TUNE : A Wearable Neuromodulation Device to Improve Self-control and Restore Urinary Function by bijoy prasad saha

DEGREE PROJECT TUNE : A Wearable Neuromodulation Device to Improve Self-control and Restore Urinary Function for Women with Urinary Incontinence

SPONSOR : REFLEXIONS DIGITAL PRIVATE LIMITED VOLUME : 1 OF 1 STUDENT : BIJOY PRASAD SAHA

PROGRAMME : MASTER OF DESIGN (M. DES)

GUIDE : KRISHNA AMIN-PATEL CO-GUIDE : KRISHNESH MEHTA

2017 FACULTY OF TEXTILE, APPAREL & LIFESTYLE ACCESSORY DESIGN (APPAREL DESIGN)

National Institute of Design Gandhinagar

The Evaluation Jury recommends BIJOY PRASAD SAHA for the Degree of the National Institute of Design IN FACULTY OF TEXTILE, APPAREL & LIFESTYLE ACCESSORY DESIGN (APPAREL DESIGN) Herewith, for the project titled ‘TUNE : A WEArAblE NEUromodUlATioN dEvicE To improvE SElf-coNTrol ANd rESTorE UriNAry fUNcTioN for WomEN WiTH UriNAry iNcoNTiNENcE’. on fulfilling the further requirements by*

chairman members :

Jury Grade :

*Subsequent remarks regarding fulfilling the requirements :

Activity chairperson, Education

Copyright ÂŠ 2017 Student document publication, meant for private circulation only. All rights reserved. Master of Design, Apparel Design, 2014 National Institute of Design, Ahmedabad, INDIA No part of this document will be reproduced or transmitted in any form or by any means, electronically or mechanically, including photocopying, xerography and video recording without written permission from the publisher, Bijoy Prasad Saha and National Institute of Design, Ahmedabad. All illustrations and photographs in this document are under the copyright of respective people and organizations. Edited and designed by: Name: Bijoy Prasad Saha Email: bijoyprasadsaha@gmail.com Processed at: National Institute of Design. P.G. Campus, GH - 0, Gandhinagar, Gujarat, INDIA

ORIGINALITY STATEMENT I hereby declare that this submission is my own work and it contains no full or substantial copy of previously published material, or it does not even contain substantial proportions of material which have been accepted for the award of any other degree or final graduation of any other educational institution, except where due acknowledgment is made in this graduation project. Moreover I also declare that none of the concepts are borrowed or copied without due acknowledgment. I further declare that the intellectual content of this graduation project is the product of my own work, except to the extent that assistance from others in the projectâ&#x20AC;&#x2122;s design and conception or in style, presentation and linguistic expression is acknowledged. This graduation project (or part of it) was not and will not be submitted as assessed work in any other academic course. Student Name in Full: BIJOY PRASAD SAHA Signature: Date:

COPYRIGHT STATEMENT I hereby grant the National Institute of Design the right to archive and to make available my graduation project/thesis/dissertation in whole or in part in the Instituteâ&#x20AC;&#x2122;s Knowledge Management Centre in all forms of media, now or hereafter known, subject to the provisions of the Copyright Act. I have either used no substantial portions of copyright material in my document or I have obtained permission to use copyright material. Student Name in Full: BIJOY PRASAD SAHA Signature:

Date:

TUNE : A Wearable Neuromodulation Device to Improve Self-control and Restore Urinary Function for Women with Urinary Incontinence

Dedicated to Dida

â&#x20AC;&#x153;Imagination is more important than knowledge.â&#x20AC;? - Albert Einstein

Preface The Masters of Design programme at the National Institute of Design requires the student to engage in a 4-6 month long project, referred to as the graduation project in the final semester. The project is an intensive one, posing the challenges of industry oriented and using a real time design process. It may either be self sponsored or done in association with a company or organization. Irrespective of that, this project is an opportunity to apply their learning from the course in a practical field. Often one realizes that the scope of design lies far beyond demarcations of discipline and demands us to re-look at the parameters of design. In this regard, this graduation project has been a critical learning experience which was both demanding and fulfilling.

Acknowledgment I am very grateful to National Institute of Design for giving me the support and environment to develop an inquisitive mindset and proactive attitude, which helped me through the duration of the project, and will remain a valuable asset for my design practice in the years to come. I express my sincere and deepest gratitude to my project guide Krishna Amin-Patel and Krishnesh Mehta who played a pivotal role in shaping my thinking process, and has always been available whenever I have needed guidance and direction. Their critical reviews have helped me better this project manifold. I am thankful to Amit Sinha, (Discipline Lead, Apparel Design), to allow me to take this research based project as my Graduation project. I am also thankful to Guru Prasad for his valuable guidance and supporting me throughout the project. I am sincerely thankful to Mr. Kaustabh Banerjee, for believing in me and supporting me as a sponsor for this project. I would like to thank to the whole team of Reflexions Digital Pvt. Ltd. I owe my most sincere gratitude to my medical mentor Dr. Sushma Rakesh Shah, NHL medical college, Ahmedabad, played a crucial role in guiding me to understand the medical perspective of this topic, as well as providing the required medical assistance and allowing me to study and conduct interviews with the patients.

I express my immense pleasure and a deep sense of gratitude to Prof. Bhavesh Parmar, Department of Biomedical Engineering, L D College of Engineering, Ahmedabad, for his constant help in improving my understanding of biotechnology and always showing me the possibilities to reach the desired goal with his encouraging attitude. I am really grateful to Mrs. Uma Mukherjee for her special contribution to my project. I would like to thank Riti Sengupta for her contribution in framing the written content for this project, I am also thankful to Vibu Surenrdan for his critical feedback and encouragement on my project. I am also thankful to Prachi Gupta, Paridhi Diwan, Rahul Kumbhar, Kushal Karpe, Snehasish Saha, Sagar Sharma, Vidyadhar Bhandari, Freny Antony, Riturana Deori, Palash Kushum Ghosh and Shrikant Ghode from NID family for their valuable support. I am thankful to KPC Medical College, Kolkata for allowing me to conduct my research. I would like to express my heartfelt gratitude to my parents Biswajit Saha and Juthika saha, my grandmother Mrs. Bhabani Mondal and my younger brother Suvendu Saha for their emotional support and trust. I am deeply thankful to my fiancĂŠ Kanyaka banerjee for her love and constant emotional support and believing in me. I am really greatful to Mr. Kishore Krishna Banerjee, Mrs. Rama Banerjee, Bharti Banerjee and Kaninika Banerjee for their belief in me which was necessary to keep the motivation alive.

About National Institute of Design The National Institute of Design (NID) is internationally acclaimed as one of the foremost multi- disciplinary institutions in the field of design education and research. The Business Week, USA has listed NID as one of the top 25 European & Asian programmes in the world. The institute functions as an autonomous body under the department of Industrial Policy & Promotion, Ministry of Commerce & Industry, Government of India. NID has been declared ‘Institution of National Importance’ by the Act of Parliament, by virtue of the National Institute of Design Act 2014. NID is recognized by the Dept. of Scientific & Industrial Research (DSIR) under Ministry of Science & Technology, Government of India, as a scientific and industrial design research organization. NID has been a pioneer in industrial design education after Bauhaus and Ulm in Germany and is known for its pursuit of design excellence to make Designed in India, Made for the World a reality. NID’s graduates have made a mark in key sectors of commerce, industry and social development by taking role of catalysts and through thought leadership. NID Gandhinagar is situated in the city of Gandhinagar, in Gujarat. As part of expansion plan, NID has built a

BIJOY PRASAD SA H A | M .D E S 2 0 1 7 | GRADUATION PROJECT | NID

new postgraduate campus at Gandhinagar, the capital of Gujarat State. Commerce and Industry Minister Kamal Nath laid the foundation stone for this campus and it consists of a jewellery and automobile design center along with lifestyle accessory design, new media design, toy and game design, strategic design management, transportation and information design centres. NID’s R&D Campus at Bengaluru was set up as a joint initiative of and funding from the Department of Industrial Policy and Promotion (DIPP), Ministry of Commerce and Industry and the Ministry of Information Technology, Government of India and was inaugurated in March 2006. R&D Campus commenced with two research intensive PG Programmes namely Design for Retail Experience and Design for Digital Experience, from the academic year 2007-2008. Currently five Master’s programmes are offered from this campus. NID’s Research & Development Campus addresses the immediate need for an exclusive Design Research center in the country, by fostering the creative design spirit and sighting new opportunities and frontiers through NID’s design acumen nurtured over the four decades of intense teachinglearning process.

About Apparel Design In the globalization era, the apparel segment in India like many other traditional product segments, is undergoing an astounding change of perception. With mounting western influences and a focus on revival of traditional fashion elements, diversity in India is seeing new faces. NID is a reflection of deep cultural influences and facilitates the changing social perception. The Apparel Design department is committed to support and contribute in the sustainable development of the society and in the field of design. Through productive and innovative ideas, the students try to cover the expanding field of sustainability which encompasses the environment, the people, the crafts and the culture of our country. The students also practice extensive research in the fields of production feasibility and craft revivals. The course intelligently blends the traditional revivals with the modern methods. The designers strive hard to collaborate with the multi-faceted he faceted fields of design in the apparel and other segments. Graduates of this programme can seek work in the broad areas of the Apparel Industry which include Ready to Wear, Specialized Fashion, Active Sports Wear, Functional Clothing, Design Education, Costume Design, Design Research etc.

About Sponsor Reflexion Digital Pvt Ltd. Formed in 2000, with a view towards providing complete communications solutions to business enterprises and to partner them in their quest to reach out to their stakeholders in the best manner possible, Reflexions Digital Pvt. Ltd. (RDPL) has evolved into a one-stop solution destination for all business communication requirements. Strictly adhering to the three 3 Cs - Creativity, Cost Effectiveness and Customer Satisfaction, we take pride in being able to understand the client’s brief and replicate it through dovetailed designs and content. Today, Reflexions is a proud partner to the nation’s biggest brands like Tata Steel, Tata Tiscon, Nest-In, Tata Shaktee, Tata Coffee, State Bank of India, Shyam Steel, Apollo Hospitals, Columbia Asia, Nirma, Berger Paints, Pravesh Doors, Tractors India Pvt Ltd, Caterpillar and many others. Over the years, RDPL has forayed into different verticals in a bid to provide a complete 360 degree approach to their services which include Web Services, Print, Visual Merchandising, Communication Campaigns and

Animation. The Agency has also been a big player in Rural Activationhelping clients reach out to their TG in rural India and executing it through tableaux activities which comprises charting out the entire campaign including designing of the van, branding collaterals, AVs, skits , manpower allocation, route devising and finally execution. Simultaneously, RDPL has been adeptly handling corporate events nationally and internationally, where its responsibilities include the entire event management starting from getting artistes on board, stage and décor set up, branding, developing AVs etc. Exhibitions and stall designs are another area where the Company is steadily making a mark, an example being its recent success and the appreciation received for its stall design at Municipalika in Mumbai. With offices in India and now in Bangladesh, Reflexions is all set to service a larger client base in the future and help brands connect with their consumers in a better and more enriching manner.

Synopsis Graduation Project Proposal INTRODUCTION INCONTINENCE Incontinence is a medical term that describes any accidental or involuntary loss of urine from the bladder (urinary incontinence) or bowel motion or feces from the bowel (fecal or bowel incontinence). Simply it is inability to control voluntary activities specifically related to urinary or fecal reflexes. Incontinence is not a life-threatening disease but affects all the strata of the society. It is a common and distressing problem and can negatively affect one’s quality of life. People living with the condition are often embarrassed to discuss their problems to anyone, including their doctor. In fact the ‘World Health Organization’ (WHO) calls incontinence ‘one of the last medical taboos’.

SOCIAL RELEVANCE Incontinence affects more than 200 million people worldwide according to the World Health Organization. Incontinence is often seen as a woman’s problem, but that’s not the reality. Women are more likely than men to have incontinence (32% of the female population experience it, compared to 13% of the male population), but men are just as likely as women to develop incontinence problem. It’s also a myth that incontinence only happens to older people. While it’s more likely, though not inevitable, that you may lose bladder control as you get older, anyone can develop symptoms at any age.

While in India, 36% women, aged above 20 years, are facing incontinence problems and approximately 19% of the male population has incontinence issues. As of the estimated percentage of people suffering from incontinence, 20-33% of them are young adults. As per study it is found that, the number of individuals living with incontinence is likely to increase as the population ages, since the prevalence of the condition tends to increase with age. Majority of India’s population is young. The youth is more likely to be affected by the hitherto unacknowledged domain of inability management. So, it is more likely for the youth to face the incontinence problem in the coming future to come. The negligence could leave us under prepared and make a strong impact on our nation’s strength.

SCOPE OF THE PROJECT The incontinency issue being a social taboo, it cannot be solved by direct introduction of product driven solution. It needs a much deeper understanding of ‘life of incontinent people’. This can be possible only with design driven research to systematically approach with design thinking for ‘wicked problem’ like incontinence. Being a student of National Institute of Design, I would like to target incontinent people, for introducing incontinent

free lifestyle. This could be achieved by designing and developing products or rethinking in a system design approach to come up with a holistic solution for inability management.

RESEARCH AND DELIVERABLES Whole research in the domain of health care would be done as follows. Secondary research will be done by understanding physiological, neurological and psychological conditions of incontinent people, as well as information available on research papers, books, and Internet. During primary research there would be interviews with doctors, specialists, patients and their families. Also there would be a market/ company strategy study in third phase of research. Methodologies for collecting data would include interviews, focus group discussions co-design workshops with all stake holders. I have to collaborate with some hospitals to help me in conducting research with doctors and patients. In terms of deliverables there could be a product or a system design depending on most effective way of implementation.

Contents Incontinence

The neural control of urinary and urogenital system

301

Medical physiology

341

Continence

Mechanism of Action of Neuromodulation to Treat Urinary Incontinence Symptoms

Female pelvic anatomy

Ideation sketching

357

Urothelial cell biology

Anthropometric data analysis

365

The neural control of micturition

107

Design iteration

373

Pathophysiology of urinary incontinence

117

Graphics, icons and logo

391

Medical diagnosis

147

Digital renders and visualization

403

Types of treatment

169

Packaging design

407

Available continence products and solutions for management

191

Prototype development

413

Social aspects

211

3D renders and representation of product

423

Field research

233

Final product

436

Concept direction

263

Functions of the device and user instructions

449

Technology study for final concept

271

â&#x20AC;&#x2DC;Tuneâ&#x20AC;&#x2DC; mobile app

459

Neuromodulation

279

Circuit development

467

Neuromodulation for urninary dysfunction

289

Conclusion

471

Transcutaneous electrical nerve stimulation (TENS)

297

Bibliography

477

Incontinence

WHAT IS INCONTINENCE ? Incontinence is a medical term that describes any accidental or involuntary loss of urine from the bladder (urinary incontinence) or bowel motion or feces from the bowel (fecal or bowel incontinence). Simply it is inability to control voluntary activities specifically related to urinary or fecal reflexes. Incontinence is a widespread condition that ranges in severity from ‘just a small leak’ to complete loss of bladder or bowel control.

TYPE OF URINARY INCONTINENCE:

can not empty completely, causing small amounts of urine leakage.

STRESS URINARY INCONTINENCE (SUI) TRANSIENT URINARY INCONTINENCE This is the most common kind of Urinary Incontinence, especially among women who given birthmor gone through the Menopause. In this case ‘Stress‘ refers to physiological pressure. when the bladder and muscles involved inurinary control are placed under sudden extra pressure, the person may urinate involuntarily.

This is a temporary form of Incontinence, usually caused by a short-lived medical condition, people who have severe constipation, who have an inflamed bladder, urethra or vagina or who are recovering from surgery.

URGE URINARY INCONTINENCE (UUI)

Fecal or Bowel IncontInence

Also known as ‘Reflex Incontinence‘ or ‘Overactive Bladder’, This is the second most common type of Urinary Incontinence. there is sudden, involuntary contraction of bladder wall that causes an urge to urinate that can not be stopped.

Fecal incontinence is the inability to control bowel movements, causing stool (feces) to leak unexpectedly from the rectum. Also called bowel incontinence, fecal incontinence ranges from an occasional leakage of stool while passing gas to a complete loss of bowel control.

MIxED URINARY INCONTINENCE (MUI)

TYPE OF FECAL INCONTINENCE:

Mixed Urinary Incontinence involves more than one type of Incontinence, mostly occurs in older women, who often have a mixture of Urge and Stress Urinary Incontinence.

URGE BOWEL INCONTINENCE

TYPE OF INCONTINENCE: •

URINARY INCONTINENCE

•

FECAL OR BOWEL INCONTINENCE

URINARY INCONTINENCE (UI) Urinary Incontinence also known as ‘Involuntary Urination‘ is any leakage of urine. It is a common and distressing problem, which may have a lagre impact on quality of life. Urinary Incontinence is often a result of an underlying medical condition but is under-reported to medical practitioners.

When the individuals has a sudden urge to go to the toilet but is unable to get there in time.

OVERFLOW URINARY INCONTINENCE PASSIVE BOWEL INCONTINENCE This s more common in men with prostate gland problems, a damaged bladder, or a blocked urethra. An enlarged

Nothing is felt to indicate that a bowel movement is about to occuur.

prostate gland can obstruct the bladder . The bladder can not hold as much urine as the body making, or the bladder

BIJOY PRASAD SA H A | M .D E S 2 0 1 7 | GRADUATION PROJECT | NID

Prevalence of Urinary and Faecal Incontinence Incontinence is a common symptom that may affect all ages, and there is a wide range of severty and nature of symptoms. Incontinence is not a life-threatning disease, but the symptoms may seriously influence the physical, psychological and social well being of the affected individuals. It ia common and ditressing problem which negetively affects one’s quality of life. Peole living with the condition are often embrassed to discuss it to any one, including doctors. According to the ‘World Health Organization’ (WHO) Incontinence ‘one of the last medical taboos’. Incontinence affects more than 200 million people worldwide according to the World Health Organization. Incontinence is often seen as a woman’s problem, but that’s not the reality. Women are more likely than men to have incontinence, but men are just as likely as women to develop incontinence problem. It’s also a myth that incontinence only happens to older people. While it’s more likely, though not inevitable, that you may lose bladder control as you get older, anyone can develop symptoms at any age. 32% of the female population experience incontinence, compared to 13% of the male population. Approximately 25%-45% of women suffer from Urinary Incontinence. The percentage of Urinary Incontinence increases with age, 20%-30% of young women, 30%-40% middle aged women and upto 50% of older women suffers from Urinary Incontinence.on estimated to experience OAB symptoms. 346 million individuals or 8% of the world population estimated to experience some type of U 28

Figure 1: Estimated Number of Individuals with Certain Lower Urinary Tract Symptoms By Year & Sex- World Population (In Millions) [Data from: INCONTINENCE, Editors: PAUL ABRAMS, LINDA CARDOZO, SAAD KHOURY & ALAN WEIN, International Continence Society (ICS), 5th edition, 2013 ]

BIJOY PRASAD SAH A | M.DES 2017 | GRADUATION PROJECT | NID

Approximately 7%-18% of suffer from Fecal Incontinence. The percentage of Fecal Incontinence increases with age, !%-3% of young women, 5%-7% of middle aged women and upto 20% of older women suffers from Fecal Incontinence. While in India, 35%-45% women, aged above 20 years, are facing incontinence problems and approximately 19% of the male population has incontinence issues. As of the estimated percentage of people suffering from incontinence, 20-33% of them are young adults. As per study it is found that, the number of individuals living with incontinence is likely to increase as the population ages, since the prevalence of the condition tends to increase with age. A majority of people with Incontinence have not sought help, and this is confirmed also in recent publications. Reasons given by people for not seeking help include: not regarding incontinence as abnormal or serious, considering incontinence to be a normal part of ageing, having low expectations of treatment and thinking they should cope on their own. Some studies also confirm the notion that embarrassment may be an important reason for not seeking help.There is an association between help seeking and condition-specific factors like duration, frequency and amount, and peopleâ&#x20AC;&#x2122;s perceptions of the impact of incontinence, but other more personal characteristics like individual health care behaviour and attitudes may also play a role. Only a small proportion of incontinent communityresiding women have had surgery, medication, or exercise regimens. In addition to seeking help from the formal health care system, common responses to symptoms of

Figure 2: Estimated Worldwide Number of Individuals with LUTS including OAB and Incontinence by Region (In Millions) [Data from: INCONTINENCE, Editors: PAUL ABRAMS, LINDA CARDOZO, SAAD KHOURY & ALAN WEIN, International Continence Society (ICS), 5th edition, 2013 ]

illness are self-management and self-treatment behaviour. The major method of actively managing Incontinence among community residents is the use of absorbent products. It is obvious that millions of men and women suffer from their Incontinence, and that for many of them good treatment options are available. However, for many persons with very mild or occasional Incontinence it is probably adequate not to seek help from the health care system. Others are satisfied with just information and understanding about the causes and in many cases self care may be quite appropriate.

measurement of Incontinence should be performed in cluding, its types and severity to move the research ahead. Longitudinal study designs are needed to estimate incidence of Incontinence and describe the course of the condition and its different forms and to investigate its risk factors and possible protective factors. There is still little knowledge with regard to prevalence, incidence, and other epidemiological data in developing countries. It is recommended that fundamental research regarding prevalence, incidence and other epidemiological data in developing countries should be encouraged, and tailored to the cultural, economic and social environment of the population under study.

It is recommended that more sustained research on

BIJOY PRASAD SA H A | M .D E S 2 0 1 7 | GRADUATION PROJECT | NID

Figure 3: Estimated number of individuals with UI 2008, 2013 and 2018 grouped according to type of incontinence. [Data from: INCONTINENCE, Editors: PAUL ABRAMS, LINDA CARDOZO, SAAD KHOURY & ALAN WEIN, International Continence Society (ICS), 5th edition, 2013 ]

Figure 4: Estimated number of individuals with LUTS 2008, 2013 and 2018 grouped according to gender. [Data from: INCONTINENCE, Editors: PAUL ABRAMS, LINDA CARDOZO, SAAD KHOURY & ALAN WEIN, International Continence Society (ICS), 5th edition, 2013 ]

BIJOY PRASAD SAH A | M.DES 2017 | GRADUATION PROJECT | NID

SUMMARY

Figure 5: Prevalence of Incontinence by age group and their perceptions about this. [Data from: INCONTINENCE, Editors: PAUL ABRAMS, LINDA CARDOZO, SAAD KHOURY & ALAN WEIN, International Continence Society (ICS), 4th edition, 2009]

BIJOY PRASAD SA H A | M .D E S 2 0 1 7 | GRADUATION PROJECT | NID

•

46% of the 4.2 billion of the adult world population ( 20 and over) experience any LUTS.

•

455 million individuals or 11% of the world population estimated to experience OAB symptoms.

•

346 million individuals or 8% of the world population estimated to experience some type of UI.

•

SUI is the most common type of incontinence in 2008 and 2018.

•

136 and 164 million individuals are estimated to experience SUI in 2008 and in 2018 respectively.

•

49 and 60 million individuals are estimated to experience UUI in 2008 and in 2018 respectively.

•

53 and 65 million individuals are estimated to experience MUI in 2008 and in 2018 respectively.

•

Assuming LUTS prevalence rates remain stable for the next ten years, 2.3 billion individuals are estimated to experience LUTS by the year 2018, an increase of 18% from 2008.

•

Male: estimated 597 million in 2008, 713 million in 2018.

•

Female: estimated 760 million in 2008, 901 million in 2018.

•

Asia region is estimated to carry the highest burden of LUTS. Estimated 1.2 billion individuals in Asia regions may experience any LUTS.

Risk Factors for Incontinence Incontinence is a stigmatising condition in many populations, which creates a high risk for respondent bias in incontinence epidemiology. Perhaps because of stigma, incontinence is also associated with low rates of presentation for care. Epidemiological and clinical studies conducted in various populations reveal a number of variables related to Incontinence including several possible risk factors or contributing variables. Most of the data regarding risk factors for the development of Incontinence have been derived from cross sectional studies of volunteer and clinical subjects. Risk factors like smoking, menopause, restricted mobility, chronic cough, chronic straining for constipation, and urogenital surgery have not been as rigorously studied as age, parity, and obesity. This provides us with information of limited generalizeability and restricts the level of inference regarding causality. Well-controlled analyses of potential risk factors and predictors are limited. Little is known about their relative and absolute value. Risk factors or causes of Incontinence need to be investigated in a prospective or longitudinal design in order to establish the temporal ordering between risk factors and onset of Incontinence. Unfortunately, very few longitudinal studies of Incontinence have been conducted. Therefore this review of health relaed factors is based primarily on cross sectional studies and can only identify correlates.

BIJOY PRASAD SAH A | M.DES 2017 | GRADUATION PROJECT | NID

Risk Factors for Urinary Incontinence in Women

AGE • AGE OBESITY

•

PARITY PREGNANCY MODE OF DELIVERY

•

MANOPAUSE & REPRODUCTIVE HOMONES HYSTERECTOMY LOWER URINARY TRACT INFECTION ISCHAMIC HEART DISEASE DIABETES HIGH IMPACT ExERCISE DEPRESSION

The prevalence of Urinary Incontinence increased steadily with age and there is significant association between age and Urinary Icontinence. Though age was significant, there were no differences between the middle-aged and older women. Some studies have found that age was a significant risk factor for both urge incontinence and stress incontinence. Incontinence is not to be considered normal with aging; however, there are changes in the bladder and the pelvic structures that occur with age and which can contribute to Urinary Incontinence Further, Urinary Incontinence is often attributable to medical problems or diseases that can disrupt the mechanisms of continence (e.g., diabetes mellitus, cognitive impairment), many of which are more common among older adults.

Increases intraabdominal pressure, predisposing to SUI, while coexisting metabolic syndrome predisposes to UUI.

PARITY OBESITY • •

FUNCTIONA IMPAIRMENT COGNITIVE IMPAIRMENT SMOKING •

•

Obesity is well established as a factor that can cause UI or contribute to the severity of the condition. It is believed that the added weight of obesity, like pregnancy, may bear down on pelvic tissues causing chronic strain, stretching and weakening of the muscles, nerves, and other structures of the pelvic floor. Data from several studies indicate that UI in women is associated with higher body mass index and greater weight. there are positive associations between Body Mass Index (BMI) and both Urge Urinary Incontinence(UUI) and stress Urinary Incontinence (SUI). Obesity

BIJOY PRASAD SA H A | M .D E S 2 0 1 7 | GRADUATION PROJECT | NID

•

Parity is considerd as the most important risk factors for the Urinary Incontinence. First, childbirth may result in pelvic floor laxity as a consequence of weakening and stretching of the muscles and connective tissue during delivery. Second, damage may occur as a result of spontaneous lacerations and episiotomies during delivery. The result of these events can be impaired support of the pelvic organs and alteration in their positions. A third possibility is that the stretching of the pelvic tissues during vaginal delivery may damage the pudendal and pelvic nerves, as well as the muscles and connective tissue of the pelvic floor, and can interfere with the ability of the striated urethral

• •

sphincter to contract promptly and efficiently in response to increases in intraabdominal pressure or detrusor contractions. Urinary Incontinence is most common in women who had four or more children. Studies found that women over 30 years old at their first delivery were at higher risk, while another found that increasing age at the first delivery had an influence on UI.

MANOPAUSE & REPRODUCTIVE HOMONES

LOWER URINARY TRACT INFECTION

•

PREGNANCY •

•

UI in women is often assumed to attributable to the effects of pregnancy and childbirth. UI is common among pregnant women. Incontinence during pregnancy has been shown to be a predictor of postpartum incontinence, as well as a risk factor for incontinence at 5 years past delivery. there is evidence that women who are incontinent during pregnancy may be predisposed to experiencing UI at later times in their lives, such as during a subsequent pregnancy or as they age. However, it is still questionable whether pregnancy itself contributes to UI in later life or whether it is attributable to factors associated with childbirth.

•

Clinically, it has long been understood that urinary symptoms are an integral part of the transition from the premenopausal to the postmenopausal state. The atrophic changes increase susceptibility to urinary tract infections and can cause storage symptoms (such as urinary frequency and urgency), dysuria, vaginal dryness, and dyspareunia. Given the evidence that atrophy of these tissues can be reversed with estrogen, and that estrogen replacement reduces UI in some cases, it seems reasonable to propose that estrogen loss contributes to the problem. Postmenopausal women were mom likely to have UI on a daily basis or more frequently, compared to the premenopausal women. A significant increase in the incidence of UI occurred 10 years before the menopause, and an even larger increase was found at menopause. women who experienced a surgical menopause had a higher prevalence of UI compared to those who experienced a natural menopause. Studies have found an increased risk of incontinence in women taking hormones for menstrual disorders and in older women taking estrogen.

MODE OF DELIVERY

HYSTERECTOMY

•

Urinary tract infection has long been considered a contributor to It, a condition to be resolved as a transient cause of UI. Several studies support this by reporting an association between UI and history of UTI, recurrent UTI, or symptoms of cystitis . Regardless of whether they are caused by infection, disease, normal processes, or unknown factors, several urinary tract symptoms have proven to be correlated with UI. Symptoms such as blood in the urine, cloudiness or foul smell in urine, burning with urination, trouble starting urine flow, inability to shut off urine flow, needing to push and strain while urinating, or needing to urinate more than once to empty bladder has emerged as one of the most critical set of correlates and potential precursors of UI.

ISCHAMIC HEART DISEASE • •

Ischaemic heart disease is associated with many risk factors for UI. ischaemic heart disease is a risk factor for incident UI, its effects might be mediated by cardiac failure, or polypharmacy.

DIABETES

• • • •

There is growing evidences that vaginal delivery may predispose a woman to Incontinence more than a cesarean section. Vaginal delivery is belived to cause ‘Pelvic Neuropathy‘that could instigate UI. Thre are obsteric risk factors, including ‘‘forcep delivery’ and use of ‘episiotomy‘. There are strong relation between UI and Forecep delivery and Vacuum extraction. Induced Labor has also been imlicated as a factor contributing to Urinary Incontinence.

•

When asked about the onset of UI, many women will report that it began immediately following hysterectomy. A hysterectomy with oophorectomy puts a woman into surgical menopause, which could indicate a hormonal mechanism. Alternatively, the development of post-hysterectomy UI might be caused by nerve damage during the procedure or to disturbances of musculofascial attachments of the bladder to the surrounding pelvic wall.

•

• •

Many cross sectional studies have reported urinary incontinence to be more common in women with either type 1 or type 2 diabetes than among women with normal glucose levels even after extensive adjustment for known risk factors. It may have wide impacts for both SUI and UUI. Despite a host of plausible pathophysiological mechanisms by which diabetes might induce incontinence, it remains unclear whether it truly has a causal role.

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HIGH IMPACT EXERCISE

COGNITIVE IMPAIRMENT

•

Evaluating associations between physical activity and incontinence remains complex. It is clear that high impact exercise such as gymnastics or trampolining is a direct cause of stress UI. In this case heavy weight lifting of overstretched body movements may cause for a weak pelvic floor muscle, thus resulting UI.

•

Patients lacking mental orientation had a 3.6 times greater risk of being incontinent than those with normal mental status;and the presence of dementia increased the risk. UI in persons with dementia concluded that UI is common in patients with dementia and is more prevalent in demented than in nondemented older individuals.

SUMMARY • •

DEPRESSION •

Several cross-sectional studies have documented an association between depression and incontinence. It seems plausible both that the stigma of UI leads to depression (for example by reducing a woman’s social network), and depression is likely to increase the bother of UI symptoms.

SMOKING

•

FUNCTIONA IMPAIRMENT • •

•

Another set of health related correlates that have been substantiated in several studies are functional impairments, particularly mobility limitations. Mobility problems include having experienced a fall during the last 12 months, being diagnosed with arthritis, currently using equipment to get around, being restricted from going out, and several performance measures of lower body physical functions. Other large studies of older adults have shown that UI was associated not only with mobility impair-ment but also with sensory impairment (impaired vision), which may contribute to mobility limitations. There is evidence of an association between UI and stroke as well as Parkinson’s disease. UI may be a direct consequence of neurological damage caused by these diseases or an indirect result of the physical limitations they impose.

Smoking has been implicated as a risk factor for incontinence in women. Although the mechanism is unknown, but it is thought that smoking may contribute to chronic coughing or interfere with collagen synthesis. Smoking is also known as bladder irritant, which may cause for Over Active Bladder. Smoking was a risk factor for incontinence in young women, and women in the 12-month postpartum period.

• •

• OTHER FACTORS Other published articles have reported correlations between Ul and several other variables, including fasting blood glucose, previous gynecological surgery, constipation, fecal incontinence, use of diuretics, caffeine consumption, suturing, genital prolapse, radiation, impaired function of the levator muscles, childhood enuresis, respiratory problems, and sleep disturbance etc.

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• • •

It is very pprominent that every direct or indirect risk fastor for Urinary Incontinence are wide spreaded. Few of the major rosk factors are very common among the women population. Pregnancy, labour and vaginal delivery are significant risk factors for later UI. Additional evidence has now established body mass as an important, modifiable risk factors for UI. Poor physical function also appears to be an independent risk factor for UI in older women. Diabetes is a risk factor for UI in most studies. While diabetic neuropathy and/or vasculopathy are possible mechanisms by which diabetes could lead to UI. Menopause, as generally defined, does not appear to be an independent risk factor for stress UI. Hysterectomy remains a possible risk factor for later UI. Moderate to severe dementia in older women is a moderate to strong independent risk factor for UI Other potential risk factors, including smoking, diet, depression, constipation, UTIs, and exercise, while associated with UI, have not been established as aetiological risk factors.

Risk Factors for Urinary Incontinence in Men

The epidemiology of UI in men has not been investigated to the same extent as for females. the prevalence rates of UI continue to be reported to be less in men than in women by a 1:2 ratio.

aids to walking, as well as diagnosed arthritis are significantly greater among incontinent than continent men. UI are more likely among men whose ‘activities of daily living’ are impaired, specifically those who are unable to change clothes and unable to walk outside.

AGE LOWER URINARY TRACT INFECTION FUNCTIONA IMPAIRMENT

The type and age distribution of UI appear to be different between the sexes and risk factors, although less investigated in men, seem to be different.

•

COGNITIVE IMPAIRMENT NEUROLOGICAL DISORDERS

It is also important not to consider UI as an isolated problem in men, but rather as a component of a multifactorial problem. Often other urogenital symptoms (LUTS) such as weak stream, hesitancy, and dribbling, or erectile dysfunction, exist.

DIABETES

dementia is a most common risk factors for the occurrence of UI. In general, most studies find similarities between men and women (see subsection on women) for functional and cognitive impairment as risk factors for UI.

NEUROLOGICAL DISORDERS AGE

Due to differences in anatomy and pathophysiology of UI in men and women, there is a different distribution in incontinence subtypes. Recent studies confirmed our previous reports of the predominance of urgency incontinence (40-80%), followed by mixed forms of UI (10-30%), and stress incontinence (<10%). The predominance of urge type incontinence among men, and its close relation to overactive bladder with and without incontinence. Another factor is the close association between urge UI and prostate gland disease, infections, or bowel dysfunction. There is relatively little research concerning conditions and factors that may be associated with UI in men, and clear risk factors are more seldom scientifically documented. However, a few available studies have identified potential risk factors, which are described below.

• •

•

LOWER URINARY TRACT INFECTION •

LUTS like urgency, nocturia, feeling of incomplete voiding and reduced flow are typically associated with UI. Studies have also reported that urinary tract infections and cystitis are strongly associated with male UI.

FUNCTIONAL AND COGNITIVE IMPAIRMENT •

As in women, increasing age is correlated with increasing prevalence of UI. studies has shown that age is an independent risk factor for incontinence. Compared to women, however, there seems to be a more steady increase in prevalence in men with increasing age.

Many specific neurological diseases may lead to UI. Detrusor hyper-reflexia is seen commonly in mengingo-myelocele patients and in spinal injuries, Parkinson’s disease and multiple sclerosis. Areflexic bladder dysfunction due to a cauda equina lesion or diabetes might cause overflow or a paralysed pelvic floor and hence stress incontinence. studies showed that men who suffered stroke were at an increased risk for UI.

DIABETES •

Several reports have not found diabetes to be a factor significantly associated with UI in men. However studies showed that diabetic men were significantly more likely to have UI.

Mobility problems such as use of a wheelchair or

BIJOY PRASAD SAH A | M.DES 2017 | GRADUATION PROJECT | NID

Risk Factors for Overactive Bladder and Nocturia OAB is a term to describe the clinical problem of urgency and urgency incontinence from a symptomatic rather than from a urodynamic perspective. Previously various terms, such as ‘irritable bladder’ or ‘unstable bladder’ have been used. According to the International Continence Society, OAB is a symptom-defined condition characterised by urinary urgency, with or without urgency urinary incontinence, usually with increased daytime frequency and nocturia. The ICS defines urinary urgency as sudden compelling desire to pass urine, and the term OAB is appropriate if there is no proven infection or other obvious pathology.

The causes and risk factors of urinary urgency and/or OAB are not well studied. Available studies, that have identified potential risk factors, are summarised below.

•

Most of the studies shows older individuals reported more OAB than younger ones. OAB increases with age. However, while OAB is agerelated, it may not be age-dependent. In some studies, OAB was not associated with age after adjustment for other factors/ confounders. Besides increasing age, also having urgency in childhood predicts having urgency in later life.

AGE GENDER OBESITY

According to the ICS, as stated earlier, nocturia is also a component of OAB. However, there is an ongoing debate on the definitions, especially regarding urinary urgency and OAB.

MENTAL HEALTH

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• •

Urologists have traditionally defined nocturia as frequency of urination at night without reference to urine amount, while internists have assumed that nocturia results from an increased amount of urine produced with less focus on other urinary symptoms. By the ICS definitions, nocturia refers to waking at night one or more times to void, and nocturnal polyuria (NP) to the production of an abnormally large volume of urine during sleep. Nocturnal urinary incontinence or nighttime bed wetting (enuresis) differs from nocturia.

OAB has been divided into ‘OAB wet’ (OAB with urgency urinary incontinence) and ‘OAB dry’ (OAB without urgency urinary incontinence).

AGE

LIFESTYLE

GENDER • •

RACE & ETHNICITY

Most studies OAB was more common among women. Typically OAB is more common among women especially in younger ages.

REPRODUCTIVE FACTORS & PELVIC SURGERY

OBESITY

SPECIFIC CONDITION

•

PELVIC ORGAN PROLAPSE

•

Obesity is a risk factor for the onset of OAB in women but not among men. OAB is associated obesity. Similarly, among obese women, increasing obesity was associated with OAB after adjustment for age, mode of delivery, and parity. Increased waist circumference was associated with prevalence of OAB.

LIFESTYLE •

For women drinking carbonated drinks could be onset for OAB.

•

• •

Alcohol, coffee and tea consumption are also could be risk factors for the onset of OAB (defined as having either urgency, UUI, or a combination of these). Among men, consumption of beer can cause for OAB. For women smoking can cause for OAB.

•

Mental health: Urinary frequency, urgency, and nocturia is associated with previously experienced sexual, physical, and emotional abuse for both genders and for all ethnic groups. Other conditions: urgency is associated with almost double the risk of hypertension and heart disease in women and with more than double the risk of diabetes in men. Urgency or OAB has also been reported to be common among patients with diabetes, stroke and asthma.

•

RACE & ETHNICITY • • •

higher prevalence of urgency, was found in indigenous woman than in non-indigenous women. OAB is significantly more common among AfricanAmerican and Hispanic male opulation. Prevelance of OAB is more in lower economic group than higher economic group,

•

SUMMARY

REPRODUCTIVE FACTORS & PELVIC SURGERY • •

• •

• • •

Urinary urgency is a common symptom during pregnancy. The association of the post-menopausal years with increased urgency or OAB has been reported in several studies. Radical hysterectomy is related to increased prevalence of pelvic floor problems. Both prolapse surgery and stress incontinence surgery are associated with a risk of urgency or urgency incontinence. Using oral contraceptives pills may cause for OAB. Women with vaginal delivery has more chance to face OAB than cesarean sections. Women with cervical cancer reported higher chance to face OAB.

SPECIFIC CONDITION •

Pelvic organ prolapse: Number of studies showed that pelvic organ prolapse is associated with 2-6 times higher risk of having urgency incontinence.

•

• •

Overactive bladder (syndrome) (OAB) has been defined as urinary urgency, with or without urgency urinary incontinence, usually with increased daytime frequency and nocturia (in the absence of infection or other obvious pathology). Studies have shown that OAB increases with age, and that OAB is a dynamic condition, with not only substantial progression but also remission rates. OAB has been suggested to be associated with an increased risk of falls, fractures, and impaired quality of life. Individuals with benign prostatic hyperplasia, pelvic organ prolapse and mental health problems typically report urinary urgency more often than those without

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Risk Factors for Pelvic Organ Prolapse PREGNANCY, PARITY AND OBSTETRIC FACTORS

Pelvic organ prolapse (POP) refers to loss of support for the uterus, bladder, colon or rectum leading to prolapse of one or more of these organs into the vagina. The condition may occur at rest and is often aggravated by increases in intra-abdominal pressure during daily activities.

•

AGE PREGNANCY, PARITY, AND

The stages of prolapse severity are arbitrarily defined, and there is no clear differentiation between normal anatomic variation and mild POP. For research purposes there is consensus for use of the POPQ system until further evidence might clarify the distinction between normal variation and mild prolapse.

OBSTETRIC FACTORS

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OBESITY RACE AND HEREDITARY FACTORS MENOPAUSE AND

The distress experienced by the woman is most relevant clinically, but there is insufficient evidence at present to define POP by symptoms, as the symptoms of POP are non-specific, and overlap with many other pelvic floor disorders. “Feeling a bulge in the vagina”, the most common symptom attributed to prolapse, has shown a moderate correlation with the severity of prolapse in an affected population.

•

Several studies have shown an association of prolapse with parity and parity is the strongest risk factor for the development of prolapse in women under age 59. There are many aspects of childbirth to consider in assessing risk : The potential effects of pregnancy, of vaginal delivery, instrumented delivery, episiotomy, birth weight, time and management of the second stage, type of anesthesia, and others. Women with more than 4 childbirth has high chance to face POP.

REPRODUCTIVE HORMONES SMOKING BOWEL DYSFUNCTION GYNECOLOGIC SURGERY OTHER FACTORS

Other symptoms, like urinary and faecal incontinence, voiding and defecatory difficulty, and sexual dysfunction frequently coexist, but correlate weakly at best with the severity or site of POP in an affected population. The stages of prolapse severity are arbitrarily defined, and there is no clear differentiation between normal anatomic variation and mild conditions of POP.

AGE •

Pelvic organ prolapse is frequently co-exists with other pelvic floor disorders, such as urinary and fecal incontinence.

•

Surgery for prolapse is uncommon in women under age 30 and over age 80, and there is a steady rise in incidence in between. In comparison to women aged 5o or less, POP is lesser than age between 50-60 and above 60 it is more higher.

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Rate of pelvic organ prolapse surgery in relation to mode of delivery and time from first childbirth.

OBESITY • • •

Studies has shown an increased risk for uterine prolapse for overweight and obese women. Similar increases were found for rectocele and cystocele.

•

RACE AND HEREDIATARY FACTORS • •

Data from studies provides strong evidence of genetic risk factors for incontinence and prolapse. Studies demonstrate increased risks for urinary incontinence among first degree relatives of probands. This appears to apply for all subtypes of urinary incontinence, and to have a plausible biological gradient, with higher risks among relatives of women with severe incontinence.

•

A few studies have investigated a possible association between prolapse and the use of oral contraceptives or postmenopausal hormones. Post-menopausal women, past use of hormone therapy was associated a slightly decreased risk in uterine prolapse and cystocele.

SUMMARY

GYNECOLOGIC SURGERY

MENOPAUSE AND REPRODUCTIVE HORMONES •

Constipation and straining at stool as a young adult before the onset of recognized POP is significantly more common in women who subsequently developed POP. Bowel dysfunction as a young adult, defined as straining with bowel movements or a bowel frequency of <2 times per week was associated with uterovaginal prolapse.

•

Hysterectomy is often suggested as a risk factor for later development of prolapse. After hysterectomy, women are uniquely at risk of prolapse of the vaginal cuff. As the prevalence of hysterectomy at mid-life is high, this may place a large number of women at risk for later development of vaginal vault prolapse. Datas also shows prevalence of rectocele and cystocele in menopausal women is high who had undergone hysterectomy. Repair of prolapse in one site seems to predispose to prolapse in another anatomic site.

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OTHER FACTORS •

SMOKING • •

•

Smoking is often posited as a risk factor for prolapse. Smoking may contribute to chronic coughing and can be cause for weak pelvic muscle floor.

BOWEL DYSFUNCTION

•

Chronic constipation with repeated prolonged defecatory straining efforts has been shown to contribute to progressive neuropathy, pelvic floor dysfunction, and prolapse.

•

Pelvic floor muscle dysfunction has been associated with prolapse. There are evidence for progressive decreases in pelvic floor muscle strength with increasing age and parity. This decrease in pelvic floor muscle strength was a significant independent determinant of the risk of POP. Vaginal childbirth and aging have been implicated as a major inciting event for pelvic neuropathy. Occupational physical stress has been examined as a contributing factor for POP. who are traditionally exposed to repetitive heavy lifting might face POP.

•

Pelvic organ prolapse is a common condition affecting women. Prolapse coexists with other pelvic floor disorders. Hysterectomy for prolapse and increasing age, parity and body mass index are consistent risk factors associated with the condition. Posterior vaginal wall prolapse and perineal descent are the specific pelvic defects most frequently associated with symptoms of obstructive defaecation. Vaginal hysterectomy and hysterectomy performed for pelvic organ prolapse are the strongest risk factors for having secondary pelvic floor surgery. Childbirth is associated with an increased risk for pelvic organ prolapse later in life and increasing number of deliveries is positively associated with the risk. Life style factors and socio-economic indices may be associated with the risk of pelvic organ prolapse.

BIJOY PRASAD SAH A | M.DES 2017 | GRADUATION PROJECT | NID

Risk Factors for Fecal Incontinence OBESITY

Fecal Incontinence (FI) is the involuntary loss of faeces – solid or liquid. Anal Incontinence (AI) includes these events as well as the involuntary loss of flatus, which is felt by many patients to be an equally disabling disorder.

AGE GENDER

This is the loss of fluid, sometimes faeculent, often following a normal continent defaecation. This is an important condition to distinguish from other manifestations of incontinence because most authors that report very high prevalence rates of AI include leakage in their questionnaires and thus may include these individuals with this very common symptom. However in these individuals there is often no detectable sphincter abnormality.

OBESITY CHILDBIRTH &

Data shows an increased risk of AI in obese women. Studies found a reduction in anal leakage in women after bariatric surgery and weight loss, though other factors including diet and activity change may have been responsible for the improvement.

CHILDBIRTH AND MODE OF DELIVERY

MODE OF DELIVERY DIARRHEA

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SURGERY NEUROLOGICAL & OTHER DISEASES

The accuracy of AI prevalence estimates may also be diminished by difficulty in ascertaining those figures due to the common underreporting of AI and patients’ reluctance to report symptoms or to seek treatment. It has been shown that women are more willing to report AI than men. In addition, the character (incontinence of solid faeces, diarrhoea, or flatus, or merely anal seepage) and frequency (daily versus episodic) of reported AI varies greatly in each report, and indeed between individuals. So, prevalence depends heavily on the definition of AI.

• •

•

CONSTIPATION •

AGE •

The prevalence of AI varied from 12.6% to 26.8% in general population.

Studies shows that association of age and anal incontinence and found age to be the most significant of all assessed associations.

GENDER •

AI have been based upon the assumption that women, particularly for individuals under the age of 65 years, are far more at risk for AI than men. Injury to the pudendal nerve or sphincter muscle from prior obstetric trauma is described as the primary risk factor.

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Anal sphincter integrity after vaginal delivery and correlated this with continence stated that 77%-83% (depending on parity) of AI in women was due to sphincter disruption, the only predictor of AI was 3rd4th degree sphincter rupture during birth. Thus incontinence occurs after pregnancy regardless of the method of delivery. This implies that other mechanisms cause incontinence during pregnancy, perhaps trauma in the pelvic inlet. The higher injury in the pelvis may be related to AI in pregnant women can be found in the association of hysterectomy with AI, an association seen more prominently with abdominal hysterectomy than vaginal hysterectomy, and for flatus only. Pelvic nerve injury during surgery is the postulated reason for this difference.

DIARRHEA •

•

The importance of diarrhea of liquid stool in FI cannot be overemphasized, but evidence shows that 51% of individuals with chronic diarrhea are incontinent. Non-infectious causes of diarrhoea must also be considered, such as inflammatory bowel disease.

SURGERY •

• • •

Several operations nonetheless frequently can result in AI. Examples are midline internal sphincterotomy, lateral internal sphincterotomy, fistulectomy, fistulotomy, ileo-anal reservoir reconstruction, low anterior rectal resection, total abdominal colectomy, and ureterosigmoidostomy. The risk of lateral internal sphincterotomy for anal fissure causing AI. Incontinence after hemorrhoidectomy has also been reported to be high. Mixing urine and stool has been found to have a predictable effect on anal sphincter control, as does diarrhea, in patients having ureterosigmoidostomy after urinary bladder resection.

•

the frequent co-existence of constipation and AI, similar to the frequent coexistence of urinary incontinence and AI.

SUMMARY

NEUROLOGICAL& OTHER DISEASES • •

•

Several specific diseases have been anecdotally associated with AI in case series, and mechanisms to explain the associations have been found. Examples are diabetes, stroke, multiple sclerosis, Parkinson’s disease, systemic sclerosis, myotonic dystrophy, amyloidosis, spinal cord injury, imperforate anus, Hirschsprung’s disease, retarded or interrupted toilet training, procidentia, and any illness causing diarrhoea (HIV, IBD, radiation, infection). Many of these conditions directly affect patient mobility and ability to perform daily living activities or they cause diarrhoea or faecal impaction.

• • • • • •

Anal and urinary incontinence commonly coexist, particularly in the elderly and in nursing home residents. The prevalence of anal incontinence increases with age, but is present in all age groups and both genders. AI is almost as common in men as in women. Mode of delivery does not seem to be a significant factor in the development of obstetric anal incontinence, i.e., AI develops after Cesarean delivery as often as after vaginal delivery. Obesity is perhaps the most modifiable risk factor for AI. As populations age, co-morbid disease becomes a significant component of faecal incontinence risk. Surgery, neurological diseases, and stroke are examples. Cognitive and ADL impairment are associated with faecal incontinence.

CONSTIPATION •

Constipation may alternate with diarrhea in irritable bowel syndrome making defaecation chaotic and often very urgent. Just as often retained faeces lead to anal seepage that cannot be held.

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Stress

Guilt Feeling

Depression

Shame

Loss of Self-respect

Embarrassment

Poor Self-confidence

Emotional Wellbeing

Cellulitis Skin Infections

Social Withdrawl

Bacterial Infections

Reduce personal activities

Urinary Tract Infection

Relationship Problems

Fungal Infections

Social insularity

Decubitus Ulcers

Loss of independence

Falls and Fractions Sexual Dysfunction Sleep Deprivation

Impact of Incontinence on Quality of Life Incontinence is frequently associated with a negative impact of quality of life of the patient. It is not really a disease, but rather a symptom, as a result of either a bladder or sphincter disorder. Although it is not a lifethreatening condition, incontinence has a physical and psychological affect on the patients, while at the same time it charges them with an additional financial burden. According to the World Health Organization (WHO), health is defined as the “condition of total physical, emotional and social health and prosperity”, disproving the previous opinion of the absence, mostly, of disease or disability. Even though, the prevalence of incontinence is similar to other chronic diseases, research with regards to its effect on the quality of life.

Frequency, nocturia, urgency, as well as urge incontinence have also been shown to increase the risk of falls, which may lead to fractures and other morbidities.

Incontinence, in whichever form, sweepingly affects the life of the patients. It is conceived as a lack of health which generates feelings of anger and sadness, as well as embarrassment and depression. Patients avoid social gatherings and lose self-confidence, which has a proportional impact on their social interactions, their sexual life and emotional health. Apart from the emotional repercussions, however, incontinence is a risk factor for other physical conditions and diseases, while simultaneously being a financial burden on the patient and his or her family.

Incontinent people often report having low self confidence, feeling ashamed and embarrassed and feeling unattractive to others. Each of these is an obstacle to good psychological well-being. There is also a wealth of evidence that women with incontinence have coexisting psychiatric illnesses. Data shows major depression was three times more common in women with incontinence than in continent women.

The contact of urine with skin also aids in the creation of paratrimma, as well as folliculitis. The perineal dermatitis or incontinence dermatitis refers to the dermatitis caused by urinary or fecal incontinence. It causes severe pain and inflammation in the vagina, the perineum and the buttocks. The increased humidity of the skin ultimately causes a mechanical damage. Therefore, urinary incontinence is a major risk factor for decubitus ulceration.

The direct relationship between incontinence, stress and depression is already adequately documented. It seems that the main impact urinary incontinence has on patient,s lives, in terms of social and recreational withdrawal, stems from the fear and anxiety related to becoming incontinent in public and the possibility that others may find out, rather than distress related to the leakage of urine itself. Evidence suggests that people with urge incontinence or overactive bladder suffer greater psychological distress and anxiety than those with stress incontinence.

This is an important point to consider, as co morbid depression can augment the feelings of low self-esteem and embarrassment associated with incontinence, leading to increased social withdrawal. Incontinent peoples are burdened with anxieties and feelings of embarrassment and shame and they live in constant fear that others will discover their condition. Women’s sexual function and relationships with their partners are significantly affected by their incontinence, thus augmenting their feelings of low self-confidence.

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Furthermore, major depression has been shown to be more common in incontinent women, adding to the cycle of low self-esteem, increased social withdrawal and, ultimately, a reduction in quality of life.

SUMMARY • • • • • • • •

•

Feelings of stigma and humiliation. Social and recreational withdrawal. Fear and anxiety related to being incontinent in public. Reduced intimacy, affection and physical proximity. Loss of concentration and ability to perform physical tasks. Reluctance to visit new places. The quality and amount of sleep is affected, especially in women with an overactive bladder. Women may be woken up several times a night and there may be enuresis or incontinence on the way to the bathroom. Risk of falling, especially in the elderly.

Medical Physiology

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Functional Organization of the Human Body and Control of the “Internal Environment” The human body is complex, like a highly technical and sophisticated machine. It operates as a single entity, but is made up of a number of operational parts that work interdependently. Each part is associated with a specific, and sometimes related, function that is essential for the well-being of the individual. The component parts do not operate independently, but rather in conjunction with all the others. Should one part fail, the consequences are likely to extend to other parts, and may reduce the ability of the body to function normally. Integrated working of the body parts ensures the ability of the individual to survive.

contributes to body needs. In complex organisms such as the human body, cells with similar structures and functions are found together, forming tissues. Organs are made up of a number of different types of tissue and carry out a specific function. Systems consist of a number of organs and tissues that together contribute to one or more survival needs of the body. The human body has several systems, which work interdependently carrying out specific functions.

CELLS AS THE LIVING UNITS OF THE BODY ‘Anatomy’ is the study of the structure of the body and the physical relationships involved between body parts. ‘Physiology’ is the study of how the parts of the body work, and the ways in which they cooperate together to maintain life and health of the individual. ‘Pathology’ is the study of abnormalities and how they affect body functions, often causing illness.

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• • •

LEVELS OF STRUCTURAL COMPLExITY Within the body there are different levels of structural organisation and complexity. The lowest level is chemical. Atoms combine to form molecules, of which there is a vast range in the body. Cells are the smallest independent units of living matter and there are millions in the body. They are too small to be seen with the naked eye, but when magnified using a microscope different types can be distinguished by their size, shape and the dyes they absorb when stained in the laboratory. Each cell type has become specialised, and carries out a particular function that

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The basic living unit of the body is the cell. Each organ is an aggregate of many different cells held together by inter cellular supporting structures. Each type of cell is specially adapted to perform one or a few particular functions. The entire body, contains about 100 trillion cells. Although the many cells of the body often differ markedly from one another, all of them have certain basic characteristics that are alike. For instance, in all cells, oxygen reacts with carbohydrate, fat, and protein to release the energy required for cell function. the general chemical mechanisms for changing nutrients into energy are basically the same in all cells, and all cells deliver end products of their chemical reactions into the surrounding fluids. Almost all cells also have the ability to reproduce additional cells of their own kind. Fortunately, when cells of a particular type are destroyed, the remaining cells of this type usually generate new cells until the supply is replenished.

ExTRACELLULAR FLUID—THE ‘INTERNAL ENVIRONMENT’ About 60 per cent of the adult human body is fluid, mainly a water solution of ions and other substances. Although most of this fluid is inside the cells and is called intracellular fluid, about one third is in the spaces outside the cells and is called extracellular fluid. This extracellular fluid is in constant motion throughout the body. It is transported rapidly in the circulating blood and then mixed between the blood and the tissue fluids by diffusion through the capillary walls. In the extracellular fluid are the ions and nutrients needed by the cells to maintain cell life. Thus, all cells live in essentially the same environment—the extracellular fluid. For this reason, the extracellular fluid is also called the internal environment of the body.

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“HOMEOSTATIC” MECHANISMS OF THE MAjOR FUNCTIONAL SYSTEMS

molecules. Therefore, large amounts of fluid and its dissolved constituents diffuse back and forth between the blood and the tissue spaces, as shown by the arrows. This process of diffusion is caused by kinetic motion of the molecules in both the plasma and the interstitial fluid. That is, the fluid and dissolved molecules are continually moving and bouncing in all directions within the plasma and the fluid in the intercellular spaces, and also through the capillary pores. Few cells are located more than 50 micrometers from a capillary, which ensures diffusion of almost any substance from the capillary to the cell within a few seconds.Thus, the extracellular fluid everywhere in the body—both that of the plasma and that of the interstitial fluid—is continually being mixed, thereby maintaining almost complete homogeneity of the extracellular fluid throughout the body.

The term homeostasis is used by physiologists to mean maintenance of nearly constant conditions in the internal environment. Essentially all organs and tissues of the body perform functions that help maintain these constant conditions. For instance, the lungs provide oxygen to the extracellular fluid to replenish the oxygen used by the cells, the kidneys maintain constant ion concentrations, and the gastrointestinal system provides nutrients.

ExTRACELLULAR FLUID TRANSPORT AND MIxING SYSTEM—THE BLOOD CIRCULATORY SYSTEM Extracellular fluid is transported through all parts of the body in two stages. The first stage is movement of blood through the body in the blood vessels, and the second is movement of fluid between the blood capillaries and the inter cellular spaces between the tissue cells.

ORIGIN OF NUTRIENTS IN THE EXTRACELLULAR FLUID

All the blood in the circulation traverses the entire circulatory circuit an average of once each minute when the body is at rest and as many as six times each minute when a person is extremely active. As blood passes through the blood capillaries, continual exchange of extracellular fluid also occurs between the plasma portion of the blood and the interstitial fluid that fills the intercellular spaces. The walls of the capillaries are permeable to most molecules in the plasma of the blood, with the exception of the large plasma protein

RESPIRATORY SYSTEM

FIgURE 1: general organization of the circulatory system.

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Each time the blood passes through the body, it also flows through the lungs. The blood picks up oxygen in the alveoli, thus acquiring the oxygen needed by the cells. The membrane between the alveoli and the lumen of the pulmonary capillaries, the alveolar membrane, is only 0.4 to 2.0 micrometers thick, and oxygen diffuses by molecular motion through the pores of this membrane into the blood in the same manner that water and ions diffuse through walls of the tissue capillaries.

GASTROINTESTINAL TRACT. A large portion of the blood pumped by the heart also passes through the walls of the gastrointestinal tract. Here different dissolved nutrients, including carbohydrates, fatty acids, and amino acids, are absorbed from the ingested food into the extracellular fluid of the blood.

alveoli; the respiratory movement of air into and out of the lungs carries the carbon dioxide to the atmosphere. Carbon dioxide is the most abundant of all the end products of metabolism. KIDNEYS

LIVER AND OTHER ORGANS THAT PERFORM PRIMARILY METABOLIC FUNCTIONS Not all substances absorbed from the gastrointestinal tract can be used in their absorbed form by the cells. The liver changes the chemical compositions of many of these substances to more usable forms, and other tissues of the body—fat cells, gastrointestinal mucosa, kidneys, and endocrine glands—help modify the absorbed substances or store them until they are needed. The liver also eliminates certain waste products produced in the body and toxic substances that are ingested. MUSCULOSKELETAL SYSTEM How does the musculoskeletal system contribute to homeostasis? The answer is obvious and simple: Were it not for the muscles, the body could not move to the appropriate place at the appropriate time to obtain the foods required for nutrition. The musculoskeletal system also provides motility for protection against adverse surroundings, without which the entire body, along with its homeostatic mechanisms, could be destroyed instantaneously.

Passage of the blood through the kidneys removes from the plasma most of the other substances besides carbon dioxide that are not needed by the cells. These substances include different end products of cellular metabolism, such as urea and uric acid; they also include excesses of ions and water from the food that might have accumulated in the extracellular fluid. The kidneys perform their function by first filtering large quantities of plasma through the glomeruli into the tubules and then reabsorbing into the blood those substances needed by the body, such as glucose, amino acids, appropriate amounts of water, and many of the ions. Most of the other substances that are not needed by the body, especially the metabolic end products such as urea, are reabsorbed poorly and pass through the renal tubules into the urine.

The nervous system is composed of three major parts: the sensory input portion, the central nervous system (or integrative portion), and the motor output portion. Sensory receptors detect the state of the body or the state of the surroundings. For instance, receptors in the skin apprise one whenever an object touches the skin at any point. The eyes are sensory organs that give one a visual image of the surrounding area. The ears are also sensory organs. The central nervous system is composed of the brain and spinal cord. The brain can store information, generate thoughts, create ambition, and determine reactions that the body performs in response to the sensations. Appropriate signals are then transmitted through the motor output portion of the nervous system to carry out one’s desires. An important segment of the nervous system is called the autonomic system. It operates at a subconscious level and controls many functions of the internal organs, including the level of pumping activity by the heart, movements of the gastrointestinal tract, and secretion by many of the body’s glands. HORMONE SYSTEMS

Undigested material that enters the gastrointestinal tract and some waste products of metabolism are eliminated in the feces. LIVER

REMOVAL OF CARBON DIOxIDE BY THE LUNGS

Among the functions of the liver is the detoxification or removal of many drugs and chemicals that are ingested. The liver secretes many of these wastes into the bile to be eventually eliminated in the feces.

NERVOUS SYSTEM

GASTROINTESTINAL TRACT

REMOVAL OF METABOLIC END PRODUCTS

At the same time that blood picks up oxygen in the lungs, carbon dioxide is released from the blood into the lung

REGULATION OF BODY FUNCTIONS

Located in the body are eight major endocrine glands that secrete chemical substances called hormones. Hormones are transported in the extracellular fluid to all parts of the body to help regulate cellular function. For instance, thyroid hormone increases the rates of most chemical reactions in all cells, thus helping to set the tempo of bodily activity. Insulin controls glucose metabolism; adrenocortical hormones control sodium ion, potassium ion, and protein metabolism; and parathyroid hormone

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controls bone calcium and phosphate. Thus, the hormones provide a system for regulation that complements the nervous system. The nervous system regulates many muscular and secretory activities of the body, whereas the hormonal system regulates many metabolic functions.

PROTECTION OF THE BODY

REPRODUCTION Sometimes reproduction is not considered a homeostatic function. It does, however, help maintain homeostasis by generating new beings to take the place of those that are dying. This may sound like a permissive usage of the term homeostasis, but it illustrates that, in the final analysis, essentially all body structures are organized such that they help maintain the automaticity and continuity of life.

IMMUNE SYSTEM The immune system consists of the white blood cells, tissue cells derived from white blood cells, the thymus, lymph nodes, and lymph vessels that protect the body from pathogens such as bacteria, viruses, parasites, and fungi. The immune system provides a mechanism for the body to (1) distinguish its own cells from foreign cells and substances and (2) destroy the invader by phagocytosis or by producing sensitized lymphocytes or specialized proteins (e.g., antibodies) that either destroy or neutralize the invader. INTEGUMENTARY SYSTEM The skin and its various appendages, including the hair, nails, glands, and other structures, cover, cushion, and protect the deeper tissues and organs of the body and generally provide a boundary between the bodyâ&#x20AC;&#x2122;s internal environment and the outside world. The integumentary system is also important for temperature regulation and excretion of wastes and it provides a sensory interface between the body and the external environment. The skin generally comprises about 12-15% of body weight.

CONTROL SYSTEMS OF THE BODY

structure contributes its share to the maintenance of homeostatic conditions in the extracellular fluid, which is called the internal environment. As long as normal conditions are maintained in this internal environment, the cells of the body continue to live and function properly. Each cell benefits from homeostasis, and in turn, each cell contributes its share toward the maintenance of homeostasis. This reciprocal interplay provides continuous automaticity of the body until one or more functional systems lose their ability to contribute their share of function. When this happens, all the cells of the body suffer. Extreme dysfunction leads to death; moderate dysfunction leads to sickness.

The human body has thousands of control systems in it. The most intricate of these are the genetic control systems that operate in all cells to help control intracellular function as well as extracellular function. Many other control systems operate within the organs to control functions of the individual parts of the organs; others operate throughout the entire body to control the interrelations between the organs. For instance, the respiratory system, operating in association with the nervous system, regulates the concentration of carbon dioxide in the extracellular fluid. The liver and pancreas regulate the concentration of glucose in the extracellular fluid, and the kidneys regulate concentrations of hydrogen, sodium, potassium, phosphate, and other ions in the extracellular fluid.

The purpose of study of this chapter is to understand the overall organization of the body and the means by which the different parts of the body operate in harmony. To summarize, the body is actually a social order of about 100 trillion cells organized into different functional structures, some of which are called organs. Each functional

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The Cell and Its Functions ORGANIzATION OF THE CELL Each of the 100 trillion cells in a human being is a living structure that can survive for months or many years, provided its surrounding fluids contain appropriate nutrients. Cell has two major parts are the nucleus and the cytoplasm. The nucleus is separated from the cytoplasm by a nuclear membrane, and the cytoplasm is separated from the surrounding fluids by a cell membrane, also called the plasma membrane. The different substances that make up the cell are collectively called protoplasm. Protoplasm is composed mainly of five basic substances: water, electrolytes, proteins, lipids, and carbohydrates.

PHYSICAL STRUCTURE OF THE CELL The cell is not merely a bag of fluid, enzymes, and chemicals; it also contains highly organized physical structures, called intracellular organelles. The physical nature of each organelle is as important as the cellâ&#x20AC;&#x2122;s chemical constituents for cell function. For instance, without one of the organelles, the mitochondria, more than 95% of the cellâ&#x20AC;&#x2122;s energy release from nutrients would cease immediately.

movement of water and water-soluble substances from one cell compartment to another because water is not soluble in lipids.

MEMBRANOUS STRUCTURES OF THE CELL

CELL MEMBRANE

Most organelles of the cell are covered by membranes composed primarily of lipids and proteins.These membranes include the cell membrane, nuclear membrane, membrane of the endoplasmic reticulum, and membranes of the mitochondria, lysosomes, and Golgi apparatus. The lipids of the membranes provide a barrier that impedes the

The cell membrane (also called the plasma membrane), which envelops the cell, is a thin, pliable, elastic structure only 7.5 to 10 nanometers thick. It is composed almost entirely of proteins and lipids. The approximate composition is proteins, 55% ; phospholipids, 25%; cholesterol, 13%; other lipids, 4%; and carbohydrates, 3%.

FIgURE 1: Reconstruction of a typical cell, showing the internal organelles in the cytoplasm and in the nucleus.

FIgURE 3: Cell Organelles

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ORGANELLES The cytoplasm is filled with both minute and large dispersed particles and organelles.The clear fluid portion of the cytoplasm in which the particles are dispersed is called cytosol; this contains mainly dissolved proteins, electrolytes, and glucose. Dispersed in the cytoplasm are neutral fat globules, glycogen granules, ribosomes, secretory vesicles, and five especially important organelles: the endoplasmic reticulum, the Golgi apparatus, mitochondria, lysosomes, and peroxisomes.

NUCLEUS Every cell in the body has a nucleus, with the exception of mature erythrocytes (red blood cells). Skeletal muscle and some other cells contain several nuclei. The nucleus is the largest organelle and is contained within a membrane similar to the plasma membrane but it has tiny pores through which some substances can pass between it and the cytoplasm, i.e. the cell contents excluding the nucleus. The nucleus contains the body’s genetic material, which directs the activities of the cell. This is built from DNA and proteins called histones coiled together forming a fine network of threads called chromatin. Chromatin resembles tiny strings of beads. During cell division the chromatin replicates and becomes more tightly coiled forming chromosomes. The functional subunits of chromosomes are called genes. Each cell contains the total complement of genes required to synthesise all the proteins in the body but most cells

synthesise only the defined range of proteins that are appropriate to their own specialised functions. This means that only part of the genome or genetic code is used by each cell. Metabolic processes occur in a series of steps, each of which is catalysed by a specific enzyme and each enzyme can be produced only if the controlling gene is present. This is the ‘one gene, one enzyme’ concept. Therefore, when a gene is missing the associated enzyme is also missing and the chemical change it should catalyse does not occur. This means that the intermediate metabolite upon which the enzyme should act accumulates. In physiological quantities such metabolites are harmless but when they accumulate they may become toxic. There are a number of diseases caused by such inborn errors of metabolism, e.g. phenylketonuria, abnormal haemoglobin and some immune deficiencies. MITOCHONDRIA Mitochondria are sausage-shaped structures in the cytoplasm, sometimes described as the ‘power house’ of the cell. They are involved in aerobic respiration, the processes by which chemical energy is made available in the cell. This is in the form of ATP, which releases energy when the cell breaks it down. Synthesis of ATP is most efficient in the final stages of aerobic respiration, a process requiring oxygen. RIBOSOMES These are tiny granules composed of RNA and protein. They synthesise proteins from amino acids, using RNA as the template. When present in free units or in small clusters in the cytoplasm, the ribosomes make proteins for use within the cell. Ribosomes are also found on the outer

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surface of rough endoplasmic reticulum. ENDOPLASMIC RETICULUM Endoplasmic reticulum is a series of interconnecting membranous canals in the cytoplasm. There are two types: smooth and rough. Smooth ER synthesises lipids and steroid hormones, and is also associated with the detoxification of some drugs. Rough ER is studded with ribosomes. These are the site of synthesis of proteins that are ‘exported’ (extruded) from cells, i.e. enzymes and hormones that pass out of their parent cell to be used by other cells in the body. GOLGI APPARATUS The Golgi apparatus consists of stacks of closely folded flattened membranous sacs. It is present in all cells but is larger in those that synthesise and export proteins. The proteins move from the endoplasmic reticulum to the Golgi apparatus where they are ‘packaged’ into membrane bound vesicles called secretory granules. The vesicles are stored and, when needed, move to the plasma membrane, through which the proteins are exported. LYSOSOMES Lysosomes are one type of secretory vesicle formed by the Golgi apparatus. They contain a variety of enzymes involved in breaking down fragments of organelles and large molecules (e.g. RNA, DNA, carbohydrates, proteins) inside the cell into smaller particles that are either recycled, or extruded from the cell as waste material. Lysosomes in white blood cells contain enzymes that digest foreign material such as microbes.

Membrane Physiology, Nerve, and Muscle TRANSPORT OF SUBSTANCES THROUGH THE CELL MEMBRANE the extracellular fluid contains a large amount of sodium but only a small amount of potassium. Exactly the opposite is true of the intracellular fluid. Also, the extracellular fluid contains a large amount of chloride ions, whereas the intracellular fluid contains very little. But the concentrations of phosphates and proteins in the intracellular fluid are considerably greater than those in the extracellular fluid.These differences are extremely important to the life of the cell.

of water as well as selected ions or molecules; these are called channel proteins. Others, called carrier proteins, bind with molecules or ions that are to be transported; conformational changes in the protein molecules then move the substances through the interstices of the protein to the other side of the membrane. Both the channel proteins and the carrier proteins are usually highly selective in the types of molecules or ions that are allowed to cross the membrane.

THE LIPID BARRIER OF THE CELL MEMBRANE, AND CELL MEMBRANE TRANSPORT PROTEINS

Transport through the cell membrane, either directly through the lipid bilayer or through the proteins, occurs by one of two basic processes: diffusion or active transport. Although there are many variations of these basic mechanisms, diffusion means random molecular movement of substances molecule by molecule, either through intermolecular spaces in the membrane or in combination with a carrier protein. The energy that causes diffusion is the energy of the normal kinetic motion of matter. By contrast, active transport means movement of ions or other substances across the membrane in combination with a carrier protein in such a way that the carrier protein causes the substance to move against an energy gradient, such as from a low-concentration state to a highconcentration state. This movement requires an additional source of energy besides kinetic energy. Following is a more detailed explanation of the basic physics and physical chemistry of these two processes.

The lipid bilayer is not miscible with either the extracellular fluid or the intracellular fluid. Therefore, it constitutes a barrier against movement of water molecules and water-soluble substances between the extracellular and intracellular fluid compartments.However a few substances can penetrate this lipid bilayer, diffusing directly through the lipid substance itself; this is true mainly of lipid-soluble substances. The protein molecules in the membrane have entirely different properties for transporting substances. Their molecular structures interrupt the continuity of the lipid bilayer, constituting an alternative pathway through the cell membrane. Most of these penetrating proteins, therefore, can function as transport proteins. Different proteins function differently. Some have watery spaces all the way through the molecule and allow free movement

‘DIFFUSION’ VERSUS ‘ACTIVE TRANSPORT’

DIFFUSION

FIgURE 4: Transport pathways through the cell membrane, and the basic mechanisms of transport.

Small substances diffuse down the concentration gradient crossing membranes by: • Dissolving in the lipid part of the membrane, e.g. lipid-soluble substances: oxygen, carbon dioxide, fatty acids, steroids.

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•

Passing through water-filled channels, or pores in the membrane, e.g. small water-soluble substances: sodium, potassium, calcium.

FACILITATED DIFFUSION This passive process is utilised by some substances that are unable to diffuse through the semipermeable membrane unaided, e.g. glucose, amino acids. Specialised protein carrier molecules in the membrane have specific sites that attract and bind substances to be transferred,

OSMOSIS Osmosis is the movement of water down its concentration gradient across a semipermeable membrane when equilibrium cannot be achieved by diffusion of solute molecules. This is usually because the solute molecules are too large to pass through the pores in the membrane. The force with which this occurs is called the osmotic pressure. Water crosses the membrane down its concentration gradient from the side with the lower solute concentration to the side with the greater solute concentration. This dilutes the more concentrated solution, and concentrates the more dilute solution. Osmosis proceeds until equilibrium is reached, at which point the solutions on each side of the membrane are of the same concentration and are said to be isotonic.

‘ACTIVE TRANSPORT’ OF SUBSTANCES THROUGH MEMBRANES

At times, a large concentration of a substance is required in the intracellular fluid even though the extracellular fluid contains only a small concentration. This is true, for instance, for potassium ions. Conversely, it is important to keep the concentrations of other ions very low inside the cell even though their concentrations in the extracellular fluid are great. This is especially true for sodium ions. Neither of these two effects could occur by simple diffusion because simple diffusion eventually equilibrates concentrations on the two sides of the membrane. Instead, some energy source must cause excess movement of potassium ions to the inside of cells and excess movement of sodium ions to the outside of cells. When a cell membrane moves molecules or ions “uphill” against a concentration gradient (or “uphill” against an electrical or pressure gradient), the process is called active transport. Different substances that are actively transported through at least some cell membranes include sodium ions, potassium ions, calcium ions, iron ions, hydrogen ions, chloride ions, iodide ions, urate ions, several different sugars, and most of the amino acids.

PRIMARY ACTIVE TRANSPORT Primary active transport, also called direct active transport, directly uses metabolic energy to transport molecules across a membrane. Most of the enzymes that perform this type of transport are transmembrane ATPases. A primary ATPase universal to all animal life is the sodium-potassium pump, which helps to maintain the cell potential. The sodium-potassium pump maintains the membrane potential by moving three Na+ ions out of the cell for every two K+ ions moved into the cell. Other sources of energy for Primary active transport are redox energy and photon energy (light). An example of primary active transport using Redox energy is the mitochondrial electron transport chain that uses the reduction energy of NADH to move protons across the inner mitochondrial membrane against their concentration gradient. An example of primary active transport using light energy are the proteins involved in photosynthesis that use the energy of photons to create a proton gradient across the thylakoid membrane and also to create reduction power in the form of NADPH.

TYPES OF PRIMARY ACTIVE TRANSPORTERS Active transport is divided into two types according to the source of the energy used to cause the transport: primary active transport and secondary active transport.

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P-type ATPase: sodium potassium pump, calcium pump, proton pump.

2. 3. 4.

F-ATPase: mitochondrial ATP synthase, chloroplast ATP synthase. V-ATPase: vacuolar ATPase. ABC (ATP binding cassette) transporter: MDR, CFTR, etc.

SODIUM-POTASSIUM PUMP Among the substances that are transported by primary active transport are sodium, potassium, calcium, hydrogen, chloride, and a few other ions. The active transport mechanism that has been studied in greatest detail is the sodium-potassium (Na+-K+) pump, a transport process that pumps sodium ions outward through the cell membrane of all cells and at the same time pumps potassium ions from the outside to the inside. This pump is responsible for maintaining the sodium and potassium concentration differences across the cell membrane, as well as for establishing a negative electrical voltage inside the cells. This pump is also the basis of nerve function, transmitting nerve signals throughout the nervous system.

FIgURE 5: Postulated mechanism of the sodium-potassium pump. ADP, adenosine diphosphate; ATP, adenosine triphosphate; Pi, phosphate ion.

SECONDARY ACTIVE TRANSPORT

cell membrane. This phenomenon is called co-transport; it is one form of secondary active transport.

When sodium ions are transported out of cells by primary active transport, a large concentration gradient of sodium ions across the cell membrane usually developsâ&#x20AC;&#x201D;high concentration outside the cell and very low concentration inside.This gradient represents a storehouse of energy because the excess sodium outside the cell membrane is always attempting to diffuse to the interior. Under appropriate conditions, this diffusion energy of sodium can pull other substances along with the sodium through the

For sodium to pull another substance along with it, a coupling mechanism is required. This is achieved by means of still another carrier protein in the cell membrane. The carrier in this instance serves as an attachment point for both the sodium ion and the substance to be co-transported. Once they both are attached, the energy gradient of the sodium ion causes both the sodium ion and the other substance to be transported together to the interior of the cell.

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Membrane Potentials and Action Potentials Electrical potentials exist across the membranes of virtually all cells of the body. In addition, some cells, such as nerve and muscle cells, are capable of generating rapidly changing electrochemical impulses at their membranes, and these impulses are used to transmit signals along the nerve or muscle membranes. In still other types of cells, such as glandular cells, macrophages, and ciliated cells, local changes in membrane potentials also activate many of the cells’ functions. The present discussion is concerned with membrane potentials generated both at rest and during action by nerve and muscle cells.

despite the high potassium ion concentration gradient. In the normal mammalian nerve fiber, the potential difference required is about 94 millivolts, with negativity inside the fiber membrane. Figure-B shows the same phenomenon as in Figure-A, but this time with high concentration of sodium ions outside the membrane and low sodium inside.These ions are also positively charged.This time, the membrane is highly

RESTING MEMBRANE POTENTIAL OF NERVES The resting membrane potential of large nerve fibers when not transmitting nerve signals is about –90 millivolts. That is, the potential inside the fiber is 90 millivolts more negative than the potential in the extracellular fluid on the outside of the fiber.

BASIC PHYSICS OF MEMBRANE POTENTIALS MEMBRANE POTENTIALS CAUSED BY DIFFUSION “Diffusion Potential” Caused by an Ion Concentration Difference on the Two Sides of the Membrane. In Figure-A, the potassium concentration is great inside a nerve fiber membrane but very low outside the membrane. Let us assume that the membrane in this instance is permeable to the potassium ions but not to any other ions. Because of the large potassium concentration gradient from inside toward outside, there is a strong tendency for extra numbers of potassium ions to diffuse outward through the membrane. As they do so, they carry positive electrical charges to the outside, thus creating electropositivity outside the membrane and electronegativity inside because of negative anions that remain behind and do not diffuse outward with the potassium.Within a millisecond or so, the potential difference between the inside and outside, called the diffusion potential, becomes great enough to block further net potassium diffusion to the exterior,

permeable to the sodium ions but impermeable to all other ions. Diffusion of the positively charged sodium ions to the inside creates a membrane potential of opposite polarity to that in Figure-A, with negativity outside and positivity inside. Again, the membrane potential rises high enough within milliseconds to block further net diffusion of sodium ions to the inside; however, this time, in the mammalian nerve fiber, the potential is about 61 millivolts positive inside the fiber.

ACTIVE TRANSPORT OF SODIUM AND POTASSIUM IONS THROUGH THE MEMBRANE—THE SODIUM-POTASSIUM (NA+-K+) PUMP

FIgURE 6:A, Establishment of a “diffusion” potential across a nerve fiber membrane, caused by diffusion of potassium ions from inside the cell to outside through a membrane that is selectively permeable only to potassium. B, Establishment of a “diffusion potential” when the nerve fiber membrane is permeable only to sodium ions. Note that the internal membrane potential is negative when potassium ions diffuse and positive when sodium ions diffuse because of opposite concentration gradients of these two ions.

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We already know all cell membranes of the body have a powerful Na+-K+ that continually pumps sodium ions to the outside of the cell and potassium ions to the inside. This is an electrogenic pump because more positive charges are pumped to the outside than to the inside (three Na+ ions to the outside for each two K+ ions to the inside), leaving a net deficit of positive ions on the inside; this causes a negative potential inside the cell membrane. The Na+-K+ also causes large concentration gradients for sodium and potassium across the resting nerve membrane.

NERVE ACTION POTENTIAL many central nervous system neurons, the potential merely approaches the zero level and does not overshoot to the positive state.

Nerve signals are transmitted by action potentials, which are rapid changes in the membrane potential that spread rapidly along the nerve fiber membrane. Each action potential begins with a sudden change from the normal resting negative membrane potential to a positive potential and then ends with an almost equally rapid change back to the negative potential. To conduct a nerve signal, the action potential moves along the nerve fiber until it comes to the fiber’s end.

REPOLARIzATION STAGE Within a few 10,000ths of a second after the membrane becomes highly permeable to sodium ions, the sodium channels begin to close and the potassium channels open more than normal. Then, rapid diffusion of potassium ions to the exterior re-establishes the normal negative resting membrane potential. This is called repolarization of the membrane.

The uppe p figure shows the changes that occur at the membrane during the action potential, with transfer of positive charges to the interior of the fiber at its onset and return of positive charges to the exterior at its end. The lower panel shows graphically the successive changes in membrane potential over a few 10,000ths of a second, illustrating the explosive onset of the action potential and the almost equally rapid recovery.

To explain more fully the factors that cause both depolarization and repolarization, we need to understand the special characteristics of two other types of transport channels through the nerve membrane:

The successive stages of the action potential are as follows:

THE VOLTAGE-GATED SODIUM CHANNELS and THE VOLTAGE-GATED POTASSIUM CHANNELS.

RESTING STAGE VOLTAGE-GATED SODIUM CHANNEL—ACTIVATION AND INACTIVATION OF THE CHANNEL

This is the resting membrane potential before the action potential begins. The membrane is said to be “polarized” during this stage because of the –90 millivolts negative membrane potential that is present. DEPOLARIzATION STAGE

FIgURE 7: Typical action potential record method

At this time, the membrane suddenly becomes very permeable to sodium ions, allowing tremendous numbers of positively charged sodium ions to diffuse to the interior of the axon. The normal “polarized” state of –90 millivolts is immediately neutralized by the inflowing positively charged sodium ions, with the potential rising rapidly in

the positive direction. This is called depolarization. In large nerve fibers, the great excess of positive sodium ions moving to the inside causes the membrane potential to actually “overshoot” beyond the zero level and to become somewhat positive. In some smaller fibers, as well as in

The upper panel of Figure (next page)shows the voltagegated sodium channel in three separate states. This channel has two gates—one near the outside of the channel called the activation gate, and another near the inside called the inactivation gate. The upper left of the figure depicts the state of these two gates in the normal resting membrane when the membrane potential is –90 millivolts. In this state, the activation gate is closed, which prevents any entry of sodium ions to the interior of the fiber through these sodium channels.

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Therefore, after the sodium channel has remained open for a few 10,000ths of a second, the inactivation gate closes, and sodium ions no longer can pour to the inside of the membrane. At this point, the membrane potential begins to recover back toward the resting membrane state, which is the repolarization process. Another important characteristic of the sodium channel inactivation process is that the inactivation gate will not reopen until the membrane potential returns to or near the original resting membrane potential level. Therefore, it usually is not possible for the sodium channels to open again without the nerve fiberâ&#x20AC;&#x2122;s first repolarizing.

PROPAGATION OF THE ACTION POTENTIAL However, an action potential elicited at any one point on an excitable membrane usually excites adjacent portions of the membrane, resulting in propagation of the action potential along the membrane.

VOLTAGE-GATED POTASSIUM CHANNEL AND ITS ACTIVATION

FIgURE 8: Characteristics of the voltage-gated sodium (top) and potassium (bottom) channels, showing successive activation and inactivation of the sodium channels and delayed activation of the potassium channels when the membrane potential is changed from the normal resting negative value to a positive value.

