to describe the situation in which there is a strong sensation to go to the toilet and void or lose urine and when someone is in the process of getting there in time. However there were also patients who complained of frequent voiding and the feeling of needing to void who were often not incontinent. The compelling sensation was particularly regarded as abnormal. In 1988 Paul Abrams called this sensation “urgency,” defined as: a strong desire to void accompanied by fear of leakage or fear of pain (1988). [1] Although anyone could more or less understood which group of patients was meant, it was not easy to test this definition: not every patient had a fear of leakage or fear of pain. In 2002 this was further specified and explained as: the complaint of a sudden compelling desire to pass urine, which is difficult to defer. [2] Again, it was not easy to define what was sudden, compelling, and difficult to defer.

In 2002 the ICS defined overactive bladder complaints as: a medical condition referring to the symptom of urgency with or without urge incontinence, usually with frequency and nocturia. Other pathology like a urinary tract infection should be ruled out or treated. Urgency is the most important symptom here. It is a sensory sensation that makes you go to the toilet often (=frequency). If you have to do that at night it is called nocturia and if you do not get in time to the toilet it causes incontinence. It also means that urgency alone constitutes the OAB symptom syndrome. It is felt to be important to distinguish urgency, which is regarded as pathological, from urge which is the normal, healthy strong sensation to go to the toilet. This is difficult to understand for non–native English speakers because the translation of urgency or urge to another language is very often exactly the same. However, many contributions have been made by key experts on OAB in the past in order to explain the difference and also its pathophysiological mechanism. Chris Chapple contributed in 2005 to the discussion with the following. “It is important to differentiate between ‘urge’ which is a normal physiologic sensation, and urgency which we consider pathological. Central to this distinction is the debate over whether urgency is merely an extreme form of ‘urge.’ If this was a continuum, then normal people could experience urgency, but in the model we propose, urgency is always abnormal. ”[3] Michel and Chapple postulated that urgency originates in pathology while urge does not. “The mechanisms of urgency differ from those involved in the symptom of urge, which occurs during a physiologic bladder filling (C-fibers supposed to convey urgency and A-delta-fibers supposed to convey urge).” [4] Jerry Blaivas noted that: “Urgency is comprised of at least two different sensations. One is an intensification of the normal urge to void and the other is a different sensation. The implications of this distinction are important insofar as they may have different etiologies and respond differently to treatment.” [5]

So this all means that urge is a healthy sensation and urgency a not-healthy sensation, the latter based on pathology, the first on normal physiology. To attach frequency, nocturia, and incontinence to the driver of the syndrome had three consequences. The first was that to include and exclude patients in studies one had to find a translation of urgency into a workable definition. For frequency, for instance, this meant more than 8 times per 24 hours. The second was that the applied definition would influence the prevalence OAB. The third and most important consequence was that one had the feeling that a patient fitted into a pathological entity whereas the whole complex could also be a symptom without pathophysiological backing.

The late Norman Zinner addressed this point in an elegant debate with Paul Abrams in Neurourology and Urodynamics. He started by saying : “So OAB is urgency, with or without incontinence, usually with frequency and nocturia. This implies that incontinence, frequency and nocturia alone is not OAB. It also means that urgency without frequency, nocturia or incontinence, is OAB. So urgency alone is OAB, but what is it? We need descriptive terms like urgency to communicate, but not to make them medical terms and a 'syndrome' out of a constellation of unproven ambiguities.” [6] Paul Abrams responded to that by saying that perhaps his relationship to the term “OAB” is rather like his relationship to the motor car: I deprecate its effect on the environment, but I am not about to give it up! [7] Zinner stated that the phrase OAB is misleading because it “makes it too easy for clinicians to feel they have made a diagnosis when they have not.”[8]

So although there still is a debate about the existence, meaning, and pathophysiological backing of urgency and the OAB syndrome, every clinician dealing with a patient group that fits the definition knows what is meant by it.

The used definition, the translation in various languages, the validation process of questionnaires, and the interpretation of the respondents account for the number of people affected by OAB.