INACTIVATION OF THE SODIUM CHANNEL The upper panel of Figure shows a third state of the sodium channel. The same increase in voltage that opens the activation gate also closes the inactivation gate. The inactivation gate, however, closes a few 10,000ths of a second after the activation gate opens. That is, the conformational change that flips the inactivation gate to the closed state is a slower process than the conformational change that opens the activation gate.

The lower panel of Figure shows the voltage-gated potassium channel in two states: during the resting state (left) and toward the end of the action potential (right). During the resting state, the gate of the potassium channel is closed, and potassium ions are prevented from passing through this channel to the exterior. When the membrane potential rises from â&#x20AC;&#x201C;90 millivolts toward zero, this voltage change causes a conformational opening of the gate and allows increased potassium diffusion outward through the channel. However, because of the slight delay in opening of the potassium channels, for the most part, they open just at the same time that the sodium channels are beginning to close because of inactivation. Thus, the decrease in sodium entry to the cell and the simultaneous increase in potassium exit from the cell combine to speed the repolarization process, leading to full recovery of the resting membrane potential within another few 10,000ths of a second.

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FIgURE 9: Propagation of action potentials in both directions along a conductive fiber

SPECIAL CHARACTERISTICS OF SIGNAL TRANSMISSION IN NERVE TRUNKS

MYELINATED AND UNMYELINATED NERVE FIBERS Figure 10 shows a cross section of a typical small nerve, revealing many large nerve fibers that constitute most of the cross-sectional area. However, a more careful look reveals many more small fibers lying between the large ones. The large fibers are myelinated, and the small ones are unmyelinated. The average nerve trunk contains about twice as many unmyelinated fibers as myelinated fibers.

Figure 11 shows a typical myelinated fiber. The central core of the fiber is the axon, and the membrane of the axon is the membrane that actually conducts the action potential. The axon is filled in its center with axoplasm, which is a viscid intracellular fluid. Surrounding the axon is a myelin sheath that is often much thicker than the axon itself. About once every 1 to 3 millimeters along the length of the myelin sheath is a node of Ranvier. The myelin sheath is deposited around the axon by Schwann cells in the following manner: The membrane of a Schwann cell first envelops the axon. Then the Schwann cell rotates around the axon many times, laying down multiple layers of Schwann cell membrane containing the lipid substance sphingomyelin. This substance is an excellent electrical insulator that decreases ion flow through the membrane about 5000-fold. At the juncture between each two successive Schwann cells along the axon, a small uninsulated area only 2 to 3 micro meters in length remains where ions still can flow with ease through the axon membrane between the extracellular fluid and the intracellular fluid inside the axon. This area is called the node of Ranvier.

VELOCITY OF CONDUCTION IN NERVE FIBERS The velocity of action potential conduction in nerve fibers varies from as little as 0.25 m/sec in small unmyelinated fibers to as great as 100 m/sec (the length of a football field in 1 second) in large myelinated fibers. FIgURE 10: Cross section of a small nerve trunk containing both myelinated and unmyelinated fibers.

FIgURE 11: Function of the Schwann cell to insulate nerve fibers. A, Wrapping of a Schwann cell membrane around a large axon to form the myelin sheath of the myelinated nerve fiber. B, Partial wrapping of the membrane and cytoplasm of a Schwann cell around multiple unmyelinated nerve fibers (shown in cross section).

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EXCITATION—THE PROCESS OF ELICITING THE ACTION POTENTIAL Basically, any factor that causes sodium ions to begin to diffuse inward through the membrane in sufficient numbers can set off automatic regenerative opening of the sodium channels. This can result from mechanical disturbance of the membrane, chemical effects on the membrane, or passage of electricity through the membrane. All these are used at different points in the body to elicit nerve or muscle action potentials: mechanical pressure to excite sensory nerve endings in the skin, chemical neurotransmitters to transmit signals from one neuron to the next in the brain, and electrical current to transmit signals between successive muscle cells in the heart and intestine. ExCITATION OF A NERVE FIBER BY A NEGATIVELY CHARGED METAL ELECTRODE The usual means for exciting a nerve or muscle in the experimental laboratory is to apply electricity to the nerve or muscle surface through two small electrodes, one of which is negatively charged and the other positively charged. When this is done, the excitable membrane becomes stimulated at the negative electrode. The cause of this effect is the following: Remember that the action potential is initiated by the opening of voltage-gated sodium channels. Further, these channels are opened by a decrease in the normal resting electrical voltage across the membrane. That is, negative current from the electrode decreases the voltage on the outside of the membrane to a negative value nearer to the voltage of the negative potential inside the fiber. This decreases the electrical voltage across the membrane and allows the sodium channels to open, resulting in an action potential. Conversely, at the positive electrode, the injection of positive charges on the outside of the nerve

membrane heightens the voltage difference across the membrane rather than lessening it. This causes a state of hyperpolarization, which actually decreases the excitability of the fiber rather than causing an action potential.

THRESHOLD FOR ExCITATION, AND “ACUTE LOCAL POTENTIALS” A weak negative electrical stimulus may not be able to excite a fiber. However, when the voltage of the stimulus is increased, there comes a point at which excitation does take place. Figure 12 shows the effects of successively applied stimuli of progressing strength. A very weak stimulus at point A causes the membrane potential to change from –90 to –85 millivolts, but this is not a sufficient change for the automatic regenerative processes of the action potential to develop. At point B, the stimulus is greater, but again, the intensity is still not enough. The stimulus does, however, disturb the membrane potential locally for as long as 1 millisecond or more after both of these weak stimuli. These local potential changes are called acute local potentials, and when they fail to elicit an action potential, they are called acute subthreshold potentials. At point C in Figure 12, the stimulus is even stronger. Now the local potential has barely reached the level required to elicit an action potential, called the threshold level, but this occurs only after a short “latent period.” At point D, the stimulus is still stronger, the acute local potential is also stronger, and the action potential occurs after less of a latent period. Thus, this figure shows that even a very weak stimulus causes a local potential change at the membrane, but the intensity of the local potential must rise to a threshold level before the action potential is set off.

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FIgURE 12: Effect of stimuli of increasing voltages to elicit an action potential. Note development of “acute subthreshold potentials” when the stimuli are below the threshold value required for eliciting anaction potential. “REFRACTORY PERIOD” AFTER AN ACTION POTENTIAL, DURING WHICH A NEW STIMULUS CANNOT BE ELICITED A new action potential cannot occur in an excitable fiber as long as the membrane is still depolarized from the preceding action potential.The reason for this is that shortly after the action potential is initiated, the sodium channels (or calcium channels, or both) become inactivated, and no amount of excitatory signal applied to these channels at this point will open the inactivation gates. The only condition that will allow them to reopen is for the membrane potential to return to or near the original resting membrane potential level. Then, within another small fraction of a second, the inactivation gates of the channels open, and a new action potential can be initiated. The period during which a second action potential cannot be elicited, even with a strong stimulus, is called the absolute refractory period.

Contraction of Skeletal Muscle About 40 per cent of the body is skeletal muscle, and perhaps another 10 per cent is smooth and cardiac muscle. Some of the same basic principles of contraction apply to all these different types of muscle.

PHYSIOLOGIC ANATOMY OF SKELETAL MUSCLE All skeletal muscles are composed of numerous fibers ranging from 10 to 80 micrometers in diameter. Each of these fibers is made up of successively smaller subunits. In most skeletal muscles, each fiber extends the entire length of the muscle. Except for about 2% of the fibers, each fiber is usually innervated by only one nerve ending, located near the middle of the fiber.

SARCOLEMMA The sarcolemma is the cell membrane of the muscle fiber. The sarcolemma consists of a true cell membrane, called the plasma membrane, and an outer coat made up of a thin layer of polysaccharide material that contains numerous thin collagen fibrils. At each end of the muscle fiber, this surface layer of the sarcolemma fuses with a tendon fiber, and the tendon fibers in turn collect into bundles to form the muscle tendons that then insert into the bones.

MYOFIBRILS; ACTIN AND MYOSIN FILAMENTS Each muscle fiber contains several hundred to several thousand myofibrils, which are demonstrated by the many small open dots in the cross-sectional view of Figure13-C. Each myofibril (Figure 13-D and E) is composed of about 1500 adjacent myosin filaments and 3000 actin filaments, which are large polymerized protein molecules that are responsible for the actual muscle contraction.

FIgURE 13 : Organization of skeletal muscle, from the gross to the molecular level. F, g, H, and I are cross sections at the levels indicated.

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Figure 13-E also shows that the ends of the actin filaments are attached to a so-called z disc. From this disc, these filaments extend in both directions to which itself is composed of filamentous proteins different from the actin and myosin filaments, passes crosswise across the myofibril and also crosswise from myofibril to myofibril, attaching the myofibrils to one another all the way across the muscle fiber. The portion of the myofibril (or of the whole muscle fiber) that lies between two successive z discs is called a sarcomere. When the muscle fiber is contracted the length of the sarcomere is about 2 micrometers. At this length, the actin filaments completely overlap the myosin filaments, and the tips of the actin filaments are just beginning to overlap one another. We will see later that, at this length, the muscle is capable of generating its greatest force of contraction. SARCOPLASM The many myofibrils of each muscle fiber are suspended side by side in the muscle fiber. The spaces between the myofibrils are filled with intracellular fluid called sarcoplasm, containing large quantities of potassium, magnesium, and phosphate, plus multiple protein enzymes. Also present are tremendous numbers of mitochondria that lie parallel to the myofibrils. These supply the contracting myofibrils with large amounts of energy in the form of adenosine triphosphate (ATP) formed by the mitochondria. SARCOPLASMIC RETICULUM Also in the sarcoplasm surrounding the myofibrils of each muscle fiber is an extensive reticulum, called the

sarcoplasmic reticulum. This reticulum has a special organization that is extremely important in controlling muscle contraction.The very rapidly contracting types of muscle fibers have especially extensive sarcoplasmic reticula.

GENERAL MECHANISM OF MUSCLE CONTRACTION

The initiation and execution of muscle contraction occur in the following sequential steps:

calcium ions that have been stored within this reticulum. 7. The calcium ions initiate attractive forces between the actin and myosin filaments, causing them to slide alongside each other, which is the contractile process. 8. After a fraction of a second, the calcium ions are pumped back into the sarcoplasmic reticulum by a Ca++ membrane pump, and they remain stored in the reticulum until a new muscle action potential comes along; this removal of calcium ions from the myofibrils causes the muscle contraction to cease

1. An action potential travels along a motor nerve to its endings on muscle fibers. 2. At each ending, the nerve secretes a small amount of the neurotransmitter substance acetylcholine. 3. The acetylcholine acts on a local area of the muscle fiber membrane to open multiple â&#x20AC;&#x153;acetylcholinegatedâ&#x20AC;? channels through protein molecules floating in the membrane. 4. Opening of the acetylcholine-gated channels allows large quantities of sodium ions to diffuse to the interior of the muscle fiber membrane. This initiates an action potential at the membrane. 5. The action potential travels along the muscle fiber membrane in the same way that action potentials travel along nerve fiber membranes. 6. The action potential depolarizes the muscle membrane, and much of the action potential electricity flows through the center of the muscle fiber. Here it causes the sarcoplasmic reticulum to release large quantities of

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MOLECULAR MECHANISM OF MUSCLE CONTRACTION SLIDING FILAMENT MECHANISM OF MUSCLE CONTRACTION. Figure 14 demonstrates the basic mechanism of muscle contraction. It shows the relaxed state of a sarcomere (top) and the contracted state (bottom). In the relaxed state, the ends of the actin filaments extending from two successive z discs barely begin to overlap one another. Conversely, in the contracted state, these actin filaments have been pulled inward among the myosin filaments, so that their ends overlap one another to their maximum extent. Also, the Z discs have been pulled by the actin filaments up to the ends of the myosin filaments.Thus, muscle contraction occurs by a sliding filament mechanism. The actin filaments to slide inward among the myosin filaments is caused by forces generated by interaction of the cross-bridges from the myosin filaments with the actin filaments. Under resting conditions, these forces are inactive, but when an action potential travels along the muscle fiber, this causes the sarcoplasmic reticulum to release large quantities of calcium ions that rapidly surround the myofibrils.The calcium ions in turn activate the forces between the myosin and actin filaments, and contraction begins. But energy is needed for the contractile process to proceed. This energy comes from highenergy bonds in the ATP molecule, which is degraded to adenosine diphosphate (ADP) to liberate the energy. In the next few sections, we describe what is known about the details of these molecular processes of contraction.

FIGURE 14: Relaxed and contracted states of a myofibril showing (top) sliding of the actin filaments (pink) into the spaces between the myosin filaments (red), and (bottom) pulling of the Z membranes toward each other.

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Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling TRANSMISSION OF IMPULSES FROM NERVE ENDINGS TO SKELETAL MUSCLE FIBERS: THE NEUROMUSCULAR jUNCTION The skeletal muscle fibers are innervated by large, myelinated nerve fibers that originate from large motoneurons in the anterior horns of the spinal cord. Each nerve fiber, after entering the muscle belly, normally branches and stimulates from three to several hundred skeletal muscle fibers. Each nerve ending makes a junction, called the neuromuscular junction, with the muscle fiber near its midpoint. The action potential initiated in the muscle fiber by the nerve signal travels in both directions toward the muscle fiber ends.With the exception of about 2% of the muscle fibers, there is only one such junction per muscle fiber.

PHYSIOLOGIC ANATOMY OF THE NEUROMUSCULAR JUNCTIONâ&#x20AC;&#x201D;THE MOTOR END PLATE. Figure 15-A and B shows the neuromuscular junction from a large, myelinated nerve fiber to a skeletal muscle fiber. The nerve fiber forms a complex of branching nerve terminals that invaginate into the surface of the muscle fiber but lie outside the muscle fiber plasma membrane. The entire structure is called the motor end plate. It is covered by one or more Schwann cells that insulate it from the surrounding fluids. Figure 15-C shows an electron micrographic sketch of the junction between a single axon terminal and the muscle fiber membrane. The invaginated membrane is called the synaptic gutter or synaptic trough, and the space between the terminal and the fiber membrane is called the synaptic space or synaptic cleft. This space is 20 to 30 nanometers wide. At the bottom

FIGURE 15: Relaxed and contracted states of a myofibril showing (top) sliding of the actin filaments (pink) into the spaces between the myosin filaments (red), and (bottom) pulling of the Z membranes toward each other.

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MUSCLE ACTION POTENTIAL

of the gutter are numerous smaller folds of the muscle membrane called subneural clefts, which greatly increase the surface area at which the synaptic transmitter can act. In the axon terminal are many mitochondria that supply adenosine triphosphate (ATP), the energy source that is used for synthesis of an excitatory transmitter acetylcholine. The acetylcholine in turn excites the muscle fiber membrane. Acetylcholine is synthesized in the cytoplasm of the terminal, but it is absorbed rapidly into many small synaptic vesicles, about 300,000 of which are normally in the terminals of a single end plate. In the synaptic space are large quantities of the enzyme acetylcholinesterase, which destroys acetylcholine a few milliseconds after it has been released from the synaptic vesicles.

1. Resting membrane potential: about –80 to –90 millivolts in skeletal fibers—the same as in large myelinated nerve fibers. 2. Duration of action potential: 1 to 5 milliseconds in skeletal muscle—about five times as long as in large myelinated nerves. 3. Velocity of conduction: 3 to 5 m/sec—about 1/13 the velocity of conduction in the large myelinated nerve fibers that excite skeletal muscle.

SPREAD OF THE ACTION POTENTIAL TO THE INTERIOR OF THE MUSCLE FIBER BY WAY OF “TRANSVERSE TUBULES”

SECRETION OF ACETYLCHOLINE BY THE NERVE TERMINALS When a nerve impulse reaches the neuromuscular junction, about 125 vesicles of acetylcholine are released from the terminals into the synaptic space. Some of the details of this mechanism can be seen in Figure 16, which shows an expanded view of a synaptic space with the neural membrane above and the muscle membrane and its subneural clefts below. On the inside surface of the neural membrane are linear dense bars, shown in cross section in Figure 16. To each side of each dense bar are protein particles that penetrate the neural membrane; these are voltagegated calcium channels. When an action potential spreads over the terminal, these channels open and allow calcium ions to diffuse from the synaptic space to the interior of the nerve terminal.The calcium ions, in turn, are believed to exert an attractive influence on the acetylcholine vesicles, drawing them to the neural membrane adjacent to the dense bars. The vesicles then fuse with the neural membrane and

FIgURE 16: Release of acetylcholine from synaptic vesicles at the neural membrane of the neuromuscular junction. The proximity of the release sites in the neural membrane to the acetylcholine receptors in the muscle membrane, at the mouths of the subneural clefts.

The skeletal muscle fiber is so large that action potentials spreading along its surface membrane cause almost no current flow deep within the fiber. Yet, to cause maximum muscle contraction, current must penetrate deeply into the muscle fiber to the vicinity of the separate myofibrils. This is achieved by transmission of action potentials along transverse tubules (T tubules) that penetrate all the way through the muscle fiber from one side of the fiber to the other, as illustrated in Figure 17. The T tubule action potentials cause release of calcium ions inside the muscle fiber in the immediate vicinity of the myofibrils, and these calcium ions then cause contraction. This overall process iscalled excitation-contraction coupling.

empty their acetylcholine into the synaptic space by the process of exocytosis. Although some of the aforementioned details are speculative, it is known that the effective stimulus for causing acetylcholine release from the vesicles is entry of calcium ions and that acetylcholine from the vesicles is then emptied through the neural membrane adjacent to the dense bars.

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ExCITATION-CONTRACTION COUPLING Figure 17 shows myofibrils surrounded by the T tubuleâ&#x20AC;&#x201C; sarcoplasmic reticulum system. The T tubules are very small and run transverse to the myofibrils. They begin at the cell membrane and penetrate all the way from one side of the muscle fiber to the opposite side. Not shown in the figure is the fact that these tubules branch among themselves so that they form entire planes of T tubules interlacing among all the separate myofibrils.Also, where the T tubules originate from the cell membrane, they are open to the exterior of the muscle fiber. Therefore, they communicate with the extracellular fluid surrounding the muscle fiber, and they themselves contain extracellular fluid in their lumens. In other words, the T tubules are actually internal extensions of the cell membrane Therefore, when an action potential spreads over a muscle fiber membrane, a potential change also spreads along the T tubules to the deep interior of the muscle fiber. The electrical currents surrounding these T tubules then elicit the muscle contraction. Figure 17 also shows a sarcoplasmic reticulum, in yellow. This is composed of two major parts: (1) large chambers called terminal cisternae that abut the T tubules, and (2) long longitudinal tubules that surround all surfaces of the actual contracting myofibrils.

FIgURE 17: Transverse (T) tubuleâ&#x20AC;&#x201C;sarcoplasmic reticulum system. Note that the T tubules communicate with the outside of the cell membrane, and deep in the muscle fiber, each T tubule lies adjacent to the ends of longitudinal sarcoplasmic reticulum tubules that surround all sides of the actual myofibrils that contract. This illustration was drawn from frog muscle, which has one T tubule per sarcomere, located at the Z line. A similar arrangement is found in mammalian heart muscle, but mammalian skeletal muscle has two T tubules per sarcomere, located at the A-I band junctions.

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RELEASE OF CALCIUM IONS BY THE SARCOPLASMIC RETICULUM One of the special features of the sarcoplasmic reticulum is that within its vesicular tubules is an excess of calcium ions in high concentration, and many of these ions are released from each vesicle when an action potential occurs in the adjacent T tubule. Figure 18 shows that the action potential of the T tubule causes current flow into the sarcoplasmic reticular cisternae where they abut the T tubule. This in turn causes rapid opening of large numbers of calcium channels through the membranes of the cisternae as well as their attached longitudinal tubules. These channels remain open for a few milliseconds; during this time, enough calcium ions are released into the sarcoplasm surrounding the myofibrils to cause contraction. CALCIUM PUMP FOR REMOVING CALCIUM IONS FROM THE MYOFIBRILLAR FLUID AFTER CONTRACTION OCCURS. Once the calcium ions have been released from the sarcoplasmic tubules and have diffused among the myofibrils, muscle contraction continues as long as the calcium ions remain in high concentration. However, a continually active calcium pump located in the walls of the sarcoplasmic reticulum pumps calcium ions away from the myofibrils back into the sarcoplasmic tubules.This pump can concentrate the calcium ions about 10,000-fold inside the tubules. In addition, inside the reticulum is a protein called calsequestrin that can bind up to 40 times more calcium.

FIgURE 18: Excitation-contraction coupling in the muscle, showing (1) an action potential that causes release of calcium ions from the sarcoplasmic reticulum and then (2) reuptake of the calcium ions by a calcium pump.

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Contraction and Excitation of Smooth Muscle CONTRACTION OF SMOOTH MUSCLE examples of multi-unit smooth muscle are the ciliary muscle of the eye, the iris muscle of the eye, and the piloerector muscles that cause erection of the hairs when stimulated by the sympathetic nervous system.

Smooth muscle is composed of far smaller fibers, usually 1 to 5 micrometers in diameter and only 20 to 500 micrometers in length. In contrast, skeletal muscle fibers are as much as 30 times greater in diameter and hundreds of times as long. Many of the same principles of contraction apply to smooth muscle as to skeletal muscle. Most important, essentially the same attractive forces between myosin and actin filaments cause contraction in smooth muscle as in skeletal muscle, but the internal physical arrangement of smooth muscle fibers is very different.

UNITARY SMOOTH MUSCLE

TYPES OF SMOOTH MUSCLE The smooth muscle of each organ is distinctive from that of most other organs in several ways: (1) physical dimensions, (2) organization into bundles or sheets, (3) response to different types of stimuli, (4) characteristics of innervation, and (5) function. Yet, for the sake of simplicity, smooth muscle can generally be divided into two major types, multi-unit smooth muscle and unitary (or single-unit) smooth muscle.

MULTI-UNIT SMOOTH MUSCLE This type of smooth muscle is composed of discrete, separate smooth muscle fibers. Each fiber operates independently of the others and often is innervated by a single nerve ending, as occurs for skeletal muscle fibers. Further, the outer surfaces of these fibers, like those

FIgURE 19 : Multi-unit (A) and unitary (B) smooth muscle.

of skeletal muscle fibers, are covered by a thin layer of basement membrane–like substance, a mixture of fine collagen and glycoprotein that helps insulate the separate fibers from one another.

The term “unitary” is confusing because it does not mean single muscle fibers. Instead, it means a mass of hundreds to thousands of smooth muscle fibers that contract together as a single unit. The fibers usually are arranged in sheets or bundles, and their cell membranes are adherent to one another at multiple points so that force generated in one muscle fiber can be transmitted to the next. In addition, the cell membranes are joined by many gap junctions through which ions can flow freely from one muscle cell to the next so that action potentials or simple ion flow without action potentials can travel from one fiber to the next and cause the muscle fibers to contract together.This type of smooth muscle is also known as syncytial smooth muscle because of its syncytial interconnections among fibers. It is also called visceral smooth muscle because it is found in the walls of most viscera of the body, including the gut, bile ducts, ureters, uterus, and many blood vessels

The most important characteristic of multi-unit smooth muscle fibers is that each fiber can contract independently of the others, and their control is exerted mainly by nerve signals. In contrast, a major share of control of unitary smooth muscle is exerted by non-nervous stimuli. Some

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CONTRACTILE MECHANISM IN SMOOTH MUSCLE CHEMICAL BASIS FOR SMOOTH MUSCLE CONTRACTION mainly through these bonds that the force of contraction is transmitted from one cell to the next.

Smooth muscle contains both actin and myosin filaments, having chemical characteristics similar to those of the actin and myosin filaments in skeletal muscle. It does not contain the normal troponin complex that is required in the control of skeletal muscle contraction, so the mechanism for control of contraction is different.

Interspersed among the actin filaments in the muscle fiber are myosin filaments. These have a diameter more than twice that of the actin filaments. In electron micrographs, one usually finds 5 to 10 times as many actin filaments as myosin filaments.

Chemical studies have shown that actin and myosin filaments derived from smooth muscle interact with each other in much the same way that they do in skeletal muscle. Further, the contractile process is activated by calcium ions, and adenosine triphosphate (ATP) is degraded to adenosine diphosphate (ADP) to provide the energy for contraction.

To the right in Figure 20 is a postulated structure of an individual contractile unit within a smooth muscle cell, showing large numbers of actin filaments radiating from two dense bodies; the ends of these filaments overlap a myosin filament located midway between the dense bodies. This contractile unit is similar to the contractile unit of skeletal muscle, but without the regularity of the skeletal muscle structure; in fact, the dense bodies of smooth muscle serve the same role as the z discs in skeletal muscle.

There are, however, major differences between the physical organization of smooth muscle and that of skeletal muscle, as well as differences in excitationcontraction coupling, control of the contractile process by calcium ions, duration of contraction, and amount of energy required for contraction.

PHYSICAL BASIS FOR SMOOTH MUSCLE CONTRACTION Physical Basis for Smooth Muscle Contraction Smooth muscle does not have the same striated arrangement of actin and myosin filaments as is found in skeletal muscle. Instead, electron micrographic techniques suggest the physical organization exhibited in Figure 20. This figure shows large numbers of actin filaments attached to socalled dense bodies. Some of these bodies are attached to the cell membrane. Others are dispersed inside the cell. Some of the membrane dense bodies of adjacent cells are bonded together by intercellular protein bridges. It is

FIgURE 20: Physical structure of smooth muscle. The upper left-hand fiber shows actin filaments radiating from dense bodies. The lower lefthand fiber and the right-hand diagram demonstrate the relation of myosin filaments to actin filaments

There is another difference: Most of the myosin filaments have what are called â&#x20AC;&#x153;sidepolarâ&#x20AC;? cross-bridges arranged so that the bridges on one side hinge in one direction and those on the other side hinge in the opposite direction. This allows the myosin to pull an actin filament in one direction on one side while simultaneously pulling another actin filament in the opposite direction on the other side. The value of this organization is that it allows smooth muscle cells to contract as much as 80% of their length instead of being limited to less than 30%, as occurs in skeletal muscle.

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NERVOUS AND HORMONAL CONTROL OF SMOOTH MUSCLE CONTRACTION Although skeletal muscle fibers are stimulated exclusively by the nervous system, smooth muscle can be stimulated to contract by multiple types of signals: by nervous signals, by hormonal stimulation, by stretch of the muscle, and in several other ways. The principal reason for the difference is that the smooth muscle membrane contains many types of receptor proteins that can initiate the contractile process. Still other receptor proteins inhibit smooth muscle contraction, which is another difference from skeletal muscle.

junctions, and they function in much the same way as the skeletal muscle neuromuscular junction; the rapidity of contraction of these smooth muscle fibers is considerably faster than that of fibers stimulated by the diffuse junctions.

NEUROMUSCULAR JUNCTIONS OF SMOOTH MUSCLE

The most important transmitter substances secreted by the autonomic nerves innervating smooth muscle are acetylcholine and norepinephrine, but they are never secreted by the same nerve fibers. Acetylcholine is an excitatory transmitter substance for smooth muscle fibers in some organs but an inhibitory transmitter for smooth muscle in other organs. When acetylcholine excites a muscle fiber, norepinephrine ordinarily inhibits it. Conversely, when acetylcholine inhibits a fiber, norepinephrine usually excites it.

ExCITATORY AND INHIBITORY TRANSMITTER SUBSTANCES SECRETED AT THE SMOOTH MUSCLE NEUROMUSCULAR JUNCTION

PHYSIOLOGIC ANATOMY OF SMOOTH MUSCLE NEUROMUSCULAR JUNCTIONS

FIgURE 21: Innervation of smooth muscle.

Neuromuscular junctions of the highly structured type found on skeletal muscle fibers do not occur in smooth muscle. Instead, the autonomic nerve fibers that innervate smooth muscle generally branch diffusely on top of a sheet of muscle fibers, as shown in Figure 21. In most instances, these fibers do not make direct contact with the smooth muscle fiber cell membranes but instead form so-called diffuse junctions that secrete their transmitter substance into the matrix coating of the smooth muscle often a few nanometers to a few micrometers away from the muscle cells; the transmitter substance then diffuses to the cells. Furthermore, where there are many layers of muscle cells, the nerve fibers often innervate only the outer layer, and muscle excitation travels from this outer layer to the inner layers by action potential conduction in the muscle mass or by additional diffusion of the transmitter substance. The axons that innervate smooth muscle fibers do not have typical branching end feet of the type in the motor end plate on skeletal muscle fibers. Instead, most of the

fine terminal axons have multiple varicosities distributed along their axes.At these points the Schwann cells that envelop the axons are interrupted so that transmitter substance can be secreted through the walls of the varicosities. In the varicosities are vesicles similar to those in the skeletal muscle end plate that contain transmitter substance. But, in contrast to the vesicles of skeletal muscle junctions, which always contain acetylcholine, the vesicles of the autonomic nerve fiber endings contain acetylcholine in some fibers and norepinephrine in othersâ&#x20AC;&#x201D;and occasionally other substances as well. In a few instances, particularly in the multi-unit type of smooth muscle, the varicosities are separated from the muscle cell membrane by as little as 20 to 30 nanometers, the same width as the synaptic cleft that occurs in the skeletal muscle junction.These are called contact

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But why these different responses? The answer is that both acetylcholine and norepinephrine excite or inhibit smooth muscle by first binding with a receptor protein on the surface of the muscle cell membrane. Some of the receptor proteins are excitatory receptors, whereas others are inhibitory receptors. Thus, the type of receptor determines whether the smooth muscle is inhibited or excited and also determines which of the two transmitters, acetylcholine or norepinephrine, is effective in causing the excitation or inhibition.

MEMBRANE POTENTIALS AND ACTION POTENTIALS IN SMOOTH MUSCLE

MEMBRANE POTENTIALS IN SMOOTH MUSCLE

ACTION POTENTIALS WITH PLATEAUS

The quantitative voltage of the membrane potential of smooth muscle depends on the momentary condition of the muscle. In the normal resting state, the intracellular potential is usually about -50 to -60 millivolts, which is about 30 millivolts less negative than in skeletal muscle.

Figure 22 C shows a smooth muscle action potential with a plateau. The onset of this action potential is similar to that of the typical spike potential. However, instead of rapid repolarization of the muscle fiber membrane, the repolarization is delayed for several hundred to as much as 1000 milliseconds (1 second). The importance of the plateau is that it can account for the prolonged.

ACTION POTENTIALS IN UNITARY SMOOTH MUSCLE.

contraction that occurs in some types of smooth muscle, such as the ureter, the uterus under some conditions, and certain types of vascular smooth muscle.

Action potentials occur in unitary smooth muscle (such as visceral muscle) in the same way that they occur in skeletal muscle. They do not normally occur in many, if not most, multi-unit types of smooth muscle, as discussed in a subsequent section. The action potentials of visceral smooth muscle occur in one of two forms: (1) spike potentials or (2) action potentials with plateaus.

EFFECT OF LOCAL TISSUE FACTORS AND HORMONES TO CAUSE SMOOTH MUSCLE CONTRACTION WITHOUT ACTION POTENTIALS

SPIKE POTENTIALS Typical spike action potentials, such as those seen in skeletal muscle, occur in most types of unitary smooth muscle. The duration of this type of action potential is 10 to 50 milliseconds, as shown in Figure 22 A. Such action potentials can be elicited in many ways, for example, by electrical stimulation, by the action of hormones on the smooth muscle, by the action of transmitter substances from nerve fibers, by stretch, or as a result of spontaneous generation in the muscle fiber itself, as discussed subsequently.

Probably half of all smooth muscle contraction is initiated by stimulatory factors acting directly on the smooth muscle contractile machinery and without action potentials. Two types of non-nervous and nonâ&#x20AC;&#x201C;action potential stimulating factors often involved are (1) local tissue chemical factors and (2) various hormones. FIgURE 22: A, Typical smooth muscle action potential (spike potential) elicited by an external stimulus. B, Repetitive spike potentials, elicited by slow rhythmical electrical waves that occur spontaneously in the smooth muscle of the intestinal wall. C, Action potential with a plateau, recorded from a smooth muscle fiber of the uterus.

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Continence

The Urinary System The urinary system plays a vital part in maintaining homeostasis of water and electrolyte concentrations within the body. The kidneys produce urine that contains metabolic waste products, including the nitrogenous compounds urea and uric acid, excess ions and some drugs. The urinary system is one of the excretory systems of the body. It consists of the following structures:

filtrate at variable rates, depending on the needs of the body. Ultimately, the kidneys “clear” unwanted substances from the filtrate (and therefore from the blood) by excreting them in the urine while returning substances that are needed back to the blood. The kidneys serve multiple functions, including the following: •

• 2 kidneys, which secrete urine. • 2 ureters, which convey the urine from the kidneys to the urinary bladder. • 1 urinary bladder where urine collects and is temporarily stored. • 1 urethra through which the urine is discharged from the urinary bladder to the exterior

MULTIPLE FUNCTIONS OF THE KIDNEYS IN HOMEOSTASIS One important function of the kidneys—to rid the body of waste materials that are either ingested or produced by metabolism. A second function that is especially critical is to control the volume and composition of the body fluids. For water and virtually all electrolytes in the body, the balance between intake (due to ingestion or metabolic production) and output (due to excretion or metabolic consumption) is maintained in large part by the kidneys. This regulatory function of the kidneys maintains the stable environment of the cells necessary for them to perform their various activities. The kidneys perform their most important functions by filtering the plasma and removing substances from the

• • • • • •

Excretion of metabolic waste products and foreign chemicals. Regulation of water and electrolyte balances. Regulation of body fluid osmolality and electrolyte concentrations. Regulation of arterial pressure. Regulation of acid-base balance. Secretion, metabolism, and excretion of hormones. Gluconeogenesis.

PHYSIOLOGIC ANATOMY OF THE KIDNEYS

GENERAL ORGANIzATION OF THE KIDNEYS AND URINARY TRACT The two kidneys lie on the posterior wall of the abdomen, outside the peritoneal cavity. Each kidney of the adult human weighs about 150 grams and is about the size of a clenched fist. The medial side of each kidney contains an indented region called the hilum through which pass the renal artery and vein, lymphatics, nerve supply, and ureter, which carries the final urine from the kidney to the bladder, where it is stored until emptied. The kidney is surrounded by a tough, fibrous capsule that protects its delicate inner structures.

FIgURE 1: general organization of the kidneys and the urinary system.

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If the kidney is bisected from top to bottom, the two major regions that can be visualized are the outer cortex and the inner region referred to as the medulla. The medulla is divided into multiple cone-shaped masses of tissue called renal pyramids. The base of each pyramid originates at the border between the cortex and medulla and terminates in the papilla, which projects into the space of the renal pelvis, a funnel-shaped continuation of the upper end of the ureter. The outer border of the pelvis is divided into open-ended pouches called major calyces that extend downward and divide into minor calyces, which collect urine from the tubules of each papilla. The walls of the calyces, pelvis, and ureter contain contractile elements that propel the urine toward the bladder, where urine is stored until it is emptied by micturition.

RENAL BLOOD SUPPLY Blood flow to the two kidneys is normally about 22% of the cardiac output, or 1100 ml/min. The renal artery enters the kidney through the hilum and then branches progressively to form the interlobar arteries, arcuate arteries, interlobular arteries (also called radial arteries) and afferent arterioles, which lead to the glomerular capillaries, where large amounts of fluid and solutes (except the plasma proteins) are filtered to begin urine formation. The distal ends of the capillaries of each glomerulus coalesce to form the efferent arteriole, which leads to a second capillary network, the peritubular capillaries, that surrounds the renal tubules. The renal circulation is unique in that it has two capillary beds, the glomerular and peritubular capillaries, which are arranged in series and separated by the efferent arterioles, which help regulate the hydrostatic pressure in both sets of capillaries. High hydrostatic pressure in the glomerular capillaries (about 60 mm Hg) causes rapid

FIgURE 2: general organization of the kidneys and the urinary system.

fluid filtration, whereas a much lower hydrostatic pressure in the peritubular capillaries (about 13 mm Hg) permits rapid fluid reabsorption. By adjusting the resistance of the afferent and efferent arterioles, the kidneys can regulate the hydrostatic pressure in both the glomerular and the peritubular capillaries, thereby changing the rate of glomerular filtration, tubular reabsorption, or both in

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response to body homeostatic demands. The peritubular capillaries empty into the vessels of the venous system, which run parallel to the arteriolar vessels and progressively form the interlobular vein, arcuate vein, interlobar vein, and renal vein, which leaves the kidney beside the renal artery and ureter.

THE NEPHRON IS THE FUNCTIONAL UNIT OF THE KIDNEY Each kidney in the human contains about 1 million ephrons, each capable of forming urine. The kidney cannot regenerate new nephrons.Therefore, with renal injury, disease, or normal aging, there is a gradual decrease in nephron number.After age 40, the number of functioning nephrons usually decreases about 10% every 10 years; thus, at age 80, many people have 40% fewer functioning nephrons than they did at age 40. This loss is not life threatening because adaptive changes in the remaining nephrons allow them to excrete the proper amounts of water, electrolytes, and waste products. Each nephron contains (1) a tuft of glomerular capillaries called the glomerulus, through which large amounts of fluid are filtered from the blood, and (2) a long tubule in which the filtered fluid is converted into urine on its way to the pelvis of the kidney.

the distal tubule, which, like the proximal tubule, lies in the renal cortex. This is followed by the connecting tubule and the cortical collecting tubule, which lead to the cortical collecting duct. The initial parts of 8 to 10 cortical collecting ducts join to form a single larger collecting duct that runs downward into the medulla and becomes the medullary collecting duct. The collecting ducts merge to form progressively larger ducts that eventually empty into the renal pelvis through the tips of the renal papillae. In each kidney, there are about 250 of the very large collecting ducts, each of which collects urine from about 4000 nephrons.

The glomerulus contains a network of branching and anastomosing glomerular capillaries that, compared with other capillaries, have high hydrostatic pressure (about 60 mm Hg). The glomerular capillaries are covered by epithelial cells, and the total glomerulus is encased in Bowmanâ&#x20AC;&#x2122;s capsule. Fluid filtered from the glomerular capillaries flows into Bowmanâ&#x20AC;&#x2122;s capsule and then into the proximal tubule, which lies in the cortex of the kidney.

FIgURE 3: Section of the human kidney showing the major vessels that supply the blood flow to the kidney and schematic of the microcirculation of each nephron.

From the proximal tubule, fluid flows into the loop of Henle, which dips into the renal medulla. Each loop consists of a descending and an ascending limb. The walls of the descending limb and the lower end of the ascending limb are very thin and therefore are called the thin segment of the loop of Henle. the macula densa plays an important role in controlling nephron function. Beyond the macula densa, fluid enters

FIgURE 4: Basic tubular segments of the nephron. The relative lengths of the different tubular segments are not drawn to scale.

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MICTURITION Micturition is the process by which the urinary bladder empties when it becomes filled. This involves two main steps: First, the bladder fills progressively until the tension in its walls rises above a threshold level; this elicits the second step, which is a nervous reflex called the micturition reflex that empties the bladder or, if this fails, at least causes a conscious desire to urinate. Although the micturition reflex is an autonomic spinal cord reflex, it can also be inhibited or facilitated by centers in the cerebral cortex or brain stem.

PHYSIOLOGIC ANATOMY OF THE BLADDER The urinary bladder is a smooth muscle chamber composed of two main parts: (1) the body, which is the major part of the bladder in which urine collects, and (2) the neck, which is a funnel-shaped extension of the body, passing inferiorly and anteriorly into the urogenital triangle and connecting with the urethra. The lower part of the bladder neck is also called the posterior urethra because of its relation to the urethra. The smooth muscle of the bladder is called the detrusor muscle. Its muscle fibers extend in all directions and, when contracted, can increase the pressure in the bladder to 40 to 60 mm Hg. Thus, contraction of the detrusor muscle is a major step in emptying the bladder. Smooth muscle cells of the detrusor muscle fuse with one another so that low-resistance electrical pathways exist from one muscle cell to the other. Therefore, an action potential can spread throughout the detrusor muscle, from one muscle cell to the next, to cause contraction of the entire bladder at once. On the posterior wall of the bladder, lying immediately above the bladder neck, is a small triangular area called the

FIgURE 5:: Anatomy of Urinary Bladder in female.

trigone. At the lowermost apex of the trigone, the bladder neck opens into the posterior urethra and the two ureters enter the bladder at the uppermost angles of the trigone. The trigone can be identified by the fact that its mucosa, the inner lining of the bladder, is smooth, in contrast to the remaining bladder mucosa, which is folded to form rugae. Each ureter, as it enters the bladder, courses obliquely

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through the detrusor muscle and then passes another 1 to 2 centimeters beneath the bladder mucosa before emptying into the bladder. The bladder neck (posterior urethra) is 2 to 3 centimeters long, and its wall is composed of detrusor muscle interlaced with a large amount of elastic tissue. The muscle in this area is called the internal sphincter. Its

natural tone normally keeps the bladder neck and posterior urethra empty of urine and, therefore, prevents emptying of the bladder until the pressure in the main part of the bladder rises above a critical threshold. Beyond the posterior urethra, the urethra passes through the urogenital diaphragm, which contains a layer of muscle called the external sphincter of the bladder. This muscle is a voluntary skeletal muscle, in contrast to the muscle of the bladder body and bladder neck, which is entirely smooth muscle. The external sphincter muscle is under voluntary control of the nervous system and can be used to consciously prevent urination even when involuntary controls are attempting to empty the bladder.

INNERVATION OF THE BLADDER The principal nerve supply of the bladder is by way of the pelvic nerves, which connect with the spinal cord through the sacral plexus, mainly connecting with cord segments S-2 and S-3. Coursing through the pelvic nerves are both sensory nerve fibers and motor nerve fibers. The sensory fibers detect the degree of stretch in the bladder wall. Stretch signals from the posterior urethra are especially strong and are mainly responsible for initiating the reflexes that cause bladder emptying.

FIgURE 6: Urinary bladder and its innervation..

The motor nerves transmitted in the pelvic nerves are parasympathetic fibers. These terminate on ganglion cells located in the wall of the bladder. Short postganglionic nerves then innervate the detrusor muscle.

sphincter. These are somatic nerve fibers that innervate and control the voluntary skeletal muscle of the sphincter.

the blood vessels and have little to do with bladder contraction.

In addition to the pelvic nerves, two other types of innervation are important in bladder function. Most important are the skeletal motor fibers transmitted through the pudendal nerve to the external bladder

Also, the bladder receives sympathetic innervation from the sympathetic chain through the hypogastric nerves, connecting mainly with the L-2 segment of the spinal cord. These sympathetic fibers stimulate mainly

Some sensory nerve fibers also pass by way of the sympathetic nerves and may be important in the sensation of fullness and, in some instances, pain.

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TRANSPORT OF URINE FROM THE KIDNEY THROUGH THE URETERS AND INTO THE BLADDER Urine that is expelled from the bladder has essentially the same composition as fluid flowing out of the collecting ducts; there are no significant changes in the composition of urine as it flows through the renal calyces and ureters to the bladder. Urine flowing from the collecting ducts into the renal calyces stretches the calyces and increases their inherent pacemaker activity, which in turn initiates peristaltic contractions that spread to the renal pelvis and then downward along the length of the ureter, thereby forcing urine from the renal pelvis toward the bladder. The walls of the ureters contain smooth muscle and are innervated by both sympathetic and parasympathetic nerves as well as by an intramural plexus of neurons and nerve fibers that extends along the entire length of the ureters. As with other visceral smooth muscle, peristaltic contractions in the ureter are enhanced by parasympathetic stimulation and inhibited by sympathetic stimulation. The ureters enter the bladder through the detrusor muscle in the trigone region of the bladder, as shown in Figure-5. Normally, the ureters course obliquely for several centimeters through the bladder wall. The normal tone of the detrusor muscle in the bladder wall tends to compress the ureter, thereby preventing backflow of urine from the bladder when pressure builds up in the bladder during micturition or bladder compression. Each peristaltic wave along the ureter increases the pressure within the ureter so that the region passing through the bladder wall opens and allows urine to flow into the bladder. In some people, the distance that the ureter courses through the bladder wall is less than normal, so that contraction of the bladder during micturition does not always lead to complete occlusion of the ureter. As a

result, some of the urine in the bladder is propelled backward into the ureter, a condition called vesicoureteral reflux. Such reflux can lead to enlargement of the ureters and, if severe, can increase the pressure in the renal calyces and structures of the renal medulla, causing damage to these regions.

PAIN SENSATION IN THE URETERS, AND THE URETERORENAL REFLEx The ureters are well supplied with pain nerve fibers. When a ureter becomes blocked (e.g., by a ureteral stone), intense reflex constriction occurs, associated with severe pain. Also, the pain impulses cause a sympathetic reflex back to the kidney to constrict the renal arterioles, thereby decreasing urine output from the kidney. This effect is called the ureterorenal reflex and is important for preventing excessive flow of fluid into the pelvis of a kidney with a blocked ureter.

FILLING OF THE BLADDER AND BLADDER WALL TONE; THE CYSTOMETROGRAM Figure -7 shows the approximate changes in intravesicular pressure as the bladder fills with urine.When there is no urine in the bladder, the intravesicular pressure is about 0, but by the time 30 to 50 milliliters of urine has collected, the pressure rises to 5 to 10 centimeters of water. Additional urineâ&#x20AC;&#x201D;200 to 300 millilitersâ&#x20AC;&#x201D; can collect with only a small additional rise in pressure; this constant level of pressure is caused by intrinsic tone of the bladder wall itself. Beyond 300 to 400 milliliters, collection of more urine in the bladder causes the pressure to rise rapidly.

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FIgURE 7: Normal cystometrogram, showing also acute pressure waves (dashed spikes) caused by micturition reflexes.

Superimposed on the tonic pressure changes during filling of the bladder are periodic acute increases in pressure that last from a few seconds to more than a minute. The pressure peaks may rise only a few centimeters of water or may rise to more than 100 centimeters of water. These pressure peaks are called micturition waves in the cystometrogram and are caused by the micturition reflex.

MICTURITION REFLEx As the bladder fills, many superimposed micturition contractions begin to appear, as shown by the dashed spikes. They are the result of a stretch reflex initiated by sensory stretch receptors in the bladder wall, especially by the receptors in the posterior urethra when this area begins to fill with urine at the higher bladder pressures. Sensory signals from the bladder stretch receptors are conducted to the sacral segments of the cord through the pelvic nerves and then reflexively back again to the bladder through the parasympathetic nerve fibers by way of these same nerves. When the bladder is only partially filled, these micturition contractions usually relax spontaneously after a fraction of a minute, the detrusor muscles stop contracting, and pressure falls back to the baseline. As the bladder continues to fill, the micturition reflexes become more frequent and cause greater contractions of the detrusor muscle. Once a micturition reflex begins, it is â&#x20AC;&#x153;self-regenerative.â&#x20AC;? That is, initial contraction of the bladder activates the stretch receptors to cause a greater increase in sensory impulses to the bladder and posterior urethra, which causes a further increase in reflex contraction of the bladder; thus, the cycle is repeated again and again until the bladder has reached a strong degree of contraction. Then, after a few seconds to more than a minute, the selfregenerative reflex begins to fatigue and the regenerative cycle of the micturition reflex ceases, permitting the bladder to relax. Thus, the micturition reflex is a single complete cycle of (1) progressive and rapid increase of pressure, (2) a period of sustained pressure, and (3) return of the pressure to the basal tone of the bladder. Once a micturition reflex has occurred but has not succeeded in emptying the bladder,

the nervous elements of this reflex usually remain in an inhibited state for a few minutes to 1 hour or more before another micturition reflex occurs. As the bladder becomes more and more filled, micturition reflexes occur more and more often and more and more powerfully. Once the micturition reflex becomes powerful enough, it causes another reflex, which passes through the pudendal nerves to the external sphincter to inhibit it. If this inhibition is more potent in the brain than the voluntary constrictor signals to the external sphincter, urination will occur. If not, urination will not occur until the bladder fills still further and the micturition reflex becomes more powerful.

FACILITATION OR INHIBITION OF MICTURITION BY THE BRAIN

presents itself. 3. When it is time to urinate, the cortical centers can facilitate the sacral micturition centers to help initiate a micturition reflex and at the same time inhibit the external urinary sphincter so that urination can occur. Voluntary urination is usually initiated in the following way: First, a person voluntarily contracts his or her abdominal muscles, which increases the pressure in the bladder and allows extra urine to enter the bladder neck and posterior urethra under pressure, thus stretching their walls. This stimulates the stretch receptors, which excites the micturition reflex and simultaneously inhibits the external urethral sphincter. Ordinarily, all the urine will be emptied, with rarely more than 5 to 10 milliliters left in the bladder.

The micturition reflex is a completely autonomic spinal cord reflex, but it can be inhibited or facilitated by centers in the brain. These centers include (1) strong facilitative and inhibitory centers in the brain stem, located mainly in the pons, and (2) several centers located in the cerebral cortex that are mainly inhibitory but can become excitatory. The micturition reflex is the basic cause of micturition, but the higher centers normally exert final control of micturition as follows: 1. The higher centers keep the micturition reflex partially inhibited, except when micturition is desired. 2. The higher centers can prevent micturition, even if the micturition reflex occurs, by continual tonic contraction of the external bladder sphincter until a convenient time

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Female Pelvic Anatomy

Female Pelvic Floor Anatomy THE PELVIS The pelvis is either the lower part of the trunk of the human body between the abdomen and the thighs or the skeleton embedded in it. The pelvic region of the trunk includes the bony pelvis, the pelvic cavity, the pelvic floor, below the pelvic cavity, and the perineum, below the pelvic floor. The pelvic skeleton is formed in the area of the back, by the sacrum and the coccyx and anteriorly and to the left and right sides, by a pair of hip bones. The two hip bones connect the spine with the lower limbs. They are attached to the sacrum posteriorly, connected to each other anteriorly, and joined with the two femurs at the hip joints. The gap enclosed by the bony pelvis, called the pelvic cavity, is the section of the body underneath the abdomen and mainly consists of the reproductive organs (sex organs) and the rectum, while the pelvic floor at the base of the cavity assists in supporting the organs of the abdomen. FIgURE 1: Anatomy of female pelvic bones.

BONY PELVIS The bony pelvis consists of the 2 innominate bones, or hip bones, which are fused to the sacrum posteriorly and to each other anteriorly at the pubic symphysis. Each innominate bone is composed of the ilium, ischium, and pubis, which are connected by cartilage in youth but fused in the adult. The pelvis has 2 basins: the major (or greater) pelvis and the minor (or lesser) pelvis. The abdominal viscera occupy the major pelvis; the minor pelvis is the narrower continuation of the major pelvis inferiorly. The

inferior pelvic outlet is closed by the pelvic floor. The female pelvis has a wider diameter and a more circular shape than that of the male. The wider inlet facilitates head engagement and parturition. The wider outlet predisposes to subsequent pelvic floor weakness. Numerous projections and contours provide attachment sites for ligaments, muscles, and fascial layers. Of note is the thin and triangular sacrospinous ligament, which extends from the ischial spines to the lateral margins of the sacrum and

coccyx anteriorly to the sacrotuberous sacrotuberous ligament. Its anterior surface is muscular and constitutes the coccygeus; the ligament is often regarded as the degenerate part of the muscle. The greater and lesser sciatic foramina are above and below the ligament.

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PELVIC CAVITY The pelvic cavity is a body cavity that is bounded by the bones of the pelvis and which primarily contains reproductive organs and the rectum. A distinction is made between the lesser or true pelvis inferior to the terminal line, and the greater or false pelvis above it. The pelvic inlet or superior pelvic aperture, which leads into the lesser pelvis, is bordered by the promontory, the arcuate line of ilium, the iliopubic eminence, the pecten of the pubis, and the upper part of the pubic symphysis. The pelvic outlet or inferior pelvic aperture is the region between the subpubic angle or pubic arch, the ischial tuberosities and the coccyx.

MUSCULAR SUPPORTS OF THE PELVIC FLOOR PELVIC DIAPHRAGM The levator ani and coccygeus muscles that are attached to the inner surface of the minor pelvis form the muscular floor of the pelvis. With their corresponding muscles from the opposite side, they form the pelvic diaphragm. The levator ani is composed of two major muscles from medial to lateral: the pubococcygeus and iliococcygeus muscles. The bulkier medial portion of the levator ani is the pubococcygeus muscle that arises from the back of the body of the pubis and anterior portion of the arcus tendineus. The arcus tendineus of the levator ani is a dense connective tissue structure that runs from the pubic ramus to the ischial spine and courses along the surface of the obturator internus muscle. The muscle passes back almost horizontally to behind the rectum. The inner border forms the margin of the levator (urogenital) hiatus, through which passes the urethra, vagina, and anorectum.

FIgURE 2: Muscles of the female pelvic diaphragm.

Various muscle subdivisions have been assigned to the medial portions of the pubococcygeus to reflect the attachments of the muscle to the urethra, vagina, anus, and rectum. The urethral portion forms part of the periurethral musculature, and the vaginal and anorectal portions insert into the vaginal walls, perineal body, and external anal sphincter muscle. The puborectalis portion passes behind the rectum and fuses with its counterpart from the opposite side to form a sling behind the anorectum. Other more posterior parts of the pubococcygeus attach to the coccyx.

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The thin lateral part of the levator ani is the iliococcygeus muscle, which arises from the arcus tendineus of the levator ani to the ischial spine. Posteriorly it attaches to the last 2 segments of the coccyx. The fibers from both sides also fuse to form a raphe and contribute to the anococcygeal ligament. This median raphe between the anus and the coccyx is called the levator plate and is the shelf on which the pelvic organs rest. It is formed by the fusion of the iliococcygeus and the posterior fibers of the pubococcygeus muscles. When the body is in a standing position, the levator plate is horizontal and supports the rectum and upper two thirds of vagina above it. Weakness of the levator ani may loosen the sling behind the anorectum and cause the levator plate to sag.

This opens the urogenital hiatus and predisposes to pelvic organ prolapse. Women with prolapse have been shown to have an enlarged urogenital hiatus on clinical examination. The coccygeus muscle that extends from the ischial spine to the coccyx and lower sacrum forms the posterior part of the pelvic diaphragm. It sits on the anterior surface of the sacrospinous ligament. Three-dimensional magnetic resonance imaging (MRI) of the pelvic diaphragm shows its peripheral attachments and demonstrates the urogenital hiatus. Direct innervation of the levator ani muscle on its cranial surface is primarily from the third and fourth sacral nerve roots via the pudendal nerve. The puborectalis may derive some if its innervation from a pudendal branch on the caudal side.2 Regarding the type of the striated muscle, it has been reported that the majority of the muscle fibers in the levator ani are slow-twitch fibers that maintain constant tone, with an increased density of fasttwitch fibers distributed in the periurethral and perianal areas. This suggests that the normal levator ani maintains tone in the upright position to support the pelvic viscera. Furthermore, voluntary squeezing of the puborectalis may increasethe tone to counter increased intraabdominal pressure.

UROGENITAL DIAPHRAGM (PERINEAL MEMBRANE) Another musculofascial structure, the urogenital diaphragm, is present over the anterior pelvic outlet below the pelvic diaphragm. However, there is controversy over whether this structure contains a transverse sheet of muscle extending across the pubic arch (deep transverse perinei muscle) sandwiched between superior and inferior

FIgURE 3: A crosssectional view showing position of female lower body organs.

fascia or 3 contiguous striated muscles (compressor urethrae, sphincter urethrae, and urethrovaginalis) and an inferior fascial layer called the perineal membrane. Despite the controversy, MRI scans clearly depict the structure. The more superficial ischiocavernosus and bulbocavernosus muscles, as well as the thin slips of the superficial transverse perinei, complete the inferior aspect

of the urogenital diaphragm. The structure bridges the gap between the inferior pubic rami bilaterally and the perineal body. It closes the urogenital (levator) hiatus; supports and has a sphincter-like effect at the distal vagina; and, because it is attached to periurethral striated muscles, contributes to continence. It also provides structural support for the distal urethra. The posterior triangle around the anus does not have a corresponding diaphragm or

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membrane. The ischiorectal fossae are the spaces lateral to the anus below the pelvic diaphragm. PERINEAL BODY The perineal body is a pyramidal fibromuscular structure in the midline between the anus and vagina with the rectovaginal septum at its cephalad apex. Below this, muscles and their fascia converge and interlace through the structure. Attached to the perineal body are the rectum, vaginal slips from the pubococcygeus, perineal muscles, and the anal sphincter; it also contains smooth muscle, elastic fibers, and nerve endings. During childbirth, the perineal body distends and then recoils. It is an important part of the pelvic floor; just above it are the vagina and the uterus.

FIgURE 5: Female pelvic floor anatomy and its muscles structure.

ENDOPELVIC FASCIA AND CONNECTIVE TISSUE SUPPORTS

FIgURE 4: Anatomy of female perineal body and its structure.

The bladder and urethra and the vagina and uterus are attached to the pelvic walls by a system of connective tissue that has been called the endopelvic fascia. This structure lies immediately beneath the peritoneum and is one continuous unit with various thickenings or condensations in specific areas. The endopelvic fascia is continuous with the visceral fascia, which provides a

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capsule containing the organs and allows displacements and changes in volume. The distinct regions of this structure are given individual names, specifically ligaments and fascia, with variable internal structure. Endopelvic fascia and ligaments are a mesh-like group of collagen fibers interlaced with elastin, smooth muscle cells, fibroblasts, and vascular structures. The structures that

URETHRA attach the uterus to the pelvic wall, the cardinal ligaments, derive strength from the supportive collagen forming the walls of arteries and veins. Other structures, such as the pelvic sidewall attachment of the endopelvic fascia (arcus tendineus of the pelvic fascia), are predominantly fibrous collagen.

The urethra is a complex tubular structure extending below the bladder to the external meatus. It has distinct muscular elements associated both within and without to permit its functioning for storage (continence) and voiding. The smooth muscle of the urethra is contiguous with that of the trigone and detrusor. It has a prominent inner longitudinal and a thin outer circular layer. The layers lie inside the outer striated urogenital sphincter muscle and are present throughout the upper four fifths of the urethra. The configuration of the circular muscle implies a role in constricting the lumen, and the longitudinal muscle may aid in shortening the urethra during voiding. The outer layer of the urethra is formed by the muscle of the striated urogenital sphincter that is found in the middle three fifths of the length. In its upper two thirds, the sphincterlike fibers are circular. In the distal part, the fibers exit the urethra and surround the vaginal wall as the urethrovaginal sphincter or extend along the inferior pubic rami above the perineal membrane as the compressor urethra. The muscle is composed mainly of slow-twitch fibers, well suited for maintaining constant tone. Voluntary muscle activation can also increase the constriction of the urethra when needed.

FIgURE 6: Vagina and supportive structures drawn from dissection. In level I, paracolpium suspends vagina from the lateral pelvic walls. In level II, the vagina is attached to arcus tendineus of pelvic fascia and superior fascia of levator ani muscles.

The urethral mucosa extends from the bladder transitional epithelium to the external meatus. It is derived from the urogenital sinus along with the lower vagina and vestibule. It is hormonally sensitive and undergoes changes with stimulation. The hormonally sensitive submucosal tissue contains a rich and prominent vascular plexus. Several specialized types of arteriovenous anastomoses have been demonstrated, and it is thought that they provide a watertight closure of the mucosal surface with an increase in blood flow that may occur with an increase in pressure on abdominal vessels. In addition to the muscular and vascular tissue of the urethra, there is a

considerable quantity of connective tissue interspersed within the muscle and submucosa. This tissue contains collagen and elastin fibers and is thought to add to urethral closure passively. Lastly, a series of glands are found in the submucosa, mainly along the vaginal surface of the urethra. They are most predominant in the middle and lower third of the urethra. It is the admixture of the smooth and striated muscle, connective tissue, mucosa, and submucosa that accounts for a functional sphincter. A functional urethral sphincter has intact neural control and provides watertight apposition of the urethral lumen, compression of the wall around the lumen, and a means of compensating for abdominal pressure changes.

FIgURE 7: The female urethra is composed of 4 separate tissue layers that keep it closed. The inner mucosal lining keeps the urothelium moist and the urethra supple. The vascular spongy coat produces the mucus important in the mucosal seal mechanism. Compression from the middle muscular coat helps to maintain the resting urethral closure mechanism. The outer seromuscular layer augments the closure pressure provided by the muscular layer.

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MECHANISM OF CONTINENCE The “hammock hypothesis” is a readily understood way to explain the continence mechanism. The requirements for continence include a quiescent bladder, functioning musculofascial supports, and a functional urethral sphincter mechanism. The fascial attachments connect the periurethral tissue and anterior vaginal wall to the arcus tendineus at the pelvic sidewall, whereas the muscular attachments connect the periurethral tissue to the medial border of the levator ani. Urethral support is provided by a coordinated action of fascia and muscles acting as an integrated unit under neural control. This musculofascial support provides a hammock onto which the urethra is compressed during increases in intraabdominal pressure.

SUMMARY

•

The levator plate, the shelf on which the pelvic organs rest, is horizontal when the body is in a standing position and supports the rectum and upper two thirds of the vagina above it. Weakness of the levator ani may loosen the sling behind the anorectum and cause the levator plate to sag, opening the urogenital hiatus and allowing pelvic organ prolapse.

•

The urogenital diaphragm closes the levator hiatus, supports and has a sphincter like effect at the distal vagina, provides structural support for the distal urethra, and contributes to continence in that it is attached to the periurethral striated muscles.

•

There is controversy regarding whether the anterior vaginal wall includes a suburethral fascial layer; regardless, the anterior vaginal wall provides support to the urethra by its lateral attachment to the levators and to the endopelvic fascia from the arcus tendineus of the pelvic fascia.

•

A combination of smooth and striated muscle, connective tissue, mucosa, and submucosa are necessary for a functional urethral sphincter, which provides watertight apposition of the urethral lumen, compression of the wall around the lumen, and a means of compensating for abdominal pressure changes.

•

The “hammock hypothesis” describes support of the urethra by a coordinated action of fascia and muscles, which provides a hammock onto which the urethra is compressed during increases in intra-abdominal pressure.

FIgURE 8: Lateral view of the pelvic floor with the urethra, vagina, and fascial tissues transected at the level of the vesical neck, drawn from 3-dimensional reconstruction indicating compression of the urethra by downward force (arrow) against the supportive tissues.

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Urothelial Cell Biology

The Urothelial Signaling THE UROTHELIAL SIGNALING A prerequisite for conscious bladder control is adequate sensory input to the central nervous system (CNS), and it is well established that changes in sensory mechanisms may give rise to disturbances in bladder function. For example, pelvic nerves are thought to convey sensations relating to the desire to void in contrast to sensations of bladder fullness, which are mediated by pudendal nerves. The urethra is very likely to be important in mediating the sense of “imminent” micturition. However, where the afferent impulses for bladder sensation and bladder activation are generated, and by what mechanisms, have not been fully established. However, at least two afferent signaling systems can be defined: the myogenic and mucosal pathways. Bladder filling increases activity in in-series-coupled low-threshold mechanoreceptive afferents, thereby initiating activation of the micturition reflex. Studies have identified several classes of functionally distinct bladder sensory neurons, which include muscle-mucosal and mucosal mechanoreceptors as well as chemoreceptors. Those in close proximity to the urothelium are sensitive to urothelially derived mediators resulting in increased afferent signaling. Changes in these afferent mechanisms may be associated with lower urinary tract symptoms (LUTS) for example detrusor overactivity (DO) and urinary incontinence (UI).

FUNCTIONAL ANATOMY A. MUCOSA The bladder wall has three well-defined layers: the mucosa (innermost portion), the muscularis propria, and the adventitia/ serosa (FIGURE 1). The mucosa (urothelium,

basement membrane, lamina propria) also contains some smooth muscle cells, muscularis mucosae. Since this structure is not very well defined in the human.bladder, it may be questioned whether the human bladder, unlike the gut, has a true “submucosal” layer. However, the term is sometimes used to denote the part of the lamina propria closest to the muscularis propria.

B. UROTHELIUM The uroepithelium, or urothelium, lines the renal pelvis, ureters, bladder, upper urethra, and glandular ducts of the prostate and forms the interface between the urinary space and the underlying vasculature, connective, nervous, and muscular tissues. The urothelium is a transitional epithelial tissue, composed of at least three layers : a basal cell layer attached to a basement membrane, an intermediate layer, and a superficial or apical layer composed of large hexagonal cells known as “umbrella cells”. The apical surface of umbrella cells possesses a unique asymmetric unit membrane (AUM), whose protein components have been well studied. Tight junctions, localized between the superficial umbrella cells, are composed of multiple proteins such as the occludins and claudins. These proteins, along with uroplakins, which are crystalline proteins that assemble into hexagonal plaques, contribute to the urothelial barrier function. In contrast, the region of the bladder neck and stratified epithelium of the urethra do not express these types of urothelial differentiation markers. Some have suggested that urothelial cells have cytoplasmic projections that anchor them to the basement membrane. A urothelial glycosaminoglycan (GAG) layer (FIGURE 1) covers the umbrella cells and has been

suggested to contribute to urothelial barrier function. The major part of the urinary tract shows similarity between a number of species and is lined with a fully differentiated urothelium. In contrast to the proximal urethra, there appears to be little difference between the urothelium of the trigone and the detrusor. Here the urothelium transitions to a stratified or columnar epithelium accompanied by a lack of urothelial-specific differentiation markers. Similar to the lung epithelium, urethral epithelial cells express microvilli (FIGURE 3) on the apical surface. The presence of cilia or microvilli may have a number of functions including ability to increase the cell surface area, as well as affect bacterial adherence and fluid transport. There are at least three urothelial lineages consisting of the ureter/renal pelvis, detrusor/trigone, and bladder neck/proximal urethra. The functional significance of these findings has yet to be determined.

C. LAMINA PROPRIA A focus of current LUT research has been afferent mechanisms and the processes of how afferent information is generated and conveyed to the CNS in the control of micturition. One of the pathways defined involves the bladder mucosa, but attention has been given mainly to the urothelium. However, the urothelium may be regarded as one part of a signaling system involving also the lamina propria (LP). The LP lies between the basement membrane of the mucosa and the muscularis propria (detrusor muscle, FIGURE 1) and is composed of an extracellular matrix

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FIgURE 1: Components of the bladder wall. Left: counterstained transverse section through normal human urinary bladder. Right: cartoon depicting bladder wall components.

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containing several types of cells, including fibroblasts, adipocytes, interstitial cells, and sensory nerve endings. In addition, LP contains a rich vascular network, lymphatic channels, elastic fibers, and smooth muscle fascicles (muscularis mucosae). Notably, the thickness of the LP varies within the bladder. The morphological characteristics of the LP, muscularis mucosae, and the detrusor muscle are important for pathological tumor staging of bladder cancer. However, LP is not only a landmark, but also a functionally active structure essential for, e.g., afferent signaling. 1. INTERSTITIAL CELLS/MYOFIBROBLASTS A dense layer of spindle-shaped cells has been described in bladder upper lamina propria in both humans and animals. These spindle-shaped bladder cells have been categorized heterogeneously as interstitial cells (ICs), interstitial cells of Cajal (ICC), interstitial Cajal-like cells (ICLC) cells, myofibroblasts, or telocytes. The cells described by Wiseman et al. had close contacts with nerves containing small clear vesicles with and without dense cores, implying that they had an efferent and afferent nerve supply. It has been questioned whether or not the normal human bladder contains myofibroblasts, which are generally considered to be smooth-musclelike fibroblasts found in many tissues of the body, where they generally have functions in growth, repair, and wound healing. Significantly, myofibroblasts are contractile and immunopositive for filaments such as actin, vimentin, desmin, and myosin, and they contain fibronexus junctions. However, bladder ICs, even if they are excitable and show spontaneous electrical activity, do not seem to have any contractile properties. The cells have been identified morphologically and by use of different cellular markers (including c-Kit). Mukerji et al. observed muscarinic (M2 and M3) receptor immunoreactivity on cells in the lamina propria resembling

FIgURE 2: Urinary bladder urothelium and associated tight junctions. A: cartoon depicting multiple epithelial cell layers within the urothelium. B: immunohistochemical staining of mouse urothelium with an antibody to uroplakin III showing staining of superficial umbrella cells.

ICs, suggesting that these cells could respond to cholinergic signaling. The role of bladder ICs, including those in the LP, has not been established. The ICs in the LP and within the detrusor may serve different functions. Available evidence suggests that the LP ICs may constitute a structural and functional link between urothelial cells and sensory nerves and/or between urothelial cells and detrusor smooth muscle cells. Moreover, these cells might be involved in the pathophysiology of urinary tract disorders.

body and bladder neck, there was a gradual increase in the number of nerves in the LP and these nerves might have a sensory function. Throughout the bladder neck itself, the nerves formed an extensive plexus adjacent to the urothelial lining (possibly making synaptic connections within urothelial cells). Given the location in close proximity to the urothelium, it is not surprising that changes in urothelial structure and function can occur with either pelvic nerve stimulation or neural activation following spinal cord injury.

2. AFFERENT NERVES

D. BARRIER FUNCTION

Different types of nerves have been described in the LP. In the fundus and adjacent part of the body, nerves were rarely encountered, but in the lower part of the bladder

The urothelium plays a critical role as a permeability barrier to urine, and an intact barrier is a prerequisite for normal afferent signaling from the bladder. Several features of

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urothelial repair is not well understood. Both physiological and psychological stress can result in a failure of urothelial and suburothelial “defensive” systems and thereby promote changes in both urothelial barrier and signaling function. For example, alterations in proteins including proteoglycans and bacterial defense molecules may lead to distinctive changes in urothelial structure and play a role in bacterial adherence. In this regard, urinary tract infections produced by uropathogenic Escherichia coli (UPEC) are initiated by bacterial adherence to uroplakin proteins on the apical surface of umbrella cells.

FIgURE 3: Ultrastructural features of urethral epithelium. Right: images depict “open type” paraneurons within the dog urethra. A: paraneuron reaching the lumen. B and C: scanning EM identifies microvillous cells among the epithelial cells.

the superficial or umbrella cell layer aid the bladder in maintaining normal barrier function as the bladder fills and empties. These include a number of tight-junction proteins in addition to specialized lipids and uroplakin proteins in the umbrella cell apical membrane. The uroplakins have important functions including maintaining the urothelial barrier in part by preventing proteins as well as ionic and nonionic substances from gaining access. Distension of the bladder during filling is accompanied by a change in shape of the superficial epithelium. In addition, there is also an increase in vesicular traffic (i.e.exocytosis/ endocytosis) which adds membrane to the apical or superficial cell surface, thereby permitting increases in bladder volume without loss of barrier function. Studies have revealed that stretch-induced exocytosis is likely to

involve a number of signaling molecules including epidermal growth factor receptor. These processes allow the bladder to accommodate increasing volumes of urine during filling without compromising barrier function.

Although the urothelium maintains a tight barrier, a number of factors (e.g., mechanical or chemical trauma, infection) can modulate the barrier function. When the barrier is compromised, the urothelium is unable to maintain the integrity of the bladder-urine interface. The result can be changes in the function of underlying cells within the bladder wall and sensory symptoms of urgency, frequency, and pain during bladder filling and voiding. Thus a complex chemical information transfer exists between the urothelium and cells within the bladder wall and disruption in this “sensory web” may be involved in bladder dysfunction.

Basal epithelial cells, which have been suggested to have stem-cell-like properties, typically exhibit very slow proliferative rates. There is some suggestion that urothelial cell turnover and differentiation may not be influenced by cyclic mechanical changes. The processes underlying urothelial repair are complex, involving several structural elements, signaling pathways, trophic factors, and the cellular environment. Furthermore, the interaction between these biochemical signals and mechanical forces in the bladder during the course of

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UROTHELIUM-LAMINA PROPRIA INTERACTIONS NORMAL BLADDER FILLING: THE â&#x20AC;&#x153;SENSORY WEBâ&#x20AC;? It is likely that a cascade of urothelial inhibitory and stimulatory transmitter/mediators are involved in the transduction mechanisms underlying the activation of afferent fibers during bladder filling. The mucosal activation pathway (the sensory web) includes the urothelium, the afferent (and efferent) nerves, the ICs of the lamina propria, and possibly the muscularis mucosae (FIGURE 4). The suburothelial ICs are extensively linked by gap junctions and may serve as intermediaries between the urothelium and afferent nerves, and possibly between nerves and detrusor muscle. Whether or not the muscle cells of the muscularis mucosae will contribute is still unclear. However, it is clear that communication between these different structures ensures normal function of the organ and may explain how the effect of various neurotransmitters/mediators when given intravesically can modify bladder function by changing neurotransmission, the spontaneous activity of the detrusor smooth muscle, and thereby bladder function. There is substantive evidence that urothelial cells are able to respond to a number of stimuli (physical as well as chemical). In turn, the urothelium can signal (via substances they release, often termed volume regulation) to cells in the bladder wall. In this manner, the urothelium is likely to play an important role in the complex transfer of information to and from the nervous system. The urothelium is able to respond to a wide variety of mechanical stresses during bladder filling and emptying by activating a number of possible transducer proteins. Possibilities of mechanical signals include bladder pressure, tension in the urothelium or bladder wall, torsion, geometrical tension, and movement of visceral organs. Recent studies have demonstrated that urothelial

FIgURE 4: Hypothetical model depicting possible interactions between bladder nerves, urothelial cells, smooth muscle, interstitial cells, and blood vessels. Urothelial cells can also be targets for transmitters released from nerves or other cell types. Urothelial cells can be activated by either autocrine (i.e., autoregulation) or paracrine (release from nearby nerves or other cells) mechanisms.

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cells release transmitters (such as ATP) during changes in hydrostatic pressure (in ranges that normally trigger micturition). Activation of transducer proteins by a variety of mechanical stimuli could also involve indirect mechanisms such as changes in the cytoskeleton, cell surface molecules such as integrins, or coactivation of urothelial channel proteins. The urothelium can also respond to changes in urine tonicity. Alterations in the composition of urine are a type of stress; the urine contents can vary in both their rate of delivery as well as the particular constituents. Additional lines of evidence suggest that urothelial cells participate in the detection of both physical and chemical stimuli. As mentioned, bladder nerves (afferent and efferent) are localized in close proximity to, and some within, the urothelium. In addition, urothelial cells express numerous receptors/ion channels similar to what is found in both nociceptors and mechanoreceptors elsewhere in the body, and these cells secrete a number of transmitters or mediators capable of modulating, activating, or inhibiting sensory neurons. Examples of neuronal “sensor molecules” (receptors/ion channels) that have been identified in urothelium (TABLE: 1) include receptors for purines, adenosine, norepinephrine, ACh, proteaseactivated receptors (PARs), amiloride- and mechanosensitive epithelial sodium channels (ENaC), bradykinin, neurotrophins, CRF, estrogens, endothelins, and various TRP channels. The expression of these various receptors enables the urothelium to respond to a number of “sensory inputs” from a variety of sources. These inputs include increased stretch during bladder filling, soluble factors (many found in the urine), or chemical mediators/peptides/transmitters released from nerves, inflammatory cells, and even blood vessels. Thus various stimuli can lead to secretion of chemical substances capable of modulating the activity of underlying smooth muscle, as well as nearby sensory

TABLE 1: Properties of ionic channels/receptors expressed within the urinary bladder urothelium.

neurons. For example, urothelial-specific overexpression of nerve growth factor (NGF) results in increased bladder nerve “sprouting” and increased voiding frequency. It has been shown that urothelial-derived NO can be released in response to mechanical as well as chemical stimulation and may either facilitate or inhibit the activity of bladder afferent nerves conveying bladder sensation. In this regard, activation of urothelial receptors and release of inhibitory mediators may explain, in part, the mechanism of action for therapies (e.g., β 3-AR agonists) in treatment of bladder disorders such as the overactive bladder (OAB).

systems may express similar receptor subtypes. Accordingly, epithelial cells could use multiple signaling pathways, whose intracellular mechanisms differ according to location and environmental stimuli. This would permit a greater flexibility for the cell to regulate function and respond to complex changes in their surrounding microenvironment. Whether urothelialsensor molecules all feed into a diverse array of signaling pathways or share similarities with systems such as olfaction, whereby hundreds of receptors share identical transduction cascades, is yet to be uncovered.

There is evidence that epithelial cells in different organ

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INVOLVEMENT OF THE UROTHELIUM IN â&#x20AC;&#x153;SENSINGâ&#x20AC;? CHEMICAL AND MECHANICAL STIMULI The importance of the urothelium and underlying suburothelium of the urinary bladder in mechanosensory control, and the role of afferent pathways including urothelium/ suburothelium/interstitial cell function in the pathophysiology for OAB is increasingly recognized. This has revealed a greater variety of targets to manage OAB other than those concerned with smooth muscle contraction. This section will be concerned with identification of potential novel targets and the identification of biomarkers that can objectively measure the extent and progression of OAB. Signal transduction mechanisms are subclassified into seven different categories G-protein coupled receptors, ligand-gated ion channels, ion channels, nuclear receptors, catalytic receptors, transporters, and enzymes.

1. SEVEN TRANSMEMBRANE SPANNING RECEPTORS (7-TM, METABOTROPIC RECEPTORS) A. ACETYLCHOLINE (ACH)-MUSCARINIC RECEPTORS The urinary bladder is profusely supplied with autonomic nerve fibres, which form a dense plexus among the detrusor smooth muscle cells. The majority of these nerves contain acetyl cholinesterase, and while they occur in profusion throughout the muscle coat of the bladder, some muscle bundles are more richly innervated than others. The majority of the autonomic nerves innervating the detrusor muscle is considered to be excitatory cholinergic and contraction of the normal human detrusor is mediated almost exclusively through muscarinic receptor stimulation by released acetylcholine.

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Detrusor strips from normal human bladders produce little response to single stimuli and require repetitive activation of intrinsic nerves to induce a response that is completely abolished by atropine, suggesting that it is purely cholinergic.

Hence, activation of either M2 or M3 subtypes elicits bladder contraction. Evidence suggests that the detrusor possesses both M2 and M3 receptors. Although M2 receptors predominate in receptor binding studies, it is the M3 receptor that is thought to mediate contraction.

Molecular cloning studies have revealed five distinct genes for muscarinic ACh receptors in rats and humans, and it is now generally accepted that five receptor subtypes correspond to these gene products. Muscarinic receptors are coupled to G-proteins; M2 and M4 are inhibitory (Gi); M1, M3 and M5 are facilitatory (Gq). The signal transduction systems of M1, M3 and M5 preferentially couple to phosphoinositide hydrolysis leading to mobilization of intracellular Ca2+, whereas activation of M2 and M4 receptors inhibits adenylate cyclase activity.

Desensitization of muscarinic ACh receptors is one mechanism to reduce the sensitivity of detrusor smooth muscle to incoming stimuli, and is mediated by phosphorylation of the receptor by guanosine phosphate binding protein-coupled receptor kinase (GRK). Failure of the desensitizing mechanism could contribute to detrusor overactivity with bladder outlet obstruction. In addition to ACh released from peripheral nerve endings, non-neuronal ACh may also be present when released from

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bladder urothelium or suburothelium. This ACh fraction is increased by stretch of the bladder wall, and is increased with patient age. At present its function is unknown but may contribute to the pathogenesis of OAB. The principal treatment for overactive bladder (OAB) is the use of anticholinergic drugs that were initially believed to inhibit the effect of parasympathetic ACh on the detrusor. However, there is now evidence to suggest that anticholinergic drugs could interact with sensory pathways. Stimulation of muscarinic receptor pathways can depress sensory transduction by a mechanism independent of changes in bladder tone, suggesting that muscarinic receptor pathways and ACh could contribute to normal or pathological bladder sensations, however, there is no apparent evidence in the clinical setting. Recent studies have described muscarinic receptors on the mucosa as well as the detrusor.

B. ADRENERGIC β-RECEPTORS With many animals, sympathetic nerve activity to the bladder increases during the urine storage phase, although this remains to be definitively shown in humans. In addition, there is both relaxation of bladder smooth muscle via an adrenergic β-receptor and contraction of urethral smooth muscle via adrenergic α1-receptors. However, solabegron and other β-adrenoceptor agonists, such as isoprenaline, evoke potent concentration-dependent relaxation of isolated human bladder strips. There are three adrenergic β-receptor subtypes (β1, β2, β3) and relaxation of bladder smooth muscle has been regarded as mediated by the adrenergic β2-receptor and the β3-receptor was thought to be related only to fat metabolism. In human bladder tissue it is regarded that the β3-adrenoceptor (β3AR) is the most significant functional subtype with gene

expression of the β3-adrenoceptor (β3-AR) and relaxation of human detrusor via this receptor have been reported. In the near future, the role of the β3-AR will be important and several β3-agonists (KUC- 7483, YM-178, FK-175) have been developed. The β-Adrenergic Receptor is Gs-protein-coupled and its activation elevates intracellular cAMP; the pathway believed to be a key mediator in relaxation of smooth muscle. Downstream effectors activated via cAMP include plasma membrane K+ channels, such as the largeconductance, Ca2+-activated K+ (BK, Maxi-K) channel. β-AR-mediated relaxant mechanisms also include cAMPindependent signalling pathways, supported by numerous pharmacological and electrophysiological lines of evidence. The β3-AR is recognized as an attractive target for drug discovery. On the other hand, activation of the β1- or β2-AR can cause undesirable side effects such as increased heart rate or muscle tremors. The role of the urothelium in bladder responses to β-AR agonists is not yet clear.Studies shows β3-ARs are involved in mediating inhibitory effects of β-AR agonists on detrusor contractions via the urotheliu. β3-AR mRNA has been found in the urothelium as well as the detrusor muscle and suggests multiple site of actions in the lower urinary tract.

C. CANNABINOIDS, GPR18, GPR55, GPR119 In recent years cannabinoids, the active components of Cannabis sativa linnaeus (marijuana) and their derivatives, are drawing renewed attention because of their diverse pharmacological activities such as cell growth inhibition, anti-inflammatory effects, and tumour regression. The cannabinoid receptor has two subtypes, CB1 and CB2,

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which are both G-protein-coupled receptors. Cannabinoid receptors are activated by endogenous ligands. CB1 is found expressed in human urinary bladder tissue from patients with hypersensitivity and overactivity disorders, and the amount correlates with changes of symptoms. CB1-immunoreative nerve fibres were significantly increased in the suburothelium of patients with bladder pain symptoms (BPS) and idiopathic detrusor overactivity (IDO), and in detrusor layer in IDO patients, as compared with control. increased expression of CB1 on nerve fibres may be related to bladder pain in bladder pain symptoms and urgency in IDO and support clinical trials of CB1 agonists in bladder disorders.

D. GABAB Stimulation of spinal GABAergic mechanisms by intrathecal application of GABAA and GABAB receptor agonists could be effective for the treatment of detrusor overactivity in spinal cord injured rats. Gabapentin has also revealed efficacy in the treatment of DO of neurogenic origin. Preliminary results have shown significant modifications of urodynamic indexes, particularly of the DO, whereas the symptomatic score evaluation and the voiding diary data have demonstrated a significant lowering of the irritative symptoms. These data support the rationale that DO may be controlled by modulating the afferent input from the bladder and the excitability of the sacral reflex center and suggest a novel method with oral gabapentin to treat OAB patients.

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E. GLUTAMATE METABOTROPIC RECEPTORS

F. PROSTANOID RECEPTORS

2. LIGAND-GATED ION-CHANNELS

Glutamate receptors consist of two major classes, the ionotropic receptors which form ligand-gated cation channels and the metabotropic receptors (mGluRs) which are a family of G-protein coupled receptors activating distinct signal transduction pathways in neurons. The former includes N-methyl-D-aspartate (NMDA), Îą-amino3-hydroxy- 5-methyl-lisoxazole-4-propionic acid (AMPA), and kainite receptors have an essential role in the control of micturition reflexes. Less is known about the functional roles of mGluRs in the lower urinary tract. They comprise eight subtypes (mGluR1 to mGluR8), which are placed into three groups on the basis of sequence homology, transduction mechanism and agonist pharmacology: group I (mGluR1 and mGluR5), group II (mGluR2 and mGluR3) and group III (mGluR4, mGluR6, mGluR7, mGluR8).

Prostanoid receptors are activated by the endogenous ligands prostaglandin PGD2 (D), PGE2 (E), PGF2Îą (F), PGH2 (H), prostacyclin PGI2 (I) and thromboxane A2 (T). Prostanoids may affect excitationcontraction coupling in detrusor smooth muscle in two ways, directly by effects on the smooth muscle, and/or indirectly via effects on neurotransmission.

Ligand-gated ion channels (LGICs) are integral membrane proteins containing a pore that allows the regulated flow of selected ions across the plasma membrane. Ion flux is passive and driven by the electrochemical gradient for permeant ions. The channels are opened, or gated, by a neurotransmitter binding to an orthosteric site(s) that triggers a conformational change that results in a different conducting state. Among eight ligand-gated ion channels (5-HT3, nicotinic-ACh, GABAA, glutamate- ionotropic, glycine, P2x, and zn2+-activated channel), only P2x channels will be discussed.

Glutamate is involved in many CNS functions, and drugs acting on the different glutamate receptors may affect not only micturition. Most previous work with lower urinary tract function has used ionotropic glutamate receptors, however the mGluRs should be of value to study further. Blockade of mGluR1, mGluR5 or both increased bladder capacity and mGluR1 and mGluR5 additively interacted to transmit afferent signals from the bladder. Thus, a group I mGluR antagonist, which blocks both mGluR1 and mGluR5, would have a more beneficial effect than a drug targeting either mGluR1 or mGluR5 alone. This provides a further promising target to treat storage dysfunctions including OAB and urgency urinary incontinence. Similar data has also indicated that glutamic acid has a transmitter function in bladder and somato-bladder reflex mechanisms and raises the possibility that mGluR5 may be a target for pharmacological treatment of lower urinary tract disorders.

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The prostanoid receptor most important for detrusor function has not been established.