Studies from Milsom and Stewart et al. claimed that about 13–17% of the population suffer from OAB. [9, 10] This equates to about 49 million people in Europe; the prevalence increases with age. OAB is more present in women than in men. Others found other percentages. Wen et al. looked at prevalences in a Chinese population of more than 10 000 people. He found that OAB dry is present in 1.1% of the Chinese population and in 1.0% when one uses the OAB Symptom Score. OAB increases with age and more men than women suffer from it. [11]

OAB is also a chronic disease. Despite all the effort that is put in by caretakers, 88% of women that have OAB will still have it after 10 years. [12]

If the amount of bother is taken into account one must conclude that, as compared to the voiding phase and the post-micturition phase of the micturition cycle, the filling phase problems like OAB cause more bother. [13] OAB bother also compares well in comparison to other chronic diseases like diabetes mellitus or hypertension. [14]

Various reports have been published that look at the costs of the diagnosis and the treatment of overactive bladder complaints. Apart from that, the remnant costs after failed or not-100%-successful treatment of containment are also substantial. If the costs of disability for work are taken into account too, the total costs are very impressive. A study from Onukwugha et al. estimated the disease-specific total costs of OAB from the societal perspective and using an average costing method in the USA. [15]. This was done by analyzing a population-based survey, a claims data analysis, and the published literature. They applied the data in those community dwelling adults reporting the presence of urinary urgency or urgency urinary incontinence as “often” on a Likert scale. Based on the data they estimated the disease related cost at 25 billion dollars. If even the real cost were 25% of this figure one must conclude that OAB has a high impact on society, let alone on the individual patient.

References

1 Abrams P, BlaivasJ G, Stanton SL, et al. The standardisation of terminology of lower urinary tract function.

Neurourol Urodyn

. 1988; 7:403–426.

2 Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function.

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2002;

21

: 167–178.

3 Chapple CR, Artibani W, Cardozo LD, et al. The role of urinary urgency and its measurement in the overactive bladder symptom syndrome: current concepts and future prospects.

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2005;

95

:335–340.

4 Michel MC, Chapple CR. Basic mechanisms of urgency: preclinical and clinical evidence.

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(2):298–307.

5 Blaivas JG, Panagopoulos G, Weiss JP, Somaroo C. Two types of urgency.

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2009; 28:188–190.

6 Zinner NR. OAB: Are we barking up the wrong tree?Neurourol Urodyn. 2011;

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:1410–1411.

7 Abrams P. Response to OAB: Are we barking up the wrong tree?

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8 Zinner NR. Author's response to Paul Abram's response to OAB.

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9 Milsom I, Abrams P, Cardozo L, et al. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study.

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10 Milsom I, Stewart WF, Van Rooyen JB, et al. Prevalence and burden of overactive bladder in the United States.

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(6): 327–336.

11 Wen JG, Li JS, Wang ZM, The prevalence and risk factors of OAB in middle-aged and old people in China.

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. 2014; 33(4):387–391.

12 Garnett S, Swithinbank L, Ellis-Jones J, Abrams P. The long-term natural history of overactive bladder symptoms due to idiopathic detrusor overactivity in women.

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13 Coyne KS, Wein AJ, Tubaro A, et al: The burden of lower urinary tract symptoms

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(Suppl 3):4–11 (EpiLUTS).

14 Kobelt G, Kirchberger I, Malone-Lee J. Quality-of life aspects of the overactive bladder and the effect of treatment.

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15 Onukwugha E, Zuckerman IH, McNally D, et al. The total economic burden of overactive bladder in the United States: a disease-specific approach.

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(4 Suppl): S90–97.

CHAPTER 2Pathophysiology

Mathieu Boudes and Dirk De Ridder

Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium

KEY POINTS

Urinary incontinence caused by detrusor overactivity (DO) remains a major problem for many people with neurological disorders. According to the Standardization published by the International Continence Society, DO is an urodynamic observation characterized by involuntary detrusor contractions during the filling phase which may be spontaneous or provoked. [1]

DO may also, whenever possible, be classified as neurogenic detrusor overactivity (NDO) when there is a relevant neurological condition, or idiopathic detrusor overactivity (IDO) when there is no defined cause. A variety of neurological diseases that affect brain structures and spinal pathways involved in the coordination of lower urinary tract function may cause NDO, including multiple sclerosis, spinal cord injury (SCI), meningomyelocele (MMC), stroke, cerebral palsy, and so on.