G. TACHYKININS Tachykinin receptors are activated by the endogenous peptides: substance P (SP), neurokinin A (NKA), neurokinin B, neuropeptide K and neuropeptide g (N-terminally extended forms of neurokinin A). The enogenous receptor for substance P is the Gprotein coupled NK1 receptor. The hexapeptide agonist septide appears to bind to an overlapping but non-identical site to SP on the NK1 receptor. Initial clinical trials revealed that Aprepitant, a NK1 receptor antagonist, may show efficacy for the treatment of OAB, suggesting that receptor antagonism may represent a novel therapeutic approach to treating OAB. A dose-finding study was performed as the first step in the clinical development of cizolirtine citrate. Its therapeutic potential at 400mg bid in OAB has been evidenced and has provided further clinical evidence that modulation of tachykinins could be an effective way to treat OAB.

P2x receptors have a trimeric topology with two putative transmembrane domains, where the endogenous ligand is ATP and gate primarily Na+, K+ and Ca2+, exceptionally Cl-. The native receptors may occur as either homopolymers (e.g. P2x1 in smooth muscle) or heteropolymers. Afferent signals originating from the bladder are regulated by spinal P2x3 and P2x2/3 receptors and establish directly an endogenous central presynaptic purinergic mechanism to regulate visceral sensory transmission. P2x3 and P2x2/3 antagonists may therefore may be promising to treat lower urinary tract dysfunction, such as OAB, and possibly other debilitating sensory disorders, including chronic pain states. After bladder outlet obstruction with overactivity the expression of M2, M3 and P2x3 receptors is increased in rat urothelium, suggesting that changes in urothelium P2x3 receptor expression may mediating afferent sensory responses in the urinary bladder. The exact mechanisms that underline mechanosensory transduction in bladder afferent terminals remain ambiguous; however, a wide range of ion channels and

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receptors have been identified at bladder afferent terminals and implicated in the generation and modulation of afferent signals. The expression and/ or function of these ion channels and receptors may be altered in animal models and patients with overactive and painful bladder disorders. Some of these ion channels and receptors may be potential therapeutic targets for bladder diseases. However, it has also been shown that with detrusor from idiopathic DO patients there was a selective absence of P2x3 and P2x5 that may impair control of detrusor contractility and contribute to the pathophysiology of urge incontinence.

3. ION-CHANNELS Ion channels are pore-forming proteins that allow the flow of ions across either plasma membranes or those of intracellular organelles. Many ion channels (i.e most Na+, K+, Ca2+ and some Cl- channels) are voltage-gated, but others (i.e. certain K+ and Cl- channels, TRP channels, ryanodine receptors and IP3 receptors) are relatively voltage-insensitive and are gated by second messengers and other intracellular and/or extracellular mediators. Many ion channels, such as K+, Na+, Ca2+, HCN and TRP channels, share several structural similarities. Others, such as Cl- channels, aquaporins and connexins, have completely different structural properties. At present, ion channels (including ligand-gated ion channels) represent the second largest target for existing drugs after G protein-coupled receptors. However, the advent of novel, faster screening techniques for compounds acting on ion channels suggests that these proteins represent promising targets for the development of additional, novel therapeutic agents.

releasing signalling molecules (NO, ATP) makes this tissue an attractive additional target to detrusor smooth muscle. One or multiple mechanosensitive ion channels play a role in transduction of hydrostatic pressure changes, which supports the view that not only tissue stretch or tension, but also pressure is an important parameter for mechanosensing bladder fullness.

A. ACID-SENSING (PROTON-GATED) ION CHANNELS (ASICS) Acid-sensing ion channels (ASICs) are members of a Na+ channel superfamily that includes the epithelial Na+ channel (ENaC), the FMRF-amide activated channel (FaNaC) of invertebrates. ASIC subunits contain two transmembrane domains and assemble as homo- or hetero-trimers to form protongated, voltage-insensitive, Na+ permeable, channels. ASIC1 is the dominant subunit expressed in bladder epithelium, whereas both ASIC1 and ASIC2 are expressed in detrusor smooth muscle. ASIC3 expression was much less abundant, but localized in the subepithelial region. Urothelial cells express multiple TRP and ASIC channels, whose activation elicits ionic currents and Ca2+ influx. These “neuron-like” properties might be involved in transmitter release, such as ATP, that can act on afferent nerves or smooth muscle to modulate their responses to different stimuli. Up-regulation of ASIC2a and ASIC3 in patients with bladder pain syndrome suggests involvement in increased pain and hyperalgesia. Down-regulation of TRPV1 mRNA might indicate that a different regulatory mechanism controls its expression in the human bladder

The recent demonstration that the urothelium is sensitive to both mechanical and other stimuli, and responds by

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B. EPITHELIAL SODIUM CHANNELS (ENaC) ENaCs are responsible for Na+ reabsorption by the epithelia lining the distal part of the kidney tubule, and fulfil similar functional roles in some other tissues such as the alveolar epithelium and the distal colon. This reabsorption of Na+ is regulated by aldosterone, vasopressin and glucocorticoids, and is one of the essential mechanisms in the regulation of Na+ balance, blood volume and blood pressure. of Na+ balance, blood volume and blood pressure. The degenerin ENaC family has been proposed as a transducer of sensory stimuli in several species and seem to be mechanosensitive. In human tissue the α-, β- and γ -subunits ENaC proteins and mRNA are well-expressed in urothelium from patients with and without Bladde Overactivity and the amounts are positively associated with the storage symptom score. In rat bladder the intravesical infusion of 1 mM amiloride (to block ENaC) significantly reduced the frequency of reflex voiding during bladder filling and increased bladder capacity, without any effect on the amplitude of micturition pressure.

C. K+ CHANNELS K+ channels are fundamental regulators of excitability; they control the frequency and shape of the action potential waveform, the secretion of hormones and neurotransmitters and the cell membrane potential. Their activity may be regulated by transmembrane voltage, intracellular Ca2+ and neurotransmitters. They consist of a primary pore-forming α-subunit often associated with auxiliary regulatory subunits. The three main families are the 2TM (two transmembrane domains), 4TM and 6TM families. The 2TM domain family of K+ channels are also known as

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the inward-rectifier K+ channels. This family includes the strong inward-rectifier K+ channels (Kir2.x), the G-proteinactivated inward-rectifier K+ channels (Kir3.x) and the ATP-sensitive K+ channels. Large-conductance, voltage- and Ca2+-activated K+ (Maxi-K or BK) channels regulate the resting potential and repolarisation of the action potential and play a critical role in modulating contractile tone of smooth muscle and neuronal processes. BKCa channels play an important role in controlling membrane potential and contractility of urinary bladder smooth muscle; SKCa channels are regulators of excitability in detrusor smooth muscle.

D. TRANSIENT RECEPTOR POTENTIAL (TRP) CATION CHANNELS The TRP superfamily of cation channels, whose founder member is the Drosophila Trp channel, can be divided, in mammals, into six families; TRPC, TRPM, TRPV, TRPA, TRPP and TRPML based on amino acid homologies. The TRPC (‘Canonical’) and TRPM (‘Melastatin’) subfamilies consist of seven and eight different channels, respectively (i.e. TRPC1-TRPC7 and TRPM1- TRPM8). The TRPV (‘Vanilloid’) subfamily comprises six members (TRPV1TRPV6), whereas the TRPA (Ankyrin) subfamily has only one mammalian member (TRPA1). In the bladder, afferent nerves have been identified not only in the detrusor, but also in the suburothelium, where they form a plexus immediately beneath the urothelium. The bladder epithelium plays important roles in mechanosensory transduction, bladder distention causes release of ATP which excites smalldiameter sensory neurons via P2x3 receptors. Mechanosensitive molecules in the epithelial cells are responsible for stretch-evoked ATP release and include ENaC (above) and TRP( transient receptor potential) ion channels. TRP are subclassified

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FIgURE 5: Interactions between receptors, chemical mediators released from bladder urothelial cells and afferent nerve endings in the bladder. Different receptors (bradykinin, trkA, trkB, adrenergic, cholinergic, and TRP) are expressed on urothelial cells. ATP, NO, acetylcholine (ACh), nerve growth factor (NgF), and prostaglandins (Pg) can be released from the urothelium via activation of urothelially expressed ligand receptors and/or mechanoceptive receptors such as the epithelial Na+ channel.

into seven superfamilies, and many of them are mechanoand thermo-sensing. Among several thermosensing TRP channels, TRPA1, TRPM8, TRPV1, and TRPV4 are candidates of molecular targets of the novel treatments for

OAB (Figure 21). An understanding of the physiological function of these different channels will provide insight into how they control bladder function and if they may be exploited to control dysfunction in the lower urinary tract.

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The Neural Control of Micturition

The neural control of micturition The storage and periodic elimination of urine depend on the coordinated activity of smooth and striated muscles in the two functional units of the lower urinary tract, namely a reservoir (the urinary bladder) and an outlet consisting of the bladder neck, the urethra and the urethral sphincter. The coordination between these organs is mediated by a complex neural control system that is located in the brain, the spinal cord and the peripheral ganglia. The lower urinary tract differs from other visceral structures in several ways. First, its dependence on CNS control distinguishes it from structures that maintain a level of function even after the extrinsic neural input has been eliminated. It is also unusual in its pattern of activity and in the organization of its neural control mechanisms. For example, the bladder has only two modes of operation: storage and elimination. Thus, many of the neural circuits that are involved in bladder control have switch-like or phasic patterns of activity, unlike the tonic patterns that are characteristic of the autonomic pathways that regulate cardiovascular organs. In addition, micturition is under voluntary control and depends on learned behaviour that develops during maturation of the nervous system, whereas many other visceral functions are regulated involuntarily. Owing to the complexity of the neural mechanisms that regulate bladder control, the process is sensitive to various injuries and diseases.

PERIPHERAL INNERVATION OF THE URINARY TRACT The requirement for voluntary control over the lower urinary tract necessitates complex interactions between autonomic (mediated by sympathetic and parasympathetic

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FIgURE 1: Neural pathways of Urinary system. Abbreviations: Cg, coccygeal segment; DRg, dorsal root ganglion; EUS, external urethral sphincter; IMg, inferior or caudal mesenteric ganglion; IVF, intervertebral foramen; L, lumbar; S, sacral; T, thorac

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nerves) and somatic (mediated by pudendal nerves) efferent pathways. The sympathetic innervation arises in the thoracolumbar outflow of the spinal cord, whereas the parasympathetic and somatic innervation originates in the sacral segments of the spinal cord. Afferent axons from the lower urinary tract also travel in these nerves. Sympathetic postganglionic nerves, for example the hypogastric nerve release noradrenaline, which activates β-adrenergic inhibitory receptors in the detrusor muscle to relax the bladder, α-adrenergic excitatory receptors in the urethra and the bladder neck, and α- and β-adrenergic receptors in bladder ganglia. Parasympathetic postganglionic nerves release both cholinergic (acetylcholine, ACh) and non-adrenergic, non-cholinergic transmitters. Cholinergic transmission is the major excitatory mechanism in the human bladder. It results in detrusor contraction and consequent urinary flow and is mediated principally by the M3 muscarinic receptor, although bladder smooth muscle also expresses M2 receptors. Muscarinic receptors are also present on parasympathetic nerve terminals at the neuromuscular junction and in the parasympathetic ganglia. Activation of these receptors on the nerve terminals can enhance (through M1 receptors) or suppress (through M4 receptors) transmitter release, depending on the intensity of the neural firing. Non-cholinergic excitatory transmission is mediated by ATP actions on P2x purinergic receptors in the detrusor muscle. Inhibitory input to the urethral smooth muscle is mediated by nitric oxide (NO) that is released by parasympathetic nerves. Somatic cholinergic motor nerves that supply the striated muscles of the external urethral sphincter arise in S2–S4 motor neurons in Onuf’s nucleus and reach the periphery through the pudendal nerves. A medially placed motor nucleus at the same spinal level supplies axons that innervate the pelvic floor musculature.

FIgURE 2: Efferent pathways and neurotransmitter mechanisms that regulate the lower urinary tract. Parasympathetic postganglionic axons in the pelvic nerve release acetylcholine (ACh), which produces a bladder contraction by stimulating M3 muscarinic receptors in the bladder smooth muscle. Sympathetic postganglionic neurons release noradrenaline (NA), which activates β3 adrenergic receptors to relax bladder smooth muscle and activates α1 adrenergic receptors to contract urethral smooth muscle. Somatic axons in the pudendal nerve also release Ach, which produces a contraction of the external sphincter striated muscle by activating nicotinic cholinergic receptors. Parasympathetic postganglionic nerves also release ATP, which excites bladder smooth muscle, and nitric oxide, which relaxes urethral smooth muscle. L1, first lumbar root; S1, first sacral root; SHP, superior hypogastric plexus; SN, sciatic nerve; T9, ninth thoracic root.

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Sensations of bladder fullness are conveyed to the spinal cord by 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 components of these nerves consist of myelinated (Aδ) and unmyelinated (C) axons. The Aδ-fibres respond to passive distension and active contraction and thus convey information about bladder filling. The C-fibres are insensitive to bladder filling under physiological conditions (they are therefore termed ‘silent’ C-fibres) and respond primarily to noxious stimuli such as chemical irritation or cooling. The cell bodies of Aδ-fibres and C-fibres are located in the dorsal root ganglia (DRG) at the level of S2– S4 and T11–L2 spinal segments. The axons synapse with interneurons that are involved in spinal reflexes and with spinal-tract neurons that project to higher brain centres that are involved in bladder control. A dense nexus of sensory nerves has been identified in the suburothelial layer of the urinary bladder in both humans, with some terminal fibres 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.

THE SENSORY ROLE OF NON-NEURONAL CELLS Studies have shown that non-neuronal cells also play a part in bladder sensory mechanisms.Traditionally viewed as merely a passive barrier, the urothelium is now known to have specialized sensory and signalling properties that allow it to respond to chemical and mechanical stimuli and to engage in reciprocal chemical communication with nerves in the bladder wall. These properties include the expression of nicotinic, muscarinic, tachykinin, adrenergic, bradykinin and transient-receptor-potential vanilloid receptors (such as TRPV1); responsiveness to transmitters

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FIgURE 3: A model illustrating possible chemical interactions between urothelial cells, afferent nerves, efferent nerves and myofibroblasts in the urinary bladder. Urothelial cells, myofibroblasts and afferent nerves express common receptors, including purinergic receptors (P2X and P2Y) and transient-receptor-potential receptors (TRPs), such as the capsaicin receptor (TRPV1). Urothelial cells also express TRPV2, TRPV4 and TRMP8. Activation of receptors and ion channels in urothelial cells by bladder distension or chemical stimuli can release mediators, such as ATP, nitric oxide (NO), neurokinin A (NKA), acetylcholine (ACh) and nerve growth factor (NGF), that target adjacent nerves or myofibroblasts and might also act in an autocrine or paracrine manner on urothelial cells. Neuropeptides (including NKA) released from sensory nerves and the urothelium can act on the neurokinin 2 receptor (NK2) to sensitize the mechanoreceptive afferent nerve endings. NgF released from muscle or the urothelium can exert an acute and chronic influence on the excitability of sensory nerves through an action on tyrosine kinase A (TrkA) receptors. ATP released from efferent nerves or from the urothelium can regulate the excitability of adjacent nerves through purinergic P2X receptors. ACh released from efferent nerves or from the urothelium regulates the excitability of adjacent nerves through nicotinic or muscarinic ACh receptors (nAChR and mAChR).

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released from afferent nerves; a close physical association with afferent nerves; and the ability to release chemical mediators such as ATP19, ACh and NO, which can regulate the activity of adjacent nerves and thereby trigger local vascular changes and/or reflex bladder contractions. (FIGURE 3). The presence of muscarinic and nicotinic receptors in the urothelium has focused attention on the role of ACh as a chemical mediator of neural–urothelial interactions. ACh is released from the urothelium in response to chemical or mechanical stimul. Application of a muscarinic receptor agonist to strips of rat bladder tissue induces membrane potential transients and Ca2+ transients that begin near the urothelial–suburothelial interface and then spread to the detrusor smooth muscle, raising the possibility that the urothelium could regulate the generation of spontaneous, non-voiding contractions in the bladder. Stimulation of cholinergic receptors in the urothelium induces the release of ATP and an as yet unidentified smooth-muscle relaxant factor. The function of ATP release from the urothelium has attracted considerable attention because intravesical administration of ATP induces detrusor overactivity by stimulating the purinergic receptor P2x ligand-gated ion channel 3 (P2x3) or P2x2/3 on afferent nerves. Mice that lack P2x3 receptors exhibit reduced bladder activity and inefficient voiding, suggesting that activation of P2x3 receptors on bladder afferent nerves by ATP released from the urothelium is essential for normal bladder function. The discovery of a suburothelial layer of myofibroblasts (also referred to as interstitial cells) that lie in close proximity to nerves and are extensively linked by gap junctions led to the proposal that these cells, together with afferent nerves, the urothelium and smooth muscle, might collectively have the properties to act as a stretchreceptor organ. Furthermore, the demonstration

that they express ATP-gated purinergic P2Y receptors raises the possibility that they might respond to urothelial ATP release.

CENTRAL NERVOUS SYSTEM PATHWAYS INVOLVED IN MICTURITION The regulation of micturition requires connections between many areas in the brain and extensive tracts in the spinal cord that involve sympathetic, parasympathetic and somatic systems. Parasympathetic and sympathetic preganglionic neurons (PGNs) are located in the intermediate grey matter (laminae of spinal cord sacral and lumbar segments, respectively. Parasympathetic PGNs 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 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. Afferent nerves from the bladder project to regions of the spinal cord that contain interneurons and parasympathetic PGN 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. In the brain, many neuron populations are involved in the control of the bladder, the urethra and the urethral

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sphincter. Some, such as the serotonergic neurons of the medullary raphe nuclei, the noradrenergic neurons of the locus coeruleus and the noradrenergic A5 cell group in the brain stem, are non-specific ‘level-setting’ mechanisms with diffuse spinal projections. Others are specific for micturition: these include the neurons of Barrington’s nucleus (also called the pontine micturition center (PMC)) and those of the periaqueductal grey (PAG), cell groups in the caudal and preoptic hypothalamus, and the neurons of several parts of the cerebral cortex, in particular the medial frontal cortex

REGULATION OF BLADDER FILLING AND VOIDING The neural pathways that control lower-urinary-tract function are organized as simple on–off switching circuits that maintain a reciprocal relationship between the urinary bladder and the urethral outlet. Storage reflexes are activated during bladder filling and are organized primarily in the spinal cord, whereas voiding is mediated by reflex mechanisms that are organized in the brain. BLADDER FILLING AND THE GUARDING REFLEx: Throughout bladder filling, the parasympathetic innervation of the detrusor is inhibited and the smooth and striated parts of the urethral sphincter are activated, preventing involuntary bladder emptying. This process is organized by urethral reflexes known collectively as the ‘guarding reflex’. They are activated by bladder afferent activity that is conveyed through the pelvic nerves, and are organized by interneuronal circuitry in the spinal cord. Some input from the lateral pons, which is also known as the ‘L-region’ or the ‘pontine storage center’, might facilitate sphincter reflexes or have a role in involuntary sphincter control. Pharmacological and electrophysiological studies have

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a | Urine storage reflexes. During the storage of urine, distention of the bladder produces low-level vesical afferent firing. This in turn stimulates the sympathetic outflow in the hypogastric nerve to the bladder outlet (the bladder base and the urethra) and the pudendal outflow to the external urethral sphincter. These responses occur by spinal reflex pathways and represent guarding reflexes, which promote continence. Sympathetic firing also inhibits contraction of the detrusor muscle and modulates neurotransmission in bladder ganglia. A region in the rostral pons (the pontine storage center) might increase striated urethral sphincter activity.

b | Voiding reflexes During the elimination of urine, intense bladderafferent firing in the pelvic nerve activates spinobulbospinal reflex pathways (shown in blue) that pass through the pontine micturition center. This stimulates the parasympathetic outflow to the bladder and to the urethral smooth muscle (shown in green) and inhibits the sympathetic and pudendal outflow to the urethral outlet (shown in red). Ascending afferent input from the spinal cord might pass through relay neurons in the periaqueductal grey (PAG) before reaching the pontine micturition center. Note that these diagrams do not address the generation of conscious bladder sensations, nor the mechanisms that underlie the switch from storage to voiding, both of which presumably involve cerebral circuits above the PAG. R represents receptors on afferent nerve terminals. FIgURE 4: Neural circuits that control continence and micturition.

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indicated that the circuitry that feeds bladder afferent activity to midbrain and pontine centres and transmits efferent signals from the pons to the sacral cord allows the spinobulbospinal voiding-reflex pathway to function as a switch that is either in a completely ‘off ’ mode (storage) or a maximally ‘on’ mode (voiding). During bladder filling the parasympathetic efferent pathway to the bladder, including a population of PMC neurons, is turned off, but at a critical level of bladder distension the afferent activity arising from tension receptors in the bladder switches the pathway to maximal activity. Lesions in brain areas that lie rostral to the pons (for example, the diencephalon and the cerebral cortex) can alter the set-point of the voiding reflex, indicating that the switching circuit is tonically modulated by inhibitory and excitatory influences from the forebrain. Operating in this way, the reflex circuitry shown in FIG. 4, would lead to involuntary bladder emptying (that is, incontinence) whenever the bladder volume reached a critical level. However, in continent individuals the firing of the voiding reflex is under strict voluntary control, enabling one to plan to void at a socially acceptable time and place. The decision to void, which is a crucial aspect of human behaviour, is based on a combination of factors, including one’s emotional state, an appreciation of the social environment and the sensory signals arising from the bladder. Knowledge of the extent to which one’s bladder content is comfortable and ‘safe’ is central in this process. Thus, voluntary control of the bladder and the urethra has two important aspects, namely registration of bladder filling sensations and manipulation of the firing of the voiding reflex. The PAG has a pivotal role in both. On the one hand it receives and passes ascending bladder signals to higher brain centres and into the realm of conscious sensation. On the other hand it receives projections from many higher brain centres and also controls the primary input to the PMC; during bladder filling, therefore, such higher brain centres (particularly the prefrontal cortex) can suppress the excitatory signal

to the PMC and thus prevent voiding or incontinence; when voiding is consciously desired, they can allow the PMC to be excited. Our understanding of the processing of bladder sensations in humans has been greatly advanced in recent years by the advent of functional brain imaging. Imaging studies have shown activation of the PAG during bladder filling (FIG. 5); this is in keeping with its postulated role in receiving bladder afferents and relaying them (perhaps through the thalamus) to the insula, where normal visceral sensations, such as desire to void, are thought to be mapped. Consistent with this postulate, the insula was active in most imaging studies of urine storage and its activation apparently increased with bladder filling. By contrast, bladder cooling did not significantly activate the PAG, suggesting that afferents related to noxious bladder stimulation might follow a different pathway to the thalamus and the cerebral cortex. The PAG has multiple afferent and efferent connections, not only with the thalamus, the prefrontal cortex and the insula, but also with other higher brain centres. The influence of these centres — the anterior cingulate cortex particularly — probably determines how much attention one pays to signals coming from bladder afferents and how one reacts to them, whether by deciding to void or by recruiting mechanisms (for example, urethral sphincter contraction) that allow voiding to be postponed. The dorsal part seems to be especially strongly activated by bladder distension in subjects with “poor bladder control”, suggesting a strong emotional reaction to a situation the subjects experienced as threatening. This pattern of abnormal activity might help to distinguish an abnormal sensation of urgency from a strong but normal desire to void. Both clinical observations and observations from functional imaging strongly suggest that in humans

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the frontal lobes play an important part in determining the appropriateness of micturition. For example, the right inferior frontal gyrus, which is part of the prefrontal cortex, was active during storage in all the studies on which FIG 5A is based. The prefrontal cortex is thought to be the seat of planning complex cognitive behaviours and the expression of personality and appropriate social behaviour and has a role in attention and response-selection mechanisms. It has strong and direct connections with the PAG, suggesting that it might be responsible for tonic suppression of voiding that is relaxed only when voiding is both desired and socially appropriate. In keeping with this postulate, in subjects who cannot sustain such suppression (that is, in subjects who have poor bladder control) the prefrontal cortex responds abnormally weakly to bladder filling. The prefrontal cortex has multiple connections with the anterior cingulate gyrus and both regions have direct or indirect connections with the PAG, the hypothalamus and other areas that are associated with autonomic control. The caudal hypothalamus has direct access to the PMC (FIG 5B) and responded to changes in bladder volume or sensation in two imaging studies. This might represent a further layer of control of the micturition reflex that permits voiding only if it is judged ‘safe’ to do so. The existence of a pontine storage center in humans (FIG 4A) is not certain, but several imaging studies have shown activation near the expected location (that is, ventrolateral to the PMC) during storage or withholding of urine.

BLADDER VOIDING: Excitation of the PMC activates descending pathways that cause urethral relaxation and, some seconds later, activation of the sacral parasympathetic outflow. This results in contraction of the bladder and an increase in intravesical pressure and the flow of urine. Relaxation of

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FIgURE 5: Figure 6 | Brain areas involved in the regulation of urine storage. A. A meta-analysis of positron-emission tomography and functional MRI studies that investigated which brain areas are involved in the regulation of micturition reveals that the thalamus, the insula, the prefrontal cortex, the anterior cingulate, the periaqueductal grey (PAG), the pons, the medulla and the supplementary motor area (SMA) are activated during the urinary storage. B. A preliminary conceptual framework, based on functional brain-imaging studies, suggesting a scheme for the connections between various forebrain and brainstem structures that are involved in the control of the bladder and the sphincter in humans. Arrows show probable directions of connectivity but do not preclude connections in the opposite direction.

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the urethral smooth muscle is mediated by activation of the parasympathetic pathway to the urethra, which triggers the release of NO, and by the removal of adrenergic and somatic cholinergic excitatory inputs. Secondary reflexes elicited by the flow of urine through the urethra facilitate bladder emptying.

the species83.84. For example, dopamine elicits inhibitory effects on micturition through D1-like receptors and facilitatory effects through D2-like receptors.

In study participants who were unable to void, slightly different prefrontal activation was seen, together with a more ventral region of pontine activation that supported the existence of a pontine storage center (see FIG 4A). Another PET study confirmed the involvement of the insula, the PAG and the PMC in voiding. These observations seem to be compatible with the concept outlined above — that voluntary voiding implies interruption of the tonic suppression (by the prefrontal cortex) of PAG input to the PMC.

NEUROTRANSMITTERS: Various neurotransmitters have been implicated in the central control of the lower urinary tract. Putative excitatory transmitters include glutamic acid, tachykinins, pituitary-adenylate-cyclase-activating polypeptide, NO and ATP. Glutamic acid, acting on NMDA (N-methyl-daspartate) and non-NMDA receptors, seems to be the essential transmitter in spinal and supraspinal reflex pathways that control the bladder and the external urethral sphincter. Inhibitory amino acids (GABA (γ-aminobutyric acid) and glycine) and opioid peptides (enkephalins) exert a tonic inhibitory control in the PMC and regulate bladder capacity. These substances also have inhibitory actions in the spinal cord. Some transmitters (dopamine, serotonin (5-hydroxytryptamine, 5-HT), noradrenaline, ACh and nonopioid peptides, including vasoactive intestinal polypeptide and corticotropin-releasing factor) have either inhibitory or excitatory effects, depending on the type of receptor that is activated, the receptors’ location in the CNS and

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Pathophysiology of Urinary Incontinence in women

Pathophysiology of Urinary Incontinence PATHOPHYSIOLOGY OF URGE URINARY INCONTINENCE IN WOMEN The International Continence Society defines urgency as “the complaint of a sudden compelling desire to pass urine, which is difficult to defer”.. The “overactive bladder” (OAB) is a symptom syndrome which is defined by the presence of urgency, with or without urgency incontinence, but usually with frequency and nocturia in the absence of infection or other obvious pathology. OAB symptoms are suggestive of urodynamically demonstrable detrusor overactivity (DO; involuntary detrusor contractions) during the filling phase which may be spontaneous or provoked. However, OAB is not interchangeable with DO regardless of whether they are associated with reported urgency. The pathophysiology of the OAB syndrome and DO is still incompletely known, but most probably multifactorial. DO may be further characterised as neurogenic when there is a relevant neurological condition. The dependence of lower urinary tract (LUT) functions on complex central neural networks makes these functions susceptible to a variety of neurological disorders. Non-neurogenic aetiologies may be related to outflow obstruction, aging and female anatomical incontinence, but most cases are idiopathic. There may be two possible origins of OAB symptoms: 1) decreased capacity to handle the afferent signals in the brain, and 2) abnormally increased afferent signals from the bladder and /or urethra.

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MECHANISMS UNDERLYING INCREASED AFFERENT ACTIVITY Two theories probably contribute in varying proportion to the complex mechanisms underlying the genesis of DO and the associated storage symptoms comprising OAB, have been put forward: THE UROTHELIUM-BASED HYPOTHESIS: Changes in urothelial receptor function and neurotransmitter release as well as in the sensitivity and coupling of the suburothelial interstitial cell network lead to enhancement of involuntary contractions. THE MYOGENIC HYPOTHESIS: Changes to the excitability and coupling of smooth muscle cells with other myocytes or interstitial cells lead to the generation of uninhibited contractions.

THE UROTHELIUM-BASED HYPOTHESIS There is increasing evidence that urothelial cells play an important role in modulation of bladder activity by responding to local chemical and mechanical stimuli and then sending chemical signals to bladder afferent nerves. It has been shown that urothelial cells express various “sensor molecules” such as receptors of bradykinin, neurotrophins, purines (P2x and P2Y), norepinephrine (NE) (α and β ), ACh (nicotinic and muscarinic), epithelial Na + channels (ENaC), and a number of transient receptor potential (TRP) channels. These sensor molecules respond to mechanical as well as chemical stimuli and in turn release chemicals such as ATP, prostaglandins (PG), nerve growth factor (NGF), ACh, and NO. These agents are known to have excitatory or inhibitory actions on afferent nerves, which are located close to or in the urothelium.

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FIgURE 1: Mechanisms involved in increased afferent input from the bladder: the urothelium-based and myogenic theories.

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The urothelium interacts closely with the underlying suburothelial layer, in particular the interstitial cell network contained within it, so that the whole structure can be regarded as a functional unit. The suburothelium is an area composed of nerves, blood vessels, and connective tissue in intimate contact with the urothelium. Recently, the roles of the urothelium and suburothelial myofibroblasts in afferent activation have become the focus of intense interest. The C-fibre afferents generally have endings in the suburothelial layer of the bladder wall, but in some cases, they also penetrate the urothelium. ATP was the first neurotransmitter demonstrated to be released directly from the urothelium. Nonvesicular ATP release is evoked by chemical stimuli or by stretch proportional to the extent of bladder distension. Both P2x and P2Y purinergic receptor subtypes have been identified in the bladder urothelium. It is now thought that these may respond to urothelial-derived adenosine triphosphate (ATP) release in autocrine and paracrine signalling. By acting on structures such as nerves and interstitial cells in the suburothelial space, it is thought to trigger the underlying afferent signalling bladder fullness and pain and possibly even to activate the micturition reflex. After successful treatment with botulinum toxin injection, a reduced immunoreactivity correlated well with a reduction in urgency Sugaya et al recently reported that improvement of OAB symptoms with antimuscarinic treatment was significantly correlated with a decrease in urinary ATP level in female patients with OAB. All five muscarinic subtypes are expressed throughout the urothelial layers with a specific localisation of the M2 subtype to the umbrella cells and M1 to the basal layer, with M3 receptors more generally distributed. Release

of ACh from human urothelial and suburothelial sites increases with age, as well as during bladder stretch, and represents a functional, non-neuronal, alternative cholinergic system. At therapeutic doses, antimuscarinics act mainly during the filling phase and exert little effect on detrusor contraction during emptying. This lends support to the suggestion that urothelial muscarinic receptors might be involved in the generation of afferent impulses. Urothelial cells express both Îą and Î˛ adrenoceptor subtypes, stimulation of which has been shown to trigger the release of ATP and nitric oxide (NO), respectively. Stimulation of urothelial Î˛ adrenoceptors also triggers an urothelially-derived inhibitory factor. In addition to the changes in ACh-release mentioned above, several specific alterations in urothelial function and ultrastructure have been demonstrated in OAB. Expression of the mechanosensitive ENaC is increased significantly in human obstructed bladders in comparison to unobstructed controls and correlates significantly with storage symptom scores. It is possible that increased expression of mechanosensitive channels such as ENaC in the urothelium enhances substance release upon bladder stretch. Bladder biopsies from patients with both idiopathic detrusor overactivity (IDO) and neurogenic detrusor overactivity (NDO) have shown increased urothelial TRPV1 expression. This may be in accordance with the fact that intravesical vanilloids (resineferatoxin) have been shown to improve OAB symptoms in patients with idiopathic detrusor overactivity as well as with hypersensitivity disorders.

gap junction can be identified in the bladder wall. These myofibroblasts make close apposition to unmyelinated nerves (afferent C-fibre nerves). The studies investigating human myofibroblasts show that the cells can respond to ATP by generating an intracellular Ca2+ transient, which is mediated by a P2Y receptor, most likely including a P2Y6. On the basis of these observations, it has been hypothesised that the close relation between nerves and myofibroblasts allows for an amplification of the afferent system in its response to stimulatory mediators such as ATP. Overall, up-regulation of urothelial function and increased release of various chemical mediators and known neurotransmitters may influence afferent nerve activity to generate OAB symptoms, although the precise mechanism by which these processes interact with neural tissue to achieve signal transduction remains to be clarified.

This sensory process is more complex than originally thought. A suburothelial layer of myofibroblasts (interstitial cells) that or a functional syncitium through connexin 43

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THE MYOGENIC HYPOTHESIS Myogenic changes may contribute to the pathophysiology of idiopathic detrusor overactivity. On the basis of observation that denervation is consistently found in detrusor biopsy specimens from patients with various forms of non-neurogenic detrusor overactivity, it has been proposed that partial denervation of the detrusor may alter the properties of smooth muscle, leading to increased excitability and increased coupling between cells. Thus, local contraction (activity) that occurs somewhere in the detrusor will spread throughout the bladder wall, resulting in coordinated myogenic contraction of the whole bladder. In addition, this local contraction in the bladder wall has been shown to generate afferent discharge. Localized distortion of the bladder wall simulates afferent activity, which would precipitate a feeling of urgency and detrusor overactivity. Although the relationships between intercellular communication and spontaneous mechanical activity and the degree of involvement of different types of connexins (Cxs) need further study, Cx45 and Cx43 appear to be the most prominent Cxs expressed in human detrusor smooth muscle tissue and cultured cells. Observations in tissue biopsies from patients with neurogenic DO and urgency symptoms clearly demonstrated an increase in the presence of Cx43-derived gap junction channels in detrusor muscle. In addition, another population of cells in the bladder known as interstitial cells has been proposed for a pacemaking role in spontaneous activity of the bladder. c-kit tyrosine kinase inhibitors, which inhibit interstitial cell activity, decreased the amplitude of spontaneous contractions in human bladder, interstitial cells may also be involved in the emergence of detrusor overactivity because of enhanced autonomous detrusor muscle activity.

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FIgURE 2: The myogenic hypothesis of the mechanisms involved in increased afferent input from the bladder.

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OTHER LOCAL FACTORS

MECHANISMS INVOLVED IN ABNORMAL HANDLING OF THE AFFERENT SIGNALS IN THE BRAIN

ISCHAEMIA Ischaemia has been proposed as a pathophysiological factor of OAB/DO. Recent studies suggest that arterial obstructive disease, such as atherosclerosis, may cause OAB in both men and women via ischaemia, hypoxia and oxidative stress in the bladder. DO associated mitochondrial stress may have a central role in epithelial damage, smooth muscle cell injury and neurodegeneration. Superoxide dismutase and aldose reductase up-regulation in the overactive bladder imply intrinsic defensive reaction against free radicals that apparently fails to prevent oxidative damage and neurodegeneration. HIF, TGF-β, VEGF and NGF up-regulation in the ischaemic bladder was accompanied by the loss of mitochondrial structural integrity, fibrosis, and the degeneration of microvasculature and nerve fibres. These observations may suggest the role of ischaemia in the overactive bladder with impaired contraction, as reported in elderly patients without obstruction. Ischaemia may be a key factor in aging associated LUTS.

The ‘neurogenic hypothesis’ suggests that damage to the central inhibitory pathways, or sensitisation of afferent nerves, leads to the unmasking of primitive voiding reflexes which trigger overactive detrusor contraction. Plasticity both in the peripheral innervation and within the CNS may have a pathophysiological role in DO, and increased release of nerve growth factor has been reported, which may alter the neural regulation of detrusor muscle. Peripherally, neurological diseases might cause a sensitisation of C fibres that are silent under normal circumstances, thereby leading to the emergence of a C-fibre-mediated reflex.

INFLAMMATION

While many neurological diseases predispose patients to neurogenic detrusor overactivity (NDO), the only populations that have been systematically studied are adults with multiple sclerosis, adults with spinal cord injury (SCI) and children and young adults with myelodysplasia. As a sensation it can be affected by neurological disorders and may, therefore, be perceived differently in patients with neurological lesions.

Recent studies have noted signs of inflammation in bladder biopsy specimens from OAB patients. Increases in cytokines, chemokines, and growth factors have been reported in the urine of OAB patients. Consistent association of increasing serum CRP levels and OAB has been also demonstrated. All together, these results support the hypothesis for the role of inflammation in the development of OAB.

NEUROGENIC DETRUSOR OVERACTIVITY Recent advances in functional brain imaging have made it possible to directly study the supraspinal control system operating during bladder filling. Comparisons between brain response in subjects with normal bladder function and those with OAB may give us a neural correlate of urgency and possible origins of OAB symptoms.

inhibition of micturition, which corresponds to uninhibited overactive bladder. Higher brain centres provide an additional level of urinary control, which is responsible for conscious sensation, volition and emotional response. Key higher centres include the prefrontal cortex, insular cortex and anterior cingulate gyrus, and functional brain imaging has shown changes in higher CNS activity in OAB. Although such observations have been made infrequently, they do point to some key areas for consideration. For example, the participation of several brain areas in urinary control may explain why brain diseases and senile cerebral atrophy are risk factors for lower urinary tract dysfunction. Variation in observations between individuals implicates a diversity of processes in the mechanisms that underlie OAB, although these are expressed clinically in the common manifestation of OAB. The increased activity observed in certain regions of the brain in patients with OAB may actually be compensatory, to counteract urgency, rather than being responsible for the symptom. This confounds interpretation of function, and there are many questions that still need to be answered. In humans, the cerebral cortex (medial frontal lobes) and the basal ganglia are thought to suppress the micturition reflex. Thus, damage to the brain induces DO by reducing suprapontine inhibition.

1. SUPRAPONTINE LESIONS

A. STROKE (CEREBRAL INFARCTION )

It is generally accepted that suprapontine lesions such as cerebrovascular disease and Parkinson’s disease produce DO. The patient with a suprapontine lesion loses voluntary

The mechanism of DO induced by cerebral infarction or Parkinson’s disease has been further studied using animal models. In the central nervous system, a glutamatergic

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pathway is known to play a role in both excitatory and inhibitory regulation of micturition. Cerebral infarction may alter a balance between the facilitatory and inhibitory mechanism that results in up-regulation of an excitatory pathway and downregulation of a tonic inhibitory pathway.

B. PARKINSON’S DISEASE Parkinson’s disease (PD) is characterised by the degeneration of dopamine-producing cells in the substantia nigra of the midbrain and Lowy body formation. PD is the most common cause of parkisonnism which is the neurological syndrome bearing the hallmarks, hypokinaesia and postural instability. Urgency occurs in 33-54% of patients with PD. Neurogenic DO was seen in 45-93% of PD patients. The most widely accepted theory of pathophysiology of DO in PD is that basal ganglia inhibits the micturion reflex in the normal situation via D1 receptors, and that cell depretion in the substantia nigra in PD results in loss of D1-mediated inhibition and consequently DO. The absence of dopaminergic tone via D1 receptors may cause a dysfunction in GABA regulation in the periaqueductal gray (PAG) and DO. Alteration in brain activation sites in response to bladder filling may be related to the pathophysiology of DO in patients with PD.

sensation is a typical feature. In humans with spinal cord lesions, NDO is likely to be mediated by capsaicin-sensitive C-fibre afferents. Clinical experience with capsaicin supports the role of these C-fibre afferents in the pathophysiology of NDO. Capsaicin has been used for the treatment of NDO in patients with spinal cord injury or multiple sclerosis. When administered intravesically, capsaicin increases bladder capacity, reduces micturition contraction pressure, decreases autonomic dysreflexia and reduces the frequency of incontinence. Increased TRPV1, P2x3 and pan-neuronal marker (PGP9.5) staining in suburothelial nerves and increased TRPV1 staining in the basal layer of the urothelium have been observed in patients with neurogenic bladder due to SCI and multiple sclerosis.

2. SPINAL CORD LESIONS

Treatment of NDO patients with intravesical capsaicin or resiniferatoxin reduces the density of TRPV1, P2x3 and PGP9.5 immunoreactive nerve fibres and urothelial TRPV1 immunoreactivity in those patients exhibiting symptomatic improvement. Injections into the bladder wall of botulinum neurotoxin type A (BoNT/A), an agent that blocks the release of neurotransmitters from afferent and efferent nerves, and from urothelial cells, also reduces NDO and the density of TRPV1- and P2x3-immunoreactive nerves. These results indicate that an abnormality of the C-fibre afferent innervation contributes to NDO.

A spinal cord lesion above the lumbosacral level eliminates voluntary and supraspinal control of micturition, leading to DO mediated by spinal reflex pathways. Disruption below the level of the pons leads to unsustained and uncoordinated detrusor contractions often associated with uncoordinated sphincter overactivity (detrusorsphincter dyssynergia, DSD). Impairment or loss of bladder

Following SCI changes in the electrophysiological properties of bladder afferent neurons have also been observed consisting in multiple action potentials (tonic firing) in response to long depolarizing current pulses. In addition, A-type K+ channels are suppressed in parallel with an increased expression of TTx-sensitive Na+ currents, thereby increasing excitability of C-fibre bladder

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afferent neurons. These electrophysiological changes contribute to the emergence of the C-fibre-mediated spinal micturition reflex following SCI.

PREGNANCY, CHILDBIRTH AND THE PELVIC FLOOR Despite the great achievements made in modern obstetric practice in developed countries during the last 100 years, delivery remains the most stressful and dangerous event the female pelvic diaphragm is submitted to during a woman’s lifespan. During pregnancy, muscular, connective and nervous pelvic structures are already subjected to anatomical, morphological, functional and hormonal changes. During vaginal delivery, the pelvic floor undergoes an enormous amount of stretching to allow the passage of the newborn through it. During the pregnancy and just after delivery, the functions sustained by the pelvic floor (urinary and faecal continence, pelvic organ containment and sexual function) often begin to fail. Evident or hidden injuries of the pelvic floor may manifest themselves through symptoms of urinary and faecal incontinence, prolapse or sexual dysfunction, with a considerable impact on quality of life. If several mechanisms of birth trauma have already been investigated, a lot needs to be understood regarding the role of pregnancy on the pelvic floor. The growing knowledge of the consequences of childbirth and pregnancy on the pelvic floor, offers the chance to develop prevention and treatment strategies. It is important that contributing obstetric factors are identified and their occurrence minimised, in order to focus efforts on preventable risk factors.

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EFFECT ON THE COLLAGEN

MECHANISM OF BIRTH INjURY TO THE PELVIC FLOOR

During pregnancy, hormones affect the biochemical composition of the solid matrix and hydration phases constituting all pelvic floor tissue. Remodelling mechanisms lead to changes in the organisation, orientation, and diameter of the collagen fibres as well as the crimp structure of the collagen fibrils reinforcing each tissue. Such effects can significantly affect the short and long-term viscoelastic properties of the vaginal wall, the pubovisceral muscles, and the perineal body, for example. They will largely determine (a) the extent and rate at which these structures can be stretched by an expulsive force acting cyclically on the fetal head, and (b) the resistance to stretch provided by those structures.

Strong epidemiological evidence links vaginal childbirth and the development of postpartum incontinence and prolapse. There would seem to exist three major mechanisms by which vaginal delivery might contribute to the pelvic floor trauma: a) muscle trauma, b) connective tissue damage, c) nerve injury, d) vascular damage.

The more a tissue exhibits creep behaviour, the further it will stretch under a constant load. And the more it exhibits relaxation behaviour, the more the stress in a tissue will decrease over time when held at a constant length, thereby helping to lower the risk of rupture in the next loading cycle. Were a tissue to exhibit viscoplasticity, it would behave as a solid below a critical level of stress, but above that level, it would flow like a viscous liquid. There is evidence that tensile failure in some soft tissues can be predicted by the product of the stress times the strain extent in the tissue, so mechanisms that lower one or both these variables will reduce the risk of rupture. Pregnancy is known to significantly affect the instantaneous stiffness and relaxation behaviour of vaginal tissues. There may be a group of women at an inherent increased risk of developing incontinence due to abnormalities in collagen, as the collagenous component of the connective tissue contributes to structural support of the bladder neck.

A. MUSCLE TRAUMA The effect of delivery on muscular structure has been widely investigated, and all the studies done to quantify pelvic floor muscle stretch induced during the second stage of labour as a model in which the fetal head progressively engaged and then stretched the iliococcygeus, pubococcygeus and puborectalis muscles. The largest tissue strain reached a stretch ratio (tissue length under stretch/ original tissue length) of 3.26 in the medial pubococcygeus muscle, the shortest, most medial and ventral levator ani muscle. Regions of the ileococcygeus, pubococcygeus, and puborectalis muscles reached a maximal stretch ratio of 2.73, 2.50, and 2.28, respectivel. Tissue stretch ratios were proportional to fetal head size: for example, increasing fetal head diameter by 9% increased medial pubococcygeus stretch by the same amount. The authors demonstrated that the medial pubococcygeus muscles undergo the largest stretch of any levator ani muscles during vaginal birth and it is therefore at the greatest risk of stretchrelated injury (Figure:3). Studies showed that the area of the levator hiatus needs a distension of between 25% and 245% to allow the passage of the fetal head, considering as average a cross-sectional fetal head areaof 68 cm2, based on Caucasian biometric data.

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FIgURE 3: Simulated effect of fetal head descent on the levator ani muscles in the second stage of labour. From Lien et al, Obstet gynecol 2004.

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Women delivered by forceps have a higher rate of levator ani injury compared with spontaneous delivery controls, but the length of the second stage of labour does not influence the effect of the forceps on the levator ani muscle. The levator ani muscle plays an independent role in pelvic organ support. The levator hiatus is the “hernial portal” through which female pelvic organ prolapse develops and damage to the levator ‘plate’ leads to a weakening of muscular supports to the pelvic organs and an increase in load carried by connective tissue and fascia. It has been demonstrated that increasing pelvic organ prolapse is associated with increasing urogenital hiatus size. once a certain degree of pubovisceral impairment was reached, the genital hiatus opened and a prolapse developed; the larger the pubovisceral impairment, the larger the anterior wall prolapse became. But the aetiological role of LAM integrity in bladder dysfunction is still not completely clear.

B. NERVE INJURY A geometric model has been used to predict the stretch ratios in the nerves innervating the levator ani, urethra, and anal sphincter during the second stage of vaginal labour. The results showed that the inferior rectal branch exhibited the maximum strain, 35%, and this strain varied by 15% from the scenario with the least perineal descent to that with the most perineal descent. The strain in the perineal nerve branch innervating the anal sphincter reached 33%, whereas the branches innervating the posterior labia and urethral sphincter reached values of 15% and 13%, respectively. It was concluded that during the second stage (a) nerves innervating the anal sphincter are

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stretched beyond the 15% strain threshold known to cause permanent damage in the nonpregnant appendicular nerve, and (b) the degree of perineal descent is shown to influence pudendal nerve strain. Pudendal nerve lesions usually result in demyelination of the fibres; axonal breaks may occur in severe cases where there is no recovery of the tissues. Neuromuscular abnormal pelvic floor activation patterns may also contribute to the development of postpartum pelvic floor disorders. Electroneuromyography studies have shown that 80% of primigravidae developed evidence of partial denervation with signs of reinnervation and increase in the density of nerve fibres in the postpartum period after vaginal delivery. The latency time of pudendal nerve motor fibres increased after 2 to 3 days following vaginal delivery, but values normalised after 6 months in 66%. Most nerve lesions spontaneously recover within a year by regenerative processes. However, pudendal nerve damage, even with partial reinnervation of the external anal sphincter muscle, may persist and become more marked in the long term. Neurophysiological tests revealed nerve damage in 36% of women with persistent SUI at 3 months postpartum. Compared with nulliparous control subjects, patients with SUI and POP had changes in the levator ani and external anal sphincter consistent with either motor unit loss or failure of central activation, or both.

PERINEAL TRAUMA A. EPIDURAL ANALGESIA DURING LABOUR Regional anesthesia for the relief of labour pain has become more popular during the past 20 years. Despite interest in its possible obstetric consequences, little attention has been paid to its potential effects on the pelvic floor and perineal injury.

The available published data describe controversial results. Some studies suggest that epidural analgesia, by enabling relaxation of the pelvic floor, leads to greater control of crowning of the fetal head and consequently fewer perineal tears, but prolongation of the second stage may also increase the incidence of pudendal nerve damage. Epidural analgesia is associated with differences in rates of severe perineal trauma during vaginal deliveries. Epidural analgesia is associated with an increase in the rate of severe perineal trauma because of the more frequent use of operative vaginal delivery and episiotomy. Epidural analgesia is an independent risk factor for severe perineal tears. Among women who had epidural analgesia, had severe perineal tears. Epidural analgesia is associated with an increase in severe perineal trauma as a result of an associated three-fold increased risk of instrument use. Instrument use in vaginal delivery more than triples the risk of severe perineal tears. B. ROLE OF EPISIOTOMY The episiotomy, a surgical incision in the perineum made to enlarge the vaginal opening and facilitate delivery, was originally introduced on the assumption that it would improve maternal and neonatal outcomes and rapidly became a part of standard obstetric care. However, since the 1980s, routine use of episiotomy has been challenged, based on the lack of evidence of benefits of the procedure and the publication of multiple studies reporting increased blood loss at delivery, perineal scar breakdown and infection, postpartum pelvic pain, and dyspareunia. Some studies have demonstrated increased incidence of third and fourth-degree lacerations associated with the use of midline episiotomy The resulting damage to the internal and external anal sphincters.

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PATHOPHYSIOLOGY OF STRESS URINARY INCONTINENCE IN WOMEN Stress Urinary Incontinence is frequently associated with a decline in the electrophysiological function of the pudendal nerve. The striated urethral sphincter, and the pelvic floor muscle. Most recent studies continue to support the findings of prolonged pudendal nerve terminal motor latency in SUI. Many patients with urodynamic SUI shows, urethral mobilty, although it is not yet known that it is about that mobility which permits urethra to open during stress. Some patients who present with minimal mobility have primary or residual sphincter insufficiency in related to a decline in striated sphincter mjuscle mass and function as measured by electrophysiological studies of pudendal nerve and sphincter function and MRI and sonographic estimates of muscle mass.

THE FEMALE UROGENITAL DIAPHRAGM: URETHRAL SPHINCTER LOCATION The proximal one-third of the urethra is shown surrounded by a sleeve of striated muscle continuous with a longer ascending cone which extends to the vaginal introitus. Manometric and electrophysiological recordings from this proximal onethird of the urethra have shown that it generates the highest level of resting pressure and electromyographic activity. This portion of the urethra is an intra-pelvic structure located immediately posterior to the pubic bone. In the past, much has been made of the loss of this intra-pelvic position in stress incontinence. It had been suggested that when the urethra descended away from its intra-abdominal

position, intra-abdominal forces no longer constricted it during straining. This concept has survived and been modified into the â&#x20AC;&#x153;hammock hypothesisâ&#x20AC;? which suggests that the posterior position of the vagina provides a backboard against which increasing intra-abdominal forces compress the urethra. Data supporting this hypothesis are drawn from urethral pressure transmission studies showing that continent patients experience an increase in intra-urethral pressures during coughing. This pressure increase is lost in stress incontinence and may be restored following successful operations designed to stabilize or elevate the sub-urethral vaginal wall. The urethra is supported posteriorly and inferiorly by the anterior vaginal wall. The superior vaginal sulcus, most clearly found in nullipara, exists at this junction of

Successful operation can restore urethral position but not restore urethral function.

The factors necessary for the urethra to remain closed at rest and during increased abdominal pressure have been well characterised, but their functional inter-relationships are still not fully understood. These factors include: 1) healthy, functioning striated sphincter controlled by pudendal innervation, 2) well vascularised urethral mucosa and sub-mucosa, 3) properly aligned and functioning intrinsic urethral smooth muscle, and 4) intact vaginal wall support.

FIgURE 4: EUS in 18 weeks female foetus: A anterior view, B lateral view, C oblique view, D superior view, E inferior view -From Wallner et al., Eur Urol 2009.

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the lower and middle third of the vaginal wall. This point represents the two lateral insertion points of the vaginal â&#x20AC;&#x153;hammock â&#x20AC;&#x153;. Portions of the pubococcygeus muscle attach to these sulci within the pelvis and can produce elevation during voluntary contraction. Immediately anterior to the proximal urethra are found the reflections of the endopelvic fascia are found. The most prominent of these, the pubourethral ligaments, are sufficiently condensed to form distinct and recognisable ligaments on either side of the pubis. Although these structures form one continuous complex, they are distinguished by their names, as posterior and anterior pubo-urethral ligaments. The posterior pubo-urethral ligaments, which can be seen at the time of retropubic surgery, are the more familiar of these. These are strong fascial condensations which most likely maintain their characteristics throughout life. Previous investigators, however, have suggested that elongation of these structures may be responsible for the loss of urethral support seen in stress incontinence.

The striated external urethral sphincter (EUS), both in foetuses and adults, has a superior horseshoe structure covering the urethra and an inferior one surrounding the anterolateral aspect of the urethra and the lateral part of the vagina.

thirds of the vagina, and show that during coughing and stressful manoeuvres, the levator hiatus is shortened in an anterior direction by the contraction of the pubococcygeus muscles Thus, the pelvic organs receive support from the shape and active contraction of the levator muscles.

Moreover, while the lower one-third of the vagina is oriented more vertically in the nullipara, the upper twothirds of the vagina deviate horizontally. This orientation is due: 1) to the posterior attachments of the cervix by the cardinal and utero-sacral ligaments and 2) to the anterior position of the levator hiatus. Barium vaginograms have demonstrated this horizontal angulation of the upper two-

Modifications of the genital hiatus determining an increase in the genitohiatal distance can be associated with urodynamic stress incontinence. loss of both active and passive organ support during rest and especially during straining.

Different authors have described the striated external urethral sphincter (EUS), both in foetuses and adults as a superior horseshoe structure covering the urethra and an inferior one surrounding the anterolateral aspect of the urethra and the lateral part of the vagina (Figure 9). The LAM is an important element in maintaining urinary continence. The topographical relationship between the EUS and the LAM female, the inferior part of the EUS is firmly attached to the LAM by a tendinous connection. This determines an anterior bending of the midurethral zone when a simultaneous contraction of the LAM and EUS occurs, closing the urethral lumen and maintaining continence. The functional integrity of this connection between the EUS and the LAM is therefore crucial to avoid urinary incontinence. FIgURE 5: Muscles of the female pelvic floor.

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EFFECT OF CHILDBIRTH, VAGINAL PROLAPSE AND URETHRAL POSITION ON URINARY CONTINENCE Labour and delivery alter vaginal and pelvic anatomy and innervation in several ways as has been discussed in other sections of this chapter. Each of these may contribute to the eventual development of urinary incontinence: A. PUDENTAL NERVE Direct crushing or traction on the pudendal nerve has been discussed above and has previously been suggested as a primary cause of sphincter incompetence in stress incontinence. The pudendal nerve, which projects from Onuf’s nucleus and traverses Alcock’s canal before entering the ischiorectal fossa and innervating the EUS, can be injured during vaginal delivery, particularly in the area between the sacrospinous and sacrotuberous ligaments. Two different mechanisms of pudendal nerve damage during delivery have been described: 1) nerve compression and stretching which may cause an elongation of the 13% of its motor branch innervating the EUS, 2) a reduced at 8% stretch and complete ischemia at 15% stretch of the nerve as shown in a tibial nerve rat model. Thus, pudendal nerve ischemia likely occurs during vaginal delivery as a result of both stretch and compression. B. CARDINAL AND UTERO-SACRAL LIGAMENTS Cardinal and utero-sacral ligaments may be stretched or torn, resulting in anterior displacement of the uterus during straining or under the influence of gravity. C. THE VAGINA The vagina itself may be torn away from its intrapelvic attachments with subsequent loss of the superior vaginal sulcus. There may be direct attenuation of the vaginal

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FIgURE 6: Two sectional views comparing the organ’s positions in nonpregnant and pregnant women.

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wall itself, manifested by loss of vaginal rugae and a thin appearance. There are four distinct kinds of vaginal injuries: paravaginal, central, distal, and cervical, the first two being the most commonly seen in women with stress incontinence. These defects have been identified by sonographic examination. D. LEVATOR MUSCLES Finally, stretching, tearing and avulsion of the levator muscles result in a longer and wider levator hiatus. Consequently, the perineum is displaced anteriorly and posteriorly under stress and temporarily fails to support the pelvic organs. These changes in the levator hiatus with or without associated relaxation of cervical support result in chronic anterior displacement of pelvic organs with a loss of both active and passive organ support during rest and especially during straining.

anatomical defects in the majority of patients with urodynamic stress incontinence (USI), less is understood about the exact effect of these defects, and indeed, vaginal position itself, on urethral closure.

URETHRA WEAKNESS AND INTRINSIC SPHINCTER DEFICIENCY (ISD) the term intrinsic sphincter deficiency (ISD), focusing attention on urethral elements which appear to be independent of vaginal position and mobility. These elements include pudendal innervation, striated sphincter mass and function, and urethral smooth muscle, mucosa and submucosal cushions.

When ISD was first introduced as a concept to explain surgical failures and the presence of stress incontinence in the absence of vaginal mobility, the diagnostic tendency was to consider the cause of stress incontinence as a dichotomy, due either to hypermobility (displacement, or prolapse of the vaginal wall) or ISD. The typical patient with ISD was described as having low urethral closure pressures, a â&#x20AC;&#x153;stovepipeâ&#x20AC;? appearance on cystoscopy, and opening or funnelling of the urethra under resting or minimal increases in intra-abdominal pressures on radiographic images. The common causes were thought to be surgical injury, ischemia following previous pelvic or vaginal surgery or radiation damage. It appears now, that these examples of ISD may represent the most advanced or extreme forms.

In the patient with SUI these changes typically give rise to a rotational descent of the proximal urethra away from its retropubic position. The most common characteristic anatomical change, present in four out of five cases of incontinence, is loss of the posterior urethro-vesical angle so that the urethra and trigone tend to come into line. It is clear that the distinguishing topographic pathological feature is depression of the urethrovesical junction to the lowest level of the bladder during the peak of the straining effort. It is also clear that the spatial relationships of the bladder and urethra to the symphysis make no difference in either the incidence or severity of stress incontinence. Although we have considerable knowledge about

FIgURE 7: A. A normal competent sphincter unit keeps the urethra closed during physical stress (e.g. coughing) despite a certain mobility of the urethra. B. Hypermobility of the urethra and bladder neck during physical stress (e.g. coughing) can lead to an opening of the urethra and bladder neck despite an ade-quate activity of the urethral sphincter. C. Decrease in urethral sphincter activity can lead to an opening of the urethra and bladder neck without increase of normal mobility of the urethra.

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URETHRAL HYPERMOBILITY Currently, these appear to be a shift away from this simple categorisation of stress incontinence as being due either to hypermobility or ISD. This has arisen in part because of the development of the concept of Valsalva Leak Point Pressure. Just as the concept of VLPP blurred the previous distinction between simple ISD and simple hypermobility, long term outcome studies of correction of hypermobility have suggested that there may be more urethral weakness among patients with hypermobility than had been previously considered.

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Long term outcome studies of stress incontinence surgery have shown that there is a much greater failure rate of many of the commonly performed stress incontinence operations than had been generally appreciated, and that slings providing direct sub-urethral support seemed to give the greatest long term protection against recurrence of incontinence. Since slings had traditionally been the procedure of choice for recurrent incontinence or â&#x20AC;&#x153;Type IIIâ&#x20AC;? (now ISD) incontinence.

that age-related reduction in muscle mass, slowed reflexes or repeated episodes of prolapse may all contribute to the condition. The high rate of intrinsic sphincter deficiency in patients with urethral hypermobility indicates that the incidence with stress incontinence may be greater than previously believed, and may influence the apparently higher failure rates after bladder neck suspension.

Though age is a significant, independent predictor of ISD in the setting of urodynamic stress incontinence, suggesting

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FIgURE 8: Mechanism off Urethral Control : The urethra is 3 to 4 cm in length and can be considered to consist of four unequal regions. Region 1 contains the internal.urethral sphincter. The lumen is surrounded by smooth muscle and the bladder neck. In region?, the middle portion, the fumen is surounded by the striated sphincter urethra muscle as well as smooth muscle. In region 3, the lumen is surrounded by the striated ure mrovaginal sphincter, which also loops around the vagina, and the compressor urethrae muscle. The striated muscles in regions 2 and 3 are referred to collectively as the external urethral sphincteiv The internal and external sphincters form the sphincter complex, which maintains tone and prevents involuntary voiding. In region 4, the smooth muscle that originates in region 1 terminates in the fibrous tissue surrounding the external urethral meatus.

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PATHOPHYSIOLOGY OF SPELVIC ORGAN PROLAPSE (POP) IN WOMEN Anatomical support of pelvic viscera is mainly provided by the levator ani muscle complex and connective tissue attachments of the pelvic organs: vaginal support arises from the connective tissue attachments between the vagina and the pelvic sidewall, the vaginal wall, and the levator ani muscles

laterally, to the arcus tendineus and fascia of the levator ani muscles (Level II). This attachment stretches the vagina transversely between the bladder and the rectum. The structural layer that supports the bladder (pubocervical fascia) is composed of the anterior vaginal wall and its attachment through the endopelvic fascia to

the pelvic side wall. Similarly, the posterior vaginal wall and endopelvic fascia (rectovaginal fascia) form the restraining layer that prevents the rectum from protruding forward. The vaginaÂ´s lower third (Level III) fuses with the perineal membrane, levator ani muscles and perineal body, without any intervening paracolpium (Figure: 10). Damage

Two mechanical principles explain how the uterus and vagina are normally held in place. First, the uterus and vagina are attached to the walls of the pelvis by the endopelvic fascia that suspends the organs from the pelvic sidewalls. Second, the levator ani muscles costrict the lumens of these organs closed, forming an occlusive layer on which the pelvic organs may rest. The levator ani complex consists of the pubococcygeus, the puborectalis, and iliococcygeus muscles. These muscles are tonically contracted at rest and act to close the genital hiatus and provide a stable platform for the pelvic viscera. Decline of normal levator ani tone by denervation or direct muscle trauma, results in an open urogenital hiatus, weakening of the horizontal orientation of the levator plate, and a bowl-like configuration. The supportive connective tissues are a continuous, highly interdependent sheet in which all components interact to achieve support of the vagina and, therefore, of the pelvic organs. DeLancey has introduced the concept of dividing the connective tissue support of the pelvis into three levels, with level I, II and III representing apical, midvaginal and distal support respectively. The upper portion of the paracolpium (Level I) consists of a relatively long sheet of tissue that suspends the vagina by attaching it to the pelvic side wall, and it is responsible for suspending the apex of the vagina after hysterectomy. In the middle third of the vagina, the paracolpium attaches the vagina

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FIGURE 9: The muscles of the superficial pelvic floor and deep pelvic floor..

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to the upper suspensory fibres of the paracolpium causes a different type of prolapse from damage to the mid-level supports of the vagina. Defects in the support provided by the mid-level vaginal supports (pubocervical and rectovaginal fascia) result in cystocele and rectocele, while loss of the upper suspensory fibres of the paracolpium and parametrium is responsible for the development of vaginal and uterine prolapse. These defects usually occur in varying combinations and this is responsible for the diversity of clinical problems encountered within the overall spectrum of pelvic organ prolapse. For conceptual purposes the supportive connective tissue has been related to structural elements of the pelvic floor: the uterosacral ligaments (level I); the paravaginal attachments (endopelvic fascia) that connect the lateral vaginal walls to the arcus tendineous fascia pelvis (ATFP) and the fascia of the levator ani muscles (level II); the perineal membrane and the perineal body (level III). Table 2 lists the structural elements of pelvic organ support, their possible damage and subsequent site of pelvic organ prolapse. The integrity of muscular, connective and nerve structures is essential to guarantee normal pelvic organ support. If one of these factors fails, the other might be able to compensate to a certain degree. The aetiology of pelvic organ prolapse is thought to be multifactorial with contributions from both environmental and genetic risk factors. Environmental factors that contribute to POP include vaginal delivery, chronic increases in intra-abdominal pressure, obesity, advanced age and oestrogen deficiency. Table 3 lists anatomical and functional determinants of

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normal pelvic organ support. It also summarises the possible nature of failure and its potential causes as well as the established and theoretical risk factors. Vaginal delivery has been considered the main causal factor in the development of pelvic organ prolapse for some years. However, if it is true that all women undergo pelvic floor stretching during vaginal delivery, not all of them develop a further prolapse; moreover, pelvic floor dysfunction has also been described in women who gave birth by caesarean section only and in nulliparous women. Therefore, vaginal delivery does not totally explain the origin and progression of pelvic floor descent in all women. This supports the hypothesis that other causes, besides obstetrics, are involved in the aetiology of pelvic organ prolapse: connective tissue deficiencies, genetic predisposition, sexual hormones, pregnancy, ageing, menopause, obesity, neuropathies, ethnicity and family history. In the last decade, attention has increasingly focused on understanding the molecular basis of POP and the recognition of the potential molecular markers and their modulators in pelvic floor supportive tissues in order to identify women predisposed to develop POP. 1. ALTERATION OF COLLAGEN, ELASTIN AND SMOOTH MUSCLE OF THE VAGINAL AND SUPPORTIVE TISSUE It has been demonstrated that young women with POP are more likely to have connective or neurological tissue diseases and congenital abnormalities. TABLE 1: Pelvic floor musculature anatomic origins, insertions, innervation and function.

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Women with Marfan or Ehlers-Danlos syndrome have high rates of POP. Intrinsic joint hypermobility is another well recognised connective tissue disease that is associated with pelvic descent. This finding supports the hypothesised aetiological role of connective tissue disorders as a factor in the pathogenesis of this conditions.

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The vaginal wall is comprised of four layers: a superficial layer of non-keratinised stratified squamous epithelium; a subepithelial dense connective tissue layer composed primarily of collagen and elastin; a layer of smooth muscle referred to as the muscularis; and a layer of adventitia, composed of loose connective tissue. The subepithelium and muscularis together are thought to confer the greatest tensile strength to the vaginal wall. In the normally supported vagina, the supportive connective tissues pull the vagina up and back away from the vaginal introitus over the levator ani muscles. A normally supported vagina, in turn, provides support to the bladder, urethra, uterus and rectum. Disruptions of - or damage to - these connective tissue structures and injury to the vaginal wall are thought to be two important mechanisms causing prolapse. The connective tissue of the vagina and supportive tissues contains a fibrillar component (collagen and elastin) and a non-fibrillar component (noncollagenous glycoproteins, hyaluronan, and proteoglycans). In addition, and with the exception of the arcus tendineous, these tissues contain a significant amount of smooth muscle. The fibrillar component is thought to contribute the most to the biomechanical behaviour of these tissues. The quantity and quality of collagen and elastin are maintained through a precise balance between synthesis, posttranslational modification, and degradation. Therefore, the integrity of the vagina and its supportive connective tissues are essential for keeping the pelvic organs in their normal anatomic position. Evaluation of these tissues from a biochemical perspective enables us to better discern the complex interplay between structural composition and supportive capacity. Collagen types I, III and V are the main structural components of vaginal epithelium and endopelvic fascia and they are thought to be the principal determinants

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FIgURE 10: Level I (suspension) and level II (attachment). In level I the paracolpium suspends the vagina from the lateral pelvic walls. Fibers of level I extend both vertically and also posteriorly towards sacrum. In level II vagina is attached to arcus tendineus fasciae pelvis and superior fascia of levator ani.

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TABLE 2: Structural elements of pelvic organ support, their possible damage and subsequent site of pelvic organ prolapse. The levels of support and anatomical defects are derived from the anatomical studies of DeLancey.

TABLE 3: Determinants of normal pelvic organ support. Possible sites of failure and possible causes, established and theoretical risk factors.

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2. NEUROLOGICAL FACTORS of tissue strength. Type I collagen confers strength to tissues while type III contributes to elasticity. Type III collagen is the primary collagen subtype in the vagina and its supportive structures. The ratio of collagen I to III is an indicator of tensile strength: the higher the amount of collagen type III, the lower is the mechanical strength. In women with prolapse, MMP-2 mRNA expression is increased with a concurrent decrease in the inhibitor TIMP-2. Recent data also indicate increased MMP-1 expression and decreased collagen I in the uterosacral ligaments of women with POP. In contrast, collagen I and III mRNA expression was increased in vaginal tissue from women with POP. Mismatches between mRNA and protein data are often found when examining proteins in the extracellular matrix. Thus, gene expression should always be confirmed with protein expression. These discrepancies also suggest the possibility that different pathways in the extracellular matrix may be activated depending on injury type and severity, mechanical load and environmental factors. Despite discrepancies in the precise MMP/TIMP or collagen type, the reported data and numerous other publications indicate that women with POP show an abnormal pelvic extracellular matrix metabolism with increased collagen remodelling. The general amount of collagen in the parametria is reduced in pre and postmenopausal women with pelvic organ prolapse compared with women without prolapse. Collagen III is increased in vaginal subepithelium and muscularis in patients with prolapse relative to patients without prolapse, independent of age and parity. Collagen III is the primary subtype in the arcus tendineus fascia pelvis; a decrease in the ratio of collagen I/(III+V) is

associated with menopause in the absence of hormone therapy and a restoration of this ratio to premenopausal levels with hormone therapy. Elastin is primarily laid down during fetal development and rarely synthesised in adult tissues. In contrast to the other tissues in which elastin fibres do not experience a turnover in a lifespan, there is cyclical remodelling of elastin fibres in the reproductive tract. A massive degradation of elastin occurs at the time of parturition, followed by postpartum resynthesis, allowing recovery of reproductive tissues to their pre-pregnancy state. Studies shows that a significant decrease in the endogenous inhibitors of elastases with increase in elastolytic activity in vaginal tissue from women with stress urinary incontinence and pelvic organ prolapse compared with control subjects. Therefore, these data suggest that the proper degradation, synthesis, and regeneration of elastic fibres are essential for maintaining pelvic organ support. A recent study by Moon et al., evaluated the alteration of elastin metabolism in women with pelvic organ prolapse in a prospective case-control study: their results showed that expression of neutrophil elastase and matrix metalloproteinase-2 mRNA was higher in women with than in those without POP. Childbirth is an important risk factor for POP, not only for the mechanical trauma that the pelvic floor is submitted to: inflammatory pathways are activated during the complex process of tissue healing after birth trauma.

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Integrity of the pelvic innervation is essential for normal pelvic function. The changes in neurophysiological parameters seen after childbirth were interpreted to reflect neuromuscular injury caused by forces exerted on the sacral plexus, pudendal nerves, and pelvic floor muscles. Abnormal findings have also been found in women with prolapse or stress incontinence. Histologically, there were smaller and fewer nerve bundles in women with posterior vaginal wall prolapse compared with women without prolapse. It has been demonstrated that the density of peptidecontaining nerves in the periurethral tissue and in the levator ani muscle in women with prolapse is reduced. The pudendal nerve innervates the voluntary urethral and anal sphincters, but it does not innervate the levator ani muscles, which receive their own nerve supply from the sacral plexus. Therefore, there is currently no clear evidence whether the neurological damage is responsible, together with the mechanical damage of stretching, for the visible levator defects. Information from electrodiagnostic studies has demonstrated that birth causes changes in mean motor unit duration after vaginal birth and changes in pudendal nerve conduction patterns. Prolongation of the pudendal nerve terminal motor latency (PNTML) is thought to be a result of pudendal nerve damage during vaginal delivery. Although it has not been proved in studies, it is reasonable to assume that periods of pain and discomfort after childbirth (e.g., perineal tears and episiotomy) and especially pain related to attempted PFM contraction could lead to a temporary nonactivation of the PFM. This could be the origin of disturbances in behavioural patterns, which would need to be readjusted. In combination with a particularly vulnerable pelvic floor neural control,

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whose complexity only evolved phylogenetically after the attainment of the upright stance, such a temporary disturbance of neural control after childbirth may persist, although the pelvic tear(s) resulting from vaginal delivery would have fully recovered. Therefore, the effects of vaginal delivery on pelvic floor nerves are still controversial. While it seems logical that vaginal delivery causes some neuromuscular injury which would predictable to the development of pelvic organ dysfunction, many details are uncertain.

3. PREGNANCY AND PELVIC FLOOR MUSCLE REMODELLING Several of the changes occurring prior to delivery are in all likelihood normal physiological changes and may be secondary to hormone-induced collagen alterations. Hormonal alterations are essential to prepare the body and to adjust the musculature and connective tissue for vaginal birth. The high progesterone levels during pregnancy influence the pelvic floor structures: progesterone has smooth muscle-relaxing and oestrogen-antagonising effects, reducing the tone in the ureters, bladder and urethra. The connective tissue of the rectus sheath fascia and the obturator fascia could be stretched to greater length during pregnancy, but it is also much weaker. In some women, these changes may be irreversible and further stretching beyond physiological limits may result in permanent dysfunction.

FIgURE 11: Cross-section of female pelvis in which nerve emerges from S2, S3, and S4 extends between the uterus and the anus and into labium minora, labium majora and the clitoris

Pregnancy confers remarkable changes to the vaginal wall that include increased distensibility, decreased stiffness and maximal stress. Elastinopathy alone is insufficient to

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cause significant changes in these properties, but prolapse confers additional alterations in distensibility and stiffness that are similar to those changes that have been observed in pregnancy. These changes may contribute to the poor durability of many restorative surgical procedures for prolapse.

is causal and which of them is associated (e.g., forceps delivery is used when there has been a prolonged second stage of labour, and both of these factors increase in largesized infants). The role of childbirth in causing damage to the levator ani muscle (LAM), which is associated with both vaginal

delivery and with pelvic organ prolapse, is probably the mediating mechanism in these injuries. Recent investigations using techniques such as magnetic resonance imaging (MRI) and three-four dimensional ultrasound have focused on the morphology of the levator ani complex and its integrity after delivery.

4. CHILDBIRTH Undoubtedly, vaginal delivery constitutes a traumatic event for the pelvic floor: it may affect the pelvic nerves, the pubococcigeus-puborectalis muscle complex, the pelvic fascial structures or the anal sphincter. However, all women sustain trauma to their pelvic floor during vaginal birth, but only some experience long term injury. In the anterior compartment, childbirth may result in disruption of the ‘endopelvic fascia’, in particular of paraurethral and paravaginal structures. Analogous to increased bladder descent after childbirth, there is a highly significant increase in caudal displacement of the rectal ampulla after childbirth. The rectovaginal septum and Denonviller’s fascia are the connective structures involved in the posterior compartment damage that appears as a rectocele. It has recently been shown that vaginal childbirth also results in an increased prevalence of true rectocele, i.e. presumpted defects of the rectovaginal septum. Such defects are strongly associated with symptoms of pelvic organ prolapse. Specific features of injury during vaginal birth influence whether a woman develops prolapse later in life. Several factors, that can be grouped together as descriptors of difficult vaginal delivery, are associated with increased occurrence of prolapse: forceps delivery, a prolonged second stage of labour, and large infant birth weight. Unfortunately, because of the overlapping nature of these different factors, it is difficult to determine which of them

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FIgURE 12: Sectional views comparing the organ’s positions in nonpregnant and pregnant women.

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FIgURE 13 &14: Levator ani defect early postpartum in a patient had spontaneous vaginal delivery (acquisition screen gE Voluson-e ÂŽ System). A. In the multiplanar mode, the axial plane (lower left) and the rendered image (lower right) show an unilateral levator discontinuity on the right side of pubococcigeal-puborectalis muscle. B. Eight slices obtained with TUI in coronal-C plane in the same patients: the discontinuity (arrow) is demonstrated in at least three consecutive slices at and above the plane of minimal hiatal dimension (frames *,-1,-2,-3). From Albrich et al, BJOG 2011.

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5. OBSTETRIC AND MATERNAL FACTORS Increasing vaginal parity is the strongest risk factor for pelvic organ prolapse in women younger than 60 years. Study showed that the risk of pelvic organ prolapse rose with increasing parity. Women who had undergone one or more vaginal deliveries had a significantly greater risk of developing symptomatic pelvic organ prolapse than did those who had only caesarean sections, after adjusting for age, parity, and obesity. Other obstetric factors that have been associated with an increased risk of pelvic organ prolapse, albeit less consistently, are high infant birth weight, vaginal delivery of a macrosomic infant, prolonged second stage of labour, and age <25 years at first delivery. Studies alo showing younger age (25 versus 28 years of age) as well as older age (more than 30 years) at first delivery as a risk factor for the development of pelvic organ prolapse. Despite the strong relationship between obstetric factors and pelvic organ prolapse, most cases of symptomatic cases arise a long time after vaginal childbirth, and most women who bear children do not have symptomatic prolapse.

The female lower urinary tract is a target organ for the action of the two sex steroid hormones, oestrogen and progesterone. Steroidal hormones exert their effect on tissue through an interaction with specific intracellular receptors. Hormone receptor affinity may be at the root of the differences between women with pelvic floor diseases and normal controls. Progesterone receptors have been found to have greater expression in women with POP than in women without POP. Several polymorphisms are present in the progesterone receptor gene that can alter its expression.

7. OBESITY Increasing body-mass index also seems to have a role in the development of pelvic organ prolapse. An high BMI increases the risk of prolapse and specifically for progressive rectoceles. Increased waist circumference was associated with more pelvic organ prolapse in some studies. Women who are overweight and obese are at high risk of developing pelvic organ prolapse.

8. CONSTIPATION 6. HORMONES As age has been clearly shown to affect the prevalence and progression of POP, it is intuitive to believe that declining sex hormone levels observed with ageing may contribute to biochemical changes observed within tissue. However, several researchers studying hormonal status and prolapse have failed to find an association between oestrogen status and prolapse.

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Repetitive straining, such as that seen in patients with chronic constipation or workers whose jobs entail heavy lifting, has also been associated with pelvic organ prolapse. Spence-Jones et al. reported that straining at stool as a young adult was more typical in women with prolapse than in those without the disorder.

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Medical Diagnosis

Initial Assessment of Urinary Incontinence Individuals with UI can be identified through routine screening, or the patient may initiate discussion about incontinence problems. The initial assessment of UI should help the health care provider understand the type of incontinence, while identifying potentially modifiable contributing factors. Most primary treatment options, such as lifestyle modifications and behavioral treatments, do not vary by type of UI. However, it is important to determine the type of UI since some treatment options do vary according to incontinence. Equally important, establishing the type of UI will lead the health care provider to a list of possible underlying causes, or differential diagnosis of the urinary symptoms. Most causes of UI are non-life threatening, however symptoms of incontinence may also herald life-threatening or more severe disease such as bladder cancer when associated with haematuria; when more specialised testing will be required immediately. Finally, assessing the level or bother and desire for intervention from information obtained from the patient or caregiver is essential for guiding the nature of the treatmentplan.

A. HISTORY The general history should include questions relevant to precipitating and aggravating factors of urinary loss, time of onset and duration of symptoms, and degree of bother. Acute. symptoms can be defined by documenting patterns of fluid intake and output, acute infection, recent surgery or trauma. Chronic symptoms should prompt queries about a history of congenital abnormalities, neurological disease, relevant surgery or general health. Information should be obtained concerning medications with known or possible

effects on the lower urinary tract. The general history in women should also include assessment of menstrual, obstetric, sexual and bowel function. The reader is referred to the report on Epidemiology for specific risk factors to be considered during the medical history, and to the report on Frail Elderly for a list of co-morbidities and medications that can cause or contribute to UI.

B.BLADDER DIARIES The micturition time chart records the timing of voids in 24 hours; the frequency-volume chart additionally includes the urinary volume voided, and the bladder diary which may include incontinence episodes, pad usage, fluid intake, and the degree of urgency and incontinence. Documentation of the frequency of an individual’s lower urinary tract symptoms and the voided volume for at least 24 hours can be extremely helpful both in the initial assessment urinary incontinence, may be therapeutic as it provides insight into bladder behaviour, can be utilised to monitor the effectiveness of treatment during follow-up. The frequency-volume chart is used to describe a chart that records the time of each micturition and the volume voided for at least 24 hours, although 2-3 days of recording generally provide more useful clinical data. The bladder diary refers to a more comprehensive instrument that may include the individual’s daily type and volume of fluid intake, pad usage, incontinence episodes, and the degree of incontinence. Episodes of urgency and sensation might also be recorded, as might be the activities performed during or immediately preceding the involuntary loss of urine. •

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KEY qUESTIONS IN THE INITIAL ASSESSMENT OF URINARY INCONTINENCE

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STRESS URINARY INCONTINENCE: Do you sometimes leak urine when you cough or sneeze or when you exert yourself, such as when lifting a heavy object?

•

URGENCY URINARY INCONTINENCE: Do you sometimes feel an urge to void that is so sudden and strong that you sometimes don’t make it to the bathroom on time?

• • •

How long have the symptoms been present? How often do you leak urine and how much do you leak? Circumstances surrounding urine leakage e.g. sexual activity, change in position, provocation by running water or ‘key in the latch’? Nocturnal symptoms or enuresis? Association with other lower urinary tract or pelvic organ prolapse symptoms? Impact on personal and social life? Amount and type of fluid intake e.g. coffee, tea, alcohol? Episodes of urinary tract infection or haematuria? Previous treatment attempts (successful and unsuccessful)? Mobility problems? Cognitive deficits? Neurological deficits? Problems with constipation or faecal incontinence? Number of pregnancies and the type of delivery, with complications? Previous prostate, pelvic or abdominal surgeries or radiation treatment? Coexisting diseases (diabetes, heart disease, neurological impairment)? Types of medications consumed?

• • • • • • • • • • • • • • •

A bladder diary is recommended in order to document and communicate both objective information and to objectify observations by the patient during the diary period. Although never completely diagnostic, diary patterns may characterise normal and abnormal

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states. The ideal duration of a diary is not clear. A 1-day frequency volume chart which includes the first morning void the following day is a reasonable tool to gain insight into voiding habits during normal daily routine. A 3-day FVC or diary is recommended for accurate assessment of LUTS and for confirming a consistent clinical pattern in day-to-day practice. For atypical clinical patterns or clinical research, a 7-day diary may be recommended.

C. URINALYSIS The urinalysis is a fundamental test that should be performed in all urological patients. Although in many instances a simple dipstick urinalysis provides the necessary information, a complete urinalysis includes both chemical and microscopic analysis.

FIgURE 1: A sample of bladder diary format.

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Urine dipstick testing, as opposed to microscopy, is satisfactory for urinalysis in the diagnosis of acute uncomplicated cystitis. In relation to urinary incontinence, dipstick urinalysis is not a diagnostic test, but a screening test, utilised to detect haematuria, glucosuria, pyuria and bacteriuria. Haematuria can indicate important pathology such as urothelial carcinoma in situ, leading to lower urinary tract storage symptoms including incontinence. Glucosuria is relevant, as a potential indicator of diabetes mellitus. This can cause symptoms via several mechanisms including polyuria secondary to osmotic diuresis. Diabetic peripheral autonomic neuropathy affecting bladder innervation may be associated with impaired bladder emptying and chronic urinary infection The examiner should note that a patient does not generally demonstrate glucose into the urine until the blood sugar is >180 mg/dl. Consequently, a dipstick urinalysis may fail to reveal intermittently high sugars or mild diabetics. If diabetes is suspected, then a random or fasting blood

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sugar is preferred. In the evaluation of urinary incontinence and lower urinary tract symptoms, the value of urinalysis can be illustrated by the finding that 60% of women without detrusor overactivity will develop detrusor overactivity at the time of UTI. The importance of urinalysis in the basic assessment of patients with urinary incontinence and lower urinary tract symptoms is not dependent on gender, age or aetiology. Indeed, it has been recommended in the evaluation of geriatric patients including nursing home residents who are incontinent, in pre and postmenopausal women, and in older women reporting urinary incontinence. In the latter context, it has even been observed that clinically significant urine samples can even be obtained from disposable diapers in elderly incontinent women. The clinical relevance of asymptomatic bacteriuria (without pyuria) and pyuria (without bacteriuria) in the elderly is controversial, as eradication of bacteruria appeared to have no effect on the resolution of incontinence, and may not deserve any treatment.

patients with neurogenic bladder disease.Several studies have compared volumes measured with portable ultrasound scanners versus catheterisation and found portable scanners to be 85-94% accurate. Since PVR may vary, one measurement of PVR may not be sufficient. PVR should probably be measured several times to increase its reliability. Varying degrees of decreased bladder emptying or urinary retention may be a cause of LUTS that are associated with symptoms of decreased urinary storage. The decision to perform a PVR in disease specific sub-groups of incontinent patients should be based on an association of the condition with poor bladder emptying, whereas in individual patients this decision may be based on symptoms or physical findings. Residual urine determination by bladder scan is preferable to catheterisation due to the increased morbidity associated with instrumentation. Non-invasive ultrasound measurement of PVR is as accurate as measurement by catheterisation and is therefore the preferred method.