Overactive bladder syndrome (OAB) is a symptom complex including urgency, with or without urge incontinence, but usually with frequency and nocturia. This symptom combination is suggestive of detrusor overactivity which can be demonstrated by urodynamics, but it can also be due to other forms of urethrovesical dysfunction.

Introduction

Urinary incontinence caused by detrusor overactivity (DO) remains a major problem for many people with neurological disorders. According to the Standardization published by the International Continence Society, DO is an urodynamic observation characterized by involuntary detrusor contractions during the filling phase which may be spontaneous or provoked. [1] DO may also, whenever possible, be classified as neurogenic detrusor overactivity (NDO) when there is a relevant neurological condition, or idiopathic detrusor overactivity (IDO) when there is no defined cause. A variety of neurological diseases that affect brain structures and spinal pathways involved in the coordination of lower urinary tract function may cause NDO, including multiple sclerosis, spinal cord injury (SCI), meningomyelocele (MMC), stroke, cerebral palsy, and so on. Overactive bladder syndrome (OAB) is a symptom complex including urgency, with or without urge incontinence, but usually with frequency and nocturia. This symptom combination is suggestive of detrusor overactivity which can be demonstrated by urodynamics, but it can also be due to other forms of urethrovesical dysfunction.

Next to DO, sphincteric problems may complicate the clinical picture. Sphincter overactivity and underactivity can both occur. The coordination between bladder and sphincter can be lost, leading to bladder emptying disorders and increased intravesical pressures. Of all these problems DO with sphincter overactivity is probably the most important, since persistent high intravesical pressures may lead to vesico-ureteral reflux and subsequent renal damage.

The underlying mechanisms are complex and involve changes in afferent and efferent processing and also include histological changes in the bladder wall (Figure 2.1).

Figure 2.1 Changes in the innervation can lead to impairment of afferent and efferent signaling at different levels.

Source: Adapted from Andersson 2004. [2] Reproduced with permission of Nature Publishing Group.

This chapter will give a short pragmatic overview of the current understanding of the pathophysiology of neurogenic bladder disorders and will give some information about animal models that are being used to study this condition.

The innervation of the bladder

The voluntary control over the bladder function requires complex peripheral and central innervation.

The central innervation

The brain

Different parts of the brain are important for the regulation of the micturition cycle. These centers include the pontine micturition center (also known as Barrington's nucleus), the cerebral cortex, the paraventricular nucleus (PVN), the medial preoptic area (MPOA) and periventricular nucleus (PeriVN) of the hypothalamus, the periaqueductal gray (PAG), the locus coeruleus (LC) and subcoeruleus, the red nucleus (Red N.), the raphe nuclei, and the A5 noradrenergic cell group. [3]

During the storage phase, afferent input from the spinal cord will travel to the PAG. From there the information is sent to the hypothalamus and thalamus, the anterior cingulate cortex (ACC), the insula and the lateral prefrontal cortex (LPFC). The lateral prefrontal cortex relates to the medial prefrontal cortex (MPFC). At this site the decision to void or not to void is made. During the filling phase, the MPFC will inhibit the PAG and subsequently the PMC. At the initiation of the voiding phase, the MPFC will no longer inhibit the PAG and PMC and voiding will occur through relaxation of the urethral sphincter and contraction of the detrusor (Figure 2.2) The PMC will send motoric output signals to the sacral nuclei. During voiding afferent input is continuously sent to the PAG until the bladder is empty. [4]

Figure 2.2 The different parts of the brain that play a part in the control of the filling and emptying phase of the bladder cycle.

Source: Adapted from Fowler 2008. [4] Reproduced with permission of Nature Publishing Group.