D. POST VOIDING RESIDUAL

EVALUATION OF THE FEMALE PATIENT The post voiding residual urine (PVR) is the volume of urine remaining in the bladder following a representative void. Both bladder outlet obstructionand low bladder contractility contribute to the development of PVR measurement can be accomplished within a few minutes of voiding either by catheterisation, or by calculation of bladder volume using a portable ultrasound scanner or formal ultrasonography. It is difficult to determine the value of post-void residual determination in the initial assessment of urinary incontinence since most studies producing data on PVR have not been in patients with UI. However, the populations studied have included women with UI, and incontinent

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1. ESTABLISHING THE TYPE OF URINARY INCONTINENCE IN WOMEN A. SIMPLE HISTORY QUESTIONS FOR WOMEN A meta-analysis was conducted by Holroyd-Leduc et al. using literature abstracted from 1960-2007 to determine the reliability of several questions for establishing the type of urinary incontinence in women. The reader is referred to the systematic review for a list of all studies included in the analysis for each type of incontinence. In summary, if a woman responds “yes” to

the question, “Do you lose urine during physical exertion, lifting, coughing, laughing or sneezing?” she is twice as likely to experience stress urinary incontinence. The question to diagnose urgency urinary incontinence is even more reliable. A woman who responds “yes” when asked “Do you ever experience such a strong and sudden urge to void that you leak before reaching the toilet?” is four times as likely to have urgency incontinence. Positive answers to both these questions strongly suggest mixed urinary incontinence. According to the meta-analysis by Holroyd-Leduc et al., comprehensive assessment including the history, physical exam and targeted investigation, still holds the most value for diagnosing stress urinary incontinence and urgency urinary incontinence in female patients.

B. ACCURACY OF THE GENERAL PHYSICAL ExAMINATION IN WOMEN No studies were found that addressed the accuracy of components of the general physical examination for diagnosing the type of urinary incontinence in women. Nonetheless, it is recommended that a thorough physical examination, including but not restricted to the abdomen, rectum, gynaecological/ pelvic regions and neurological system be performed for ruling out certain risk factors as well as significant associated or underlying pathology, such as significant prolapse, obstruction, neurological disease and malignancy. Height and weight should be recorded so that the body mass index can be calculated.

1. ABDOMINAL ExAMINATION Observation of the abdomen may yield evidence of scars from previous surgeries or increased abdominal striae. Increased abdominal striae may be found in association

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with other markers of abnormal collagen metabolism, and are more likely in patients with prolapse and stress incontinence. An attempt should be made to palpate the kidneys, particularly where a voiding dysfunction or neurogenic bladder dysfunction are suspected. A distended bladder may be identified by abdominal palpation or by suprapubic percussion.

2. NEUROLOGICAL ExAMINATION A neurological examination should be performed with particular attention to the sacral neuronal pathways. Saddle anesthesia will occur with lesions affecting S2-S4. Assessment of gait, abduction and dorsiflexion of the toes (S3) and sensory innervation to the labia minora (L1-L2), sole and lateral aspect of the foot (S1), posterior aspects of the thigh (S2), and cutaneous sacral reflexes (bulbocavernosus and anal reflexes) are additional features of the neurological exam that may be assessed. A rectal examination will provide a subjective assessment of resting and voluntary anal tone (S2-S4). For patients with possible neurogenic lower urinary tract dysfunction, a more extensive neurological examination is required. In the elderly, full cognitive and mobility assessments are also recommended. An evaluation of hand dexterity should be performed when self-catheterisation is being considered as a treatment option for incontinence associated with chronic urinary retention.

Presently there are few scientific data documenting the parameters of a normal pelvic examination in women of various ages and with various obstetrical histories. The components of the examination have not been universally agreed upon. It seems intuitive that the examination should include an assessment of: • The bony architecture, • Pelvic floor muscle tone and muscle mass, • Connective tissue support, • the epithelial lining of the vagina, • The size,location, and mobility of the uterus, and Innervation of the pelvic floor structures. It is important to establish the oestrogen status as oestrogen receptors are present within the lower urinary tract, and have been shown to influence cell proliferation. Women with oestrogen deficiency may complain of urgency and frequency and recurrent urinary tract infections may develop because of lossof urethral mucosal coaptation. In women of reproductive age, symptoms may vary with the menstrual cycle.

4. SPECIALISED TESTS FOR DIAGNOSIS UI IN WOMEN Three special manoeuvres can be performed during the initial assessment of urinary incontinence: the stress test, the Q-tip test, and the pad test. The post-void residual urine volume and use of a urinalysis in the initial assessment of women with urinary incontinence are also discussed.

3. GYNAECOLOGICAL ExAMINATION A. STRESS TEST Gynaecological examination should include inspection of the perineal and genital regions as well as a digital vaginal examination to evaluate pelvic floor muscle strength. Inspection of the vulva and perineum allows a description of the skin and the presence of any abnormal anatomical features, features of prolapse.

The stress test involves observation for urine loss with coughing or Valsalva maneouvre.

leakage on coughing or during a Valsalvamaneouver is considered a positive test, and a sign of stress urinary incontinence. The results obtained during a filled–bladder test are more accurate than the results obtained during an emptybladder test. Doing a more complicated stress test that uses a step-wise approach to bladder filling and combines supine and standing testing does not further improve diagnostic accuracy for stress urinary incontinence. The stress test performed with coughing appears to be a reliable test. Reliability data are not available for tests performed using the Valsalva maneouvre. The cough stress test demonstrated superiority over the pad test with a sensitivity, specificity, and positive and negative predictive values of 90%, 80%, 98%, and 44% for diagnosing stress urinary incontinence.

B. Q-TIP TEST The Q-tip test has traditionally been used to assess mobility of the urethro-vesical junction. The test involves placement of a lubricated cotton swab or Q-tip in the urethra to the level of the bladder neck while the woman is in the lithotomy position. Change in the axis of the free end of the swab is then measured while the woman performs a Valsalva maneouvre. The free end should remain horizontal if no anatomical defect is present. If the free end moves above the horizontal, urethral hypermobility is suspected, this can occur in patients with stress urinary incontinence. Results of the analysis suggested that a positive Q-tip test does not accurately predict the diagnosis of stress urinary incontinence in women. More specialised testing with pelvic floor ultrasound and other imaging techniques appears to be gradually replacing the Q-tip test for a more advanced assessment of bladder neck hypermobility.

This procedure can be performed while the patient is in the lithotomy position or standing. Instantaneous urine

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C. PAD TEST A pad test involves the continuous wearing of continence pads for a set period of time. The objective of pad testing is to quantify the volume of urine lost by weighing a perineal pad before and after some type of leakage provocation. This test has also been used in an attempt to distinguish continent from incontinent women, rather than for distinguishing the type of urinary incontinence. Pad tests can be divided into shortterm tests, usually performed under standardised office conditions, and long-term tests, usually performed at home for 24–48 hours. Pad tests are generally performed with a full bladder or with a fixed known volume of saline instilled into the bladder before beginning the series of exercises. There is wide variation in the pad weight gain in incontinent women participating in clinical trials. Although some studies have found high test-retest correlations in pad tests, other studies have reported low inter-subject and intra-subject reliability. The correlation coefficient between total leakage during two long-term tests appears to exceed of standard 1hour tests.

PELVIC ASSESSMENT: PELVIC FLOOR STRENGTH AND PELVIC ORGAN PROLAPSE A. ASSESSMENT OF PELVIC FLOOR MUSCLE STRENGTH Voluntary pelvic floor muscle contraction should be evaluated during the initial assessment by vaginal digital palpation. Any or all of the following factors can be assessed including muscle strength (static and dynamic), voluntary muscle relaxation (absent, partial, complete), muscular endurance (ability to sustain maximal or near maximal force), repeatability (the number of times a contraction to maximal or near maximal force can be performed), duration, coordination, and displacement. If

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possible, it is desirable to document findings for each side of the pelvic floor separately to allow for any unilateral defects and asymmetry. The ICS report on the standardisation of terminology of pelvic floor muscle function and dysfunction provides a fuller description of the assessment of pelvic floor muscle function including the following: •

•

Normal pelvic floor muscles: Pelvic floor muscles which can voluntarily and involuntarily contract and relax. Overactive pelvic floor muscles: Pelvic floor muscles which do not relax, or may even contract when relaxation is functionally needed, for example, during micturition or defaecation. Underactive pelvic floor muscles: Pelvic floor muscles which cannot voluntarily contract when this is appropriate. Non-functioning pelvic floor muscles: Pelvic floor muscles where there is no action palpable.

All examinations for pelvic organ prolapse should be performed with the woman’s bladder empty (and if possible an empty rectum). The patient should be examined in the position that best demonstrates prolapse according to the patient. The degree of prolapse may be worse later in the day than it is earlier in the day. The hymen always remains the fixed point of reference for prolapse description. Pelvic organ prolapse is defined as the descent of one or more of the anterior vaginal wall, posterior vaginal wall, the uterus (cervix), or the apex of the vagina (vaginal vault or cuff scar after hysterectomy) at the level of the hymen or beyond. Most clinicians are generally comfortable with the terms cystocele, rectocele, vaginal vault prolapse, and enterocele, which have historically been used interchangeably with the terms anterior, posterior or apical vaginall prolapse. 1. 2. 3.

B. ASSESSMENT OF PELVIC PROLAPSE

Urinary incontinence and pelvic organ prolapse are separate clinical entities that often coexist. Significant protrusions of the vagina can obstruct voiding and defaecation. It is important to assess pelvic organ prolapse in a woman with incontinence, because repair of one pelvic support defect without repair of concurrent asymptomatic pelvic support defects can predispose to accentuation of unrepaired defects and new symptoms. The term stress incontinence on prolapse reduction (occult or latent stress incontinence) was recently introduced to describe the development of stress urinary incontinence after of reduction of co-existent prolapse by surgical repair or pessary insertion.

Stage 0: No prolapse is demonstrated. Stage I: Most distal portion of the prolapse is more than1 cm above the level of the hymen. Stage II: Most distal portion of the prolapse is 1 cm or less proximal to or distal to the plane of the hymen. Stage III: The most distal portion of the prolapse is more than 1 cm below the plane of the hymen. Stage IV: Complete eversion of the total length of the lower genital tract is demonstrated.

PELVIC ORGAN PROLAPSE QUANTIFICATION (POP-Q) Different systems have been used to describe pelvic organ prolapse (POP), however lack objectivity and validation. The need for an objective, site-specific method of quantifying and staging POP lead to the design and validation of the POP-Q system. The POP-Q records defects relative to the hymenal remnants in centimetre gradients. These measurements are further staged according to the distal-most defect.

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Figure 2 (a & b): Six sites (Aa, Ba, C, D, Bp, Ap), genital hiatus (gh), perineal body (pb) and total vaginal length (tvl) used for POP-Q and the three by three grid for recording quantitative description of pelvic organ support.

Figure 3 (a & b): Shows prolapse staging by the position of the leading edge of the cervix.

Anterior vaginal wall prolapse is defined as descent of the anterior vagina so that the urethra-vesical junction (a point 3cm proximal to the external urinary meatus) or any anterior point proximal to this is less than 3cm above the plane of the hymen.

vaginal wall. Anterolateral protrusion into the vaginal canal may represent unilateral or bilateral detachment of the pubocervical fascia along the anterolateral vaginal sulcus from its attachment to the arcustendineus fascia pelvis (white line). Central protrusions of the anterior vaginal wall may represent defects in the pubocervical fascia below the trigone and base of the bladder. Advanced prolapse of the upper anterior vaginal wall may obstruct a well-supported bladder neck.

On vaginal examination, there may be loss of the transverse crease between the lower and middle thirds of the anterior vaginal wall and descent of the anterior

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Prolapse of the apical segment of the vagina is defined as any descent of the vaginal cuff scar (after hysterectomy) or cervix, below a point that is 2cm less than the total vaginal length above the plane of the hymen. Descent of the cervix or of the vaginal apex following hysterectomy, below the level of the ischial spines is evidence of a defective vaginal suspension mechanism. Posterior vaginal wall prolapse is defined as any descent of the posterior vaginal wall so that a midline point on the posterior vaginal wall 3cm above the level of the hymen or any posterior point proximal to this, less than 3cm above the plane of the hymen. The well-supported posterior vaginal wall should not cross the longitudinal axis of the vaginal canal. Posterior protrusions into the vaginal canal are most commonly caused by defects in the recto-vaginal fascia allowing protrusions of the small bowel (enterocoele) and/or rectum (rectocele). Normally, the anterior vaginal wall lies upon the posterior vaginal wall. Therefore, protrusions of the posterior vaginal wall can affect the function of the urethra and blad der that lie upon the anterior vaginal wall. For example, distal loss of support in the posterior segment may result in a bulge that compresses the urethra and affects voiding. The system has not been widely adopted in clinical practice particularly by non-urogynaecologists; owing somewhat to difficulty in learning the assessment. Despite the difficulties highlighted with the adoption of the POP-Q, reproducibility and reliability of the assessment system have been demonstrated. Sexual function in women with prolapse before and after treatment has been investigated in a number of studies, using the POP-Q as an objective measure of prolapse. Figure 4: Pelvic structural supports.

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Urodynamic Testinge WHAT IS URODYNAMICS? Urodynamics are a means of evaluating the pressureflow relationship between the bladder and the urethra for the purpose of defining the functional status of the lower urinary tract. The ultimate goal of urodynamics is to aid in the correct diagnosis of lower urinary tract dusfunction based upon its pathophysiology. Urodynamic studies should assess both the filling and storage phase, as well as the voiding phase of bladder and urethral function. In addition, provocative tests can be added to try to recreate symptoms and assess pertinent characteristics of urinary leakage. The term ‘Urodynamic studies’ (UDS) was defined by the International Continence Society (ICS) in 1988 as to ‘involve the assessment of the function and dysfunction of the urinary tract by any appropriate method’. The conventional experts view, endorsed in the previous standardisations and consultations, is that urodynamics is a series of more or less agreed-upon clinical tests, such as flow studies, filling cystometry, pressure-flow studies and urethral (closure) -function measurements. These measurements can be combined with simultaneous electromyography (EMG) recording and/or with imaging by either xrays or ultrasound. Also implicitly agreed upon is that urodynamics is the way to determine, in an objective manner, which dysfunction causes people to have lower urinary tract symptoms (LUTS) and or signs of UI. The attempt to gain understanding of an individual’s lower urinary tract (LUT) functioning, on the basis of test observations, in relation to what is known about normal, or expected abnormal, physiology, is what constitutes urodynamics.

Urodynamic studies can answer questions such as: ‘What is the cause, or causes of increased voiding frequency in this patient’ as well as: ‘Why does this patient have urinary incontinence?’ These questions not only can be posed for individual patients but also can form part of clinical or laboratory research.

including post voiding features, (residual urine, or after contraction) should be tested, analysed, and documented, even if only storage or voiding signs or symptoms have been expressed by the patient.

WHAT SHOULD BE THE ROLE OF URODYNAMIC STUDIES IN CLINICAL PRACTICE?

A. To identify all factors that contribute to the LUT symptoms (e.g. urinary incontinence) and assess their relative importance;

Urodynamic testing should be applied to objectively measure and document the entire lower urinary tract function and or dysfunction when it can have therapeutic consequences, bearing the individual patients’ symptoms, and all other relevant circumstances, in mind. Urodynamic testing can show signs such as (significant) residual urine or underactive detrusor which is often not specifically noticed by the patient, even when neurologically unaffected. Especially, but not uniquely in patients with relevant neurological abnormalities, upper urinary tract signs (dilatation) can exist or develop without any (new) symptom. Furthermore the patient can present with symptoms such as, ‘urinary frequency’, ‘nocturia’ or ‘recurrent urinary tract infections’, which are difficult or impossible to reproduce in the usual UDS- laboratory. The importance of urodynamic testing is thus to reproduce the dysfunction of the lower urinary tract and to determine the cause of the signs and or symptoms of urinary tract functional disease. The implicit consequence of this is also that ideally at least one complete filling (storage) and pressureflow (voiding) cycle, that adequately represents the patients problem (e.g. with regard to volumes)

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The role of urodynamic studies in broad clinical perspective can be:

B. To obtain information about all other aspects of LUT function or dysfunction whether or not expressed as a symptom or recognisable as a sign; C. To allow a prediction of the possible consequences of LUT dysfunction for the upper urinary tract; D. To allow a prediction of the outcome, including undesirable side effects, of a contemplated treatment; E. To confirm the effects of intervention or understand the mode of action of a particular type of treatment for a LUT dysfunction; especially a new and or experimental (pre-routine) one; F. To understand the reasons for failure of previous treatments for urinary incontinence, or for LUT dysfunction in general (after unsatisfactory treatment).

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THE TESTS OF CONVENTIONAL URODYNAMICS 1. UROFLOWMETRY 2. FILLING CYTOMETRY This is the non-invasive measurement of urine flow rate. The patient voids into a flow meter in private ideally with a normal to strong (but not uncomfortable) desire to empty their bladder. Urine flow rate is continuously measured and displayed graphically. Various parameters from the trace are automatically calculated and printed out together with the trace. After control for artefacts in automated calculations, the maximum flow rate, the volume voided and shape of the curve are usually the principal determinants of whether or not the patient is emptying their bladder in a normal way. If an abnormal voiding is obtained, it is good clinical practice to repeat the assessment to check that the result is reproduced, or not.

This is the measurement of the pressure inside the bladder to assess its storage capabilities. It is an invasive test which involves a catheter being placed into the bladder, usually transurethrally, and another catheter being placed rectally or vaginally (or sometimes through an abdominal stoma) to measure abdominal pressure. Subtracting the abdominal pressure, indirectly measured via vagina, rectum or stoma, from the pressure measured inside the bladder (intravesical pressure) gives a representation of pressure changes due to the action of the detrusor smooth muscle or due to the (lack of) viscoelasticity of the bladder to volume change, measured and expressed as bladder compliance.

Several factors, such as patient apprehension, can give an abnormal recording in patients who have no voiding difficulty. Asking the patient about what she or he thinks about the voiding; whether the voiding (including the volume) was an adequate representation of the real voiding (compare with voiding diary) and if necessary further explanation is absolutely relevant and must be regarded as standard (good urodynamic) practice. Repeating the assessment can eradicate the effect of such confounding factors and will confirm or refute the validity of earlier assessments.

During this assessment, the bladder is usually filled with normal saline solution, or x-ray contrast solution in the case of videourodynamics, either through a separate catheter placed transurethrally or through the filling channel of a dual lumen catheter if such is used to measure intravesical pressure. Usually the filling rate is much faster than physiological bladder filling so that, depending on the urodynamic capacity (and related to information from the voiding diary), the bladder is filled in about10 min.

Figure 5: UROFLOWMETRY methods and graph

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The intravesical and abdominal pressure and the calculated detrusor pressure are monitored as the bladder is filled and before the patient has been given â&#x20AC;&#x2DC;permission to voidâ&#x20AC;&#x2122;. The storage ability of the bladder is assessed in terms of the volumes required to elicit various sensations from the patient, its capacity, its compliance (passive muscle adaptation to volume stretch and detrusor muscle relaxation) as distinct from the absence of (phasic detrusor

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pressure rises. The filling (storage) phase of cystometry is the method of demonstrating urodynamic stress incontinence (USI) by means of coughing or straining, on request of the clinician. Good urodynamic practice demands that abdominal pressure, and intravesical pressure, as well as subtracted detrusor pressure are evaluated to diagnose urinary bladder storage function.

3. PRESSURE-FLOW STUDIES (VOIDING CYSTOMETRY) This is a measurement of the mechanics of micturition. When the filling (storage) phase of cystometry is complete, the patient is given ‘permission to void’ and will empty their bladder on a flow meter whilst intravesical, abdominal and detrusor pressures are being recorded. The simultaneous measurement of flow rate and pressure enables voiding to be assessed and pressure flow analysis can help determine whether slow urine stream is due to bladder outlet obstruction or to an underactive detrusor contraction or to a combination of those.

Figure 6: Video Cytometry process.

the bladder (and or abdomen). The maximum pressure measured in the urethra is assumed to give an indication of the urethral closure function.

5. ABDOMINAL LEAK POINT PRESSURE This is another concept to estimate the urethra’s (bladder outlet’s) ability to contain urine within the bladder. Intra -abdominal pressure is measured whilst the patient is asked to increase their abdominal pressure by valsalva or by coughing. The abdominal pressure required to produce leakage from the bladder gives an indication of the closure function of the urethra since higher closure pressures (‘better function’) require higher abdominal pressure increments to cause leakage.

TECHNOLOGICAL INNOVATIONS IN URODYNAMICS

4. URETHRAL PRESSURE PROFILOMETRY

1. AIR-CHANGED CATHETERS FOR PRESSURE MEASUREMENT

This is a test to estimate the urethra and the surrounding (muscle and other-) structures’ ability to maintain the bladder outlet closed allowing the body system to contain urine within the bladder. By concept, a catheter is placed transurethrally into the bladder and then withdrawn along the urethra (usually by a mechanical puller at a constant rate). The pressure along the length of the urethra is measured and interpreted relative to the pressure inside

Single-use, air-charged catheters have been developed and used for intravesical, intra-urethral and abdominal pressure measurement in urodynamics. However, Aircharged catheters have several practical advantages over fluid-filled pressure lines because there is no hydrostatic pressure effect to account for, so that there is no need to position external sensors at the level of the symphysis pubis. There is also no need to flush the system through

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to exclude air; a process that is essential in a fluidfilled pressure-sensing environment. Also, there are no fluctuation artefacts in pressure produced when the patients move. However, although air-charged catheters may make urodynamics easier to set up, the conduct and interpretation of a urodynamic study still requires an experienced, appropriately trained practitioner. Air-charged catheters may provide an acceptable alternative to other techniques for measuring the pressure closing the female urethra. But there have been no studies to show whether aircharged catheters provide a superior alternative to fluid-filled lines for measuring intravesical and intra-abdominal pressure in urodynamics.

2. OBJECTIVE ASSESSMENT OF BLADDER SENSATION Bladder sensation during urodynamics is usually recorded by the simple expedient of asking the patient to inform the investigator when they experience different sensations. This is an ICS standardised, but subjective measurement which can be confounded by the investigators inadvertently distracting the patient whilst bladder filling is being carried out. Bladder (filling) sensation has received increasing attention since (urinary) urgency and ‘early’ filling sensation are clinically important and some treatments are believed to or initiated to influence LUT sensation. A patient-activated, keypad ‘urge score’ device to measure sensations during bladder filling was introduced to enable patient perceptions of bladder filling and the successive stages of increasing bladder sensation to be recorded without prompting or intervention by the investigator. The device provided reliable and repeatable measures of different bladder sensations.

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relevance in the diagnosis of (female) urinary incontinence.

3. URETHRAL RETRO-RESISTANCE PRESSURE In the measurement of urethral retro-resistance pressure (URP), a small meatal plug is inserted just inside the female urethra and saline is pumped into the urethra until the pressure reaches the value sufficient to overcome the resistance offered by the urethra when the fluid flows into the bladder. The pressure required to achieve and maintain an open bladder outlet is taken to be a measure of urethral closure function. But after positive first reports of urethral retro-resistance pressure measurements it was shown that this measurement does not give any better information about urethral closure function than the urethral pressure profile or valsalva leak point pressure. Even urethral retroresistance pressure measurements are not used in clinical routine as an alternative to (cystometry or) urethral pressure measurements made with conventional urodynamic equipment to diagnose the type of (female) urinary incontinence.

4. URETHRAL PRESSURE REFLECTOMETRY

5. ULTRASOUND IMAGING Imaging and ultrasound in relation to UI will be discussed in a separate chapter. We will only give a short summary of ultrasound in relation with urodynamic observations. The measurement of detrusor wall thickness has been used in a number of studies as a screening test for DO or BOO with a variety of measurement techniques using transvaginal, transabdominal or transperineal ultrasound. Different protocols were used and measured different parts of the bladder for example the dome, the trigone or the anterior bladder wall. This has resulted in contradictory data. Some data showed a smaller bladder capacity in overactive bladder (OAB) wet or DO, and an association between increased detrusor wall thickness and DO on urodynamic testing. Also, observations of an association of ultrasound detrusor wall thickness and BOO have been reported. Most researchers conclude that overlap of the results and the relatively low predictive value should be improved before bladder wall thickness is used in clinical practice.

In 2005, Klarskov et al reported on an in vitro study of pressure reflectometry for the simultaneous measurement of cross-sectional area and pressure in a collapsible biological tube and subsequently the technique of urethral pressure reflectometry (UPR), to assess the female urethra, was presented in 2007. The team postulated that these parameters had the potential to provide more physiological information about the urethra than could be obtained from conventional urethral studies. Preclinical measurements of urethral pressure reflectometry opening pressure and cross sectional area (‘dynamics’) have provided some insight into urethral closure function and dynamics, but, as yet have no clinical

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Imaging, Neurophysiological Testing and Other Tests IMAGING IN URINARY INCONTINENCE AND PELVIC FLOOR DYSFUNCTION I. IMAGING OF THE UPPER URINARY TRACT Generally speaking, there is no need for upper tract imaging in patients with UI unless any of the previously described conditions is suspected or diagnosed. The objectives of UUT in the incontinent patient are as follows: •

•

Evaluation of the upper urinary tract when the presence of an ectopic ureter or ureterovaginal fistula are suspected. Evaluation of the kidneys whenever UI is related to bladder dysfunction with high storage pressures (e.g. in neurogenic voiding dysfunction, chronic retention with overflow or low compliance bladders). Exclusion of hydronephrosis in cases of UI associated with severe uterine prolapse.

TECHNIqUES Upper tract imaging modalities include intra-venous urogram (IVU), ultrasound sonography (USS), computerised tomography (CT scan), magnetic resonance imaging (MRI), and isotope scanning. The choice of the imaging modality also depends on availability, expertise, and local management policies. Generally speaking, low cost and low risk techniques such as USS are preferred. Unless otherwise described, the following considerations regarding the different imaging modalities are based on expert opinion.

A. ULTRASONOGRAPHY

C. COMPUTERISED TOMOGRAPHY

USS is the gold standard technique for primary imaging of the upper urinary tract because of the relatively low cost of the equipment and the examination, its wide availability, the lack of any exposure to ionising radiation. Renal USS is independent on kidney function and provides a good evaluation of kidney morphology. Concomitant renal disorders such as urinary lithiasis and neoplasms can also be diagnosed. In patients with LUTD, the detection of hydronephrosis is of importance and it can be related to either vesico-ureteral reflux or obstruction.

High quality information of the upper urinary tract anatomy can be obtained using multidetector helical CT scans and 3D reconstruction software. Differently from IVU which only acquires images in the antero-posterior or oblique CT acquires images in the axial plane. Pictures can then be reconstructed in 2D along any plane or in 3D whenever required. CT scan can be used irrespective of renal function when no iodinated contrast medium is used. Whenever hydronephrosis is present, urine can be used to delineate the collecting system reducing the need for contrast agents. In general, intravenous contrast medium is required to highlight specific anatomic characteristics. CT scan is often used after a first line evaluation with USS and it has replaced IVU almost entirely. Sev eral authors have reported the use of CT scan to detect ectopic ureter, in cases where the diagnosis is suspected, despite a normal IVU and ultrasound. In these cases the small size and poor function of the ectopic moiety make diagnosis difficult by IVU.

Whenever hydronephrosis is diagnosed on USS, other imaging modalities are often used to evaluate renal function, the degree of obstruction or vesico-ureteral reflux. USS is an ideal technique to follow the degree of hydronephrosis over time or the response to treatment.

B. INTRAVENOUS UROGRAPHY IVU is the original radiographic examination of the upper urinary tract which allows evaluation of upper urinary tract anatomy and function. A number of different conditions such as renal dysfunction, obstruction, congenital anomalies, fistula, stones and tumours may be detected. IVU is the appropriate first study in cases of extraurethral incontinence. When ectopic ureter is suspected (although this condition can also be responsible for urethral incontinence), delayed films and tomography are important because the renal unit or moiety associated with an ectopic ureter is often poorly functioning.

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D. MAGNETIC RESONANCE IMAGING MRI shares some of the advantages of CT over IVU in the evaluation of the upper urinary tracts. Furthermore acquisition can be performed along any plane and pictures can then be presented in a 2D or 3D fashion. The paramagnetic contrast medium is free of allergic reaction risk although its use in the upper urinary tract remains dependent upon renal function and concerns about its nephrotoxicity have been recently raised. The development of the uro-MRI technique has gained an increasing role for the technology in the evaluation of hydronephrosis and

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IMAGING OF THE LOWER URINARY TRACT urinary tract anomalies as an alternative to IVU.

E. ISOTOPES Isotopes are used primarily to examine morphological and functional characteristics of the upper urinary tract. Isotope scanning can be used to identify the location of a small kidney which is otherwise difficult to image with radiological techniques. Renography is used to examine the differential function of the two kidneys, to identify disorders of urine transit and to quantify obstruction of the upper urinary tract. There are many physiological factors and technical pitfalls that can influence the outcome including the choice of radionucleotide, timing of diuretic injection, state of hydration and diuresis, fullness or back pressure from the bladder, variable renal function and compliance of the collecting system. Diuresis renography with bladder drainage is recommended when obstructive uropathy is suspected

Imaging of the UUT is NOT indicated in theevaluation of non-neurogenic stress, urgency or mixed UI. Imaging of the UUT is indicated in cases of neurogenic UI with high risk of: •

• • •

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Renal damage (due to high detrusor pressure, e.g. myelodysplasia, spinal cord injury, and low compliance bladder). Chronic retention with UI. Untreated severe POP. Suspicion of extra-urethral UI by upper tract anomaly.

The use of imaging of the LUT in patients with UI dates back 40 years, particularly in female patients. The techniques have changed, over the decades from static to dynamic imaging, from qualitative to quantitative information. Although some of the techniques are now more than 50 years old their clinical value remains at best, unclear.

1. x-RAY IMAGING Voiding cystourethrogram (VUCG) was the mainstay of x-ray imaging of the LUT but it has been replaced almost entirely by USS because of its ease of use, low cost and availability. While CT has not gained acceptance because of the exposure of ionising radiations, MRI took the lead as the most promising imaging modality because it offered a comprehensive view of the pelvis and enabled visualisation of the position of visceral organ in relation to bony reference points. 3D and 4D USS recently offered volume acquisition with limitations in terms of the volume that can be acquired. Continuous technical development in imaging technology and techniques made this research area particularly interesting. Positive-pressure urethrography has been used for the diagnosis of female urethral diverticula, it was shown to be more sensitive than voiding cystourethrography although MRI is the gold standard for the diagnosis of diverticula and planning surgical repair. The possibility of imaging what was usually perceived during physical examination such as bladder neck mobility or POP increased the usefulness of USS. Research in the field of MRI first looked into the possibility of fast dynamic acquisition to image the displacement of visceral organs

during effort to better qualify POP and then moved into morphological imaging of the pelvic organs muscular support to investigate the physiopathology of genital prolapse. x-ray imaging of the urinary bladder and urethra has been used to assess the female urinary tract in women suffering UI to evaluate urethral/bladder neck hypermobility and to assess associated conditions such as urethral obstruction, vesico-urethral reflux, diverticula, fistula, stones and tumours. In males the purpose of voiding cystourethrography has been mainly to locate infravesical obstruction. Videourodynamics has been by some regarded as the “gold standard” in the evaluation of LUTD.

2. ULTRASONOGRAPHY Ultrasonography has been used in the evaluation of urinary incontinence as early as 1980. Over the past three decades the quality of the ultrasound image and its processing has improved beyond what could have been imagined during the 70’s. Various new developments, such as the use of contrast medium, colour Doppler, 360 degree transducers and three- and four dimensional imaging have been introduced and have led to more widespread use of ultrasonography in the evaluation of the lower urinary tract and pelvic floor disorders. Ultrasonography is cheaper than x-ray imaging, it is often preferred by physicians because the imaging studies can be performed in their own office as part of the physical examination and it is also more acceptable to patients because of the lack of for radiation exposure. However ultrasound itself produces problems by needing to be

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in direct contact with the patient even during dynamic manoeuvres and the resolution is dependent on the frequency of the probe used. The higher the ultrasound frequency, the better the resolution but there is reduced penetration into the tissues.

TYPES OF ULTRASONOGRAPHY Different imaging approaches have been used, such as abdominal, transvaginal, transrectal, perineal and transurethral. Synonyms for the perineal approach are transperineal, introital, labial or translabial access, all use a similar method and there does not appear to be a substantive difference between these terms, a common agreed term needs to be decided upon.

A.THE URETHRA AND BLADDER NECK Ultrasonography may result in variable images of the urethra, since the echogeneity of the structures depends on the position of the transducer in relation to the urethra. This may produce confusing images, especially in the dynamic process of pelvic floor contraction and Valsalva manoeuvre. With the use of ultrasonography, thickness and length of the urethral sphincter muscle can be measured and urethral volume calculated. Intra-urethral ultrasonography has been used for this purpose although complete imaging of the lateral parts of the sphincter are difficult due to the higher frequencies emitted by these probes, others have used two- or three-dimensional ultrasonography of the urethra. Figure 7: Eample of standing, lateral views on VCUG.

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B. BLADDER NECK

D. PELVIC FLOOR MUSCLES

The bladder neck and proximal urethra are easily visible on all types of ultrasonography without the need for catheterisation. Measurements are usually taken at rest, during straining (Valsalva manoeuvre), and sometimes during a cough and squeeze. The position and movements are measured in relation to the lower margin of the symphysis pubis. The axis of the urethra in relation to a vertical or horizontal line can be measured in degrees and provide the degrees of urethral rotation or bladder neck mobility. Other parameters are the posterior urethrovesical angle and the anterior urethrovesical angle. A number of studies have validated the use of ultrasonography in the assessment of the position and mobility of the bladder neck and proximal urethra.

Ultrasonography can be used to assess pelvic floor muscles and their function. Contraction of the pelvic floor results in displacement of pelvic structures that can easily be imaged on ultrasound such as the cranial lift of the

urethra in relation to the symphysis pubis during a maximal squeeze but also the dimensions of the genital hiatus or the posterior anorectal angle can serve this purpos. Comparison with traditional measurements of

C. DETERMINATION OF THE POST VOID RESIDUAL URINE AND BLADDER WALL THICKNESS Ultrasonography is the gold standard technique for measuring bladder volume and post-void residual urine. Ultrasonographic data have been compared with residual volumes obtained by in and out catheterisation under ultrasound control and were found satisfactory. Automated ultrasound systems for measuring bladder volume and post-void residual have been developed and have been found to be more accurate than standard ultrasound measurements, furthermore they can be used by health care providers with no training in ultrasound imaging. These machines are widely used and are, in general, experienced as reliable enough for clinical use, however, in the case of ascites or an ovarian cyst for example, the estimated urinary volumes can be incorrect, and in post partum women.

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Figure 8: Perineal midsagittal two-dimensional view at rest and on contraction. Levator contraction with ventrocranial displacement of the urethra. Measurement of minimal dimension of genital hiatus (from symphysis pubis to levator ani muscle)

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pelvic floor muscle strength has been performed, and good correlations with palpation and perineometry have been found. Direct measurement of the pelvic floor muscles is possible with the use of two and three-dimensional perineal ultrasonography. An alternative technique makes use of a 360 degree rectal probe intravaginally. The thickness of the muscles as well as the hiatal area can be measured. Hiatal dimensions and pelvic floor muscle thickness have been extensively validated and have good test retest and inter observer characteristics.

3. MRI (MAGNETIC RESONANCE IMAGING)

A.CONVENTIONAL MRI

The role of magnetic resonance imaging (MRI) in evaluating pelvic floor disorders has been established in recent years and continues to evolve. This technique provides unparalleled images of pelvic floor muscles, connective tissue, and organs. In addition to the detailed static picture of the pelvic organ support system anatomy, MR can also reveal the downward movement of each pelvic compartment during increases in abdominal pressure. Advances in MR imaging, equipment and software have significantly improved image quality and now MRI provides ever more detailed pictures of anatomy and function. At present active investigation is ongoing to see how this imaging might result in a better understanding of these diseases and improve their diagnosis and management.

Standard MRI consists of two dimensional image acquisitions. Usually conventional T1 images and spin echo T2 weighted images are obtained. Proton density T2 weighted scans provide excellent softtissue definition (Figure 9). However, the long imaging time of conventional MRI hampers its ability to evaluate the movement of organs that are characteristic of POP.

E. PELVIC ORGAN PROLAPSE In cases of mild and moderate pelvic organ prolapse, perineal ultrasonography can be used, for the investigation of the prolapse. Ultrasonography should, however, only be used in addition to the patients history and clinical examination. In cases of severe pelvic organ prolapse, ultrasonographic assessment is not possible due to transducer dislocation by the prolapse. The ultrasonographic imaging of the anterior compartment (i.e. bladder, bladder neck and urethra) is the easiest to perform, and the majority of scientific studies deal with this compartment. Research in ultrasonography imaging of the pelvic floor has flourished over the last decade although the clinical benefit of it remains uncertain. Standardisation of imaging techniques and terminology are eagerly awaited. Imaging of pelvic floor muscle in relation to POP is a promising area because of the possible insight into the pathophysiology of the condition and treatment outcome.

Although women might present with symptoms isolated to one of the pelvic compartments, they often have concomitant defects in other compartments or pelvic structures. In these women, imaging can provide information to extend what can be determined on physical examination. Ultrasound and fluoroscopy have been used to improve diagnosis and the role of MRI in pelvic floor dysfunction is rapidly developing. MRI provides detailed images of bladder neck and urethral mobility, rectocele, cystocele, enterocele and uterine prolapse, in a single non-invasive study without exposing the patient to ionizing radiation. MRI also provides a multiplanar thorough evaluation of pelvic organs including the uterus, ovaries, ureters, kidneys, and levator muscles, as well as the urethra, that is unavailable by any other imaging modality. MRI can identify ureteral obstruction, hydronephrosis, and uterine and ovarian pathology.

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Figure 9 : Sagittal mid pelvic section showing anatomical detail visible in static images made with Proton Density sequence.

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C. THREE DIMENSIONAL MRI

B.ULTRA FAST IMAGE ACQUISITION AND MR SEQUENCES Pelvic organ movement during Valsalva is identifiable using very fast single-shot MR sequences. These sequential images are obtained approximately once per second, either as a series of images covering the entire pelvis (static imaging) or repetitively in one plane while the patient is straining (dynamic imaging). The patients are placed in the supine position with legs slightly spread apart, and knees bent and supported by a pillow. Most pelvic floor details can be seen without the need for bowel preparation, premedication, instrumentation or contrast medium but often, especially with MR defaecography, ultrasound gel or other suitable agents are used to enhance visibility of the rectum and vagina. During a typical study of pelvic organ movement two sets

of images are obtained. The first set consists of static sagittal and para-sagittal images covering the pelvis from left to right sidewall. These images are used to select the mid-sagittal plane for the dynamic second set of images. This static sequence also allows for anatomic delineation of the pelvic sidewalls and muscular and fascial components of the pelvic floor. The perineal membrane and the levator ani musculature, as well as the anal sphincter anatomy, are also clearly demonstrated. Dynamic MRI allows detection of POP that may not be evident on conventional static sequences, as it permits both structural and functional evaluation. For example, in women with lower urinary tract symptoms evaluation of the urethra may be of added value.

Figure 10: The rest and strain image taken from a mid-sagittal dynamic MR sequence revealing cystocele and uterine descent.

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The nature of MRI technique where a series of parallel images are made allows them to represent a 3D block of tissue. Three dimensional (3D) MRI provides precise detail of the bony and muscular pelvic structures (Figure 11) so that 3D models can be constructed based on these detailed images. In this technique, static or dynamic images are reconstructed using consecutive planes in the axial, sagittal and coronal dimensions. Anatomic variations of the insertion and path of the pubococcygeus and iliococcygeus muscles can be seen. 3D models made from multi-slice scans during a maximal Valsalva have allowed direct measurements of changes in the relationship between the vagina and pelvic walls. 3D MRI enables evaluation of paravaginal defects, apical descent and vaginal widening.

Figure 11: Pelvic Organs as seen from caudal on a 3D reconstruction from Magnetic resonance images.

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CONCLUSIONS Clinical research involving diagnostic accuracy and clinical benefit of imaging studies and other diagnostic tests is particularly difficult. Recommendation of a diagnostic test is based upon the evidence that the outcome of it provides valuable information for patient management and this often involves evaluating the outcome of surgery. Safety tests - Intended to protect patientsâ&#x20AC;&#x2122; health, they are indicated in all patients complaining of urinary incontinence. They include urinalysis and measurement of post-void residual urine. While a consensus is easily achieved for urinalysis, the clinical benefit and costeffectiveness of PVR measurement in the primary evaluation of urinary incontinence needs to be confirmed in prospective studies. Tests with specific and selected indications. Upper urinary tract imaging (as well as renal function assessment) may be indicated in cases of neurogenic urinary incontinence with risk of renal damage, chronic retention with incontinence, incontinence associated with severe genitourinary prolapse and suspicion of extraurethral incontinence. No other imaging technique is recommended in the primary evaluation of uncomplicated urinary incontinence and/or pelvic organ prolapse.

option. Imaging of the CNS should be considered when a neurological disorder is suspected on the basis of clinical, imaging and neurophysiological findings. Urethrocystoscopy is indicated in cases of incontinence with microscopic haematuria, in the evaluation of recurrent or iatrogenic cases, in the evaluation of vesico-vaginal fistula and extra-urethral urinary incontinence. Pelvic floor ultrasound is widely used as an adjunct to physical examination in patients with urinary incontinence and/or pelvic organ prolapse. Although the technique is rapidly evolving and much progress has been made in clinical research in this field. MRI of the pelvic floor is rapidly gaining popularity in the evaluation of enteroceles and in the morphological analysis of pelvic floor muscles although evidence of its clinical benefit is still lacking. Both ultrasonography and MRI are the most rapidly evolving techniques and hold promises for potential future clinical applications.

Cystourethrography remains a reasonable option only in the preoperative evaluation of complicated and/or recurrent cases. Video urodynamics, is the gold standard in the evaluation of neurogenic incontinence, particularly in the paediatric population, although the clinical benefit of it remains unclear. In female urinary incontinence videourodynamics is not recommended except under specific complex circumstances. MRI remains the gold standard for the diagnosis of urethral diverticula although ultrasonography is a good alternative

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Types of Treatment

Pharmacological Treatment of Urinary Incontinence The function of the lower urinary tract (LUT) is to store and periodically release urine, and is dependent on the activity of smooth and striated muscles in the bladder, urethra, and pelvic floor. The bladder and the urethra constitute a functional unit, which is controlled by a complex interplay between the central and peripheral nervous systems and local regulatory factors. Malfunction at various levels may result in bladder control disorders, which roughly can be classified as disturbances of filling/storage or disturbances of voiding/emptying. Failure to store urine may lead to various forms of incontinence (mainly urgency and stress incontinence), and failure to empty can lead to urinary retention, which may result in overflow incontinence. A disturbed filling/storage function can, at least theoretically, be improved by agents decreasing detrusor activity, increasing bladder capacity, and/or increasing outlet resistance.

Studies in humans and animals have identified areas in the brainstem and diencephalon that are specifically implicated in micturition control, including Barringtonâ&#x20AC;&#x2122;s nucleus or the pontine micturition center (PMC) in the dorsomedial pontine tegmentum. These structures directly excite bladder motoneurons and indirectly inhibit urethral sphincter motoneurons via inhibitory interneurons in the

medial sacral cord. The periaqueductal grey (PAG) receives bladder filling information, and the pre-optic area of the hypothalamus is probably involved in the initiation of micturition. According to PET-scan and functional imaging studies in humans, these supraspinal regions are active during micturition.

Many drugs have been tried, but the results are often disappointing, partly due to poor treatment efficacy and/or side effects. The development of pharmacologic treatment of the different forms of urinary incontinence has been slow, but several promising targets and drug principles have been identified.

CENTRAL NERVOUS CONTROL In the adult individual, the normal micturition reflex is mediated by a spinobulbospinal pathway, which passes through relay centers in the brain (Figures1- 4). In infants, the central pathways seem to be organized as on-off switching circuits, but after the age of four to six years, voiding is initiated voluntarily by the cerebral cortex.

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Figure 1: Components of the micturition reflex.

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PERIPHERAL NERVOUS CONTROL Bladder emptying and urine storage involve a complex pattern of efferent and afferent signalling in parasympathetic, sympathetic, somatic, and sensory nerves. These nerves are parts of reflex pathways, which either keep the bladder in a noncontracted state, enabling urine storage at low intravesical pressure, or which initiate micturition by relaxing the outflow region and contracting the bladder smooth muscle. Contraction of the detrusor smooth muscle and relaxation of the outflow region result from activation of parasympathetic neurones located in the sacral parasympathetic nucleus (SPN) in the spinal cord at the level of S2-S4. The postganglionic neurones in the pelvic nerve mediate the excitatory input to the human detrusor smooth muscle by releasing acetylcholine (ACh) acting on muscarinic receptors. The pelvic nerve also conveys parasympathetic fibres to the outflow region and the urethra. These fibres exert an inhibitory effect and thereby relax the outflow region. This is mediated partly by release of nitric oxide, although other transmitters might be involved.

released in response to electrical stimulation of detrusor tissues, and the normal response of detrusor tissues to released noradrenaline is relaxation. The somatic innervation of the urethral rhabdosphincter and of some perineal muscles (for exam ple compressor urethrae and urethrovaginal sphincter), is provided by the pudendal nerve. These fibers originate from sphincter motor neurons located in the ventral horn of the sacral

spinal cord (levels S2-S4) in a region called OnufÂ´s nucleus. Most of the sensory innervation of the bladder and urethra reaches the spinal cord via the pelvic nerve and dorsal root ganglia. In addition, some afferents travel in the hypogastric nerve. The sensory nerves of the striated muscle in the rhabdosphincter travel in the pudendal nerve to the sacral region of the spinal cord.

Most of the sympathetic innervation of the bladder and urethra originates from the intermediolateral nuclei in the thoraco-lumbar region (T10-L2) of the spinal cord. The axons travel either through the inferior mesenteric ganglia and the hypogastric nerve, or pass through the paravertebral chain and enter the pelvic nerve. Thus, sympathetic signals are conveyed in both the hypogastric and pelvic nerves. The predominant effects of the sympathetic innervation of the lower urinary tract are inhibition of parasympathetic pathways at spinal and ganglion levels, and mediation of contraction of the bladder base and the urethra. However, the adrenergic innervation of the bladder body is believed to inactivate the contractile mechanisms in the detrusor directly. Noradrenaline (norepinephrine) is

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Figure 2: Activity in the micturition reflex during storage. The pontine micturition center is inhibited by impulses from the prefrontal cortex, afferent impulses unable to initiate micturition. Activities in the hypogastric and pudendal nerves keep the bladder relaxed and the outflow region contracted.

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The most important afferents for the micturition process are myelinated Aδ-fibres and unmyelinated C-fibres travelling in the pelvic nerve to the sacral spinal cord, conveying information from receptors in the bladder wall to the spinal cord. The Aδ-fibres respond to passive distension and active contraction, thus conveying information about bladder filling.

C-fibres have a high mechanical threshold and respond primarily to chemical irritation of the bladder mucosa or cold. Following chemical irritation, the C-fibre afferents exhibit spontaneous firing when the bladder is empty and increased firing during bladder distension. These fibres are normally inactive and are therefore termed ”silent fibres”.

PATHOGENESIS OF BLADDER CONTROL DISORDERS Bladder control disorders can be divided into two general categories: disorders of filling/storage and disorders of voiding. Storage problems can occur as a result of weakness or anatomical defects in the urethral outlet, causing stress urinary incontinence. Failure to store also occurs if the bladder is overactive, as in the overactive bladder (OAB) syndrome. OAB is often assumed to be caused by detrusor overactivity, even if this does not always seem to be the case. DO/OAB can occur as a result of sensitization of afferent nerve terminals in the bladder or outlet region, changes of the bladder smooth muscle secondary to denervation, or consequent upon damage to the central nervous system (CNS) inhibitory pathways, as can be seen in various neurological disorders, such as multiple sclerosis, cerebrovascular disease, Parkinson’s disease, brain tumors, and spinal cord injury. Urinary retention and overflow incontinence can be observed in patients with urethral outlet obstruction, decreased detrusor contractility, or both, neural injury, and/ or diseases that damage nerves (e.g. diabetes mellitus), or in those who are taking drugs that depress the neural control of the bladder or bladder smooth muscle directly.

Figure 3: Activity in the micturition reflex during voluntary voiding. The inhibitory impulses from the prefrontal cortex pontine micturition center are removed and afferent impulses are able to initiate micturition. Activities in the hypogastric and pudendal nerves are inhibited, the outflow region is relaxed, and the bladder is contracted by the activity in the pelvic nerve.

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BLADDER CONTRACTION Normal bladder contraction in humans is mediated mainly through stimulation of muscarinic receptors in the detrusor muscle. Atropine-resistant (non-adrenergic, non-cholinergic: NANC) contractions have been reported in normal human detrusor and may be caused mainly by adenosine triphosphate (ATP). ATP acts on two families of purinergic receptors: an ion channel family (P2x) and a Gprotein-coupled receptor family (P2Y). Seven P2x subtypes and eight P2Y subtypes have been identified. Various studies suggested that multiple purinergic excitatory receptors are present in the human bladder. Excitatory receptors for ATP are present in parasympathetic ganglia, afferent nerve terminals, and urothelial cells. P2X3 receptors, which have been identified in small-diameter afferent neurons in dorsal root ganglia, have also been detected immunohistochemically in the wall of the bladder and ureter in a suburothelial plexus of afferent nerves. A significant degree of atropine resistance may exist in morphologically and/or functionally changed bladders, and has been reported to occur in hypertrophic bladders, interstitial cystitis, neurogenic bladders, and in the aging bladder.

MUSCARINIC RECEPTORS The neurotransmitter ACh acts on two classes of receptors, the nicotinic and the muscarinic receptors. While the former play a role in the signal transduction between neurones or between neurones and skeletal muscle (e.g. in the distal urethra), the signal transduction between parasympathetic nerves and smooth muscle of

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the detrusor involves muscarinic receptors. Importantly, the endogenous muscarinic receptor agonist ACh is not necessarily derived only from parasympathetic nerves in the urinary bladder, but can also be formed and released non-neuronally by the urothelium. Five subtypes of muscarinic receptors have been cloned in humans, which are designated M1-M5. Based upon structural criteria and shared preferred signal transduction pathways, the subtypes can be grouped into M1, M3 and M5 on the one hand and the subtypes M2 and M4 on the other.

bladder dysfunction. This could involve, e.g., an enhanced expression of such receptors and/or an increased functional responsiveness.

Apparently, most muscarinic receptors in the bladder are found on the smooth muscle cells of the detrusor. While the detrusor expresses far more M2 than M3 receptors, it appears that detrusor contraction under physiological conditions is largely if not exclusively mediated by the M3 receptor. Under physiological conditions M2 receptorselective stimulation causes little contraction, but rather appears to act mainly by inhibiting Î˛-adrenoceptormediated detrusor relaxation. At present the functional role of muscarinic receptors in the urothelium has largely been studied indirectly, i.e. by investigating the effects of urothelium removal or of administration of pharmacological inhibitors. These data indicate that muscarinic stimulation of the urothelium causes release of an as yet unidentified factor which inhibits detrusor contraction. Some data indicate that muscarinic receptors in the urothelium may partly act by releasing nitric oxide (NO). Assuming an involvement of muscarinic receptors in physiological voiding contractions of the bladder, numerous studies have explored whether an overactivity of the muscarinic system may play a causative role in

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DRUGS USED FOR TREATMENT OF OVERACTIVE BLADDER SYMPTOMS AND DETRUSOR OVERACTIVITY It has been estimated millions of people in the world are affected by urinary incontinence, and an abundance of drugs has been used for treatmen. As underlined by International Continence Society (ICS), drugs may be efficacious in some patients, but they do have side effects, and frequently are not continued indefinitely. Hence it would be worth considering them as an adjunct to conservative therapy.

drugs act during the storage phase by decreasing the activity in afferent nerves (both C and AÎ´ -fibres) from the bladder. As mentioned previously, muscarinic receptors are found on bladder urothelial cells where their density can be even higher than in detrusor muscle. The role of the urothelium in bladder activation has attracted much interest, but whether the muscarinic receptors on urothelial cells can

influence micturition has not yet been established. During the storage phase, ACh and ATP may be released from both neuronal and non-neuronal sources (eg, the urothelium) and directly or indirectly (by increasing detrusor smooth muscle tone) excite afferent nerves in the suburothelium and within the detrusor. These mechanisms may be important in the pathophysiology of OAB/DO and represent possible targets for antimuscarinic drugs.

1.ANTIMUSCARINIC (ANTICHOLINERGIC) DRUGS MECHANISM OF ACTION Antimuscarinics block, more or less selectively, muscarinic receptors irrespective of location. The common view is that in OAB/DO, the drugs act by blocking the muscarinic. receptors on the detrusor muscle, which are stimulated by ACh, released from activated cholinergic (parasympathetic) nerves. Thereby, they decrease the ability of the bladder to contract. However, antimuscarinic drugs act mainly during the storage phase, decreasing urgency and increasing bladder capacity, and during this phase, there is normally no parasympathetic input to the lower urinary tract. Furthermore, antimuscarinics are usually competitive antagonists. This implies that when there is a massive release of ACh, as during micturition, the effects of the drugs should be decreased, otherwise the reduced ability of the detrusor to contract would eventually lead to urinary retention. Undeniably, high doses of antimuscarinics can produce urinary retention in humans, but in the dose range used for beneficial effects in OAB/DO, there is little evidence for a significant reduction of the voiding contraction. However, there is good experimental evidence that the

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Figure 4: Important sites of action of antimuscarinics.

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2. DRUGS ACTING ON MEMBRANE CHANNELS CLINICAL USE OF ANTIMUSCARINICS

A. CALCIUM ANTAGONISTS

The clinical relevance of efficacy of antimuscarinic drugs relative to placebo has been questioned. Herbison et al. [2003] stated in a widely discussed article: “Anticholinergics produce significant improvements in overactive bladder symptoms compared with placebo. The benefits are, however, of limited clinical significance” Large meta-analyses of studies performed with the currently most widely used drugs, clearly show that antimuscarinics are of significant clinical benefit.

Calcium channels play an important role in the regulation of free intracellular calcium concentrations and thereby contribute to the regulation of smooth muscle tone. Two major groups of calcium channels include the voltagegated and the store-operated channels. While both can contribute to the maintenance of smooth tone in general, store-operated calcium channels apparently contribute only to a limited if any extent to the regulation of bladder smooth muscle tone. On the other hand, various types of voltage-operated calcium channels have been implicated in the regulation of bladder smooth muscle including Q-type and L-type channels. The latter appears to be of particular importance as inhibitors of L-type channels have repeatedly been shown to inhibit bladder contraction.

The durability of the effects of antimuscarinics is not known and the relapse (deteriorate after a period of improvement) rate of symptoms after discontinuation of treatment has not been systematically studied. Several studies have documented that the persistence with prescribed antimuscarinic therapy for overactive bladder is low. The most common causes seem to be lack of efficacy and adverse effects. However, there is some evidence suggesting that the tolerability of the different antimuscarinics may differ.

Larger studies with clinical endpoints related to effects of calcium channel inhibitors have not been reported in incontinent patients. At present, there is no clinical evidence to support a possible use of calcium channel inhibitors in the treatment of bladder dysfunction.

Even if the use of antimuscarinics are associated with many adverse effects, they are generally considered to be ‘safe’ drugs. However, among the more serious concerns related to their use is the risk of cardiac adverse effects and increases in heart rate. Since mean changes in HR reported in population studies might not be applicable to an individual patient, and particularly in patients at risk of cardiac disease, even moderate increases in HR might be harmful.

B. POTASSIUM CHANNEL OPENERS

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In a similar fashion to calcium channels, potassium channels also contribute to the membrane potential of smooth muscle cells and hence to the regulation of smooth muscle tone. Numerous types of potassium channels exist. With regard to bladder function, ATPdependent (KATP) and big calcium-activated (BKCa) channels have been studied most intensively. The BKCa channels also appear to be important physiologically as their activation can cause hyperpolarization of bladder smooth muscle cells and by this mechanism they can contribute to the relaxation of bladder smooth muscle by,

e.g., β-adrenoceptor agonists. But potassium channel openers are believed to mainly act directly on smooth muscle cells, they may also at least in part affect bladder function by modulating the activity of afferent neurones. While the above data demonstrate the potential of potassium channel openers to inhibit non-voiding detrusor contractions, these channels are expressed not only in bladder, but also e.g. in vascular smooth muscle. Therefore, potassium channel openers may also affect cardiovascular function, and in effective doses may considerably lower blood pressure. This consideration has led to a considerable hesitancy to study potassium channel openers in OAB patients.

3. α-ADRENOCEPTOR ANTAGONISTS

It is well documented that α1-AR antagonists can ameliorate lower urinary tract symptoms in men. Currently used α1-AR antagonists are considered effective for treatment of both storage and voiding symptoms in men with LUTS. In females, treatment with OAB, α1-AR antagonists seem to be ineffective. In some studies voiding symptoms in women with functional outflow obstruction, or LUTS, were treated (with modest success) with an α1-AR antagonist. It should be remembered that in women, these drugs may produce stress incontinence

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4. β-ADRENOCEPTOR AGONISTS In isolated human bladder, non-subtype selective β-AR agonists like isoprenaline have a pronounced inhibitory effect, and administration of such drugs can increase bladder capacity in man. However, the β-ARs of the human bladder were shown to have functional characteristics typical of neither β1-, nor β2- ARs, since they could be blocked by propranolol, but not by practolol or metoprolol (β1) or butoxamine (β2).

serotonin and noradrenaline, but its mode of action in DO has not been established. Even if it is generally considered that imipramine is a useful drug in the treatment of DO. It is well established that therapeutic doses of tricyclic antidepressants, including imipramine, may cause serious toxic effects on the cardiovascular system.

making it is the most relevant clinically. BoNT/A is available in three different commercial forms, with the proprietary names of Botox®, Dysport®, xeomin®, and Prosigne. Although the toxin is the same, it is wrapped by different proteins which modify the relative potency of each brand.

DULOxETINE

The generally accepted mechanism by which β-ARs induce detrusor relaxation in most species, is activation of adenylyl cyclase with the subsequent formation of cAMP.

Most of the information available about intravesical application of BoNT/A derives from the use of onabotA (Botox®). However, in addition to sub-type A, some studies have investigated the effect of detrusor injection sub-type B, rimabotulinumtoxinB (proprietary names being Miobloc™ or Neurobloc™ according to countries).

Since β-ARs are present in the urothelium, their possible role in bladder relaxation has been investigated. A number of β3-AR selective agonists are currently being evaluated as potential treatment for OAB in humans including GW427353 (solabegron) and YM178.

In a placebo-controlled study, the drug showed efficacy in patients with OAB. Episodes of urgency incontinence were also significantly reduced by duloxetine.

5. ANTIDEPRESSANTS Several antidepressants have been reported to have beneficial effects in patients with DO. The use of antidepressants was shown to be an independent risk factor for lower urinary tract symptoms suggestive of benign prostatic hyperplasia in a community based population of healthy aging men.

However, the high withdrawal rate observed across all studies in which the drug was evaluated fou SUI, affecting 20-40% of the patients at short-term and up to 90% in long-term studies, do not predict clinical utility of duloxetine in OAB.

BoNT consists of a heavy and a light chain linked by a disulphide bond. In the synaptic cleft the toxin binds to synaptic vesicle protein or SV2 by the heavy chain before being internalized by the nerve terminal along with the recycling process of synaptic vesicles. In the human bladder SV2 and SNAP-25 expression has been demonstrated in parasympathetic, sympathetic and sensory fibers. Almost all parasympathetic nerves express the two proteins. As these nerves play a fundamental role for detrusor contraction during voiding, the blockade of ACh release is believed to play an essential role in detrusor hypo- or acontractility that follows BoNT/A injection in the bladder.

6. TOXINS IMIPRAMINE BOTULINUM TOxIN Imipramine is the only drug that has been widely used clinically to treat this disorder. Imipramine has complex pharmacological effects, including marked systemic antimuscarinic actions and blockade of the reuptake of

The most frequent side effects reported after intradetrusor BonT/A injection are bladder pain and urinary infections.

Botulinum toxin (BonT) is a neurotoxin produced by Clostridium botulinum, Of the seven subtypes of BONT, sub-type A (BONT-A) has the longest duration of action,

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DRUGS USED FOR TREATMENT OF STRESS INCONTINENCE IN WOMEN Many factors seem to be involved in the pathogenesis of stress urinary incontinence (SUI) in women: urethral support and function, bladder neck support and function of the nerves and musculature of the bladder, urethra, and pelvic floor. Pure structural factors cannot be treated pharmacologically. However, SUI in women is generally thought to be characterized by decreases in urethral transmission pressure and, in most cases, resting urethral closure pressure. It, therefore, seems logical that increasing urethral pressure should improve the condition. Factors which may contribute to urethral closure include the tone of the urethral smooth and striated muscle (the rhabdosphincter) and the passive properties of the urethral lamina propria, in particular its vasculature. The relative contribution to intraurethral pressure of these factors is still subject to debate. However, there is ample pharmacological evidence that a substantial part of urethral tone is mediated through stimulation of α-ARs in the urethral smooth muscle by released noradrenaline. A contributing factor to SUI, mainly in elderly women with lack of estrogen, may be lack of mucosal function. The pharmacological treatment of SUI aims at increasing intraurethral closure forces by increasing the tone in the urethral smooth and striated musculature, either directly or through increased motorneuron activity. Several drugs may contribute to such an increase, but relative lack of efficacy or/and side effects have limited their clinical use.

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1. α-ADRENOCEPTOR AGONISTS

3. SEROTONIN-NORADRENALINE UPTAKE INHIBITORS

In patients with stress incontinence, alpha agonist treatment results in contraction of the internal urethral sphincter and increases the urethral resistance to urinary flow. Sympathomimetic drugs, estrogen, and tricyclic agents increase bladder outlet resistance to improve symptoms of stress urinary incontinence. Several drugs with agonistic effects on peripheral α-ARs have been used in the treatment of SUI. Relatively recently, a central role of noradrenaline (NA) in increasing the excitability of urethral rhabdosphincter motorneurons in the rat analogue of Onuf’s nucleus, an effect due at least in part to α1-AR receptor dependent depolarization. This could contribute to the mechanism by which NA reuptake inhibitors improve SUI [Yashiro et al, 2010].

A. IMIPRAMINE Imipramine, among several other pharmacological effects has classically been reported to inhibit the reuptake of noradrenaline and serotonin in adrenergic nerve endings. In the urethra this could be expected to enhance the contractile effects of noradrenaline on urethral smooth muscle. In patients with persistent incontinence the functional urethral length was extended significantly but was shortened with stress despite imipramine therapy. Studies suggests that imipramine could be an alternative treatment in selected cases with stress incontinence.

2. β-ADRENOCEPTOR AGONISTS

B. DULOxETINE

ß-AR stimulation is generally conceded to decrease urethral pressure, but ß2-AR agonists have been reported to increase the contractility of some fast contracting striated muscle fibers and suppress that of slow contracting fibers of others. Some β-AR agonists also stimulate skeletal muscle hypertrophy – in fast twitch more so than slow twitch fibers. Studies reported an increase in urethral pressure with clinical use of clenbuterol and to speculate on its potential for the treatment of SUI. The positive effects were suggested to be a result of an action on urethral striated muscle and/ or the pelvic floor muscles.

Duloxetine hydrochloride is a combined norepinephrine and serotonin reuptake inhibitor, which has been shown to significantly increase sphincteric muscle activity during the filling/storage phase of micturition of irritated bladder function. Bladder capacity was also increased in this model, both effects mediated centrally through both motor efferent and sensory afferent modulation. Thor et al. [2007] described the mechanisms of action and the physiologic effects of duloxetine. 5HT (serotonin) and NA terminals are dense in spinal areas associated with lower urinary tract functioning especially around the pudendal nerve neurons in Onuf’s nucleus. These are projections from separate areas in the brain stem.

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HORMONAL TREATMENT OF URINARY INCONTINENCE Glutamate is the primary excitatory neurotransmitter in the spinal cord, activating the pudendal neurons in Onuf’s nucleus causing contraction of the urethral rhabdosphincter. The rhabdosphincter innervation is proposed as distinct from that of the levator ani [Thor and de Groat, 2010]. The responsiveness of the rhabdosphincter motor neurons to glutamate is modulated (facilitated) by 5HT (through 5HT2 receptors) and NA (through α1 -ARs). 5HT and NA, however, only modulate, and, when micturition occurs, glutamate excitation and the rhabdosphincter contraction cease. Excitatory effects on urethral sphincter activity are shared to a lesser extent by receptors for 5HT1A (indirect through a supraspinal stimulation), TRH, Vasopressin, NMDA and AMPA; inhibitory effects are similarly mediated by κ2 opioid, α1 ARs, GABA-A, GABA-B and glycine receptors [Thor and de Groat, 2010]. Some CNS penetrant selective 5HT2C agonists have been found to increase urethral muscle tone and inhibit micturition reflexes in animal models, and these are additional candidates for clinical development for the treatment of SUI.

I. OESTROGENS OESTROGENS AND THE CONTINENCE MECHANISM The oestrogen sensitive tissues of the bladder, urethra and pelvic floor all play an important role in the continence mechanism. For women to remain continent the urethral pressure must exceed the intra-vesical pressure at all times except during micturition. The urethra has four oestrogen sensitive functional layers all of which have a role in the maintenance of a positive urethral pressure 1) epithelium, 2) vasculature, 3) connective tissue, 4) muscle. Two types of oestrogen receptor, (α and β) have been identified in the trigone of the bladder, urethra and vagina as well as in the levator ani muscles and fascia and ligaments within the pelvic floor. After the menopause oestrogen receptor α has been shown to vary depending upon exogenous oestrogen therapy. In addition exogenous oestrogens affect the remodeling of collagen in the urogenital tissues resulting in a reduction of the total collagen concentration with a decrease in the cross linking of collagen in both continent and incontinent women. Studies in both animals and humans have shown that oestrogens also increase vascularity in the peri-urethral plexus which can be measured as vascular pulsations on urethral pressure profilometry.

ESTROGENS FOR STRESS URINARY INCONTINENCE The role of oestrogen in the treatment of stress urinary incontinence has been controversial despite a number of reported clinical trials [Hextall, 2000]. Some have given promising results but this may have been because they

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were small observational and not randomised, blinded or controlled. The situation is further complicated by the fact that a number of different types of oestrogen have been used with varying doses, routes of administration and duration of treatment. Though few studies showed that there was a significant subjective improvement for all patients and those with urodynamic stress incontinence. However, assessment of the objective parameters revealed that there was no change in the volume of urine lost, Maximum urethral closure pressure increased significantly.

OESTROGENS FOR URGENCY URINARY INCONTINENCE AND OVERACTIVE BLADDER SYMPTOMS Oestrogen has been used to treat post menopausal urgency and urge incontinence for many years but there have been few controlled trials to confirm that it is of benefit [Hextall, 2000]. Symptoms of an overactive bladder increase in prevalence with increasing age and lower urinary tract symptoms and recurrent urinary tract infections are commonly associated with urogenital atrophy. Whilst the evidence supporting the use of oestrogens in lower urinary tract dysfunction remains controversial. Some studies concluded that local oestorgen therapy for incontinence may be beneficial although there was little evidence of long term effect. The evidence would suggest that systemic hormone replacement using conjugated equine oestrogens may make incontinence worse. They report that there are too few data to comment reliably on the dose type of oestrogen and route of administration.

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Conservative Management of Urinary Incontinence in women Conservative treatment is any therapy not involving surgical treatment of incontinence. In this chapter some comparison studies has been done between therapy and lifestyle interventions (also called lifestyle interventions), physical therapies, scheduled voiding regimens, complementary and alternative medicines, antiincontinence devices, supportive rings/pessaries for pelvic organ prolapse (POP) and medications with a direct comparison with conservative management. Conservative therapies are considered relatively low cost, non-invasive approaches, with minimal adverse effects that are typically guided by a healthcare professional and depend on user participation. It is generally accepted that conservative measures are part of the initial counselling at the primary care level of individuals suffering from either UI or POP. Conservative therapy is also indicated for those for whom other treatments are inappropriate, for example, those unwilling to undergo or unfit for surgery and women who plan future pregnancies (as these may adversely affect surgery). Other indications include individuals awaiting surgery or who wish to delay surgery and those whose symptoms are not serious enough for surgical intervention.

A. PREVENTION WEIGHT LOSS Obesity is an important independent risk factor for the prevalence of UI. Massive weight loss significantly decreases UI in morbidly obese women. Moderate weight loss maybe effective in decreasing UI especially if combined with exercise. For morbidly and moderately obese women weight loss should be considered a first line treatment to reduce UI prevalence. PHYSICAL ACTIVITY There is good prospective fro studies suggesting that moderate exercise decreases the incidence of UI in middleaged and older women; this effect may be mediated by weight control. PHYSICAL FORCES (ExERCISE AND WORK) Strenuous exercise may unmask the symptom of SUI during provocation. There is currently no evidence that strenuous exercise causes the condition of UI. Evidence suggests that women engaged in occupations with heavy lifting may be predisposed to genital prolapse and/or UI.

I. LIFESTYLE INTERVENTIONS

SMOKING

A number of lifestyle factors may play a role in either the development or resolution of UI. Few randomised controlled trials (RCTs) by International continence society (ICS) have been carried out to assess the effect of a specific lifestyle change on UI.

Smokers were more likely to report UI than nonsmokers in some studies. Amongst women with SUI, current smoking was positively associated with UI severity after adjusting for confounders. After adjusting for age, parity, type of delivery, prepregnancy and Body mass index, smokers had a 1.3 fold higher risk factorsof reporting UI.

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Two studies have reproted that nicotine produces phasic contraction of isolated bladder muscle probes. Few studies reported an apparent paradoxical local estrogenic effect of nicotine on the vagina, resulting in a decrease in vaginal pH and an increase in lactobacilli. Data suggest that smoking increases the risk of more severe UI. Smokers may have a different mechanism causing their UI than non-smokers. DIETARY FACTORS DIET: Data showed that after adjusting for age, physical functioning, SUI at baseline, obesity, smoking and certain dietary factors, the incidence of SUI at one year was increased in women consuming more total fat, saturated fatty acids and monounsaturated fatty acids, as well as those that consumed more carbonated beverages, zinc or vitamin B12 at baseline. The incidence of SUI was reduced in those that ate more vegetables, bread and chicken at baseline. Higher intake of vitamin D, protein and potassium were also associated with decreased risk of onset of OAB in women. The same data source was used to test the hypothesis that carotenoid, vitamin C and calcium intakes were associated with UI in women, they found that high dose vitamin C and calcium were positively associated with incontinence whilst vitamin C from food and drinks were negatively associated with incontinence. CAFFEINE: Few RCT found a clinical effect of decreasing caffeine, The experimental group had statistically significant reduction in urgency episodes; the number of Incontinence episodes decreased as well.

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FLUID INTAKE: STUDIES found that when fluid intake was decreased, women with SUI decreased the number of incontinence episodes; similarly, women with DO significantly decreased voiding frequency, urgency and incontinence episodes.

women. The role of PFMT in the treatment of UUI came later, when it was recognized that PFM contraction can also be used to occlude the urethra to prevent leakage during detrusor contraction, as w ell as inhibit and suppress detrusor contraction.

CONSTIPATION

Finally, morphological and functional changes after PFMT indicated a relationship between improved PFM coordination and increased PFM mobility and also to striated urethral sphincter hypertrophy. For treating SUI the objective behind PFMT is to improve the timing (of contraction), strength and stiffness of the PFMs and urethral sphincter function.

PFMT FOR TRAT SUI & MUI Studies found women who reported straining at stool were more likely to report SUI and urgency. There appears to be an association between straining and pudendal nerve function. The mean pudendal nerve terminal motor latency increased after straining, correlated with the amount of descent, and returned to resting by four minutes after a strain. OTHER There are many other lifestyle interventions suggested either by healthcare professionals for the treatment of UI, including reducing emotional stress, wearing non-restrictive clothing, utilising a bedside commode, decreasing lower extremity oedema and treating allergies and coughs. There is no evidence to support these interventions for UI; support for these interventions is all anecdotal in nature.

2. PELVIC FLOOR MUSCLE TRAINING (PFMT) Pelvic floor muscle training (PFMT) remains a key factor in the prevention and treatment of UI. Because pelvic floor muscle (PFM) integrity appears to play an important role in the continence mechanism, there is a biological rationale to support the use of PFMT in preventing and treating UI in

In healthy continent women, activation of the PFM before or during physical exertion seems to be an automatic anatomic response. This PFM ‘reflex’ contraction is a feed-forward loop and might precede bladder pressure rise by 200-240 milliseconds. An intentional and effective PFM contraction, prior to and during effort or exertion, compresses the urethra and increases the urethral pressure, preventing urine leakage. Active, volitional contraction of PFM to occlude the urethra during physical activity is now routinely combined with PFM exercise to improve strength and tone. The bladder neck is supported by a strong, toned PFM (resistant to stretching), limiting its downward movement during effort and exertion, thereby preventing urine leakage. Intensive strength training may reinforce structural support by permanently elevating the levator plate to a higher position inside the pelvis and enhancing the hypertrophy and stiffness of the connective tissues. In a pre and post PFM training study using an MRI reconstruction method, a significant reduction in the internal surface area of the levator ani was observed after PFMT; this suggests an increase in passive tone of the levator ani, which in turn is indicative of the state of PFM tone increased urethral stability at rest and during effort.

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PFMT TO TREAT UUI PFMT can also be used in the management of urgency and urge urinary incontinence (UUI). In 1975 Godec observed that a detrusor muscle contraction can be inhibited by a PFM contraction that has been induced by electrical stimulation (EStim) and Burgio demonstrated that a detrusor contraction can be inhibited by a voluntary PFM contraction. During urine storage, bladder distension produces low-level vesical afferent firing, which in turn stimulates the pudendal nerve outflow to the external urethral sphincter thereby increasing intraurethral pressure, an effect he termed a ‘guarding reflex’ for continence. And inhibition involves an automatic (unconscious) increase in tone for both the PFMs and the urethral striated muscle. Thus, voluntary PFM contractions may be used, often as part of a broader urge suppression strategy, to treat UUI. Generally, patients are instructed not to rush to the toilet in response to any urge sensation, because it can trigger detrusor contraction and increase intra-abdominal pressure. The strategy involves remaining still, repeatedly contracting PFMs, and waiting for the urge to pass. After inhibiting the urgency to void and the detrusor contraction, the patient can learn to reach the toilet in time to avoid

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urine leakage. However, the number, the duration, the intensity and the timing of the PFM contraction required to inhibit a detrusor muscle contraction is not known. This focus on urge suppression strategies, often combined with PFM exercise, is commonly called behavioural training. Behavioural training also involves teaching the concept of using volitional PFM contraction to occlude the urethra and prevent urine loss during uninhibited detrusor contraction. Further, patients can also be taught to be more vigilant about PFM tone when they begin to sense bladder fullness and consciously maintain resting tone rather than allowing the pelvic floor relaxation that immediately precedes and coordinates with detrusor contraction. PFMT is better than no treatment, a placebo drug or an inactive control treatment for women with SUI, UUI, or MUI. Women treated with PFMT were more likely to report a cure or improvement and a better quality of life; they also indicated fewer daily leakage episodes and had less urine leakage on the pad and paper towel test than those in the control group in immediately after treatment and in the long term. Moreover, the treatment effect appears to be enhanced where PFMT is based on sound muscle training principles such as specificity, overload progression, correct contraction.

Figure 5: Kegel exercise basic steps for pelvic muscle floor training.

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3. WEIGHTED VAGINAL CONES EStim is provided by clinic-based mains powered machines or portable battery powered stimulators with a seemingly infinite combination of current types, waveforms, frequencies, intensities, electrode types and placements. Without a clear biological rationale it is difficult to make rationale choices about different ways of delivering EStim. Additional confusion is created by the relatively rapid developments in the area of EStim, and a wide variety of stimulation devices and protocols have been developed even for the same condition.

Weighted vaginal cones (VCs) were developed as a method for testing PFM function and to provide progressive muscular overload during PFM strengthening exercises. In theory, when a cone is inserted into the vagina, the sensation of â&#x20AC;&#x2DC;losing the coneâ&#x20AC;&#x2122; provides strong sensory feedback that prompts the PFMs to contract to prevent the cone from slipping out. Women start in a standing position with a weighted cone held inside the vagina for at least one minute, incrementally adding time and increased cone weight whilst standing or walking. The goal is to walk around for 20 minutes without losing the cone; the gradual increase in cone weight maintains muscle overload over the course of the exercise programme. There are varous cone weights and sizes. However, the effectiveness of the VC training method is unclear. Of note is that the PFM contraction is not the only reason the cone is retained and because orientation of the vagina is not completely vertical, some women can retain the cone without actually contracting the pelvic floor. Radiology has also demonstrated that the cones can rest in a transverse position. Depending on the axis of the vagina, women need to produce different force intensities to retain the cone. Though, using VCs as a measure of PFM function does not appear to be a valid method. Finally, some women may find it impossible to insert the cones due to a narrowed vaginal opening or, conversely, to retain it due to an enlarged vaginal opening, prolapse, or an insufficient PFM contraction, one incapable of holding even the lightest cone. The evidence from these four RCTs suggests that VCs are better than control treatments for subjective reporting of cure or cure/improvement and QoL impact in the treatment of SUI. However, VC treatment may be inappropriate in some cases due to potential reported side effects.

Finally, the nomenclature used to describe EStim remains inconsistent. EStim has not only been described based on the type of current being used (e.g. faradic, interferential), but also on the structures targeted (e.g. neuromuscular), the current intensity (e.g. low-intensity, or maximal stimulation), and the proposed mechanism of action (e.g. neuromodulation). Figure 6: Weighted vaginal cones

4. ELECTRICAL STIMULATION (ESTIM) The literature concerning EStim in the management of UI remains difficult to interpret, due to the lack of a wellsubstantiated biological rationale underpinning the use of EStim. However, the theoretical basis of stimulation interventions is emerging with increasing understanding of the neuroanatomy and physiology of the central and peripheral nervous systems. The mechanisms of action may vary depending on the cause of UI and the structure being targeted e.g. PFM or detrusor, peripheral or central nervous system. In general, the aim of EStim for women with SUI appears to be to improve the function of the PFM, while for women with UUI the objective seems to be to inhibit detrusor overactivity (DO).

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A lot studies has been done, some approaches to treatment are now rare, such as the use of faradic current or external electrodes. There was considerable variation in the intervention protocol. Although the biological rationale and purpose of EStim might be different depending on diagnosis, there was no consistency in the EStim protocols used for women with SUI, UUI, MUI, or DO. Included studies were generally assessed as having a high risk of bias. EStim might be more effective than no treatment in improving (not necessarily curing) symptoms in women with SUI, UUI or DO, although this may not result in cure.

5.MAGNETIC STIMULATION (MSTIM) MStim has been developed for noninvasive stimulation of both central and peripheral nervous systems. MStim

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for the treatment of UI was reported for the first time in 1999 by Galloway. In contrast to EStim, extracorporeal magnetic innervation (more commonly called magnetic stimulation) stimulates the PFM and sacral nerve roots without insertion of an anal or vaginal probe For treatment, the individual is positioned in a chair. Within the seat is a magnetic field generator (therapy head) that is powered and controlled by an external power unit. A concentrated steep gradient magnetic field is directed vertically through the seat of the chair. When seated, the individualâ&#x20AC;&#x2122;s perineum is centred in the middle of the seat, which places the PFM and sphincters directly on the primary axis of the pulsing magnetic field. Because of this, all tissues of the perineum can be penetrated by the magnetic field. In contrast to electrical current, the conduction of magnetic energy is unaffected by tissue impedance, creating a theoretical advantage in its clinical application compared to EStim as structures such as sacral roots or pudendal nerves can be magnetically stimulated without discomfort or the inconvenience of a vaginal or rectal probe.

the anterior component coming to rest just under the symphysis pubis, thus providing a supportive shelf for the descending pelvic organs. As there is no evidence to support the use of a specific type of pessary, choice is based on experience and trial and error. It is generally accepted that the ring pessary should be tried first because of ease of insertion and removal, and if this fails, other pessaries can be used. the ring pessary is successful in grades II and III prolapse, but for higher grades, a Gellhorn pessary was more effective. By contrast, a randomised crossover trial of the ring versus the Gellhorn pessary, did not demonstrate any difference in effectiveness between the two types of pessaries. Factors that predict the type of treatment chosen for POP have been evaluated in various studies. Stusies shows that patients who refused a pessary were significantly younger and had a higher incidence of urodynamic stress urinary

incontinence (SUI). More patients with stage III prolapse refused while more patients with stage IV accepted pessary trial. There is no agreement in the literature on what is considered successful fitting of a pessary. Minor complications after pessary insertion range from vaginal discharge, erosion, bleeding pain and constipation as can be seen inreported high complication rate after pessary use.

7. COMPLEMENTARY AND ALTERNATIVE MEDICINES There is minimal evidence that complementary and alternative medicines (CAMs) may influence physiologic function and/or health outcomes. CAMs include those therapies that are not part of the traditional biomedical model, such as meditation, imagery, hypnosis, acupuncture and naturopathic and herbal remedies.

Possible advantages of MStim are that it is performed through full clothing, needs no probes, skin preparation, or physical or electrical contact with the skin surface. On the other hand, the need for repeated clinic based treatment sessions is a potential disadvantage. MStim of the sacral nerve roots and pelvic floor is said to be effective for both UUI and SUI, although the mechanism of action is not fully understood.

6. PESSARIES Pessaries offer a non-surgical option for the treatment of urinary incontinence and pelvic organ prolapse (POP). A range of vaginal pessaries exist which can be broadly divided into two types: support and space-filling pessaries. Support pessaries lie along the vaginal axis, with the posterior component sitting in the posterior fornix and Figure 7: Type of pessaries.

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Surgery for Urinary Incontinence in Women 1. URETHRAL BULKING AGENTS Injectable therapy using bulking agents composed of synthetic materials, bovine collagen, or autologous substances augment the urethral wall and increase urethral resistance to urinary flow. More recently, investigations of stem cell injections have shown promise for use. The injection of bulking agents to treat a dysfunctional urethra is a minimally invasive method of correcting intrinsic sphincteric deficiency that results in stress urinary incontinence but is being performed less frequently in current practice. Evidence in major reviews shows low efficacy rates compared with surgical incontinence therapies, a need for repeat treatments because of symptom recurrence, and problems with the injection of some synthetic agents. However, initial research on the injection of stem cells shows promise with regard to efficacy and durability. Overall, injections of urethral bulking agents can help the group of patients that is unfit or unwilling to undergo surgery for incontinence. Injectable agents have been used to manage stress urinary incontinence for more than a decade, but their application has been limited by placement, durability, antigenicity, and other compatibility issues. The lack of a single, reproducible response from one agent has led to the development and application of several agents that provide reasonable efficacy with minimal associated morbidity. The continuous development of techniques and materials provides the basis for newer bulking agents. Likewise, recent research has shown promise in the use of stem cells in periurethral injections.

Urethral bulking procedures are designed to treat stress urinary incontinence due to intrinsic sphincter deficiency by artificially inflating the submucosal tissues of the bladder neck and urethra. These procedures involve injecting synthetic and autologous fillers into the wall of the urethra to aid in coaptation of the mucosa. Bulking the bladder neck with particulate matter effectively closes the lumen of the urethra by improving urethral coaptation and restores the mucosal seal mechanism of continence. However, issues with migration, leakage, and resorption of injected agents challenge therapeutic durability. Bulking procedures are minimally invasive and are useful for treating women with incontinence who wish to avoid open surgical procedures for various reasons. Methods used to bulk the female urethra include transurethral and periurethral injection techniques. The delivery techniques for the male urethra are largely transurethral. Careful patient selection appears to be important but is not essential for a successful outcome when this form of minimally invasive therapy is considered, especially in less active patients who are at a higher risk for the complications inherent to more invasive procedures. Bulking agents provide an option in the management of women with stress incontinence. Optimization of results is dependent upon repeat injections to achieve and sustain efficacy. Additionally, efficacy with at least some bulking agents appears to diminish with time and may be inferior to surgical interventions. Overall complication rates associated with bulking agents appear to be relatively low.

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Figure 8: The bulking agent being injected into the submucosa of the bladder neck and proximal urethra.

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2. MID-URETHRAL SLING (MUS) Mid-urethral sling procedures are operations designed to help women with stress incontinence. Stress incontinence may be cured or improved with pelvic floor exercises and lifestyle modifications, but if these strategies fail then surgery may be recommended. The most frequently offered type of operation is a mid-urethral sling procedure, a simple day case procedure that has been performed for more than 3 million women worldwide to date. The operation involves placing a sling of polypropylene mesh about 1cm wide (suture material that is woven together) between the middle portion urethra and the skin of the vagina. Normally the muscle and ligaments, which support the urethra, close firmly when straining or exercising to prevent leakage. Damage or weakening of these structures by childbirth and/or the aging process can result in this mechanism failing, leading to urine leakage. Placing a sling underneath the urethra improves the support and reduces or stops leaking. There are three main routes for placing the sling: the retropubic route, the trans-obturator route and the “single incision” or “mini-sling”. There is no clear advantage of one over the other, except for some women with severe stress incontinence where the retropubic route appears to be more successful. Minislings are still in the initial phases of investigation. Although they are less invasive than the other methods they may not be quite as effective in controlling stress incontinence in the longer term, or in women with severe incontinence.