The spinal cord

The regulation of micturition requires connections between the brain and sympathetic, parasympathetic, and somatic systems in the spinal cord. Parasympathetic and sympathetic neurons are located in the intermediate gray matter of the spinal cord sacral and lumbar segments. Parasympathetic neurons send dendrites into the dorsal commissure and into the lateral funiculus and lateral dorsal horn of the spinal cord and exhibit an extensive axon collateral system that is distributed bilaterally in the cord. A similar axon collateral system has not been identified in sympathetic preganglionic neurons. The somatic motor neurons that innervate the external urethral sphincter are located in the ventral horn (lamina IX) in Onuf's nucleus, have a similar arrangement of transverse dendrites, and have an extensive system of longitudinal dendrites that travel within Onuf's nucleus.

Interneurons in the lumbosacral spinal cord are located in the dorsal commissure, the superficial dorsal horn, and the parasympathetic nucleus. Some of these interneurons send long projections to the brain, whereas others make local connections in the spinal cord and participate in segmental spinal reflexes.

Afferent nerves from the bladder project to regions of the spinal cord that contain interneurons and parasympathetic dendrites. Pudendal afferent pathways from the urethra and the urethral sphincter exhibit a similar pattern of termination. The overlap between bladder and urethral afferents in the lateral dorsal horn and the dorsal commissure indicates that these regions are probably important sites of viscerosomatic integration that might be involved in coordinating bladder and sphincter activity. [5]

The peripheral innervation

Innervation of the LUT arises from three sets of nerves: (i) pelvic, (ii) hypogastric, and (iii) pudendal. The three nerves convey both motor and sensory input onto the LUT. Whereas the pelvic nerve provides an excitatory input to the bladder, the hypogastric nerve provides inhibitory input to the bladder and excitatory input to the bladder outlet. The pudendal nerve innervates the striated muscle of the sphincter and the pelvic floor.

The sympathetic innervation originates in the thoracolumbar of the spinal cord. Sympathetic postganglionic nerves release noradrenaline, which by activating β3-adrenergic receptors on the detrusor muscle is known to relax the bladder and to contract the urethra and the bladder neck with the activation of α-adrenergic receptors. It is worth noting that the last drug developed to relieve patients from OAB specifically targets β3-adrenergic receptors. [6]

The parasympathetic and somatic nerves arise from the sacral segments of the spinal cords and convey both efferent and afferent information. Excitation of parasympathetic efferents causes release of acetylcholine and non-adrenergic, non-cholinergic (NANC) neurotransmitters. The acetylcholine, which is generally seen as the main neurotransmitter in the voiding cycle, and of ATP at the nerve endings. [7] These transmitters act on muscarinic (mainly mAChR2 and mAChR3) and purinergic (mainly P2X1) receptors, respectively, to cause detrusor smooth muscle contraction. [8, 9] The relative importance of both signaling molecules is highly dependent on the species, which means that data from animal research must be interpreted with care when translated to human pathology. [10] In rats, ATP plays a substantial role in the initiation of the voiding contraction, whereas its role seems to be much less important in humans. [10, 11] Little is known about the effect of the NANC transmitters release in bladder function. They have been reported to modulate urothelium and lamina propria contractility properties in pigs. [12] Moreover, in diabetic and spinal cord injury rats [13, 14], the contraction induced by NANC is modified compared to controls animals. Interestingly, those changes in bladder function may involve additional, P2X-receptor independent mechanisms. [13] However, to date, there is no clear consensus on the molecules hidden behind the NANC.

Somatic cholinergic motor nerves that supply the striated external urethral sphincter arise in S2–S4 motor neurons in Onuf's nucleus and travel through the pudendal nerves. At the same spinal level another (more medial) motor nucleus innervates the pelvic floor muscles.

Sensory information from the bladder travels through the pelvic and hypogastric nerves, whereas sensory input from the bladder neck and the urethra is carried in the pudendal and hypogastric nerves. The afferent nerves consist of myelinated (Aδ) and unmyelinated (C) axons. The thin, myelinated Aδ-fibres convey information about bladder filling. The C-fibers are insensitive to bladder filling under physiological conditions (they are therefore termed “silent” C-fibers) and respond primarily to noxious stimuli such as chemical irritation or cooling. The cell bodies of Aδ-fibers and C-fibers are located in the dorsal root ganglia (DRG) at the level of S2–S4 and T11–L2 spinal segments. A dense nexus of sensory nerves has been identified in the suburothelial layer of the urinary bladder in both humans and animals, with some terminal fibers projecting into the urothelium. This suburothelial plexus is particularly prominent at the bladder neck but is relatively sparse at the dome of the bladder and is thought to be critical in the sensory function of the urothelium.