RETRO-PUBIC SLING During the retro-pubic operation the sling is placed through a small cut made in the vagina over the mid point

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Figure 9: Normal Anatomy.

Figure 10: Retropubic Sling.

of the urethra. Through this the two ends of the sling are passed from the vagina, passing either side of the urethra to exit through two small cuts made just above the pubic bone in the hairline, about 4-6 cm apart. The surgeon will then use a camera (cystoscope) to check that the sling is correctly positioned and not sitting within the bladder. The sling is then adjusted so that it sits loosely underneath the urethra and the vaginal cut stitched to cover the sling over. The ends of the sling are cut off and they too are covered over.

TRANSOBTURATOR SLING The transobturator approach to the operation also requires a small incision to be made in the vagina at the same place as for the retro-pubic operation. The ends of the sling are through two small incisions made, this time, in the groin. Each end of the sling passes through the obturator foramen, which is a gap between the bones of the pelvis. The ends are cut off once the sling is confirmed to be in the in the correct position and the skin closed over them.

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research suggests that if it is initially successful in controlling stress incontinence then it is still likely to be working up to at least 17 years later. The other retropubic and transobturator procedures are likely to have similar long term success rates. There is no completely â&#x20AC;&#x153;risk freeâ&#x20AC;? operation for stress incontinence. The three methods of placing the sling have their own specific risks but all can be complicated by: Urinary tract infections , Bleeding, Difficulty passing urine (voiding difficulty), Sling exposure (very occasionally the sling can appear in the wall of the vagina a few weeks, months or years after an operation), Bladder or urethral perforation, Urgency and urge incontinence (Women who have bad stress incontinence often experience urgency and urge incontinence, the leakage of urine associated with the sensation of urgency), Pain etc.

Figure 11: Transobturator Sling.

Figure 12: Minisling.

MINISLING

The sling (or tape) prevents leakage by supporting the urethra and mimicking the ligaments that have been weakened by having babies and the aging process. Once the sling is in position, tissues grow through the holes in the weave and so anchor it in position. This may take 3 to 4 weeks.

The mini-sling procedure is similar to the initial part of retropubic approach, except that the ends of the sling do not come out onto the skin and are anchored in position by one of a number of different fixation techniques.

The most common retropubic operation to be carried out is the TVT (Tension-free Vaginal Tape). This is also the operation that has been done for the longest time, and

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3. NEUROMODULATION Neuromodulation therapy incorporates electrical stimulation to target specific nerves that control LUTS. Neuromodulation includes pelvic floor electrical stimulation (ES) using vaginal, anal and surface electrodes, interferential therapy (IF), percutaneous tibial nerve stimulation (PTNS), and sacral nerve stimulation (SNS). Neuromodulation has been reported to be effective for the treatment of both overactive bladder (OAB) with or without urgency incontinence (UUI) and stress urinary incontinence (SUI). Since Caldwell first used implantable electrodes for ES to treat urinary incontinence, ES has been recognized to be effective for urinary incontinence. However, neuromodulation has not been widely accepted as a first-line treatment for urinary incontinence, because of little physiological and technical information, and it is used when other methods have failed.

system. Recently, a minimally invasive approach to percutaneous placement of the tined lead electrode into the foramen requiring no incisions and no additional fascial anchoring has been developed. This tined lead can be used in the first stage of the SNS procedure, thus offering the possibility of a longer screening duration and no need to change a lead in the second stage. Scheepens et al. reported that change of the permanent placement of the SNS from the abdomen to the buttock resulted in less pain and fewer infections postoperatively, and a reduction of operating time. The unilateral SNS may fail due to malposition of the electrode and local fibrosis. Hohenfellner et al. modified SNS to allow direct and bilateral stimulation of the sacral spinal nerves.

SACRAL NEUROMODULATION

ALTERNATIVE TECHNIqUES OF SACRAL NERVE STIMULATION PUDENDAL NERVE STIMULATION USING THE ‘BION’ The Bion ( Advanced BionicsCorp./Boston Scientific, Valencia, CA) is a miniature, wireless, implantable, one channel neurostimulator that is approximately 2.3 mm long and 3 mm in diameter. The first generation Bion requires multiple recharges during the day. However a newer generation has longer battery life and does not require frequent recharges. The Bion is currently in clinical trials for the treatment of chronic pudendal neuralgia and for chronic pudendal nerve stimulation for the relief of urinary urge incontinence. The procedure requires a special introducer/stimulator which is used to locate the nerve and implant the Bion adjacent to the pudendal nerve within Alcock’s canal. This minimally invasive, wireless, and welltolerated procedure may reduce the degree of detrusor overactivity incontinence, even in patients in whom sacral neuromodulation fails.

Sacral nerve stimulation (SNS)is an implant type of neuromodulation, that uses mild electrical pulses to continuously stimulate the sacral nerves which innervate the lower urinary tract. SNS induces modulation for both excitatory and inhibitory effects on the bladder, and thus the SNS has been indicated for various types of lower urinary tract dysfunction refractory to conservative treatment, such as UUI, pelvic pain and urinary retention. The most rewarding group was found to be patients with refractory UUI. A percutaneous nerve evaluation (PNE) of the S3 roots is recommended as a temporary screening test to determine the response to neuromodulation, and satisfactory responders are implanted with a permanent (chronic)

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Figure 13: Implanted sacral nerve stimulator device.

Figure 14: The Bion device in Alcock’s canal for pudendal neuralgia.

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PERCUTANEOUS TIBIAL NERVE STIMULATION (PTNS) Percutaneous Tibial Nerve Stimuation (PTNS) is a low-risk, non-surgical treatment. PTNS works by indirectly providing electrical stimulation to the nerves responsible for bladder and pelvic floor function. During PTNS treatment, the patientâ&#x20AC;&#x2122;s foot is comfortably elevated and supported. Also during treatment, a slim needle electrode is placed near the nerve at the ankle known as the tibial nerve. A device known as the Urgent PC Stimulator is connected to the electrode and sends mild electrical pulses to the tibial nerve. These impulses travel to the sacral nerve plexus, the group of nerves at the base of the spine responsible for bladder function.

The exact mechanism of PTNS on bladder function is unclear but it is thought that this is mediated through the retrograde stimulation of the sacral nerve plexus. The posterior tibial nerve is a peripheral nerve with mixed sensory and motor fibres. It originates from spinal roots L4 through S3, which also contribute directly to sensory and motor control of the urinary bladder and pelvic floor. A recent study suggests that a plastic reorganisation of cortical network triggered by peripheral neuromodulation could be a mechanism of action of PTNS.

No infections or failures of the PTNS mechanism were detected in the present study, although there were rare cases of minor bleeding and a temporary painful feeling at the insertion site. Most studies reported that there were no serious adverse events associated with PTNS for OAB. In conclusion, PTNS is safe, and is associated with statistically significant improvements in patient-assessed OAB symptoms. Although initial studies showed promise, a more comprehensive evaluation of PTNS is needed to support its universal use for treating the OAB.

Figure 15 & 16: Percutaneous Tibial Nerve Stimuation (PTNS) method for trearting Urge Urinary Incontinence.

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Available Continence Products & Solutions for Management

Available Continence Products for Urinary incontinence Management for women Not all incontinence can be cured completely and even those who are ultimately successfully treated may have to live with incontinence for a time, for example, whilst they wait for surgery or for pelvic floor muscle training to yield its benefits. Still others depending on their frailty, severity of incontinence and personal priorities may not be candidates for treatment or may choose management over attempted cure. For all such people, the challenge is to discover how to deal with their incontinence so as to minimise its impact on their quality of life. This usually involves using some kind of continence product(s) to control or contain leakage of urine. Managing incontinence successfully with products is often referred to as contained incontinence, managed incontinence or social continence, in recognition of the substantial benefits it can bring to quality of life even though cure has not been achieved. Selecting suitable continence products is critical for the well-being and quality of life of patients and carers. The ability to contain and conceal incontinence enables individuals to protect their public identity as a â&#x20AC;&#x153;continent personâ&#x20AC;? and avoid the stigma associated with incontinence. Failure to do so can result in limited social and professional opportunities, place relationships in jeopardy and detrimentally affect emotional and mental wellbeing. The ability to contain and conceal incontinence enables carers to feel confident that the person they care for will not be embarrassed publicly. It reduces the level of care required in relation to maintaining hygiene, skin care and laundry for the person who is dependent upon continence products. Fortunately there is a diverse range of different products to choose from. Furthermore, the range of products actually

accessible to users can vary enormously between and within countries, depending on the funding available, healthcare policy and the logistics of supply. The choice of appropriate products for an individual with incontinence is influenced by the resources and care available and patient / carer preference, as well as assessment of specific client characteristics and needs. The stigma associated with incontinence means that another measure by which the success of products is judged is their ability to conceal the problem. Such concealment may involve compromises: for example, in order to prevent leakage from a product, those with a larger capacity than strictly necessary may be preferred but this can in itself introduce issues to do with discretion when the product is worn. The intimate and stigmatised nature of incontinence means that issues relating to selfimage can affect some patientsâ&#x20AC;&#x2122; preferences. This may be especially marked in younger people for whom body-image may be particularly important and for whom disruption to normal social and interpersonal development may result in isolation or lack of access to normal experiences.

FEMALE HANDHELD URINALS Handheld urinals are portable devices designed to allow a person to empty their bladder when access to a toilet is not possible or convenient, often due to limited mobility, hip abduction or flexibility. They can be especially helpful for those suffering from frequency and / or urgency. Female handheld urinals come in a variety of shapes and sizes. Most are moulded in plastic but they may be made from metal or (for single use items) cardboard. Some are designed for use in particular postures, like standing, sitting or lying down. Some have handles to facilitate grip and positioning. Some are intended to empty into a drainage bag during or after use.

There are nubmer of products and medical devices are for better management of urinary incontinence for female poulataion. These all solutions can be catagorized in so many ways like: products for management the condition, maintenance products, containing solutions, preventive solutions, cure products, therapeutic products, digital assistance for pelvic floor muscle exercise, surgical devices, nonivasive devices, intravaginal products, iserting products and devices, absorbent products etc.

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Figure 1: Female handheld urinal with a storage bag.

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ABSORBENT PRODUCTS Absorbent products (commonly known as pads) are available in a wide range of sizes and absorbencies encompassing light through to very heavy incontinence. Most pads are bodyworn but some are used on the bed or chair. Mobile and independent community dwelling women of all levels of incontinence are reported to generally prefer small pads and are often willing to change them frequently rather than use larger products and change them less often. Conversely, dependent, immobile individuals may prefer the security of larger products despite relatively low urine volumes due to their dependence on others for pad changing. Absorbent products may be classified into two broad categories - disposable (single-use) and washable (reusable) - with each category dividing into two subcategories: bodyworn products (worn on the person) or underpads (placed under the person). Within each subcategory are different design groups such as diapers and pull-ups which are subdivided by size (to fit users of different sizes) and / or absorbency.

Figure 2: A variety of female handheld urinal products.

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Figure 3: A disposable T-shaped diaper.

Figure 4: A reusable diaper brief.

Figure 5: A disposable pull-up for heavy incontinence.

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Figure 6: Disposable inserts for light and heavyincontinence

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Figure 7: Disposable underpad for bed and chair.

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BODYWORN URINALS A female body urinal is disposable urinal to be worn by female incontinent patients. It consists of an adjustable belt having a flexible sheet attached thereto. A urine collecting pouch depends from the sheet, with a disposable vaginal pad provided between the wearer’s body and the sheet. The major challengewith this type of product is in achieving a comfortable and aesthetically acceptable leakproof seal with the body. Various designs have sought to achieve this by holding a collection device over the urethral meatus with the help of suction, straps, adhesive or close-fitting underwear. While none have found widespread success and usage, they are available commercially in some countries.

INTRAURETHRAL DEVICES

INTRAURETHRAL OCCLUSIVE DEVICE.

‘iNFLOW’ INTRAURETHRAL VALVE-PUMP

Urethral inserts are silicone cylinders that are selfinserted or removed at the patient‘s discretion. They are intended for day-time use, especially during vigorous physical exercise. These devices have external retainers or flanges to prevent intravesical migration and proximal balloons to hold the device in place. They act by causing occlusion either in the urethra itself or at the external urethral meatus.

The inFlow™ Intraurethral Valve-Pump is a non-surgical urinary prosthesis for women with incomplete bladder emptying due to impaired detrusor contractility (IDC). The inFlow mimics normal urination, providing a convenient and dignified alternative to urinary catheters. (It is not an incontinence device.) The inFlow is normally replaced every 29 days, but can be easily and safely removed at any time, even by patients. Adverse events are similar to those for urinary catheters.

Intraurethral devices have demonstrated high efficacy, but have been associated with urinary tract infection, hematuria and discomfort.

The inFlow urinary prosthesis is a system with two components:

Intraurethral occlusive devices may be considered for women with stress incontinence but they are invasive devices with high cost and have had limited evaluation.

1. inFlow device – a sterile, single-use urethral insert in a 3-7cm long biocompatible silicone housing, packaged with a disposable introducer to accommodate individual anatomic variations. 2. Activator – a hand-held magnetic remote control required to operate the internal valvepump mechanism in the inFlow device. The Activator comes with a Base Station for recharging its internal battery.

Figure 8: A typical female bodyworn urinal.

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Figure 9: A female intraurethral occlusive device.

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Figure 10: (Top)The inFlow with Introducer and after being deployed. (Bottom) Activator with chargable base station.

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INTRAVAGINAL DEVICES Support of the bladder neck to correct urinary stress incontinence has been achieved, with varying success, utilizing traditional tampons, pessaries and contraceptive diaphragms, and intravaginal devices specifically designed to support the bladder neck.

POISE IMPRESSA Poise Impressa Bladder Supports is an over the counter bladder support that helps prevent urine leaks, instead of absorbing them. Inserted into the vagina like a tampon, Impressa gently lifts and gives support to the urethra â&#x20AC;&#x201D; the tube above the vagina that leads urine out of the bladder. This added support helps prevent urine from leaking out.

Figure 11 & 12: Poise Impressa device and it,s applying process.

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‘FINESS’ EXTERNAL URETHRAL BARRIER

The urethral barrier device is a small, singleuse disposable foam shield that is worn externally over the urethral meatus. It is held in place by an adhesive hydrogel and is easily removed for voiding. Control of incontinence will not be complete in the majority of patients. This is due largely to limitations of the device and the inability of symptoms to completely predict the type of urinary incontinence. The device does not have sufficient adhesive power to prevent urine leakage associated with urge incontinence because the device may be dislodged with a normal voiding effort. Likewise, the device does not have sufficient adherence to control

all stress incontinence and limited clinical experience suggests that it would be ineffective for severe stress incontinence, such as intrinsic sphincter deficiency. The results suggest that the device is safe. Irritative symptoms occurred in a minority of the subjects and rarely resulted in discontinuation of the device. The incidence of irritation with the external urethral barrier is acceptably low in this self-selected population of study participants. This external urethral barrier is a new device for women with mild to moderate stress urinary incontinence. The results of this study indicate that it is a safe and effective alternative to absorbent products.

Figure 13 & 14: ‘Finess’ external urethral barrier device and it’s placement process.

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CATHETERS Urinary catheters can provide an effective way of draining the bladder in either the shortterm or longterm, by intermittent or indwelling catheterisation, where alternative strategies are unsuitable or unsatisfactory. However, indwelling catheters are rarely completely trouble free and the risk of catheter related complications is high, with substantial detrimental impact on patients, carers and healthcare services. It is generally agreed that catheter use should be avoided wherever possible and only adopted for those for whom alternative strategies are unsuitable or unsatisfactory, after careful assessment of the patient and their particular problem.

INTERMITTENT CATHETERISATION Intermittent catheterisation (IC) is the act of passing a catheter into the bladder to drain urine via the urethra, or a catheterisable channel. The urine can be drained into a toilet, urinal, plastic bag, or other reservoir. The catheter is removed immediately after drainage. This technique avoids many of the problems associated with indwelling catheters. Intermittent catheterisation may be carried out using a sterile technique in some care settings, but clean intermittent catheterisation (CIC) or clean intermittent selfcatheterisation CISC is widely accepted as a safe technique for people who are self-caring in their own homes. CIC provides much greater convenience than urethral catheterisation, without unacceptable increases in infection rate, and has become a method of choice for management of bladder drainage for neurogenic and nonneurogenic bladder dysfunctions. Urinary tract infection is well-recognised as the most frequent complication of intermittent catheterisation. The accumulation of urine in the bladder provides a reservoir for infection, but it has also been proposed that

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the increased intravesical pressure reduces the vascular supply to the bladder tissue rendering it more susceptible to bacterial invasion. A post-void residual urine volume of 150ml has been demonstrated to be an independent risk factor for the development of UTI. INDWELLING CATHETERISATION Indwelling catheters may be used in the short-term to manage an acute need for controlled bladder drainage or as part of a long-term management strategy. Catheters may be inserted into the bladder urethrally (UC) or suprapubically (SPC) through an incision in the abdominal wall. The continued requirement for indwelling catheterization should be reviewed at regular intervals and the catheter removed promptly if no longer necessary, since catheter use is associated with a number of risks. catheter use is associated with a number of risks. The major complication associated with short-term, indwelling catheters used in acute care, is nosocomial (healthcare acquired) catheter-associated urinary tract infection (CAUTI), which can lead to life-threatening bacteraemia in vulnerable groups and may also contribute to reservoirs of antibiotic resistant microorganisms.

Figure 15: Catheter disassembled.

Figure 16 & 17: Indwelling Foley catheter for women & closed urinary drainage method.

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URETHRAL SLING Urethral sling surgery, also called mid-urethral sling surgery, is done to treat urinary incontinence. A sling is placed around the urethra camera.gif to lift it back into a normal position and to exert pressure on the urethra to aid urine retention. The sling is attached to the abdominal (belly) wall. The sling material may be muscle, ligament, or tendon tissue taken from the woman or from an animal, such as a pig. It may also be composed of synthetic material such as plastic that is compatible with body tissues or of absorbable polymer that disintegrates over time. These surgeries involve incisions, so hospitalization is required. To allow the urinary tract to heal, a thin, flexible tube (catheter) is placed into the bladder through the urethra or belly wall to allow urine to drain. Figure 18 & 19: Mid urethral sling position. A sling mesh with operating tools. Like any surgery, urinary incontinence surgery comes with risks. Although uncommon, potential complications include: Temporary difficulty urinating and incomplete bladder emptying (urinary retention), Development of overactive bladder, which could include urge incontinence, Urinary tract infection, Difficult or painful intercourse etc.

Figure 20: Pubovaginal sling operation procedure.

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RE-ADjUSTABLE SLING FOR FEMALE TRT REMEEx SYSTEM The TRT Remeex System is the only long term readjustable sling for Female SUI. This prothesis allows a reliable readjustment of the sling urethral support whenever needed during patientâ&#x20AC;&#x2122;s lifetime. Surgeon can provide a long-term continence, and avoid re-operating again a patient with a sling failure. Conventional surgery for female stress incontinence is usually successful but recurrent cases are difficult to treat. This study of 20 such cases treated by the Remeex TRT system shows symptomatic benefit up to 5 years following insertion of the device. The benefit of this procedure is that the sling can be adjusted to the correct tension in the optimum leak position and circumstances, and anytime thereafter without the need to repeat the entire operation. As a result, the voiding dysfunction rate and need to intermittent self-catheterise is reduced, even with a low pressure urethra. The cost per procedure and complication rate is higher that standard TVT, and the device may occasionally need removal due to persistent seroma. However, the improved quality of life makes this operation an attractive option in recurrent cases of female stress incontinence.

Figure 21 & 22: The TRT Remeex sling.

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Figure 23: Implanted adujustable switch in pubic region.

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INFLATABLE ARTIFICIAL SPHINCTER The evolution of the artificial urinary sphincter has affected the current surgical options for urinary incontinence With its unique features, the artificial urinary sphincter (AUS) has been an attractive option for the treatment of urinary incontinence regardless of gender. For female AUS implantation is a safe and effective surgical option for the treatment of urinary incontinence of various etiologies. An inflatable artificial (human-made) sphincter is a medical device that keeps urine from leaking when the urinary sphincter no longer works well. When need to urinate, the cuff of the artificial sphincter can be relaxed so urine can flow out.

incontinence, a leakage of urine that occurs with activities such as walking, lifting, exercising, or even coughing or sneezing. The procedure is recommended for Women who have urine leakage usually try other treatment options before having an artificial sphincter placed. The artificial urinary sphincter is safe and effective in management of urinary incontinence in both males and females. For female urinary incontinence. Despite being effective with a high satisfaction rate, the pitfall of the AUS remains the high complication, reoperation and explantation rates. Evolution in the design of the device and surgical technique has reduced but not eliminated these problems.

Figure 24: An artificial urinary sphincter device for women.

An artificial sphincter has three parts: •

• •

A cuff, which fits around the urethra, the tube that carries urine from your bladder to the outside of body. When it is inflated (full), the cuff closes off the urethra to stop urine flow or leakage. A balloon, which is placed under your belly muscles. It holds the same liquid as the cuff. A pump, which is placed underneath the skin in a woman’s lower belly or leg. The pump inflates the cuff.

AUS implantation is not without untoward complications. Studies reported an overall complication rate of 37%. Common complications includes: • • • •

Damage to the urethra, bladder, or vagina. Difficulty emptying your bladder, which may require a catheter. Urine leakage that may get worse. Failure, infection, or wearing away of the device that requires surgery to remove it.

Artificial sphincter surgery is done to treat stress

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Figure 25: An artificial urinary sphincter,s implantation position .

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IMPLANTED SACRAL NERVE STIMULATOR DEVICE InterStim The Medtronic InterStim therapy system works by applying electrical stimulation to the sacral nerves (S2, S3 or S4). Electrical stimulation of the sacral nerve allows for activation or inhibition of effector organs that the sacral nerves innervate (bladder, urinary and anal sphincters and pelvic floor). Patients undergo a test stimulation to temporarily experience the effects of the therapy on their symptoms. Test stimulation can be performed either with a temporary lead, that is removed following test stimulation, or with a permanent lead that remains implanted and is connected to the neurostimulator in a “staged implant.” Patients with a successful test stimulation result may proceed with surgical implantation of the neurostimulation system for long-term therapy.

upper buttock (or abdomen). After recovering from surgery, the neurostimulator is programmed by the physician using the physician programmer (loaded with the InterStim application software). Based on patient feedback, programming adjustments can be made by the physician. Additionally, the physician can allow the patient to make certain adjustments in pulse amplitude using the patient programmer. At any time, the patient can turn the stimulator ON or OFF using either the patient programmer or the control magnet.

Figure 27: InterStim device.

Test stimulation involves the use of an external test stimulator, lead, and accessories. The neurostimulation system involves the use of a neurostimulator, lead, lead extension and external patient and physician programmers. The InterStim Therapy System is implanted in a “two-phase” fashion: test stimulation to evaluate whether the patient will respond to the therapy and if the patient exhibits at least a fifty percent decrease in the number of incontinent episodes in a week, permanent implantation of the InterStim Therapy System. During the chronic implant phase the percutaneous extension and test stimulator are removed and replaced with the implanted lead extension and implanted neurostimulator. After connecting the lead extension to the lead, the extension is tunneled to the upper buttock (or abdomen) where it is connected to the neurostimulator. The neurostimulator is implanted subcutaneously in the

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Figure 26: InterStim implantation site an osition.

Figure 28: InterStim implantation procedure.

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PERCUTANEOUS TIBIAL NERVE STIMULATION DEVICE URGENT PC DEVICE Percutaneous Tibial Nerve Stimuation (PTNS) is a low-risk, non-surgical treatment. PTNS works by indirectly providing electrical stimulation to the nerves responsible for bladder and pelvic floor function. A device known as the Urgent PC Stimulator is connected to the electrode and sends mild electrical pulses to the tibial nerve. These impulses travel to the sacral nerve plexus, the group of nerves at the base of the spine responsible for bladder function. Percutaneous tibial nerve stimulation therapy is provided in the outpatient clinic setting. A 34-gauge needle electrode is inserted approximately 5 cm cephalad to the medial malleolus and posterior to the tibia. with a surface electrode on the arch of the foot; percutaneous nerve stimulation at a current level of 0.5â&#x20AC;&#x201C;9 mA at 20 Hz is performed initially for 30 minutes weekly for 12 weeks, followed by occasional treatments as needed based on patient symptoms. The posterior tibial nerve is a mixed sensory-motor nerve, containing axons passing through the L4â&#x20AC;&#x201C;S3 spinal roots. The sacral roots also contain the peripheral nerves involved in the sensory and motor control of the bladder and pelvic floor, and are the same spinal tracts targeted by sacral neuromodulation. Electrical stimulation of these nerves inhibits bladder activity by stimulating large diameter somatic afferent fibers, which in turn evokes a central inhibition of the micturition reflex pathway in the spinal cord or the brain. Although it is likely that stimulation of the sacral roots, (SNS), stimulation of the pudendal nerve, and stimulation of the tibial nerve (PTNS) all affect central components of the neural circuits controlling the bladder, there may be significant differences.

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Figure 29: A: Urgent PC PTNS device. B & C : using procedure of PTNS device.

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INTRAVAGINAL PELVIC FLOOR STIMULATOR ‘ELISE’ PELVIC FLOOR ExERCISER The Elise Pelvic Floor Exerciser is simple and easy to use, with an elegant, slim-line design and rechargeable battery for enhanced mobility. A drug-free, non-surgical solution, the Elise Pelvic Floor Exerciser provides freedom from the use of containment pads and can help sufferers return to a normal lifestyle. The Elise sends a gentle stimulation to your pelvic floor through a vaginal probe, working your pelvic floor muscle for you and enabling you to develop your own muscle control. Along with pelvic floor exercises, the Elise gently strengthens and tones your pelvic floor muscle which in-turn improves the symptoms of incontinence (bladder weakness). Sessions last for just 20 minutes a day and should be used for a period of 12 weeks. Many see improvements within as little as 3-4 weeks. Figure 30: The Elise Pelvic Floor Exerciser. ‘INTONE’ PELVIC FLOOR STRENGTHENER InTone treats the underlying causes of incontinence—weak pelvic floor muscles and an over-active detrusor muscle. Intone combines the non-invasive treatment approaches of electrical stimulation. InTone provides a Voice Guided Exercise Program, Visual Biofeedback, an Inflatable Probe and Muscle Stimulation at specific frequencies in an alternating manner to cure incontinence. Inflation customizes fit to each patient and presses stimulation contacts against the muscle wall ensuring a deep muscle contraction and patient comfort. High Frequency Stimulation strengthens the levator ani of the pelvic floor and the external urethral sphincter, elicits a full contraction of the pelvic floor providing neuromuscular re-training. And low Frequency Stimulation calms spasms of the detrusor muscle

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Figure 31: InTone Pelvic Floor strengthener.

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NON INVASIVE PELVIC FLOOR STRENGTHENER INNOVOTHERAPY Innovotherapy is a non-invasive way to restore your pelvic floor, treating the primary cause of urinary leaks rather than just masking the symptoms. Using a hand held controller that is attached to a two part garment, Innovotherapy sends targeted impulses via a set of conductive pads (attached to your upper thigh and buttocks) to safely and effectively activate all the muscles of the pelvic floor or to calm your bladder. It is a proven technology which has been designed to optimally strengthen your pelvic floor with 180 perfect contractions per session, allowing the device to do your pelvic floor exercises for you. For ultimate results the full Innovotherapy programme involves completing five x 30 minute sessions per week over a 12 week period. No need to hide away in the bathroom either, INNOVOÂŽ is designed for home use, so user can simply pop the garments on under comfy pants or shorts and still be in the same room as your family if she wish.

Figure 32: (top) Innovo therapy method. (bottom) innovo stimulator device with pads.

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PELVIC FLOOR EXERCISE TRAINER ELVIE Elvie, the device (which has to inserted in the vagina) takes the idea of “personal training” to improve the condition or strengthen the pelvic mussle floor for incontinent person or who wants to prevent themselves from earliy stages after giving childbirth. Elvie has multiple sensors including a dynamometer, which helps the device measure force applied to any spot on the pod. That means ladies can use this anywhere, while walking or standing in addition to lying down. Means pelvic floor workout can be done any time and anywhere. As per TechCrunch report, some women told Elvie’s creators they wanted to be able to do Kegels anywhere, so the female team figured out a way to make them comfortable and effective no matter where you are. The accompanying app offers workouts that can teach you the correct way to work your pelvic floor (by lifting up instead of pressing down) with feedback in real time, and users can track their progress via a personalized score. Though it will not be considered as a medical product, but still it can be seen as a preventive solution for vaginal health. Threre few more similar products are also available in market like, KaGoal, SKEA etc with similar features and functions.

Figure 33: Elvie device with the App.

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MOBILE APP Tät Tät is a research project at Umeå University. The app Tät®II is a new complex, interactive app, developed for women with urge incontinence (urinary leakage associated with a sense of urgency) and mixed incontinence (leakage associated with a sense of urgency and with physical exertion). The effect of treatment via the app Tät®II is being assessed in an ongoing study.

reminders helped and motivated them to perform their training regularly,” Asklund explained. For women who’d prefer to manage their incontinence themselves, this is an option worth trying, she says: “There are many health apps, but very few are evaluated in research studies.”

Essentially, Tät is a training program for your pelvic floor. It guides you through progressively challenging exercises to build up strength; when you master one, you move on to the next. And for each exercise, graphics illustrate how long, and how intensely, you should contract your muscles. The app also offers lifestyle advice, and lets you set reminders so you stick to your regular “workouts.” To find out whether Tät actually makes a difference, researchers from Umeå University in northern Sweden split 123 women with stress incontinence into two groups. One group used the app for three months. The other group, a control, received no treatment. According to the authors, who published their findings in the journal Neurology and Urodynamics, Tät yielded “clinically relevant improvements.” At the end of the study period, participants in the app group had fewer leaks per week, used fewer pads, and reported better quality of life. “Two thirds of the women using the app were satisfied with the treatment outcomes,” lead author Ina Asklund, PhD, told Health in an email. One of the aspects of Tät they appreciated most Its accessibility. “Women experienced that the app was suitable for this kind of [pelvic floor] training since they carried their smartphones with them at all times, and the

Figure 34: Few screenshots from Tat app.

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Social Aspects

Socio-psychological Impacts of Urinary Incontinence on Quality of Life Urinary incontinence is frequently associated with a negative impact of quality of life of the patient. It is not really a disease, but rather a symptom, as a result of either a bladder or sphincter disorder. Urinary incontinence (UI) is a relatively common condition in middle-aged and older women. Although it is not a life-threatening condition, UI negatively impacts health-related quality of life (QOL) by affecting daily living activities, sexual and interpersonal relationships, psychological well being and social interactions. Incontinence, in whichever form, sweepingly affects the life of the patients. It is conceived as a lack of health which generates feelings of anger and sadness, as well as embarrassment and depression. Patients avoid social gatherings and lose self-confidence, which has a proportional impact on their social interactions, their sexual life and emotional health. Apart from the emotional repercussions, however, incontinence is a risk factor for other physical conditions and diseases, while simultaneously being a financial burden on the patient and his or her family. Even though, the prevalence of urinary incontinence is similar to other chronic diseases, research with regards to its effect on the quality of life of the patients have started only recently in the last fifteen years. Researchers have designed, developed and suggested the use of various questionnaires which are completed by the patients themselves, whereby via the appropriate questions the degree of the effect of urinary incontinence on the patients’ health and generally on their quality of life is revealed, graded and evaluated more objectively. Urinary incontinence is an obstacle in good physical and

social well-being and consequently it is an obstacle to the patient’s maintenance of general fitness. Self-confidence is reduced by the disability to control the bladder and by matters such as cleanliness, which already contribute to the psychological problems. Often, too, this may be accompanied by alienation from family and friends and this may be additionally detrimental to the patient’s selfconfidence. Urinary Incontinence is related to reduced personal and social life and to reduced total quality of life. It may seriously affect sociability, and the social gatherings the patient attends are modified so that possible unpleasant moment and embarrassment by sudden loss of urine are avoided. Urge incontinence especially may have an especially intense and negative impact on the quality of life as it affects social presence, psychological mood, work environment, family surroundings and fitness and sexual life. Urge incontinence affects healthy way of life than incontinence by effort, because a hyperactive bladder is harder to control, more often it will interrupt sleep or other daily activities. RELATIONSHIP FACTORS The relationships of husband and wife can be significantly affected by urinary incontinence.Nilsson et al. showed that 38% of women and 32% of men reported that the female partner’s incontinence impacted negatively on their relationship. Furthermore, 20% of women and 17% of men reported reduced intimacy, affection and physical proximity. One quotation from the study which illustrates these statistics reads: ‘I become nervous and cannot

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actually relax. I am anxious about smelling bad and urine leakage when we are closely intimate’. SOCIAL WITHDRAWAL This is another key area of daily living affected in women who experience urinary incontinence,who are often forced to give up outside activities such as swimming, dancing, long walks and other physical exercise. Study shows that women with mixed incontinence perceived their urine leakage to be a greater barrier to exercise than those with pure stress or urge incontinence. Women suffering from urinary incontinence are being forced to give up such activities due to the psychological distress they experience and by doing so they ultimately lead a more sedentary lifestyle. Obese women with urinary incontinence can find themselves stuck in a vicious cycle. They are often advised to lose weight before undergoing surgery, but they cannot exercise due to their urine leakage during physical activity.They therefore abstain from exercising and are more likely to gain weight, postponing their surgery for incontinence further. The wider health implications for these women are of even more concern. They are potentially increasing their risk of developing other more serious and costly medical conditions such as type II diabetes and ischaemic heart disease. That’s how majority of these group of people stops going out of home, avoid social gathering, social interaction for the fear of being incontinant in publically and feeling of shamed and disgust. And this fear leading to social withdrawl and isolation.

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OCCUPATIONAL RESTRICTION Urinary incontinence is common among employed women and has a potential impact on working life and performance. Symptoms of urinary incontinence shown to cause occupational restriction as a result of worries regarding feeling wet and smelling of urine. These concerns can lead to loss of concentration, loss of ability to perform physical tasks and interruption of work for toilet breaks.

include the need to pack protective materials such as sanitary pads, in case of urine leakage, thinking of a way to dispose of used pads and the need to change into dry clothing. Each of the points mentioned above demonstrates the degree to which urinary incontinence has a potential impact: it is an inconvenience for these women and they may become reluctant to travel. QUALITY OF SLEEP

Ultimately, each of these has a negative impact on womenâ&#x20AC;&#x2122;s work performance and, of equal importance, their self-confidence at work. It was also shown that urinary incontinence is, indeed, common at work: 37% of employed women reporting urine leakage at work. It was also seen that the negative impact that urinary incontinence had on the working life of women increased as the severity of urinary symptoms increased. FEAR OF TRAVELS Travelling or going somewhere can be a stressful time for anyone.For women suffering from urinary incontinence, what should be an enjoyable trip can often become a daunting and traumatic experience. These women often feel reluctant to visit new places and worry that there will be no toilets nearby or that there will be no bathroom facilities at all. Public toilets is a concern and travel on transport without toilet facilities can seem like a nightmare for them. This concern is more common in women suffering from an overactive bladder, as the worry of urgency and urge incontinence without access to a toilet worsens the condition and a vicious cycle develops. The end result of all of these concerns is that the woman is likely to stay at home and not travel. There are also practical issues in relation to travel. These

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The quality and amount of sleep is most negatively affected in those suffering from an overactive bladder. Women may be woken up several times a night with the urgent need to urinate and they may not always make it to the bathroom in time, either wetting the bed (enuresis) or being incontinent on the way to the bathroom. Even in the absence of real urgency, nocturia is a common (and occasionally the only) symptom of an overactive bladder. As well as the sleep disturbance caused by getting up several times per night, there is a risk of falling, especially in the elderly,with the potential for fracturing the neck of femur and all its associated morbidity and mortality. Women suffering from stress incontinence may feel uncomfortable if they leak urine while in bed; for example when turning over, changing position or coughing. Furthermore,wearing protective pads in bed can be uncomfortable and irritating,which can have a negative impact on the quality of sleep. PSYCHIATRIC MORBIDITY As demonstrated above, urinary incontinence can have a negative impact on many aspects of daily living. Psychological morbidity is common in women with urinary incontinence and is likely to result directly from the impact

on quality of life. These women often report having low selfconfidence, feeling ashamed and embarrassed and feeling unattractive to others. Each of these is an obstacle to good psychological well-being. There is also a wealth of evidence that women with incontinence have coexisting psychiatric illnesses. Datas showed that major depression was three times more common in women with urinary incontinence than in continent women. This is an important point to consider, as comorbid depression can augment the feelings of low self-esteem and embarrassment associated with incontinence, leading to increased social withdrawal. It is, therefore, vital to screen for and treat comorbid depression in women with urinary incontinence. The association between psychiatric illness and incontinence is thought to be multidirectional. Historically it was felt that neurotic and anxiety states were the cause of unstable bladder contractions and urge incontinence and there is certainly a neuropharmacological hypothesis to explain this: urge incontinence has been associated with alterations in neurotransmitters, leading to uninhibited contractions of the detrusor muscle. Incontinent women are burdened with anxieties and feelings of embarrassment and shame and they live in constant fear that others will discover their condition. Womenâ&#x20AC;&#x2122;s sexual function and relationships with their partners are significantly affected by their incontinence, thus augmenting their feelings of low self-confidence. Furthermore, major depression has been shown to be more common in incontinent women, adding to the cycle of low self-esteem, increased social withdrawal and, ultimately, a reduction in quality of life.

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THE IMPACT OF URINARY INCONTINENCE ON FEMALE SEXUAL DYSFUNCTION Urinary incontinence (UI) is a common disorder that affects a large number of women and their quality of life. A total of 423 million people worldwide are estimated to present with UI by 2018. Incontinent women have been reported to present urinary leakage during sexual penetration and orgasm, difficulties reaching orgasm, and less desire, lubrication, and satisfaction. For those women who experience leakage of urine during sexual activity, it has been suggested that UUI and SUI show a stronger association with leaking urine during orgasm and during penetration, respectively. Sexual health is important to the self worth, emotional well being, and overall quality of life of women in midlife. However, urinary incontinence, which is prevalent in this population, has a negative impact on sexual function. Urinary Incontinence had a significant impact on women’s sexual life. Women with UI had a higher probability of sexual abstinence compared with women without UI. Furthermore, women with UI showed less sexual desire, sexual comfort, and sexual satisfaction than their counterparts despite having a similar frequency of sexual activity. FEMALE SExUAL RESPONSE Master and Johnson at the 60’s and 70’s concluded that sexual response occurrs in a linear and sequential fashion involving four phases: arousal, plateau, orgasm and resolution. In the end of the 70’s Helen Kaplan proposed a modification of the sexual response model, reinforcing the role of sexual desire and grouping it in three phases: desire, arousal and orgasm. In various studies the use of this model of linear sexual response was successively questioned in relation to its applicability in women: many

do not present this sexual response, and are considered inadequate, even if they do not considered themselves as such. The sequence of phases was also questioned, since there was an overvaluation of biological and physical phenomena in detriment of conditionings of female sexual pleasure and satisfaction. Basson (2001) presented a non-linear model of female sexual response integrating emotional, psychological, and cognitive aspects and external sexual stimulants. According to this model, sexual response starts with sexual desire (spontaneous or not, externally or through cognitive motivation). Sexual arousal includes subjective sensation of arousal or physiological arousal with poor correlation between them. The presence of sexual desire and sexual arousal are not sequential although both are important to achieve sexual satisfaction. This model is adopted by International Consensus on Sexual Medicine, International Classification of Diseases (ICD) and also by the diagnostic and statistical manual of mental diseases. Women’s sexuality and sexual function are complex issues, and the role of UI is not completely clear. The effect of UI on sexuality is associated not only with leaking urine during sexual penetration or orgasm but also with several confounding variables, such as aging, pelvic surgery, hormonal influence, self-image perception, and chronic diseases, which are risk factors for sexual dysfunction and present a high prevalence in women with UI. Various observational study designed to identify factors that might contribute to sexual dysfunction in women with UI. Few studies have compared the sexuality of incontinent and continent women with similar demographic characteristics. Their findings showed that the worst sexual dysfunction scenario, which is abandoning a sexual

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life, in women with UI was significantly more prevalent than in their counterparts. Evaluated report shows sexually active women, the UI group had less sexual desire, sexual comfort, and sexual satisfaction than their counterparts, despite having a similar frequency of sexual activity Leaking urine during sexual intercourse was reported as an embarrassing condition by most of incontinent women. Results showed that women with UI were more likely to present with sexual abstinence. UI is one of several variables that could interfere with sexuality. SExUALITY AND URINARY INCONTINENCE Although it is assumed that there is a high probability of influence of urinary incontinence on sexual life, the studies present very different results probably due to the great variability of investigation methods. Urinary incontinence may trigger problems related to sexual female life, namely: loss of urine during coitus (coitus incontinence), night losses associated to urgency and fear of bedwetting. Fear of malodorous and urinary incontinence during coitus are associated with alteration of image and self-esteem responsible for low frequency of sexual activity among incontinent women. In elderly population, in the presence of a sexual partner, the occurrence of urinary incontinence has a negative impact on sexuality. Urinary incontinence related to coitus has been described in two ways: urinary incontinence associated to penetration and associated to orgasm. Incontinence associated to penetration is associated to SUI and is related to probable intrinsic dysfunction of sphincter. Coitus urinary incontinence associated to orgasm has been related to detrusor overactivity. Several papers studied the relationship of different kinds

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of urinary incontinence and sexuality. Studies concluded that urgency symptoms, especially in the presence of MUI, were associated to anxiety disturbances, mood disturbances (depression symptoms) and low quality of life of SUI in the context of sexual life. UUI related to reduction to lubrication and increase of pain associated to sexual activity. MUI was related to reduction of sexual satisfaction while SUI did not present any impact on sexual relation. SExUALITY AFTER URINARY INCONTINENCE TREATMENT Conservative treatment of urinary incontinence using pelvic floor muscle training (PFMT) presented an improvement of functional parameters of the domains desire, arousal and orgasm, regardless the type of urinary incontinence. This benefit is mainly relevant in patients with an initial evaluation with significant disturbances of sexual function. The studies pointed an improvement of sexual function with the strengthening of pelvic floor muscles in SUI, including patients with coitus incontinence associated to penetration. Surgical treatment of urinary incontinence has been studied in the context of SUI treatment. It is cited an improvement of sexual function in patients with SUI that also presented coitus urinary incontinence. Women without incontinence during coitus prior to intervention did not present improvement of sexual function even in the presence of improvement of global quality of life. In a percentage of patients submitted to surgical correction of SUI using suburethral slings there is prejudice of sexual function, including reduction of libido, dyspareunia or sexual inactivity. Surgical treatment of UUI (through sacral neuromodulation) is poorly studied in relation to sexual

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function and the existent studies involve small samples of patients but in general show improvement of questionnaire evaluation of sexual function. First line of treatment of clinical treatment of OAB syndrome and UUI includes anti-muscarinic and beta3-agonists. There are very few studies about the repercussion of those drugs on sexual function. Only studies of oxibutinin and tolterodin have been published on the subject. Oxibutinin lowered coitus incontinence, associated shame/disturbance and improved sexual life, relationship with partner and increase of sexual interest. Tolterodin showed a higher sexual and mental health.

neuromodulation has a positive influence on both domains, but for definite conclusion more studies are necessary.

CONCLUSIONS The presence of urinary incontinence is associated to stigma, fear, embarrassment and shame related to clinical condition, with repercussion on self-esteem and disturbance of personal, social and sexual life. Urinary incontinence affects negatively female sexual life. Fear of intimacy associated to sex activity is evident in view of the lower frequency of sexual activity and low sexual satisfaction among incontinent women. The development of adaptation strategies to incontinence may reduce the impact that the loss of urine may have on sexual activity, but these techniques have greater benefit on stress urinary incontinence. Conservative treatment (PFMT) of urinary incontinence improves quality of life and sexuality, regardless the type of incontinence. Studies demonstrate an improvement of quality of life and sexual function after surgical treatment of SUI. After treatment of UUI, it is identified an improvement of quality of life and sexual function in individuals who receive anticholinergics. Sacral

BIJOY PRASAD SAH A | M.DES 2017 | GRADUATION PROJECT | NID

INCONTINENCE AS SOCIAL TABOO A majority of people with UI have not sought help. Generally reasons given by people for not seeking help include: not regarding incontinence as abnormal or serious, considering incontinence to be a normal part of ageing, having low expectations of treatment and thinking they should cope on their own.

women have had surgery, medication, or exercise regimens. In addition to seeking help from the formal health care system, common responses to symptoms of illness are self-management and self-treatment behaviour. The major method of actively managing UI among community residents is the use of absorbent products.

misconceptions:

•

URINARY INCONTINENCE IS INEVITABLE PART OF AGING.

Incontinence is not a life-threatening disease but affects all the strata of the society. It is a common and distressing problem and can negatively affect one’s quality of life. People living with the condition are often embarrassed to discuss their problems to anyone, including their doctor. In fact the ‘World Health Organization’ (WHO) calls incontinence ‘one of the last medical taboos’.

It is obvious that millions of women suffer from their UI, and that for many of them good treatment options are available. However, for many persons with very mild or occasional UI it is probably adequate not to seek help from the health care system. Others are satisfied with just information and understanding about the causes and in many cases self care may be quite appropriate.

•

URINARY INCONTINENCE IS A NORMAL PART OF BEING A WOMAN.

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URINARY INCONTINENCE CAN NOT BE TREATED.

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THERE ARE NO EFFECTIVE TREATMENTS FOR URINARY INCONTINENCE.

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OLDER ADULTS DON’T MIND BEING INCONTINENT AND WEARING PADS.

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PREVENTION IS IMPOSSIBLE.

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THE ONLY SUCCESSFUL TREATMENT FOR URINARY INCONTINENCE IS SURGERY.

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THE INDIVIDUAL IS HAVING ACCIDENTS ON PURPOSE.

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ExERCISE CAN NOT IMPROVE THE CONDITION.

•

INCONTINENCE IS EMBARRASSING, BUT NOT SERIOUS.

Some studies also confirm the notion that embarrassment may be an important reason for not seeking help. There is an association between help seeking and conditionspecific factors like duration, frequency and amount, and people’s perceptions of the impact of incontinence, but other more personal characteristics like individual health care behaviour and attitudes may also play a role. There are reports of doctors not responding, either by ignoring the statement of symptoms or by providing a dismissive explanation, and people interpreting a lack of response from the doctor as an indication that no treatment is available. In a study by ICS about management of incontinence in general practice, 30% of the women who had told their doctor about their symptoms perceived that they were offered no help. It is probable that many primary health care providers lack confidence in managing UI, and that this contributes to under treatment in those seeking help. Only a small proportion of incontinent communityresiding

SOCIAL MYTHS ABOUT INCONTINENCE Some clinicians may be uncomfortable uttering this sentence to patients, but many older adults suffering silently with urinary incontinence may be relieved to hear it. Many wrongly believe that, like wrinkled skin, incontinence comes with age. Uninformed of treatment options, incontinent older adults make do, possibly restricting social activities and feeling anxious about when the next episode will occur. Indeed, one study found that one-third of independently living incontinent older adults reported that they had never mentioned their incontinence to a physician. They felt that “it is not important enough” and that treatment is appropriate only for younger people. There are number of myths associated with urinary incontinence among women population. These myths, rooted in the insidious stereotypes and prejudices of ageism, hinder efforts for both patients and providers. Following are some of the most prevalent of these

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STIGMATIzING URINARY INCONTINENCE

BELIEFS ABOUT THE CAUSES OF INCONTINENCE It is very common belief among the general poulation that incontinence is the utterly predictable and inevitable result of a normal process of the body’s weakening with age. The disintegration of bodily systems was seen to be a normal part of the aging process, about which the individual and the medical care system could do nothing. In most of the studies informants considered normal aging to be the primary explanation for incontinence. Few of women resposes to questions about “why” incontinence occurs: “It’s just that the body’s wearing out, that’s all. I just consider that it’s my age and it’s to be expected.” “It is part of getting older, I think. I don’t think it’s a disease . . .just a body change.” Their reasons for not seeking medical care indicated that incontinence was “not important enough” to bother a doctor with and that treatment for incontinence was only appropriate for younger people. It is also seen that, this belief that incontinence is a normal, irreversible part of the aging process is often supported by interactions with health professionals. Other research shows those incontinent people who did mention their incontinence to a physician, nearly half reported that the doctor had not responded to their report, either by ignoring the statement of symptoms or by providing a dismissive explanation. They did not send patients for diagnostic evaluations and offered few interventions. This non-response by physicians has been reported by other authors as well. Nevertheless, it is clear that whatever occurs in the consulting room has the effect of normalizing incontinence- suggesting that, by its very commonality, it is a predictable, and hence normal, part of aging.

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Although urinary incontinence is thought to be the result of aging, this does not mean that people happily accept having this disorder. It assaults their sense of adulthood through its association with early childhood, when bladder control had not been established, and it compromises their ability to participate fully in normal social life. Incontinent older people are ashamed, embarrassed, and distressed by this disorder. Fears-and stereotypes-associated with public incontinence come early in life. Maintaining such control is a central aspect demanded of “normal”people. Shame and disgust are intimately linked to people’s conserns about the violation of norms to do with the body’s cleanliness and purity. We feel shame most interestingly when our bodies have let us down in a way that compromises our purity and dignity, especially when our failure is exposedfor others to see. The sharp distinction between public and private and the reorganization of one’s life that this strategy demands lead to increasing social isolation. This association of urinary incontinence with social isolation has been documented in a number of studies. An incontinent elder isolates herself at home, where loss of bladder control is tolerable, and avoids visitors because their presence would threaten these normalizing strategies. Finally, there is a group of people who are too impaired even to manage the social isolation necessary to retain public competence. These form a small portion of the incontinent elderly, but their flagrant incontinence is public information, due to their physical or cognitive inability to keep it secret. The consequences of this inability to keep a secret are truly profound. These are the incontinent people who are subject to gossip, hostile actions, and other forms of severe social ostracism.

Several studies indicate stigma is the main reason for not seeking treatment among UI women. Stigma is defined as an attribute discrediting an individual, reducing him or her “from a whole and usual person to a tainted, discounted one”, and it is typically a social process of rejection, blame, or devaluation. The stigmatization of physical or mental diseases involves not only the public stereotyping (i.e. social rejection, exclusion, or discrimination) of these patients but also the internalization (i.e. shame, humiliation, or embarrassment) of these stereotypes by the patients. UI is a stigmatized attribute, and the level of shame and embarrassment for UI is higher than that for depression and cancer. UI has frequently been linked with incompetence because control and self restraint is important to notions of adulthood. The previous research on stigma and care-seeking behaviors for UI falls short in the measurement of stigma. Self-reported single-term shyness or embarrassment was often used instead of a valid conceptualized instrument, which may obscure the association of stigma with careseeking behaviors. Women may choose to deal with the problem silently. Relevant data support the negative effect of stigma on intentions to seek care. Most of the incontinent person experienced stronger internalized shame, and expressed lower intentions to seek medical care. Thus the shameful attitude toward UI may result in less use of the healthcare resources. Feeling of shyness or embarrassment was one of the most important barriers to seeking treatment or consultation for UI. Internalized shame is characterized by blame or devaluation that results from experience, perception, or reasonable anticipation of an adverse social judgment about oneself based on a health problem.

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Due to fear of being stigmatized by others, people with internalized shame may act in ways that they undermine coping with illness, such as keeping UI in secrecy and not seeking medical help when needed. Many patients with UI would feel embarrassed about seeking help from professionals or non-professionals, and expected the negative responses to the fact that they had UI. Such selfembarrassment and adverse expectations inhibited their care-seeking behaviors. Study suggests that an excess of social rejection may likewise result in a high level of internalized shame among UI patients, which contributes to prevent women from seeking for medical care. Findings suggest that stigma is an important factor of intentions to seek care in SUI women and its association with intentions to seek care is complex and varies by its unique aspects and levels. Identifying the subpopulation by the aspects and levels of stigma is crucial to the costeffectiveness of interventions on UI. Stigma reduction strategy aimed at promoting use of health care should target the individuals with high internalized shame and low intentions to seek care.

they are culturally linked through an insistence on control of oneself and oneâ&#x20AC;&#x2122;s environment as requisite for adulthood. Maintaining bladder control is, then, more than physiological; it is central to the maintenance of a sense of self. To lose control of oneâ&#x20AC;&#x2122;s bladder is to lose control of oneâ&#x20AC;&#x2122;s life, to become dependent. Incontinence and certain other age-related disorders appear to differ from other stigmatized chronic conditions in the type of threat they pose to the social fabric. Incontinence is not a disease in the common understanding but rather is seen as a normal, irreversible part of the aging process. Its perceived universality, combined with its dirt and disorder connotations, makes incontinence especially fearful for womens.

The cultural model of urinary incontinence described here is one that depicts life as beginning as an unfinished fabric, which is then woven into a proper adult; as one lives longer and longer, the threads become worn and the adult fabric unravels again. There is incredible power and symmetry to this model that is very difficult to counter. Incontinence, because of its seeming link to the lack of bladder control of infancy, along with cognitive impairments that make some older people as illogical and undependable as a child, fit distressingly well into this symmetric model of the cycle of life. Continence and competence are not logically linked;

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A COMMON ROUTE ABOUT HOW URINARY INCONTINENCE GETS STIGMATIzE

Field Research

Primary Research The primary research for the project involved understanding of socio-medical factors thoroughly. Many complex connections were involved, along with stigma and shame factors about the symptoms. In order to categorize and later analyses the data, interviews and discussions with the doctors, patients, patient family were conducted. The methods used include, apart from interview settings, focus group discussion, ethnography and shadowing.

SOCIAL GROUP The selected social group comprised of women population above 35 years of age. The group consisted of 5 women, from two different geographical locations. 3 of the women belonged to Gujarat, while 2 were from West Bengal. The members had a wide difference in age. All of them suffered from urinary incontinence, and few of them had

this condition for a very long time. The studied women were from different economic backgrounds. The women all spoke in their native language. The role of each woman in the family, and their daily activities were all very different from one another.

As part of the feild research for this project, it was important to interact with the patients and collect firsthand. A questionnaire was prepared, with a set of detailed questions, which was refered to while the interviews were conducted. The intent of conducting these interviews are: •

•

• • • •

• •

To understand the condition of patients from different economic groups and their perspective about the symptoms. To understand the psychology of the patient with regard to urinary incontinence, in terms of what bothers them and the stigma factors associated with this condition To understand the prevalent quality of life of these patients. To understand their awareness and opinions about available solutions. To understand the socio-medical perspectives. To make a comparative study between expectations and availability, which will subsequently inform the proposed solution. To understand what the desired solutions of the patients are. To locate the hidden factors of the issue, which are usually overlooked during research.

The interviews were conducted in two environments : i) The hospital ii) The patient’s home.

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qUESTIONNAIRE SETTING The questionnaire was developed after understanding the symptoms, the complete medical condition and consulting the doctors. As a result, many of the questions were technical. The conducted interviews were done not only to understand the socio-cultural factors, but to find out the physical patterns of the condition. The following aspects were kept in mind while preparing the questionnaire: - self image, social life, family, cultural factors, importance, dependance, trust, happiness, sharing, memory, care, love, lifestyle, support, help seeking, aspiration, shame and disgust, dignity, hygenieic factors, eductaion, beliefs (social), dreams, sorrow, wishes, compromise, maintainence, physical condition, fear, security, feelings, confidence, inferiority, regrets, sense of belonging, QOL, living standard, emotions, hopes, engagement, smells, moods, understanding, acceptance, adaptibility, routine, activity, knowledge, myths,living space, postivity, silence etc. NOTE: All of the questions were not applicable to all patients because of the diversity in the selected group.

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qUESTIONNAIRE FOR PATIENT INTERVIEW UNDESTANDING THE RELATIONSHIP 1. Relationship between patient and her family? 2. Relationship between patient and her husband? 3. Relationship between patient and the doctors? 4. What major roles do you play in your family? 5. Who all are the family members who take care of you most? 6. Who are the family members you trust most? BACKGROUND OF PATIENT 1. Name? 2. Age? 3. Profession? 4. Earning sources? 5. Number of childbirth? (Vaginal or cesarean delivery and) Where? 6. Prenatal care and postnatal care? 7. Rest period after delivery? 8. Gap between next childbirth? 9. Number of abortion? 10. After giving birth did you face any kind of health related issues? (urinary) 11. Since when you are facing UI? 12. For the first time when you experienced/ noticed the UI issue? 13. The person you share or consult this issue for the first time? When? 14. Early age life and story? 15.Do you smoke or drink alcohol? Or any kind of passive smoking?

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PHYSICAL CONDITION 1. What all are the other health related issues you are facing? How long? 2. What kind of UI you are having? 3. How long it’s been? 4. What kind of treatment you are taking? And why? 5. Any improvement happened since you started treatment? 6. Any other health issues occurred due to the treatment? 7. What kind of physical changes happened due to having UI? 8. What kind of treatment would you like to do for UI? – Therapy, lifestyle change, medicine, surgery, inserting devices etc? 9. Do you have chronic cough? 10. Do you have any constipation related issues for longer time? 11. Any kind of backache problem? (spinal cord injury or back problems) 12. Do you follow any regular exercise? 13. What kind of strain works (was) do you have? 14. Do you have Diabetes? 15. Do you face Urinary tract infection often? KNOWLEDGE ABOUT URINARY INCONTINENCE 1. Do you know what kind of UI you are having? 2. Do you know this happened? And how? 3. How do you manage yourself with this problem? 4. What kind of caring or maintenance products do you use to manage yourself? 5. Do you know what all types of products are available to manage UI? 6. Do you think it’s curable? 7. You want to compare UI with which serious disease? 8. Do believe UI is curable?

5. Types of work you do now and used to do? SOCIALIzING ASPECTS 1. How do you socialize with people? 2. What all are the ways of socializing? 3. Where do you prefer to socialize most? Why? 4. Where and with whom you feel comfortable and uncomfortable while socializing? 5. How you use to socialize with people before having the diesease? EMOTIONAL CONDITION 1. How do you see yourself in your family? 2. How do you want see yourself? 3. Show me some of your photos. 4. Which song you can say perfectly depicts your emotion about this condition? 5. With which movie you can relate your emotion about this condition? 6. How would you see if any of you relative of friend is also having the same disease? 7. If you get some magic power to apply to you what would you do? 8. Do you face frequent mood swings? 9. Do you believe that doctor can cure your issues? 10. Are you afraid of anything? (apart from UI) 11. Do you have any kind of anxiety issues? 12. Any kind of hypertension? 13. Have you been gone through any kind of trauma? MICTURITION PROCESS

DAILY LIFESTYLE 1. What kind of works you have in your daily life? 2. Do you follow any kind of lifestyle routine for UI? 3. How do you spend your whole day? 4. Do you have any kind of outside activities?

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1. Usually how many times you go to toilet? 2. Before urination do you get any sensation or feeling (mild or strong)? 3. Do you prefer any one’s help during urination? 4. Do you feel any kind of satisfaction after urinating? 5. How do you feel during urination?

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6. Is it possible to hold your urine when you start getting strong sensation? 7. Do you need to force or strain during urination? 8. Do you feel any kind of pain or burning sensation? 9. How many times you urinate in day and night time? MANAGEMENT AND CARING PRODUCTS 1. What kind of products or devices do you use to manage yourself? 2. Do you practice any types of kegel exercise? Any improvements? 3. How do you see all these products in your life? 4. How much you trust all these products? 5. Do you feel that you have been dependent on these products? 6. What are the love factors about these products? 7. What are hate factors about these products? 8. Would you like to prefer surgery for a long term solution? Why? 9. Apart from surgery what kind of product you would like to imagine for a long term solution? 10. Would you prefer any sort of inserting product (through vagina) for cure and better condition? Why? 11. What kind of ultimate solution do you expect from your doctor? 12. If your doctor told you to use some new products what would you do? 13. Hygienic factor with products? CONJUGAL LIFE AND SExUAL SENSATION

FEAR ABOUT UI 1. What kind of fear you have with the disease? 2. What kind of fear you have with your treatments? 3. What kind of fear you have about your social relationship with family and others? 4. Fear about surgery? 5. Fear about inserted products? 6. Fear about exercise therapy? 7. Fear about life? 8. Fear about otherâ&#x20AC;&#x2122;s perception about your condition? SHAME AND SOCIAL STRATA 1. What are worst situation you have faced (facing) for with UI? 2. How do you feel when a person came to know about your this matter? 3. Do you think disease affected your social life and social image? How? 4. How do you manage yourself if something happens in public? HOPES 1. What would like to remove / add/ or change with whole concept of incontinence ? 2. Do you think it could be solved from outside of the body? 3. Can you trust on an electronic device to get control over your urination? 4. What kind of solution do you expect ?

1. How do you see your husband in your life? 2. Do you think UI affected your conjugal life? 3. Do you have any kind of sleep disorder? 4. Do you sleep together with your husband? 5. When you started facing menopause? 6. Do you feel any kind of sexual sensation? 7. Was there any kind of changes in sexual life or sexual behavior after your delivery? 8. What was the sexual routine before menopause?

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PATIENT’S INTERVIEW IN HOSPITAL SETTING The interviews in the hospital were conducted under the guidance of my mentor, Dr. Sushma Rakesh Shah, Faculty of Gynecology, in The V.S Hospital, Ahmedabad. The interviewees were patients who had been suffering from the disease over a prolonged period of time and were under treatment by Dr. Shah. Arranging the interview with incontinent women took longer than I had anticipated, but after a month of searching, selecting and convincing we were able to identify 18 patients who could be interviewed. However, there were further problems. Dr. Shah identified patients and found their contact details in the hospital’s record book. The junior students in the hospital too helped in finding contacts. Once I had a list of phone numbers, I started calling them. Most of the phone numbers belonged to male members of the patient’s family. A major issue was the fact that almost all the people I was calling were conversant only in Gujarati, so communication became difficult. Further, many of them would deny that the patient was their family member, and say there was no one by that name they knew. Dr. Shah helped me by calling the patient’s family herself. This improved the situation slightly - a few of the patients agreed to be interviewed. Reaching the patients involved a long channel of communication, and even then many of the family members did not allow direct interaction with the patient. From the initial 18 patients that we had identified, I was able to speak to only 7 of them.

facts or manipulate them - real data was very necessary for this research. However, with no other option, I had to conduct the interviews in the hospital setting. After another week’s preparation, the interviews were conducted on 25th May, 2017, in the Gynecology O.P.D on the ground floor of the hospital. Each patient was given a different time slot so that they would not have to wait for a long time. I called up the patients that morning, to confirm if they were going to come for the interview. Only 3 out of the 7 patients responded positively. It was an extremely hot day, with a temperature of 46 degrees. Most of the patients travel by public transport, such as local buses. So, maybe the families were hesitant to send the patients out in the uncomfortable heat.

Dr. Shah asked the patient’s families if they would be comfortable with one of her student’s visiting their house and conducting a study. Most of them were not comfortable with the idea of me visiting their residences. I was hesitant about interviewing the patients in the hospital, within a clinical set up because I was worried that the patients would not feel comfortable or ready to disclose any information. I did not want them to filter the

Three patients were interviewed that day: Hamidaben, aged 40, Sama Banu, aged 51, and Famida Banu, aged 35.

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with the translation and asking sensitive questions. The room temperature was comfortable, proper seating arrangements had been made and the nurse offered them cold water to make them feel relaxed. The door was kept open, as a few family members were sitting outside the room. I started conversing with them about usual things - where they belonged to, how they had come, if they had eaten before coming. about their families and their daily lives. I also asked them about their recent condition with respect to the disease. After a while I started interviewing them using the prepared questionnaire.

Dr. Shah told me that she faced this problem with the patients often. Even during the treatment, their visits are irregular. They stop coming to the hospital suddenly, and return much later only if the situation worsens. From this behavior, I guessed that maybe the patients expect that only a few visits to the doctor can cure or improve their condition, or they are ashamed to disclose their problem when neighbors or relatives question them about frequent visits to the hospital. Infact, Dr. Shah told me that many of the patients would request her for surgery on the very first visit because they do not want to return to the hospital time and again.

The patients had to travel a long way to reach the hospital. Hamidaben and Sama Banu were accompanied by their families while Famida Banu came alone. I interviewed them in the O.P.D chamber of the Gynecology O.P.D Department. I was helped by a middle aged nurse Geetaben (aged 46)

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PATIENT PROFILE The patient profile setting involved taking into consideration factors such as age, religion, income group, cultural background, place of belonging and education. The selection for patients was done keeping in mind a certain diversity in terms of the factors listed. A more detailed profile setting for each patient is outlined in the following course of the document.

NAME : HAMIDABEN

NAME : SAMA BANU

NAME : FAMIDA BANU

AGE: 40 PROFESSION: HOUSEWIFE RELIGION: MUSLIM FROM: AHMEDABAD

AGE: 51 PROFESSION: PEON IN SCHOOL RELIGION: MUSLIM FROM: AHMEDABAD

AGE: 35 PROFESSION: FOOD SELLING RELIGION: MUSLIM FROM: AHMEDABAD

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INTERVIEW AND DISCUSSION WITH PATIENTS

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PATIENT INTERVIEW DATA MAPPING Three patients were involved in this research - much lower than the number which was initially expected. Constrained time compelled me to interview this limited number of patients. As a result, the quantitative data that I had expected from the research could not be collected. Hence, my analysis comes from a focus on qualitative data, collected after thoroughly interviewing each patient.

- From the above data, it can be inferred that most of these patients belong to lower middle and lower income group and receive none or poor education. - They share a distant relationship with their family members and communicate with very few people about their discomfort. -Younger patients are more likely to discuss the problem with their spouse or family while older patients feel more shy towards opening up. - Patients limit themselves to socializing with family members or neighbors only and do not venture to far places after getting this condition because traveling is uncomfortable. - They feel emotionally vulnerable and feel they are the only ones who suffer from this condition. They are hesitant to share also because they feel other women do not suffer from this. - Initially, they think that the doctor will be able to solve the condition very easily but they realise later that this is not possible. - Most of them have given birth to more or more children

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through normal delivery. - Most of them help in earning for the family by doing small odd jobs such as selling food or they are housewives.

- The reason for getting this condition was explained by the doctor by saying it is caused by aging.

- Most of them have received none or poor pre and postnatal care.

- Prior to beginning of treatment, the diagnosis done on patients is not proper because diagnosis involves expensive methods, for many of which proper apparatus is not available in hospital.

- Their visits to hospital are irregular and hence treatment is discontinuous.

- Out of the three patients studies, one was suffering from mixed incontinence and two from stress incontinence.

- They visit doctor after a prolonged time from which the condition started to show symptoms.

- Hamidaben and Sama Banu had already undergone sling operation while Famida Banu had not been performed surgery on.

- The relation between patient and spouse, especially physical, has suffered. They become more conscious and inhibited after sharing their condition with spouse. - The interviewed families came from Muslim families who practice cleanliness stringently during month of Ramadan. They have to bathe multiple times during this time and fear of leakage during prayers.

- They are reluctant to speak in a detailed way about the sympto s even with doctor and other medical staff.

- Patients often suffer from sleep disorder.

- The patients are not comfortable using products which can be inserted through the vagina because there is stigma attached to it. They will not be able to share this with their husband and also it is against their religion. . - They are scared that family members or their children will distance themselves if they find out about their condition.

- They do not attach enough importance to the condition and do not take their symptoms seriously.

- Patients suffer from fear of surgery and also that the condition might become worse post-surgery.

- They have all faced embarrassing situation, specially outside home which has caused their social life to pause.

- The family is unaware of the situation, and even if they are aware they do not attach enough importance to the condition or take patient for treatment regularly.

- The patients use long pieces of cloth, folded up inside under garments as a solution. Some of them insert the cloth inside the vagina while traveling, making them more likely to suffer from UTI. Many of them frequently suffer from UTI and fever.

- The patients do not get the much required mental support from family and hence want to share everything with the doctor. The doctor can not give so much time to each patient. This leaves the patient feeling insecure.

- Commonly administered treatment includes medicine, and when medicine fails to work - sling operations. -Even after undergoing sling operations, the condition persisted and expected relief was not achieved. - They do not have any knowledge about exercises or alternative therapies to help their condition. -They do not have any knowledge about urinary incontinence and trust the doctor completely for treatment.

- They are constantly afraid of emitting stench of urine and embarrassing themselves in a public place . - Most of them do not have knowledge about adult diapers. Rarely, if they do, they can not afford this redcurrant expenditure. - The patients are not sexually active because they are scared about leakage and stench of urine during intercourse.

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- The patients seek a long term solution, which will not require recurrent expenditure. The only long term solution they are aware of is surgery. They have no knowledge about other solutions. - They desire that the solution will restore the normal everyday life, as they had previous to the condition. They are willing to undergo any kind of method of treatment to get this permanent cure, but the solution has to be self administrated.

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DISCUSSION WITH DOCTORS The research was done in consultation with three doctors, among whom one was my mentor Dr. Sushma Rakesh Shah. The other doctors were Dr. A. Mondal, KPC Medical College, Kolkata and Dr. Dileep Karmakar, Head of the Department, Urology, Calcutta National Medical College. An in-depth discussion with doctors was conducted to understand their perspectives and the major hurdles they faced in treating the disease. The data from this discussion can be mapped as:

vii) Although patients prefer to get cured by medicine, doctorâ&#x20AC;&#x2122;s suggest surgery as a last resort. The sling operation sometimes relieves the patient but most of the time worsens the situation. viii) The doctors often find themselves frustrated about lack of resources, lack of patient participation and lack of knowledge about new interventions.

i) The tests which the doctors ask the patients to do are usually not completed, mainly due to financial reasons or unavailability of the required devices in a government hospital. Hence diagnosis is not done properly. ii) Unavailability of proper resources and technology. iii) Patients are unwilling to disclose all their problems and symptoms to the doctor. This causes a communication gap and makes diagnosis further difficult. Often urinary incontinence is detected much later in relation to some other disease. iv) The patients were irregular in their visits to the hospital and treatment was discontinuous. v) The patients are not consistent with their answers and often sensitive to many questions. Most of the patients are uneducated who have not had much exposure. vi) Medicines which are administered are not as effective as expected because of erratic treatment and also due to the several side-effect of medicines. The doctors themselves are often in a dilemma about what drugs to prescribe because the diagnosis of urge versus stress incontinence remains unclear from the diagnosis.

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PATIENT’S INTERVIEW IN HOME SETTING INTERVIEW : 1 The patient is my friend’s grandmother, who had been my acquaintance for the last 8 years. I came to know that she was suffering from urinary incontinence only after starting the project. A nurse (ayah) has been appointed to take care of her, and has been looking after her for the last 10 years. She is lovingly called Burima and is 60 years of age. The grandmother is highly dependant on Burima. Burima comes to work at 7 AM in the morning, before the grandmother wakes up and leaves at 8 or 9 PM, everyday of the week. She hardly ever misses a day. The two share a close bond and treat each other with respect. The grandmother trusts the nurse, and does not look at her as an employee but a member of the family.

NAME : UMA MUKHERJEE

PARTICIPANT OBSERVATION SPACE ORIENTATION (LIVING AREA AND OTHER SPACES) Observations made about the space inhabited by the patient are as follows: -During the interview I was sitting on the bed of the patient. I could feel the plastic sheet under her bedsheets. - The room was quite spacious. The distance between the bed and the door of the attached bathroom is only one step. - The furniture in the room is old and beautiful. -There are three windows in the room which are kept open during the day time.

AGE: 77 PROFESSION: HOUSE WIFE RELIGION: HINDU FROM: SALTLAKE, KOLKATA

- There was an A/C in the room.

BIJOY PRASAD SA H A | M .D E S 2 0 1 7 | GRADUATION PROJECT | NID

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- There was a plastic box in a tray on her bed with filled of medicine, one scissor, Small papers, TV remotes along with a half filled water bottle. - There is a television in the room, towards which the patient faces while lying down, placed on a table, just beside the bathroom door. - There is a big wall mounted cupboard, spanning an entire wall towards the head side of the bed. -There are two plastic chairs placed in the room. - Her walker is placed by her head side. - The room was well-lit.

Overall the smell of her living room is mixed with lot of natural and artificial smells. In sense of natural smells, most prominent were smell of vegetables, kept under her bed and in the corner of the room. Old, mild and musty kind of smells were present mainly due to old furniture, paper and other stuff and also maybe due to less amount of sunlight entering the room. The smell of detergent is strong probably because the bedsheets are changed every morning. At night, the smell is predominantly that of mosquito liquid Many times there is a strong smell of deoderant or perfume.

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IN-DEPTH INTERVIEW The interviews conducted in the hospital had to be done within limited time and hence detailed observation became difficult. Hence, I conducted interviews with dialogue, which were transcripted in detail from the interviews in home setting, which could be used for ethnographical analysis. I chose to conduct the interview in my mother tongue so that I can understand them better without a language barrier. UNDERSTANDING THE RELATIONSHIP • Relationship between patient and her family? A: [poribarer sobar sathei khub valo somporko..] • Relationship between patient and her husband? A: [N/A] • Relationship between patient and the doctors? A: [Onyo sob problemer jonyo tader sathe valo somporko.. tobe ei problem niye ami onek gulo doctor dekhiyechi keo e kichu improvement korte pareni..S] • What major roles do you play in your family? A: [Ekhon toh kichu korte pari na… tobe kajer lokder diye rannar kajkormo koriye neoa… r khabar somai nilar (maid) sahajyo niye khabar bere d isobar… r bajar er hisab rakaha eisob e.. ] • Who all are the family members who take care of you most? A: [Amar aya Jogomaya.. kishore (Son in Law).. r amar dui Natni(Granddaughter) burai r chutai.. r sobai e..] • Who are the family members you trust most? A: [Amar meye r amar dui Natni] BACKGROUND OF PATIENT •Name? A: Uma Mukherjee (W) •Age?

A:77 • Profession? A: Housewife • Earning sources? A: Husband’s pension • Number of childbirth? (Vaginal or cesarean delivery and) Where? A: Two (both are normal delivery) • Prenatal care and postnatal care? A: 5-6 Months • Gap between next childbirth? A: 4years • Number of abortion? A: NA • After giving birth did you face any kind of health related issues? (urinary / menstruation) A: Darao mone kore bolchi…., delivery howar por ami ekdom patla fin fine roga hoye gechilam. Doctor amake bolechilo SUTIKA hoyeche amar. Sei jonyo Baper barite ese ektu besi din chilam ar valo kore kawa dawao korechilam. (Lough) Esob kotha kokhono jibone moneo poreni.. ekhon mone parachho). • Since when you are facing UI? A: Since last 41 years. It’s become devastating after 2003 (almost last 14 years). [Last 41 bochor dhore bhugchi… Tobe 2003 er por theke eta otirikto hoye giyeche] • For the first time when you experienced/ noticed the UI issue? A: [Ekdom prothom dikei notice korechilam ei problem ta, tobe poriman ta chilo onek kom ar tate bisesh osubidha hoto na. ami tokhon jante perechilam ei somosya amar maa er o chilo r pore amar bon er o chhilo. Ar se somai barite lok o kom chilo r bolar moto o keu chilo na. Ar prothom dike serokom kono osubidha hoto na bole byapar ta gaye lagai ni] • The person you share or consult this issue for the first

BIJOY PRASAD SA H A | M .D E S 2 0 1 7 | GRADUATION PROJECT | NID

time? When? A: [Sobar prothom bor kei bolechilam tobe onek pore, jokhan somosya ta onek bere chilo, tobe doctor doctor er kache jaini kokhono onar sathe] • Early age life and story? A: [School er somai thekei maa ke kaje sahajyo kortam. Biyer age maa ke somosthyo rokom ghorer kajei help kortam Ar biyer por barir sob kaj eka hat e korechi. kajer poriman chilo prochur] • Do you smoke or drink alcohol? Or any kind of passive smoking? A: My husband used to smoke as well my father in law. PHYSICAL CONDITION •What all are the other health related issues you are facing? How long? A: [1970 te amader ek accident hoi tokhon amar paa bhenge jai o tarper paa e plate bosate hoi. Tachara Knee teo problem ache Arthritis. Pore 16 bochor agey cancer o dhora pore tobe camo niye sustho hoye gechilam. Bortoman e amar main somosya holo cholte pari na khub kosto kore sudhu khabar somai ta ber hoi. Cholar problem ta suru hoi jokhan last ami bathroom pore abar paa bhangi.] •What kind of UI you are having? A: [amar problem ta hoto jokhon amar kashi ba sneezing hoto ba bose achi hotat kore uthle. Tobe ekhon ar bujhte pari na kohkon hoye jai]. • What kind of treatment you are taking? Since when? And why? A: [Husband thaka kalin kokhono ami doctor er kache jai ni problem niye. Se somai er jonyo serokom kosto o hoto na, ar jodio ba hoto toh hoto tate osubidha kichu chilo na. • Ei khane asar por (2003) prothombar amar jamai doctor er kache niye jai. Se chilen amader family doctor. • Amai tini medicine diyechilen (VESIGUARD). ]

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• Any improvement happened since you started treatment? A: [Onek bochor dhore chalye esechilam oi medicine. Kintu tate kono improvement hoini bole oi medicine ta palte onyo ekta osudh diyechilo. tateo kono kaj hoi ni bole ami medicine khawa bondho kore diyechi. Infact kono medicine e kaj koreni. Kono kichu diye ei obosthar improvement korte pareni doctor. 2004 er por theke khub kosto peyechi ei somosya tar jonyo. Ses e Jamai jor kore Diaper use korte raji koralo tao ei kichu bochor agei. Tar por theke ektu norte chorte pari, tar age toh bed theke norte partam na.] • Any other health issues occurred due to the treatment? A: [Na.] Holeo hoi toh bujhe pari ni, eto gulo problem ache tai.] • What kind of physical changes happened due to having UI? A: [Na serokom kono effect hoi ni. Tobe suye suye mota hoye giyechi.. he he.. (lough)..] • What kind of treatment would you like to do for UI? – Therapy, lifestyle change, medicine, surgery, inserting devices etc? A: [-Surgery te toh jaboi na]. • Jodi medicine e kaj kore tahole toh ami 100 ta medicine kheteo raji achi, tobe ta kaj korte hobe. • Routine o ami mante parbo na sob somai. Ar amar r o onek kaj thake tai • Inserting product toh ami young age eo use kortam na. ema eta kokhono hoi naki iss…. (With a Shy expression) ] • Do you have chronic cough? A: [Yes. Sordi kashir problem amar choto bela thekei. Biyer pore seta r o bere chilo, majhe modhye sojyasayi hoye jetam. Ekhono ami ei somosyai bhugchi] • Do you have any constipation related issues for longer time? A: [Yes. Young age theke amar ei somosya khub beshi porimane chilo. 3-4 din bade bade potty hoto. Khub bhugechi ami eta niye, tobe ekhon almost thik achi.]

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• Any kind of backache problem? (spinal cord injury or back problems) A: No • Do you follow any regular exercise? A: [Agey onek exercise korechi, nije nijei kortam. Pore physiotherapist er sathe kortam. Pore pa avenge jaoar por ar korte parini] • What kind of strain works (was) do you have? A: [Agey kortam. Tobe ekhon r na.] • Do you have Diabetes? A: No. • Do you face Urinary tract infection often? A:[ Na serokom hoini kokhono. Tobe hain koyek bar kepe kepe jor esechilo r oi jaiga te jolon r byatha o hoyechilo. Grand daughter: Hain maa tomar hoyechilo tokhon tumi diaper use korte na. Tokhon ini kapor dhokaten. Granny: iss esob bolis na… chup kor (Felt ashamed). Asole keu chilo na toh, Maa o chilo na amar je bolbo. Khub kosto hoto… bar bar urine beriye jeto… ei ghor theke berote partam na. tokhon ami ei sob nijer budhhi lagiye nijeke maintain korar chesta kortam. Fole majhe modhye oi karon e jor asto.] KNOWLEDGE ABOUT URINARY INCONTINENCE • Do you know what kind of UI you are having? A:[ Na jani na. Doctor o kokhono kichu boleni. Ki karon e eta hoyeche!] • Do you know this happened? And how? A: [Na Jani na. tobe age er jonyo e hoitoh hoyeche.] • How do you manage yourself with this problem? A: [Last 5-7 years dhore ami diaper byabohar korchi. Tar agey ami khub kosto kore nijeke manage kortam. 38 bochor boyos e swami ke hariyechi. Nije ek chele meyeke boro korechi. R chele ke toh rakhteo parlam na.. (Sigh..)… Ami amar jewellery bhenge kosto kore songsar chaliyechi, konodin karo kache hat patini. Ar husband o chilo na kei baa mar care korbe r kakei ba boltam esob kotha… Sigh! ] • What kind of caring or maintenance products do you use

to manage yourself? A: Jokhon theke kishore (son in law) jor kore diaper ene dilo tarpor theke ektu kore confidently chola fera korte parchi, shanti te ghumate pari serokom kono tension thake na. tobe ekhono jokhon ami khete dite jaoar age ami toilet kore jai… jate khete bose kono somosya na hoi. ] • Do you know what all types of products are available to manage UI? A: [Hain ekta duto product er byapare sune chilam amr meyer theke. Kichu dekheochilam… tobe ami ei dhoroner kono jinis use er pokhye noi jeta nijer sorir er modhye probesh korate hobe.] • Do you think it’s curable? A: [Amar mone hoi eta curable. Boyes er karon e toh egulo hoyei thake. Tobe Jodi kono person bole se cure kore debe take ami biswas korbo ki kore?] • Do you consider that UI is serious dieses? A: [Ekdom prothom dike bhabtam je eta kono boro somosya noi.. kintu jokhon poriman ta ar o barte thaklo amar kosto o barte thaklo tokhan eta ekta serious matter hoye gechilo. Ajke amar kache ekta aya rekhechi bole amar kosto ta kom hoye Jodi aj aya na rakhtam tahole amar ki durabostha hoto bolo toh. Ajke aya rekhechi bole amar problem ta keu feel korche na bole amio feel korchi na. Ar lojja jinis tao se bhabe dekhte hochhe na.] DAILY LIFESTYE • What kind of works you have in your daily life (used to do)? A: [Agey toh sob e korechi, mane somosto rokomer ghorer kaj. Ranna kora, bason dhoa, kapor kacha, ghor mocha, thakur pujo kora, dine 50 bar upor niche kora.. sob rokom kaj. • Ta chara jibone eto kosto dekhechi nijer husband er accident e death nijer chokher samne, cheler mrityu o dekhechi tobe saririk bhabe venge porini kokhono… tar poreo sob kaj korechi. • Ei somai amar sara diner kaj bolte sokalr rannar lok asle

BIJOY PRASAD SAH A | M.DES 2017 | GRADUATION PROJECT | NID

rannar jinis potro dekha sona kora.. sokale ekbar kitchener baire bose sob sobji, masala bar kore deoa. Fer chan kore nijer ghorer thakur ke pujo dewa. Tarpor dupurer khabar bara nila r brumar sahajyo niye. Fer sobar khawa hole tv serial dekhte dekhte ghumiye ni ektu. Fer bikele ghum theke uthe abar tv dekhi ekhanei suye suye. Dinner somai abar ekbar bairer ghore jai.. sobar khawa hole ghore giye tv dekhte dekhte ghumiye jai. Ghumate ektu rat hoi tobe.] • Do you follow any kind of lifestyle routine for UI? A: [Na.. kono Routine follow kora hoi na se bhabe.] • How do you spend your whole day? A: [Agei ja bollam sebhabei ami whole day spend kori.] • Do you have any kind of outside activities? A: [Ekhon toh kono outside activity nei… ei paa niye ki bhabe korbo osob? Tobe age jokhan ei barite shift korechilam(2003) tokhan majhe modhye bikele bus e kore garihat chole jetam ektu paichari kore ektu misti kheye abar bus niye ferot astam. R se somai ei side toh chilo puro faka tai okhane chole jetam. R kokhono kokhono bajar korte jetam. Srokom bolte etai chilo amar outside activity.] SOCIALIzING ASPECTS • How do you socialize with people? A:[ekhon r kono rokom melamesha hoy na…] • What all are the ways of socializing? A: [phonei kotha hoi.. majhe modhye onek relatives ase barite… amar r kothao jaoa hoi na kothao… ki korei ba jabo] • Where do you prefer to socialize most? Why? A: [ei obosthai socialize kora bolte amar ghorei bose amar closed relative ra. Tobe ami prefer kori sofar ghore bosate… kenona okhane bosao jaigao besi] • Where and with whom you feel comfortable and uncomfortable while socializing? A: [Sofar ghorei beshi comfortable] • How you use to socialize with people before having the dieses? A: [agey onek mishuke chilam jokhan c.i.t road er barite thaktam. para protibeshi o onek bondhu bandhab der

satheo onek mela mesha kortam. Tobe ekhon r ta hoar kono sujog nei.] EMOTIONAL CONDITION • How do you see yourself in your family? A: [Amar family te role bolte r ki… kajer lokder ke dekhasuno kora, oder bola ki ranna korbe, bajar e ki darker ei sob e. Financial matter toh kishore e dekhe. Tobe ami khub perfectionist… sob kichu chim cham rakhte pochondo kori, kono jinis jeno edik theke odik na hoi. Ek kale nijei kortam esob ekhon kajer lok der diye sob poriskar rakhi…. Jemon dhoro keu amar ghore keu ele se jeno sob poriskar dekhe.. valo bhabe boste pare… amar je sorir kharap ba je koste ami bhugchi se jeno eto tuku o tern a pai.. baa mar ghorer obostha dekhe se ta andaj o korte pare.] • How do you want see yourself? A: [he he… ki r dekhte chai nijeke.. bhalo bhabe thaki sustho thaki… ei problem ta Jodi thik hoy thaloe r o ektu valo bhabe thakte parbo. ] • Show me some of your photos. • Which song you can say perfectly depicts your emotion about this condition? • With which movie you can relate your emotion about this condition? • How would you see if any of you relative of friend is also having the same disease? A: [Amar maa r boner ei problem chilo seta jani… kintu baki kader ei same somosya ache ta jani na.. amar boner hanchi kasha hole beriye jeto setai jani. ] • If you get some magic power to apply to you what would you do? A: [ami nijeje puro sustho kore debo.. r Jodi bolo ei somosya tar bisoye tahole ami chaibo ager young boyeser moto control koral khomota fire pete. He he……….. (Loughs)…. Ki sob ajgubi kotha bolchi… e ki r hoi naki!....] • Do you face frequent mood swings? A: [mon kharap thakto agey… kintu tar karon chilo swami ke harano o cheleke harano… tobey ei somosya niye mon

BIJOY PRASAD SA H A | M .D E S 2 0 1 7 | GRADUATION PROJECT | NID

kharap serokom kichu hoto na… amar jomoj natni hoar por se dukho o kome giyechilo. Tobe diaper use korar age kokhono kokhono khit khite hoye jetam nijeke samalte samalte. ] • Do you believe that doctor can cure your issues? A: [ etodin Dhore toh dekhachhi .. medicine o change koreche.. tateo kichu hoi ni.. last bar jokhan dekhai doctor bolechilo MRI korte.. ami r korai ni.. diaper ei ami thik achi.. R e jinis boyes ghotito karone hoi.. E cure kora sombhob noi.. thik korte gele amake abar young korte hobe.. ha ha.. ] • Do you have any kind of bad childhood memories? (Childhood fear or abused) A: [na. sebhabe bolle oi dui incident.] • Are you afraid of anything? (apart from UI) A: [na… serokom kichu nei.] • Do you have any kind of anxiety issues? A: [Sebhve kich nei… tobe ghum khub kom hoi… hoito oi problem ta mathai chole bole… diner bela kajer aya tat hake bole ektu nischinte ghumate pari, tai dupurer ghum tab halo hoi.] • Any kind of hypertension? A: [Agey hoto ei problem tar jonyo… kokhono kokhono khub mon theke lojjito bodh kortam.. tobe kokhono konodin kauke bujhte di ni amar kosto. ] • Have you been gone through any kind of trauma? A: [oi dui incident. Tachara r kich na..] MICTURITION PROCESS • Usually how many times you go to toilet? A: [eta bolis na re.. etai toh pagol kore dichhe… diner ta bhebe bolte hobe.. tobey rater ta hisab ta rakhi. 30 min ontor ami toilet e jai, jotokhan jege thkai. Abar ghumale etar jonyo ghum o bhenge jai. Tar jonyo jol o kom khai. R ei karonei toh 3 bar bathroom e poreo gechi. Tar jonyoi toh paa ta bhanglo. R amar chola fera sob bondho hoye gelo.] • Before urination do you get any sensation or feeling (mild or strong)?