Alteration at any level of the neuronal control of micturition could theoretically induce NDO. Indeed, a modified afferent activity, decreased capacity of the CNS to process afferent information, decreased suprapontine inhibition, or increased sensitivity to contraction-mediated transmitters in the bladder might be involved in NDO genesis. [2, 15]

The genesis of the NDO: three hypothesis

Three main hypotheses have been proposed to explain the pathophysiological basis of DO: neurogenic, [15] myogenic, [16] and integrative. [17]

The neurogenic hypothesis

The neurogenic hypothesis arises from the observation that plasticity occurs in neuronal control of the bladder after trauma. Various changes in peripheral and central neural pathways could lead to bladder overactivity. These include (i) a reduction in peripheral of central inhibition; (ii) an enhancement of excitatory transmission in the micturition reflex pathway; (iii) increased primary afferent input from the bladder; and (iv) emergence of bladder reflexes that are resistant to central inhibition. Therefore, the damage to central inhibition, or sensitization of peripheral afferent terminals, in the bladder wall can unmask primitive voiding reflexes that trigger bladder overactivity.

The myogenic hypothesis

In NDO animal models and patients, the detrusor ultrastructure is modified, which may facilitate the propagation of electrical coupling between muscle cells, leading to increased excitability. [18] The myogenic hypothesis suggests that the common feature underlying detrusor overactivity in animals and humans is a change in the properties of smooth muscle that allows local activity to spread throughout the bladder wall. The hypothesis stipulates that even though there is a close relationship between end organs and their innervations, and alteration in one is likely to result in alterations in the other, the myogenic basis of bladder overactivity does not preclude the involvement of alterations in the neuronal pathways of the micturition reflex.

The integrative hypothesis

The integrative hypothesis proposes that interstitial cells, urothelium, and peripheral nerves contribute to normal generation of micromotions (localized spontaneous activity) of the bladder wall, leading to low pressure sensing of the filling state. In patients or animal models, the micromotions are enhanced; with a wider propagation of spontaneous activity and sending of exaggerated sensory information, giving rise to urgency. [19–22]

The link to the clinic

Depending on the localization and extension of the neurological lesion of pathology the clinical picture can change. Usually these pathologies are classified as being suprapontine, suprasacral-infrapontine, or infrasacral. This classification relates to the important relay centers that are involved in the neural control of bladder, sphincter, and pelvic floor (brain centers controlling the PMC, the spinal cord with the parasympathetic nuclei and Onuf’s nucleus, and the peripheral innervation).

Knowledge about the exact nature and localization of the neurological problem will allow the clinician to predict the urological phenotype to some degree (Figure 2.3).

Figure 2.3 Depending on the location of the neurological lesion, several types of bladder and sphincter behavior can be expected.

Suprapontine lesions

The processing of afferent and efferent information may become problematic. Generally speaking the central inhibition of the micturition reflex during the filling phase will become less efficient. Urgency with or without DO can occur. During the voiding phase few or no abnormalities are seen, since the spinal mechanisms are still intact, provided that the PMC can be activated. Examples are Parkinson’s disease, early multiple sclerosis, traumatic brain injury, brain tumors, cerebrovascular accidents, and so on.

Suprasacral-infrapontine lesions

Afferent information (especially from Aδ fibers) can no longer travel through the spinal tracts and efferent signals traveling down may not reach the sacral centers. C-fiber dependent sacral reflexes will become apparent, leading to inappropriate detrusor contractions and poor coordination between the bladder outlet and the detrusor. High intravesical pressures can arise as a consequence of inappropriate detrusor contractions against a closed sphincter. This phenomenon is called “detrusor-sphincter dyssynergia.” These high intravesical pressures can lead to vesico-ureteral reflux with subsequent renal insufficiency. Examples are spinal cord injury, multiple sclerosis, spinal compression, transverse myelitis, and so on.