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A: [kokhono kokhono bujhte pari.. tobe sensation thake. Toilet jete hobe oi feel jokhon bujhe pari .. taratari bathroom e chole jai.. dhore rakhar kono khomota nei ar.. ] • Do you prefer any one’s help during urination? A: [hain sometimes… tobe se amar oi aya e kore.. r kau ke ami bolteo parbo na…] • Do you feel any kind of satisfaction after urinating? A: [matahi toh ota choltei thake…ei holo toh abar hobe.. ei chinta ta sob somai cholte thake.. ebhabe ekta manush ki bhabe benche ache bhabo?...] • How do you feel during urination? A: [Kichui feel korina.. nije thekei je tuku hoi… kono jor laganor khomotao nei..] • Is it possible to hold your urine when you start getting strong sensation? A: [Ekdom e na… songe songe bathroom e chole jai tai jonyo.. ] • Do you need to force or strain during urination? A: [Na kono force dite hoi na.. nije thekei je tuku hoi bas.. ] • Do you feel any kind of pain or burning sensation? A: [na..] MANAGEMENT AND CARING PRODUCTS • What kind of products or devices do you use to manage yourself? A: [ami sudhu Diaper e use kori..] • Do you practice any types of kegel exercise? Any improvements? A: [Na ei karoner jonyo kono exercise korini kokhono..] • How do you see all these products in your life? A: [Ei diaper er importence ho marattok.. eta chara toh ami bachboi na… ota chara amar uthbar o shakti nei.. ] • How much you trust all these products? A: [ei jinis tar upor e toh vorosa kore ektu norte chorte parchi… poriskar o thakte parchi.. dine 2-3 bar diaper bodlai ami.. sara rat e ektai pore thaki. • Eta pore thakle moner jor pai ami… ] • Do you feel that you have been dependent on these

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products? A: [ami toh totally dependent er upor.. eta chara amar cholbe na.. tobe kichu company er prouct oto valo na.] • What are the love factors about these products? A: [Ami ei jinis take biswas kori.. r ami moner jor pai eta pore thakle.. ] • What are hate factors about these products? A: [Ektai sudhu somosya.. ami pant er moto diaper gulo byabohar kori.. toh nije uthe porte pari na.. jogmaya (aya) amai help kore… tobe Jodi ami nijei porte khulte partam tahole toh khub bhalo hoto..] • Would you like to prefer surgery for a long term solution? Why? A: [kore se koto ta labh hobe seta dekhar bisoi.. tobe ei boyose r noi… amar paa eo toh surgery holo kintu ami ar hatte parlam na..] • Apart from surgery what kind of product you would like to imagine for a long term solution? A: [emon kono product jeta porar por ami moner jor fire pabo.. jemon diaper porle pai…] • Would you prefer any sort of inserting product (through vagina) for cure and better condition? Why? A: [Ekdom e na… agei bolechi.. ] • What kind of ultimate solution do you expect from your doctor? A: [He he… amake puro puri thik kore dik.. (lough)…] • If your doctor told you to use some new products what would you do? A: [Emon kichu product jeta ami nije nijei byabohar korte parbo erokom kichu.. r jeta porle moner jor fire pabo.. diaper pore jeta feel kori serokom.. • Tobe erokom kichu noi jeta abar onyo kono rog badhai.. ]

moto bishoi noi… toh ‘support’ r ekta boro factor..] • What kind of fear you have with your treatments? A: [ami sudhu medicine e khetam.. onyo kichu toh try korini. Medicine e amar kono voi nei..] • What kind of fear you have about your social relationship with family and others? A: [Etat jonyo amar bairer lokeder sathe social relationship ektu kom hoyeche thik e.. tobe etodin dhore amar je ei somosya ta ami kauke bujhte di ni.. tobe ekta mone bhoi chilo seta oi Lojja.] • Fear about surgery? A: [Guarantee ki ache ache se thik hoye jabe.. R e korte giye Jodi onyo kono problem suru hoye jai.] • Fear about inserted products? A: [e toh ami amar husband keo bolte partam na.. nijer onger modhye onyo kichu probesh korno ei dharona tai ami mene nite parbo na. R eta keu Jodi jante pare se voi tai ei dharonar birodhita korbe.] • Fear about exercise or therapy? A: [Jodi exercise kore ei obosthar improvement hoi tate kono problem nei… tobe barir baire giye kothao exercise korte ba therapy nite gele ektu voi thakbe.. jodi keu jigges kore kothai jai ami…] • Fear about life? A: [life niye serokom kono voi nei… tobe ebarite asar age jokhan eka thaktam tokhan voi lagto.] • Fear about other’s perception about your condition? A: [Ei somosyar kotha onyora na janlei bhalo… Jodi keu jante pare tahole lojjito bodh hote pare, moner jor kome jai..]

FEAR ABOUT UI

• What are worst situation you have faced (facing) for with UI? A: [Ekbar hoye chilo kishore r Ramar samne.. oder purono barite.. khate bose kotha bolchilam, jei dariyeche somane urine beriye jachhe r ora seta dekche… tokhan ami bhison lojjito hoye giyechilam.. tokhan kishore bojhachhilo ete

• What kind of fear you have with the disease? A: [amader jonyo voi bolte prothom hochhe ‘lojja’.. tarpor onyo ekta bishoi holo kar sathe share korbo setai bujhe uthte pari na.. basically eta nijer maa chara kauke bolar

SHAME AND SOCIAL STRATA

BIJOY PRASAD SAH A | M.DES 2017 | GRADUATION PROJECT | NID

lojjar kichu na eta ekdhoroner osukh.. tarpor nila (maid) ese ekta kapor diye muche niye gelo… se somai tara prothom jante pare amar ei osubidhar byapare… tokhan se karoneo lojja pelam amar jeta holo setar jonyo r tar sathe ora je jante parlo ei bishoi ta tate khub atmosamman e legechilo.. etai sob theke kharap situation chilo amar jonyo. ] • How do you feel when a person came to know about your this matter? A: [Ekhon toh relative der modhye onekei jane eta.. tobe notun keu jante parle odvut feel hoi.. amar mot e ei jinis ta lokjon na jante parley valo.. ] • Do you think this condition affected your social life and social image? How? A: [Se toh agei bolechi.. hain ei karon e amar melamesha toh ekebarei kome geche.. r aj Jodi ami aya na rakhte partam ta hole amar obostha ar o hoito kharap hoto.. lokjon apariskar bhabto amai.. ghore hoitoh keo aste chaito na.. ] • How do you manage yourself if something happens in public? A: [Erokom toh kokhono hoi ni amar sathe… Jodi hoto tahole bolte partam..]

khomota pawa jai se toh vison e valo hoi… tahole toh ar diaper o porte hobe na..(Happy)….. ami amar moner jor fire pabo… R tumi bolcho toh ki biswas korbo.. erokom Jodi

kichu ase r doctor bolle nichoi byobohar kpre dekhbo.. ] • What kind of solution do you expect ? A: [Emon kichu jate ami puro puri thik hoye jai…. (ha ha..)]

HOPES • What would like to remove / add/ or change with whole concept of incontinence ? A: [Doctor ra jeno bhalo bhabe bujhe treatment kore.. ekta kono boro support darker sobsomai er jonyo jate moner jor thake je keu tar obostha bujhte parbe… R je dhoroner e solution hok na keno seta jeno se nijey byabohar korte pare.. tar jonyo take onyo karo sahajyo nite na hoi…] • Do you think it could be solved from outside of the body? A: [ki bhave hboe…? Jodi serokom kichu hoi tahole toh khub e valo hoi… ] • Can you trust on an electronic device to get control over your urination? A: [Jodi kono kichu body r baire lagiye ami control korar

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INTERVIEW : 2

IN-DEPTH INTERVIEW

The patient is a family relative of one the doctors whom I spoke to for my project, Dr. A Mondal of KPC Medical College. A nurse (ayah) has been appointed to take care of her. The woman is highly dependant on the nurse who is there at all time with her. The woman is very quiet and hardly talks. She is disciplined and strict and prefers to speak to the point. She is in a good physical condition, can walk around and do light daily activities. She watches T.V and does puja most of the time.

UNDERSTANDING THE RELATIONSHIP

PARTICIPANT’S OBSERVATION SPACE ORIENTATION - The family stays in the third floor apartment of a building. - She has her own room and watched television most of the time. - There is an attached bathroom with the room.

NAME: SWAPNA SANYAL AGE: 72 PROFESSION: HOUSE WIFE RELIGION: HINDU FROM: : DHAKURIA, KOLKATA

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• Relationship between patient and her family? A: [sobar sathei valo somporko..] • Relationship between patient and her husband? A: [Valo somporko.] • Relationship between patient and the doctors? A: [Valo.. Jokhan nijer jamai e amar doctor..] • What major roles do you play in your family? A:[Serokom kono major role toh nei amar.. bas puja kora chara.. ] • Who all are the family members who take care of you most? A: [Amar aya..] • Who are the family members you trust most? A:[Jamai (Son in Law)] BACKGROUND OF PATIENT • Name? A: Swapna Sanyal • Age? A:77 • Profession? A:Housewife • Earning sources? A: Husband’s pension • Number of childbirth? (Vaginal or cesarean delivery and) Where? A: 1 (normal delivery) • Prenatal care and postnatal care? A: 5 Months • Gap between next childbirth? A: N/A • Number of abortion?

A: N/A • After giving birth did you face any kind of health related issues? (urinary / menstruation) A: [Delivery’r somai excessive bleeding hoyechilo.. r hain tarpor 2 mas moto urination er somosya hoyechil..] • Since when you are facing UI? A: [last 22 bochor dhore] • For the first time when you experienced/ noticed the UI issue? A: [ Tokhan amar boyos 53 ba 54 chilam toh majhe modhye toilet peyeche bujhte partam.. kintu korte giye dekhtam already kichuta hoye geche.. suru te 3 bochor obdi gaye lagai ni.. pore amar hasband amar jamai ke bole.. se nijei doctor] • The person you share or consult this issue for the first time? When? A: [Amar husband tarpor amar jamai] • Early age life and story? A: [Biyer agey maa ke sob kaj e help kortam.. sob kichu maa er thekei sikhechilam.. biyer por kolkatai chole asi.. ekla hat e puro sansar chaliyechi.. meyeke boro korechi.. ] • Do you smoke or drink alcohol? Or any kind of passive smoking? A: No. PHYSICAL CONDITION • What all are the other health related issues you are facing? How long? A: [Amar 14 bochor dhore Osteo Artherities ache, knee replacement o hoye geche.] • What kind of UI you are having? A: [amar problem ta holo bar bar toilet pai… r constant mathar modhye cholte thake.. toilet korar por o mone hoi complete hoi ni.. ei karone onek somai beriyeo jai bujhte pari na] • What kind of treatment you are taking? Since when? And

BIJOY PRASAD SAH A | M.DES 2017 | GRADUATION PROJECT | NID

why? A: [ami Medicine e nichhi onek bochor dhore (Vesiguard).. keno na amar jamai nije ekjon Urologist..] • Any improvement happened since you started treatment? A: [Hain ektu improvement hoyeche.. tobe to majhe modhye medicine o kaj kore na.. .] • Any other health issues occurred due to the treatment? A: [Na.. er jonyo r kichu hoi ni.] • What kind of physical changes happened due to having UI? A: [Na kono Physical changes hoi ni.. ] • What kind of treatment would you like to do for UI? – Therapy, lifestyle change, medicine, surgery, inserting devices etc? A: [-Surgery to ekdom e na… Medicine e kono somosya nei.. therapeutic treatment ba exercise korte amar kono problem nei.. R inserting product toh bhaboi na.. ] • Do you have chronic cough? A: [No] • Do you have any constipation related issues for longer time? A:[Na e somosya amar kokhono hoi ni] • Any kind of backache problem? (spinal cord injury or back problems) A: No • Do you follow any regular exercise? A: [Hain last 20 years dhore ami regular exercise korchi.. barite lok ese korai] • What kind of strain works (was) do you have? A: [Agey chilo onek… ekhon nei..] • Do you have Diabetes? A: No. • Do you face Urinary tract infection often? A:[Hain eta khub hoi amar.. majhe modhye khub jala kore o pain hi.. sathe jor o ase..]

KNOWLEDGE ABOUT URINARY INCONTINENCE • Do you know what kind of UI you are having? A:[ Na jani na.. (UUI)] • Do you know this happened? And how? A: [Na Jani na. tobe boyes ekta karon.] • How do you manage yourself with this problem? A: [Amar aya e puro din amake poriskar rakhe.. tachara jokhan obostha ektu besi kharap hoi ami diaper pori.. age kapor use kortam] • What kind of caring or maintenance products do you use to manage yourself? A: [Product bolte majhe modhye Diaper use korte hoi.. R kichu nei.] • Do you know what all types of products are available to manage UI? A: [Jamai bolechilo ache kichu typer product.. tobe osob ami use korte chain a.. tar theke exercise r medicine e bhalo.. khub beshi hole diaper..] • Do you think it’s curable? A: [Amar mone hoi na..] • Do you consider that UI is serious dieses? A: [Eta toh kono jibohani rog toh noi.. tobe ei condition er jonyo onek kichu kharap hyecehe...]

A: [Oi je bollam toh... ebhabei kete jai puro din.. ] • Do you have any kind of outside activities? A: [Ekdom e nei.. last 12 bochor dhore.. tar agey chilo..] SOCIALIzING ASPECTS • How do you socialize with people? A:[Barite keo asle.. r Phone e kotha hoi] • What all are the ways of socializing? A: [phonei kotha hoi sudhu.. R barite je sob lokera ase tader sathe.. r kokhono barite get together hole.. ] • Where do you prefer to socialize most? Why? A: [Barir baire toh jete chai.. kintu moner bhoi e jete parina.. Jodi urine hoye jai, ei bhebe. Sekhetre barite bhalo.] • Where and with whom you feel comfortable and uncomfortable while socializing? A: [Amar nijer ghore r hall e..] • How you use to socialize with people before having the dieses? A: [agey toh kono somosya e chilo na.. onek rokom bhave melamesha hoto.. flat er samne ekta park ache okhane hatte jetam bikele .. oneker sathe dekha hoto.. tachara relative de barrio jawa hoto.. r o onek bhave interaction hoto manushder sathe]

DAILY LIFESTYE

EMOTIONAL CONDITION

• What kind of works you have in your daily life (used to do)? A: [Agey sob rokom ghorer kaj korechi.. ekhon kichui korte hoi na.. sokale ghum theke uthe chan kore agey pujo kori nijer ghorei.. tarpor meditation kori,.. tarpor newspaper pori, kajer meye take rannar instruction di, dupure khey ghumai, bikele uthe T.V dekhi.. kokhono golper boi pori.. ] • Do you follow any kind of lifestyle routine for UI? A: [Yes… tar jonyo e valo thaki ektu..] • How do you spend your whole day?

• How do you see yourself in your family? A: [Ekhon r ki.. kono bhabe moner jore beche achi.. swami chole jaoar por r shokto hote hoyechilo nijeke.. ami kokhono kar o upor dependent hote chai ni.. kintu eka thakte hobe bole meye r jamai amake nijeder kache ene rekheche… tobe amar somostho khoroch ami nijei kori..] • How do you want see yourself? A: [Je kichu din bachbo jate onyo kar o upor vorsha korte na hoi.. Sustho thaki, bhalo thaki.. ] • Show me some of your photos.

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• Which song you can say perfectly depicts your emotion about this condition? • With which movie you can relate your emotion about this condition? • How would you see if any of you relative of friend is also having the same disease? A: [R kar ache ami sotti e jani na.. r karo sathe discuss o korte chaina.. ] • If you get some magic power to apply to your this condition what would you do? A: [sob rokomer saririk somsya thik kore debo.. ha ha.. r uriner problem ta niramoi kore debo] • Do you face frequent mood swings? A: [Hain hoi.. tobe sometimes..] • Do you believe that doctor can cure your issues? A: [ etodin dhore ache somosya ta… treatment o choche.. kintu doctor cure korte parbe kin a tate sondeho ache] • Do you have any kind of bad childhood memories? (Childhood fear or abused) A: [na temon kichu nei ] • Are you afraid of anything? (apart from UI) A: [kokhono kokhono insecured feel kori.. ek toh meyer barite thakchi .. (e amar jamai er 2nd wife. Amar meye mara geche tar ekta bachha o ache)..] • Do you have any kind of anxiety issues? A: [Hain.. khub hoi..] • Any kind of hypertension? A: [Yes.. ghumate parina onek somai.. tai ami meditation o kori..] • Have you been gone through any kind of trauma? A: [Meyer mrityu] MICTURITION PROCESS • Usually how many times you go to toilet? A: [Every 40-45 minutes diner bela, r rate ektu kom bar jai.. tobe winter r monsoon e ektu besi bar jai..] • Before urination do you get any sensation or feeling (mild

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or strong)? A: [Hain khub strong sensation pai ami..] • Do you prefer any one’s help during urination? A: [Ekdom e na.. amar darker o porena..] • Do you feel any kind of satisfaction after urinating? A: [Ami kokhono satisfy feel kori na.. mathar modhye sob somai cholte thake urine jete hobe..] • How do you feel during urination? A: [Mone hoi ekhono urine roye geche...] • Is it possible to hold your urine when you start getting strong sensation? A: [Kichutei hold kora possible noi.. chaileo hold korte parina..] • Do you need to force or strain during urination? A: [Na kono force apply korte hoi na.. tobe seser dike mone hoi r o hobe r o hobe..] • Do you feel any kind of pain or burning sensation? A: [na..] MANAGEMENT AND CARING PRODUCTS • What kind of products or devices do you use to manage yourself? A: [ami sudhu Diaper e use kori.. tao sobsomai noi.. jokhan problem ektu besi hoi tokhon] • Do you practice any types of kegel exercise? Any improvements? A: [Hain ami exercise kori roj..kintu kegel exercise noi..] • How do you see all these products in your life? A: [Emnite ami diaper pochhondo kori na.. kintu onek somai porte hoi.. se hisabe se somai eta jothestho guruttopurno amar jonyo..] • How much you trust all these products? A: [diaper porte na pochhondo korleo.. onek somai trust korte hoi.. ] • Do you feel that you have been dependent on these products? A: [Hain amar mone hoi ami Jodi eta continuous use kori tahole ami dependent hoye jabo.. ]

• What are the love factors about these products? A: [Diaper pore thakle comfortably baire kothao jaoa jai.. ar confident feel hoi.. ] • What are hate factors about these products? A: [urinary infections hoi amar..] • Would you like to prefer surgery for a long term solution? Why? A: [Surgery kono bhabei korate chai na.. Voi hoi r o kharap obostha na hoye jai.. r ei age toh noi e.. ] • Apart from surgery what kind of product you would like to imagine for a long term solution? A: [emon Kichu jeta ei obosthar improvement korte parbe.. jeta use korte amar lojjabodh hobe na.. ] • Would you prefer any sort of inserting product (through vagina) for cure and better condition? Why? A: [Na Na.. eta korte parbo na..] • What kind of ultimate solution do you expect from your doctor? A: [Cure kore dite.. ] • If your doctor told you to use some new products what would you do? A: [Hain korte pari.. Tobe seta nije nijei jate byabohar korte pari.. tahole valo hoi] CONJUGAL LIFE AND SExUAL SENSATION • How do you see your husband in your life? A:[ Sob theke impoetant figure r support chilo amar jibone] • Do you think UI affected your conjugal life? A: [ Hain o avoid korto.. hoto smell er jonyo.. ] • Do you have any kind of sleep disorder? A: [Hain.. ei karone amader dujoner e problem hoto..] • Do you sleep together with your husband? A: [ei somosya suru hoar prothom koyek bochor sathei gumatam.. pore khub problem start hoai o alada ghore ghumato..]

BIJOY PRASAD SAH A | M.DES 2017 | GRADUATION PROJECT | NID

• When you started facing menopause? A: [Ei problem start hoar agei hoyechilo..] • Do you feel any kind of sexual sensation? A: [ei problem barar pore o feel hoto.. kintu ager theke onek kome giyechilo. ] • Was there any kind of changes in sexual life or sexual behavior after your delivery? • What was the sexual routine before menopause? FEAR ABOUT UI • What kind of fear you have with the disease? A: [Sudhu eta mone hoi keu jante parle ki bhabe amar byapare.. Lojjito mone hoi khub..] • What kind of fear you have with your treatments? A: [Jate obostha r o kharap na hoye jai..] • What kind of fear you have about your social relationship with family and others? A: [Bhoi hoi ei jonyo sobai hoito amai pochondo kore na.. ager moto kache ese boste chai na.. Manosik bhabe durbol hoye gechi onek..] • Fear about surgery? A: [Jodi condition ar o kharap hoye jai..] • Fear about inserted products? A: [Eta toh kono bhabei possible noi... ekhetre voi bolte ei concept tai onek opomanjonok..] • Fear about exercise or therapy? A: [Exercise korte kono voi nei.. tobe nijer ghorer baire na holei besi bhalo hoi..] • Fear about life? A: [Ami chole gele amar natni ta ki korbe.. nijer maa tao toh chole giyeche.. or jonyo e beche achi ami..] • Fear about other’s perception about your condition? A: [Ei obosthar kotha keu janle manosik obostha r o kharap hoye jai.. nijeke choto mone hoi..]

UI? A: [ Khub kharap obostha hoyechilo.. bolte parbo na.. (Sorry)..] • How do you feel when a person came to know about your this matter? A: [Bollam toh nijeke choto mone hoi.. ] • Do you think this condition affected your social life and social image? How? A: [Obosyoi amar social life kharap hoyeche.. ekhon toh kothao kar o bari jeteo voi lage.. Jodi okhane giye kichu hoi.. se je khub boro lojjar karon hobe.. ] • How do you manage yourself if something happens in public? A: [Jani na… (Sigh)..] HOPES What would like to remove / add/ or change with whole concept of incontinence ? A: [........] • Do you think it could be solved from outside of the body? A: [Seta kora ki sombhob.. hole seta ki kore kaj korbe.. ?] • Can you trust on an electronic device to get control over your urination? A:[Kaj korbe kina use korar porei bujhte parbo.. tobe seta lagiya ami sute boste parbo toh.. r chola ferao kora jabe toh… ?] • What kind of solution do you expect ? A: [Emon kichu jate ami puro puri thik hoye jai..]

SHAME AND SOCIAL STRATA • What are worst situation you have faced (facing) for with

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PATIENT INTERVIEW DATA MAPPING INTERVIEW: 1 UNDERSTANDING THE RELATIONSHIP - lack of trust on doctors and available treatment methods, due to little or no improvement over the years. - trusts and communicates more with female members of the family - her daughter, her two granddaughters and her nurse. BACKGROUND OF PATIENT - has become forgetful about the past or is shy about sharing incidents from her younger days. - has been suffering over a very long period of time. - initially attached very less importance to the condition, thinking it was not very serious. - did not find any mental support of trust in family members to disclose her condition. - confided in her husband much later when the symptoms increased very much but has never visited the doctor accompanied by her husband. PHYSICAL CONDITION - did not visit doctor while husband was alive because i) discomfort level was lower ii) the little discomfort she had did not bother her. - visited doctor with her son in law for the first time. - during treatment she was given a medicine which she took for a long time but it did not improve her condition. A second medicine was given, which also did not help even after long-term consumption. Hence she stopped taking medicines. - She is willing to consume as many medicines as required, only if some improvement can be noticed, which she has

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not noticed from any medicine so far. - she has found no satisfactory remedy to her condition, though wearing diapers at least allows her to move a little, before which she was confined only to the bed. Her son in law convinced her to use diapers. - She is not willing to use any intra-vaginal device. - Previously she used to exercise on her own. Now, she is assisted by a physiotherapist for her knee problem. - She has suffered from UTI, something which feels ashamed to admit. Use of remedies like cloth may have been a source of infection. - She has no one to whom she can completely open up even though she is close to her family. She constantly feels insecure.

husband and her son, but has remained strong throughout. However, eith old age she is becoming anxious. - She is very glad that a nurse attends to her. Otherwise she and her family would both face more problems and she would feel ashamed. SOCIALIzING ASPECTS -She can not visit relatives, and is restrained at home. - Communicates with friends and relatives over the phone or when they come to visit her at her place. - She prefers to interact with visitors in the hall room and not her room because it is more spacious. - She has become more introvert after this condition and can not mingle as easily as she could.

KNOWLEDGE ABOUT URINARY INCONTINENCE EMOTIONAL CONDITION - No knowledge about the details of condition, and reasons for it. She assumes it is due to aging. - Has been using diapers for past 5-7 years which has improved her life. She sleeps better, can move around a little more. - She still needs to visit the toilet many times a day, because she is scared of leakage during eating or other daily activities. - Lost her husband when she was very young and single handedly raised two children. All this time she has been independent and not bowed to anyone for help. - No knowledge about recent products available in the market. - Believes this condition can not be cured and does not trust anyone to cure it, also believes such conditions are inevitable due to old age. - She has suffered emotionally in life. She has lost her

- Her major roles in her family are supervising the maids. - Before she would take care of the cleaning herself but not she instructs the maid to do so. She is very particular about cleanliness and wants anyone who visits her room to be comfortable. She does not want them to feel as if there is a problem or she is suffering. - Her mother and sister too suffered from this condition but she does not know anyone else who did. Her life would be much better if only this problem gets cured. - She desires to be healthy and have complete control over her micturation as she had before but believes this is not possible. - She used to suffer mood swings because she had to constantly clean herself, which improved after using diapers. - Her happiness has improved greatly after the birth of her

BIJOY PRASAD SAH A | M.DES 2017 | GRADUATION PROJECT | NID

own granddaughters and has helped ease the burden of losing her husband and son. - She believes that in order to become absolutely rid of this condition she has to become young again! Medicines and diapers are a relief, but she does not trust any doctor to cure her, now that it has been so long she is suffering this condition. - Suffers from insomnia at night because of the condition. Sleeps better in the afternoon because her nurse is there and she feels more secure to sleep. MICTURITION PROCESS - Has to go to the toilet frequently - every half an hour at night. This is a huge irritation. She has fallen down in the toilet thrice and once fractured her leg, due to which movement has become poor. - She can feel the urge at times and rushes to the toilet the moment she gets the urge because she is not capable of holding the urine in. - Only her nurse assists her in the toilet sometimes as she is ashamed to ask other family members. - This concern of urinating is always on her mind and she is scared if leakage all the time. This makes her mentally restless. - Does not feel any particular sensation during urination. MANAGEMENT AND CARING PRODUCTS. -uses diapers, which she is very Dependant on to maintain personal hygiene and cleanliness. It also gives mental support and reassurance. - does not exercise. - her desired product will one which is easy to use, by

herself and also will cure her completely and will have no side effects. FEAR ABOUT UI - the main fear about the disease is the shame factor. - she can not share the problem with anyone and missed her mother to whom she could have opened up. Lack of emotional support, even though she is close to her family is another major fear. - has become more distant with extended family but does not share her problems with them or let them understand this condition. - she is not open to the idea of surgery and does not trust it can cure her, think it may lead to more problems. - she does not accept products which have to be inserted within the vagina because it is a social stigma to her and she is scared of others finding out. - she is open to the idea of exercise to improve her condition but does not want to exercise outside because she does not want people to find out. - She has not other insecurity apart from this in her life as her family is with her and she does not have to stay alone.

HOPES - that doctors have a better understanding of the condition to treat it better. - emotional and mental support from family to have some mental strength. - the desired product should be such that she does not need help from others to use it. - the desired solution will be best if can be treated from outside the body, without any invasive treatment. - she will be very pleased to have a device which will give her better control over her condition and she can control the device herself, from outside the body without inserting. - she will trust such an electronic device if recommended by the doctor. She will not have to use diapers anymore and will also get her mental strength back

SHAME AND SOCIAL STRATA - once she had continuous leakage in front of son in law in his house and this was an extremely embarrassing situation for her. - felt embarrassed and insulted that others got to know of her condition which she did not want. - had she not had a nurse to help her clean, she fears people would think her unclean and no one would even come into her room.

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INTERVIEW: 2

UNDERSTANDING THE RELATIONSHIP - She has a close relationship with the doctor, who is her son in law and trusts him the most in the family. - She does not have any major work to attend to in the family apart from puja. - A nurse has been appointed, who takes care of her at all hours.

problem with medication or exercise. She is also not open to trying any invasive product. - She has been regularly doing exercise for the last 20 years, assisted by a physiotherapist. - She would previously do a lot of strenuous physical work before, but ever since the condition, she does not do it anymore. - She frequently suffers from UTI, with burning sensation during micturation and fever.

BACKGROUND OF PATIENT KNOWLEDGE ABOUT URINARY INCONTINENCE - Patient had suffered excessive blood loss during delivery of her baby, after which she had difficult urination for two months. -Patient has been suffering from UI for the last 22 years - She first started noticing the condition when she was 53 or 54 years of age. At times she would feel the urge to micturate, but on going to the toilet she would realise that she had already leaked. For the first three years she had not paid any heed to this. - She first shared her condition with her husband, and then with her son-in-law. - She came to live in the city of Kolkata from her native place when she was married. - She single-handedly raised her daughter and son.

- She thinks condition is due to old age. - Nurse helps her to keep herself clean, and uses diaper when her condition worsens. She used cloth previously. - She is not aware to new products to treat her condition nor she is open to using them. She prefers diapers, medicine and exercise. - She does not not think her condition is curable. - She quality of life has been affected majorly by her condition.

EMOTIONAL CONDITION She has to stay mentally strong to lead life, especially after her husbandâ&#x20AC;&#x2122;s death. She does not want to be Dependant on anyone. - She is financially independent. - Does not know anyone suffering from the disease and does not want to discuss it either. - She occasionally has mood swings. - She does not believe she can get cured because she has been suffering from very long. - Suffers from anxiety, hypertension and sleep disorder. - The loss of her daughter has been very traumatic for her. MICTURITION PROCESS

- Follows a disciplined and restricted lifestyle to stay better - No outdoor activities since past 12 years.

- She has to urinate every 40-45 minutes during the day, less frequently at night. During winters or monsoons the numbers of times increases. - Experiences strong urge before urination. - Needs no assistance during urination. - Does not feel satisfies after micturation is complete and fears leakage constantly. She also feels some residual amount is left after. - Can not hold urine even after she tries very hard once she gets the urge.

SOCIALIzING ASPECTS

MANAGEMENT AND CARING PRODUCTS

- Talks to relatives over phone or when they visit her, maybe during a family gathering. - Wants to go outdoors but can not because of fear of leakage. -Feels comfortable while socializing in her own house.

- uses only diaper, but does not like using it. - no knowledge of Kegel exercise. - does not use regularly though she feels she will become completely dependant if she uses these products regularly. - Her desired product will be one which she will not feel shame in using, can be used by herself, not one which needs to be inserted through vagina and will cure her

DAILY LIFESTYE

PHYSICAL CONDITION -She constantly feels the urge to urinate and keeps fearing of leaking any moment. Even after urinating she feels that the micturition is not complete. - Leakage happens frequently. - She has been on medication (Vesiguard) for a long time. - Medication has helped improve her condition but sometimes fails to work. - She is not open to the idea of surgery, though she has no

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permanently. CONjUGAL LIFE AND SEXUAL SENSATION - Before husbandâ&#x20AC;&#x2122;s death he was an important pillar of support, though their physical intimacy reduced after the disease and he started sleeping in a different. FEAR ABOUT UI - She feels scared that people might get to know about her condition. - Scared that everyone wants to maintain a distance from her and does not want to sit near to her because of this. - Has become emotionally weak. - Fears surgery might make condition worse. - Open to exercising within the house but not outside. SHAME AND SOCIAL STRATA - Does not want to discuss embarrassing situations that she has faced. - Has ruined her social life, she feels reluctant to go to any bodyâ&#x20AC;&#x2122;s house. HOPES Something which does not need to be inserted and allows for movement freely.

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SHADOWING Shadowing provides a rich, comprehensive data set about the patterns of actions, interdependence and motivations of users. Observation is enhanced with information about mood, body language, pace and timing in order to give a full picture of the world from the userâ&#x20AC;&#x2122;s point of view. Process. 1) DOMAIN AND DEMOGRAPHICS Locate the right venue to research and the appropriate person(s) within that venue to follow. This period could also involves preliminary research into the roles, language/ terminology used and issues at hand. 2) SECURE ACCESS This is a critical step, as it could take as long to gain access as it does to complete the entire shadowing period. Access needs to be as unrestricted as possible and could involve contacting third parties for proper permissions. 3) DEVELOP TRUST The goal of shadowing is to gain insider status. Once the access has been given, the researcher must create a healthy rapport with the person being shadowed. If the participant does not feel comfortable, critical information could be missed. This method involves a great deal of trust, and the researcher must continually work at managing the relationship throughout the shadowing period. 4) SHADOWING

field notes. The researcher asks frequent questions for clarification and prompts the participant to give a running commentary on his or her actions and choices. 5) RECORD The researcher records and compiles the field notes from the shadow period and adds debriefing notes to maintain freshness of experience. If the shadow period continues over multiple shifts or days, debriefing must be done after each immersion. 6) ANALYSIS The researcher analyzes the large data set that has been accumulated during the shadowing period. Methods of data summary and presentation could include storyboarding, narratives and persona/character sketches.

Shadowing was done with one patient, in her house - Uma Mukherjee. As her granddaughter is my friend I got access because the patient was also familiar with me. In order to understand the patient very closely and understand her viewpoints I observed her activities and the spaces she uses for these activities for 7-8 days. The purpose of this study was to observe the gaps between what she says and what she does to understand aspects which remained unsaid. I also observed closely her attitude, her silences, her sense of belonging, her importance of the family and how she associated with them, her moods and her body language. This gave me a whole picture of the patientâ&#x20AC;&#x2122;s life.

The researcher closely follows an individual over a set period of time while writing an almost-continuous set of

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DIALOGUE MAPPING FOR ETHNOGRAPHY

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ETHNOGRAPHIC DATA ANALYSIS - The patient established at the very beginning of the interview that there is a lack of trust on doctors and available treatment methods. Even after having gone to several doctors the patient has not been cured. Thus, the patient believes that her condition can never be cured. - The patient shows trust and communicates more with the female members of the family. There is a deficit of mental support from family. - I was perhaps the first person who had interviewed the patient about her life, physical and mental condition in such detail. When I asked about personal incidents such as pregnancy, the patient mentioned how she has not recalled such memories in a very long time. - The patient has been suffering from this condition for almost 41 years and did not pay heed to the problem initially, till the symptoms increased. Though she suffers and faces several problems due to her condition, there is a sense of pride and self-respect when she mentions that she has braved her condition for so long.

unthinkable to her. - Patient frequently suffers from UTI, with burning sensation during micturation and fever. The patient feels ashamed to admit this and only speaks about it after her granddaughter mentions this to me. Earlier, she would use insert pieces of old cloth through the vaginal opening to absorb leakage. This was perhaps the source of infection. She asks her granddaughter to not discuss this and explains that she had to use cloth in order to find a selftreating remedy for her condition. Her explanation also hints at how she received little or no mental support during the early stages of the condition, which lead to further deterioration. - Patientâ&#x20AC;&#x2122;s knowledge about the condition and its reasons are poor. She believes that the condition is due to old age. She has perhaps been told that such symptoms are inevitable due to aging and believes this herself.

- The patient does not feel medicine or exercise can cure her because they have not improved her condition even after a long time.

- She is a strong woman who is fiercely independent. Having lost her husband at a young age, she singlehandedly raised her children. The loss of her husband and her son shattered her but she remained strong. She is proud of the fact that she never needed to ask others for her help. The trauma of her life has strengthened her, and so she constantly says that her condition is a much lesser source of pain compared to what she has faced in life. The patient justifies and reasons with herself to make herself mentally stronger towards her condition. There is a comparative reasoning involved in order to nullify her present pain due to her condition.

- The patient is completely opposed to using a product which needs to be inserted through the vagina. She feels ashamed and the idea of such a product seems

- Even though her son-in-law had to convince her to use diapers initially, she feels relieved by both his concern and care towards her as well as by using the diaper. The diaper

- During the time when her husband was alive, her condition had already started to show its symptoms. However, the happiness she felt because of having her husband with her in her life overpowered the discomfort that the condition made her feel.

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makes her feel more reassured, especially during sleeping at night. However, the shame of leakage is still strong within her mind and she feels unclean. Thus, before eating she makes it a point to visit the toilet. - She constantly mentions the trauma (Koshto) associated with her condition. The trauma is often more mental and emotional than physical. Initially the trauma was not so much - but as the symptoms became worse, she started to get affected not just physically but emotionally as well. The loss of her husband meant that she lost the last person she could confide in. This traumatized her more. - She is very dependant on her nurse, who takes complete care of her and keeps her clean. She mentions that had she not been able to afford a nurse, her family members would have to take up the responsibility of managing her. This would have made her feel like a burden to them. Because the nurse always takes care of her, she does not have to disturb her family and this reduces the shame factor. Otherwise, she would have felt more ashamed by her condition. The fact that her family would have to face problems because of her bothers her more than the discomfort of her condition. - The patient does not leave the house and does not have the metal condition to venture outdoors either. As a result, socializing is limited to phone conversations. Sometimes, relatives come to visit her at her home. She is comfortable with her immediate and close family sitting in her room while interacting, but prefers others to sit in the hall room while talking. She further justifies this by saying that this is because there is more space in the hall room. However, this is because she is conscious of smell or other factors related to her condition which she does not want others to know of.

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- The patient has limited role within the family, engages in light work within the house and does not have much work outside the house. - She always wants her room to be very clean. She constantly emphasizes on this which suggests how she wants to appear hygienic. She is concerned that whoever visits her room should not get any odor or sense her condition. - She wishes to regain complete control over micturation like in her young days, but jokes saying that this is absurd and not possible. This also shows that how it is firmly ingrained in her mind that cure is not possible. - She is very dependant on diapers and this is like a life-line to her. She can sleep peacefully in the afternoon because her nurse is there, but her sleep at night is disturbed. This again shows her insecurity and her dependence on the nurse to feel assured. - She suffers from sleep disorder. While going to sleep, the thought that she would have to visit the toilet every 30 minutes keeps disturbing her. This feeling does not allow her to sleep well and she feels scared and disturbed throughout the night. - If patient needs help during urination she only asks her nurse for it, she feels ashamed to ask anyone else, even her daughter. There is again a sense of dependence on the nurse. - The patient yet again emphasizes on her dependence on diapers. She can not imagine every day life without it and whatever little movement she is allowed will also completely cease if she can not use it. She is of the mind

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set that the diaper helps her keep clean and gives her a certain amount of confidence. This once again shows her psychological dependence on diapers. - The only complaint she had about the diaper is that it makes her dependant on a second person. Her nurse has to help her wear it and remove it. She said that she would feel very relieved if the solution could be used on her own, without any external help. This shows how she craves to feel independent and self-sufficient. The shame factor will also be reduced incase of such a product. - She says that she wants the solution to be such that it gives her a sense of reassurance like using diaper gives her. This says how, to her, the diaper is the maximum degree of relief that she feels from her condition. She sees the diaper as a solution, instead of going for treatment which will cure her, instead of just being a means to maintain hygiene or cleanliness. The patient seeks immediate relief as opposed to long term care and treatment. - The patient speaks in the collective noun, saying ‘we’ when she talks about the fears she faces due to her condition. The biggest fear, as has been already said earlier, is the shame. The second, is the lack of a person to confide in due to this condition. The only person she would be comfortable to share everything with was her mother. She again emphasizes on the word ‘support’ showing the void of a support system, though she does not specify what kind of support she expects.

in others in hope for sympathy. This shows how she has convinced herself to stay mentally strong. - The other fear she speaks of are products that need to be inserted through her vagina. This a big taboo to her and she says she would be ashamed to even think of such a solution, given the social stigma surrounding such an invasive product. She would not even have been comfortable to share the idea of using such a device with her husband, leave alone use it. The fact that someone would get to know and judge her or stigmatize her for using such a product is alarming to her. - She is also afraid of going outside the house for exercise or therapy. She is reluctant to go for treatment of this kind to any place away from her house because she does not want people to question her about her whereabouts. She again says that she does not want anyone to know about her condition, because if she gets to know that someone else knows about her situation, she will feel more ashamed and this will lower her self confidence even more. - She says she wishes for a cure which will give her a sense of support and self reliance at all times. She says that is open to the idea of an electronic device that can be attached to her body externally and does not need to be inserted. Such a product will allow her to regain her control as before and free her from the need of using diapers as well.

- She has distanced herself from her relatives and extended family due to her condition but she says that she never allowed anyone to understand the reason for her withdrawal. She is secretive about this and this gives her a sense of independence - the fact that she did not confide

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CATEGORIES AND PROMINENT PHRASES PROMINENT PHRASES 1. long-term suffering 2. desires improvement 3. dissatisfied with treatment 4. dependence 5. shame 6. self -confidence 7. frustration 8. trauma 9. false beliefs 10. desire to stay clean 11. false self-image projection 12. mental support/ confidant 13. needs 14. secretive 15. sense of loss 16. distance from family 17. lack of social life 18. short -term and immediate relief 19. fear 20. self-care 21. non-invasive product 22. ease of movement 23. control 24. self-reliance 25. acceptance

- sound of plastic chair moving against floor - sound of plastic packet of vegetables under her bed - sound of plastic containers opening and closing -sound of plastic bucket 2) CREAKING SOUNDS - creaking of bed -creaking of old furniture - door creaking - creaking sound of walker 3) SOUND OF TELEVISION - the television is switched on during all hours while she is awake at a high volume. The patient wants to mask sounds like sounds of flush etc. which she finds embarrassing by turning on the T.V volume.

- smell of incense sticks - smell of sweets -smell of room freshener - smell of detergent - Smell of mosquito repellant liquid - Smell of female deoderant/perfume - smell of phenyl (lemon-scented) -smell of food (rice, sabzi/masala) - an old musty smell Overall the smell of her living room is mixed with lot of natural and artificial smells. In sense of natural smells, most prominent were smell of vegetables, kept under her bed and in the corner of the room. Old, mild and musty kind of smells were present mainly due to old furniture, paper and other stuff and also maybe due to less amount of sunlight entering the room.

4) SOUND OF BATHROOM FLUSH 5) SOUND OF PEOPLE TALKING - patient talking to nurse - patient talking to granddaughters - patient talking to daughter - patient talking to son-in-law

SOUNDS

6) OTHER SOUNDS:

1)SOUNDS OF PLASTIC

-constant sound of fan - sound of ringing bell during morning aarti - sound of floor being swept - sound of tap running - other sounds of water

- plastic sheet under the bed sheet - medicine packets - shuffling sound of wrappers - small plastic bottles

SMELLS

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The smell of detergent is strong probably because the bed sheets are changed every morning. At night, the smell is predominantly that of mosquito liquid Many times there is a strong smell of deodorant or perfume.

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ANALYSIS OF CATEGORIES The patient constantly mentions the trauma (8) she faces because of her condition. The long term suffering (1) has made her frustrated (7), led her to believe that her condition cannot be cured (9) and also to be dissatisfied with her treatment (3). She also believes that the condition is due to old age (9). Her condition has made her dependant (4) on her nurse and diapers, which further frustrates (7) her as it shakes her self-confidence (6). In order to make herself feel confident (6) she has projected an image (11) of strength and resilience (6). Another source of trauma (8) is the lack of mental support or a confidant ( 12). Because she does not have anyone to confide (12) in she has become secretive (14) about her condition. Her being secretive (14) also sheds light on her need (13) to feel loved, wanted and intimacy. Her condition has distanced her from her family (16), intensifying her need (13) for mental support (12). She feels unclean and has become obsessed with cleanliness (10), again showing a projection of a self-image (11). The condition makes her feel shame (5) which is another cause for trauma (8) and lack of social life (17). She believes (9) that the diaper is her biggest support and she is hesitant to go for regular treatment. This further highlights her dissatisfaction with her treatment (3). It also shows her want for short-term relief (18) as opposed to long term treatment. She feels fear (19) and unaccepted (25) and this traumatizes (8) her more. In order to regain her previous quality of life (13), she desires a product which will help her get rid of her dependence (4), allow self-care (20) and self-reliance (24) ( again establishes need for self-confidence (6)), give her better control (23), be non-invasive (21) and allow for easy movement (22). Such a solution will reduce her trauma (8).

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SYNTHESIS Through the analysis of categories one can conclude that the trauma (koshto) is the primary issue faced by the patient. The need for mental strength (moner jor) is the other key metaphor from her interview. Trauma relates not only to her physical discomfort but to other important categories such as emotional frustration, lack of mental support, long-term suffering, lack of selfconfidence, constant dependence, dissatisfaction with present treatment and several unfulfilled needs. The metaphor ‘moner jor’ (mental strength) has extensive interconnections to several themes not only in the patient’s life but also related to my presence in their life as well as my frame itself. It can be seen at multiple levels, as referring to control over one’s urges, strength and resilience, self confidence, the desire to be independent and to be secretive, led by the belief that seeking support will make her seem weak. The feeling of shame and the fear of being stigmatized due to the condition is firmly established in her interview. The most prominent sounds in the room are also clearly of plastic. This can be interpreted as how, because of the waterproof property of plastic, it is used extensively by her. The sound of the plastic sheet, the sound of a plastic chair on which she sits (easy to clean), sound of plastic wrapper of medicine somewhere correlate to the trauma of dependence and alienation that she faces. The sound of television constantly on also hints at how she wants to mask her condition. The most prominent smell is that of perfume and phenyl in her room. This tells us how she tries to mask the trauma she faces through this smell.

even though she does not state so clearly but establishes this many times through her dialogue. The metaphor also extends to her past experiences and life world. Having lost her husband and her son, she is now living with her daughter’s family. There is a constant sense of trying to stay emotionally strong, as even after receiving respect and care from the family she feels estranged. She expresses her concern as she feels that she cannot confide completely on anyone. Trauma and mental strength therefore is a central theme of her life and physically as well as mentally a prime task of her everyday routine on multiple levels. The sound of plastic and the smell of perfume throughout the day are a reminder of how she wants to mask her condition and the shame due to it.

The themes of koshto (trauma) and moner jor (mental strength) are significant to the patient also in terms of her everyday life, beyond the condition. Self respect, confidence and independence are important to her and the need for a source of support is unacceptable to her,

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ARTIFACTS

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Concept Direction

Scope of Intervention From the patient’s interview, data analysis and ethnographic synthesis, the patient’s expectations from the solution became clear. They were expecting a kind of product which could be a self-administered solution, without involving a second person. This would nullify the shame factor and feeling of dependence on others due to the condition. The patients are not open to the idea of intra-vaginal products because of the stigma associated with it. Thus they desire a non-invasive product which can be used externally. From the synthesis it beomes evident that the lack of selfconfidence becomes a major emotional drawback of the condition. Thus, the patient expects a solution which will instill self confidence by allowing them to regain control. After looking at the available solutions, and comparing them with the patient’s expectations plotted from the ethnographic study, a huge gap was found. Most of the available solutions seem undignified and kind of insulting to them. Even though such products are often medically efficient to treat the symptoms of urinary incontinence, the patient refrains from using it due to the socio-cultural gap between user and solution. This gap is because, the products are developed on the basis of medical and physiological understanding, with no emphasis on social, cultural, geographic and user centric research. The satisfaction of user from using available products or solutions was poor. Products such as diaper are not a cure for the condition but simply a means to provide temporary relief and support. In many of the products, it was observed that risk factors, complications and side effects were quite high. These are the reasons why most of the available products have not been accepted by urinary incontinent people and are thus unsuccessful.

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Further, it can be observed that the solution does not target any specific phase of the symptom, and provides only maintenance as opposed to regaining control and long term improvement of the condition. In my research, I have studied and understood the physiological and medical factors of this condition in various phrases. In-depth study of patient as well as the socio-cultural setting, and the associated stigma factors has shown that a single solution or product is not enough to treat this condition as the condition itself is a ‘wicked’ problem. This means that, the solution to the problem, gives rise to further problems, which need other measures to be treated, thus complicating the treatment process. The solution thus needs to be a group of strategic solutions which are interconnected with each other, such that the patient accepts the solution and is also physiologically benefited from it. This ‘package’ of solutions will be such that a maximum number of phases can be targeted (SUI, UUI amd MUI) thus relieving them of more symptoms and enhances their quality of life.

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INTERVENTION BUILDING As per user expectation from enthnographic analysis, understanding the symptoms thoroughly from medical and physiological perspective and critically analyzing available solutions in the market study, it can be seen that the design intervention can be done from several levels of symptoms. It can be preventive, exercise based or therapeutic or control level but the approach has to be in dignified way. According to social research, the solution needs to be such that the patient can have a degree of trust and emotional dependence on the solution. The solution should be personalized, non invasive and cost effective. They patient has repeatedly said that they can not see improvement which makes them dissatisfied with treatment, so there needs to be feedback system (healthtracking) for patient to understand tangible improvement. The device should improve self confidence, self esteem, be easy to use and less risk effects and side effects. So by considering all these factors, it can be seen that therapy and exercise can be the perfect way to target this condition. Though many therapy and exercise based products are available in the market, their acceptance is quite low due to earlier discussed stigma factor or they need the patient to visit a clinic or therapeutic center regularly. Hence this solution needs to be personalized, so that they can they can self treat themselves as per their convenience. Further, involvement of a second person becomes nullified.

product, so that others do not understand that she is undergoing therapy, ridding her of associated shame. Also, the patient will not be space bound and can move freely after using such a wearable product. I thus decided that the solution would make maximum impact, keeping in mind all the factors from research and mapping the scope of intervention, if is a wearable therapeutic device. The solution however needs to be a system level solution as the problem has already been explained as a wicked problem. It is imperative to ensure that the patient uses the device continuously, as irregularity plays an important part in making treatment difficult. In order to rid patient of shame factor, improve social image and self-confidence, and track the improvement of the patient they patient requires a personalized assistant which will give patient emotional support as well as be a reminder to follow a regular therapy regimen. This feedback system will encourage the patient to continue therapy and see visible results. So I decided to design an app which will work as a tracking tool for their condition and improvement. The app will further assists the patient with Kegel exercises along with therapy, ensuring overall treatment.

As the ethnographic analysis has revelaled, the patient feels embarrassed and disgusted to discuss their condition and symptoms even with their own children. Thus it will be very beneficial to the patient if the solution is a wearable

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DESIGN STRATEGY

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SOLUTION SYNTHESIS

RE-BRIEF

Design and develop a wearable neuromodulation device with therapeutic approach for women with symptoms of urinary incontinence, in order to improve self control and restore urinary function.

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Technology Study for Final Concept

Electrical Stimulation Electrical stimulation or neuromuscular electrical stimulation (NMES) is a technique used to elicit muscle contraction using electrical impulses. Electrodes, controlled by a unit, are placed on the skin over a predetermined area. Electrical current is then sent from the unit to the electrodes and delivered into the muscle causing a contraction.

INTERFERENTIAL CURRENT (IFC) ELECTRICAL STIMULATION.

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TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION (TENS)

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Electrical stimulation use dates back to ancient time when electric eels were used to treat painful spines and limbs. In this lesson, we will study the characteristics of electricity and its use in rehabilitation. By understanding how different wave forms effect muscle and nerve function, we can safely and effectively select a variety of electrical stimulation options to maximize patient progress toward goals in the plan of care.

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Intended for strengthening muscles, increasing muscle size, improving muscular endurance, and accelerating muscle recovery. Stimulation of denervated muscle to maintain viability. Designed to make the muscles contract strongly.

Intended for relaxing muscle spasms, preventing muscle atrophy, increasing blood circulation, maintaining or increasing range of motion, and especially for re-educating the neuromuscular system. Effective for neurological rehabilitation, as the stimulation is automatically controlled to turn muscle contractions into functional movements.

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Transcutaneous electrical nerve stimulation (TENS) is the use of electric current produced by a device to stimulate the nerves for therapeutic purposes. Covers the complete range of transcutaneously applied currents used for nerve excitation although the term is often used with a more restrictive intent, namely to describe the kind of pulses produced by portable stimulators used to treat pain. Most pervasive type of electrical stimulation,

RUSSIAN STIMULATION

ELECTRICAL MUSCLE STIMULATION (EMS) •

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FUNCTIONAL ELECTRICAL STIMULATION (FES)

There are several Types of Electrical Stimulation, electrical stimulation can be defined as: - Electrical muscle stimulation (EMS). - Interferential current (IFC) electrical stimulation. - Functional electrical stimulation (FES). - Russian stimulation. - Neuromuscular electrical stimulation (NMES) - Transcutaneous electrical nerve stimulation (TENS).

Neural implantation for long term muscle activation to perform functional activities. Intended for symptomatic relief of acute, chronic, and post-traumatic or post-surgical pain. Similar to TENS, but generally more effective and powerful.

Essentially the same as EMS, but typically focused on therapeutic use.

Intended for strengthening muscles, increasing muscle size, improving muscular endurance, and accelerating muscle recovery. Similar to EMS, but uses high frequency, sinusoidal stimulation waveforms. Popularized in the 1970s when Russian researchers used EMS to enhance the training of Olympic athletes.

NEUROMUSCULAR ELECTRICAL STIMULATION (NMES) •

Stimulation of innervated muscle to restore function including musclestrength, reduction of spasm/ spasticity, prevention of atrophy,and muscle reeducation.

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UNDERSTANDING HOW DIFFERENT TYPES OF ELECTRICAL STIMULATION WORKS

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characterIstIcs oF electrIcIty and current Flow electrIcal stImulatIon To safely and effectively apply electrical stimulation to the human body, it is importance to understand the characteristics of electricity and current flow. Key Terms: • CHARGE = Strength • CURRENT = Rate of Flow • VOLTAGE = Driving Force • RESISTANCE or IMPENDENCE = opposition

Ionic Flow occurs in the body because like charges REPEL and opposite charges ATTRACT.

tissues depending on water content •

High water content decreases impendance and increased conductivity: deeper layers of the skin, nerve, and muscle.

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Low water content increases impedance: bone, fat, tendon, and fascia are poor conductors due to low water content, also the outer layer of the skin called epidermis.

Anode = positive (+) electrode, Anion = negative (-) ion Cathode = negative (-) electrode, often referred to as”active” electrode Cation = positive (+) ion

OHM’S LAW : TISSUE HEALTH: Tissue health will change impedance: • Impedance Increases with edema, ischemia, atherosclerosis, scarring, and denervation. • Impedance Decreased with open wounds and abrasions.

Law defines the relationship between electrical current, voltage, and resistance. Current = Voltage/Resistance. Current flow is directly proportional to voltage: INCREASE Voltage = INCREASE Current, DECREASE Voltage = DECREASE Current. Current flow is inversely proportional to resistance: INCREASE Resistance = DECREASE Current, DECREASE Resistance = INCREASE Current. Biological tissues such as nerve and muscle membrane have the ability to simultaneously store and electric charge and oppose change in current flow. This characteristic is called capacitance. Skin and adipose act as resistors, or oppose current slow. Current always takes the “path of least resistance” when faced with multiple resistors.

At rest, a nerve holds a positive charge on the inside and negative on the outside.

Impedance should be minimized as much as possible in order to use the lowest intensity for patient comfort. Impendence can be reduced by: 1. Cleaning the patient’s skin with alcohol to remove oil and dirt before electrode application. 2. Clipping excess body hair under electrodes. 3. Warming the treatment area of the body prior to stimulation. CLINICAL CONSIDERATIONS:

IMPEDANCE CURRENT WILL FLOW UNDER 2 CONDITIONS: 1. There is an energy source creating a difference in electrical potential 2. There is a conducting pathway between the two potentials

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Impedance, or resistance to current flow, and conductivity is influenced by: TISSUE TYPE: Tissue impedance and conductivity vary through the body

Since adipose (fat) is a resistor, causing increased impedance, a body part covered with a thick layer of adipose tissue may require an increase in intensity to elicit the desired response. That intensity may not be tolerated by the patient, rendering electrical stimulation an unappropriate modality for that patient.

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CONSTANT CURRENT vs. CONSTANT VOLTAGE STIMULATOR

2. ALTERNATING CURRENT (AC)

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2. BIPHASIC - two phase, bidirectional wave with one positive phase and one negative phase. • Like Alternating Current in that the electrodes change polarity. • Can be symmetrical (identical phases that cancel each other out) or asymmetrical (non-identical phases that can be either balanced with no net charge or unbalance yielding a net charge). • Most commercial TENS units and some battery powered neuromuscular units produce asymmetrical biphasic waves; Variable Muscle Stimulator (VMS) units and some battery powered neuromuscular units produce symmetrical biphasic waves.

CONSTANT CURRENT STIMULATORS • Constant current produce a constant current independent of resistance encountered. The voltage adjusts to maintain constant current flow. The advantage of this type of of stimulator is to ensure a consistency physiologic response during the treatment. The negative is potential pain when the voltage increases to overcome resistance.

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3. PULSED CURRENT (PULSED) •

CONSTANT VOLTAGE STIMULATORS • Constant Voltage Stimulators, conversely, produce a constant voltage. The current adjusts to depending on changes in resistance. This unit is advantageous in preventing discomfort with changes in resistance, such as an electrode losing full contact, but quality of response can be decreased with these automatic resistance changes.

CURRENT CLASSIFICATION

Uniterupted bidirectional flow of charged particles changing direction at least once per second. Electrodes continuously changes polarity each cycle, therefore no build-up of charge under the electrodes. Often used in interferential or Russian commercial stimulators.

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Can be unidirectional (like DC) or bidirectional (like AC). Flow of charged particles stops periodically for less than 1 second before the next event. Pulses can occur individually or in a series

High voltage comercial machines.

3. POLYPHASIC - bidirectional wave with three or more phases in bursts.

WAVEFORMS • Waveform is a visual representation of the pulse Waveforms are diagrammatic only and rarely reflect what is actually going into the patient.

All polyphasic pulses are bursts but not all bursts are polyphasic.

CLINICAL CONSIDERATIONS There are three basic waveforms used in commercial therapeutic electrical stimulation units: direct current, alternating current, and pulsed current. 1. DIRECT CURRENT (DC) • Continuous unidirectional flow of charged particles with a duration of at least 1 second. • One electrode is always the anode (+) and one is always the cathode (-) for the entire event. • There is a build-up of charge since it is moving in one direction causing a strong chemical effect on the tissue under the electrode.

CLASSIFICATION OF WAVEFORMS WAVEFORM COMFORT: 1. MONOPHASIC - single phase, unidirectional pulse from baseline to either positive OR negative. • Suould not confuse this with Direct Current (DC). The similarity is that one electrode is always positive and one electrode is always negative, however, pulsed monophasic waves have interuptions, shorter duration, and less strength than DC making this wave unable to perform like DC. Monophasic waveforms do not cause the same magnitude of chemical changes as DC.

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• • • •

Symmetrical biphasic waveforms are most often reported to be most comfortable. Symmetrical biphasic was preferred to stimulate large muscle groups. No biphasic preference for stimulation of smaller muscle groups. Preference varied by person and another waveform tried if one is not tolerated well.

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WAVEFORM SELECTION • • • • •

All waveforms are capable of activating peripheral nerves. Symmetrical biphasic waveforms pose the least risk for skin reaction. Monophasic waveforms are most appropriate for wound healing. Asymmetrical balanced biphasic waveforms may be more useful to stimulate small muscle groups. Monophasic and symmetrical biphasic waveforms generate greater torque with muscle contraction and were less fatiguing than polyphasic waveforms.

CLINICAL LEVELS OF STIMULATION AND VOCABULARY It is important to know the vocabulary listing in the and goal of these levels. FREQUENCY Number of electrical pulses delivered to the body in one second.Also called pulses per second (pps), hertz (Hz) with AC.Higher frequencies cause higher levels of fatigue due to less time between bursts/pulses. Impendence decreases when frequency increases. Frequencies of 1-120pps meets most therapeutic goals Stimulation at 50pps tends to be more comfortable than 35pps. DUTY CYCLE Ratio of on time to off time Current flows during ‘on time’ and ceases during ‘off time’ Percentage of on time divided by the sum of the on and off time. Example, on time is 5 seconds, off time is 20 seconds = 1:4

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ratio or 5 sec/(5+20sec) = 20% Clinically speaking, muscle contractions elicited through electrical stimulation are more fatiguing, so longer off time allows for recovery/rest and fends off fatigue.

•

1 - 8 seconds 2 second ramp up is often adequate for comfort. Ramp down or off can increase patient comfort and provides opportunity to actively hold a contraction after the stimuli has ended.

ELECTRODES There are many choices of electrode shape, size, and configuration to fit the need of the patient and therapeutic goal for electrical stimulation.

RAMP TIME

ACCOMMODATION

TYPES OF ELECTRODES

Gradual increase in amplitude over time from zero to peak amplitude. • Can use ramp up and/or ramp down, variable • Fixed on some commercial machines, ranging from

Nerve cell will not generate an action potential after a period of time, no longer responding to electrical current, without an increase in intensity. Modulation, or varying one or more parameter, can prevent adaptation to the stimulus.

METAL PLATE ELECTRODES: Early version, limited sizes, required wet sponge conduction medium, difficult to secure in place. CARBON - IMPREGNATED RUBBER ELECTRODES: Degrade over time and become non-uniform with “hot spots”, many shapes and sizes, rinse and dry after each use and replaced every 12 months to ensure conductivity. SELF-ADHERING OR SINGLE USE ELECTRODES: Flexible conductors, convenient application, no strapping or taping to keep in place, resealable bag for multiple uses, often high impendence, possibility of cross-contamination, used most frequently these days. CONFIGURATION OF ELECTRODE SET UP 1. MONOPOLAR - single electrode from one channel. Active electrode placed directly over target tissue, often smaller in size. 2. BIPOLAR - two electrodes from one channel. Patient will feel excitatory response under both electrodes, eliciting motor response or electrode placed over motor point. 3. QUADPOLAR - electrodes from 2 or more channels, each lead with 2 electrodes. Interferential, large area, pain management, sensory stimulation of larger fiber.

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Neuromodulation

Neuromodulation DEFINING NEUROMODULATION Neuromodulation is among the fastest-growing areas of medicine, involving many diverse specialties and impacting hundreds of thousands of patients with numerous disorders worldwide. In the past decade, neuromodulation has witnessed significant advances with regard to the science, mechanisms, clinical applications, and technology development. These advances have been coupled with the rapid growth of the neuromodulation device industry and improvements in current devices and development of next generation neuromodulation systems. Neuromodulation is “technology impacting on the neural interface.” It is the process of inhibition, stimulation, modification, regulation or therapeutic alteration of activity, electrically or chemically, in the central, peripheral or autonomic nervous systems. It is the science of how electrical, chemical, and mechanical interventions can modulate the nervous system function. Neuromodulation is inherently non-destructive, reversible, and adjustable. Neuromodulation is inherently non-destructive, reversible, and adjustable. The INS (the International Neuromodulation Society) defines neuromodulation as a field of science, medicine, and bioengineering that encompasses implantable and non-implantable technologies, electrical or chemical, for the purpose of improving quality of life and functioning of humans. At the present time, neuromodulation implantable devices are either neural stimulators or microinfusion pumps. These devices are being utilized for the management of chronic pain, movement disorders, psychiatric disorders, epilepsy, dismotility disorders, disorders of pacing, spasticity, and others.

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The term neuromodulation can be defined as a technology that impacts upon neural interfaces and is the science of how electrical, chemical, and mechanical interventions can modulate or change central and peripheral nervous system functioning. It is a form of therapy in which neurophysiological signals are initiated or influenced with the intention of achieving therapeutic effects by altering the function and performance of the nervous system.

• • • • • •

Spasticity from spinal cord injury, cerebral palsy, or multiple sclerosis Diabetes Abdominal disorders such as irritable bowel syndrome or dysmotility syndromes Psychiatric disorders such as depression, obsessive– compulsive disorder and Tourette’s syndrome Movement disorders such as dystonia

Neuromodulation is the field of science, medicine, and bioengineering that encompasses implantable and nonimplantable technologies, electrical and chemical, that improve life for humanity. Neuromodulation is technology that impacts upon the neural interface. Among the technologies that neuromodulation encompasses are the following: • • • • • • •

Neurostimulation Neuroaugmentation Neural prosthetics Functional electrical stimulation (FES) Assistive technologies Neural engineering Brain–machine interface

Neuromodulatory devices are used for a growing number of indications including: • • • • •

Pain (ischemic, visceral, and neurogenic) Angina pectoris Peripheral vascular disease Epilepsy Urinary disorders

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Figure 1: Uses of neuromodulatory devices, both electrical and chemical, to treat a myriad of disorders of the human body.

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Fundamentals oF neuromodulatIon usIng electrIcal stImulatIon Neuromodulation and neurostimulation therapies and interventions are built upon a foundation of an understanding of neural structures and the behavior of the neural circuits of the nervous system. In the context of neuromodulation and neuroprostheses, electrical stimulation is applied to restore function to people who are unable to move, see or hear or to alter behavior such as seen in varied disorders of motor, sensory and cognitive functions. Rules have evolved over the past fifty years or so on ways to apply the electrical stimulus so that the response does not diminish as a result of its application. These include the choice of current rather than voltage pulses, biphasic rather than monophasic pulses and charge-balanced pulses rather than chargeimbalanced pulses.

OVERVIEW When electrical currents are delivered to the nervous system to elicit or inhibit neural activity, two things can happen: first the current creates a potential field that can alter the state of the voltage-gated ion channels, proteins that are embedded in the membranes of neural elements; and second, electrochemical reactions occur at the electrode–tissue interface. Altering the state of voltage-gated ion channels can initiate or suppress a propagated action potential, which, in turn, effects the release of neurotransmitter at the terminal end of the axon. Uncontrolled electrochemical reactions, at the electrodetissue interface, can cause damage to the electrode or injury to the target tissues. There are three concepts that has to keep in mind and

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consider while choosing Neuromodulation as a mode of treatments: First, electrical activation of the nervous system is more than causing paralyzed limbs to move, sound sensations in the deaf individual, and visual sensations in the blind person; it is about controlled and targeted release of neurotransmitters. Second, the science underpinning electrical activation technology is the knowledge of the voltage-gated ion channel, particularly the voltage-gated sodium ion channel. Third, the electrode is the business end of any neural prostheses; what happens there can determine the longterm viability of the device. Using the above three concepts as a foundation, one can more easily understand the rationale for making decisions about choices for stimulation parameters and how these choices impact the utility and longevity of a device intended to modulate the behavior of a neural circuit or activate the nervous system to restore function.

SOME BASIC CONCEPTS An electrode forms the interface between the neuromodulation hardware and the targeted nervous tissue. Electrical stimulation is achieved by connecting two opposite poles of a stimulus source to the tissue. Conventional current flows from the positive pole of a stimulus source to the negative pole, while electrons (negative charges) flow in the opposite direction.

ANODE AND CATHODE: The electrode at which oxidation reactions occur (increased positive valence or electron removal) is defined as the anode, and the electrode at which reduction occurs (decreased positive valence or electron gain) is defined as the cathode. VOLTAGE AND CURRENT: Neuromodulation is effected by application of electrical charge to the tissues. Voltage is a measure of the energy carried by the charge, being the “energy per unit charge” (Volts), while current is the rate of flow of charge (Amperes). STIMULUS CHARACTERISTICS: Electrical charge applied to effect stimulation of neural tissue can be characterized temporally by its voltage or current. The basic unit of applied charge, a voltage or current pulse, is defined by its duration (pulse width), amplitude (Volts or Amperes) and pulse shape (rectangular, triangular, sinusoidal). The repetition rate of the individual pulses is the stimulus frequency or pulse rate. ELECTRODE CHARACTERISTICS: The size (area) of the electrode– tissue interface determines the charge and current density of the applied stimulus, which decreases with increasing electrode area. The current density of the applied pulse decreases inversely with the distance from the electrode. EFFECT OF AxON DIAMETER: The effects of an applied electrical field are greater on the larger diameter axons because the larger diameter axons have a larger separation between nodes of Ranvier. The effect can be either depolarization or hyper-polarization.

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Smalldiameter axons require higher stimulus amplitude for the generation of action potentials than large-diameter axons. NERVE DEPOLARIzATION/ExCITATION: When the transmembrane potential of an axon is decreased to a level where sufficient numbers of voltagegated sodium ion channels are switched from the restingexcitable state to an active state, it causes a propagated action potential to be initiated. This state change occurs when a net transmembrane current, flowing from the inside to the outside of the cell occurs, and is usually caused by the application of a cathodic stimulus applied near the site of excitation. NERVE HYPERPOLARIzATION: When the transmembrane potential is increased from the resting state (becoming more negative), the voltagegated sodium ion channels are less likely to be gated into the active state. This state change occurs when the net transmembrane current is negative, flowing from the outside of the cell to the inside of the cell, and is usually caused by the application of an anodic stimulus applied near the site of hyperpolarization.

outside, which is close to the Nernst potential for both K+ and Cl-, a value determined by the difference in ion concentration between the two sides of the membrane. K+ and Cl- concentrations determine resting potential across the nerve membrane. The resting nerve membrane is poorly permeable to Na+ and the Na+ Nernst potential is about 155 mV, which drives the inward current flow during the action potential.

VOLTAGE-GATED ION CHANNELS Voltage-gated ion channels are a class of transmembrane proteins that are activated by changes in electrical potential difference across the cell membrane. The necessary actor in causing both depolarization and repolarization of the nerve membrane during the action potential is the voltage-gated sodium channel.

VOLTAGE-GATED SODIUM CHANNEL—ACTIVATION AND INACTIVATION OF THE CHANNEL Figure 1 shows the voltage-gated sodium channel in three separate states. This channel has two gates—one near the outside of the channel called the activation gate, and another near the inside called the inactivation gate. The figure depicts the state of these two gates in the normal resting membrane when the membrane potential is –90 millivolts. In this state, the activation gate is closed, which prevents any entry of sodium ions to the interior of the fiber through these sodium channels. ACTIVATION OF THE SODIUM CHANNEL When the membrane potential becomes less negative than during the resting state, rising from –90 millivolts toward zero, it finally reaches a voltage usually somewhere between –70 and –50 millivolts, hat causes a sudden conformational change in the activation gate, flipping it all the way to the open position. This is called the activated state; during this state, sodium ions can pour inward through the channel, increasing the sodium permeability of the membrane as much as 500 to 5000 fold. INACTIVATION OF THE SODIUM CHANNEL

RESTING POTENTIAL ACROSS THE NERVE MEMBRANE Three major ions are separated across a nerve membrane at rest. The concentration of Na+ and Cl- is much higher in the extracellular space than in the intracellular space, while K+ is higher on the inside of the cell membrane compared to the extracellular space. The resting potential of the membrane is about 270 mV, inside with respect to

Figure 2: Characteristics of the voltage-gated sodium channel, showing successive activation and inactivation of the sodium channels when the membrane potential is changed from the normal resting negative value to a positive value.

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Figure 1 shows a third state of the sodium channel. The same increase in voltage that opens the activation gate also closes the inactivation gate. The inactivation gate, however, closes a few 10,000ths of a second after the activation gate opens. That is, the conformational change that flips the inactivation gate to the closed state is a slower process than the conformational change that opens the activation gate.

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ACTION POTENTIALS Na+ movement from the outside to the inside depolarizes, or raises the transmembrane potential. Nav are concentrated at nodes of Ranvier, several thousand per square micron, so there are tens of thousands of channels involved in generating an action potential at a single node. When a large number of Nav open, in short succession, more Na+ moves in than K+ moves out of the membrane and the membrane potential moves positively, which in turn increases the probability that activatable Nav will open, meaning many miniature current sources act in close succession to depolarize the nerve membrane, driving the potential from about 270 mV to approximately 120 mV or higher. This rapid change in membrane potential is recognized as the all or none action potential. Since all Nav close shortly after opening, transition to the inactivatable state, Na+ movement is terminated and K+ movement from inside to outside the membrane restores the membrane potential to the resting state. A propagated action potential is created when the transient change in membrane potential at one node of Ranvier gives rise to a potential difference inside the axon between that

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node and an adjacent node. The transient depolarization causes positive charge to move to the next adjacent node of Ranvier, which depolarizes the adjacent node causing activatable Nav to open in short succession, leading to another action potential and the process continues to the terminal end of the axon where a neurotransmitter is released to act on an adjacent cell or to act systemically when released into the blood.

ELECTRICALLY GENERATING ACTION POTENTIALS Charge can be neither created nor destroyed, which is a fundamental law of physics. However, charge can be separated and when it is separated there exists a potential difference to recombine the charge. The magnitude of the potential difference is inversely proportional to the separation distance. Holding these ideas, two points need to be kept in mind throughout the following presentation. First, at resting membrane potentials charge is separated across a nerve membrane, more positive charge outside and more negative charge inside. Second, if we provide a pathway to inject charge we must provide a pathway to remove it and if charge flows into a cell it must flow out of the cell somewhere else. Charge flow, per unit time, is defined as current. As current flows in a resistive medium, like tissues, a potential difference arises along the pathway it follows. Points where the more charge is flowing have a higher potential gradient compared to points where less charge is flowing. Consider now that we have placed two electrodes in the same conducting tissue space, occupied by an axon, and that one of the electrodes, the stimulating electrode, is much closer to the axon than the other electrode; the distant electrode will be referred to as the return/ indifferent electrode. Current injected into the tissue at the stimulating electrode disperses as it moves away from the injection site; the current density being highest near the

injection site. This means that the potential difference between equally spaced points closer to the injection site will be higher than the potential difference for similarly spaced points further from the injection site. When a 100 ms duration cathodic current pulse is applied to the stimulating electrode, negative charge is injected into the tissue at the highest current density close to the stimulating electrode. The negative charge injected counters the positive charge outside the membrane and the negative charge inside the axon moves away from the membrane. A negative charge moving away from the inside of the membrane is effectively the same as a positive charge moving from the inside to the outside of the membrane. This is called a capacitive current. In other words, the membrane capacitance is discharged by the stimulus pulse. So, what has happened is that the cathodic pulse has the effect of driving a positive current from the inside of the axon to the outside of the axon with the bulk of the current flowing through the node of Ranvier that is closest to the stimulating electrode. Inward flowing current is distributed over the nodes adjacent to the stimulating electrode. The magnitude of the current density is lowered, by more than half, at nodes flanking the node of Ranvier nearest to the stimulating electrode. Current flow through the relevant nodes is illustrated in Figure 3. Current flowing out of the node of Ranvier closest to the stimulating electrode reduces the potential across the membrane at this site and Nav, in this patch of membrane, will have an increased probability of transitioning from the closed-activatable state to the open-conduction state allowing Na+ to move to the inside of the membrane and further lowering the transmembrane potential. If the net Na+ inflow exceeds the net K+ outflow a regenerative action potential will follow with all activatable Nav opening at that node, setting the scene for a propagated action potential along the axon and to cause the release of a

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Figure 3: A stimulating electrode and current entering and exiting nodes of Ranvier for two nerve fibers, the nerve in the lower panel has an axon that is twice the diameter of the axon in the upper panel. The stimulating electrode is the same distance from the node in both cases. However, since r1 is less than r1â&#x20AC;&#x2122; the extracellular potential, which is proportional to 1/r at the adjacent nodes, will be less in the case of the larger axon, which means that the activating function, will be larger for the large diameter fiber than it will be for the smaller diameter fiber.

neurotransmitter at the terminal end. When the depolarizing current is insufficient to open enough Nav channels before K+ flows out to repolarize the membrane, it is unable to generate an action potential. This would be termed a subthreshold stimulus. If an anodic pulse, rather than the cathodic pulse, is delivered, the current flow through the respective nodes of Ranvier is reversed. The inward current flow at the node nearest the electrode causes the transmembrane potential to increase (hyperpolarize) and this will not generate an action potential. However, at the flanking nodes, positive current exits the membrane, which causes depolarization, and may potentially trigger an action potential. Note,

however, that the exiting current is distributed over many nodes rather than a single node as in the case of the cathodic pulse. For an action potential to be created with an anodic pulse the current pulse would need to be substantially higher in magnitude than is required for a cathodic pulse. Thus comes the rule of thumb that the threshold for generating a propagated action potential is lower for a cathodic pulse than for an anodic pulse. The change in transmembrane potential, resulting from an applied stimulus, can be described mathematically and is given by the second spatial difference of the electric field along the axon, also referred to as the activation function.

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neuromodulatIon and neuronal PlastIcIty NEUROPLASTICITY Neuroplasticity, also known as brain plasticity or neural plasticity, is an umbrella term that describes lasting change to the brain throughout an individual’s life course. The term gained prominence in the latter half of the 20th century, when new research showed that many aspects of the brain can be altered (or are “plastic”) even into adulthood. This notion is in contrast with the previous scientific consensus that the brain develops during a critical period in early childhood and then remains relatively unchanged (or “static”). Neuroplasticity can be observed at multiple scales, from microscopic changes in individual neurons to larger-scale changes such as cortical remapping in response to injury. Behavior, environmental stimuli, thought, and emotions may also cause neuroplastic change through activitydependent plasticity, which has significant implications for healthy development, learning, memory, and recovery from brain damage. At the single cell level, synaptic plasticity refers to changes in the connections between neurons, whereas non-synaptic plasticity refers to changes in their intrinsic excitability.

NEUROSTIMULATION AND NEURONAL PLASTICITY There is an increasing body of evidence, both from the research and clinical arenas, that chronic neurostimulation can effect permanent changes in neural organization. Case studies and small case series of patients undergoing motor cortex stimulation for post-stroke pain have demonstrated improved motor function in a subset of

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patients with motor weakness. Evidence suggest that motor cortex stimulation may improve motor function by amplifying the activity of marginally functioning motor neurons. These findings were considered in the planning of clinical trials for MCS for stroke, the results of which appear to be promising (Brown et al., 2006; Kim et al., 2008; Levy et al., 2008). Direct evidence of cortical plasticity with neurostimulation has been demonstrated in a primate model of ischemia (Plautz et al., 2003). Following induced ischemia to the motor cortex, subthreshold stimulation of the peri-infarct motor cortex was performed. Along with improvement in motor function, cortical mapping demonstrated the emergence of new motor maps in the peri-infarct motor cortex. A brief report demonstrated sensory cortical map plasticity in a single patient undergoing chronic spinal cord stimulation for lower extremity complex regional pain syndrome using MEG. The cortical evoked responses to tactile stimulation of the lower extremity shifted with spinal cord stimulation, suggesting dynamic plasticity induced by SCS (Mogilner et al., 2000).

understanding of the dynamic and evolving nature of both cortical and subcortical representational topography. Neuronal representational plasticity can occur rapidly, over large distances in the nervous system, and across multiple sensory and motor modalities. This plasticity appears in some cases to correlate with improvement in function, but in other cases may in fact result in untoward consequences such as chronic pain. In parallel, over the same time period, it has been seen dramatic growth and evolution in the field of neuromodulation. Similar to neuronal plasticity, the beneficial effects of neuromodulation on disease states can occur rapidly and across multiple modalities. The intriguing evidence from a small but ever-increasing clinical and basic science research suggests that neuromodulation may exert its effects via, at least in part, facilitation of beneficial plastic changes in the nervous system, as well as modification of abnormal reorganization occurring as a result of various disease states.Future work will undoubtedly elucidate these interactions in great detail, and will likely allow future neuromodulation technology to harness the innate ability of reorganization and self-repair of the nervous system.

The recent report by Schiff and colleagues of medial thalamic stimulation following severe traumatic brain injury in a single patient suggest that neuromodulation may facilitate neuronal reorganization (Schiff et al., 2007). Improvements in several behaviors were noted to persist even after turning the stimulator off for significant periods of time. Advances in basic and clinical neurosciences over the past 20 years have brought with them a completely new

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Neuromodulation for Urinary Dysfunction

neuromodulatIon For urInary dysFunctIon

Lower urinary tract symptoms (LUTS) include storage, voiding, and postmicturition symptoms. Neuromodulation therapy incorporates electrical stimulation to target specific nerves that control LUTS. Neuromodulation includes pelvic floor electrical stimulation (ES) using vaginal, anal and surface electrodes, interferential therapy (IF), magnetic stimulation (MS), percutaneous tibial nerve stimulation (PTNS), and sacral nerve stimulation (SNS). Neuromodulation has been reported to be effective for the treatment of both overactive bladder (OAB) with or without urgency incontinence (UUI) and stress urinary incontinence (SUI). Since Caldwell first used implantable electrodes for ES to treat urinary incontinence, ES has been recognized to be effective for urinary incontinence. However, neuromodulation has not been widely accepted as a first-line treatment for urinary incontinence, because of little physiological and technical information, and it is used when other methods have failed. For the treatment of OAB, the treatment of choice has been drug therapy using anticholinergic drugs or β3 adrenoceptor agonist. However, drugs are sometimes associated with adverse events, such as dry mouth, dyspepsia, nausea and constipation, and some patients are refractory to these drugs. The cure rate of bladder training varies from 25 to 97%, possibly depending on the patient’s cognitive ability or motivation. Neuromodulation may be an effective alternative to drug therapy for OAB. For the treatment of SUI, pelvic floor muscle training (PFMT) has been widely accepted as a first choice of treatment. The improvement rates of incontinence by PFMT have been reported to be 50–70%, but the cure rates, no more than 15–30%, and a low patient compliance (dropout rate of 39%) has also been reported. It has been

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reported that more than 30% of women with SUI have been shown to be unable to contract the pelvic floor muscle on their first attempt. ES is effective in patients who are initially unable to identify and contract the correct pelvic floor muscles (PFM). Clenbuterol, a β2-adrenpoceptor agonist, has been reported to be effective for SUI. However, the effect of the drug is limited to mild–moderate SUI. Biofeedback training is effective in controlling the correct contraction of the pelvic floor muscles and in visualizing the strength and duration of any contraction, but it is time consuming and patient’s motivation is more necessary. Surgical procedures have been used for severe SUI. Success rate in pubovaginal sling or tension free vaginal tape or trans obturator tape has been reported to be more than 80%. However, these surgical procedures sometimes cause complications, such as bleeding, pelvic pain, voiding difficulties, and de novo or persistent UUI. Neuromodulation can be alternative to these conservative therapies or surgeries for SUI. A combination of PFMT and neuromodulation can be more effective than monotherapy, and it can reduce the duration of the neuromodulation.

An animal study demonstrated the inhibition of detrusor contraction by stimulation of perineal skin or legs by pinch, and by distention of the anus, colon, seminal vesicles and vagina, which were termed as somato-vesical or viserovesical reflex. From this concept, the mechanism of ES is considered to be the stimulation of afferent pudendal nerve through the skin of the perineal area, intravaginally or intrarectally. However, the stimulation of thigh muscle, skin above the sacral segmental area, as well as direct stimulation of tibial nerve and pudendal nerve has also been reported to be effective for bladder inhibition. For the treatment of OAB, low frequencies have been reported to be effective for reflex detrusor inhibition, but low frequencies such as 5Hz may cause irritation. Thus frequencies ranging from 10 to 20 Hz are mostly used. However, there are several other protocols including stimulation at a combination of 12.5 and 50 Hz, or 10 or 150 Hz, and a random frequency of 4–10Hz, depending on investigators. Thus the optimum condition has not been determined. Pulse durations varied from 0.1, 0.2, 0.3 and 1msec.

MECHANISMS OF NEUROMODULATION FOR SUI MECHANISM OF NEUROMODULATION FOR OAB The mechanism of neuromodulation for OAB with or without UUI, probably due to detrusor overactivity (DO) has been reported to be the reflex inhibition of detrusor contraction by the activation of afferent fibers within the pudendal nerve by three actions, i.e., the activation of the hypogastric nerve, the direct inhibition of the pelvic nerve within the sacral cord and the supraspinal inhibition of the detrusor reflex.

The mechanism of neuromodulation for SUI is contraction of the PFMs through an effect on the muscle fibers as well as through the stimulation of pudendal nerves. Thus for the treatment of SUI, relatively high frequencies ranging from 20 to 50 Hz, with a pulse duration of 1–5msec have been reported to be effective for urethral closure and PFM contraction. However, there are several other protocols including stimulation at 12.5–100 Hz. Intermittent stimulation has also been recommended because muscle fatigue may be avoided, especially during high frequency

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stimulation. The on/off duty cycle used during stimulation varies; 1:2–1:3, 2:1 and 1:1. POST-STIMULATION EFFECTS Post-stimulation effect, or re-education effect, which means that the effects can last several weeks to 3 months, or even for several years after finishing the treatment, has been reported. Bratt et al., made a questionnaire survey on long-term effect 10 years after electric stimulation on the pelvic floor in women with urinary incontinence and reported that residual effect was noted in 22% of patients with UUI and 30% of those with SUI. They also reported that, among 27 women who had been treated with ES because of DO 9–13 years earlier, 78% still had UUI, which was, however, a minor problem among a third of them. Sixty percent of their patients were satisfied with ES and 78% of patients would have recommended ES. Studies also showed if incontinence relapses, restimulation can be periodically carried out. The results may be augmented in conjunction with PFMT. Susset et al., underwent biofeedback and vaginal ES in the treatment of SUI twice a week for 6 weeks and reported the overall success rate of 64%.

PELVIC FLOOR ELECTRICAL STIMULATION

use are usually used. Vaginal, anal, and surface electrodes are used for pelvic floor ES. The vaginal electrode is most popular for women and usually cylinder-shaped, and the anal electrode, that is bullet shaped. Because intravaginal and anal plug electrode is intolerable for some patients due to pain, discomfort or mucosal injury, surface electrodes stimulating the dorsal nerve of clitoris has been used as a less invasive ES therapy for OAB (Transcutaneous electrical neurostimulation: TENS). The electrodes were usually positioned at the S2-4 dermatome (perianal region), so that detrusor-mediated voiding is most influenced. However, ES applied to the quadriceps and hamstring muscles, abdomen and inside thighs, suprapubic region and the skin directly over the third sacral foramina has been reported to inhibit detrusor overactivity (DO).

EFFICACIES OF PELVIC FLOOR ES FOR OAB (INCLUDING UUI), SUI AND MIxED URINARY INCONTINENCE Cure and improvement rates of ES for OAB or UUI have been reported to be 5–50 and 54–91%, respectively. The effectiveness of neuromodulation should be verified by RCTs. However, the controlled study on physical treatments is very difficult to achieve because the use of non-functioning stimulator as control is too easy for the patient to reveal. Kaya et al., compared physical therapies (including IF, PFMT and bladder training), anticholinergics and these combination in 46 patients with DO, and reported that physical therapy and combinations groups were significantly more effective in increasing bladder capacity, and decreasing number of voids and number of incontinence episodes. No obvious side-effects were reported in the ES Groups.

The frequency and period of stimulation vary, according to investigators, from twice daily to once weekly, for 15–30 min each, for from a month, 6 weeks or 3–5 months. Although the majority of studies use daily exercise programs sessions for muscle strengthening. Miller et al., have reported that 14 weeks of stimulation is necessary before significant objective improvements are seen.

In another study comparing the effects of ES and PTNS in the treatment of OAB, both treatments were effective, but the number of patients who describe themselves as cured in the ES group was significantly higher than PTNS.

As to the intensity of electrical stimulation, the stronger the contraction, the better the results. Thus intensity of stimulation is usually set at maximum tolerable limit.

Cure and improvement rates in SUI have been reported to be 30–50 and 60–90%, respectively. There were seven placebo-controlled RCTs for SUI, of which five showed significant superiority to placebo. Although both PFMT and ES were effective for SUI.

This treatment emerged with the concept relying on the carry-over effect, that is, the desired therapeutic effects have outlasted the actual stimulation, to make the external stimulation techniques more effective. For short-term ES, external stimulation devices of home

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Various studies reported that there is strong evidence to suggest that ES alone is no more effective than PFMT alone, and ES plus PFMT is more effective than PFMT alone.

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APPROACH OF ELECTRICAL STIMULATION

Neuromodulation offers an alternative to patients who have failed more conservative treatments and may be considering irreversible surgical options. Electrical stimulation has been used to treat a broad range of disorders of both bladder filling/storage and emptying/ voiding, with varying degrees of success (Table1). As illustrated in the table, the stimulation can be applied peripherally or centrally; acutely, subacutely, or chronically; and by nonimplantable or implantable electrodes â&#x20AC;&#x201C; all depending on the purpose of the therapy.

PUTATIVE MECHANISM OF ACTION OF SACRAL NEUROMODULATION Two main theories exist regarding the mechanism of action of sacral neuromodulation. First, direct activation of efferent fibers to the striated urethral sphincter reflexively causes detrusor relaxation. Second, selective activation of afferent fibers causes inhibition at spinal and supraspinal levels. Accumulating evidence suggests that activation of somatic sacral afferent inflow at the sacral root level that, in turn, affects the storage and emptying reflexes in the bladder and central nervous system accounts for the positive effects of neuromodulation on both storage and emptying functions of the bladder. By monitoring somatosensory evoked potentials (SEP) during sacral neuromodulation, Malaguti et al. concluded that sacral neuromodulation therapy works by sacral afferent activity and concomitant activation of the somatosensory cortex (Malaguti et al, 2003). Since sacral neuromodulation has been proven clinically effective for both storage (urgency â&#x20AC;&#x201C; frequency and urgency incontinence) and emptying (non-obstructive

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Table 1: Potential applications of electrical stimulation in the treatment of voiding dysfunction

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urinary retention) dysfunctions of the bladder, isolating the mechanism of action has been challenging. The ability to volitionally store and evacuate urine is modulated by several centers in the brain. It is thought that patients with overactive bladder may have suffered an insult that effectively unmasks involuntary bladder contractions. Sacral neuromodulation of these primitive reflexes may restore normal micturition. Sacral neuromodulation may affect detrusor overactivity by suppressing or inhibiting interneuronal transmission in the bladder reflex pathway ( de Groat and Saum, 1976 ; Kruse and de Groat, 1993 ; Leng and Chancellor, 2005 ). This inhibition may, in part, modulate the sensory outflow from the bladder through the ascending pathways to the pontine micturition center (PMC), thereby, preventing involuntary contractions by modulating the micturition reflex circuit. In clinical practice, sacral neuromodulation improves abnormal bladder sensations, involuntary voids, and detrusor contractions. Interestingly, voluntary voiding is preserved. This may be due to selective avoidance of normal sensory ascending outflow pathways of the bladder from A Î´ -fibers to the PMC, as well as initiation of the descending pathways from the PMC to sacral efferent outflow pathways. Currently, sacral neuromodulation is prescribed for those patients with urgency, frequency, and urge incontinence who have failed traditional conservative measures such as bladder retraining, pelvic floor biofeedback, and medications and for whom more invasive procedures such as enterocystoplasty or urinary diversion might be inadvisable or has been declined. Recently, several studies have tried to more accurately identify which patients will or will not respond to sacral neuromodulation, however,

predictive factors remain difficult to find.

TECHNIQUE

Indications for neuromodulation are expanding. Several populations of patients with voiding dysfunction have some component of the indicated symptom complex that includes urgency, frequency, urge incontinence, or urinary retention. The current expansion of indications for neuromodulation has developed into areas of neurogenic bladder, spinal cord injury, and neurogenic stress urinary incontinence.

SACRAL NERVE STIMULATION

CONTRAINDICATIONS Patients with physical limitations that prevent them from achieving normal pelvic organ function, such as patients with functional urinary incontinence and patients who are non-compliant, should not be offered this therapy. Sacral neuromodulation is relatively contraindicated for those patients who have an anticipated need for future magnetic resonance (MR) imaging and patients who plan to become pregnant. The main concern with MRI and implantable stimulator/ pacemaker-type devices is that heating of the leads has been demonstrated in vivo and in vitro (Roguin et al, 2004 ; Martin, 2005). While some question the clinical significance of the small temperature changes with the leads, the potential exists to elicit nerve damage. Additionally, there is some concern that the magnetic field from MR imaging may damage the pulse generator.

The implantable device system consists of a lead with a quadripolar electrode which is mostly placed in sacral foramen S3 (or in Alcockâ&#x20AC;&#x2122;s canal in pudendal nerve stimulation), an extension cable and a neurostimulator which is placed subcutaneously. Usually the implantation consists of two stages. In the first stage, a definitive lead is placed adjacent to the dorsal S3 root (figure 2). The lead is connected to an external neurostimulator device through a subcutaneous tunnel. The effect of the neurostimulation is evaluated during a testing period of one to four weeks. If the urinary symptoms improve more than 50%, the patient is qualified for the second stage. In the second stage, the extension is dislodged and the permanent implantable pulse generator (IPG) is placed into the soft tissue of the gluteal region. Some surgeons prefer to do a one-stage procedure. In this case, the patient undergoes a sacral neuromodulation (SNM) test, in which temporary leads are used. This is called percutaneous nerve evaluation (PNE). If the symptom improvement exceeds 50%, the definitive lead and the IPG are inserted during one intervention. After permanent IPG implantation the stimulator settings can be fine-tuned and the system can be turned off and on noninvasively through an electronic programming device.

Due to the unknown teratogenic potential of electrical stimulation it has been considered contraindicated in pregnant women with various voiding dysfunctions.

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SELECTIVE NERVE STIMULATION PUDENDAL NERVE STIMULATION Sacral neuromodulation is thought to improve bladder storage by inhibiting the micturition reflex via electrical stimulation of sensory afferent fibers, in particular by depolarization of AÎą and AÎł somatomotor fibers that affect the pelvic floor and external sphincter and thus inhibit detrusor activity. Many of the sensory afferent nerve fibers contained in the sacral spinal nerves originate in the pudendal nerve, thereby making the pudendal nerve an ideal target for neuromodulating inhibition of the micturition reflex. Direct pudendal nerve neuromodulation stimulates more pudendal afferents than SNS and may do so without the side effects of off-target stimulation of leg and buttock muscles. Thus, techniques for direct pudendal nerve stimulation at alternative locations to the sacral foramen are being developed. DORSAL GENITAL NERVE STIMULATION The most superficial, terminal branch of the pudendal nerve is the dorsal genital nerve (dorsal clitoral nerve in females). The dorsal genital nerve is located at the level of the symphysis pubis and is a pure sensory afferent branch carrying sensory information from the glans of the clitoris. As a pure sensory afferent nerve branch of the pudendal nerve, the dorsal genital nerve contributes to the pudendal-pelvic nerve reflex that has been proposed as a mechanism of bladder inhibition. In experimental and clinical studies, direct electrical stimulation of the dorsal genital nerve appears promising in producing an inhibition of the micturition reflex. Figure 1 A & B: Site of stimulation of sacral root by the tined lead.

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Figure 2: (top) Definitive IPG in subcutaneous tissue of gluteal region and (bpttom)Optimal lead placement with the lead positioned with electrodes 2 and 3 straddling the ventral surface of the sacrum.

Results in laboratory animals and in persons with spinal cord injury have demonstrated that electrical stimulation of the dorsal genital nerves inhibits bladder contractions (Craggs and McFarlane).

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POSTERIOR TIBIAL NERVE STIMULATION

CONCLUSIONS

The posterior tibial nerve is a mixed sensory and motor nerve containing fibers originating from spinal roots L4 through S3 which modulate the somatic and autonomic nerves to the pelvic floor muscles, bladder and urinary sphincter. Based on translational findings of traditional Chinese acupuncture practices, McGuire et al used transcutaneous stimulation of the common peroneal or posterior tibial nerve to inhibit detrusor overactivity.

Neuromodulation includes pelvic floor ES using vaginal, anal and surface electrodes, IF, MS, PTNS, and SNS. Neuromodulation may be effective for various LUTS, especially for overactive bladder and stress and mixed urinary incontinence. The therapeutic effects of neuromodulation depend on artificial activation of nerves. The stimulation intensity is high enough to elicit activity in the relevant nerves. An optimal electrode configuration and proper positioning is crucial. Although neuromodulation remains infrequently used, due to widespread lack of information about the physiological and technical principles, it is also effective as an adjunctive therapy.

Percutaneous tibial nerve stimulation (PTNS) (Urgent PC, CystoMedix, Anoka, MN) is approved by the FDA. A small gauge stimulating needle is inserted approximately 5 cm cephalad to the medial malleolus and just posterior to the tibia. Electrical stimulation is then applied at a level just below the somatic sensory threshold for a total of thirty minutes. Sessions are repeated weekly for 10 â&#x20AC;&#x201C; 12 weeks. PTNS is minimally invasive and well tolerated.

While clearly still in its infancy, neuromodulation has enjoyed wide success in the field of voiding dysfunction with applications to a broad range of problems including both storage and emptying disorders. Due to refinements in technique and technology it is a truly minimally invasive therapy which has provided inestimable quality of life improvements for certain patient populations, particularly those with overactive bladder. Expanding indications for neuromodulation will likely dominate the literature in the years to come as comfort with technology increases and more challenging patient subgroups such as the neurogenic and pediatric populations are addressed.

Figure 3 : Method of posterior tibial nerve stimulation (PTNS).

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Transcutaneous Electrical Nerve Stimulation (TENS)

Transcutaneous Electrical Nerve Stimulation INTRODUCTION Transcutaneous electrical nerve stimulation (TENS involves the application of electrical currents to the skin primarily for the purposes of pain relief. It is a safe, noninvasive treatment that can be self-administered.

from. Despite widespread use, the clinical efficacy of TENS remains ambiguous.

This came in the form of Melzack and Wallâ&#x20AC;&#x2122;s gate control theory of pain (Melzack and Wall, 1965), which proposed that a gate existed in the dorsal horn of the spinal cord which could regulate the amount of incoming nociceptive traffic via small diameter afferent nerve fibers. This gate could be closed by a range of stimuli which activate large diameter afferent fibers such as touch, pressure, and electrical currents.

The clinical application of TENS involves the delivery of a low voltage electrical current from a small batteryoperated device to the skin via surface electrodes. The majority of TENS devices offer variable frequency (pulse rate), pulse duration, intensity (amplitude), and type of output (the pattern in which the pulses are delivered: burst, continuous, or modulated).

GENERAL PRINCIPLES OF APPLICATION OF TENS

A modulated output is produced by varying pulse duration, frequency, and/or amplitude in a regular and cyclical manner with the hope of avoiding accommodation of nerve fibers to a constant stimulus (e.g. amplitude modulation involves a cyclical modulation in amplitude from zero increasing gradually to a preset peak level, and then decreasing gradually back to zero again). TENS devices typically use a pulsed current with a rectangular shaped waveform; waveforms are usually monophasic, symmetrical biphasic, or asymmetrical biphasic. The amplitude is directly related to the magnitude

Shortly after the theory was published, initial studies emerged which showed the effective use of percutaneous electrical stimulation for chronic neuropathic pain (Wall and Sweet, 1967). However, it was Dr. Norman Shealy who made a significant discovery for the use of transcutaneous electrical nerve stimulation for pain relief. Around this time, dorsal column stimulation (DCS), a new technique for pain relief, was developed. DCS, now called spinal cord stimulation or SCS, involved the surgical implantation of electrodes over the dorsal columns of the spinal cord which were then activated by an external battery-operated device (Shealy et al., 1967). Meyer and Fields (1972) were among the first to report on the clinical use of TENS for the relief of chronic pain. Technological advances have subsequently produced todayâ&#x20AC;&#x2122;s wide range of stimulators with an even wider range of stimulation parameters for clinicians to choose

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Figure 1: TENS stimulation modes.

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or intensity of the current being delivered. Intensity is measured in milliamperes (mA) (or millivolts if the device is designed to deliver constant voltage) and generally ranges from 30 to 100 mA, often yielding sensations of tingling or pins-and-needles. The pulse duration is the length of time during which each pulse is delivered. Longer pulse durations give rise to increases in the total electrical charge delivered. As the pulse duration is increased in the usual range from 40 to 400 microseconds (ms), the patient may feel a spreading/radiating and/or deepening/ penetrating sensation. The pulse rate (frequency) is the number of pulses delivered per second (Hz). The range of pulse rate is generally 1 Hz to 200 Hz. Combinations of these different stimulation parameters are used to produce four main modes of TENS: Conventional or high frequency TENS (frequency typically above 100 Hz, short pulse duration (50–80 ms), low intensity); Acupuncture-like or low frequency TENS (frequency usually 1–4 Hz, long pulse duration (,200 ms), high intensity); Burst TENS (high internal frequency trains of pulses (,100 Hz) delivered at a low frequency, typically 1–4 Hz); and Brief–Intense TENS (high frequency and long pulse duration pulses delivered at a high intensity) (see Figure 1). In terms of application, the clinician has four different electrode placement sites to choose from: the painful area; the peripheral nerve supply to the painful area, spinal nerve roots dermatomal distribution, and acupuncture/ motor/trigger points. Self-adhesive electrodes are most commonly used although some clinicians still use a carbon rubber electrode and gel application. If tape is required to secure the latter type of electrode in place, care must be taken to ensure the tape is applied evenly to ensure

uniform distribution of the current.

THEORIES OF TENS ANALGESIA

Relatively few adverse effects have been reported with TENS. Precautions for and contraindications to TENS are mostly empirical, reflecting “common sense” and include: impaired sensation, impaired alertness/ cognition, use in the region of the anterior neck or eyes (e.g. where carotid sinuses are located), history of contact allergy to the electrode gel (which commonly contains propylene glycol) or tape, epilepsy, use over broken or irritated skin, use while operating machinery, or pregnancy (however, TENS is frequently used for pain relief during labor). In addition, TENS has been shown to interfere with some types of pacemakers.

Two theories are commonly utilized to support the use of TENS. The gate control theory of pain is most commonly utilized to explain the inhibition of pain by TENS. According to the gate control theory of pain, stimulation of large diameter Ab afferents inhibits nociceptive C-fiber evoked responses within the dorsal horn. There is now much more detailed data on mechanisms of actions of TENS that includes anatomical pathways, neurotransmitters and their receptors, and the types of neurons involved in the inhibition. Release of endogenous opioids has been used to explain the actions of TENS, particularly low frequency stimulation. Recent data support this theory for low frequency TENS as well as for high frequency TENS stimulation.

The successful application of TENS involves a degree of trial and error. Several attempts are typically required, before the optimal stimulation parameters and electrode site are determined for a patient. The application time should be kept to 30 minutes for the first trial to allow monitoring for adverse effects and subsequently increased to one hour at a time, repeated as many times as necessary. A 30 minute break between applications over the same skin area is recommended to avoid skin irritation associated with prolonged use. The intensity of the TENS should be increased to produce what the patient feels is a “strong but comfortable” sensation.

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SUMMARY POINTS • • •

•

TENS is a safe, non-invasive modality widely used in clinical practice. TENS can be used to treat both acute and chronic pain. The clinical application of TENS involves a degree of trial and error in determining the most appropriate stimulation parameters and electrode placement sites. Low frequency and high frequency TENS produce analgesia through different mechanisms that primarily involve central inhibitory mechanisms.

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The Neural Control of Urinary & Urogenital System

Neuromodulation and neurostimulation therapies and interventions are built upon a foundation of an understanding of neural structures and the behavior of the neural circuits of the nervous system. As this understanding has increased, so have our capabilities to intervene with increasing efficiency and efficacy with neuromodulatory interventions. When the intervention will be as a form of electronic device, and the stimulation method is non-invasive, as per the published research papers and studies, TENS (Transcutaneous Electrical Nervre Stimulation) is the most effective technique to implement. But before establishing the functions of the device and how it will work by stimulating the targeted nerve fibers in order to achieve the desired effects on the urinary function, it is very important to have a indepth understanding of the neurophysiological function and structure of urinary and urogenital system. Before finding the most effective and accurate stimulation sites of the particular dermatome and mapping their position, it is first necessary to understand the neural pathways of the urinary system and their innervation on muscles and lower organs. Also there has to be a critical understanding of the complex nature and functions of the neural control of the urinary system to calculate and establish the functions of the the device and develope the research hypothesis. So this chapter will deals with individual components regulating the neural control of the urinary bladder, with the focus on factors and processes involved in the two models of operation of the bladder: storage and elimination.

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The Neural Control of Urinary System urothelIum The urothelium can be thought of as a first responder to various types of stress that can include physiological, psychological and disease related factors. Alterations of bladder urothelium at the molecular and structural levels have been reported in both patients and animals modeled for various bladder disorders. It is likely that many therapies currently used in the treatment of bladder disease may target urothelial receptors and/or their release mechanisms.

ANATOMY AND BARRIER FUNCTION The urothelium is the epithelial lining of the lower urinary tract between the renal pelvis and the urinary bladder. Urothelium is composed of at least three layers (the exact number of layers is species dependent): a basal cell layer attached to a basement membrane, an intermediate layer, and a superficial or apical layer composed of large hexagonal cells (diameters of 25-250 μm) known as ‘umbrella cells’. The ability of the bladder to maintain the barrier function, despite large alterations in urine volume and increases in pressure during bladder filling and emptying, is dependent on several features of the umbrella cell layer.

UROTHELIAL CELLS AND REPAIR The processes underlying urothelial repair is complex, involving several structural elements, signaling pathways, trophic factors and the cellular environment. Furthermore, the interaction between these biochemical signals and mechanical forces in the bladder during the course of

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an important role in the generation of urinary bladder dysfunction.

urothelial repair is not well understood. Though the urothelium maintains a tight barrier to ion and solute flux, a number of local factors or stressors such as tissue pH, mechanical or chemical trauma, hormonal changes or bacterial infection can modulate the barrier function of the urothelium. Both physiological and psychological stress can result in a failure of urothelial and suburothelial ‘defensive’ systems and thereby promote changes in both urothelial barrier and signaling function. Disruption of urothelial function can also be induced by more remote pathological conditions that influence neural or hormonal mechanisms. The changes are blocked by pretreatment with a ganglionic blocking agent, suggesting an involvement of efferent autonomic pathways in the acute effects of spinal cord injury on bladder urothelium. Other types of urothelial-neural interactions are also likely, based on the recent reports that various stimuli induce urothelial cells to release chemical mediators that can in turn modulate the activity of afferent nerves. This has raised the possibility that the urothelium may have a role in sensory mechanisms in the urinary tract. In summary, modification of the urothelium and/or loss of epithelial integrity in a number of pathological conditions can result in passage of toxic/irritating urinary constituents through the urothelium or release of neuroactive substances from the urothelium. This may lead to changes in the properties of sensory nerves and in turn sensory symptoms such as urinary frequency and urgency. Thus chemical communication between the nervous system and the urothelial cells may play

ROLES FOR UROTHELIAL CELLS IN VISCERAL SENSATION While urothelial cells are often viewed as bystanders in the process of visceral sensation, recent evidence has supported the view that these cells function as primary transducers of some physical and chemical stimuli and are able to communicate with underlying cells including bladder nerves, smooth muscle and inflammatory cells. The urothelium is able to respond to a wide variety of mechanical stresses during bladder filling and emptying by activating a number of possible transducer proteins. Possibilities of mechanical signals include bladder pressure, tension in the urothelium or bladder wall, torsion, geometrical tension, movement of visceral organs and even urine tonicity. Alterations in the composition of urine are a type of stress whose contents can vary in both their rate of delivery as well as the particular constituents. Additional lines of evidence suggest that urothelial cells participate in the detection of both physical and chemical stimuli. Bladder nerves (afferent and efferent) are localized in close proximity, and some within, the urothelium. In addition, urothelial cells express numerous receptors/ ion channels similar to that found in both nociceptors and mechanoreceptors. And finally, these cells secrete a number of transmitters or mediators capable of modulating activating or inhibiting sensory neurons.

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A) UROTHELIAL-NEURONAL SIGNALING: Recent studies have shown that both afferent and autonomic efferent nerves are located in close proximity to the urothelium. Peptidergic, P2x- and TRPV1immunoreactive nerve fibers presumed to arise from afferent neurons in the lumbosacral dorsal root ganglia are distributed throughout the urinary bladder musculature as well as in a plexus beneath and extending into the urothelium. In humans with neurogenic detrusor overactivity intravesical administration of resiniferatoxin, a C-fiber afferent neurotoxin, reduces the density of TRPV1 and P2x3 immunoreactive suburothelial nerves, indicating that these are sensory nerves.In addition, immunohistochemical studies have also revealed both adrenergic (tyrosine hydroxylase) positive as well as cholinergic (choline acetyltransferase, ChAT) positive nerves in close proximity to the urothelium. B) INVOLVEMENT OF THE UROTHELIUM IN “SENSING” CHEMICAL AND MECHANICAL STIMULI: The involvement of urothelial function in sensory signaling is suggested by the finding that urothelial cells express various receptors that are linked to mechano- or nociceptive sensations. Examples of neuronal “sensor molecules” (receptors / ion channels) that have been identified in urothelium include receptors for purines (P2X and P2Y) adenosine (A1, A2a, A2b and A3), norepinephrine (α and β), acetylcholine (muscarinic and nicotinic), protease-activated receptors (PARs), amiloride- and mechanosensitive epithelial sodium channels (ENaC), bradykinin (B1 and B2), neurotrophins (p75, trkA, EGF

family Erb1-3), corticotrophin releasing factor (CRF1 and CRF2), estrogens (ERα and ERβ), endothelins and various TRP channels (TRPV1, TRPV2, TRPV4, TRPM8 and TRPA1).The expression of these various receptors enable the urothelium to respond to a number of “sensory inputs” from a variety of sources. These inputs include increased stretch during bladder filling, soluble factors (many found in the urine) such as epidermal growth factor (EGF), or chemical mediators/peptides/transmitters such as substance P, calcitonin gene-related peptide (CGRP), corticotrophin releasing factor (CRF), acetylcholine, adenosine or norepinephrine released from nerves, inflammatory cells and even blood vessels. Various stimuli can lead to secretion of numerous chemical substances such as neurotrophins, peptides, ATP, acetylcholine, prostaglandins, prostacyclin, nitric oxide (NO) and cytokines that are capable of modulating the activity of underlying smooth muscle as well as nearby sensory neurons. For example, urothelial-specific overexpression of NGF results in increased bladder nerve ‘sprouting’ and increased voiding frequency.It has been shown that urothelial-derived NO can be released in response to mechanical as well as chemical stimulation and may either facilitate or inhibit the activity of bladder afferent nerves conveying bladder sensation.In this regard, activation of urothelial receptors and release of inhibitory mediators may explain in part, the mechanism of action for therapies (e.g. β3-adrenergic receptor agonists) in treatment of bladder disorders such as OAB. The mechanism underlying release of chemical mediators from the urothelium, including whether all sensory “inputs” stimulate membrane turnover (i.e. vesicular exocytosis) is not well understood. What little is known about the roles and dynamics of membrane- bound cytoplasmic

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vesicles in urothelial cell physiology is derived from measurements of membrane capacitance and microscopy of fixed tissues and cells. For example, there is evidence that once released, ATP can act as an important autocrine mediator, which can induce membrane turnover as well as enhance both stretch induced exocytosis and endocytosis. Alterations in membrane turnover can not only increase apical surface area (as described above) but also regulate the number and function of receptors and channels at the cell surface. There is evidence that epithelial cells in different organ systems may express similar receptor subtypes Accordingly, epithelial cells could use multiple signaling pathways, whose intracellular mechanisms differ according to location and environmental stimuli. This would permit a greater flexibility for the cell to regulate function and respond to complex changes in their surrounding microenvironment. Whether urothelial sensor molecules all feed into a diverse array of signaling pathways or share similarities with systems such as olfaction, whereby hundreds of receptors share identical transduction cascades, is yet to be uncovered.

ACETYLCHOLINE AND THE UROTHELIUM There is evidence that the urothelium expresses the full complement of muscarinic receptors as well as enzymes necessary for the synthesis and release of acetylcholine. Further, the urothelium is able to release acetylcholine following both chemical and mechanical stimulation The mechanism underlying acetylcholine release from urothelium may be through organic cationic transporters (OCTs) rather than vesicular exocytosis, differing from that of bladder nerves. Once released, urothelialderived

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acetylcholine is likely to exert effects via a number of sites including smooth muscle, nerves as well as urothelial associated-muscarinic or nicotinic receptors, the latter that could contribute to feedback mechanisms modifying urothelial function. In addition, stimulation of urothelialcholinergic receptors elicits release of mediators such as nitric oxide, prostaglandin as well as ATP, which could alter bladder sensation by stimulating nearby sensory afferent nerves. Thus, targeting muscarinic receptors and/or urothelial synthesis or release mechanisms may play an important role in the treatment for a number of bladder disorders. By inhibiting SNARE-dependent exocytotic processes, botulinum toxin A (BoNT/A) can prevent the release of transmitters from bladder nerves as well as translocation of various receptors and channels to the plasma membrane

CLINICAL SIGNIFICANCE OF THE SENSORY WEB

FIgURE 1: Hypothetical model depicting possible interactions between bladder nerves, urothelial cells, smooth muscle, interstitial cells, and blood vessels. Urothelial cells can also be targets for transmitters released from nerves or other cell types. Urothelial cells can be activated by either autocrine (i.e., autoregulation) or paracrine (release from nearby nerves or other cells) mechanisms.

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Defects in urothelial sensor molecules and urothelialcell signaling are likely to contribute to the pathophysiology of bladder diseases. For example, a number of bladder conditions (BPS/IC, spinal cord injury (SCI), chemicallyinduced cystitis) are associated with augmented release of urothelial-derived ATP, which is likely to result in altered sensations or changes in bladder reflexes induced by excitation of purinergic receptors on nearby sensory fibers. ATP can also act in an autocrine manner that would act to facilitate its own release from urothelial cells. Augmented expression/release of urothelial-derived chemical mediators is likely to reduce the threshold for activation of nearby bladder afferents. Thus, the urothelium has the potential for amplifying signals, both within the urothelium and the bladder wall and contributing to a gain of function in sensory processing.

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neuro anatomy oF urInary system The storage and periodic elimination of urine depend on the coordinated activity of smooth and striated muscles in the two functional units of the lower urinary tract, namely a reservoir (the urinary bladder) and an outlet consisting of the bladder neck, the urethra and the urethral sphincter. The coordination between these organs is mediated by a complex neural control system that is located in the brain, the spinal cord and the peripheral ganglia. The lower urinary tract differs from other visceral structures in several ways. First, its dependence on CNS control distinguishes it from structures that maintain a level of function even after the extrinsic neural input has been eliminated. It is also unusual in its pattern of activity and in the organization of its neural control mechanisms. For example, the bladder has only two modes of operation: storage and elimination. Thus, many of the neural circuits that are involved in bladder control have switch-like or phasic patterns of activity, unlike the tonic patterns that are characteristic of the autonomic pathways that regulate cardiovascular organs. In addition, micturition is under voluntary control and depends on learned behaviour that develops during maturation of the nervous system, whereas many other visceral functions are regulated involuntarily. Owing to the complexity of the neural mechanisms that regulate bladder control, the process is sensitive to various injuries and diseases.

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efferent pathways. The sympathetic innervation arises in the thoracolumbar outflow of the spinal cord, whereas the parasympathetic and somatic innervation originates in the sacral segments of the spinal cord. Afferent axons from the lower urinary tract also travel in these nerves. Sympathetic postganglionic nerves, for example the hypogastric nerve release noradrenaline, which activates β-adrenergic inhibitory receptors in the detrusor muscle to relax the bladder, α-adrenergic excitatory receptors in the urethra and the bladder neck, and α- and β-adrenergic receptors in bladder ganglia. Parasympathetic postganglionic nerves release both cholinergic (acetylcholine, ACh) and non-adrenergic, non-cholinergic transmitters. Cholinergic transmission is the major excitatory mechanism in the human bladder. It results in detrusor contraction and consequent urinary flow and is mediated principally by the M3 muscarinic receptor, although bladder smooth muscle also expresses M2 receptors. Muscarinic receptors are also present on parasympathetic nerve terminals at the neuromuscular junction and in the parasympathetic ganglia. Activation of these receptors on the nerve terminals can enhance (through M1 receptors) or suppress (through M4 receptors) transmitter release, depending on the intensity of the neural firing. Non-cholinergic excitatory transmission is mediated by ATP actions on P2x purinergic receptors in the detrusor muscle. Inhibitory input to the urethral smooth muscle is mediated by nitric oxide (NO) that is released by parasympathetic nerves. Somatic cholinergic motor nerves that supply the striated muscles of the external urethral sphincter arise in S2–S4 motor neurons in Onuf’s nucleus and reach the periphery through the pudendal nerves. A medially placed motor

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aFFerent neurons

nucleus at the same spinal level supplies axons that innervate the pelvic floor musculature. Sensations of bladder fullness are conveyed to the spinal cord by 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 components of these nerves consist of myelinated (Aδ) and unmyelinated (C) axons. The Aδ-fibres respond to passive distension and active contraction and thus convey information about bladder filling. The C-fibres are insensitive to bladder filling under physiological conditions (they are therefore termed ‘silent’ C-fibres) and respond primarily to noxious stimuli such as chemical irritation or cooling. The cell bodies of Aδ-fibres and C-fibres are located in the dorsal root ganglia (DRG) at the level of S2– S4 and T11–L2 spinal segments. The axons synapse with interneurons that are involved in spinal reflexes and with spinal-tract neurons that project to higher brain centres that are involved in bladder control. A dense nexus of sensory nerves has been identified in the suburothelial layer of the urinary bladder in both humans, with some terminal fibres 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.

OVERVIEW: PROPERTIES OF AFFERENT NEURONES This switches during maturation when the bladder contracts and the sphincter opens to facilitate voiding. This switch relies on sensory signals, which provide the input to the reflex circuits that control bladder filling and emptying and are also the source of both non-painful sensations of fullness and pain. Dysfunction leads to a number of distressing disorders such as overactive bladder syndrome (OAB) and Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) with symptoms including urgency, pain and urinary incontinence. Currently available therapeutic approachesare aimed primarily at reducing bladder contraction in order to relieve intravesical pressure and maintain continence. Interest in bladder afferent signalling has been fuelled by the recent realization that symptoms are a feature of dysregulated storage rather than exaggerated contractile responses and therefore targeting afferent mechanisms may be a rational approach to treatment. Our understanding of bladder afferent signalling has been advanced by studies that are designed to reveal firstly, the morphological features of the afferent terminations in both the periphery and spinal cord; secondly, identify the receptors and ion channels present on these terminations that determine afferent excitability and, thirdly, by recording electrophysiologically the action potentials in afferent fibres it has been possible to characterize the stimulusresponse functions of the various populations of afferents conveying sensory information towards the CNS.

PATHWAYS TO THE SPINAL CORD Afferent fibres reach the lower urinary tract via pelvic,

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hypogastric (lumber splanchnic) and pudendal nerves. These nerves are mixed nerves that also contain the efferent parasympathetic, sympathetic and motor fibres supplying the bladder, urethra and sphincters. DRGs supplying pelvic and pudendal afferents originate in the thoracic, lumbar and sacral regions while hypogastric afferents arise mainly from the rostral lumbar dorsal root ganglia. The central projections of these DRG neurons carry the sensory information from the lower urinary tract to second order neurons in the spinal cord. These second order neurons provide the basis for spinal reflexes and ascending pathways to higher brain regions involved in micturition and in mediating sensation. The cell size of bladder DRGs is consistent with there being 2 populations of afferent with one connecting to small unmyelinated C-fibre afferents and the other to finely myelinated A-delta fibres. These cell bodies can be further classified according to the presence or absence of certain biochemical markers, namely peptidergic and nonpeptidergic. Many unmyelinated afferents are peptidergic, containing calcitonin-gene related peptide (CGRP) and many of these also contain substance P as well as various other peptides. However, some small myelinated fibres also express CGRP. Non-peptidergic neurones can be identified by labelling for isolectin IB4, which recognizes terminal sugar residues on the cell membrane. Both small and medium sized DRGs are labelled with IB4. This nonpeptidergic subgroup also expresses P2x3 receptors, which is predominantly found in small unmyelinated fibres. TRPV1 and other sensory markers described below are expressed on both peptidergic and non-peptidergic populations.

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FUNCTIONAL PROPERTIES OF BLADDER AFFERENTS Recording from bladder afferents has confirmed the diversity of afferent populations described above based on morphology. Conduction velocity measurements confirm the predominance of fibres conducting action potentials in the A-delta and C-fibre range. The majority of these are mechanosensitive, responding to bladder filling with a range of thresholds from volumes that would be encountered under normal bladder filling to extreme levels of distension that would be considered noxious and give rise to pain. Those with lower thresholds have small myelinated axons while unmyelinated fibres have generally higher thresholds for activation. Other afferents do not respond to bladder filling. Some can be activated by intraluminal chemicals such as hypertonic saline, capsaicin or ATP, suggesting they may function as chemoreceptors. Others may be so called â&#x20AC;&#x153;silent afferentsâ&#x20AC;? that have been described elsewhere including the gastrointestinal tract. These afferents can be sensitized during inflammation suggesting a role in signaling pain. Mechanosensitivity can arise either directly as a consequence of mechanosensitive ion channels on the sensory nerve ending or secondary to chemicals released in response to stimulation, which in turn activate the ending secondary to stimulation of ligand-gated ion channels. As outlined below there is considerable debate as to the role of the urothelium in sensory signaling. One attempt to resolve this has been to dissect off the urothelium and lamina propria and determine the impact on mechanosensitivity. In the case of muscular and serosal mechanoreceptors removal of the urothelium has little impact on distension response, suggesting these endings may be directly responsive, although the nature of the mechanosensitive ion channels has yet to be elucidated.

FIGURE 3: LUT afferent nerve classes and distribution. A, fiber classes in bladder wall and urethra. B, in pelvic nerve 4 types of mechanosensitive fibers were identified by stretch, stroke and probe. C, proportion of afferent fiber types recorded in pelvic nerve. D, low and high threshold receptive fields of pelvic nerve muscle fibers based on response to stretch. E, receptive fields of 4 pelvic nerve fiber classes (Kanai and Andersson, 2010)..

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In contrast the response of muscular-urothelial endings to distension is markedly attenuated following removal of the surface layers of urothelium. The same is true for the mucosal endings. This could imply that the urothelium is involved in transducing stimuli. However, an alternative view might be that dissection causes damage to the underlying nerves that are no longer able to respond to any stimulus. An alternative approach to determining the role of the urothelium may rely on pharmacological manipulations that interfere with urothelial signaling. In this respect the response of low threshold mechanoreceptors was unchanged in calcium-free buffer, which would be expected to prevent urothelial mediator release through exocytosis. More recent studies in the mouse identified similar populations of afferents and used a systematic classification system to establish the relative proportion of these different types of afferents in the pelvic and lumbar splanchnic nerve supply. The basis for classification and the relative distribution of the terminals and projecting pathway is shown in Figure 3. Another important observation in this study was the finding that both low threshold and high threshold mechosensitivity became heightened following exposure to inflammatory mediators which has implications for our understanding of how sensory signaling is altered in disease and a basis for altered micturition and sensations such as pain. There are also recent studies that identified and characterized sacral afferents responding to ‘flow’ through the urethra. These are important observations whereby properties of these flow-responsive afferents seem to parallel that of cutaneous afferents. This could be important in terms of restoration of bladder emptying following spinal cord injury.

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MODULATING AFFERENT SENSITIVITY

ROLE OF THE UROTHELIUM IN SENSORY SIGNAL TRANSDUCTION

The relationship between stimulus and response is not fixed but can be changed acording to the mechanical and chemical environment of the sensory ending. Contractions can distort the afferent ending while connective tissue elements will transmit or dissipate stimulus energy within the tissue determining for example whether a response is rapidly or slowly adapting to maintained stretch. Similarly, chemicals released from a variety of cells within the bladder wall and particular the urothelium and lamina propria will influence afferent firing.

Recent evidence suggests instead that the urothelium possesses sensory functions and may transduce mechanical and chemical stimuli to underlying structures including smooth muscle, fibroblastlike cells, immune cells and bladder nerves including the terminals of afferents which are located in close proximity, or even within, the urothelium. The recent evidence supporting involvement of a number of these urothelially-derived factors in sensory signaling and the therapeutic potential of targeting these signalling pathways is considered below:

Many mediators are released during inflammation, injury and ischemia, from platelets, leukocytes, lymphocytes, macrophages, mast cells, glia, fibroblasts, blood vessels, muscle and neurons. Each cell type may release several of these modulating agents. Some mediators act directly on sensory nerve terminals, while others act indirectly, causing release of yet other agents from nearby cells. This “inflammatory soup” acts on sensory nerve terminals to modify signalling (this is often referred to as “plasticity”). Local mediators may include neurotrophins, amines, purines, prostanoids, proteases, and cytokines. They produce their effects on visceral afferent nerves by three distinct processes First, they can act directly, by opening ion channels on the nerve terminals. Secondly, they can sensitize endings, without causing direct stimulation, but causing hyperexcitability to other chemical and mechanical stimuli. Thirdly, as is the case for neurotrophins, they can change the phenotype of the afferent nerve over long periods.

1. NITRIC OxIDE Enzymes responsible for the generation of nitric oxide (NO) are expressed in both the urothelium and in the adjacent nerve fibres. However, NO may be involved in bladder dysfunction since expression of NOS is elevated in neurogenic bladder. Munoz et al. recently found that while electrical stimulation-evoked release of some urothelial mediators (ATP) was attenuated by disruption of the urothelium, release of NO was maintained which may suggest that under these conditions NO is derived from suburothelial structures. Interestingly, NO release triggered by cholinoreceptor stimulation was lost after urothelial disruption, consistent with NO derived from multiple sources including the urothelium. A recent study by Aizawa et al. (2010) suggests that NO is able to inhibit afferent activity, an observation consistent with earlier cystometric analysis of the effect of activating the NO pathway

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4. BOTULINUM TOxIN

2. PURINERGIC SIGNALLING ATP acting via purinergic receptors modulates bladder function mediated by both afferent and efferent pathways involved in urine storage and emptying. It is well established that the urothelium releases ATP in response to stretch and that this acts in a paracrine fashion to influence the function of myofibroblasts and bladder afferent nerves. P2x2 and P2x3 receptors are expressed on unmyelinated afferent fibres innervating the bladder, and thus the hypothesis has been put forward that mechanosensitivity, at least in those afferents in proximity to the urothelium, involved ATP release by stretch and activation of P2x2 and P2x2/3 receptors on the afferents. Adenosine is also produced and released by the urothelium, and may play important roles in modulating sensory afferent\ function and smooth muscle contraction. In the normal bladder, it is believed that a balance between the excitatory effects of ATP and inhibitory effects of NO release may determine micturition thresholds and frequency and that this balance may be disturbed in bladder disorders. This suggests that the balance between ATP and NO is altered in bladder dysfunction. 3. CHOLINERGIC MECHANISM The discovery that ACh can be released from the human bladder urothelium has led to the concept that cholinergic mechanisms could contribute to sensory signalling. This concept has been reinforced by clinical findings showing that anticholinergic drugs, the current mainstay for the treatment of bladder overactivity, appear to exhibit efficacy during the bladder storage phase when parasympathetic cholinergic activity is minimal. A number of studies have examined the effect of cholinoreceptors on bladder afferent firing. Matsumoto et al found that stimulating muscarinic receptors induced

bladder hyperactivity, and that this was blocked by inhibiting the M2 receptor, suggesting that M2 receptors play a role in cholinergic modulation of bladder afferent excitability. Masuda et al (2009) found that pharmacological activation of muscarinic receptors reduced micturition reflexes in the rat suggesting that muscarinic receptor activation leads to reduced afferent signalling.Such inhibition has been observed in afferent recording studies using isolated bladder preparations in which any secondary effects on muscle tone could be controlled. In these studies blocking cholinesterase activity to augment endogenous cholinergic activity lead to attenuated(reduced) afferent signalling that could be reversed by antimuscarinics. How ACh and muscarinic receptor pathways could modulate transmission is unclear. It is possible that there is a direct action and in this respect DRG neurons retrogradely labelled from the bladder have been shown to express M2, M3 and M4 receptors. However, stimulation of muscarinic receptors on the urothelium causes the release of other excitatory and inhibitory mediators including ATP and NO.It is possible therefore that muscarinic receptors modulation of afferent activity is indirect via the release of a secondary mediator. Such a view is supported by the observation that bladder hypersensitivity, triggered by cholinergic stimulation was abolished by inhibition of P2x receptors, suggesting that muscarinic receptors and purinergic receptors may work in tandem to modulate afferent transmission. These studies highlight the complex nature of cholinergic signalling in the bladder, and indicate that more research is necessary to fully understand whether muscarinic receptors on the afferent limb could become a therapeutic target for OAB.

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Botulinum toxin A (BoNT/A) inhibits the vesicular release of acetylcholine following uptake into presynaptic nerve terminals and proteolytic cleavage of the SNARE protein SNAP-25 which prevents docking and fusion of synaptic vesicles at the neuro-muscular junction. BoNT/A was first clinically used in the bladder to treat neurogenic bladder overactivity caused by spinal cord injury. Since then, intravesical injections of BoNT/A has proved a highly effective treatment for patients with detrusor overactivity, with numerous studies reporting improvements in the sensory symptoms of urgency and urinary frequency. 5. TRANSIENT RECEPTOR POTENTIAL (TRP) CATION CHANNELS A number of different members of the transient receptor potential (TRP) channel family are expressed in the bladder mostly in association with sensory nerve fibres involved in mechanotransduction and nociception. TRPV1, TRPV2, TRPV4, TRPM8, and TRPA1, have all been shown to be expressed in the bladder. TRPV1 has been shown to play an integral role in modulating the excitability of bladder afferents and the generation of hypersensitivity, induced by bladder inflammation. It is through desensitization of this receptor that agents like resiniferatoxin act to treat symptoms in OAB. TRPA1 is also expressed in the bladder and is particularly associated with C-fibre endings in the suburothelium that co-localize CGRP. Agonists acting at the receptor cause bladder hyper-reflexia and is suggested to play a role in mechanotransduction and in signalling pain. TRPM8 was first described as a cold receptor and interest in its role in the bladder stems from the observation that instillation of cold saline into the bladder elicits a contractile response (at pressures or volumes below the

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neural control oF Female PelVIc Floor muscles and rhaBdosPhIncters threshold for normal voiding). This response to a cooling stimulus. 6. CANNABINOID The multi-centre CAMS study (Cannabinoids in Multiple Sclerosis) reported that the use of cannabis based extracts significantly improved symptoms of urge incontinence and detrusor overactivity in patients with multiple sclerosis. This observation has provoked interest in the study of expression and function of cannabinoid receptors in the bladder.

The urethral rhabdosphincter and pelvic floor muscles are important in maintenance of urinary continence and in preventing descent of pelvic organs (i.e. pelvic organ prolapse, POP). Because of the importance of understanding pelvic floor function, recent clinical and preclinical studies have focused on this topic.

1. STRUCTURAL ELEMENTS OF THE PELVIC FLOOR

bowl is lined with striated muscle: the iliococcygeus and pubococcygeus (which together comprise the levator ani - LA - muscle), the coccygeus, and puborectalis muscles. The muscles are attached to the bone and to each other with various connective tissue supports. These three components, bone, muscle, and connective tissue provide support of the pelvic viscera (i.e. rectum, vagina, and bladder) but also allow for excretory and sexual function.

The pelvic floor in women is a bowl-shaped structure comprised of bone, muscle, and connective tissue. The rim of the bowl is formed by the bones of the pelvic girdle (sacrum, ilium, ischium, and pubis). The “bottom” of the

The viscera, as well as striated muscles that serve as true sphincters - urethral and anal rhabdosphincters, attach to pelvic floor muscles and each other by connective tissue but do not attach directly to bone. The

7. ADRENORECEPTORS Alpha-1-adrenoreceptor (α1-AR) antagonists are the current first line for treatment of lower urinary tract symptoms (LUTS). recent data report an improvement in other symptoms, such as frequency, nocturia and urgency, suggesting that they may also act via the afferent system to influence storage function. Adrenoreceptors have been detected throughout the urothelium and on the sensory neurones innervating the bladder. In contrast to the α-adrenoreceptors, the beta adrenoreceptors (βARs) mediate relaxation of the bladder smooth muscle in response to sympathetically released noradrenaline. The β3-AR subtype is the predominant isoform responsible for relaxation of the human detrusor and β3-AR agonists are currently in clinical trials for the treatment of OAB.

Figure 4: Muscles of the pelvic floor diaphragm.

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urethrovaginal sphincter, the compressor urethrae muscle, the ischiocavernosus, and bulbospongiosus muscles are additional striated perineal muscles that are intimately associated with the viscera. During embryogenesis, the rhabdosphincter and perineal muscles develop from the cloaca with a two-week delay in striated muscular differentiation compared to the LA and other skeletal muscles. Furthermore, rhabdosphincters are completely separated from the LA muscles by connective tissue. Thus, the striated muscles associated with the viscera (i.e. rhabdosphincters) are quite distinct from the striated skeletal muscle of the pelvic floor (e.g. LA). The urethral rhabdosphincter has been referred to by many names, including the external urethral sphincter, the striated urethral sphincter, the striated urethralis muscle and other names. The term “external urethral sphincter” is downplayed because the urethral rhabdosphincter is not really external to the lower urinary tract; it surrounds the middle of the urethra. Therefore the term urethral rhabdosphincter is recommended.

not describe any contribution of the LA muscle from the pudendal nerve.

2. PERIPHERAL INNERVATION OF THE FEMALE LEVATOR ANI (LA) MUSCLES

Clarity regarding pudendal versus LA nerve innervations is also important because attributes ascribed to pudendal nerve involvement may be more correctly desscribed to LA nerve involvement. For example, the intrapelvic positioning of the LA nerve on the surface of the muscles may expose it to damage as the fetal head passes through the birth canal and may contribute to the correlation between parity and POP. This positioning also allows exposure to electrical current applied with a St. Mark’s electrode situated in the rectum with subsequent EMG activation of the LA muscle. The LA nerve positioning, close to the ischial spine, also risks entrapment by sutures used for various POP suspension surgeries or may account for dyspareunia, pelvic pain, and/or

The LA muscle of the pelvic floor is innervated by the LA nerve in human, The LA nerve primarily arises from sacral spinal roots (e.g. S3-S5 in humans) and travels along the intrapelvic face of the LA muscle with a high degree of variability in branching patterns. In humans, there is some controversy whether or not the pudendal nerve also innervates the LA muscle. In human female fetus samples, a contribution to LA innervation by the pudendal nerve was only seen in about half the samples. A recent detailed study of women 45-55 years of age, using an elaborate Sihler’s stain to trace branches down to single fibers, did

Thus, divergent techniques support the conclusion that only the LA nerve innervates the LA muscles with no significant contribution from the pudendal nerve in nonhuman species. These direct observations, coupled with the distinct embryological origins of LA muscles versus rhabdosphincter and perineal muscles, as well as a respective “compartmentalization” of the rhabdosphincter and perineal muscles by connective tissue, are in line with distinct “special somatic” motor innervation of the rhabdosphincter by the pudendal nerve versus typical skeletal motor innervation of the LA muscle by the LA nerve. The work in human female fetal samples suggests that an innervations of the LA muscle by the pudendal nerve should be considered, especially during the perinatal period. Whether these pudendal branches to the LA muscle recede during maturation or aging should also be considered in light of the difficulty identifying them in older women.

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recurrent prolapse associated with such surgery. Finally, since the ischial spine is a landmark for transvaginal “pudendal nerve” block, the possibility that this procedure also anesthetizes the LA nerve should be considered.

3. REFLEX ACTIVATION OF PELVIC FLOOR MUSCLES There is little preclinical information regarding reflex control of pelvic floor muscles associated with visceral function (e.g. micturition). A recent study in female rabbits showed that during bladder filling (i.e. the storage phase), the pubococcygeus muscle was active, while during micturition it was quiet. The same study showed the opposite relationship for the ischiocavernosus and bulbospongiosus muscles, which were silent during bladder filling but active during micturition. One study in the male rat indicated that the pubocaudalis muscle is active during bladder contractions and shows high frequency bursting like the urethral rhabdosphincter EMG. A recent detailed study of pelvic floor muscle activity in female rats during bladder filling and voiding also found that “pelvic floor muscle” activity was highly variable during bladder filling and voiding, while the rhabdosphincter EMG activity was reliable.

4.PERIPHERAL INNERVATION OF URETHRAL AND ANAL RHABDOSPHINCTERS The urethra and anal canal are surrounded by bands of striated muscle fibers; the urethral and anal rhabdosphincters, respectively as they pass through the pelvic diaphragm. The muscles do not attach to skeletal structures and thus act as true sphincters (i.e. contraction

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A. LEVATOR ANI NERVE

B. PUDENDAL NERVE

FIgURE 5: A: Sagittal drawing of medial surface of a womanâ&#x20AC;&#x2122;s pelvic floor showing the course of the LA nerve (LAN) from the sacral roots (S3-S5) across the internal surface of coccyeus (Cm), iliococcygeus (ICm) puborectalis (PRm) and Pubococcygeus (PCm) muscles. S=sacrum; C=coccyx; IS=ischial spine; OIm=obturator internus muscle; ATLA=arcus tendineus LA; U=urethra; V=vagina; R=rectum. B. Drawing of a posterior view of the hip muscles showing the course of the pudendal nerve (PN) from the S2-S4 roots across the lateral surface of the superior gemellus (Sg) and obturator internus (OIm) muscles, through the pudendal canal (PC), and its branching into the inferior rectal nerve (IRN) and perineal nerve (PeN). P=periformis muscle; STL=sacroturberous ligament; C=coccyx; IS=ischial spine; SSL=sacrospinous ligament; S=sciatic nerve; EAS=external anal sphincter; Ig=inferior gemellus muscle.

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FIgURE 6: Schematic diagram illustrating two patterns of innervation of the levator ani muscles (LAM)—superior view. The nerves traveling on the superior surface of LAM are shown as a continuous line and the nerves coursing inferior to LAM are illustrated by a dashed line.

a: “Classical” IRN distribution. The inferior rectal nerve (IRN) originated from the pudendal nerve (PN, shown in green). The PN branches into the dorsal nerve of the clitoris, perineal nerve, and the IRN. The perineal nerve and the IRN send branches that enter the inferior surface of the iliococcygeus (ICM), pubococcygeus (PCM), and puborectalis (PRM) muscles. The dorsal nerve of the clitoris terminates in the clitoris (not shown). b: Variant IRN distribution. LAM innervates with an IRN variant (shown in blue) that originates directly from the sacral nerve plexus (S3 and/or S4 roots). The IRN variant courses superior to the coccygeus muscle, sends branches to the superior surface of the ICM, and penetrates the coccygeus–sacrospinous ligament complex. The variant IRN then travels inferior to the LAM and sends branches to the inferior surfaces of PCM and PRM. PN divides into the dorsal nerve of the clitoris and the perineal nerve with distribution similar to that shown in a. The levator ani nerve (LAN) arises directly from S3 and/or S4 sacral nerve roots (shown in yellow) and travels on the superior surface of the LAM to innervate the ICM, PCM, and PRM.. (Source: Innervation of the levator ani muscles: description of the nerve branches to the pubococcygeus, iliococcygeus, and puborectalis muscles, by- Bogdan A. grigorescu, george Lazarou, Todd R. Olson, Sherry A. Downie, Kenneth Powers, Wilma Markus greston & Magdy S. Mikhail, International Urogynecology Journal, 2007)

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produces virtually no movement except constriction of the lumen). In addition, there are small, thin bands of striated muscle (compressor urethra, urethrovaginal sphincter, bulbocavernosus, and ischiocavernosus) that surround the urethra, vagina, and/or rectum and have connective tissue attachments to the perineal body. The urethral rhabdosphincter, anal rhabdosphincter, bulbocavernosus, and ischiocavernosus muscles are innervated by the pudendal nerve, which originates from the S2-S4 sacral roots and passes along the lateral surface of the internal obturator and coccygeus muscles and through Alcockâ&#x20AC;&#x2122;s canal. As the nerve passes through the canal, it branches into the inferior rectal nerve (which innervates the anal rhabdosphincter), the perineal nerve (which innervates the urethral rhabdosphincter, the bulbospongiosus muscle, the ischiocavernosus muscle, superficial transverse perineal muscle, and the labial skin), and the dorsal nerve of the clitoris. The branches of the perineal nerve are more superficial than the dorsal nerve of the clitoris and, in most cases, travel on the superior surface of the perineal musculature. The terminal branch of the perineal nerve to the striated urethral sphincter travels on the surface of the bulbocavernosus muscle then penetrates the urethra to innervate the sphincter from the lateral aspects. The specific innervation of the smaller bands of muscles attached to the perineal body has not been characterized. The rhabdosphincter of both men and women contain neuronal nitric oxide synthase (nNOS), which is contained in a subpopulation (43%) of the muscle fibers, as well as nerve fibers, with concentration at the neuromuscular junction in humans. Additionally, nNOS has been localized to pudendal motor neurons, which innervate the rhabdosphincter in rats, cats, monkeys, and humans. nNOS is responsible for producing the transmitter nitric oxide (NO). While NO is known to increase cGMP levels in many types of smooth muscle; its role in control of striated

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Figure 7: Sagittal drawing of medial surface of a womanâ&#x20AC;&#x2122;s pelvic floor showing the origin of pudendal nerve and its innervation to levator ani muscle.

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muscle and in neuromuscular transmission is not well established.

B) AFFERENT INNERVATION OF THE URETHRAL AND ANAL RHABDOSPHINCTERS

The possibility that the urethral rhabdosphincter receives a “triple innervation” from somatic, parasympathetic, and sympathetic nerves was raised in early histological studies. However, this has been disputed by subsequent studies that showed no physiological effects of autonomic nerve stimulation on striated sphincter function and showed that the autonomic fibers are only “passing through” the outer layer of striated muscle to reach the inner layers of smooth muscle.

Various studies have characterized primary afferent neurons sending axons into the pudendal nerve. However this nerve carries the innervations to many visceral structures (e.g. urethra, genitalia, rectum, vagina) in addition to skin and rhabdosphincters, thus it is difficult to specifically characterize the sensory innervation of the sphincters per se. Nevertheless, the paucity of large sensory neurons in sacral dorsal root ganglia following application of tracers to the pudendal nerve suggests that the sensory innervation of the rhabdosphincters does not contain large myelinated fibers that innervate these sensory organs that typically innervate muscle spindles, Golgi tendon organs, or Pacinian corpuscles.

A) URETHRAL AND ANAL RHABDOSPHINCTER MOTOR NEURONS Pudendal motor neurons that innervate the urethral and anal rhabdosphincters (and bulbocavernosus and ischiocavernosus) muscles are situated along the lateral border of the sacral ventral horn in Onuf’s nucleus in human. Studies in human show that urethral rhabdosphincter motor neurons occupy a ventrolateral position and anal rhabdosphincter motor neurons occupy a dorsomedial position within the confines of Onuf’s nucleus. Sphincter motor neurons are different from motor neurons that innervate skeletal muscles. They are densely packed within the confines of Onuf’s nucleus and exhibit tightly bundled dendrites that run rostrocaudally within the confines of the nucleus. rhabdosphincter motor neurons and preganglionic neurons receive inputs from similar spinal regions. Finally, the arrangement of peripheral motor nerve terminals bilaterally at dorsolateral and ventrolateral positions in the urethra may also provide symmetrical force generation.

The spinal terminals of pudendal primary afferent fibers are distributed throughout laminae I, V, VII, and the dorsal gray commissure, while labeling in laminae III and IV is well-defined and restricted to the medial third of the dorsal horn.

5. REFLEX ACTIVATION OF URETHRAL AND ANAL RHABDOSPHINCTERS

Rhabdosphincter motor neurons can be activated via segmental and descending pathways. The segmental inputs can be activated by stretch receptors and nociceptors in the bladder or urethra or genitalia. Electrophysiological studies in cats show that stimulation of either pelvic nerve or pudendal nerve afferent fibers can activate polysynaptic spinal segmental reflexes. Studies in rats also show that electrical stimulation of afferent axons in the pelvic nerve elicits reflexes in pudendal nerve efferent fibers or the urethral rhabdosphincter.

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Previously, the afferent inputs from the urinary bladder have been emphasized as being of primary importance for activation of the segmental reflex by pelvic nerve stimulation because bladder distension will activate the urethral rhabdosphincter. This reflex activation is often referred to as the “guarding reflex” or “continence reflex”. However, recent studies are placing greater emphasis on urethral afferent fibers. It is tempting to speculate that the guarding reflex is actually activated more vigorously by urethral afferent fibers if urine inadvertently begins to pass through the bladder neck and into the proximal urethra, with a requirement for a rapid closure of the more distal urethral sphincter (i.e. guarding against urine loss) compared to simple bladder distension or increases in intravesical pressure.

The greater importance of urethral afferent fibers is also suggested by experiments where bladder afferent fibers are electrically stimulated. For example, in studies by McMahon et al, electrical stimulation of pelvic nerve fibers close to the bladder was not able to evoke pudendal nerve firing in a large proportion of cats but placement of electrodes more centrally on the pelvic nerve was able to evoke firing. Furthermore, it was possible to consistently evoke a reflex when the stimulus was applied more centrally on the pelvic nerve, which would include fibers from the urethra. Since the more central electrode placement would also activate colonic and genital afferent fibers, additional experiments are needed to specifically compare urethral versus bladder versus colonic afferent fibers in evoking the “guarding reflex”. Electrical stimulation of pudendal afferent fibers also evokes a spinal reflex to activate the rhabdosphincter in cat and rat. Since some urethral afferent fibers (as

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Red stellate shapes and lines represent excitatory neurons and their axonal pathways, respectively; while the black oval shape and line represent an inhibitory interneuron and its axonal pathway. Simulation of the pelvic nerve activates a polysynaptic spinal reflex arc (Pathways of reflex action) that produces an evoked potential recorded from axons of sphincter motor neurons in Onuf’s nucleus at a latency of about 10 msec. In addition, this stimulation also activates inhibitory interneurons that, after 50 msec delay, produce inhibition of sphincter motor neurons for about 1,000 msec (see text for details). Presumably this arrangement allows low frequency pelvic afferent activity (1 Hz) to increase sphincter activity during urine storage and to inhibit sphincter activity when the pelvic afferent activity markedly increases (> 5 Hz) as might occur with very large bladder volumes or during a micturition contraction. The model includes gABAergic, glycinergic, or enkephalinergic inhibitory neurons located in the dorsal gray commissure.

FIgURE 8: Drawing of proposed model for spinal and Supraspinal excitation and inhibition of rhabdosphincter pudendal motor neurons with an example of the evoked potential recorded by an electrode on the pudendal nerve in response to electrical stimulation of the pelvic nerve at 0.5 Hz and a table showing the predominant effects of various receptor subtypes on evoked potentials recorded from the pudendal nerve or urethral rhabdosphincter.

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In addition to spinal excitatory sphincter reflexes, Supraspinal pathways originating in the medullary nucleus retroambiguus (NRA) and the pontine “L region” can activate sphincter motor neurons during Valsalva maneuvers and during urine storage, respectively. When micturition occurs, neurons in the pontine micturition center (PMC) provide descending activation of the gABAergic, glycinergic, or enkephalinergic neurons in the dorsal gray commissure to inhibit sphincter motor neurons and allow voiding to begin. In addition to these predominant pathways, various other areas of the brain (e.g. medullary raphe serotonergic pathways, pontine locus coeruleus noradrenergic pathways, etc) provide “modulation” of the reflexes. Those excitatory and inhibitory modulatory pathways that have been explored pharmacologically are also listed in the table. For simplicity, the inhibition associated with PMC activation and the inhibition associated with pelvic nerve stimulation are shown passing through the same inhibitory interneuron. However, no evidence yet exists that this is the case.

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well as rectal, genital, and cutaneous afferent fibers) travel in the pudendal nerve, it is possible that the spinal urethral rhabdosphincter activation by pudendal afferent stimulation is also a manifestation of the “guarding reflex”.

6. INHIBITION OF URETHRAL RHABDOSPHINCTER (URS) REFLEXES DURING VOIDING Voiding is induced voluntarily or reflexively by neural circuitry in the brain. For voiding to occur, there must be contraction of the bladder and simultaneous relaxation of the urethral rhabdosphincter. These responses are mediated by descending projections from neurons in the pontine micturition center (PMC) that excite the sacral autonomic outflow to the bladder and inhibit the motor outflow to the sphincter (Figure 8). The descending inhibitory pathway from the PMC to sphincter motor neurons is thought to involve spinal GABAergic inhibitory neurons in the dorsal commissure of the sacral spinal cord (Figure 8). A role for glycinergic and enkephalinergic interneurons in the dorsal commissure has also been proposed in mediating inhibition of the sphincter during voiding. In addition to supraspinal inhibitory mechanisms, a “spinal, urine storage reflex, inhibitory center” (SUSRIC) was found that inhibited both the somatic and the sympathetic urine storage reflexes controlling the urethral rhabdosphincter and smooth muscle, respectively, in the cat. Activation of this inhibitory center by electrical stimulation of the pelvic nerve afferent fibers occurs simultaneously with the activation of the URS reflex itself. Possibly the inhibition of rhabdosphincter activity by distension of the bladder represents a physiological corollary for the inhibition of rhabdosphincter activity by high frequency electrical stimulation of pelvic nerve afferent fibers.

7. SUPRASPINAL ACTIVATION OF RHABDOSPHINCTERS AND PELVIC FLOOR MUSCLES Supraspinal activation of urethral and anal rhabdosphincter motor neurons can be mediated in response to voluntary, as well as involuntary reflexic inputs (e.g. during coughing, sneezing, vomiting) presumably from nucleus retroambiguus in the caudal medulla Nucleus retroambiguus also innervates the pelvic floor muscles, as well as abdominal muscles, consistent with a role in raising intra-abdominal pressure during Valsalva maneuvers. Generally, the pelvic floor and rhabdosphincter muscles are activated as afunctional unit when voluntarily contracted. However, differential activation of the rhabdosphincter and the pelvic floor muscles has been demonstrated, indicating distinct CNS control systems and innervation.

8. NEUROCHEMICAL ANATOMY OF RHABDOSPHINCTER MOTOR NEURONS In addition to their unique morphology, neurophysiology, and supraspinal inputs, rhabdosphincter motor neurons in Onuf’s nucleus also exhibit a plethora of unique and highly diverse neurotransmitters, receptors, ion channels, and growth factors and indicate a role in continence and/ or sexual function. A) PHARMACOLOGY OF URETHRAL AND ANAL RHABDOSPHINCTERS The excitatory amino acid neurotransmitter, glutamate, mediates initiation of action potentials in rhabdosphincter motor neurons (and subsequent rapid contraction of the muscle) by binding to NMDA and AMPA receptors . Thus it is useful to think of these transmitters as part of the “hardwired” reflex circuitry that is involved in all or none activation of consistent and reliable storage reflexes, as

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compared to monoamines and peptide transmitters. The inhibitory amino acids glycine, acting through strychnine-sensitive ionotropic receptors and GABA, acting through both GABA-A (ionotropic) and GABA-B (metabotropic) receptors are thought to be major inhibitory transmitters regulating rhabdosphincter activity. In addition to amino acid transmitters, the monoamine transmitters (norepinephrine and serotonin) are also important in modulating rhabdosphincter motor neuron activity. It was the preferential distribution of norepinephrine and serotonin terminals in Onuf’s nucleus that led to extensive animal studies of noradrenergic and serotonergic control of rhabdosphincter function and eventual clinical studies of duloxetine, a norepinephrine and serotonin reuptake inhibitor, as a treatment for stress urinary incontinence. Elegant studies in humans using magnetic stimulation of brain and sacral nerve roots have indicated that duloxetine increases the excitability of rhabdosphincter motor neurons to both supraspinal and segmental inputs to increase urethral pressures. Importantly, duloxetine’s ability to increase urethral rhabdosphincter activity did not interfere with the inhibition of sphincter activity during voiding (i.e. bladder-sphincter synergy was well maintained). Multiple adrenergic receptor subtypes play a role in control of rhabdosphincter motor neurons, and the results with norepinephrine reuptake inhibitors indicate that these receptors can be activated by endogenous norepinephrine. Strong evidence exists that a1 adrenoceptors excite rhabdosphincter motor neurons. Findings also indicate that norepinephrine is working through a second messenger system to close TASK K+ channels and increase rhabdosphincter motor neuron excitability (manuscript in preparation, Yashiro, Thor, Burgard, et al., 2012). In addition to the depolarization, increase in membrane resistance, and decrease in

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rheobase, norepinephrine also increased excitability of rhabdosphincter motor neurons by reducing the afterhyperpolarization and increasing the firing frequency of the neurons. Excitatory effects of α1 adrenoceptor stimulation on rhabdosphincter neurons are supported by clinical studies where decreases in rhabdosphincter activity were seen after administration of prazosin to human subjects. On the other hand, strong evidence exists that α2 adrenoceptor stimulation has the opposite effect, i.e. inhibition, of rhabdosphincter activity. Importantly, reflex activity in the sympathetic pathway to the urethral and anal smooth muscle (i.e. the hypogastric nerve) shows similar adrenergic pharmacology - an enhancement of activity by α1 adrenoceptors and inhibition of activity by α2 adrenoceptors. Multiple subtypes of serotonin (5-hydroxytrptamine, 5-HT) receptors are also involved in modulating rhabdosphincter motor neuron excitability. Strong evidence exists that 5-HT2 receptors can excite sphincter motor neurons. Immunohistochemical and molecular studies in humans and dogs have shown that 5-HT2A, 5-HT2B, and 5-HT2C receptor subtypes are associated with Onuf’s nucleus motor neurons.

9. LEVATOR ANI AND RHABDOSPHINCTER NEUROPATHY Childbirth is a risk factor for development of pelvic organ prolapse (POP). Furthermore, various studies have indicated damage to the innervation of the pelvic floor muscles, which might be expected to initiate pelvic descent and prolapse. Early studies using pudendal nerve terminal latency as a measure of nerve damage were met with skepticism for many reasons, however with more sophisticated analyses using EMG interference patterns

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a more recent series of elegant studies have provided evidence that LA nerve damage accompanies parturition in about 25% of women with approximately 1/3 of those continuing to show evidence of nerve damage at 6 months after parturition. Importantly, women undergoing elective Caesarian section (i.e. without preceding labor) showed no signs of LA nerve damage. Furthermore, changes in function of the urethral rhabdosphincter were also associated with pregnancy (i.e. before labor), and these remained evident at 6 months postpartum. In rabbits, it has also been shown that multiparous females have thinner, longer, and weaker pubococcygeus muscles than nulliparous females, which may indicate nerve damage also occurs in this species. A recent study comparing continent and incontinent women also demonstrated that incontinent women showed evidence of poor neuromuscular function of the rhabdosphincter, and the authors indicated that there was a correlation with age. Because the pelvic floor supports the viscera, damage to the LA innervation and subsequent muscle flaccidity was thought to promote POP. To test this expectation experimentally, the LA muscles were bilaterally denervated in 7 squirrel monkeys, which is a species that shows ageand parity- correlated POP similar to humans. Surprisingly, these monkeys showed no POP following this procedure for 2-3 years after surgery, despite showing statistically significant decreases in LA muscle mass and myocyte diameter, as well as vacuolization of the muscle. Thus, these experiments suggest that, in the absence of childbirth, the pelvic floor muscle innervation plays a minor role in providing visceral support and suggests that the connective tissue plays the major role. In women, the appearance of levator ani muscle abnormalities in magnetic resonance images after vaginal delivery concluded that frank damage of the LA muscle (and presumably the associated connective tissue) is correlated with sphincter damage, prolapsed and incontinence. Thus, future research might focus on the changes in pelvic

Table 1: Neuronal markers preferentially associated with rhabdosphincter motor neurons in Onuf’s nucleus.

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ligaments or extracellular matrix that occur with pregnancy, childbirth, and aging. Possibly after childbirth and stretching of the pelvic connective tissue, the muscle plays a compensatory role. Relative contribution of LA and pudendal nerves to continence mechanisms during sneezing in rats and cats. Analysis of the urethral closure mechanisms during sneeze-induced stress conditions in anesthetized female rats and cats has revealed that pressure increases in the middle portion of the urethra are mediated by reflex contractions of the rhabdosphincter as well as the pelvic floor muscles.

SUMMARY Neural control of the pelvic floor (LA and coccygeus) is provided by the LA nerve, while the urethral and anal rhabdosphincters are controlled by the pudendal nerve. LA motor neurons are similar in morphology to other skeletal motor neurons, showing large α and small γ neuronal populations diffusely distributed in the sacral ventral horn. One distinguishing feature, however, is projections from LA motor neurons into Onuf’s nucleus, the location of rhabdosphincter motor neurons. Presumably these projections coordinate pelvic floor and rhabdosphincter function. This proposed coordination of visceral and rhabdosphincter activity with pelvic floor muscle activity is one important area for future research. Rhabdosphincter muscles and their innervation are remarkably different from skeletal muscles. The rhabdosphincter striated muscles do not have Golgi tendon organs and muscle spindles, which are common in skeletal muscles. In addition, the rhabdosphincters are intimately associated with the urethra and anal canal and participate extensively in voiding and sexual function. Thus it should not be surprising that rhabdosphincter motor neurons are quite distinctive from skeletal muscle motor neurons. In contrast to the diffuse distribution of LA motor neurons in the sacral ventral horn, the rhabdosphincter motor neurons are

densely packed within Onuf’s nucleus (and homologous nuclei in other species). Finally, rhabdosphincter neurons exhibit a number of unique membrane properties that may contribute to simultaneous activation and which are distinctive from skeletal muscle motor neurons. Important species differences exist in the spinal localization of anal sphincter neurons. Other distinguishing characteristics of rhabdosphincter motor neurons are their unique morphology, their association with abundant neurotransmitters and receptors, a diverse physiology, and a rich pharmacology. These differences presumably reflect their integral role in coordinating somatic and visceral function during micturition, defecation, and copulation. Denervation of both the pelvic floor and the rhabdosphincters has been associated with childbirth and aging.

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eFFerent Pathways to the Bladder

Three main neural pathways regulate lower urinary tract efferent activity: 1) sacral parasympathetic (pelvic) nerves provide excitatory input to the bladder; 2) thoracolumbar sympathetic nerves provide inhibitory input to the bladder and excitatory input to the bladder neck and urethra; and 3) sacral somatic (pudendal) nerves innervate the striated muscles of the sphincters and pelvic floor. Parasympathetic and sympathetic pre-ganglionic neurons release acetylcholine, which acts on nicotinic receptors to activate post-ganglionic fibres. Parasympathetic post-ganglionic fibres terminate predominately at the detrusor muscle and release acetylcholine, resulting in detrusor contraction during voiding. Studies in animals have shown that sympathetic post-ganglionic fibres predominately terminate at the mucosal and urothelial level, releasing noradrenaline (NA), contributing to bladder relaxation during storage (via stimulation of beta-adrenergic receptors expressed in detrusor).

1. PREGANGLIONIC NEURONS Parasympathetic preganglionic neurons are locatedsin the lateral part of the sacral intermediolateral graysmatter in a region termed the sacral parasympatheticsnucleus. The neurons are small, fusiform-shapedscells which send dendrites into lateral lamina I of thesdorsal horn, the lateral funiculus and medially into the dorsal grey commissure.

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In spinal cord injured patients, where disruption to pathways at pre-ganglionic levels is observed, several groups have used neural stimulation techniques to restore normal bladder function. Stimulating parasympathetic pre-ganglionic roots at S3 with implanted electrodes elicits two principal responses: at low levels of stimulation, the external urethral sphincter, external anal sphincter and pelvic floor muscles are contracted. At high levels of stimulation, parasympathetic activation contracts the detrusor muscle, leading to efficient emptying of the bladder when the sphincter muscle relaxes. The recent increase in the use of sacral neuromodulation for the treatment of detrusor overactivity has resulted in numerous potential theories of its actions, including stimulation of efferents, direct effect on the muscle, stimulation of the afferents, induction of spinal plasticity, and modifications of cortical activation. The DGC (dorsal grey commissure) also contains a group of interneurones, which have recently received more attention as main players in the guarding reflex.

2. GANGLIA The peripheral ganglia are the link in the relay of autonomic innervation to the lower urinary tract and reproductive organs, along with a substantial part of the extrinsic motor innervation of the lower bowel. There are species differences in organization and neurochemistry of pelvic ganglion cells and their spinal inputs. Large mammals have a plexus of pelvic and intramural ganglia, containing both sympathetic and parasympathetic neurons.

small clusters of autonomic ganglion cells are present in the adventitial connective tissue and among the detrusor muscle bundles.

3. TRANSMITTERS A. GLUTAMATE Glutamate is present in the terminals of primary afferent neurons in the spinal cord along with interneurons and fibres originating in the medulla oblongata. In general, glutamatergic neurons tend to be excitatory, contrasting with generally inhibitory effects of glycinergic neurons; however, excitatory/ inhibitory effects of transmitters can be reversed by the nature of the post-synaptic neuron. Thus, glutamatergic neurons can indirectly have an inhibitory effect if an inhibitory neuron is interposed before the ultimate target. Glutamate acts on spinal neurons through a variety of receptor subtypes. These include NMDA receptors, which are important in controlling polysynaptic reflex pathways at the lumbosacral levels. The NMDAR1 glutamatergic receptor subunit is present in the spinal cord of male rats, and is expressed in the SPN. Glutamate is present in the dorsal root ganglion cells supplying the bladder, and the NMDAR1 sub-unit is also present in L6 dorsal root ganglion cells of the rat. In female rats intrathecal injection of an NMDA receptor antagonist decreases bladder contraction pressure. With ageing, there is a decrease in the density of glutamatergic synaptic inputs, which may influence urinary tract function.

The bladder wall itself contains intramural ganglia, and

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B. GLYCINE/ GAMMA AMINE BUTYRIC ACID Glycinergic and GABAergic interneurones have a major role in neural control processes mediating bladder function. Glycinergic/ GABAergic projections to the lumbosacral cord inhibit the micturition reflex and also inhibit glutamatergic neurons. Clinically, detrusor overactivity can be inhibited by GABA receptor activation. C. SEROTONIN Spinal reflex circuits involved in voiding function have a dense serotonergic innervation. Activation of the central serotonergic system can suppress voiding by inhibiting the parasympathetic excitatory input to the urinary bladder, and 5-HT elicits a prolonged activation of thoracic sympathetic preganglionic neurons. Inhibitory effects on bladder activity are most likely mediated primarily by 5-HT1A receptors. The transmitter released by inhibitory interneurons has not been identified. Activation of 5-HT1A and 5-HT3 receptors also inhibits afferent input passing from the bladder to the brain. Blockade of 5-HT1A receptors in raphe neurons would increase raphe neuron firing and enhance serotonergic control of spinal reflex mechanisms. This effect would promote urine storage by enhancing sphincter activity and depressing bladder activity. Indeed, 5-HT1A receptor activation is associated with increased rhabdosphincter activity in spinal intact but not spinalised animals. D. ADRENERGIC Descending catecholaminergic neurones are primarily located in the upper medulla or pons. In clinical use, non-selective 1- adrenergic antagonists influence urine

flow and storage phase lower urinary tract symptoms; the two effects probably occur by different mechanisms, and central or peripheral locations may be responsible. Reflex bladder activity is modulated by at least two spinal 1-adrenergic mechanisms. Firstly, there is inhibitory control of reflex bladder contractions, probably by modulation of afferent processing. Secondly, there is excitatory modulation of the amplitude of bladder contractions due to regulation of the descending glutamatergic limb of the spinobulbospinal bladder reflex pathway. Blood pressure, vascular resistance and tissue blood flow are also regulated by -adrenergic receptors. Aging is thought to impact pelvic blood flow and thus, bladder function. Pharmacological blockade of the vascular 1B-adrenoceptor may increase pelvic blood flow and contribute to an improvement in bladder dysfunctions associated with aging and/or hypertension. E. SUBSTANCE P Substance P- containing terminals are closely apposed to both sympathetic and parasympathetic preganglionic neurons projecting to the major pelvic ganglion. Functionally, substance P affects micturition reflex activity; intrathecal administration of Substance P at spinal levels L5–S1 induces bladder contraction. Substance P also increases the firing rate of sympathetic preganglionic neurons. Studies in the rat show that substance P levels decline with ageing in both the dorsal and ventral regions of the lumbosacral cord. Substance P-immunoreactive innervation of the dorsolateral nucleus (supplying the EUS) is not obviously altered with ageing.

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F. PURINERGIC ATP is released together with noradrenaline and neuropeptide Y from sympathetic nerves. It is also released as a cotransmitter with acetylcholine from parasympathetic nerves supplying the bladder. Cotransmission likely offers subtle, local variations in neurotransmission and neuromodulation mechanisms.

4. PELVIC ORGAN INTERACTIONS AT THE EFFERENT NEURAL LEVEL BLADDER AND OUTLET The fundamental role of spinal and supraspinal mechanisms in maintaining normal lower urinary tract synergy, between the bladder and sphincter. In this context, the role of spinal interneurons must be considered. Involuntary bladder emptying during urine storage is considered to involve somatic nerve activity originating from cells in the lateral ventral horn, in a region called Onuf’s nucleus. Normally, cholinergic sphincter moto-neurons project to the urethral striated muscle/ rhabdosphincter via the pudendal nerve, resulting in its contraction. This contraction can be activated by bladder afferent activity conveyed through pelvic nerves, and is considered to be organized by interneuronal circuitry in the spinal cord. It is thought to come into play in response to sudden increases in bladder pressure – for example, during a cough, sneeze, laugh. With aging, there is a loss of innervations at the terminal muscle level, which is displayed as a loss of striated muscle fibres in the sphincter and thus, a loss of urethral closing pressure.

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PontIne-mIdBraIn control oF Bladder FunctIon

Synergic lower urinary tract function may also be a feature of the peripheral innervation, independent of CNS co-ordination.

5. EFFERENT INHIBITION The sympathetic pathway contributes to inhibition of parasympathetic efferent input to the detrusor smooth muscle. In isolated whole bladders, there is a high level of spontaneous contractile activity, suggesting active neural inhibition ofthe bladder during urine storage. So efferent inhibition of the bladder facilitates urine storage. In addition to efferent input, local reflexes may contribute to the inhibition of detrusor activity, probably driven by interstitial cells, so that peripheral autonomous activity increases as a result of bladder distension. This has been proposed to signify the presence of a regional regulatory influence and a peripheral “pacemaker” and various mechanisms for the propagation of activity within the bladder wall.

1. AFFERENT PATHWAYS LINKING THE BLADDER AND URETHRA TO THE PONS AND MIDBRAIN Sensations of bladder fullness are conveyed to the spinal cord by the pelvic and hypogastric nerves, while input from the bladder neck and urethra is carried in the pudendal and hypogastric nerves. Afferents arising from the bladder and urethra are mechanoreceptive (A fibres) and nociceptive (C fibres). The most important afferents for initiating micturition are those passing in the pelvic nerves, whose fibers terminate in discrete regions of the lateral aspect of the dorsal horn of the lumbar and sacral spinal cord (see for reviews). Many of these dorsal horn neurons make spinal connections that mediate segmentally organized reflex responses. However, a proportion of the spinal interneurons send ascending projections to specific nuclei in the pons and midbrain that can regulate bladder activity through a descending loop. The PAG may also play an important role in relaying bladder information to limbic and cortical brain regions as well as in integrating descending information from these regions, which provide contextual information concerning the appropriateness for micturition.