Peripheral lesions

When the innervation (afferent and efferent) between the end-organs and the spinal cord is disrupted, the bladder and sphincter become more or less denervated. Depending on the extent and nature of the lesions this can lead to an underactive bladder with severely impaired or absent bladder sensations. Clinically this will present with overflow incontinence, retention, and eventually sphincter weakness. This can be seen in a variety of conditions such as cauda equina syndromes, surgical removal of the pelvic plexus during cancer surgery for anorectal or cervical malignancies, and so on.

The neurological pathologies responsible for the development of the neurogenic bladder

Animal models

As human studies and research using human material are inherently limited because of the implications associated with such investigations, our understanding of the lower urinary tract function is incomplete. Much of our knowledge of bladder function has come from in vitro but it is difficult to extrapolate the conclusions of these types of studies. Indeed, ideally, animal models should reproduce all the facets of the human condition, but it is inconceivable that any single animal model will replicate all the aspects of a human condition which are by definition different from patient to patient, plus human bladder physiology differs from animals. For instance, the nerve-mediated contractions of rodent bladders are mediated by cholinergic and purinergic neurotransmitters whilst human bladder contraction is almost solely controlled by acetylcholine – although alternative contraction mechanisms (purinergic, non-cholinergic non adrenergic, NANC) appear in pathological states.

Therefore, animal models must be viewed as tools and not as a mirror to understand pathological mechanisms within the limit of the models.

Spinal cord transection/injury

The spinal cord injury model is the most used animal research model to study NDO. The degree of dysfunction is related to the disease process itself, the area of the spinal cord injured, and the severity of the neurological impairment. Immediately after the injury, a spinal shock phase is followed by hyperreflexia of the striated muscle, the sphincter, and the bladder, leading to a huge increase in bladder pressure that might affect bladder tissue cyto-architecture.

Plasticity of the afferent bladder neurons

Following that phase, it is commonly believed that the overactive bladder phenotype is underlined by the appearance of a C-fiber-mediated micturition reflex due to reorganization of synaptic connections in the spinal cord concomitantly with the plasticity of the dorsal root ganglion neurons. Chronic SCI is accompanied by the hypertrophy of bladder afferent neurons [23] and an up-regulation of the calcitonin gene-related peptide (CGRP) [24, 25] and pituitary adenylaceclase-activating polypeptide (PACAP) content that is likely to facilitate bladder reflex contractions and contribute to bladder dysfunction. [26, 27] Moreover, SCI also results in alteration in the electrophysiological properties of bladder-innervating sensory neurons. On the one hand, sodium current expression shifts from high-threshold tetrodotoxin (TTX)-resistant to low-threshold TTX sensitive. On the other hand, A-type potassium currents are suppressed in SCI rats. [28–30] Peptidergic and non-peptidergic sensory neuron connectivity is also altered in chronic SCI as sprouting of the central roots occurs. All together, the afferent neurons innervating the bladder are more likely to trigger action potentials with smaller stimuli. [31]

Plasticity of the spinal cord

SCI induces central reorganization with the formation of new synapses and alteration to preexisting ones. [32] The balance between excitatory and inhibitory transmission in the bladder control pathway might be altered. Indeed, the glutamatergic transmission is modified [33] with a decreased GABA A receptor activation. [34] These neurochemical alterations may be involved in bladder dysfunction.