2. BARRINGTON’S NUCLEUS: THE PONTINE MICTURITION CENTER (PMC) In 1925 Barrington was the first to describe a pontine control center for micturition in the cat through lesion studies. This region was better localized to a nucleus in the dorsal pons (now termed Barrington’s nucleus) using more discrete lesions that abolished micturition and caused urinary retention in cats and rats. In humans, comparable regions in the pons can be imaged and

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found activated when the bladder is full. Physiological studies have confirmed the role of Barrington’s nucleus in micturition. Both electrical and chemical activation of Barrington’s nucleus neurons in rats and cats initiates bladder contractions and relaxes the urethral sphincter. It’ssuggested the existence of two descending pathways from Barrington’s nucleus for initiating micturition: one direct to the parasympathetic preganglionic neurones and the other via the medial reticular formation. Micturition also requires an inhibition of the urethral sphincter to be coordinated with detrusor contraction. This is controlled by somatic motoneurons of Onuf’s nucleus. Barrington’s nucleus neurons do not project to Onuf’s nucleus. The L-region, is provide pontine control of sphincter function through its projections to Onuf’s nucleus. For coordination between the detrusor and sphincter, there should be some form of reciprocal communication between these regions. However, a lack of connections between Barrington’s nucleus and the L-region are argue against sphincter regulation by Barrington’s nucleus through this route. Additionally, Barrington’s nucleus projections onto inhibitory interneurones located in the intermediolateral cell column at the sacral segmental level have been described that may provide an inhibitory influence over Onuf’s nucleus and both glycine and GABA are thought to play a role here. Together, the anatomical and physiological findings described above point to Barrington’s nucleus as being the command center for initiating and orchestrating the act of bladder emptying. More recent evidence suggests a more complex role for Barrington’s nucleus neurons in coordinating a central response to bladder filling with the visceral response of bladder

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Figure 9 : Schematic depicting information flow between the bladder, spinal cord and brain. In the rat spinal cord interneurons relay information about the bladder to the pontine micturition center (PMC), Barrington’s nucleus and the PAg. The PMC also gets input from the PAg, lateral hypothalamus and medial preoptic nucleus. PMC neurons project to the locus coeruleus (LC) and preganglionic parasympathetic neurons of the lumbosacral spinal cord that innervate the detrusor. There are also projections to premotor neurons in the dorsal gray commissure that innervate and inhibit Onuf’s nucleus which projects to the urethral sphincter. A pontine continence center (PCC) has been proposed in the cat and is localized to the L-region of the pons. Neurons here project to Onuf’s nucleus.

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emptying through Barrington’s nucleus projections to the norepinephrine nucleus, locus coeruleus (LC).

3. BARRINGTON’S NUCLEUS, THE LOCUS COERULEUS AND CENTRAL RESPONSES TO BLADDER INFORMATION. Micturition requires a central component so that bladder emptying is coordinated with a set of behaviors. If animals are asleep they must be aroused. If engaged in some ongoing behavior that is not compatible with urination, this must be interrupted and behavior should be redirected to be compatible with the visceral response. Recent evidence suggests that neurons of Barrington’s nucleus neurons serve the role of coordinating visceral and behavioral limbs of micturition through collateral projections to the preganglionic parasympathetic spinal neurons and the major norepinephrine nucleus, locus coeruleus (LC). A. NORMAL FUNCTION The LC, a cluster of neurons lying along the wall of the fourth ventricle just dorsolateral to Barrington’s nucleus, is the major source of norepinephrine in the brain. A characteristic anatomical feature of LC neurons is their massive projection system that innervates the entire neuraxis, serving as the sole source of norepinephrine in cortex and hippocampus. The LC-norepinephrine system initiates arousal in response to diverse stimuli. A representative example of this is the increase in LC neuronal activity elicited by elevations in bladder intravesicular pressure. Recordings of LC neurons in non-human primates performing operant tasks suggest a role for the LC norepinephrine system in facilitating decisions related

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Figure 10: Brain areas involved in the regulation of urine storage. A meta-analysis of positronemission tomography and functional MRI studies that investigated which brain areas are involved in the regulation of micturition reveals that the thalamus, the insula, the prefrontal cortex, the anterior cingulate, the periaqueductal grey (PAg), the pons, the medulla and the supplementary motor area (SMA) are activated during the urinary storage.

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to task-directed behavior, i. e., whether to maintain behavior in an ongoing task or to disengage and seek alternative strategies in a dynamic environment. As bladder pressure rises towards micturition threshold the tonic excitation of LC neurons is speculated to increase arousal and facilitate disengagement from ongoing behavior and a shift towards the initiation of eliminationrelated behaviors. Thus, Barrington’s nucleus neurons are central to coordinating the descending limb of the micturition reflex with a central limb that facilitates a switch from on-going non-voiding related behavior to voiding behaviors. Importantly, the LC projects to cortical regions that are proposed to exert conscious control over micturition.

4. SUPRASPINAL INPUTS TO BARRINGTON’S NUCLEUS Afferents to Barrington’s nucleus would be positioned to initiate or regulate bladder activity and could be targets for modulating urinary function. Particularly, the lateral and ventrolateral PAG densely innervate Barrington’s nucleus. As described above, the PAG receives bladder afferent information from spinal interneurons and this may be an indirect route through which the bladder communicates with Barrington’s nucleus that is in addition to a more direct route. The PAG afferents can trigger micturition as evidenced by the finding that chemical stimulation of ventrolateral PAG can cause voiding.PAG stimulation can also elicit sphincter activation without bladder contraction suggesting an involvement in both voiding and storage functions. The lateral hypothalamus, particularly, the perifornical region is a major source of afferents to Barrington’s nucleus. Like the PAG, the lateral hypothalamus is involved in defensive responses and modulation of Barrington’s nucleus by these two afferents likely plays a role in

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Figure 11: Schematic indicating how Barrington’s nucleus projections to the LC and spinal cord coordinate visceral and central limbs of micturition and also can relay pathology between the brain and bladder. A. Barrington’s nucleus neurons in the rat get afferent information from the bladder (blue arrow). Increasing intravesicular pressure activates these neurons. Through projections to the preganglionic parasympathetic neurons in the lumbosacral spinal cord, Barrington’s nucleus initiates bladder contraction. The same neurons are positioned to activate the LC-norepinephrine system which projects to the cortex and can initiate arousal and facilitate a shift toward voiding behaviors. B. The same circuit provides a means by which bladder pathology can have neurobehavioral consequences. Particularly by activating LC neurons, this can produce hyperarousal, anxiety and sleep disturbances. Psychological stressors can impact on this circuit, perhaps through the PAg to affect bladder function. Barrington’s nucleus (BN), locus coeruleus (LC).

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urination as a component of the defense response. A third major afferent arises from the medial preoptic area and these have been demonstrated to directly contact spinal-projecting Barrington’s nucleus neurons Many of these neurons express estrogen receptor alpha, suggesting that this is an estrogen sensitive pathway. The medial preoptic region has been suggested to provide an inhibitory influence during sleep and/or sexual activity to suppress micturition.

5. THE PONTINE CONTINENCE CENTRE (PCC) The bladder’s function of urine storage requires detrusor relaxation accompanied by urethral sphincter contraction. Studies in the cat identified a pontine continence center also termed the L-region that is distinct from and lying ventrolateral to the micturition center. Neurons in this region project selectively to Onuf’s nucleus in the sacral cord, which contains the urethral sphincter motoneurones, and do not project to spinal regions influencing detrusor. The majority of neurons in this continence center, fire during the relaxation phase of bladder contractions and the onset of their firing can be prior to the initiation of bladder relaxation. Indeed, this would make sense if their prime function were to close the urethral sphincter. Another potential role for these neurons is in off-switching micturition. Supporting this, stimulation of this region stops micturition, excites the pelvic floor musculature and contracts the urethral sphincter. Conversely, bilateral lesions of the PCC cause incontinence, excessive detrusor activity, an inability to store urine and relaxation of the urethral sphincter. However, there is no anatomical evidence for connections between Barrington’s nucleus and the L-region and it has been suggested that Barrington’s nucleus and the “continence center” function independently.

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6. NEUROTRANSMITTERS & MODULATORS WITHIN BRAINSTEM NETWORKS CONTROLLING BLADDER Knowledge of the neurochemical signals within the central circuits controlling micturition is important for understanding how these circuits function and how they can be manipulated for the treatment of bladder dysfunctions. Glutamate is thought to be the primary neurotransmitter within Barrington’s nucleus neurons that innervate the preganglionic parasympathetic neurons responsible for detrusor contraction. Both NMDA and non-NMDA receptors have been implicated in this response. Barrington’s nucleus neurons express CRF mRNA and protein and a dense CRF terminal field is present in the region of preganglionic parasympathetic neurons of the rat lumbosacral spinal cord. Recent findings suggest that CRF has an inhibitory influence in this same pathway Thus, discrete chemical activation of Barrington’s nucleus neurons elicits bladder contraction that is enhanced by blocking the CRF influence in the lumbosacral spinal cord with a CRF antagonist. Interestingly, CRF excites LC neurons and this is temporally correlated with cortical EEG correlates of arousal. It is tempting to speculate that CRF release in the divergent spinal and LC projections of Barrington’s nucleus neurons serves to increase arousal while inhibiting bladder contraction. Serotonin appears to affect nervous control of bladder function at multiple levels including sensory processing of bladder wall afferents within the dorsal horn of the spinal cord and at the level of the spinal motoneurones. In all cases this appeared to be an inhibitory influence on detrusor muscle activity but excitatory on urethral sphincter. It was proposed that 5-HT1A receptors were located on the terminals of sensory afferent fibers to depress neurotransmitter release. Similarly, a

predominance of an inhibitory effect evoked from the midline raphe system extending from the pons to medulla on micturition in cats has been described. However, the site of this inhibitory action (i.e. supra-brainstem, pons or spinal cord) is unknown. A study of raphe neuronal recordings demonstrated that their firing was related to bladder pressure with 66% related to storage. These data support a role of the raphe system in suppressing micturition and facilitating external urethral sphincter activity in cats, which is consistent with earlier studies identifying a central inhibitory role for 5-HT1A receptors. Although our knowledge in how the brain regulates the detrusor has advanced, less is known of the central regulation of the urethral sphincter. Particularly, the coordination between detrusor and sphincter activity at the level of the spinal cord or its regulation by supraspinal circuits is not well understood. This is critical for understanding the pathophysiology and treatment of urinary incontinence. Very little has been done in the realm of sex differences in regulation of bladder function. Clearly, there are sex differences in certain types of bladder disorders. Notably, Barrington’s nucleus is regulated by afferents from a sexually dimorphic nucleus, the medial preoptic nucleus that are also sensitive to estrogen. Basic research studies are often performed in either male or female animals with little consideration as to the role of sex and there are no studies of systematic comparisons between male and female subjects. By contrast, brain imaging in humans have been addressing this issue. Nonetheless, the human studies are limited by the degree of anatomical resolution and do not allow for precise manipulation of specific circuit components that can be done in animals. Whereas neuroscience research has come a long way in understanding how the brain processes visual, olfactory and auditory signals, the analogous processing of visceral

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ForeBraIn control oF Bladder FunctIon

information by the brain is has received comparatively little attention. This may stem in part because of a tendency for specialize rather than integration. Electrophysiological recording technology, optogenetic methods of neuronal stimulation, computational analysis and network modeling has greatly advanced in the last decade. This technology is currently available for understanding how the brain processes information from the bladder in normal and diseased states, how neural circuits in turn respond to control bladder function and how this is organized with respect to processing other information and regulation of other behaviors. The next few years should make use of this state-of-the-art technology to advance into this frontier.

The importance of the frontal cortex and pons in the control of voiding was clearly recognized prior to functional brain imaging, which, however, has tended to obscure the older clinical evidence. Most functional imaging studies have been carried out using either positron emission tomography (PET) or functional magnetic resonance imaging (FMRI). A few used single-photon emission computed tomography (SPECT) or near infrared spectroscopy (NIRS).

1. ROLE AND IMPORTANCE OF CEREBRAL CONTROL OF VOIDING In order to understand the cerebral control of voiding it is helpful first to examine what would happen if there were no such control. Provided brainstem and midbrain are intact, micturition is organized in 2 phases, storage and voiding, governed by reflexes involving the brainstem and spinal cord. During storage (99.8% of the time in health) the urethral sphincter mechanism contracts tonically, preventing urine leakage, while the detrusor remains relaxed, so as to avoid developing a pressure that would expel urine. Urethral contraction is maintained by sacral reflexes known collectively as the ‘guarding reflex’; detrusor relaxation is ensured by absence of excitatory parasympathetic input as well as active sympathetic inhibition provided by spinal reflexes. During human voiding the urethral sphincter relaxes, facilitating urine flow, and the detrusor contracts so as to expel urine. This coordinated relaxation and contraction of urethra and bladder respectively is driven by a long-loop spinobulbospinal reflex. As the bladder fills, increasingly strong bladder afferents travel via synapses in the sacral cord to the brainstem and midbrain, where they synapse

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in the central periaqueductal gray (PAG) and possibly Barrington’s nucleus or pontine micturition center (PMC) (green lines in Figure: 12 ). There are differing views about how the brainstem circuitry is organized. One is that, if the afferent signals exceed a trigger level in the PAG, efferent fibres in the PAG are excited and they in turn excite the pontine micturition center (PMC). Another is that there is continuous communication between PAG and PMC and the trigger level is set in the PMC (DeGroat 2012, in press), which may also receive direct afferent input. Regardless, if the trigger level is exceeded, efferent signals from the PMC descend to the sacral cord (blue lines in Figure: 12 ), where they excite an indirect inhibitory pathway via the nucleus of Onuf that leads to sphincter relaxation and an excitatory pathway to the bladder that leads to detrusor contraction; thus voiding occurs. Therefore the spinobulbospinal voiding-reflex pathway functions as a switch, either “off” (storage) or “on” (voiding).

In the absence of higher control, this switching behaviour would lead to involuntary bladder emptying (i.e. incontinence) whenever the bladder volume reached a critical level sufficient to trigger the brainstem switch. However underlying this apparently simple mode of behaviour are complex networks of cerebral neurons. During storage of urine the ascending afferent signals received by the PAG are relayed to higher regions of the brain, generating unconscious changes as well as conscious bladder sensations which are factored into the assessment of whether voiding is appropriate. Crucially, motor output from these higher centres is able to suppress or promote voiding by manipulating the brainstem switch. This arrangement forms the substrate for the bladder behaviour characteristic of our species. Embarrassment

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caused by inappropriate voiding and feelings of shame about incontinence are deeply embedded in human behaviour. Voiding at a socially acceptable time and place is achieved by maintaining strict voluntary control of the voiding reflex. Knowledge of the extent to which one’s bladder content is ‘safe’ is central in this process. Thus, voluntary control of the bladder and urethra has 2 important aspects: registration of bladder filling sensations and manipulation of the voiding reflex switch. The PAG seems to have a pivotal role in both. On the one hand it receives bladder afferents and transmits them to higher brain centres and into the realm of conscious sensation. On the other hand it receives projections from many higher centres and provides critical input to the PMC. This input, together with some direct input from the hypothalamus (Figure: 12 ), normally suppresses excitation of the PMC during bladder filling, so preventing voiding or incontinence. Thus the net effect of higher control is tonic suppression of the voiding reflex. If voiding is necessary (bladder volume is adequate), and is judged (perhaps unconsciously) to be safe, and is consciously assessed to be socially acceptable, suppression can be voluntarily interrupted to allow the brainstem switch to be turned on.

Figure : 12

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Figure 13: Brainstem areas activated during storage or voiding. From Griffiths and Tadic, 2008.

Table 2: Clinical evidence for the involvement of specific brain regions in bladder control. [Data from: INCONTINENCE, Editors: PAUL ABRAMS, LINDA CARDOZO, SAAD KHOURY & ALAN WEIN, International Continence Society (ICS), 5th edition, 2013 ]

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2. WORKING MODEL OF BRAIN / BLADDER CONTROL

It has been seen that many forebrain regions respond with altered neuronal activity to bladder filling or voiding, and thus presumably form part of the brain-bladder control network . Some are part of a general â&#x20AC;&#x2DC;homeostatic afferent brain networkâ&#x20AC;&#x2122; that processes sensation and generates appropriate output for many different organ systems. This is not surprising because the ultimate purpose of bladder control is to maintain homeostasis by ensuring that the bladder is emptied regularly, yet only when safe and appropriate. Sensations such as desire to void and urgency are homeostatic emotions, that both motivate behavior and provide corresponding motor output. The brain regions involved in bladder control are believed to be organized in neural circuits that perform different tasks related to homeostasis, answering questions regarding the adequacy of bladder filling, and the safety and social appropriateness of voiding, as well as the reflex or mechanical aspects dealt with by the brainstem switch. We should therefore expect forebrain control of the switch to involve both limbic circuits (concerned with basic emotion and safety) and cortical circuits (concerned with social propriety and conscious decision-making). In the working model shown in Figure 15, the PAG and PMC form the brainstem switch. The PMC is the final efferent brain nucleus involved in bladder control. The PAG receives numerous projections from forebrain regions, including the medial and orbital prefrontal cortex. Possible pathways that connect these regions to form the neural circuits that govern bladder and urethral behaviour are shown schematically in Figure 14 and sketched provisionally in the working model (Figure 15), which incorporates as far as possible the lesion and functional imaging observations described above.

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Figure 14: An early conceptual framework that suggests a scheme for the connections between various forebrain and brainstem structures that are involved in the control of the bladder and the sphincter in humans. Arrows show probable directions of connectivity but do not preclude connections in the opposite direction. [Reproduced, with permission Fowler et al., 2008 and based on the work of Kavia et al.2005.. Data from: INCONTINENCE, Editors: PAUL ABRAMS, LINDA CARDOZO, SAAD KHOURY & ALAN WEIN, International Continence Society (ICS), 5th edition, 2013 ]

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Figure 15 : Working model of forebrain control of micturition, showing the brainstem switch and neural circuits that mediate 2 possible continence mechanisms. The normal mechanism (red) operates when there is a normal sensation of bladder filling. It depends on tonic inhibition of the brainstem switch via a long return pathway from the medial prefrontral cortex to the brainstem switch (probably via the anterior thalamic radiation, but shown for simplicity as a direct connection to the PAg). The inhibition is switched off for voiding. A backup mechanism (yellow) corresponds to the abnormal sensation or urgency. It may operate via brainstem nuclei such as the L-region (pontine storage center) or by modulating the sympathetic input to bladder and urethra. The dashed blue arrows show a possible circuit concerned with monitoring safety and/or maintaining continence without conscious sensation. PMC = pontine micturition center; PAg = periaqueductal grey; L-reg = L-region; THAL = thalamus; INS = insula; lat PFC = lateral prefrontal cortex; med PFC = medial prefrontal cortex; dACC = dorsal anterior cingulate cortex; SMA = supplementary motor area; HYP = hypothalamus; HIP = (para)hippocampal complex (may include amygdala, inferior parts of temporal lobe and parts of posterior cortex). [Data from: INCONTINENCE, Editors: PAUL ABRAMS, LINDA CARDOZO, SAAD KHOURY & ALAN WEIN, International Continence Society (ICS), 5th edition, 2013]

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CONCLUSION: CORTICAL CONTROL OF BLADDER FUNCTION

A. THE NORMAL CONTINENCE MECHANISM During urine storage, as the bladder fills it generates afferent signals (purple ascending pathway in Figure 15) that are transmitted to the brainstem switch but do not trigger it. They are relayed from the PAG via the thalamus to the insula (red circuit) and, if activation is strong enough, generate a desire to void. Propagation of this insular activity to the lateral and medial prefrontal cortex enables both a conscious decision about voiding and an assessment of social propriety and possible embarrassment. If no voiding is planned, a return pathway from the medial frontal cortex to the brainstem tonically suppresses the voiding reflex. The pathway may run directly or via the thalamus in the anterior thalamic radiation (not shown in Figure 15). The resulting red circuit is postulated to be the normal continence mechanism. When there is a normal sensation of bladder filling it exerts negative feedback on the brainstem switch, preventing incontinence. Interruption of the negative feedback, for example by white-matter damage in the mPFC-PAG pathway, leads to incontinence. During normal daily life however there is usually no conscious awareness of the bladder at all. The mechanism that monitors bladder behaviour in this situation requires further research. One possibility is a circuit involving the parahippocampal complex and hypothalamus.

and somatic (via SMA) pathways that may involve the pontine L-region. Because urgency is evoked in extreme circumstances this probably should be regarded as a back-up continence mechanism. What ascending signal activates the dACC and the SMA and generates urgency? The conventional view is that the bladder or the urethra generates abnormal – or merely greater – afferents if leakage threatens, but an alternative is that the PAG should use its knowledge of the brainstem switch to generate a signal indicating how close the switch is to being triggered. This signal, relayed via the thalamus to the dACC, would presumably evoke urgency if triggering were imminent.

C. VOIDING

The fact that voiding and continence are under forebrain control is now well established by multiple lines of evidence. Some of the brain regions involved are known with reasonable certainty, although further investigations, particularly of normal behaviour, voiding, and different age groups of both genders, will be helpful. The specific functions of these regions and the pathways connecting them are less well known but they can be speculatively organized in a working model comprising a few neural circuits that perform various tasks related to homeostasis and maintenance of continence. There is evidence that structural damage to certain critical connecting pathways causes or contributes to urgency incontinence. The working model is highly simplified, but will help understanding of functional disorders such as overactive bladder and guide new research aimed at ameliorating the scourge of urgency incontinence

Referring to Figure 15, if voiding is voluntarily decided upon in the prefrontal cortex a series of stereotypical actions follows (finding a toilet, adjusting clothing, adopting the correct posture) and ultimately the red return pathway from mPFC to brainstem PAG is silenced, removing inhibition of the voiding reflex and allowing activation of the PMC – provided that other PAG inputs, notably from the hypothalamus (reflecting safety), permit it.

B. A BACK-UP CONTINENCE MECHANISM Activation of dACC and SMA, associated with urgency, suggests the possibility of another neural circuit – in yellow in Figure 15 – in which an ascending signal from the PAG travels via the thalamus to the dACC and SMA, generates urgency and sends a descending efferent signal that suppresses bladder contraction and tightens the urethral sphincter, using sympathetic (via dACC

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Mechanism of Action of Neuromodulation to Treat Urinary Incontinence Symptoms

Mechanism of Action of Neuromodulation to Treat Urinary Incontinence Symptoms INTRODUCTION The exact mechanism of neuromodulation remains still unknown. Electrical current, applied through electrodes, activates neural structures and influences neural plasticity and afferent and efferent activity of the lower urinary tract. Neurostimulation can lead to neuromodulation. The first leads to immediate effects, whereas the latter results in more long-lasting control of lower urinary tract dysfunction through electrical modulation of a nerve. Different hypotheses have been postulated about the working mechanism of neurostimulation. One theory states that by artificially stimulating afferent sacral nerves, inhibitory stimuli are induced in efferent sacral nerves to the bladder. This could restitute the balance and coordination of spinal and/or spinobulbous reflex arcs. Another hypothesis argues that dominant activity of afferent C-fibres in neurogenic bladder dysfunction is suppressed by the neuromodulation technique. One more theory states that electrical stimulation may reset neural thresholds necessary to create action potentials. Furthermore, S3 stimulation changes bladder sensation to electrical stimulation applied by electrodes. Finally, effects on spinal cord, brain stem (periaqueductal grey) and cortical areas are possible. Beside the effect on neural structures, neurostimulation also causes chemical changes. There is an increase of beta-adrenergic neurotransmitters (stimulating bladder relaxation), a decrease of cholinergic activity and changes in other neurotransmitters. Furthermore, neurostimulation causes raised endorphins and encephalins in the

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cerebrospinal fluid, which in turn can suppress detrusor overactivity. Bladder overactivity and dysfunction can be reduced by SNM in different ways. The most important mechanism is the inhibition of sacral interneuronal transmission on the ascending part of the micturition reflex, resulting in less transfer of bladder signals to the pontine micturition center. The descending efferent pathways from the brain to the bladder are not suppressed. As a consequence the involuntary detrusor contractions are suppressed, without inhibiting voluntary voiding. Another mechanism to inhibit bladder overactivity consists of sacral nerve stimulation (SNS) directly suppressing bladder preganglionic neurons of the efferent part of the micturition reflex. De Groat et al. have indeed documented the existence of inhibitory pathways from somatic and visceral afferents to the sacral preganglionic efferent neurons. In this way, detrusor contractions can be inhibited by stimulation of the sacral posterior afferent roots, afferent anorectal branches of the pelvic nerves, afferent sensory fibres in the pudendal nerve and muscle afferents from the lower limbs.

STIMULATION APPROACH In most of the studies and experiments stimulation approaches were implanted, percutaneous, minilally invasive and intra-vaginal. But in few studies researcherâ&#x20AC;&#x2122;s

stimulation approach was noninvasive way, and in long term studies they found significant improvement in various groups of women suffering from UUI, OAB, DO, SUI and MUI. Though it has been seen that sacral nerve modulation (SNM) is more effective to treat OAB and DO, but few researchers also showed significant improvement of SUI and MUI patients by long term stimulation of pudendal nerve with using intra-vaginal electrode along with the non-invasive SNM therapy. In the result its effectively reduces the detrusor contractions and helps to strengthen the pelvic floor muscle which caues external urethral sphincter to keep contracted during bladder storage period.

INVASIVE OR IMPLANTED METHOD For implanted sacral nerve stimulation, Stimulation is normally activated on the day following surgery using the most effective electrode position of the four electrodes. For initial activation each of the four separated electrodes is tested and the electrode providing the best response is set as the cathode (â&#x20AC;&#x201C;) and the case as the anode (+). Pulse width is generally set at 210 msec, the pulse rate at 10 pulses per second, at a amplitude of 0.1 V. Pulse amplitude should be increased slowly, in increments of 0.1 V until the subject senses stimulation and/or pelvic floor muscle responses are obtained. While determining threshold voltages for the various electrodes, impedance values for the electrodes should

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be determined. The electrode with the lowest threshold is often the most effective for long term stimulation. Electrical threshold can vary not only in regard to the patient’s sensory and motor responses but also in regard to the comfort and therapeutic responses. Evaluation of stimulus parameters performed while communicating and receiving appropriate feedback from the patient. Feedback from the patient includes electrical sensation, pain, and muscle contractions. A period of 3–6 months may be necessary to find the final parameters of stimulation; that is, the best clinical response for voiding disorder, least bothersome as related to the level of the stimulation, the placement of the electrode, and preservation of long-term efficacy of the battery.

NEUROSTIMULATION RESPONSES The response to stimulation and the perception of stimulation varies from patient to patient. To obtain the optimal therapeutic response, both sensory and motor responses to stimulation should be evaluated. Beneficial responses to stimulation are normally obtained from stimulation in the S3 sacral foramen.

SENSORY—patients often describe a pulling sensation in the rectum extending forward to the scrotum or labia as well as tingling sensations that may extend to the vagina and clitoris.

NON-INVASIVE STIMULATION METHOD Non-invasive electrical stimulation techniques, defined as “a procedure which does not involve introduction of an instrument into the body”. This method called transcutaneous electrical nerve stimulation (TENS) as a technique where the electrical stimuli are passed through the intact skin. Various types of neurostimulation have been well documented in the urological treatment of patients with neurological damage, e.g. the sacral anterior root stimulator, S3 nerve route stimulation, pudendal stimulation and anal/vaginal stimulation.

The typical S3 stimulation responses includes:

By far the most important concept associated with neurostimulation of various kinds is that it can alter nervous system activity, which can continue even when electrical stimulation is not occurring, and can therefore cause neuroplasticity.

MOTOR— a ‘‘bellows’’ type contraction of the perineum. Look for a deepening and flattening of the buttock groove due to contraction of the levator ani muscles. Since S3 nerves contribute to the sciatic nerve, stimulation often causes flexing of the great toe and at times other toes as well, particularly at higher stimulation intensities.

Most transcutaneous electrical nerve stimulation (TENS) treatment is classified as neuromodulation. TENS applies a small electrical current to the skin that can usually be felt. At normal strength it will only stimulate sensory nerves. Most makes of TENS machine allow control of the shape, frequency and duration of impulses, as well as impulse

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strength. The mode of action of this treatment was thought to be a stimulation of myelinated afferent fibres to activate segmental inhibitory circuits to reduce pain, this having a secondary benefit on urinary symptoms. TENS has also been used successfully in the treatment of stress urinary incontinence. Few studies and experiments involving the use of peri-anally applied TENS for idiopathic detrusor instability (IDI) showed, on conventional urodynamics, an increase in cystometric capacity and a decrease in detrusor instability in selected women patients group. Other studies involving TENS applied to the S3 dermatome also showed an improvement in IDI (idiopathic detrusor instability) after long term treatment, assessing variables including the reduction in pad usage, frequency of micturition, incontinence episodes and urgency. For TENS stimulation on S3 dermatome the placing of electrode pads on the sacral dermatomes 2.5 cm either side of and 2.5 cm above the natal cleft was demonstrated, and the patient instructed to use TENS for 90 min twice a day. The current strength applied was set to that which the patient could tolerate, at a square-wave of 20 Hz and 200-ms duration. To achieve sacral stimulation Yokozuka et al. instructed patients to put surface electrodes on the posterior sacral foramen and to increase stimulation intensity until an anal contraction could be felt. They speculated that, in cases where there was no improvement, electrodes were not placed in the correct position or the intensity was not high enough due to associated discomfort. There is support by Takahashi and Tanaka where slight changes in electrode

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location produced considerable apparent changes in urethral pressure response. The sacral stimulation studies reported to date usually have electrodes positioned at the sacral foramina or on the buttocks overlying the S2 and S3 dermatomes. The precise positioning of electrodes on sacral sites varies between studies, presumably because the location of the sacral dermatomes is uncertain. The intensity of the stimulation current was usually set to a maximum dictated by pain threshold. In other studies, patients were instructed to set an intensity that produced a tickling sensation. Nerve trunks (roots) in these areas are located deep within foramina and it is unlikely that these were being directly stimulated at the stimulus intensity level being used. However, cutaneous nerves within the dermatomes are easy to stimulate and hence superficial sensory fibre stimulation, which may lead to both direct and indirect modulation of spinal cord reflexes mechanisms, may explain the reported effects. Furthermore, the intensity which produces anal sphincter contraction involves stimulation of motor nerves thus activating different mechanisms and indeed may cause significant discomfort to the patients. The clarification of the exact site of stimulation and of the intensity required needs to be addressed in future work, which can be calculate after long term clinical trials on larger group of patients.

STIMULATION PARAMETERS D. SKEIL and A.C. THORPE, (Departments of Neurorehabilitation and Urology, Sunderland Royal Hospital, Sunderland, UK) on their published research paper â&#x20AC;&#x2DC;Transcutaneous electrical nerve stimulation in the treatment of neurological patients with urinary symptomsâ&#x20AC;&#x2122;, stated that all patients agreeing to enter the study were

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asked to stop any anticholinergic therapy 2 weeks before the first clinic visit. And they were advised to use the TENS machine for 90 min twice a day for the 6 weeks. The settings used during TENS for urinary symptoms are similar to those for other forms of neurostimulation, i.e. square wave, ideally biphasic to reduce skin damage (although most TENS machines are unipolar to simplify the machines), short impulses of <100 ms, 5-6 Hz for pudendal nerve inhibition and 20-50 Hz for striated periurethral musculature. The TENS machines in the present study were set to 20 Hz (to cover irritative and obstructive symptoms) and 200 ms, and used for 90 min twice a day. All electrodes used throughout the study were reusable silicone gel electrodes (50*35 mm), which were connected to the TENS machine with 3.5 mm jack plugs and 2 mm banana plugs. A small amount of gel was placed on the electrodes to make good electrical contact (all patients were provided with TENS gel, which has a high viscosity, is salt-free and watersoluble). The conductive gel produces a low impedance electrode-skin interface, which provides a more consistent impedance. The electropads were placed 2.5 cm above and 2.5cm lateral to the top of the natal cleft, with one pad on each side so that polarity did not matter. The pads were secured with tape. The patients were instructed to use the TENS at a rate they could feel and with which they were comfortable. Several results from the present study support an overall improvement in urinary symptoms from TENS, including the urodynamic variables showing a trend toward improvement. All these changes would be expected to reduce the frequency of micturition, improve bladder function and reduce potential renal damage. The objective results from the present study for both

urodynamic and QOL score improvements after TENS were disappointing when compared with previous studies. The present TENS machines were set at a frequency of 20 Hz, with a 200 ms duration. Studies which used a lower frequency of 10 Hz with a similar pulse width reported significant reductions in symptom scores and significant improvements in urodynamic values in non-neuropathic patients. The mechanism by which TENS modifies detrusor function beneficially remains unclear, although TENS increases the level of cerebrospinal endorphins at various frequencies, which in turn may decrease detrusor activity, and hence may exert a central effect. TENS may also exert a more peripheral effect by directly stimulating sacral nerve roots, causing an activation of the external urethral sphincter, which in turn will inhibit detrusor activity. In another study by Yamanishi T, Yasuda K., reported Neuromodulation as effective for the treatment of stress and urgency urinary incontinence. The cure and improvement rates of pelvic floor neuromodulation in urinary incontinence are 30-50% and 60-90%, respectively. In clinical practice, vaginal, anal and surface electrodes are used for external, short-term stimulation, and sacral nerve stimulation for internal, chronic (long-term) stimulation. The effectiveness of neuromodulation has been verified in a randomized, placebo-controlled study. In their study electrodes for electrical stimulation are divided into two types: external (non-implantable) and internal (implantable), and there are two methods of stimulation: chronic (long-term, continuous) and shortterm. Frequencies of 20-50 Hz, with a pulse duration of 1-5 ms, have been reported to be effective for urethral closure. In conclusion, pelvic floor exercise with adjunctive neuromodulation is the mainstay of conservative management for the treatment of stress incontinence.

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For urgency and mixed stress plus urgency incontinence, neuromodulation may therefore be the treatment of choice as an alternative to drug therapy.

EVIDENTIAL RESEARCH TO SUPPORT THE HYPOTHESIS OF MECHANISM OF ACTION OF NEUROMODULATION Lucas Schreiner et al., on their research paper â&#x20AC;&#x2DC;Electrical Stimulation for Urinary Incontinence in Women: A Systematic Review] (2013), reported that Electrical stimulation is commonly recommended to treat urinary incontinence in women. It includes several techniques that can be used to improve stress, urge, and mixed symptoms. Tibial-nerve and intravaginal stimulation have shown effectiveness in treating urge urinary incontinence. Sacralnerve stimulation provided benefits in refractory cases. Presently available data provide no support for the use of intravaginal electrical stimulation to treat stress urinary incontinence in women. Current guidelines of ICS recommend conservative management, defined as interventions that do not involve treatment with drugs or surgery targeted to the type of incontinence, as a first-line therapy in urinary incontinence. Clinical trials have reported some efficacy in treating SUI, UUI and MUI. The electrodes can be implantable or not, and the electrical stimulation can be of long or short duration.

The exact mechanism involved in improvement of urinary symptoms through electrical stimulation is not completely understood. Reorganization of spinal reflex and regulation of cortical activity are suggested as important outcomes of electrical stimulation, which would be related to the mechanism of action of this therapy. The mechanism of action of ES was initially investigated in animal models,

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where it caused bladder relaxation by inhibiting the parasympathetic motor neurons. Other studies showed that transvaginal ES causes contractions of the pelvic floor, increasing the number of muscle fibers with rapid contraction, which are responsible for continence in situations of stress. Suprapubical electrical stimulation aims or a direct stimulation of S3 nerve roots, in order to inhibit the detrusor activity, similarly to the sacral electrical stimulation, but less invasive.

ANAL DILATATION (afferent pathway: anorectal branches of the pelvic nerve; prevents voiding during defecation), GENTLE MECHANICAL STIMULATION OF THE GENITAL REGION (afferent pathway: dorsal clitoral branches of the pudendal nerve; prevents voiding during intercourse),

J . GROEN and J.L.H.R. BOSCH, on their research paper, ‘Neuromodulation techniques in the treatment of the overactive bladder’ (2001), reported that symptoms of an overactive bladder often remain a therapeutic problem despite optimal use of conservative treatment methods including drug therapy, behavioural therapy, pelvic foor exercises and biofeedback. In the last decade, sacral nerve neuromodulation has been confirmed as a valuable addition to the therapeutic arsenal. The success of sacral neuromodulation has renewed interest in other neuromodulation techniques.

Most of the afferent fibres involved in the above inhibitory mechanisms reach the spinal cord via the dorsal roots of the sacral nerves. At least two potential mechanisms are possible:

It is unknown how neuromodulation works; indeed, it is even unknown whether neuromodulation only works at the spinal level or whether supraspinal pathways are involved. The most important spinal inhibitory mechanisms of the micturition reflex are: THE GUARDING REFLEx: increased activity of the striated urethral sphincter in response to bladder filling, reflexively inducing detrusor relaxation, EDVARDSEN’S REFLEx: increased activity of the sympathetic nervous system in response to bladder filling,

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PHYSICAL ACTIVITY; AFFERENT PATHWAY: muscle afferents from the limbs (but not from the pelvic floor; prevents voiding during fighting or fleeing).

Inhibition of afferent C fibre activity may be one of the underlying mechanisms of neuromodulation. However, it does not explain the beneficial effects of neuromodulation in patients with idiopathic detrusor instability or urgency frequency. In conclusion, the mechanism of action of neuromodulation remains in debate. Stimulation of afferent pathways seems to play a crucial role.

(i) activation of efferent fibres to the striated urethral sphincter reflexively cause detrusor relaxation; and (ii) activation of afferent fibres causes inhibition at a spinal or a supraspinal level. However, measurements of the urethral pressure profile and of urethral resistance during voiding do not indicate that the striated sphincter is activated with the stimulation parameters currently used. Interesting studies supporting the second theory are those in which the dorsal clitoral or dorsal penile nerve, purely afferent branches of the pudendal nerve, were electrically stimulated. This induced a strong inhibition of the micturition reflex and detrusor hyper-reflexia in healthy volunteers and patients with a hyper-reflexive bladder. It has been measured that the latency of the anal sphincter contraction during a peripheral nerve evaluation (PNE) test in women who were candidates for sacral neuromodulation, and concluded that this response was mediated by a polysynaptic reflex rather than the result of efferent stimulation.

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how sacral nerVe stImulatIon and neuromodulatIon works on urInary system Sacral neuromodulation has become a popular option for refractory OAB symptoms over the past 2 decades. Studies have demonstrated that it is an effective treatment for OAB, DO, UI and SUI as indicated by decreased number of voids, increased bladder capacity, strengthen pelvic floor, increased urethral sphincter contractibility and fewer leakage events. Sacral nerve stimulation can lead to excitatory or inhibitory reflexes on the bladder, depending on the force and rate. Despite the substantial usage of SN over the past two decades, the exact mechanism remains poorly elucidated. Studies have evaluated multiple sites for neuromodulation, such as the sacral, tibial, pudendal, and genital nerves. However, the most commonly described sites of noninvasive neuromodulation for treatment of urinary dysfunctions are sacral nerve root (S3) and intravaginal or perineal region. Although the exact mechanism of action is incompletely understood, it is theorized that neuromodulation moderates the normal micturition reflex by stimulating the somatic afferent inhibition of sensory processing of the bladder within the spinal cord. The most well-accepted hypothesized mechanism, and the suspected mechanism by these authors, is that the effect derives from stimulation of the alpha myelinated afferent fibers and unmyelinated C fibers in the S3 and S4 pelvic and pudendal nerve roots that affect the micturition reflex. SNM uses electrical stimulation to stimulate the sacral nerves that innervate the musculature of the pelvic floor and lower urinary tract. Using the electrical stimulation, it is able to either inhibit or incite neural reflexes.

MAGDY M. HASSOUNA reported on his research paper ‘SACRAL NEUROMODULATION IN THE TREATMENT OF URGENCYFREQUENCY SYMPTOMS: A MULTICENTER STUDY ON EFFICACY AND SAFETY’ (2000), sacral nerve stimulation or neuromodulation of the micturition reflex is an accepted concept for the management of refractory urinary symptoms through the stimulation of the afferent nerves of the pelvic floor. The mechanism by which sacral nerve stimulation affects dysfunctional bladder behavior is not fully understood. The activation of spinal inhibitory pathways through stimulation of the afferent input in the S3 nerve can account for partial explanation in patients with urgency and incontinence. However, stimulation of large sensory afferents running from the pelvic floor may also produce inhibition of the detrusor motor neurones, either directly at a spinal level or via other neural pathways.

Current theory suggests that dysfunction and anatomical change result when an unnatural bias develops between inhibitory and facilitatory neural activity in the pelvic floor. For example, over facilitation of the detrusor can result in symptoms of urgency-frequency and urge incontinence. Sacral nerve stimulation is believed to have a conditioning effect on neural excitability and can restore neural equilibrium. In consideration of these theories, sacral nerve stimulation has been demonstrated to treat effectively severe symptoms of urinary urge incontinence, and now provides clinicians with an important new option for treating patients with significant symptoms of urgencyfrequency. To explain how sacral neuromodulation works and

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the mechanisms of action in the treatment of urinary incontinence, Michael B. Chancellor and Emmauel J. Chartier-Kastler’s research papers ‘Principles of Sacral Nerve Stimulation (SNS) for the Treatment of Bladder and Urethral Sphincter Dysfunctions’ (2000) and ‘How Sacral Nerve Stimulation Neuromodulation Works’ (2005) and their experiments can be refer. Their given hypotheses are the most widely accepted theories to explain the principle behind sacral nerve stimulation (SNS) and its mechanism of action on urinary system.

MICTURITION MECHANISMS NEUROANATOMY AND NEUROPHYSIOLOGY EFFERENT PATHWAYS Knowledge of sacral and pudendal nerve anatomy is crucial to understanding the mechanisms underlying the effects of functional electrical stimulation on the lower urinary tract. The pelvic floor musculature receives a major part of its innervation via the pudendal nerve. Nerves branching to the urethral sphincter and levator ani muscle divert proximally before the pudendal nerve reaches the ischiosacral ligament. Approximately 70% of external urethral sphincter pressure is dependent upon efferent activity in the S3 ventral root, while S2 and possibly S4 contribute the remaining 30%. Sacral parasympathetic preganglionic fibers which travel in the pelvic nerve provide the major excitatory input to the urinary bladder. Preganglionic axons project to ganglion cells on the surface of the bladder. Parasympathetic ganglion cells in the bladder provide an excitatory

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input to the detrusor smooth muscle via the release of predominantly cholinergic transmitter. (Figure 1). Sympathetic pathways which originate in the thoracolumbar segments of the spinal cord provide inhibitory input to the bladder and an excitatory input to the bladder neck and proximal urethra.

At other sites in the body, C-fiber afferents transmit signals such as hot temperatures, heat, and chemicals. It is easy to understand the importance of cutaneous nociceptive afferents for the detection of external noxious stimuli and the initiation of immediate defensive reactions such as withdrawal of a hand from a hot plate. The bladder C-fiber nociceptors perform a similar function and signal the central nervous system when we have an infection or irritative condition in the bladder.

AFFERENT PATHWAYS The lower urinary tract also needs afferent fibers to function appropriately. Afferent input from the pelvic visceral organs and also somatic afferent pathways from the muscle and perineal skin are very important. Afferent nerves are critical for a person to sense bladder fullness and to initiate the micturition reflex. Somatic afferent pathways from the perineal area transmit information that can make us aware of our surrounding environment and warn us if there are noxious stimuli or tactile sexual pleasure to our genital region.

BLADDER AFFERENT NERVES: A δ AND C FIBERS The micturition reflex requires not only efferent pathways from the spinal cord to the urinary bladder but also afferent input from receptors in the bladder to the spinal cord. Integrity of afferent nerves is critical for sending signals of bladder fullness and discomfort to the brain. Bladder afferent pathways are composed of two types of axons; small myelinated A-d fibers and unmyelinated C-fibers. A-d fibers transmit signals mainly from mechanoreceptors that detect bladder fullness or wall tension. The C-fibers, on the other hand, carry information about noxious signals and initiate painful sensations.

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C-fiber bladder afferents also have reflex function to facilitate or trigger voiding. This can be viewed as a defense mechanism to eliminate irritants or bacteria. The C-fiber bladder afferents have been implicated in the triggering of reflex bladder hyperactivity associated with various disorders such as spinal cord injury and multiple sclerosis. Capsaicin and its ultrapotent analog resiniferatoxin, specific C-fiber neurotoxins, are now undergoing intravesical clinical trials for the treatment of overactive bladder and interstitial cystitis. Bladder hyperactivity and urinary incontinence are assumed to be mediated by the loss of voluntary control of voiding and the appearance of primitive voiding reflex circuitry. This can occur as a result of the reemergence of neonatal reflex patterns that were suppressed during postnatal development or the formation of new reflex circuits mediated by C- fiber afferents. Under normal conditions the latter are thought to be mechanoinsensitive and unresponsive to bladder distension (hence the name ‘‘silent C-fibers) but as a consequence of neurologic and inflammatory diseases, or possibly of aging, the silent C-fibers become sensitive to bladder distension and can trigger micturition reflexes. In theory, this type of bladder hyperactivity could be suppressed by blocking C-fiber afferent activity or by interrupting reflex pathways in the spinal cord.

Figure 1: The micturition center is located in the pons. Sympathetic outflow to the bladder is located at the T10-L2 spinal cord levels. The sacral micturition center (S2–4) receives afferent input via the pelvic nerve and sends efferent parasympathetic fibers to the bladder via the pelvic nerve. Somatic innervation to the pelvic floor projects from S2–4 and travels inthe pudendal nerve.

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MICTURITION CONTROL The normal elimination of urine is completely dependent on neural pathways in the central nervous system. These pathways perform three major functions: amplification, coordination, and timing. The nervous control of the lower urinary tract must be able to amplify weak smooth muscle activity to provide sustained increases in intravesical pressures sufficient to empty the bladder. The bladder and urethral sphincter function must be coordinated to allow the sphincter to open during micturition but to be closed at all other times. Timing represents the voluntary control of voiding in the normal adult and the ability to initiate voiding over a wide range of bladder volumes. In this regard the bladder is a unique visceral organ that exhibits predominately voluntary rather than involuntary (autonomic) neural regulation. The bladder is also an unusual organ because it is functionally ‘‘turned off’’ most of the time and then turned on in an ‘‘all-or-none’’ manner to eliminate urine. The ability to turn on micturition in a switch like fashion is facilitated by positive feedback loops in the micturition reflex pathway. Thus bladder afferent activity can activate efferent excitatory input to the bladder that can initiate a bladder contraction and a rise in intravesical pressure. This positive loop can activate more afferent firing and more intense reflex efferent activity. This positive feedback, mediated in part by supraspinal parasympathetic pathways to the pontine micturition center, is a very effective mechanism for promoting efficient bladder evacuation and for minimizing residual urine.

Figure 2: The normal micturition reflex is mediated by myelinated A d afferent nerves. The bladder is full, tension receptors sends signals to the spinal cord by the A d fibers. After processing in the brain stem, the command to contract the bladder and urinate is passed down by spinal and peripheral efferent nerves.

Figure 3: Unmyelinated C-fiber afferent fibers transmit bladder sensory input to the sacral micturition center when there are neurological, inflammatory, and idiopathic alterations to the bladder. Intravescial capsaicin selectively blocks the C-fiber.

Because of positive feedback, loss of central inhibitory controls or sensitization of bladder afferent input can lead to involuntary voiding. Thus, nature has provided other mechanisms for inhibitory modulation of the micturition reflex. These mechanisms that reside in the spinal cord and can be activated by various somatic and visceral

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afferent nerves might be viewed as a counterbalance for the bladder reflex pathways. The spinal organization of these inhibitory mechanisms has been elucidated by electrophysiological studies in animals. It has been hypothesize that these modulatory mechanisms can be activated by SNS and can thus contribute to the beneficial effects of this procedure when it is used in the treatment of patients with overactive bladders.

Figure 4: The voiding reflex with supraspinal bladder facilitation and spinal pathway urethral relaxation. Afferent fibers from the bladder project on spinal tract neurons that ascend to the brain. Descending pathways connect to parasympathetic efferent nerves to contract the bladder (bladder-bladder reflex). A spinal bladder-urethral reflex is activated via a bladder afferent innervation.

BLADDER-BLADDER REFLEx The bladder afferent (A d or C fiber) nerves connect with interneurons in the sacral spinal cord. Interneurons synapse with bladder efferent parasympathic nerves to form the bladder-bladder reflex. Interneurons from the bladder also synapse with urethral sympathetic efferents to form a bladder-urethral reflex. The bladder-bladder reflex allows the full bladder, once it is turned ‘‘on’’ to maintain contraction until the bladder is completely emptied. The bladder-urethral reflex allows the smooth muscle proximal urethra to reflexively open up during a bladder contraction.

GUARDING REFLEx The guarding reflex describes a protective mechanism against stress urinary incontinence. The guarding reflex is mediated by bladder afferent to urethral efferent. This excitatory reflex is important during micturition. The guarding reflex is activated not during micturition but rather when bladder pressure increases, as during a cough or exercise. The bladder afferents synapse with sacral level interneurons that connect and activate urethral external sphincter efferent nerves (pudendal nerve). The activation of pudendal urethral efferents contracts the external urinary sphincter and prevents stress urinary incontinence.

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There are three layers of muscle that are known to control urine flow through the urethra; an inner band of longitudinal smooth muscle, a middle band of circular smooth muscle, and an external band of striated muscle called the rhabdosphincter. The urethra is controlled by the sympathetic, parasympathetic, and somatic divisions of the peripheral nervous system. The sympathetic innervation (nerve supply) comes from the sympathetic preganglionic neurons located in the upper lumbar spinal cord along the hypogastric nerve and terminates in the longitudinal and circular smooth muscle layers in the urethra. The parasympathetic nerve supply comes from the parasympathetic preganglionic neurons in the sacral spinal cord and also terminates in the longitudinal and circular smooth muscle layers. Finally the somatic nerve

supply arises from the urethral sphincter motor neurons in the ventral horn of the sacral spinal cord; better known as Onuf’s nucleus. The pudendal nerve that extends from Onuf’s nucleus, connects directly to the rhabdosphincter muscle to control micturation. The sympathetic storage reflex or pelvic-to-hypogastric reflex is initiated when the bladder swells. Stretch receptors cause postganglionic neurons to release norepinephrine (NE). NE causes the bladder to relax and the urethra to contract, thus preventing urine loss. The somatic storage reflex or the pelvic-to-pudendal or guarding reflex is initiated when one laughs, sneezes, or coughs, which causes increased bladder pressure.

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Glutamate is the primary excitatory transmitter for the reflex. Glutamate activates NMDA and AMPA receptors which produce action potentials. These action potentials activate the release of acetylcholine causing the rhabdosphincter muscle fibers to contract. When the guarding reflex does not function normally, SUI occurs.

SACRAL AFFERENT INPUT CAN MODIFYING MICTURITION REFLEXES The voiding and guarding reflexes discussed above are activated at varying times under completely different clinical scenarios. However, they are anatomically located in close proximity at the S2â&#x20AC;&#x201C;4 levels in humans. Both sets of reflexes are under cerebral drive with inhibitory control and modulation. These reflexes can be altered by a variety of diseases that may unmask activity mediated by bladder C-fibers. It is possible to modulate these reflexes through sacral nerve stimulation and restore voluntary micturition. Animal studies have shown that somatic afferent input to the sacral spinal cord can modulate the bladderbladder and guarding reflexes. de Groat has shown that sacral preganglionic outflow to the urinary bladder receives inhibitory inputs from various somatic and visceral afferents, as well as a recurrent inhibitory pathway. Experiments have also provided information about the organization of these inhibitory mechanisms. Figure 5: The guarding reflex prevents urinary incontinence. When there is a sudden increase in intravesical pressure, such as during a cough, the spinal guarding reflex contracts the urinary sphincter to prevent urinary incontinence. The brain turns off the spinal guarding reflex to urinate.

Electrical stimulation of somatic afferents in the pudendal nerve (the nerve that innervates the anal channel and perineal region) also elicits two types of inhibitory reflexes: early inhibition (E-1) and late inhibition (L-1). Early inhibition is evident when the cells were fired by administration of an excitatory amino acid and therefore

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must have been mediated by a postsynaptic mechanism. Late inhibition, which did not occur when the cells were fired with excitatory amino acid, demonstrates disfacilitation. Disfacilitation is an inhibition of interneurons on the excitatory pathway to the parasympathetic neurons and not postsynaptic inhibition of the parasympathetic neurons. In neonatal kittens, micturition as well as defecation are elicited when the mother cat licks the perineal region. This reflex appears to be the primary stimulus for micturition since urinary retention occurs when the young kittens are separated from their mother. This perineal-to-bladder reflex is very prominent during the first 4 postnatal weeks and then becomes less effective and usually disappears by the age of 7â&#x20AC;&#x201C;8 weeks, the approximate age of weaning. In adult animals and humans, perineal stimulation or mechanical stimulation of the sex organs (vagina or penis) inhibits the micturition reflex. The overactive detrusor represents one of the most challenging problems in urology. Current treatments for the uninhibited bladder include pharmacotherapy, surgical denervation, or surgical augmentation procedures. These forms of treatment, however, may have significant adverse side effects. Functional electrical stimulation appears to be a favorable nonsurgical treatment for many patients with detrusor instability. Stimulation techniques have utilized surface electrodes, anal and vaginal plug electrodes, and dorsal penile nerve electrodes. The transcutaneous electrical nerve stimulator (TENS) unit has been widely used in those with neurological disease to manage spasticity and pain emanating from the pelvis and extremities. The success of the device relies on the common central nervous system pathways shared by dermatome and visceral somatic sensory innervation. By stimulating somatic afferent pathways, it is possible to block competing visceral afferent signals. An example of this is posterior tibial nerve stimulation. Electrical stimulation

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of this nerve or its dermatome blocks sensory afferents from the bladder. Bladder inhibition using TENS has been investigated by using anterior tibial nerve stimulation along the L4 dermatome, sacral nerve stimulation at the anterior ramus, anal and vaginal plug stimulation of pudendal afferents, as well as dorsal penile nerve stimulation. With this latter technique, butterfly electrodes are wrapped around the dorsum of the penis, and a lowfrequency current of 20â&#x20AC;&#x201C;40 mAmp is applied. Currents are progressively increased until bladder filling volumes are appreciated. In a study by Wheeler and Walter, dorsal penile nerve stimulation achieved significant increases in filling volume utilizing an average current of 42 mA to suppress detrusor activity. Pudendal afferent stimulation using surface electrodes applied to the clitoris has been shown to inhibit the overactive bladder. Though the clitoral stimulation device and parameters were identical to those used on the glans penis in the male (Chancellor, personal communications), limited success was achieved. Worthy of mention is the use of TENS of the sacral dermatomes in patients with spinal cord injuries to improve bowel evacuation.

in the treatment of refractory detrusor instability and stress urinary incontinence. Seventy three percent of the women with detrusor instability studied became asymptomatic during treatment, while 45% remained free of symptoms despite discontinuation of therapy. Many patients, however, required up to 6 months of therapy before any benefit was apparent. Extradural techniques have been used to achieve isolated pudendal nerve stimulation. Such stimulation has been used to inhibit reflex contractility of the bladder, and also to aid in the evaluation and retraining of pelvic muscle contraction in cases of dysfunctional voiding and pelvic pain syndromes. Ina casereport, chronicabacterial prostatodyniawas shown to be associated with sphincteric spasm during voiding with intraprostatic reflux of urine. It has been hypothesize that SNS depends on electrical stimulation of afferent axons in the spinal roots which in turn modulate voiding and continence reflex pathways in

Although long-term efficacy data are not currently available concerning the use of surface electrodes in dorsal penile nerve stimulation, intradural and extradural sacral electrical stimulation and stimulation of the tibial nerve have been reported to be effective in treating uninhibited detrusor contractions. Olhsson et al. reported encouraging success rates about the use of maximal electrical stimulation administered with transvaginal probes in women and transrectal probes in men. Despite a documented average 45% increase in bladder capacity, however, only half of their patients reported a 30% decrease in the frequency of micturition. Fall also reported favorable long-term results of vaginal electrical stimulation

Figure 6: Pudendal afferent nerve stimulation can inhibit the micturition reflex.

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mechanIsms oF sacral nerVe stImulatIon the central nervous system. The afferent system is the most likely target because beneficial effects can be elicited at intensities of stimulation that do not activate movements of striated muscles. One key question is what type of afferents contributes to the effects of SNS? It is likely that the effects are mediated by somatic afferents because visceral afferents, even myelinated A d fibers, would not be activated at the stimulation intensities that are effective. Before the development of brain control of micturition, at least in animals, stimulation of somatic efferent pathways can initiate efficient voiding. The somatic afferent can activate bladder efferent pathways and turn off the excitatory pathways to the urethral outlet (urinary retention). Tactile stimulation of the perineum in the cat also inhibits the bladder-sympathetic reflex component of the guarding reflex mechanism. We hypothesize that SNS can elicit similar responses in patients with urinary retention and turn off excitatory outflow to the urethral outlet and promote bladder evacuation. Sphincter activity can generate afferent input to the spinal cord that can in turn inhibit reflex bladder activity. A benefit of suppressing sphincter reflexes would be a facilitation of bladder activity. Different reflex mechanisms are involved in the SNS suppression of bladder hyperactivity. It is known that various afferent pathways projecting to the sacral cord can inhibit bladder reflexes in animals and humans. The list includes afferents from the pelvic floor and sphincter muscles, afferents from the distal colon, rectum, and anal canal, afferents from the vagina and uterine cervix, and

cutaneous afferents from the perineum. (STIMULATION FROM PERINEUM REGION) Two mechanisms have been identified in animals for somatic and visceral afferent inhibition of bladder reflexes. The most common mechanism is suppression of interneuroneal transmission in the bladder reflex pathway. It is assumed that this inhibition occurs in part on the ascending limb of the micturition reflex and therefore blocks the transfer of information from the bladder to the pontine micturition center. This action would prevent involuntary (reflex) micturition but not necessarily suppress voluntary voiding that would be mediated by descending excitatory efferent pathways from the brain to the sacral parasympathetic preganglionic neurons.

SNS inhibits afferent evoked excitatory reflexes via suppression of interneuroneal mechanisms but does not have a prominent inhibitory effect on voluntary voiding that is produced by direct supraspinal excitatory input by the pelvic ganglion neurons. This could only be turned off by postsynaptic inhibition of pelvic ganglion neurons. This can occur without somatic afferent stimulation, but is less prominent than interneuroneal inhabitation. Hyperreflexic bladder due to increased activity of supraspinal reflexes can be dampened by inhibition of ascending pathways at interneurons in the spinal cord reflexes. This will cause reduced afferent input from the bladder to the pons Also input from pelvic floor and sphincter will inhibit supraspinal reflexes.

A second inhibitory mechanism is mediated by a direct inhibitory input to the bladder preganglionic neurons. This can be induced by electrical stimulation of the pudendal nerve or by mechanical stimulation of the anal canal and distal bowel. It is not elicited by tactile stimulation of perineal afferents. The later mechanism would be much more effective in turning off bladder reflexes because it would directly suppress firing in the motor outflow from the spinal cord. It would also be expected to block nonselectively both voluntary and involuntary voiding. Thus this inhibitory response may be less important in clinical studies than responses to SNS because patients usually retain normal voiding mechanisms. The principles behind SNS can be summarized as somatic afferent inhibition of sensory processes. Pudendal afferent input to the sacral spinal cord can turn off supraspinally mediated hyperactive voiding, blocking the ascending system. Pudendal afferent input can also turn on voiding reflexes by turning off the guarding pathways.

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ELECTROPAD FOR ACTIVE MODE

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PRODUCT PACKAGING

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PRODUCT CASE

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PRODUCT CASE

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PRODUCT COMPONENTS LINEUP

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Final Product

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Functions of the Device & User Instructions

ERROR ROOT ANALYSIS

ERROR ROOT ANALYSIS PROCESS

APPLYING DOUBLE SIDED CONDUCTIVE STICKER GEL ON THE

DEFINE THE USER ERRORS

IDENTIFY PROVISIONAL ROOT CAUSES

FIxING ELECTROPAD WITH THE DEVICE

ANALYzE ERROR EVIDENCES

POWER ON THE DEVICE

INSPECT DEVICE FOR USER INTERFACE DESIGN FLAWS

OPERATION MODE SELECTION

COSIDER OTHER CONTRIBUTION FACTORS

REMOVE STICKER SURFACE FROM THE ELECTROPAD

DEVELOP A FINAL HYPOTHESIS

FIx ON THE BODY PART

6. 7.

TESTING AND REPORT THE RESULT

START BUTTON PRESS WITH VIBRATION FEEDBACK

CHANGES AND ITERATION

USER CONFIRMATION FEEDBACK ABOUT ITS WORKING OR NOT

REMOVE FROM THE BODY

TYPES OF USER ERRORS • • • • •

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DEVICE OPERATIONAL ACTION

PERCEPTION ERRORS COGNITION ERRORS ACTION ERRORS SAFETY RELATED USER ERRORS NON-SAFETY RELATED USER ERRORS

SURFACE OF THE ELECTROPAD

DETACH THE ELECTROPAD FROM DEVICE

CLEAN THE ELECTROPAD

STORE IN THE PACKAGE BOx

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POSSIBLE USER ERRORS FOUND DURING VARIOUS PHASE OF OPERATING DEVICE

•

Sticker (conductive) applying on the wrong side of the electropad. improper sticker application.

• • •

Selecting wrong electropad for desired mode. Wrong way placing and snapping with device. Not properly fit, attached and snapped all the snap buttons.

• • • •

Long time press / Multiple press. Pressing wrong switch to power it on. Confusion about its power on or not. If wanted to switch it off suddenly before attaching on the body part.

•

• • • •

Confusing wich mode to select. Wrong switch press. Wrong mode press with wrong electropad. Forgot the selected mode.

• • • •

Remove the whole adhesive due to improper application. Difficulty to peel of the sticker’s paper surface. dispalcement of gel. Forgot to remove sticker surface.

• • •

Placing the device in wrong direction. Attaching on wrong area of the body. Start with wrong placement.

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• • • • •

Start with improper attachment. Pressed start button before fixing on the body. Can not find the start button. Displacement of electropad during start button press. Double or multiple press of start button.

•

Can not feel the tigling sensation on anus area.

• • •

Drop the device in th floor. Tearing the electropad. button press during removal.

•

Tearing the electropad.

•

Washing electropad along with attached device.

• • •

Wrong placement of device in the package case. Dont understand its charging or not. Do not understand how to keep elctropads and stickers in the package case.

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FUNCTIONS OF THE DEVICE

Single Press : Power On Feedback : Red light glow on the switch Single Long Press : Power Off

Single Press : Mode Selected Feedback : Blue light glow on the switch

Single Press : Mode Selected Feedback : Orange light glow on the switch

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Single Press : Stimulation Start Feedback : Vibration & Green glow on the switch for few seconds

Data feed on TUNE app after every last use of the day

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PROGRAMME AND FUNCTIONS OF THE DEVICE

1. After press of start switch, the device has to attach on the body (or user may press the start button after fixing on the body as per user’s convenience) and the stimulation will start after 5-8 minutes. The given times can be changes as per individual user requirements, by using the ‘TUNE‘ app. 2. Total time duration of therapy session for a day is 60-90 minutes, which is divided in 3-4 slots. The user can select the number of slots of the total duration as per their wish and cofort, but it can not be less than 3 slots. 3. The active mode can be use one time in a day, for a total 90 minutes duration. Before using this mode the user have to void first so that it can provide them control over their involuntary urine leakages for one full cycle urine storage period of the bladder. 4. After using active mode in a day, there is no need of any therapy session for the same day. 5. Before completing a session (both active and therapy), the device will vibrates for few times to inform that the session is about to end. 6. After start the session, the stimulation intensity will increase slowly and user will feel a ‘‘bellows’’ type contraction of the perineum region, like a pulling sensation in the rectum and as well as tingling sensations on genital region. After several minutes if user does not fell any kind of sensations like this, it means either the device is not

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attached properly or placed in wrong site. 7.

The intensity level of stimulation can be changed by user through the ‘TUNE’ mobile app in very simple way. The stimulation intensity level has to be set as per individual user’s comfort level, but it has be strong yet tolerable for desired effects of the stimulation.

In between the stimulation if the electopad anyhow gets displaced the device will shutdown automatically.

After power on the device, with in 10 minutes if any further action does not take place, the device will automatically shutdown.

10. Incase of multiple numbers of start button press, the user will get vibrate feedback for all the press, but it will calculate the very first one within a stimulation session cycle. 11. During a stimulation period if any switch (except power button) get pressed, it will not effects or changes the stimulation session. 12. In regular basis after the last therapy session or before sleeping at night, the TUNE app will ask the user to feed few answers about the urinary health condition of that particular day (like a bladder diary manner). And in weekly basis the app will generate a visual data map to show the improvement rates of an individual user. 13. The user can share this health datas with their medical consultant in a seamless way through the TUNE mobile app.

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USER INSTRUCTION

Peel out the sticker upper surface

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Fix it on the electropad surface over the marked area

Attach the electropad with the device

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Snap all the buttons properly

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Switch on the device with power button

Select the operation mode accordingly and press start button

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Remove the back surface of the sticker from the electropad

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Place the device tail part in the origin of the natal cleft (Buttcrack)

Apply suitable pressure and fix the electropad on the sacrum region

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Wait for few minutes untilthe stimulation starts with with a vibration, and make feel a tingling sensation on the perineum region

While using the ‘Active mode’ use the active electropad (Long one), and place tail part of the electropad on the perineum region and fix it properly.

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You can set the stimulation intensity level with the ‘TUNE’ app, as per your comfort. But keep it strong as much as you can tolerate

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‘TUNE’ Mobile App

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‘TUNE’ APP

‘Tune’ app will act as a personal assistance for the users and will keep them to engage with their regular basis therapy routine. It will play a major role in improving their health condition by creating a bond with the users and continuously interacting with them through the multiple features available in the app. Tune app will also keep data and track their regular urinary health condition. Through the research it has been found that incontinent patients find it embarrassing to engage in communications regarding the symptoms, with anyone. Therefore, this app creates that personalized base which will successfully be able to eliminates the shame factor.

the most effective conservative method to treat or improve urinary incontinent patient. Through this app they will be provided with self - explanatory animation,in a playful way, so that they can follow and do the exercises themselves. This again will help them to go beyond the barrier of shame and do the exercise personally themselves. My research synthesis also established that the effect of the therapy will increase if it is accompanied with the exercise. •

On a regular basis, after the last therapy session or before sleeping at night the app will ask the user to feed a few answers about their urinary health condition of the particular day (like bladder diary manner). And on equal basis the app will generate a visual data map which will analyze and show the improvement rate of the user, in an encouraging way. Thus, boosting the patient to continue the therapy.

FUNCTION OF THE APP •

Through Bluetooth the app will connect to the device automatically and the keep a watch on whether the therapy has been taken as per the requirement.

•

The app is a personalized app and thus can be used only by the user as she can protect it with a password or her fingerprint.

•

The user will be able to set reminder for the therapy and exercise as per there convenience and as per the setting they will be notified about their daily sessions.

•

A few functions of the device can be controlled by this app like: 1.regulating the stimulation intensity level as per user’s comfort. 2.User will be able set their device fixing timing on their body as per their requirement.

•

If desired the patient can seamlessly share the data from the app with their doctor.

•

Tune app also has the facility to let the patient be connected with the doctors.

•

As previously mentioned that the total duration of therapy session will be 60 to 90 minutes for a day, and by default- it is further divided into three to four slots. The user will be able to select and alter the number of slots, through the app, as per their wish.

•

This app also has the option of kegel exercise (pelvic muscle floor exercise), which is known as one of

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APP FLOWCHART

SETTING

INITIAL PAGE

TUTORIAL PAGE

NEW USER

INITIAL DATA FEED

PASSWORD SETTING

REMINDER SETTING

START

WEEKLY IMPROVEMENT REPORT

DAILY DATA FEED REMINDER SETTING

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APP SCREEN

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Circuit Development

CIRCUIT DESIGN

FEATURES AND CAPACITY TWO DIFFERENT MODES: • •

Continuous (continuous stream) Intermittent (short bursts)

ADJUSTABLE: It can be control with three variables: • • •

Output voltage. Width of the pulses. Pulse rate.

CONTINUOUS MODE: 1. 2. 3.

Output Voltage: Adjustable from 12V to 80V. Pulse Rate: Adjustable from 4.6Hz to 410Hz. Pulse Width: Adjustable between 70 and 320 µs.

INTERMITTENT MODE : •

Duty cycle: 24% at 1.2Hz

OUTCOME CONTINUOUS MODE: The output volt=79v. The frequency=362 Hz. INTERMITTENT MODE: The output volt=82v. The frequency=108 Hz.

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Conclusion

CONCLUSION

I was inspired by the idea of overcoming the one of the last medical taboo existing in the world and it was my instincts, perseverance and belief that enabled me to overcome all the hurdles and find a most suitable solution to the symptoms of incontinence. It was a difficult task to penetrate this impenetrable widespread unspoken, under line, non-communicative disease, which can be considered a wicked problem, as it was just not the medical sphere that was challenging but also the accessibility of the patients was difficult. After my initial study and realization that 32% of women population in the world, suffers from the symptoms and in India 36% of women suffers from these symptoms of incontinence, my vision was to come up with the most appropriate solution which would give women of the world the power to control over their condition, improve their state and elevate their quality of life. Looking back, I realize that this project has been an immense learning experience. When I started the project, I had a vague idea about the process this project demanded, and I was uncertain about what the final outcome would be. The intensive research involved in the project proved instrumental in shaping my final solution. The first challenge I faced was the fact that I belong from a non-medical background. Thus, I had to first become fluent with basic biology, human anatomy, medical physiology, neuro science and the interconnections between all the body systems before I could proceed further. I had to start from a scratch only relying on my understanding. This acted as a boon because my approach to the study from was from an unbiased perspective, while gaining wisdom and knowledge in the due process. I had no repository knowledge, thus my study was not limited to my area of concern which allowed me to go beyond and explore the world of medical science.

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It was very clear from the beginning that such a wicked problem area’s solution would not lie alone in the scientific and technological intervention. Thus, the research bifurcated into two phases- firstly pure scientific research and secondly the socio- cultural study. The solution approach came from the critical process of finding the area of synergy from the synthesis of both the perspectives Therefore the personal interactions and ethnographic study of patients became a crucial part of the research, for including design intervention at several levels. Another important learning was from the challenges I faced during these ethnographic study was that while looking for patients to interview I figured out that most of the patients prefer not to discuss problems as sensitive as ‘urinary incontinence’ with an outsider. Further, the group of patients I was dealing with were often unwilling to appear for the interviews. Thus, in the absence of quantitative research, I decided to proceed with in depth and qualitative research methodology which indeed served to give better insights. Time management has been another crucial learning from this project. Often, schedules went haywire and I panicked when things did not work out as per my plan. I understood it is important to give time and be patient while working on such a project, which involved a wide array of people, ranging from patients to doctors to biomedical engineers. The methodology followed throughout the design process was system thinking approach, which involved data collections, data mapping, system mapping, data visualization, synthesis and interconnections in order to categories and structure the vast amount of information I was gathering. After collection of data and understanding, when I reached the data analysis part of my work, I

followed ethnographic methodology and it helped me to find the core meaning of this symptoms to the patients, which helped me to elicit the answer of solution approach. In my process of finding the solution, three prime field came to forefront. Firstly preventive, secondly surgical and finally cure and control. The first two methods had to be discarded because of lack of infrastructure and social acceptance. Thus, I went ahead with the third field. In order to approach that I had to evaluate the existing, available solutions in the market. While conducting this research I realized that the design product that the patient need as a solution has to be dignified to them. The solution was built upon a technology that has been existing for the last 30 years, still it is not widely accepted as the solution has not been implemented in a meaningful way. Thus, in order to reach this final product, the solution had to be structured in the format of personalized, selfadministered approach. Overall the journey of this project started from the time I decided to view towards a broader and bigger perspective that demanded a completely different apprehension of a problem and mould the solution with my design apprehension and possibilities. ‘Design’ has always intimidated me with its wide probabilities that are capable to serve real life social problems. Belonging from a humble abode, I have acknowledged ‘design’ as a tool that can be used to eliminate real life problems from its roots. This project was one such window of opportunity that paved a way to reach my limitations and then again breakthrough them with exhaustive research and system-oriented thinking to arrive at design solutions which are democratic in nature.

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I have evolved and matured as an individual and a designer in a way that has enriched a different kind of sensibility in me. Projects like this, where the journey and the final outcome is undefined demands enormous amount of perseverance diligence and responsibility. It requires meticulously focusing on the roots of the problem and handling it with the kind of accuracy it demanded. It started from the time I empathized with the problem to an extent that I subconsciously got involved with the diverse dimensions and it influenced me to subsequently look for a solution. Design for me, is both a critical decision and an interdisciplinary subject, with which I can challenge my own barriers and norms.

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FUTURE WORK

The actual prototype building of the product was not conceived at this stage due to lack of time, financial, infrastructure and other required support. Apart from this for fully functional working prototype and establishment of my hypothesis, I would have required permission from Ethical Committee for biomedical research in human. For this I would have to be a part of an organization which has the facility of incubation of healthcare product. Exact functional parameter of my product has not been calculated within my final solution because this would have required a long term clinical trial within a huge group of diverse female population. Only after that will I be able to get the required data. Thus, my first work of the future will be to find suitable organization where I can pitch the concept of my product and hypothesis and get the required amenities to take forward my solution and create a concrete functional product. But this is not where my approach stops. Once my hypothesis is established and positive, success rate is achieved this product can be ready to serve the human kind. My goal would be to make the product accessible to all, breaking the economical and class barrier, and improving the urinary health condition along with quality of life.

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Bibliography

BIBLIOGRAPHY & REFERENCES BOOKS Abrams, Paul, Cardozo, Linda, Khoury, Saad, and Wein, Alan, Incontinence, International Continence Society (ICS), 5th edition, 2013 Drife, J. O, Hilton, P, and Stanton, S.L, Micturition, Springer-Verlag, 1990 Chancellor, Michael B. and Diokno, Ananias C, The Underactive Bladder, Springer, 2016 Grant, Alison and Waugh, Anne, Ross and Wilson Anatomy and Physiology in Health and Illness, CHURCHILL LIVINGSTONE, 2004

Analysis, CRC Press, 2016 Weinger, Matthew Bret, Gardner-Bonneau, Daryle Jean, Wiklund, Michael E, Handbook of Human Factors in Medical Device Design, CRC Press, 2010 Ogrodnik, Peter J,Medical Device Design: Innovation from Concept to Market, Elsevier, 2012 Privitera, Mary Beth, Contextual Inquiry for Medical Device Design, Elsevier, 2015

Guyton, Arthur, Textbook of Medical Physiology, 13th Edition, Elsevier Saunders, 2006 Kilgore, Kevin, Implantable Neuroprostheses for Restoring Function, Elsevier Woodhead Publishing, 2015 zhou, David D. and Greenbaum, Elias, Implantable Neural Prostheses 1 Devices and Applications, Springer, 2009 Klagges , Brian, An introduction to neuromodulation, , Elsevier, 2015 Rawson, Christopher and Hindley, Judy, How Your Body Works, Mark Twain Media, 1975 Sheth, Anish and Richman, Josh, What’s Your Poo Telling You?, Chronicle Books, 2007 Sheth, Anish and Richman, Josh, What’s My Pee Telling Me?, 2009 Stolterman, Erik and Nelson, Harold G, The Design Way: Intentional Change in an Unpredictable World, The MIT Press, 2012 Haslam, Nick, Psychology in the Bathroom, Palgrave Macmillan, 2012 Pink, Sarah, Doing Sensory Ethnography, SAGE Publications Ltd, 2009 Wiklund, Michael E, Dwyer, Andrea and Davis, Erin, Medical Device Use Error: Root Cause

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ELECTRONIC JOURNAL ARTICLES ARTICLES Abrams, Paul, Cardozo, Linda, Khoury, Saad, and Wein, Alan, Incontinence, International Continence Society (ICS), 5th edition, 2013: https://www.ics.org/Publications/ICI_4/book. pdf (Accessed 19.01.2017)

Elenskaia K, Haidvogel K, Heidinger C, Doerfler D, Umek W, Hanzal E, The greatest taboo: urinary incontinence as a source of shame and embarrassment: https://www.ncbi.nlm.nih. gov/pubmed/21935649 (Accessed 23.11.2016)

Abrams, Paul, Cardozo, Linda, Khoury, Saad, and Wein, Alan, Incontinence, International Continence Society (ICS), 3rd edition, 2009: https://www.ics.org/Publications/ICI_4/book. pdf (Accessed 19.01.2017)

STAVROS CHARALAMBOUS, ARGYRIOS TRANTAFYLIDIS, Impact of urinary incontinence on quality of life: http://pelviperineology.org/june_2009/pdf/impact_of_urinary_ incontinence_on_quality_of_life.pdf (Accessed 03.08.2017)

Clare J. Flower, Derek Griffiths and William C. de Groat, The neural control of micturition: https://www.nature.com (Accessed 09.05.2017)

Abreu NS, Baracho ES, Tirado MGA & Dias RC, Quality oflife from the perspective ofelderly women with urinary incontinence, 2006: www.scielo.br/scielo.php?script=sci_ arttext&pid=S1413 (Accessed 05.08.2017)

Diane K. Newman, Stress Urinary Incontinence in Women: http://www.jstor.org/ stable/29745195 (Accessed 10.11.2017) Herschorn, Sender, Female Pelvic Floor Anatomy: The Pelvic Floor, Supporting Structures, and Pelvic Organs: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472875/ (Accessed 07.03.2017) Mota, Renato, Female urinary incontinence and sexuality: https://www.researchgate.net/ publication/309762674 (Accessed 27.06.2017) Yamanishi, Tomonori, Kaga, Kanya, Fuse, Miki, Shibata, Chiharu, Kamai, Takao,Uchiyama, Tomoyuki, Neuromodulation for the Treatment of Lower Urinary Tract Symptoms: onlinelibrary.wiley.com/doi/10.1111/luts.12087/pdf. (Accessed 13.07.2017) Lori Birder and Karl-Erik Andersson, Urothelial Signaling: https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC3768101/ (Accessed 08.03.2017) Kenneth Southall, Joshua R Tuazon, Abdul H Djokhdem, Eleanor A van den Heuvel, Walter Wittich, Jeffrey W Jutai, Assessing the stigma content of urinary incontinence intervention outcome measures, November 1, 2017: http://journals.sagepub.com/doi/ full/10.1177/2055668317738943, (Accessed 20.11.2017)

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LINDA S. MITTENE and JUDITH C. BARKER, Stigmatizing a “normal” condition: urinary incontinence in late life: https://www.ncbi.nlm.nih.gov/pubmed/7671114 (Accessed 05.08.2017) AJ Sinclair, The psychosocial impact of urinary incontinence in women: onlinelibrary.wiley. com/doi/10.1576/toag.13.3.143.27665/pdf (Accessed 01.09.2017) Elstad EA(1), Taubenberger SP, Botelho EM, Tennstedt SL, Beyond incontinence: the stigma of other urinary symptoms: https://www.ncbi.nlm.nih.gov/pubmed/20735505 (Accessed 03.09.2017) Jodie Avery, Nigel Stocks, URINARY INCONTINENCE, DEPRESSION, AND PSYCHOSOCIAL FACTORS - A REVIEW OF POPULATION STUDIES,2016: emjreviews.com/.../UrinaryIncontinence-Depression-and-Psychosocial-Factors-A-Re (Accessed 03.09.2017) LYNNE R. SHEFFLER, MD, and JOHN CHAE, MD, Neuromuscular electrical stimulation in neurorehabilitation, 2007: https://www.ncbi.nlm.nih.gov/pubmed/17299744 (Accessed 21.07.2017) Bradley C Gill, Urinary Incontinence Relevant Anatomy: emedicine.medscape.com/

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IMAGE CREDITS Images for the project are credited as listed below..Images not credited in the following list have been made by Bijoy Prasad Saha, Page, 49: Alison Grant and Anne Waugh, Ross and Wilson Anatomy and Physiology in Health and Illness, CHURCHILL LIVINGSTONE, 2004 Page, 52: Left hand side - studentconsult.inkling.com, Guyton and Hall, Textbook of Medical Physiology, 13th Edition Page, 52: Right hand side - Alison Grant and Anne Waugh, Ross and Wilson Anatomy and Physiology in Health and Illness, CHURCHILL LIVINGSTONE, 2004 Page, 54-78: studentconsult.inkling.com, Arthur Guyton, Textbook of Medical Physiology, 13th Edition, Elsevier saunders, 2006 Page, 79: https://humananatomyly.com Page, 80-81: studentconsult.inkling.com, Arthur Guyton, Textbook of Medical Physiology, 13th Edition, Elsevier saunders, 2006 Page, 86: https://www.coursehero.com Page, 87-91: studentconsult.inkling.com, Guyton and Hall, Textbook of Medical Physiology, 13th Edition Page, 95-97: PAUL ABRAMS, LINDA CARDOzO, SAAD KHOURY & ALAN WEIN, International Continence Society (ICS), 5th edition, 2013 Page, 98: https://www.nature.com, Clare J. Flower, Derek Griffiths and William C. de Groat, Nature Reviews Neuroscience 9, 453-466 (2008) Page, 104: PAUL ABRAMS, LINDA CARDOzO, SAAD KHOURY & ALAN WEIN, International Continence Society (ICS), 5th edition, 2013 Page, 108: https://www.nature.com Page, 109: https://www.researchgate.net Page, 110, 112, 114: https://www.nature.com, Clare J. Flower, Derek Griffiths and William C. de Groat, Nature Reviews Neuroscience 9, 453-466 (2008) Page, 118, 120, 122, 125, 127: Abrams, Paul, Cardozo, Linda, Khoury, Saad, and Wein, Alan, Incontinence, International Continence Society (ICS), 5th edition, 2013: https://www.ics.org Page 129: https://www.slideshare.net Page 130: https://anatomybodysystem.com Page 131: https://www.pinterest.com Page 132: http://www.peachtreegynecology.com Page 133: https://www.jstor.com Page 134: http://www.profemi.pl Page 135: https://www.obgynecologistnyc.com Page 137: https://obgynkey.com

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Page 140: https://bloominuterus.com Page 141: https://my.clevelandclinic.org Page 142, 143 Abrams, Paul, Cardozo, Linda, Khoury, Saad, and Wein, Alan, Incontinence, International Continence Society (ICS), 5th edition, 2013: https://www.ics.org Page 155: Clock wise from left to right, https://www.serviceautomoto.info http://simstr.info Page 156: http://www.sciencedirect.com Page 158: http://patients.uroweb.org Page 159: http://www.ramkrishnacarehospitals.com Page 163-166, 171, 172, 173, 175: Abrams, Paul, Cardozo, Linda, Khoury, Saad, and Wein, Alan, Incontinence, International Continence Society (ICS), 5th edition, 2013: https://www. ics.org Page 182: https://valentinbosioc.com Page 183: https://www.popsugar.com Page 184: https://www.qrcodematrix.com Page 185: http://medicalartbank.com Page 186: https://www.mayoclinic.org Page 187: https://my.clevelandclinic.org Page 188: http://www.acircal.net Page 189: https://www.sciencedirect.com Page 192: https://www.continenceproductadvisor.org Page 194: Anti-clockwise from left, https://www.crsociety.org https://www.continenceproductadvisor.org https://www.continenceproductadvisor.org https://www.continenceproductadvisor.org https://www.maxiaids.com Page 195: https://www.generaljan.com Page 196: Left hand side, https://uhyacinth21.en.ec21.com Page 196: Right hand side, https://www.continenceproductadvisor.org Page 197: Left, top to bottom https://www.medscape.com

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http://vesiflo.com Page 197: Right, top to bottom http://vesiflo.com https://craft.co/vesiflo Page 198: https://www.poise.com Page 199: https://havefiness.com/ Page 200: Clockwise from right, http://medicalj-center.info https://commons.wikimedia.org https://joemilford.wordpress.com Page 201: Clockwise from left, http://saphos.info http://urologiaquito.com https://obgynkey.com Page 202: Clockwise from left, http://www.neomedic.com http://ussurgitech.com https://vimeo.com Page 203: Bottom Left, https://urologorlov.ru Page 203: Top right, http://www.drtsn.org Page 204: Anti clockwise from left, http://www.medtronic.com https://emedicine.medscape.com http://colonsurgeonsofcharleston.com Page 205: Clockwise from left, http://www.westchesterurology.com http://www.idrarkacirmaameliyati.com https://blog.cogentixmedical.com Page 206: Clockwise from left, https://www.queenwestphysio.ca https://www.tenscare.co.uk https://www.incontrolmedical.com Page 207: https://www.restorethefloor.com Page 208: https://www.elvie.com

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Page 209: https://tatapp.com Page 211: http://www.bliblinews.com Page 274, 276, 277: https://media.lanecc.edu Page 281: https://www.elsevierdirect.com, Elliot S. Krames, P. Hunter Peckham, Ali R. Rezai, An introduction to Neuromodulation, (2009) Page 283: studentconsult.inkling.com, Guyton and Hall, Textbook of Medical Physiology, 13th Edition Page 285: studentconsult.inkling.com, Guyton and Hall, Textbook of Medical Physiology, 13th Edition Page 294: Left to right http://www.cppc.gr http://www.neuromodulation.ch Page 295: http://idrarkacirmaameliyati.com Page 298: https://www.elsevierdirect.com, Elliot S. Krames, P. Hunter Peckham, Ali R. Rezai, An introduction to Neuromodulation, (2009) Page 308: https://www.nature.com, Clare J. Flower, Derek Griffiths and William C. de Groat, Nature Reviews Neuroscience 9, 453-466 (2008) Page 309: https://www.nature.com Page 310: https://www.researchgate.net Page 313: Abrams, Paul, Cardozo, Linda, Khoury, Saad, and Wein, Alan, Incontinence, International Continence Society (ICS), 5th edition, 2013: https://www.ics.org Page 316: https://www.poz.com Page 318 Abrams, Paul, Cardozo, Linda, Khoury, Saad, and Wein, Alan, Incontinence, International Continence Society (ICS), 5th edition, 2013: https://www.ics.org Page 319: https://www.researchgate.net Page 320: https://accessmedicine.mhmedical.com Page 322, 329, 330, 331, 334, 335, 336, 337: Abrams, Paul, Cardozo, Linda, Khoury, Saad, and Wein, Alan, Incontinence, International Continence Society (ICS), 5th edition, 2013: https://www.ics.org Page 348, 349, 350, 351, 352: http://www.sciencedirect.com Page 365: http://www.modernreflexology.com Page 366, 367: http://behance.com Page 398: http://thenounproject.com Page 403: https://harlemphoto.wordpress.com

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