Parkinson animal models

Parkinson disease is one of the most common neurological causes of NDO and symptoms become more severe as the disease progresses and affect up to 90% of patients. [35] Parkinsonism can be induced in animals by administering a neurotoxin that induces DO. [36] This model has led us to understand the involvement of central dopaminergic pathways that have both excitatory and inhibitory effects on rat bladder function. Activation of the D1-like receptor might tonically inhibit the micturition reflex while D2-like receptors facilitate it. [28]

Experimental auto-immune encephalomyelitis model

The vast majority of patients with multiple sclerosis (MS) develop bladder control and NDO often refractory to antimuscarinics. Moreover, 60% of MS patients show detrusor–sphincter dyssynergia, an abnormality characterized by obstruction of urinary outflow as a result of discoordinated contraction of the urethral sphincter muscle and the bladder detrusor muscle. Myelin basic protein (MBP) can be used as an antigen for inducing experimental allergic encephalomyelitis (EAE) in rodents and has widely been used as a model for MS. It was shown that bladder walls undergo morphological changes. Indeed, a significant increase in the bladder-weight-to-body-weight ratio and marked bladder remodeling with increased luminal area and tissue hypertrophy. Despite increased amounts of all tissue components (urothelium, smooth muscle, and connective tissue), the ratio of connective tissue to muscle increased significantly in EAE mice compared with control mice [37] (Figure 2.4).

Figure 2.4 Clinical score (CS) is correlated to bladder tissue remodeling in EAE mice. (a) The bladder-weight-to-body-weight ratio increase correlates with increasing clinical score (CS) in EAE mice compared to CFA-immunized mice. (b) Histological examination showed bladder hypertrophy and lumen dilation in the EAE mice relative to the CFA control mice, corresponding with increasing CS.

Bladder dysfunction in EAE rats is transient, reversible, and leads to more frequent voiding events. Interestingly, the functional alterations occur concomitantly with hind limb paralysis and inflammatory changes in the spinal cord [38] and the bladder remodeling corresponds to EAE severity, suggesting that at least part of the urinary symptoms arise from local changes in the bladder. [39]

Multiple system atrophy

Multiple system atrophy (MSA) is a sporadic adult-onset neurodegenerative disorder that features motor impairment and autonomic dysfunction. [40] Non-motor features (i.e., urogenital dysfunction) are often premonitory of MSA onset. [41] Retrospective data analyses indicate that urological symptoms emerge early and may precede the neurological presentation by several years in the majority of MSA patients. [42]

Transgenic mice with targeted overexpression of human αSyn (hαSyn) in oligodendroglia have been developed to reproduce GCIs and to study related mechanisms of neurodegeneration relevant to the human disease. [43] Several recent neuropathological findings in transgenic mice with oligodendroglial overexpression of hαSyn under the proteolipid protein (PLP) promoter, [44, 45] including progressive neurodegeneration of the substantia nigra pars compacta (SNc), locus coeruleus, and Onuf's nucleus suggest possible urinary dysfunction in the MSA model similar to that in human MSA. [46] Indeed, in those mice, urodynamic analysis revealed a less efficient and unstable bladder with increased voiding contraction amplitude, higher frequency of non-voiding contractions, and increased post-void residual volume. MSA mice bladder walls showed early detrusor hypertrophy and age-related urothelium hypertrophy. All together, these results strongly suggest that this mice model could be used in pre-clinical studies. [47]

Histological changes

Next to the reorganization of the innervation, local changes in the bladder wall can occur as a consequence of neurological diseases. The detrusor, lamina propria, and urothelium will undergo changes that might contribute to altered generation of afferent signals and abnormal responses to efferent output.

The detrusor

At the ultrastructural level, a common feature seen in NDO bladders from patients and animal models is the presence of protrusion junctions and ultraclose abutments between the smooth muscle cells, features occurring only rarely in normal tissue. [48]

The urothelium

The urothelium is the epithelial lining of the urinary tract between the renal pelvis and the urinary bladder. Three cells layers compose the urothelium: a basal cell layer attached to the basement layer, an intermediate layer, and apically a layer composed of large cells named “umbrella cells.” Those cells are connected with tight junctions that create a physical barrier towards water, solutes, and urea. Historically, the urothelium has been viewed primarily as a barrier; it is now recognized to be a structure that reacts to chemical and physical stimuli by releasing signaling molecules. Accumulative evidences have shown that urothelium expresses many different receptors involved in noci- and mechanoception, such as neurotrophin receptor (TrkA and p75), norepinephrine (α and β), cytokines, purine receptor (P2Xs and P2Ys), transient receptor channels (i.e., TRPV4).

The urothelium is known to reciprocally communicate with afferent nerves running below and within it and some authors have hypothesized that SCI would impact the urothelial cell barrier function and its morphology unless the exact contribution of the urothelium on the development of NDO is unknown. [49] Indeed, although a lot of studies have focused on alterations in the detrusor muscle and its innervation after SCI, much less is understood about changes in the urothelium morphology and its function. Apodaca et al. described that SCI is accompanied by disruption of the urothelium with a loss of umbrella cells that induced a decrease of the transepithelial resistance and permeability to water and urea. The observed alterations are most likely due to urinary retention and overdistension of the urothelium as when the spinal reflex is recovered, between two and three weeks following the injury, the barrier function was recovered – although the apical cells remained smaller. Prior to SCI, treatment of the animals with hexamethonium (a ganglionic blocker) and capsaicin ameliorated the SCI-induced decreased of the transepithelial resistance, strongly suggesting an intimate relation between the urothelium and the nervous system. [48]

The lamina propria

The lamina propria stands between the urothelium and the detrusor and contains the interstitial cells. Because of their particular organization just underneath the urothelium, the interstitial cells have attracted the interest of many investigators because they could embody a structural and functional link between urothelial cells and sensory nerves and/or between urothelial cells and detrusor smooth muscle cells. The guinea-pig interstitial cells have spontaneous and neurogenic calcium oscillations suggesting their functional innervation and indicating that bladder ICC sub-populations are under direct control of the complex innervation that governs normal bladder function. [50]

Moreover, these cells might be involved in the pathophysiology of functional bladder disorders, where local signaling processes are thought to play important roles. In MS patients, the ultrastructural and immunohistochemical phenotype of interstitial cells show modest changes. In NDO bladders the interstitial cells express fewer actin filaments together with a decreased expression of alpha smooth muscle actin and also fewer caveolae. These changes feature a trend toward a fibroblast phenotype with a different topographical organization of those cells. Furthermore, the interstitial cells area is significantly broadened in NDO bladders with a remarkable less-dense intercellular matrix and a broadened space between cell layers. In NDO bladders, frequent close apposition of lymphocytes and ULP ICLC was found. [51, 52] In SCI rats, the lamina propria and detrusor interstitial cells are ultrastructurally damaged post-SCI with retracted/lost cell processes and were adjacent to areas of cellular debris and neuronal degradation [53] (Figure 2.5).

Figure 2.5 Morphological modification of lamina propria. Characterization of upper lamina propria interstitial cells in bladders from control (a) and (c) and MS patients (b) and (d) with CD34 (a) and (b) and SMA (c) and (d). Scale bar: 50 μm.

Source: Adapted from Gevaert 2011 [52]. Reproduced with permission of John Wiley & Sons Ltd.

The functional implications of these observations remain to be determined, but it is likely that these are some of the many elements contributing to altered bladder function in MS patients. [54]

The neuronal structure

Studies carried out in animal models have demonstrated that procedures such as spinal section of urethral obstruction lead to an increase in size of both the afferent neurons in the dorsal root ganglia [55] and the efferent neurons in the pelvic plexus. [56, 57]

Conclusions

Neurological diseases can have a devastating effect on the control of bladder, urethral sphincter, pelvic floor musculature, and bowel. Acute neurological trauma, such as spinal cord or brain injury, will have different impact than progressive diseases such as multiple sclerosis or Parkinson’s disease.

Changes can occur in the central mechanisms (brain and spinal cord), but the end organs will also undergo changes. Reorganizing nerves (e.g., the appearance of the C-fiber reflex, Figure 2.6), receptor plasticity, and even changes in the detrusor and urothelium will lead to a complex clinical picture. At this moment few animal models can be used to study these changes in detail. Much more research will be needed to elucidate these complex changes.

Figure 2.6 The C-fiber reflex. Following spinal cord injury, Aδ-fibers are overruled by C-fibers after a few days or weeks. The activation of these C-fibers can lead to unvoluntary detrusor contractions. Next to these changes in afferent innervation the bladder wall itself also undergoes changes.

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